Direct Oral Anticoagulants From Pharmacology To Clinical Practice

Direct Oral
Anticoagulants
From Pharmacology to Clinical
Practice
Riccardo Proietti
Ahmed AlTurki
Nicola Ferri
Vincenzo Russo
T. Jared Bunch
Editors
123
Direct Oral Anticoagulants
Riccardo Proietti • Ahmed AlTurki
Nicola Ferri • Vincenzo Russo
T. Jared Bunch
Editors
Direct Oral Anticoagulants

From Pharmacology to Clinical Practice
Editors
Riccardo Proietti Ahmed AlTurki
Cardiac Rehabilitation Unit Ospedale McGill University
Sacra Famiglia Fatebenefratelli Montreal, QC
Erba, Italy Canada
Nicola Ferri Vincenzo Russo

Department of Pharmaceutical Department of Medical
and Pharmacological Sciences Translational Sciences
University of Padua University of Campania
Padova, Italy “Luigi Vanvitelli” - Monaldi Hospital
Naples, Italy
T. Jared Bunch
Division of Cardiology, Department
of Internal Medicine
University of Utah School of Medicine
Salt Lake City, UT
USA
ISBN 978-3-030-74461-8 ISBN 978-3-030-74462-5 (eBook)

https://doi.org/10.1007/978-3-030-74462-5
© Springer Nature Switzerland AG 2021

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Contents
1 The Coagulative Cascade�� 1

Marina Camera
2 Clinical Indications for Direct Acting Oral Anticoagulants�� 9
Ahmed AlTurki and Riccardo Proietti
3 Pharmacokinetics and Pharmacodynamics of DOAC�� 27
Nicola Ferri
4 Drug–Drug Interaction with DOACs �� 41
Alberto Corsini and Nicola Ferri
5 Direct Oral Anticoagulant Reversal for Management of Bleeding
and Emergent Surgery�� 71
Sanela Music, John Eikelboom, and Thao Huynh
6 Risk Stratification For and Use of DOAC Therapies for Stroke
Prevention in Patient with Atrial Fibrillation �� 93
Alfredo Caturano, Raffaele Galiero, Serenella Spiezia,
and Pia Clara Pafundi
7 Use of DOAC in Patients with Kidney Disease�� 121
Riccardo Vio, Riccardo Proietti, and Lorenzo Calo’
8 Anticoagulation in Elderly Patients with Atrial
Fibrillation Authors �� 131
Andreina Carbone, Roberta Bottino, Antonello D’Andrea,
Paolo Golino, Gerardo Nigro, and Vincenzo Russo
9 The “Obesity Paradox” and the Use of NOAC�� 149
Roberta Bottino, Andreina Carbone, Biagio Liccardo, Paolo Golino,
Gerardo Nigro, and Vincenzo Russo
10 Direct Oral Anticoagulation in Cancer Patients �� 179
Roberta Bottino, Andreina Carbone, Biagio Liccardo,
Antonello D’Andrea, Paolo Golino, Gerardo Nigro,
and Vincenzo Russo
v
vi Contents
11 DOACs and Dementia in Patients with Atrial Fibrillation�� 199

Ahmed AlTurki, Hasan AlTurki, Riccardo Proietti,
and T. Jared Bunch
12 Non-vitamin K Antagonists and Cardiac Implantable Electronic
Devices�� 211
Ahmed AlTurki, Riccardo Proietti, and Vidal Essebag
13 Direct Oral Anticoagulants and Atrial Fibrillation Ablation�� 225
14 DOAC Therapy in Patients Post Left Atrial Appendage Occlusion
or Isolation�� 235
T. Jared Bunch
15 Use of Direct Oral Anticoagulants After Transcatheter
Aortic Valve Replacement �� 247
Andrea Scotti, Mauro Massussi, Antonio Landi, and George Besis
16 Use of Direct Oral Anticoagulants After Percutaneous
Coronary Intervention�� 255
Antonio Landi, Mauro Massussi, Andrea Scotti, and George Besis
17 Direct Oral Anticoagulants and Left Ventricular Thrombosis:
The Evidence for a Good Therapeutic Approach �� 271
Mauro Massussi, Andrea Scotti, Antonio Landi, and George Besis
Index�� 281
The Coagulative Cascade
1
Marina Camera
Introduction
The blood coagulation cascade is an integral part of hemostasis, a biological process

evolved as important defense mechanism to prevent bleeding from a damaged ves-
sel and to restore vascular integrity (Davidson et al. 2003). Within the hemostatic
process two distinct phases are recognized, primary and secondary hemostasis,
where different key players and mechanisms are taking part. Despite this division,
the interplay between these processes is very tight.
Primary hemostasis is initiated by accumulation and activation of platelets at the
site of vascular injury. During secondary hemostasis, activation of coagulation rein-
forces the platelet plug through deposition of an insoluble fibrin network generated
by thrombin activity on fibrinogen molecules (Smith et al. 2015).
Under normal conditions, anticoagulant mechanisms ensure careful control of
coagulation and they prevail over the procoagulant forces. Aberrant activation of
coagulation can, however, lead to the formation of intravascular clots that underpin
pathological thrombotic disorders, including myocardial infarction, stroke, and
venous thromboembolism (Furie and Furie 2008).
The restitutio ad integrum of the damaged vessel is mediated by fibrinolysis, the
last phase of hemostasis. During this process, the activation of plasminogen and
urokinase leads to accelerated degradation of blood clots, with generation of fibrin
degradation products, including d-dimers.
M. Camera (*)
Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
e-mail: [email protected]
© Springer Nature Switzerland AG 2021 1

R. Proietti et al. (eds.), Direct Oral Anticoagulants,
https://doi.org/10.1007/978-3-030-74462-5_1
2 M. Camera
The Cell-Based Model of Blood Coagulation
The coagulation cascade consists of an ordered sequence of reactions that lead to

the careful and balanced generation of thrombin, key effector enzyme, at the level
of vascular damage.
Coagulation reactions lead to activation of zymogens (inert precursors of
enzymes) to functional enzymes via limited proteolysis. At each stage, a zymogen
is converted to an active protease by cleavage of one or more peptide bonds in the
precursor molecule. The final active protease generated is thrombin with the role of
converting fibrinogen into the fibrin mesh to stabilize the platelet plug. The enzymes
generated during this process are catalytically active serine proteases, yet they have
low inherent enzymatic activity as isolated proteins. Binding of a typical clotting
protease to a specific protein cofactor on a suitable phospholipid membrane surface
markedly potentiates the protease’s activity, often by as much as five order of mag-
nitude or more (Bom and Bertina 1990). On this regard, phosphatidylserine (PS)
exposure on the membrane of activated platelets is a key event in the control of
blood coagulation (Lentz 2003).
In mammalian blood coagulation, five zymogens (factor VII [FVII]; factor IX
[FIX]; factor X [FX]; protein C [PC], and prothrombin [PT]) act with five cofactors
(tissue factor [TF]; factor V [FV]; factor VIII [FVIII]; thrombomodulin and protein
S) to control the generation of fibrin. The protein cofactors of the blood coagulation
cascade also generally circulate in the plasma as inert procofactors that must be
converted into active cofactors via limited proteolysis. When zymogens and proco-
factors are converted to the active form, an “a” is appended to the Roman numerals
(i.e., FVII → FVIIa).
According to the most recent theory, in a cell-based model, blood coagulation is
initiated by the binding of FVII to membrane-associated TF (also called tissue
thromboplastin or FIII or CD142; Fig. 1.1) leading to activation of FVIIa (Kirchhofer
and Nemerson 1996). A fraction of FVII (~1%) circulates in blood as active enzyme.
Free FVIIa is a very weak enzyme, but the TF:FVIIa complex is an extremely potent
activator of coagulation. TF binds both FVII and FVIIa.
TF has several characteristics that make it unique among the coagulation pro-
teins (Morrissey 2001). First, TF is the only coagulation factor that is not synthe-
sized by the liver and released into circulation as a mechanism to avoid unintended
activation of coagulation. Second, membrane anchoring is essential for full proco-
agulant activity. Indeed, it is an integral membrane protein constitutively expressed
at high levels by fibroblasts of the adventitial layer of the vessel wall, as well as by
epithelial cells, and at sites where bleeding could be catastrophic (brain, lungs)
(Drake et al. 1989; Fleck et al. 1990). This pattern of TF localization has been
described as a hemostatic envelope to stop bleeding at sites of injury. When the ves-
sel wall is damaged, extravascular TF-bearing cells come in contact with blood
components and the hemostatic processes take place.
Notably, a discrete amount of TF is also stored in the cytoplasm of a subpopula-
tion of platelets and it can be exposed on the cell membrane upon activation by the
common platelet agonists (Camera et al. 2003, 2010; Brambilla et al. 2015). Based
1 The Coagulative Cascade 3
TF/VII/VIIa Initiation phase
X II
IX
XI VIIa VIIa xa IIa
TF TF
Va
IXa
XIa TF-Bearing Cell
VIII
(including platelets)
X
V VIIIa
Xa
Amplification &
Va Propagation phase
X II
Prothrombin IXa Xa
IX IIa
VIIIa Va
XIa
Activated Platetet
Thrombin
Fibrinogen Fibrin Final phase
Fig. 1.1 The cell-based model of the blood coagulation cascade
on these findings, the role of platelets in secondary hemostasis has been revised by
assigning to these cells the task not only to support the activation of clotting factors,
as already known for many years, but also to trigger themselves blood clotting
(Camera et al. 2015). Neutrophils and monocytes, along with circulating microves-
icles are additional sources of TF, whose importance is increasingly been recog-
nized in a variety of thrombotic disorders (von Bruhl et al. 2012; van Es et al. 2015).
Finally, unlike the other cofactors, TF does not require proteolysis for activity.
Once formed, the TF/FVIIa complex then catalyzes the conversion of two down-
stream substrates via limited proteolysis, FIX to FIXa and of FX to FXa (Figs. 1.1
and 1.2, Extrinsic Xase). Formation of FXa is the key step in the “initiation” stage,
formerly known as “extrinsic pathway” or “TF pathway” of the coagulation cas-
cade, because it requires that plasma comes into contact with something “extrinsic”
to the blood, i.e., TF, to trigger it. The TF pathway is the mechanism of triggering
blood clotting that functions in normal hemostasis, and probably also in many types
of thrombosis (Tilley and Mackman 2006).
The initial FXa produced by this mechanism combines with FVa and generates
sufficient thrombin to induce local platelet aggregation. The amount of fibrin pro-
duced through this pathway is however by far insufficient (only 3–5%) for the
4 M. Camera
TF
VIIa
VIIIH
IX VIIIL X
X Xa
IXa
IXa
Extrinsic Xase Intrinsic Xase
Xa
Xa
VH
II
VL
Xa
Prothrombinase
Fig. 1.2 FXa generation through the extrinsic and intrinsic Xase complexes organized on a phos-
phatidylserine expressing (green phospholipids) plasma membrane. The catalytic efficiency of the
intrinsic Xase complex is highlighted by the thicker arrow. FXa assembled into the prothrombinase
complex leads to the explosive generation of thrombin during the propagation phase
stabilization of the platelet plug because of rapid FXa-dependent inactivation of

TF-FVIIa by the TF pathway inhibitor (TFPI). It is exactly at this point that the
formerly known “intrinsic pathway” or “contact pathway” of blood coagulation
gives its contribution. Indeed, the trace amounts of thrombin formed in the “initia-
tion” stage of coagulation, although insufficient to initiate significant fibrin polym-
erization, are able to back-activate FV and FVIII by limited proteolysis, along with
the conversion of FXI to FXIa that feeds back to activate FIX.
FVIII and FV are procofactors. FVIII circulates in plasma bound to von
Willebrand factor, which serves to stabilize it. FV circulates in plasma, is stored in
platelets in a partially activated form, and is released when platelets are activated.
Thrombin releases von Willebrand factor from FVIII and activates FV and FVIII to
yield FVa and FVIIIa, respectively. Once activated, the cofactors bind to the surface
of activated platelets and serve as receptors; FVIIIa serves as the receptor for FIXa,
while FVa serves as the receptor for FXa. In addition to binding FIXa and FXa,
FVIIIa and FVa bind their substrates, FX and prothrombin (factor II), respectively
(Fig. 1.2).
The formation of the intrinsic tenase (FVIIIa-FIXa) and of the prothrombinase
(FXa-FVa) complexes (Fig. 1.2) lead to the explosive generation of thrombin during
the “propagation” phase through conversion of prothrombin (FII) to thrombin (FIIa)
followed by activation of fibrinogen to fibrin that ultimately leads to generation of a

fibrin clot. FXIa, a contact factor protein of the intrinsic pathway, may be required
to produce additional FIXa if insufficient quantities are generated by the TF-FVIIa
complex, or if fibrinolysis is particularly active. The remaining components of the
intrinsic system are important in vitro, but do not appear to have an important hemo-
static role. The labile association of fibrin monomers is finally stabilized by the
formation of covalent bonds between adjacent fibrin strands, a process catalyzed by
the transglutaminase FXIIIa.
Notably, active thrombin also remain bound within the fibrin clot, where it can
rapidly cleave additional fibrinogen and reinforce the clot structure if it is mechani-
cally or enzymatically disrupted. Within the hemostatic process thrombin not only
exert a procoagulant activity. Indeed, when bound to thrombomodulin expressed on
the surface of endothelial cells activates protein C generating an antithrombotic
effect. Finally, thrombin not only is the key enzyme in the coagulation process, but
it is also a powerful platelet activator through protease-activated receptors.
The Effect of Oral Anticoagulants on the Coagulation Cascade
The direct anticoagulants (DOACs) are orally active small molecule (<500 MW)
with high specificity and relatively high affinity for a single coagulation protease.
Dabigatran binds at the active site of thrombin and rivaroxaban, apixan and edoxa-
ban bind at the active site of FXa (Fig. 1.3). DOACs are competitive inhibitors, thus
each molecule competes with substrate for binding at the active site of its target
protease. The fact that DOACs interact with the active site of the target protease
means that binding only occurs after the zymogen form of the target protease has
been activated by the coagulation reactions.
The primary physiological inhibitors of thrombin, FXa and FIXa are the plasma
serine protease inhibitors (SERPINs) antithrombin and α-1-proteinase inhibitor,
and the non-SERPIN inhibitor α-2-macroglobulin. FXa within the TF/FVIIa/FXa
complex is also inhibited by TFPI. Like the DOACs, SERPINs and α-2-
macroglobulin only interact with coagulation factors after they have been activated
to functional proteases. However, SERPINs and α-2-macroglobulin inactivate their
target proteases by formation of complexes that are essentially irreversible
(Huntington et al. 2000; Barrett and Starkey 1973). By contrast, DOACs form
reversible complexes with the active site of their target proteases.
Antithrombin and TFPI are large proteins, ≈58 kDa and 34 to 40 kDa, respec-
tively. Thus, antithrombin is sterically hindered from interacting with thrombin that
is sequestered within a fibrin clot or bound to a cofactor, such as thrombomodulin.
Likewise, FXa on a platelet surface is relatively protected from inhibition by either
antithrombin or tissue factor pathway inhibitor. By contrast, DOACs can inhibit
coagulation by acting at sites where the natural inhibitors are ineffective. Indeed,
due to their small molecular weight (<500 MW) DOACs can inhibit thrombin and
FXa at sites on cells surface where they are relatively inaccessible to the plasma
protease inhibitors (Haynes et al. 2012). They can also reach their target proteases
6 M. Camera
Inintiation
VKA VIIa VII VKA
TF
X IX
Propagation
IXa
Direct Factor Xa inhibition Xa Zymogen
Rivaroxaban
Apixaban II Prothrombin Enzyme
Edoxaban
Conversion
VKA
Activation
Direct thrombin inhibition IIa Thrombin Inhibition
Dabigatran
Fibrin formation
Fibrinogen Fibrin
Fig. 1.3 The cell-based model of the blood coagulation cascade and targets of the oral anticoagu-
lant drugs. Targets of direct oral anticoagulant as well as of Vitamin K Antagonists (VKA)
are shown
within the structure of a fibrin clot. Since dabigatran not only inhibits the procoagu-
lant effects of thrombin but also inhibits thrombin in complex with thrombomodulin
(Kamisato et al. 2016), the reduction in protein C activation could potentially exert
an unintended prothrombotic effect.
Vitamin K antagonists (VKAs) interfere with the γ carboxylation of all vitamin
K-dependent coagulation factors (FII, VII, IX, and X) as well as of the antithrom-
botic factors protein C, S, and Z (Jerkeman et al. 2000) (Fig. 1.3). Because multiple
factors are affected, the net effect of any given dose of a VKA is difficult to predict.
By contrast, the relationship between the plasma levels of a DOAC and the degree
of protease inhibition is much more predictable, thus the laboratory monitoring of
their anticoagulant activity is not needed.
The vitamin K-dependent post-translational modification of specific glutamic
acid residues is critical for the activity of the coagulation factors. Thus, while the
proteins are synthesized, their undercarboxylated forms do not have normal activity.
VKAs thereby reduce the levels of active proteases that can be produced in response
to a procoagulant stimulus rather than inhibiting them after they have been acti-
vated. If less FX is available to be activated, then less FXa/FVa complexes will be
available to trigger thrombin formation. The reduced levels of prothrombin further
slow the rate of thrombin generation. Overall, VKAs predominantly impact the
propagation phase of thrombin generation (Dargaud et al. 2013).
On the contrary, dabigatran mostly affects the amplification phase of coagula-

tion, whereas direct FXa inhibitors impact on the initiation and propagation phases
(Hoffman and Monroe 2017). Furthermore, the reversible binding of DOACs to
their targets enables FXa or thrombin produced as a result of coagulation activation
to overcome the effect of the drug, thus supporting hemostasis. This property may
contribute to the safety of DOACs including the fact that patients treated with
DOACs experience a significantly reduced incidence of intracranial hemorrhage
compared to patients treated with VKA (Granger et al. 2011; Hart et al. 2012;
Giugliano et al. 2013; Hankey et al. 2014). On this regard, based on the mechanisms
described, if a microbleeding occurs in the brain of a patient treated with a DOAC,
the large amount of TF present will trigger the coagulation cascade leading to the
generation of FXa that, by displacing DOAC, will activate the other coagulation
factors leading to fibrin generation. On the contrary, in the case of a patient treated
with a VKA, the low concentration of circulating VK-dependent zymogens will not
allow the coagulation cascade to be triggered.
Conclusions
The coagulation cascade consists of a cascade of enzyme activation events in which

serine proteases activate zymogens and procofactors in the next step of the cascade
via limited proteolysis. By taking place on the surface of activated platelets, aim of
coagulation is to lead, at the level of vascular damage, to the careful and balanced
generation of thrombin, key effector enzyme of the process with the role of convert-
ing fibrinogen into the fibrin mesh necessary to stabilize the platelet plug. This
process is protective since it evolved as important defense mechanism to prevent
bleeding from a damaged vessel. Unfortunately, the blood clotting system can also
lead to unwanted blood clots inside blood vessel. This pathologic thrombus forma-
tion (thrombosis) is a leading cause of disability and death in the developed world.
DOACs are direct competitive inhibitors of FXa and of thrombin and form
reversible complexes with the active site of their target proteases. The small molec-
ular size of DOACs allow them to inhibit FXa and thrombin assembled on the plate-
let surfaces and within a fibrin clot, sites where the natural inhibitors, such as
antithrombin, are ineffective. Unlike VKA, the relationship between the plasma
levels of a DOAC and the degree of protease inhibition is much more predictable
and therapy laboratory monitoring of their anticoagulant activity is no more needed.
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Clinical Indications for Direct Acting Oral
Anticoagulants 2
Ahmed AlTurki and Riccardo Proietti
Introduction
Anticoagulation is an important therapeutic option to prevent and treat thrombus

formation in a variety of clinical settings. While there are several options for paren-
teral therapy, oral therapy was limited to vitamin K antagonists, namely warfarin
therapy. However, there are several limitations to warfarin including the need to be
within a relatively narrow therapeutic and safety range, which requires frequent
monitoring, as well as long onset and offset effects and numerous interactions.
Direct oral anticoagulants (DOACs) are anticoagulation pharmacotherapy designed
to overcome the limitations of warfarin and are categorized into two main classes
based on mechanism of action: oral direct factor Xa inhibitors (rivaroxaban, apixa-
ban, edoxaban, and betrixaban) and direct thrombin inhibitors (dabigatran). The
advantages of DOAC therapy compared with VKAs include the absence of the need
for monitoring, more immediate drug onset and offset effects, which has important
periprocedural and bleeding management implications as well as less drug interac-
tions. In the past decade since DOACs were approved, there have been a plethora of
studies examining the safety and efficacy of DOACs across a variety of clinical set-
tings. In this chapter, clinical scenarios in which DOACs may be used will be exam-
ined and the major evidence for and against their use will be reviewed.
A. AlTurki (*)
Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada
R. Proietti
Cardiac Rehabilyitation Unit Ospedale, Sacra Famiglia Fatebenefratelli, Erba, Italy

10 A. AlTurki and R. Proietti
Nonvalvular Atrial Fibrillation
Oral anticoagulation is one of the mainstays of treatment of patients with atrial

fibrillation (AF) for the prevention of stroke and systemic embolism. The majority
of patients with AF require anticoagulation with the decision to anticoagulate being
based on the estimated risk of stroke. This is done via an assessment for clinical risk
factors that increase the risk of stroke, namely congestive heart failure, hyperten-
sion, age, diabetes mellitus, history of cerebrovascular events, and history of vascu-
lar disease with a variety of scores available to estimate the annual risk of stroke and
systemic embolism. The presence of at least one risk factor, especially age greater
than 65 years, is enough for oral anticoagulation to have a net clinical benefit and
warrant use. For many years, the only available option was vitamin K antagonists,
namely warfarin. In 2009, the situation was irrevocably altered with the publication
of the first landmark trial comparing the DOAC, dabigatran with warfarin in patients
with nonvalvular AF. This was followed by three other landmark trials as well as
numerous other studies comparing DOAC to warfarin in a variety of clinical setting
and patient subgroups with nonvalvular AF.
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) was a
trial that randomized 18,113 patients (mean age 71 years; males 64%; mean
CHADS2 score = 2.1) in a 1:1:1 ratio to receive one of the two fixed doses of dabi-
gatran (110 mg or 150 mg), in a blinded manner, with open-label use of warfarin in
patients who had nonvalvular AF and an increased risk for stroke (Connolly et al.
2009). After a median follow-up of 2 years, the annual incidence rate of stroke or
systemic embolism was 1.53%, 1.11%, and 1.69% in those receiving dabigatran
110 mg, dabigatran 150 mg, and warfarin, respectively. Both doses of dabigatran
were noninferior to warfarin (P < 0.001) and the 150-mg dose of dabigatran was
also superior to warfarin (relative risk [RR] 0.66; 95% confidence interval [CI], 0.53
to 0.82; P < 0.001). The annual incidence of hemorrhagic stroke was 0.38% per year
in those who received warfarin, compared with 0.12% in the 110 mg dabigatran
group (RR 0.31; 95% CI, 0.17 to 0.56; P < 0.001) and 0.10% in the 150 mg dabiga-
tran group (RR 0.26; 95% CI, 0.14 to 0.49; P < 0.001). The annual incidence of
major bleeding was 3.36% in the warfarin group, compared with 2.71% per year in
the 110 mg dabigatran group (RR 0.80; 95% CI, 0.69 to 0.93; P = 0.003) and 3.11%
in the 150 mg dabigatran group (RR 0.93; 95% CI, 0.81 to 1.07; P = 0.31). Dyspepsia
occurred in 5.8% in the warfarin group compared to 11.8% and 11.3% in the 110-
mg and 150-mg dabigatran groups, respectively (P < 0.001 for both comparisons).
Of note, there was a signal for increased myocardial infarction and gastrointestinal
bleeding with dabigatran in the RE-LY trial. However, in a pooled analysis of 24
studies including 588,047 patients, there was no significant association between the
use of dabigatran and the higher risk of myocardial infarction (Wei et al. 2018).
The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with
Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial
Fibrillation (ROCKET AF) was a multicenter, randomized trial that enrolled 14,264
patients with nonvalvular AF who were at increased risk for stroke to receive either
rivaroxaban or dose-adjusted warfarin (Patel et al. 2011). The annual incidence of
2 Clinical Indications for Direct Acting Oral Anticoagulants 11
stroke or systemic embolism was 2.1% in the rivaroxaban group and 2.4% in the
warfarin group (hazard ratio [HR] 0.88; 95% CI, 0.74 to 1.03; P < 0.001 for nonin-
feriority; P = 0.12 for superiority) and the annual incidence of major and nonmajor
clinically relevant 14.9% in the rivaroxaban group and 14.5% in the warfarin group
(HR 1.03; 95% CI, 0.96 to 1.11; P = 0.44). Intracranial hemorrhage (0.5% vs. 0.7%,
P = 0.02) and fatal bleeding (0.2% vs. 0.5%, P = 0.003) were significantly reduced
in the rivaroxaban group. On the other hand, major bleeding from a gastrointestinal
site was more common in the rivaroxaban group (3.2%), as compared with the war-
farin group (2.2%, P < 0.001).
In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation (ARISTOTLE) trial, 18,201 patients with AF and at least one
additional risk factor for stroke were randomized to receive either apixaban or war-
farin (Granger et al. 2011). After a median duration of follow-up of 1.8 years, the
annual incidence of stroke or systemic embolism was 1.27% in the apixaban group,
compared with 1.60% in the warfarin group (HR, 0.79; 95% CI, 0.66 to 0.95;
P < 0.001 for noninferiority; P = 0.01 for superiority). In addition, the incidence of
major bleeding was 2.13% in the apixaban group and 3.09% in the warfarin group
(HR 0.69; 95% CI, 0.60 to 0.80; P < 0.001), and the incidence of all-cause mortality
were 3.52% and 3.94%, respectively (HR 0.89; 95% CI, 0.80 to 0.99; P = 0.047).
Hemorrhagic stroke was also lower with apixaban (0.24%) than warfarin (0.47%)
(HR 0.51; 95% CI, 0.35 to 0.75; P < 0.001).
In the Effective Anticoagulation with Factor Xa Next Generation in Atrial
Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48)
trial, 21,105 patients were randomized into one of three groups (warfarin, edoxaban
60 mg, or edoxaban 30 mg) and followed for a median 2.8 years (Giugliano et al.
2013). At completion, the annual incidence of stroke or systemic embolism was
1.50%, 1.18% (HR 0.79; 97.5%CI 0.63 to 0.99; P < 0.001 for noninferiority,
P = 0.02 for superiority), and 1.61% (HR 1.07; 97.5% CI, 0.87 to 1.31; P = 0.005
for noninferiority, P = 0.44 for superiority) in the warfarin, high-dose edoxaban, and
low-dose edoxaban groups respectively. In addition, the annual incidence of hemor-
rhagic stroke was 0.47%, 0.26% (HR, 0.54; 95% CI, 0.38 to 0.77; P < 0.001), and
0.16% (HR 0.33; 95% CI, 0.22 to 0.50; P < 0.001) and the annual incidence of
major bleeding was in the warfarin, high-dose edoxaban, and low-dose edoxaban
groups, respectively. Finally, the annual incidence of intracranial bleeding was
0.85%, 0.39%, and 0.26% warfarin, high-dose edoxaban, and low-dose edoxaban
groups, respectively but the annual incidence of major gastrointestinal bleeding was
higher with high-dose edoxaban than with warfarin (1.51% vs. 1.23%), with the
lowest rate with low-dose edoxaban (0.82%).
In summary, compared to warfarin, DOACs reduce major bleeding including
intracranial hemorrhage and are noninferior with regard to prevention of stroke and
systemic embolism. Apixaban and the higher dose of dabigatran, 150 mg, were
superior to warfarin for the prevention of stroke and systemic embolism (Connolly
et al. 2009; Granger et al. 2011). Apixaban was also associated with a reduction in
mortality compared to warfarin. Pooled analyses of the four DOAC trials (Fig. 2.1)
showed that DOACs reduced stroke or systemic embolism by 19% compared with
a
NOAC (events) Warfarin (events RR(95%CI) P
RE-LYs* 134/6076 199/6022 0.66 (0.53-0.82) 0.0001

ROCKET AF6 269/7081 306/7090 0.88 (0.75-1.03) 0.12
ARISTOTLE7 212/9120 265/9081 0.80 (0.67-0.95) 0.012
RENGAGE AF-TIMI 488S 296/7035 337/7036 0.88 (0.75-1.02) 0.10
Combined (randm) 911/29312 1107/29229 0.81 (0.73-0.91) <0.0001
0.5 1.0 2.0
Favours NOAC Favours warfarin
b
Pooled NOAC Pooled warfarin RR(95%CI) P
(events) (events)
Efficacy
Ischaemic stroke 665/29292 724/29221 0.92 (0.83-1.02) 0.10
Haemorrhagic stroke 130/29292 263/29221 0.49 (0.38-0.64) <0.0001
Myocardial infarction 413/29292 432/29221 0.97 (0.78-1.20) 0.77
All-cause mortality 2022/29292 2245/29211 0.90 (0.85-0.95) 0.0003
Safety
Intracranial haemorrhage 204/29287 425/29211 0.48 (0.39-0.59) <0.0001
Gastrointestinal bleeding 751/29287 591/29211 1.25 (1.01-1.55) 0.043
0.2 0.5 1
Favours NOAC Favours warfarin
Fig. 2.1 (a) Pooled analysis of the landmark clinical trials of atrial fibrillation comparing the
incidence of stroke and systemic embolism between those receiving direct oral anticoagulants and
those receiving warfarin. (b) Combined data from the landmark trials across individual efficacy
and safety outcomes in landmark trials of atrial fibrillation that compared direct acting oral antico-
agulants and warfarin. (Used with permission from Ruff et al. (2014))
warfarin (RR 0.81, 95% CI 0.73–0.91; P < 0.0001), including a reduction in hemor-

rhagic stroke (RR 0.49, 95% CI 0.38–0.64; P < 0.0001) (Ruff et al. 2014).
Furthermore, DOACs also reduced all-cause mortality (RR 0.90, 95% CI 0.85–0.95;
P = 0.0003) and intracranial hemorrhage (RR 0.48, 95% CI 0.39–0.59; P < 0.0001),
but increased gastrointestinal bleeding (RR 1.25, 95% CI 1.01–1.55; p = 0.04).
Current guidelines now recommend that DOACs be used in preference to warfarin
for the prevention of stroke in patients with nonvalvular AF (January et al. 2019;
Andrade et al. 2020).
Subsequent studies have looked at specific clinical situations and patient sub-
groups providing insight for DOAC use in these patients. Dabigatran was a safe
alternative in patients undergoing cardioversion (Nagarakanti et al. 2011). The rates
of periprocedural bleeding was similar to warfarin in those undergoing urgent sur-
gery (Healey et al. 2012). Concomitant antiplatelet use was associated with an
increased incidence of bleeding without improving efficacy, particularly those
receiving the higher dose of 150 mg (Dans et al. 2013). Both dabigatran dosages
displayed significantly lower rates of major bleeding in patients with glomerular
filtration rate ≥80 mL/min (Hijazi et al. 2014). In a sub-analysis of RE-LY, the pres-
ence of mitral regurgitation, aortic regurgitation, aortic stenosis, or tricuspid regur-
gitation did not affect the efficacy and safety of dabigatran compared to warfarin
(Ezekowitz et al. 2016). In patients undergoing catheter ablation for AF, uninter-
rupted dabigatran was associated with fewer bleeding complications than uninter-
rupted warfarin (Calkins et al. 2017). There have been many questions put forward
as to whether DOACs provide adequate coverage in patients with bioprosthetic
valves. These concerns were addressed in the Rivaroxaban for Valvular Heart
Disease and Atrial Fibrillation (RIVER) trial in which 1005 patients with AF and a
mitral bioprosthetic valve were randomized to either rivaroxaban or warfarin
(Guimarães et al. 2020). Death from cardiovascular causes or thromboembolic
events occurred in 3.4% in the rivaroxaban group and in 5.1% in the warfarin group
(HR, 0.65; 95% CI, 0.35 to 1.20). In addition, the incidence of stroke was 0.6% in
the rivaroxaban group and 2.4% in the warfarin group (HR, 0.25; 95% CI, 0.07 to
0.88) and major bleeding was observed in 1.4% in the rivaroxaban group and 2.6%
in the warfarin group (HR 0.54; 95% CI, 0.21 to 1.35). Therefore, DOACs appear to
be noninferior to warfarin in patients with AF and bioprosthetic valves.
Venous Thromboembolism
Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary

embolism, may result in the debilitating long-term complications of post-thrombotic
syndrome and chronic thromboembolic pulmonary hypertension. In addition, pul-
monary embolism may result in pulmonary hemorrhage and death. Anticoagulation
is the mainstay therapy in VTE for prevention of complications and the standard of
care has been warfarin with initial bridging with parenteral heparin. The introduc-
tion of DOACs into clinical practice provided a possible alternative therapy that
would not require parenteral therapy allowing outpatient therapy in stable cases.
There are several situations with VTE in which DOACs have been trialed: prophy-
laxis for VTE; initial therapy for VTE; extended therapy for VTE as well as VTE in
patients with active malignancy.
There is a significant risk of VTE in hospitalized patients, with a higher risk in
acutely ill patients in intensive care units and surgical patients. The perioperative
administration of subcutaneous heparin has been shown to reduce the risk of fatal
pulmonary embolism and venous thrombosis in patients undergoing general, ortho-
pedic, and urologic surgery (Collins et al. 1988). In the Acute Medically Ill VTE
Prevention with Extended-Duration Betrixaban (APEX) trial, the efficacy, and
safety of full-dose (80 mg) and reduced-dose (40 mg) betrixaban were evaluated
relative to enoxaparin in 3065 patients (Gibson et al. 2017). The primary efficacy
outcome, which consisted of asymptomatic proximal deep vein thrombosis, symp-
tomatic deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or VTE-
related mortality, was significantly reduced among subjects treated with 80 mg of
extended-duration betrixaban versus enoxaparin (6.27% vs. 8.39%, RRR = 0.26
[0.04–0.42], P = 0.023). Major bleeding was similar between the two groups (0.49%
with betrixaban versus 0.66% with enoxaparin; P = 0.51). The Multicenter,
Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous
Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing
Rivaroxaban with Enoxaparin (MAGELLAN) was designed to assess the efficacy

and safety of rivaroxaban administered for 35 days, as compared with enoxaparin
administered for 10 days and followed by placebo (Cohen et al. 2013). The primary
efficacy outcomes, a composite of asymptomatic proximal or symptomatic venous
thromboembolism up to day 10 (noninferiority test) and up to day 35 (superiority
test), occurred in 2.7% receiving rivaroxaban and 2.7% receiving enoxaparin at day
10 (RR = 0.97; 95% CI 0.71 to 1.31; P = 0.003 for noninferiority) and in 4.4% who
received rivaroxaban and 5.7% who received enoxaparin followed by placebo at day
35 (RR 0.77; 95% CI, 0.62 to 0.96; P = 0.02). However, the principal safety out-
come, a composite of major or clinically relevant nonmajor bleeding, occurred in
2.8% and 1.2% at day 10 (P < 0.001) and 4.1% and 1.7% at day 35 (P < 0.001) in
the rivaroxaban group and in the enoxaparin group, respectively. Due to the findings
of this study, low-molecular-weight heparin remains the standard of care for VTE
prophylaxis in the medically ill population. In the Prophylaxis in Nonmajor
Orthopedic Surgery (PRONOMOS) trial, the effect of rivaroxaban (10 mg) was
compared with that of enoxaparin (40 mg) in the prevention of major VTE in 3604
patients after lower-limb nonmajor orthopedic surgery (Samama et al. 2020). Major
VTE occurred in 0.2% in the rivaroxaban group and 1.1% in the enoxaparin group
(RR 0.25; 95% CI, 0.09 to 0.75; P < 0.001 for noninferiority; P = 0.01 for superior-
ity). The incidence of bleeding did not differ significantly between the rivaroxaban
group and the enoxaparin group. Based on this trial as well as previous studies,
DOACs have been increasingly used for VTE prophylaxis in the orthopedic surgery
population. In the Apixaban for the Prevention of Venous Thromboembolism in
High-Risk Ambulatory Cancer Patients (AVERT) trial, the efficacy of apixaban
thromboprophylaxis in ambulatory patients with active cancer at intermediate-to-
high risk for venous thromboembolism, apixaban (2.5 mg twice daily) was com-
pared to placebo in 574 patients. A placebo comparator was used as there is no
evidence/recommendations for prevention of VTE in cancer patients (Carrier et al.
2018). Venous thromboembolism occurred in 4.2% in the apixaban group and
10.2% in the placebo group (HR 0.41; 95%CI 0.26 to 0.65; P < 0.001). Major bleed-
ing occurred in 3.5% in the apixaban group and in 1.8% in the placebo group (HR
2.00; 95% CI, 1.01 to 3.95; P = 0.046).
Numerous trials have demonstrated the efficacy and safety of the DOACs in the
treatment of VTE and have led to recommendations that DOACs be used as first-
line therapy for the treatment of VTE. Rivaroxaban was tested through the
EINSTEIN program with 3 separate trials assessing its efficacy and safety for the
treatment of acute pulmonary embolism, acute deep vein thrombosis, and extended
therapy. In the first trial, 3449 patients with acute DVT received either rivaroxaban
or enoxaparin plus a vitamin K antagonist (EINSTEIN Investigators et al. 2010).
The primary efficacy of recurrent venous thromboembolism occurred in 2.1% of the
rivaroxaban group versus 3.0% of the enoxaparin-vitamin K antagonist group (HR
0.68, 95%CI 0.44 to 1.04; P < 0.001). The principal safety outcome of major bleed-
ing or clinically relevant nonmajor bleeding occurred in 8.1% of the patients in each
group. In the second trial, 4832 patients who had acute symptomatic pulmonary
embolism received either rivaroxaban (15 mg twice daily for 3 weeks, followed by
20 mg once daily) or standard therapy with enoxaparin followed by an adjusted-

dose vitamin K antagonist (The EINSTEIN–PE Investigators 2012). The primary
efficacy of symptomatic recurrent venous thromboembolism was similar in both
groups: 2.1% of the rivaroxaban group versus 1.8% of the enoxaparin-vitamin K
antagonist group. The principal safety outcome of major bleeding or clinically rel-
evant nonmajor bleeding was also similar in both groups (10.3% and 11.4%, respec-
tively). Importantly, major bleeding was lower in the rivaroxaban group (1.1%) than
in the standard-therapy group (2.2%) (hazard ratio, 0.49; 95% CI, 0.31 to 0.79;
P = 0.003). Another important situation in patients with VTE is extended therapy
beyond 6 to 12 months when clinical equipoise exists as to the net clinical benefit of
extended therapy. In this scenario, low-dose aspirin had been suggested in clinical
guidelines. In the Reduced-dosed Rivaroxaban in the Long-term Prevention of
Recurrent Symptomatic Venous Thromboembolism (EINSTEIN CHOICE) trial, in
patients with VTE who had completed 6 to 12 months of anticoagulation therapy
and for whom there was equipoise regarding the need for continued anticoagulation,
two doses of rivaroxaban were compared to aspirin in 3365 patients (Weitz et al.
2017). The primary efficacy outcome, symptomatic recurrent fatal or nonfatal VTE
occurred in 1.5% receiving 20 mg of rivaroxaban, 1.2% receiving 10 mg of rivar-
oxaban, and 4.4% receiving aspirin (HR for 20 mg of rivaroxaban vs. aspirin, 0.34;
95% CI 0.20 to 0.59; HR for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14
to 0.47; P < 0.001 for both comparisons). Rates of major bleeding were similar in
all three groups: 0.5% (20 mg of rivaroxaban), 0.4% (10 mg of rivaroxaban), and
0.3% (aspirin group). In the Apixaban for the Initial Management of Pulmonary
Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial,
patients were assigned to receive either apixaban (10 mg twice daily for the first
7 days, followed by 5 mg twice daily for 6 months) or conventional therapy (enoxa-
parin at a dose of 1 mg per kilogram of body weight every 12 h for at least 5 days
and warfarin for 6 months) (Agnelli et al. 2013). Apixaban was noninferior to con-
ventional therapy with regard to the primary efficacy outcome of recurrent symp-
tomatic VTE or VTE-related mortality (2.3% vs. 2.7%; P < 0.001). Major bleeding
was lower in the apixaban group (0.6%) than in the conventional therapy (1.8%)
(RR 0.31; 95% CI, 0.17 to 0.55; P < 0.001 for superiority). In another trial, edoxa-
ban (at a dose of 60 mg once daily, or 30 mg once daily if low renal function or body
weight) was compared to warfarin in patients with acute VTE who had received
parenteral therapy (The Hokusai-VTE Investigators 2013). Edoxaban was noninfe-
rior to warfarin with respect to the primary efficacy outcome of recurrent symptom-
atic VTE (3.2% vs. 3.5%) but was superior with regard to the primary safety
outcome of major bleeding or clinically relevant nonmajor bleeding (8.5% vs.
10.3%; HR 0.81, 95% CI, 0.71 to 0.94; P = 0.004 for superiority). Dabigatran was
also shown to be noninferior to warfarin in the treatment of acute VTE (Schulman
et al. 2009). Given that both groups received parenteral therapy in the dabigatran
and edoxaban trials, it is recommended to use parenteral therapy initially before
starting dabigatran (The Hokusai-VTE Investigators 2013; Schulman et al. 2009).
Pooled analysis showed that DOACs had similar efficacy and safety compared to
warfarin for the treatment of VTE (Fig. 2.2) (Kakkos et al. 2014). Given the trend
Fig. 2.2 Pooled analysis of the landmark trials comparing direct acting oral anticoagulants and
warfarin in patients with venous thromboembolism. (a) recurrent venous thromboembolism; (b)
deep venous thrombosis; (c) fatal pulmonary embolism; (d) nonfatal pulmonary embolism. (Used
with permission from Kakkos et al. (2014))
towards less bleeding with DOACs as well as the ease of administration, DOACs
have become first-line therapy for the treatment of VTE.
The treatment of VTE in patients with active malignancy is another important
consideration. The CLOT trial had established that the standard of care was treat-
ment with low-molecular-weight heparin given its superiority over warfarin.
Recently, DOACs have been compared to the standard of care to assess for noninfe-
riority; due to the ease of administration, if DOACs were noninferior, they would
become the standard of care similar to the treatment of VTE in the general popula-
tion. In the Hokusai VTE Cancer trial, edoxaban was compared with dalteparin for
the treatment of patients with cancer-associated VTE (Raskob et al. 2017). The pri-
mary outcome, a composite of recurrent VTE or major bleeding at 12 months,
occurred in 12.8% of the edoxaban group and 13.5% of the dalteparin group (HR
0.97; 95%CI, 0.70 to 1.36; P = 0.006 for noninferiority; P = 0.87 for superiority).
Interestingly, there were less recurrent VTE events in the edoxaban group (7.9% vs.
11.3%) but more major bleeding (6.9% vs. 4.0%) compared to dalteparin. In the
Caravaggio trial, apixaban was found to be noninferior to dalteparin for the treat-
ment of patients with cancer-associated VTE (Agnelli et al. 2020). Recurrent VTE
occurred in 5.6% in the apixaban group and 7.9% in the dalteparin group (HR 0.63;
95% CI 0.37 to 1.07; P < 0.001 for noninferiority) and major bleeding occurred in
3.8% in the apixaban group and in 4.0% in the dalteparin group (HR 0.82; 95% CI,
0.40 to 1.69; P = 0.60). DOACs are now used as first-line therapy for the treatment
of patients with cancer-associated VTE.
Coronary Artery Disease
DOACs have been tested in two settings in patients with coronary artery disease:
acute coronary syndrome and secondary prevention in patients at high risk of recur-
rent major adverse cardiovascular events with stable cardiovascular disease. In the
Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy
in Subjects With Acute Coronary Syndrome ACS 2–Thrombolysis In Myocardial
Infarction 51 (ATLAS ACS 2–TIMI 51) trial, 15,526 patients with a recent acute
coronary syndrome receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxa-
ban or placebo for a mean of 13 months (Mega et al. 2011). Rivaroxaban (8.9%)
significantly reduced the primary efficacy end point, a composite of death from
cardiovascular causes, myocardial infarction, or stroke, compared to placebo
(10.7%) (HR 0.84; 95% CI 0.74 to 0.96; P = 0.008), with significant improvement
using both rivaroxaban doses. However, rivaroxaban increased the rates of major
bleeding (2.1% vs. 0.6%, P < 0.001) and intracranial hemorrhage (0.6% vs. 0.2%,
P = 0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P = 0.66)
compared to placebo. Importantly, rivaroxaban was added to standard of care dual
antiplatelet therapy (>92% of patients). Despite the promising efficacy results in
this trial, rivaroxaban is not considered a therapeutic option in acute coronary syn-
drome due to the important limitations observed. The ATLAS ACS 2–TIMI 51 trial
suffered from a significant proportion of missing data, in particular the vital status
of patients. In addition, the lack of an expected dose response (5-mg dose did not
have greater efficacy compared with the 2.5-mg dose of rivaroxaban) was also trou-
bling. Furthermore, there was divergent effects with the two doses on the primary
outcome; cardiovascular death, but not myocardial infarction, driving the treatment
benefit with 2.5 mg, whereas myocardial infarction, but not cardiovascular death,
driving benefit with the 5-mg dose (Krantz and Kaul 2013). Finally, trials using
other DOACs and a meta-analysis of studies failed to show any benefit of adding
low-dose DOAC to standard therapy with regard to major adverse cardiovascular
events (Oldgren et al. 2011, 2013; Alexander et al. 2011).
The second situation is patients at high risk of recurrent cardiovascular events
who have stable disease. These patients are often on aspirin monotherapy though
some may be receiving extended dual antiplatelet therapy; despite this therapy,
many patients have significant residual risk of cardiovascular events. In the
Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS)
trial, 27,395 participants with stable atherosclerotic vascular disease were random-
ized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily),
rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily) (Eikelboom et al.
2017). The primary outcome, a composite of cardiovascular death, stroke, or myo-
cardial infarction, was reduced in patients in the rivaroxaban-plus-aspirin group
compared to the aspirin-alone group 4.1% vs. 5.4% (HR 0.76; 95% CI 0.66 to 0.86;
P < 0.001). However, major bleeding events occurred in more patients in the
rivaroxaban-plus-aspirin group (3.1% vs. 1.9%; HR 1.70; 95% CI, 1.40 to 2.05;
P < 0.001). Interestingly, rivaroxaban alone did not significantly lower the risk of
major adverse cardiovascular events compared to aspirin alone, with a significantly
higher risk of major bleeding. The finding of this trial has led to recommendations
to consider low-dose rivaroxaban in this patient population.
Left Ventricular Thrombus
Another important indication for oral anticoagulation is the development of left

ventricular thrombus, which usually occurs after a large anterior myocardial infarc-
tion with apical akinesis and may occur in the setting of mid-ventricular hypertro-
phic cardiomyopathy with apical aneurysm formation, Takotsubo cardiomyopathy,
and post ventricular tachycardia ablation. Left ventricular thrombus can have devas-
tating complications by embolizing systemically (Vaitkus and Barnathan 1993).
Patients with left ventricular thrombus have been traditionally treated with warfarin
therapy though this was based on clinical experience and observational studies
(Cregler 1992). Data on DOAC use for left ventricular thrombus is sparse though
they are often used off-label by physicians for this indication. A systematic review
of case series up to 2018 suggested that DOAC use is a feasible alternative to war-
farin (Kajy et al. 2020). In a small randomized trial of 25 patients who received
either apixaban or warfarin, after 3 months of treatment, thrombus completely
resolved in all patients in the warfarin group and in 92% in the apixaban group (one
patient with a very large thrombus had a significant reduction in size) (Alcalai et al.
2020). There were no death, stroke, or systemic embolism in either group. There
were two patients with major bleeding in the warfarin group, and one patient dis-
continued treatment. No major bleeding events or treatment discontinuations were
recorded in the apixaban group. However, in a cohort study of 514 patients with
echocardiogram diagnosed left ventricular thrombi, anticoagulation with DOACs

was associated with a higher risk of ischemic stroke and systemic emboli than war-
farin treatment (Robinson et al. 2020). After a median follow-up of 351 days and on
multivariable analysis, anticoagulation with DOAC compared to warfarin (HR,
2.64; 95% CI, 1.28–5.43; P = 0.01) was significantly associated with stroke or sys-
temic embolism. While the study has many inherent limitations, it highlights the
urgent need for a clinical trial in this area.
Rheumatic Heart Disease
Mitral stenosis due to rheumatic heart disease significantly increases the risk of
thromboembolism. Anticoagulation with warfarin has been recommended for
patients with mitral stenosis and AF or prior embolism or left atrial thrombus.
These patients were generally excluded from DOAC trials assessing the utility of
thromboembolic prevention in patients with AF (Biase 2016). Data is limited on
the use of DOACs in rheumatic mitral stenosis. The largest experience was pub-
lished by Kim et al. (2019). There were 2230 patients enrolled from a database in
the Republic of Korea, and it included patients who were diagnosed with mitral
stenosis and AF and either were prescribed DOACs for off-label use or received
conventional treatment with warfarin. Thromboembolic events occurred at a rate
of 2.22%/year in the DOAC group, and 4.19%/year in the warfarin group (HR
0.28; 95% CI 0.18 to 0.45). Intracranial hemorrhage occurred in 0.49% of the
DOAC group and 0.93% of the warfarin group (HR 0.53; 95% CI 0.22 to 1.26).
This result is very promising though only hypothesis generating and clearly a
large, randomized trial is needed.
Heparin-Induced Thrombocytopenia
The literature is extremely limited regarding the efficacy and safety of DOACs in
heparin-induced thrombocytopenia. In a systematic review, published in 2019, of
104 cases who received DOACs, treatment with DOACs prevented new and recur-
rent thrombosis in 98% (n = 102) of cases, and bleeding complications occurred in
3% (n = 3) (Barlow et al. 2019). These results suggest that DOACs may have a role
in the treatment of heparin-induced thrombocytopenia. Current hematology guide-
lines give its use a conditional recommendation (Cuker et al. 2018).
Myocardial Injury After Noncardiac Surgery
Myocardial injury after noncardiac surgery is due to myocardial ischemia which

may be either due to supply-demand mismatch or thrombus formation and is
associated with an increased risk of mortality and major vascular complications
at 30 days as well as possible up to 2 years after noncardiac surgery (Devereaux

and Szczeklik 2020). Diagnostic criteria for myocardial injury after noncardiac
surgery are an elevated post-operative troponin measurement judged as resulting
from myocardial ischemia, during or within 30 days after noncardiac surgery,
and without the presence of symptoms or electrocardiographic findings of isch-
emia. In the dabigatran in patients with myocardial injury after non-cardiac sur-
gery (MANAGE) trial, patients ≥45 years who had undergone noncardiac surgery
and were within 35 days of myocardial injury were randomly assigned to receive
dabigatran 110 mg orally twice daily or placebo (Devereaux et al. 2018). The
primary efficacy outcome, a composite of vascular mortality and nonfatal myo-
cardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, ampu-
tation, and symptomatic venous thromboembolism, was observed less in patients
randomized to dabigatran (11%) than placebo (15%) (HR 0.72, 95% CI 0.55–0.93;
p = 0.0115). The primary safety outcome, a composite of life-threatening, major,
and critical organ bleeding, was similar in both groups (3% vs. 4%). While the
authors recommend that dabigatran be used in patients with myocardial injury
after noncardiac surgery, there are several limitations to the trial that have tem-
pered this approach including the early termination of the trial, the high propor-
tion of drug discontinuation (46%), and alteration of the primary efficacy end
point in the middle of the trial.
Heart Failure in Sinus Rhythm
Although heart failure has been shown to be an important risk factor for stroke,
attempts to lower that risk of with anticoagulation in patients without history of AF
has not borne fruit. Several smaller trials using warfarin in patients with heart failure
and sinus rhythm have not shown any net clinical benefit. This led to the design of
the A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the
Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure
and Coronary Artery Disease Following an Episode of Decompensated Heart
Failure (COMMANDER HF) trial. In this trial, 5022 patients who had chronic heart
failure, a left ventricular ejection fraction of 40% or less, coronary artery disease,
and elevated plasma concentrations of natriuretic peptides and who did not have
atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.5 mg
twice daily or placebo in addition to standard care after treatment for an episode of
worsening heart failure (Zannad et al. 2018). After a median follow-up of 21 months,
the primary efficacy outcome, a composite of death from any cause, myocardial
infarction, or stroke, occurred in 626 (25.0%) of 2507 patients assigned to rivaroxa-
ban and in 658 (26.2%) of 2515 patients assigned to placebo (hazard ratio, 0.94;
95% confidence interval [CI], 0.84 to 1.05; P = 0.27). There were no differences in
fatal bleeding or all-cause mortality between the two groups (Zannad et al. 2018).
Therefore, DOACs should not be used solely because of heart failure with
sinus rhythm.
Embolic Stroke of Undetermined Source
Cryptogenic strokes constitute 20 to 30% of ischemic strokes; the majority of cryp-

togenic strokes are considered to be embolic of undetermined source. Due to the
efficacy of anticoagulants in the prevention of embolic stroke in patients with AF,
investigators hypothesized that anticoagulants would be more effective than anti-
platelet therapy in preventing recurrent strokes in those with embolic stroke of
undetermined source. In the New Approach Rivaroxaban Inhibition of Factor Xa in
a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined
Source (NAVIGATE ESUS) trial, 7213 participants were randomly assigned to
receive rivaroxaban or aspirin (Hart et al. 2018). The annualized incidence rate of
recurrent ischemic stroke was 4.7% in the rivaroxaban group and 4.7% in the aspirin
group. The annualized incidence rate of major bleeding occurred in 1.8% in the
rivaroxaban group and 0.7% in the aspirin group (HR 2.72; 95% CI, 1.68 to 4.39;
P < 0.001). Therefore, rivaroxaban was not superior to aspirin with regard to the
prevention of recurrent stroke and was associated with a higher risk of bleeding in
those after an initial embolic stroke of undetermined source. Similarly, in the
Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing
the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus
Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source
(RE-SPECT ESUS) trial, 5390 patients were randomly assigned to receive dabiga-
tran or aspirin (Diener et al. 2019). During a median follow-up of 19 months, the
annual incidence of recurrent strokes was 4.1% in the dabigatran group and 4.8% in
the aspirin group (HR 0.85; 95% CI 0.69 to 1.03; P = 0.10). The annual incidence
of major bleeding occurred in 1.7% in the dabigatran group and 1.4% in the aspirin
group (HR 1.19; 95% CI, 0.85 to 1.66). Therefore, dabigatran was not superior to
aspirin with regard to the prevention of recurrent stroke but was not associated with
a higher risk of bleeding in those after an initial embolic stroke of undetermined
source. On the basis of these trials, DOACs are not indicated for embolic strokes of
undetermined source.
Mechanical Valves
Mechanical valves are more durable than bioprosthetic valves and are therefore
preferred in younger patients. However, unlike bioprosthetic valves, mechanical
valves require lifelong anticoagulation therapy. Warfarin is the standard of care in
this population but after the publication of the landmark trials in those with nonval-
vular AF, investigators set out to assess the efficacy and safety of DOACs in patients
with mechanical valves. The Randomized, Phase II Study to Evaluate the Safety and
Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve
Replacement (RE-ALIGN) sought to shed some light on the feasibility of DOACs
(Eikelboom et al. 2013). The trial was terminated early due to an excess of throm-
boembolic and bleeding events among patients in the dabigatran group: 5% had a
stroke event compared to no stroke events in the warfarin group and major bleeding
occurred 4% and 2% in those receiving dabigatran and warfarin, respectively. Due

to this trial, DOACs are now contraindicated in patients with mechanical valves.
There have been some criticisms of these recommendations given that it is based on
one phase 2 trial that was terminated early. Also, the trial was done using dabigatran
with the results extrapolated to all other DOACs (Aimo et al. 2018). A small obser-
vational study suggested that rivaroxaban may be safe (Durães et al. 2018). However,
at this time there are no plans for further trials with DOACs in patients with mechan-
ical heart valves.
Left Ventricular Assist Device
Anticoagulation is mandatory in patients with left ventricular assist devices. The

effectiveness and safety of DOACs in patients with left ventricular assist devices has
not been adequately investigated. In part, this is due to the results of the RE-ALIGN
trial in patients with mechanical valves. In a pilot randomized trial to assess for
feasibility in which patients with left ventricular assist devices were randomized to
receive either phenprocoumon or dabigatran in addition to aspirin for long-term
anticoagulation (Andreas et al. 2017), the trial was stopped early due to an excess in
thromboembolic complications in the dabigatran arm (50%). In AF, thrombosis is
driven by stasis and endothelial dysfunction in the left atrial appendage and the
inhibition of one key factor in the coagulation cascade in these patients is enough to
prevent thrombus formation (den Exter et al. 2020). In contrast, in patients with left
ventricular assist devices, coagulation is principally triggered by blood contact with
the artificial surfaces activating the contact pathway in which vitamin K antagonists
are more effective by inhibiting both thrombin and the tissue factor induced path-
way (den Exter et al. 2020).
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Pharmacokinetics
and Pharmacodynamics of DOAC 3
Nicola Ferri
Introduction
Oral anticoagulants are used for the treatment and prevention of stroke and venous
thromboembolism in patients with chronic non-valvular atrial fibrillation (NVAF).
Until 2010, vitamin K antagonists, such as warfarin, were the only oral anticoagu-
lants available in the clinic. However, warfarin therapy is associated with numerous
limitations: (a) delayed onset of action, (b) restricted therapeutic window, (c)
numerous interactions with other drugs or food, (d) variable and unpredictable phar-
macological response, (e) influence of the genetic polymorphism of CYP2C9 and
VKORC1, (f) requirements of frequent monitoring of the coagulation. These limita-
tions led to the development of new oral anticoagulants (NAO) or the so-called
direct oral anticoagulants (DOACs) (Yeh et al. 2015).
Physico-Chemical Properties
The chemical structure of DOACs currently approved internationally is shown in

Fig. 3.1. Dabigatran is an aromatic amide obtained by formal condensation of the
carboxy group of 2-{[(4-carbamimidoylphenyl) amino] methyl}-1-methyl- 1H-
benzimidazole 5-carboxylic acid with the secondary amino group of N-pyridin-2-
yl-beta-alanine. Dabigatran can be orally administered as the prodrug, dabigatran
etexilate which differs from dabigatran by an ethyl group at the carboxylic acid and
a hexyloxycarbonyl side chain at the amidine. Dabigatran etexilate is rapidly and
completely metabolized, via two intermediates, to dabigatran by carboxyl liver and
intestinal esterases and plasma esterases present in the portal blood (Fig. 3.1).
N. Ferri (*)
Department of Pharmaceutical and Pharmacological Sciences, University of Padua,
Padua, Italy

28 N. Ferri
CH3 O
H2C O
O
O O O N NH N
N H C NH
N N 2 O
O CH3 N H3N NH O
NH3 O O NH O CI
N CH3 O N
O N S
N CH3 N
O N
O S CI N
N
N NH O
CH3
Dabigatran etexilate Rivaroxaban Apixaban Edoxaban
Fig. 3.1 Chemical structures of DOACs. Orange boxes highlight the chemical moieties of pro-
drug of dabigatran hydrolyzed by esterases
Rivaroxaban (5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-
1,3-oxazolidin-5-yl}methyl) thiophene-2-carboxamide)) and apixaban
(1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-
tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide) are both orally adminis-
tered as active drugs.
Finally, the last DOAC that has been approved for clinical use is edoxaban
(N′-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-
methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c] pyridine-2-carbonyl)amino]cyclo-
hexyl] oxamide;4-methyl benzenesulfonic acid). Differently from the other DOACs,
edoxaban is the only one that is metabolized to form active molecules with similar
potency than parental drug.
Pharmacodymanics of DOACs
Mechanism of Action
Warfarin acts by inhibiting vitamin K epoxide reductase complex 1 (VKORC1),

also a polymorphic enzyme, which generates the reduced form of vitamin K that is
an essential co-factor for carboxylation of glutamate residues on proteins such as
coagulation factors II, VII, IX, and X by gamma glutamyl carboxylase (Ansell et al.
2008). Carboxylation of these proteins is essential for their biological activity.
Differently, DOACs directly inhibit biological activity of factor Xa (fXa) or throm-
bin (factor IIa), key proteases in the coagulation cascade (Fig. 3.2). In particular,
apixaban, rivaroxaban, and edoxaban reversibly inhibit fXa while dabigatran is a
selective inhibitor of the downstream protease thrombin (Fig. 3.2) (Wang and
Bajorek 2014).
Since fXa is the common enzyme of both extrinsic and intrinsic coagulation
pathways, rivaroxaban, apixaban, and edoxaban can inhibit the thrombin generation
from both ways, leading to a complete and effective anticoagulant action. Differently,
dabigatran acts at a downstream step of the coagulation cascade, i.e., by inhibiting
thrombin activity with a Ki of 4.5 nM (Stangier et al. 2007, 2008).
FXa has also emerged as a particularly promising target for effective anticoagu-
lation because one molecule of fXa results in the generation of more than 1000
3 Pharmacokinetics and Pharmacodynamics of DOAC 29
Intrinsic pathway
XII XIIa
Extrinsic pathway
XI XIa
IX IXa VIIa VII
Rivaroxaban
Apixaban
Edoxaban X Xa X
Va
Prothrombin Thrombin
II IIa Dabigatran
Fibrinogen Fibrin
Fig. 3.2 Schematic view of the mechanism of action of DOACs
thrombin molecules (Mann et al. 2003). Thus, inhibiting fXa may block this burst
of thrombin generation, thereby diminishing thrombin-mediated activation of coag-
ulation and platelets (Gerotziafas et al. 2007).
Apixaban is the most potent fXa inhibitor with a binding affinity (Ki) of 0.08 nM
(Stangier et al. 2007, 2008). The selectivity of action of apixaban is demonstrated
by the fact that the inhibitory potencies against thrombin, plasma kallikrein, and
chymotrypsin are around 10,000 times higher (Ki ~ 3 μM) (Pinto et al. 2007).
Rivaroxaban inhibits fXa in a concentrated manner (Ki ~ 0.4 nM) (Perzborn et al.
2005). Similarly, to rivaroxaban and apixaban, edoxaban binds the catalytic site of
the fXa with a Ki of 0.56 nM (Furugohri et al. 2008). Apixaban, rivaroxaban, and
edoxaban seem to inhibit also fXa present in the clot.
The antithrombotic effect of DOACs is primarily attributed to the inhibition of
fXa without any significant in vitro effect on platelet aggregation. However, these
drugs may decrease platelet activation in vivo indirectly via inhibition of thrombin
generation and may thereby affect thrombin-induced aggregation.
From a pharmacodynamic point of view, DOACs have a direct effect which is
maximal after 2–3 h from their administration in accordance with the time to peak
concentration (Tmax) (Table 3.1) and with the direct correlation between plasma
concentrations and anticoagulant effect. These characteristics distinguish these
drugs from warfarin, which through the inhibition of the activation of several clot-
ting factors, it takes 3–5 days to manifest its anticoagulant action (Desai
et al. 2013).
30 N. Ferri
Table 3.1 Pharmacokinetic and pharmacodynamic characteristics of DOACs

Dabigatran Rivaroxaban Apixaban Edoxaban
Target Thrombin fXa fXa fXa
Ki (nmol/L) 4.5 0.4 0.08 0.56
Bioavailability 6.5% (absolute) 80% 50% 60%
(absolute) (absolute)
Effect of food Delayed and not Increased None None
reduced absorption absorption (20 mg)
Administered with No Yesa No No
food
Vd 60–70 L 50 L 21 L >300 L
Protein bound 35% >90% 87% 40–59%
Prodrug Yes No No No
Tmax (h) 1–3 2–4 3–4 2
Half lifetime (h) 12–17 5–9 (healthy) 8–15 8–11
Metabolism (CYP) Conjugation 3A4, 2J2, and CYP 3A4 3A4
independent
P-gp substrate Yes (only prodrug) Yes Yes Yes
Substrate of other Not known BCRP/ABCG2 BCRP/ Not known
transporters ABCG2
Renal elimination 80% 35% 27% 50%
Hemodialysis 60–70% Unlikely Unlikely Possible
elimination
Administration Double daily dose Double daily dose Double Double
frequency daily dose daily dose
Vd volume of distribution, Tmax time to reach the maximal plasma concentration, CYP450
Cytochrome P 450, P-gp P-glycoprotein
a
The drug at 15 and 20 mg must be administered with food
Similar situation is observed for the reversibility of the pharmacological effect,

which is much faster for DOACs, both for short half-life and for the reversibility of
their mechanism of action, compared to warfarin.
From all these considerations, it is evident that DOACs have intrinsic character-
istics which are deeply distinct, not only from the classic vitamin K inhibitors, but
also between them. So, in order to better use these new pharmacological agents, it
is important to know and understand their pharmacological properties.
Pharmacokinetics of DOACs
Absorption
The pharmacokinetics parameters of DOACs are summarized in Table 3.1.

Dabigatran differs from the other DOACs due to its low bioavailability (6.5%)
which entails an important variability in the absorbed portion (Stangier et al. 2008).
As previously descried, in order to achieve oral absorption, dabigatran is adminis-
tered as a prodrug (dabigatran etexilate), which once it reaches the systemic circle,
it is hydrolyzed by liver and serum esterases that produce the active form of the
drug. Its absorption increases in an acid environment and, for this reason, the drug
is formulated in the presence of tartaric acid. Phase I studies with increasing doses
of dabigatran show that low oral bioavailability is not caused by a saturable first-
pass process, considering that plasma concentrations increase linearly and dose-
dependently following a first order kinetic (Stangier et al. 2007; Gong and
Kim 2013).
The capsules containing dabigatran etexilate are designed to release the drug into
the stomach allowing the absorption in the duodenum. Indeed, dabigatran is thought
to be absorbed in the lower stomach and duodenum because of the rapid time to
peak levels. The identification of the site of dabigatran absorption is also supported
by a case report showing reduced absorption in short bowel syndrome contributing
to insufficient anticoagulation and drug levels below published values of therapeutic
doses of dabigatran. The drug not absorbed will remain in the gastrointestinal tract
where could undergo to enzymatic activation dabigatran and eliminated in the feces.
Considering the pH-dependent solubility of the drug, co-administration with H2
antagonists and proton-pump inhibitors, which causes an increase in intestinal pH,
limits dabigatran bioavailability reducing its exposure by respectively 12% and
30% (Heidbuchel et al. 2013). However, this interaction is thought not to be clini-
cally meaningful (Steffel et al. 2018). On the contrary, the pharmacokinetics of
rivaroxaban, apixaban, and edoxaban are not altered by drugs that increase
gastric pH.
Co-administration of food resulted in a delay in absorption of dabigatran etexi-
late, with the median Tmax increasing from 2 to 4 h. However, bioavailability (AUC
and Cmax) was essentially unchanged in the fasted state compared with fed condi-
tions (Fig. 3.3). Thus, dabigatran can be administered either in the presence or
absence of food.
Rivaroxaban appears to be absorbed primarily in the stomach, as there is reduced
absorption (29% decrease in AUC and 56% decrease in Cmax) when the drug is
released into the proximal small intestine, with further reduction as the drug is
released more distally into the small intestine and colon (Mani et al. 2013; Douros
et al. 2014). More importantly, the bioavailability of rivaroxaban is not linear with
the administered dose. At the dose of 10 mg, the bioavailability is estimated to be
80–100%, compared to 66% at the dose of 20 mg (Stampfuss et al. 2013). The pres-
ence of food significantly increases the bioavailability of rivaroxaban (20 mg,
Fig. 3.3), and reduces the interindividual variability of its plasma concentrations
(Stampfuss et al. 2013). This effect is probably due to a positive effect of food on
the solubilization and dissolution of the drug. It is important to highlight that food
intake is meant a meal of at least 1300 Cal with a 30–40% fat content. For this rea-
son, it is fundamental to take rivaroxaban after meals (Fig. 3.3).
Apixaban is absorbed primarily in the proximal small intestine, with some gas-
tric absorption and limited colonic absorption and reaches the maximum concentra-
tion (Cmax) after 2–3 h from the oral administration (Frost et al. 2013a, b). Its
bioavailability is approximately 50% and approximately 35% of the unabsorbed
portion is eliminated with feces (Table 3.1). Unlike rivaroxaban, intestinal
32 N. Ferri
a b
rivaroxaban dabigatran
300 100
Plasma concentration
250
80
rivaroxaban (ng/ml)
rivaroxaban (ng/ml)
Fasted Fasted
200 Fed 60 Fed
150
40
100
50 20
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h) Time (h)
c d
apixaban edoxaban
180 300
160
250
140 Fasted
edoxaban (ng/ml)
apixaban (ng/ml)
Fasted
120 Fed 200
Fed
100
150
80
60 100
40
50
20
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h) Time (h)
Fig. 3.3 Effect of food on the pharmacokinetic of DOACs. (a) Rivaroxaban; (b) Dabigatran; (c)
Apixaban; (d) Edoxaban. Food determines a significant increase of rivaroxaban exposure (Cmax and
AUC) and a delay of dabigatran absorption (Tmax)
absorption of apixaban is not affected by food (Fig. 3.3) (Frost et al. 2013a, b).
Similar considerations can be made for edoxaban, which reaches its Cmax after 2 h
from the oral administration and its pharmacokinetic profile which is not affected by
the food (Fig. 3.3) (Mendell et al. 2012).
Edoxaban is rapidly absorbed after oral administration with a time to peak
plasma concentration of 1–2 h, and a bioavailability of 62% (Table 3.1). Its absorp-
tion, which is not related to solubility, occurs predominantly in the proximal small
intestine and it is limited in the colon (13%) (Parasrampuria et al. 2015). Edoxaban
has a low intrasubject variability and dose linearity suggesting a predictable and
consistent pharmacokinetic profile.
Terminally ill patients with dysphagia may result in reduced patient adherence to
medications. Therefore, solid oral formulations crushed and mixed into food or pro-
vided as a water suspension via a nasogastric tube are often utilized as alternative
methods of drug administration. However, these manipulations may alter the bio-
availability of a drug. Within this clinical setting, a phase I, open-label, randomized
trial was conducted to assess the pharmacokinetic, safety, and tolerability profiles of
the edoxaban 60-mg tablet in healthy adults when crushed and administered either
via a nasogastric tube or mixed with apple puree and ingested (Duchin et al. 2018).
The results demonstrated that edoxaban tablet crushed and administered either via
a nasogastric tube or with apple puree displays similar total exposure, although time
to maximum plasma concentration was significantly shorter for the nasogastric tube
suspension and apple puree vs. the whole tablet (Duchin et al. 2018). Thus, edoxa-
ban can be considered a valid option for patients who are unable to swallow solid
oral dose formulations. In contrast, when rivaroxaban is administered using a naso-
gastric tube followed by a liquid meal, a significant 18% reduction in Cmax was
observed, although the AUC values were similar (Mueck et al. 2014).
Dabigatran, due to the low bioavailability, and rivaroxaban, due to the once-daily
posology, are expected to have a higher variability of peak and trough concentra-
tions and may undergo more easily to clinically relevant drug–drug interaction.
In consideration of the mechanism of drug absorption in the gastrointestinal
track, it is relevant to know that all DOACs are substrate of the P-glycoprotein
(P-gp) and potentially other drug transporters (Gong and Kim 2013). The P-gp par-
tially limits the disposition of the drugs by reducing their intestinal absorption and
facilitating their elimination by the kidney and the liver (Wolking et al. 2015). For
this reason, all DOACs are expected to have important pharmacological interactions
with potent P-gp inhibitors, such as antifungals, macrolides, antiretroviral protease
inhibitors, which significantly increase DOACs absorption and thus the anticoaugu-
lant effect.
Among the cardiovascular drugs, diltiazem, amiodarone, dronedarone, quini-
dine, and verapamil are considered the most potent P-gp inhibitors and potentially
increasing the exposure of all DOACs (Steffel et al. 2018). Considering the inducers
of P-gp, rifampin, most antiepileptic drugs and St. John’s wort, should not be admin-
istered in combination with DOACs (Chap. 4) (Steffel et al. 2018).
Distribution
As shown in Table 3.1, DOACs are characterized by different volumes of distribu-

tion (Vd) and plasma protein binding (Table 3.1). Dabigatran is highly hydrophilic
with poor plasma protein binding and prevalent renal clearance, characteristics that
make this drug the only DOAC that can be hemodialyzed (Khadzhynov et al. 2013).
However, the dialysis is effective only if performed after the first hours from the last
administration, otherwise the volume of distribution of the drug (60 L), after distri-
bution is complete, prevents dialysis removal.
The plasma protein binding for rivaroxaban is high (approximately 92–95%
in vitro) and reversible. Serum albumin is the main plasma binding component.
Owing to its high plasma protein binding, rivaroxaban is not expected to be dialyz-
able. Vd at steady state is approximately 50 L, indicating its low-to-moderate affinity
to peripheral tissues (Dias et al. 2016).
Apixaban is characterized by a reduced apparent volume of distribution (21 L),
suggesting a distribution mainly in the systemic circulation, with a limited extravas-
cular localization (Mavrakanas et al. 2017). The binding to plasma proteins is 87%,
therefore not particularly high, excluding possible interactions with drugs that can
displace the binding (Table 3.1).
The mean apparent Vd of edoxaban is approximately 300 L and 100 L after oral
and intravenous administration, respectively (Ogata et al. 2010; Parasrampuria and
34 N. Ferri
Truitt 2016). This difference indicates biliary excretion of edoxaban and a possible
enterohepatic circulation through glucuronidation processes. The relatively high Vd
of edoxaban in comparison to other DOACs is not predicted to have any clinically
relevant implication on the safety or efficacy of the drug according to the large expe-
rience in the phase III trials, including patients with frailty, obesity, older age, and
mild to moderate chronic kidney disease (CKD). Edoxaban shows a relatively low
total plasma protein binding (≈55%), whereas the human-unique metabolite M-4 is
approximately 80% bound to plasma proteins over a concentration range of
0.2–2 μg/mL (Parasrampuria and Truitt 2016).
Metabolism
In general, all DOACs do not undergo to an extensive phase I and phase II metabo-
lism. As an ester prodrug, dabigatran etexilate undergoes two sequential activation
steps to form its pharmacologically active metabolite dabigatran. Following oral
administration, dabigatran etexilate is first metabolized to its intermediate metabo-
lite dabigatran ethyl ester (M2) by carboxylesterase 2 (CES2) in the intestine, and
M2 is further converted to the final active metabolite DAB by carboxylesterase 1
(CES1) in the liver (Blech et al. 2008). Once activated, dabigatran is eliminated
primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min
corresponding to the glomerular filtration rate (Stangier et al. 2007). The cumulative
urinary excretion of dabigatran accounted for less than 5% of the dose (Stangier
et al. 2007).
Dabigatran, being a polar drug, exhibits only a little oxidative metabolism.
Instead, the acylglucuronide of the carboxylate functional group is formed, and this
is the major metabolite in humans (Ebner et al. 2010). After oral administration,
approximately 20% of dabigatran is conjugated by glucuronosyltransferases to the
pharmacologically active glucuronide conjugates. Four positional isomers, 1-O,
2-O, 3-O, 4-O-acylglucuronide exist, each account for less than 10% of total dabi-
gatran in plasma (Ebner et al. 2010). Conjugates of dabigatran in urine represented
0.4% of the dabigatran dose. Thus, CYP3A4 is not involved in the metabolism of
dabigatran, excluding possible drug–drug interactions with inhibitors or inducers of
cytochromes (Heidbuchel et al. 2013).
Conversely, approximately 2/3 of a rivaroxaban dose undergo metabolic trans-
formation. Rivaroxaban is metabolized by CYP3A4/5 by about 18%, while CYP2J2
ensures metabolization of approximately 14% (Mueck et al. 2014). CYP-
independent amide bonds hydrolysis contributes other 14%. About 36% of the drug
is eliminated unchanged with urine: 30% through active renal secretion, 6% via
glomerular filtration. Thus, CYP3A4-dependent elimination is relevantly involved
in the hepatic clearance of rivaroxaban and strong CYP3A4 inhibition or induction
may affect plasma concentrations and should be evaluated in context.
Most of the hepatic clearance of apixaban is as unchanged molecule, with only a
minority being metabolized (in part via CYP3A4), which makes CYP3A4 interac-
tions of low importance for this drug (Wang et al. 2010). In addition, non-metabolic
clearance of apixaban is diverse (including excretion of the unchanged drug by
>50%), which reduces the potential for drug–drug interaction (Wang et al. 2010).
Nevertheless, apixaban should be used with caution if co-administered with strong
inducers of both CYP3A4 and P-gp and is contraindicated in combination with
strong inhibitors of both CYP3A4 and P-gp (Steffel et al. 2018).
In healthy human subjects, six phase 1 metabolites (M-1, M-2, M-4, M-5, M-6,
and M-8) and a glucuronide (M-3) metabolites of edoxaban have been detected in
plasma (Parasrampuria and Truitt 2016). M-4 is the major metabolite and it is pro-
duced from the CES1. CYP3A4 mediates the formation of M-5, while a minor
metabolite M-8 derives spontaneously (non-enzymatically) from an intermediary,
hydroxymethyl edoxaban, formed via CYP3A4/5 (Parasrampuria and Truitt 2016).
Three of the metabolites (M-4, M-6, and M-8) have anticoagulant activity, with
IC50 values for anti-FXa of 1.8 nM (M-4), 6.9 nM (M-6), and 2.7 nM (M-8), thus
similar to the parental drug (0.56 nM) (Parasrampuria and Truitt 2016). However,
due to the low plasma concentration and high protein binding, the most abundant
metabolite, M-4, is not expected to contribute significantly to the overall pharmaco-
logical activity of edoxaban. Importantly, the relative increase in edoxaban and M4
systemic exposure is identical, and the AUC ratio (M4 over edoxaban) is constant
over varying kidney function, body weight, and doses; however, a significant
increase of M4/edoxaban ratio is predictable in the presence of drugs that induce
edoxaban metabolism (see Chap. 4). Thus, unlike rivaroxaban, CYP3A4-dependent
elimination is marginally involved in the hepatic clearance of edoxaban
(Parasrampuria and Truitt 2016).
Excretion
The relative contribution of renal drug excretion varies considerably among DOACs.
Most of a dabigatran dose is excreted by the kidneys unchanged (80%) or in the
form of active glucuronides (4%). Edoxaban, rivaroxaban, and apixaban are excreted
unchanged by 50%, 33%, and 27% of the bioavailable dose, respectively (Heidbuchel
et al. 2013; Ferri and Corsini 2015). Renal clearance of dabigatran amounted to
50–100 mL/min.
The contribution of glomerular filtration, active secretion, and tubular reabsorp-
tion differs among DOACs. In particular, renal clearance of dabigatran is slightly
lower than the glomerular filtration at any level of renal impairment, indicating that
tubular reabsorption does occur to some extent (Padrini 2019). Indeed, dabigatran is
the most lipophilic compound of the group (log P = 2.37) and the only one which
does not undergo tubular secretion by P-gp. Conversely, the renal clearance of riva-
roxaban and edoxaban is four times higher than glomerular filtration rate, most
probably due to extensive tubular secretion by P-gp, as shown by the increase in the
AUCs of rivaroxaban and edoxaban by P-gp inhibitors (Padrini 2019). Lastly, apix-
aban is characterized by nearly coinciding values of renal clearance and glomerular
filtration rate, indicating lack of drug secretion and reabsorption or, rather, a null
sum of the two processes. The latter hypothesis seems more plausible, since apixa-
ban is also a substrate of P-gp but, having lipophilicity similar to that of dabigatran
(log P = 2.23), may also be reabsorbed (Padrini 2019).
36 N. Ferri
The limited involvement of renal excretion for the apixaban elimination path-
way, and a very diversified hepatic clearance, including metabolism, biliary secre-
tion, and direct elimination in the intestine, confers to this drug a greater margin of
safety in patients with partial kidney and hepatic impairment.
The renal clearance of apixaban is also lower than for all DOACs and in particu-
lar with edoxaban (15 mL/min vs. 183 mL/min) (Table 3.1). In fact, the calculation
of the clearance involves the involvement of both the Vd value and the half-life time.
With the same half-life time between edoxaban and apixaban, the much higher Vd of
the former inevitably determines a much higher clearance value. This difference is
caused by the fact that apixaban is eliminated from the kidney exclusively by glo-
merular filtration, or alternatively the active tubular secretion processes are equiva-
lent to those of tubular reabsorption. On the contrary, the renal elimination of
edoxaban involves active tubular secretion processes. These differences are clini-
cally relevant in “so-called hyperfiltration” patients in whom edoxaban loses effi-
cacy precisely because of its excessive renal elimination (Bohula et al. 2016).
The different renal clearance may determine variations of dosage and choice of
DOAC based on the pathophysiological characteristics of the patient. According to
European guidelines (Steffel et al. 2018), dabigatran is contraindicated in patients
with a creatinine clearance <30 mL/min, while rivaroxaban and edoxaban can be
used with caution at lowered dose with a clearance between 15 and 29 mL/min and
with a close monitoring of patient’s kidney function. In patients with moderate renal
insufficiency (creatinine clearance between 30 and 50 mL/min), dabigatran, rivar-
oxaban, and edoxaban can be used at lowered dose (Table 3.2). The choice of the
Table 3.2 Comparison between FDA, EMA, and HC guidelines on dose adjustment recommen-
dations in patients with atrial fibrillation and various degrees of renal impairment
Drug CLcr (mL/min) Recommendations
Dabigatran <15 Not recommended by FDA
<30 Contraindicated by EMA and HC
15–30 Dose reduction (75 mg bid) by FDA
Rivaroxaban <15 Not recommended by FDA and
contraindicated by EMA
<30 Not recommended by HC
15–50 Dose reduction (15 mg qd) by FDA and EMA
30–49 Dose reduction (15 mg qd) by HC
Apixaban Hemodialysis No dose reduction (5 mg bid) by FDA
<15 Contraindicated by EMA and HC
15–29 Dose reduction (2.5 mg bid) by EMA
Crs ≥ 1.5 mg/dL and age ≥ 80 Dose reduction (2.5 mg bid) by FDA, EMA
or body weight ≤ 60 kg and HC if two of the parameters are present
Edoxaban <15 Contraindicated by FDA, EMA, and HC
<30 Contraindicated by HC
15–50 Dose reduction (30 mg qd) by FDA
>95 Not recommended by FDA (reduced efficacy)
CLcr creatinine clearance, Crs serum creatinine, qd once daily, bid twice daily, FDA Food and
Drug Administration, EMA European Medicines Agency, HC Health Canada
posology for apixaban is based on the presence of at least two of the following
parameters: serum creatinine ≥1.5 mg/dL, age ≥ 80, or body weight ≤ 60 kg. In the
presence of this condition, apixaban should be used at lower dose with a clearance
≥30 mL/min. With a clearance between 15 and 29 mL/min, the recommended dose
of apixaban is 2.5 mg bid. The elimination characteristics of apixaban entail the
possibility of using the drug at full dose (5 mg bid) even in hemodialysis patients,
as suggested by the FDA guidelines (Table 3.2) (Heidenreich et al. 2016).
Due to the relevant renal clearance, in a pharmacokinetic study of patients
with NVAF, the edoxaban exposure has been shown to be lower in subjects with
creatinine clearance above 90 mL/min. Thus, in patients with a CrCl >95 mL/min
edoxaban has been shown a lower relative efficacy compared to warfarin. On this
basis, the Cardiorenal Division of the US Food and Drug Administration (FDA)
recommended that edoxaban should not be used in patients with a CrCl >95 mL/
min for stroke prevention in NVAF (US Food and Drug Administration 2015).
The position of FDA was not followed by other regulatory agencies both in
Europe by the European Medicines Agency (EMA), as well as in Canada
(Table 3.2).
All DOACs are, however, contraindicated in patients with severe liver impair-
ment (Child–Pugh C), while rivaroxaban is also contraindicated in case of Child–
Pugh B (Steffel et al. 2018). This difference is due to the fact that rivaroxaban is the
DOACs with a higher rate of elimination through CYP-mediated metabolism.
Unlike dabigatran, not metabolized by cytochromes, the dose of apixaban, rivar-
oxaban, and edoxaban must be reduced in case of co-administration with potent
CYP3A4 inhibitors.
Among the characteristics of DOACs, the elimination half-life time deserves
important considerations. This parameter is approximately equal to 12 h for dabiga-
tran, apixaban, and edoxaban, and significantly lower for rivaroxaban, 5–9 h
(Table 3.1). This characteristic suggests a bid administration. The ratio between the
maximum and minimum concentration at steady state in once-daily administration
is equal to 4.5 for dabigatran (Clemens et al. 2012), 10 for rivaroxaban (Mueck et al.
2014), 10 for apixaban (Frost et al. 2013a) and 10–30 for edoxaban (Ogata et al.
2010). The higher the ratio, the greater is the fluctuation of plasma levels in 24 h.
The clinical consequences of these fluctuations can lead to bleeding in the case of
the peak or thromboembolic events at minimum concentrations. It is therefore plau-
sible to minimize these variations by opting for the bid administration. However,
rivaroxaban and apixaban are administered as once daily, modality that leads to a
pharmacokinetic profile with very high peak concentrations compared to dabigatran
and apixaban. The high Cmax peak levels with rivaroxaban, together with a nonlinear
kinetic at dosages higher than 10 mg and the influence by food on its gastrointesti-
nal absorption, are associated to a high pharmacokinetic variability. A cross-over
study that directly compared rivaroxaban to apixaban, clearly demonstrated a lower
variability with a bid administration of apixaban (23% vs. 46% for apixaban and
rivaroxaban, respectively) (Frost et al. 2014). This high variability of rivaroxaban
could be associated to increased risk of gastrointestinal bleeding observed com-
pared to warfarin in the clinical trial ROCKET AF (Patel et al. 2011).
38 N. Ferri
The variability in the plasma concentration of edoxaban, administrated once

daily, is less problematic compared to rivaroxaban since the former is characterized
by a linear kinetic profile and a half-life elimination time significantly slower (12 h).
Surprisingly, when edoxaban is administered bid, a higher risk of major bleeding
was observed compared to qd (Weitz et al. 2010). This apparent discrepant effect
can be explained by high Vd that leads to the accumulation of the drug. Indeed, the
increased bleeding of edoxaban correlates with high minimum concentrations (Cmin)
that are found with the dosage bid (Weitz et al. 2010).
Conclusions
The DOACs, on the basis of their pharmacological profile and the results of clinical
trials conducted by a direct comparison to warfarin, represent an important evolu-
tion of the therapeutic armamentarium available for the treatment of patients at risk
of thromboembolic complications.
The pharmacokinetics characteristics of DOAC represent an important tool in
order to customize the treatment based on the characteristics of patients, and to
obtain the best therapeutic efficacy by minimizing adverse effects. Thus, the selec-
tion among the four currently available DOACs should be done by considering
important pathophysiological parameters, such as kidney function, dyspepsia, the
risk of bleeding and ischemic events, as well as other concomitant therapies which
could determine clinically relevant drug–drug interactions. Finally, the compliance
of bid or single daily administration should also be considered.
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Drug–Drug Interaction with DOACs
4
Alberto Corsini and Nicola Ferri
Introduction
Four direct oral anticoagulants (DOACs) have been approved for clinical use by
many regulatory medicines’ agencies around the world. The use of these drugs is
increasing in routine practice for the treatment of non-valvular atrial fibrillation
(NVAF) and venous thromboembolism (VTE). AF is the most common sustained
arrhythmia in clinical practice, especially in the elderly (Boriani et al. 2006, 2018;
Lip et al. 2014) and, even if the arrhythmia is asymptomatic, is associated with
adverse outcomes, with a significantly increased risk of stroke, death, and heart
failure (Giuseppe et al. 2014). VTE, categorized as deep venous thrombosis (DVT)
and pulmonary embolism (PE), is associated with high morbidity and a relevant
financial burden on patients and health system. Both acquired and hereditary risks
factors contribute to VTE, in particular VTE is a common complication of cancer
and its therapy (Perera et al. 2020).
Oral anticoagulant therapy significantly reduces the risk of AF-related thrombo-
embolic events and mortality, and is recommended in every patient at risk, accord-
ing to guidelines (Steffel et al. 2018a). The class DOACs are nowadays an effective
treatment with as safer profile compared to vitamin K antagonist (VKA) and are
currently implemented in “real-world” clinical practice, in patients with so-called
NVAF and VTE, settings characterized by patients with complex clinical scenarios,
in terms of comorbidities and polypharmacy. Comorbidity and polypharmacy are at
high prevalence in elderly patients, a population where the estimated prevalence of
A. Corsini
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
N. Ferri (*)
Department of Pharmaceutical and Pharmacological Sciences, University of Padova,
Padova, Italy

42 A. Corsini and N. Ferri
NVAF is particularly high (9%–10% at age over 80 years and lower than 0.1% in
patients at age below 55 years) (Go et al. 2001; Lloyd-Jones et al. 2004; Miyasaka
et al. 2006). In addition, NVAF is associated with a four- to fivefold increased risk
of embolic stroke with an estimated increased stroke risk of 1.45-fold per decade in
aging (Go et al. 2014; Coppens et al. 2013). Since VKA warfarin shows many clini-
cal significant interactions with drugs, foods, and herbal medicines (Nutescu et al.
2006; Teklay et al. 2014), resulting in frequent adjustment of its dosage in order to
achieve a safe and effective anticoagulant effect, the use of new DOACs may repre-
sent a significant clinical advantage.
Thus, in view of the need to prescribe oral anticoagulants to patients with various
concurrent diseases and on treatment with various drugs or agents, in the present
chapter, the predicted drug–drug interactions (DDIs) of DOACs will be described.
Considering that many DDIs are not specifically studied, only theoretical pharma-
cological considerations can be done of specific anticoagulant in order to predict if
an interaction is possible. In view of the increasing number of patients with onco-
logical pathologies who need treatment with anticoagulants, for VTE or NVAF
(Perera et al. 2020; Ay et al. 2017), we will include interactions between DOACs
and chemotherapies.
General Considerations
As discussed in Chap. 3, all DOACs are substrates for P-gp, therefore strong inhibi-
tion of P-gp can increase absorption and exposure of DOACs, thus increasing the
bleeding risk. On the other hand, an induction of P-gp can reduce DOACs absorp-
tion, therefore reducing their antithrombotic therapeutic effect. Indeed, an impor-
tant interaction mechanism for all DOACs consists of significant gastrointestinal
re-secretion over a P-gp transporter after absorption in the gut and in their renal
clearance (Gnoth et al. 2011).
The intensity of the inhibition or induction of P-gp transporters can help to pre-
dict the entity of the change in drug exposure (Table 4.1). This approach was adopted
by the recently published “The 2018 European Heart Rhythm Association Practical
Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with
atrial fibrillation” (Steffel et al. 2018a). Thus, strong P-gp inhibitors may increase
systemic absorption and decrease elimination of P-gp substrates resulting in
increased exposure. On this regard, it is relevant to consider that the extent of the
inter-individual variability of a drug plasma concentration may have a significant
impact of the interaction with P-gp inhibitors or inducers. For instance, dabigatran
and rivaroxaban, which are expected to have a higher variability of peak and trough
concentrations, in comparison to edoxaban and apixaban, may undergo more easily
to clinical relevant DDI (Gosselin et al. 2018; Testa et al. 2016).
Since edoxaban metabolism, by CES1, CYP3A4 and via glucuronidation, is only
marginally involved in its clearance, inhibitors or inducers of these enzymes are
unlikely involved in clinically relevant interactions with edoxaban (Parasrampuria
4 Drug–Drug Interaction with DOACs 43
Table 4.1 Inducers and inhibitors of CYP3A and P-gp

Non-P-gp
P-gp inhibitor inhibitor P-gp inducer
Strong Itraconazole, ketoconazole, Voriconazole
CYP3A clarithromycin, lopinavir,
inhibitor indinavir, ritonavir, telaprevir
Moderate Erythromycin, verapamil, Not identified Doxorubicin
CYP3A diltiazem, dronedarone
inhibitor
Weak Lapatinib, quinidine, Cimetidine Vinblastine
CYP3A cyclosporine, felodipine,
inhibitor azithromycin, ranolazine,
ticagrelor, chloroquine,
hydroxychloroquine
CYP3A Carbamazepine, phenytoin,
inducers phenobarbital, rifampin,
dexamethasone,
tocilizumab, St. John’s
Wort
Modified from Kubitza et al. (2016)
CYP Cytochrome P450, P-gp P-glycoprotein
and Truitt 2016). Indeed, unlike other direct anti-Xa inhibitors such as rivaroxaban
and apixaban, edoxaban is minimally involved in hydrolysis, conjugation, and oxi-
dation through CYP3A4 metabolism (< 4%) and theoretically we could expect
fewer DDIs with agents that strongly inhibit or induce cytochrome P450 enzymes,
in particular the CYP3A4 variant.
In the following paragraphs, we will summarize the clinical evidence of DDI of
DOACs with different classes of drugs and also some tools to predict non-studied
DDIs. These predictions are based on the pharmacological profile of DOACs and
the profile of the specific class of drugs that are being considered. The issue of how
to identify and distinguish the clinically relevant DDIs from non-relevant interac-
tions will also be discussed.
DDI with Antiarrhythmic Drugs
Many classes of cardiovascular drugs might interact with DOACs via inhibition of
P-gp and/or CYP3A4, thus leading to increase in exposure and possibly bleeding
risk. Many cardiovascular drugs are commonly prescribed with DOACs in patients
with AF.
Therefore, it is relevant to verify the possible pharmacological interaction with
drugs for the treatment of concomitant cardiovascular diseases, such as antihyper-
tensives and heart failure drugs (Table 4.2). To this end, Frost and collaborators
conducted a pharmacokinetic (PK) study with apixaban in the presence and absence
of digoxin and atenolol. Only 16% of digoxin is metabolized, while 50–70% is
Table 4.2 Predicted effects of cardiovascular drugs on DOACs exposure
Concomitant Drug Effect on DOACs concentration

Cardiovascular drugs Effect on P-gp Dabigatran Rivaroxaban Apixaban Edoxaban
and CYP
Amiodarone Moderate +12 to 60% Minor effect Modest +40%
P-gp increase of AUC
competition concentrations
Digoxin P-gp No effect No effect No effect No effect
competition
Diltiazem P-gp No effect No effect Increase significant

competition in AUC effect on
and weak (1.4-fold) AUC
CYP3A4 and Cmax predicted
inhibition (1.3-fold)
Dronedarone P-gp +70 to 100% Moderate No data: +85%

inhibitor effect, caution AUC
and CYP3A4 should be
inhibitor avoided
Quinidine P-gp +53% Extent in No PKs +77%
competition increase data AUC
unknown
Verapamil P-gp +12 to 180% No effect No PK +53%
competition data AUC
and
weak
CYP3A4
inhibition
Atenolol P-gp No PK No PK AUC and No PK
substrate data data Cmax data
unchanged
AUC area under the curve, CYP Cytochrome P450, P-gp = P-glycoprotein. Yellow: consider dose
adjustment or different DOAC if 2 or more “yellow” factors are present. Orange: consider dose
adjustment or different DOAC. Red: contraindicated/not recommended
eliminated unmodified with urine. Digoxin metabolism is also independent of

CYP450 and does not appear to induce expression of these enzymes, while it is a
substrate of P-gp. Fifty percent of atenolol is eliminated unmodified through feces,
and the second half by kidney. Therefore, atenolol is not metabolized by CYP450
and it is a substrate, as well as apixaban, of P-gp. However, beta-blockers may inter-
act with other drugs by reducing liver flow, although this should not affect the clear-
ance of apixaban, being a low hepatic extraction drug. For these reasons, the
interaction between apixaban and digoxin or atenolol is considered marginal. As
expected, the results of the PK study confirmed this hypothesis by demonstrating
the absence of interaction between apixaban and digoxin or atenolol (Frost
et al. 2017).
No significant PK changes of dabigatran are observed with digoxin, a P-gp sub-
strate, which also had a negligible impact on dabigatran blood coagulation time,
activated partial thromboplastin time (aPTT), and ecarin clotting times (ECT)
(Stangier et al. 2012). Contrary to P-gp substrates, the PK of dabigatran is signifi-

cantly influenced by the co-administration with P-gp inhibitors. For this reason,
dabigatran etexilate should be administered at least 2 h apart from doses of moder-
ate P-gp inhibitors (Hartter et al. 2013a). For instance, dronedarone increases the
systemic exposure of dabigatran by 70–100% and verapamil by 12–180% (if taken
simultaneously). In the USA, the association with dabigatran and dronedarone is
allowed at the dose of 75 mg bid with values of clearance of creatinine between 30
and 50 ml/min. Caution must be exercised with mild-moderate P-gp inhibitors,
including amiodarone, quinidine, and verapamil. In healthy subjects, the co-
administration of amiodarone increases dabigatran bioavailability by about 50–60%.
Since amiodarone has a long half lifetime, the potential for DDIs may persist for
weeks after amiodarone discontinuation. Amiodarone increases dabigatran AUC by
12% in patients with non-valvular AF (Liesenfeld et al. 2011). In a recent cohort
study, co-administration of amiodarone with dabigatran caused a more significant
increase in adjusted rate for major bleeding than with dabigatran alone (Chang
et al. 2017).
Multiple doses of dronedarone increase Cmax and AUC of dabigatran etexilate
150 mg bid by 1.73-fold and twofold, respectively (Gelosa et al. 2018). A single
400 mg dose of dronedarone doubles dabigatran AUC and Cmax, making the co-
administration contraindicated (Gelosa et al. 2018). An increased dabigatran bio-
availability is also observed with the co-administration of quinidine. Similar to
amiodarone, quinidine increases dabigatran AUC and Cmax by more than 50%
(Steffel et al. 2018a). The exposure to dabigatran, when co-administered with vera-
pamil, depends on the formulation of verapamil and timing of administration.
Indeed, exposure to dabigatran is increased when it is administered within 2 h from
verapamil, with the greatest increase observed when a single dose of immediate-
release verapamil is given 1 h before dabigatran (AUC and Cmax increase by 143%
and 179%, respectively, compared to dabigatran alone). When dabigatran is given
2 h before a double dose of extended-release verapamil, only a slight increase in
dabigatran AUC and Cmax (<20% increase) is observed. As t1/2 is not changed, the
interaction is most likely related to the absorption of dabigatran, further supporting
the notion that DDIs involving P-gp are limited to the gut. Dabigatran does not sig-
nificantly alter the PK of verapamil (Hartter et al. 2013a).
Digoxin (P-gp substrate with a narrow therapeutic window) co-administra-
tion in healthy controls does not affect rivaroxaban PK and pharmacodynamic
(PD) (Kubitza et al. 2012). Rivaroxaban does not modify digoxin profile, sug-
gesting that rivaroxaban can be co-administered with digoxin. Rivaroxaban
does not induce or inhibit any major CYP isoforms, including CYP3A4, or
P-gp/Bcrp transporters.
Mendell et al. reported results from six studies evaluating the potential PK inter-
actions between edoxaban and cardiovascular drugs such as digoxin, atorvastatin,
verapamil, quinidine, amiodarone, and dronedarone (Mendell et al. 2013a). The
relevance of the inhibition of P-gp on the final exposure of edoxaban was strikingly
demonstrated by comparing the effect of drugs display differing degrees of P-gp

inhibition, with verapamil, quinidine, dronedarone, and amiodarone recognized as
strong P-gp inhibitors (US Food and Drug Administration 2018), while digoxin and
atorvastatin are recognized P-gp substrates (US Food and Drug Administration
2018; Holtzman et al. 2006). Indeed, verapamil, quinidine, dronedarone, and amio-
darone increased the AUC of edoxaban by about 50%, while digoxin or atorvastatin
had relatively minor effects on the PK of edoxaban (Mendell et al. 2013a).
Interestingly, quinidine increases edoxaban exposure by only 35% after intravenous
administration, thus significantly less than after oral administration (+77%)
(Mendell et al. 2013a) further assessing the effect of P-gp inhibition at gastrointes-
tinal level on the bioavailability of edoxaban (Matsushima et al. 2013).
The potential clinically relevant effect of drug interaction between edoxaban and
amiodarone was also investigated by a subgroup analysis of the ENGAGE AF-TIMI
48 trial (Steffel et al. 2015). Amiodarone was associated with significantly increased
trough levels of edoxaban 60 mg (High dose, HD). Specifically, the concentrations
were 58.5 ± 53.2 ng/mL with amiodarone vs. 43.2 ± 41.1 ng/mL without amioda-
rone (Steffel et al. 2015). The SmPC does not require reduction of edoxaban dosage
with amiodarone concomitant use.
As for quinidine and verapamil, pharmacological data show a total increase in
edoxaban exposure of respectively 77% and 53% (Mendell et al. 2013a), but after
analysis of phase III data these interactions alone were not considered clinically
relevant so no dose reduction is required in the European SmPC, but caution if other
factors that might increase edoxaban exposure are present (Steffel et al. 2018a). No
action is then recommended with atorvastatin and digoxin (Steffel et al. 2018a) that
did not alter edoxaban exposure.
On this regard, it is important to point out that the characterization of edoxaban
population PK and the identification of potential intrinsic and extrinsic factors
affecting variability in edoxaban exposure, demonstrated that edoxaban exposure in
patients with moderate renal impairment receiving strong P-gp inhibitors could
potentially increase the AUC and Cmin exposure up to ∼2.5- and threefold of the
expected exposure in patients with normal renal function (Salazar et al. 2012). Thus,
in the presence of a moderate renal impairment, quinidine and verapamil may sig-
nificantly increase edoxaban exposure.
DDI with Antiplatelet and Antithrombotic Drugs
Given the common occurrence of coronary artery disease with NVAF, the possible
interactions of DOACs with antiplatelet drugs could be clinically relevant
(Table 4.3).
Dual antiplatelet therapy with aspirin and P2Y12 antagonist is currently recom-
mended after percutaneous coronary intervention (PCI) with stent placement, and
further oral anticoagulation is required for patients with NVAF (Steffel et al. 2018a).
Therapy with a DOAC, aspirin, and clopidogrel (P2Y12 inhibitor) is considered the
standard of care for patients with NVAF following coronary stent placement.
Table 4.3 Predicted effects of antiplatelet and antithrombotic drugs on DOAC exposure
Concomitant Effect on DOACs concentration

Drug
Antiplatelet Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
drugs gp and CYP
Clopidogrel No relevant PK +30-40% No significant No significant No significant
interactions AUC and Cmax effect on AUC effect on AUC effect on AUC
known/assumed of dabigatran predicted; predicted predicted;
Increase Pharmacodyna
bleeding time mically
increased
bleeding time
Ticagrelor P-gp +25% (give No data No data Predicted
inhibitor loading dose increased of
2h after AUC;
dabigatran) Pharmacodyna
mically
increased
bleeding time
Aspirin No relevant Pharmacodynamically increased bleeding time Increased
effect AUC for high
known/assumed doses of
aspirin;
Pharmacodyna
mically
increased
bleeding time
Prasugrel P-gp substrate Predicted Pharmacodynamically increased bleeding time
*Expert opinion, AUC area under the curve, CYP Cytochrome P450, P-gp P-glycoprotein. Yellow:
consider dose adjustment or different DOAC if 2 or more “yellow” factors are present
However, this triple therapy is associated with three- to fourfold increased risk of
bleeding complications (Perera et al. 2020; Steffel et al. 2018a; Lopes et al. 2019).
In detail, no PK or PD interactions were observed when apixaban was co-
administered with high-dose aspirin (325 mg once a day) (Gelosa et al. 2018).
Similarly, low dose aspirin (100 mg once a day) for 5 days does not influence the
PK of edoxaban (60 mg once a day) administered concomitantly (Gelosa et al.
2018). Low dose aspirin (100 mg) did not alter the edoxaban PK parameter, whereas
the combination with aspirin 325 mg increased edoxaban systemic exposure by
approximately 30% (AUC) and 34% for Cmax (Mendell et al. 2013b). The reason for
increased exposure with high-dose aspirin is not clear and unknown, but high-dose
aspirin did not alter the effect of edoxaban on the coagulation biomarkers and the
inhibition of platelet aggregation (arachidonic acid induced) by aspirin was not
affected by edoxaban (Mendell et al. 2013b). Nevertheless, the administration of
edoxaban with aspirin 100 mg (low dose), or aspirin 325 mg (high dose) resulted in
an approximately additive effect of the agents administered alone with a final two-
fold increase in bleeding time, thus suggesting a potential PD interaction between
the two drugs (Mendell et al. 2013b).
Rivaroxaban does not alter the effect of aspirin on platelet aggregation and aspi-
rin does not alter the effects of rivaroxaban on clotting parameters (inhibition of fXa
activity, prolongation of prothrombin time, aPTT, and HepTest) (Kubitza et al.
2006). However, in patients treated with rivaroxaban for acute VTE, the risk of
clinically relevant bleeding (such as that requiring medical intervention) is increased
in those also taking aspirin, compared with those not taking aspirin (hazard ratio
1.8) (Davidson et al. 2014).
Edoxaban exhibited similar relative efficacy and reduced bleeding compared to
warfarin, with or without concomitant use of antiplatelet therapies, including clopi-
dogrel and ticagrelor (Xu et al. 2016). Nevertheless, a potential PD interaction with
increasing risk of major bleeding is predictable in patients treated with DOACs
under mono or dual antiplatelet therapy. Indeed, some of these drugs are substrates
(clopidogrel, enoxaparin), or inhibitors (ticagrelor, naproxen) of P-gp (Wessler
et al. 2013; Oh et al. 2014; Marsousi et al. 2016), suggesting a possible PK interac-
tion with DOACs.
Concomitant antiplatelet drugs (aspirin or clopidogrel) appear to increase the
risk for major bleeding of dabigatran. This is most likely a PD interaction, indeed
the concomitant administration of dabigatran etexilate (150 mg twice daily) and
clopidogrel (75 mg once daily) in healthy controls did not influence PK and PD
profiles of either agent. However, a single loading dose (300 mg or 600 mg) of
clopidogrel administered concomitantly with dabigatran etexilate (150 mg twice
daily) increased dabigatran AUC and Cmax by 30–40% (Hartter et al. 2013b).
The interaction between ticagrelor and dabigatran has been observed showing a
significant higher exposure of dabigatran when administered simultaneously to
ticagrelor, with an increase of AUC and Cmax by 48.3% and 62.7%, respectively
(Medicines 2015). This interaction was less evident when ticagrelor was adminis-
tered 2 h after morning dose of dabigatran with an increase of AUC and Cmax of
28.8% and 24.1%, respectively. From this evidence, SmPC is indicated to follow
this staggered intake for starting a loading dose of ticagrelor (Medicines 2015). We
could predict a similar behavior also for the other DOACs.
Apixaban co-administered with prasugrel (60 mg followed by 10 mg once daily)
does not increase bleeding time or further inhibit platelet aggregation (Steffel
et al. 2018a).
DDI with NSAIDs Drugs
Patients with NVAF tend to be elderly and to have other inflammatory disorders,
which may require the use of nonsteroidal anti-inflammatory drugs (NSAIDs).
NSAIDs increase bleeding risk with DOACs due to a pharmacodynamics interac-
tion and the chronic use is not permitted by the respective SmPCs.
Mendell et al. conducted a PK study to assess the potential PK/PD interactions
between edoxaban and the NSAID naproxen (Mendell et al. 2013b). Naproxen
undergoes to an extensive metabolism through the CYP1A2 and CYP2C9, there-
fore, the likelihood of PK interaction with edoxaban is minimal, although, a PD
Table 4.4 Predicted effects of NSAIDs drugs on DOAC exposure
Concomit Effect on DOACs concentration

ant Drug
NSAIDs Effect on Dabigatran Rivaroxaban Apixaban Edoxaban

P-gp and
CYP
Naproxen P-gp No data No data +55% No effect

competition;
CYP1A2 and
CYP2C9
inhibition
AUC area under the curve, CYP Cytochrome P450, P-gp P-glycoprotein. Yellow: consider dose
adjustment or different DOAC if 2 or more “yellow” factors are present
interaction is likely. Indeed, no significant effect of naproxen was observed in sys-

temic exposure to edoxaban (AUC and Cmax), whereas it was shown an additive
effect on bleeding time (Table 4.4) (Mendell et al. 2013b). Interestingly, naproxen
has shown to increase apixaban exposure by more than 50%, an effect potentially
related to the inhibition of the intestinal efflux transporter P-gp (Frost et al. 2014).
Naproxen use has not been studied with other DOACs (Steffel et al. 2018a). For the
acute concomitant use of naproxen, edoxaban could constitute a reasonable choice
for a concomitant anticoagulant.
DDI with Statins and Lipid-Modifying Agents
Considering the high rate of CVD in the elderly, especially CHD in concomitance
with NVAF, it is quite common the co-administration of a lipid-modifying agent
and DOACs. Several statins interact with P-gp and CYP450 (Gelosa et al. 2018).
For example, atorvastatin, lovastatin, and simvastatin inhibit or compete with
P-gp mediated drug transport and are metabolized by CYP3A4. These character-
istics might lead to an increased absorption of DOACs. Lovastatin is a CYP2C9-
and P-gp inhibitor. In a population-based, nested case-control study involving
45,991 Ontario residents who started dabigatran, the use of lovastatin was associ-
ated with a higher risk of major hemorrhage. Similar effect can also be predicted
for other DOACs.
Simvastatin and lovastatin are associated with a higher risk of major hemorrhage
(compared to other statins) in patients with NVAF and receiving dabigatran.
Relevantly, the adjusted incidence rate for major bleeding was significantly lower
for concurrent use of atorvastatin with dabigatran than dabigatran alone.
Table 4.5 Predicted effects of lipid-lowering drugs on DOAC exposure

Concomitant
Drug Effect on DOACs concentration
Lipid-lowering Effect on P-gp
drug and CYP Dabigatran Rivaroxaban Apixaban Edoxaban
Atorvastatin P-gp substrate No PK No effect No data +1.7% AUC
interaction −14.2% Cmax
Simvastatin P-gp moderate Possible No data Minor effect Minor effect
lovastatin inhibitors; increased on AUC on AUC
CYP3A4 exposure predicted predicted
substrate;
Fluvastatin CYP2C9 No significant effect on AUC predicted
substrate
Fenofibrate P-gp inhibitor Minor effect on AUC predicted
Gemfibrozil CYP2C8 No significant effect on AUC predicted
inhibitor
Ezetimibe None No data, no significant effect on AUC predicted
PCSK9 None No data, no significant effect on AUC predicted
inhibitors
AUC area under the curve, CYP Cytochrome P450, P-gp P-glycoprotein
Co-administration of atorvastatin in healthy controls do not affect rivaroxaban

PK and PD and rivaroxaban does not modify atorvastatin profile. Similarly, the
PK of edoxaban is not affected by atorvastatin. Indeed, atorvastatin induces a
non-significant increase of 1.7% in edoxaban AUC and a decrease by 14.2% in
Cmax (Table 4.5) (Mendell et al. 2013a). Other statins have limited involvement in
the CYP3A4 metabolism such as pravastatin and rosuvastatin, while fluvastatin
is metabolized by CYP2C9. In this respect pravastatin, fluvastatin, and rosuvas-
tatin seem to be safer alternatives when administered concomitantly with other
drugs that are known CYP3A4 or P-gp substrates and/or inhibitors such
as DOACs.
Other commonly used lipid-lowering agents that might interact with DOAC
metabolism are fibrates. The only fibric acid that showed moderate P-gp inhibition
in vitro is fenofibrate (Yamazaki et al. 2005). Thus, the only fibrate that might alter
DOACs exposure is fenofibrate, because of the possible inhibition on the P-gp
transporter, although this interaction may be not clinically relevant.
Another cholesterol-lowering agent that can be used alone or in combination
with statins is ezetimibe. Ezetimibe does not induce or inhibit CYP3A4 or P-gp,
interactions with DOACs seem to be improbable.
Finally considering PCSK9 inhibitor evolocumab and alirocumab, no CYP and
P-gp involvement is expected as its metabolism and elimination follow the immu-
noglobulin clearance pathways, resulting in degradation to small peptides and
individual amino acids, thus no interactions are predicted with edoxaban or
other DOACs.
DDI with Antibiotics and Antifungal Drugs
It is well established that antibiotic and fungostatic medications have strong inter-
ference with VKAs, but these drugs may also alter DOACs plasmatic concentrations
by interfering with the P-gp pathway and with the CYP3A4 metabolism (Table 4.6).
Given that some antibiotics and antifungal drugs such as erythromycin, clarithro-
mycin, rifampin, ketoconazole, fluconazole, and posaconazole have moderate-to-
strong inhibition or induction of this pathways, patients treated with DOACs and
certain concomitant antibiotic treatments should require accurate evaluation and an
eventual dose adjustment.
Table 4.6 Predicted effects of antibiotics and antifungal drugs on DOACs exposure

Drug
Antibiotics Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
gp and CYP
Erythromycin P-gp subtrate; +15 to 20% +34% AUC +60% AUC +85% AUC
CYP3A4 AUC +30%
inhibition Cmax
Clarithromycin P-gp subtrate; +15 to 20% +54% AUC +60% AUC Predicted
CYP3A4 AUC +30% increase of
inhibition Cmax AUC
Rifampin P-gp/ BCRP -66% AUC -50% AUC -54% AUC AUC: -35%,
and compensatory
CYP3A4/ increase of
CYP2J2 active
inducers metabolites
Metronidazole CYP3A4 No significant effect on AUC predicted
inhibitor
Levofloxacin, CYP1A2 No significant effect on AUC predicted
ciprofloxacin inhibitor
Antifungal Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
gp and CYP
Fluconazole Moderate No data +42% AUC No data No data
CYP3A4
inhibition
Ketoconazole, potent P-gp +140 to 150% Up to 160% +100% AUC +87 to 95%
itraconazole, and BCRP AUC AUC AUC
voriconazole competition;
CYP3A4
inhibition
AUC area under the curve, BCRP breast cancer resistance protein, CYP Cytochrome P450, P-gp
P-glycoprotein. Yellow: consider dose adjustment or different DOAC if 2 or more “yellow” factors
are present. Orange: consider dose adjustment or different DOAC. Red: contraindicated/not rec-
ommended. Blue: the label for edoxaban mentions that co-administration is possible in these cases,
despite a decreased plasma level, which are deemed not clinically relevant. Since not tested pro-
spectively, however, such concomitant use should be used with caution, and avoided when possible
Among the different classes of antibiotics, the macrolides, such as clarithromy-

cin and erythromycin, are the best-known P-gp inhibitors which moderately reduce
CYP3A4 activity. Macrolide antibiotics have been associated with increased expo-
sure of DOACs.
A slight increase of dabigatran AUC and Cmax by about 19% and 15%, respec-
tively, is induced by clarithromycin 500 mg bid (Steffel et al. 2018b). The co-
administration of rivaroxaban 10 mg in combination with ketoconazole 200 mg
once daily significantly increases rivaroxaban AUC and mean Cmax by 82% and
53%, respectively (Mueck et al. 2013). Rivaroxaban clearance is also significantly
reduced by a mean of 45% with the combination. Erythromycin and clarithromycin
do not have any significant interactions with rivaroxaban, while clarithromycin has
a moderate interaction with rivaroxaban (rivaroxaban AUC and Cmax increase by
54% and 40%) (Mueck et al. 2013). The addition of rivaroxaban 10 mg to erythro-
mycin (500 mg three times daily given for 4 days) significantly increases rivaroxa-
ban AUC and Cmax (34% and 38%, respectively) and decreases rivaroxaban CL/F by
25% compared with rivaroxaban alone (Mueck et al. 2013). However, these changes
are similar to the inter-individual variability observed in patients treated with rivar-
oxaban and are not considered to be clinically relevant.
The administration of rivaroxaban 20 mg to fluconazole 400 mg (given for
4 days) significantly increases rivaroxaban AUC and Cmax by 42% and 28%, respec-
tively (Mueck et al. 2013). Concurrent use of fluconazole with rivaroxaban was
associated with increased risk of major bleeding.
Everything considered, the available data suggest that the co-administration of
rivaroxaban is acceptable with CYP3A4 and/or P-gp substrates/moderate inhibitors,
but not with strong combined CYP3A4, P-gp, and ABCG2 inhibitors (azole-
antimycotics, apart from fluconazole), which inhibit different pathways involved in
rivaroxaban clearance and elimination. An increase by 60% and 30% of AUC and
Cmax of apixaban, respectively, is induced by co-administration of clarithromycin or
erythromycin (Steffel et al. 2018b).
The entity of the DDI between edoxaban and erythromycin has been investigated
in a PK study on healthy subjects (Parasrampuria et al. 2016). Erythromycin
decreased the total apparent clearance of edoxaban by about 47%, which translated
to a significant increase in both peak (+68%) and total exposure (+85%) of edoxa-
ban. Similarly, the peak and total exposure of M4 were approximately 75% and
78% higher, respectively, when administered with erythromycin, with no change in
the formation of M4 metabolite (Parasrampuria et al. 2016). Given the decreases in
both apparent clearance and volume of distribution, these data suggest that bioavail-
ability increased, owing to inhibition of P-gp in the gut by erythromycin
(Parasrampuria et al. 2016). This pharmacological interaction is considered clini-
cally relevant and the EHRA indicated dose adjustment (Steffel et al. 2018a), in line
with the SmPC.
Open-label, randomized, two-period, two-treatment crossover study in healthy
subjects under co-treatment with ketoconazole and edoxaban has tested a possible
interaction between these two drugs (Parasrampuria et al. 2016). As predicted, keto-
conazole increased total exposure of edoxaban by approximately 90%. Exposure to
the metabolite M4 was higher when edoxaban was co-administered with ketocon-
azole, with approximately 46% higher total exposures, potentially due to increased
bioavailability without a significant alteration of its formation mediated by carboxy-
lesterase 1 (CES-1). On the contrary, both peak and total exposure to the metabolite
M6, derived from the CYP3A4 activity, was decreased by 51% and 43%, respec-
tively (Parasrampuria et al. 2016). The inhibitory effect of ketoconazole on CYP3A4
is also demonstrated by the fact that the metabolite-to-parent drug ratio was decreased
from 4.44 to 1.45 (Parasrampuria et al. 2016). From this analysis, it is indicated to
reduce the dose of edoxaban by 50% in case of a co-administration with antifungals
(itraconazole, ketoconazole, and voriconazole) (Steffel et al. 2018a). Similar indica-
tion has been decided for posaconazole, whereas fluconazole is not expected to inter-
act with edoxaban (Steffel et al. 2018a). While other DOACs are contraindicated in
this eventuality, edoxaban can be used in concomitance reducing the dosage to 30 mg
due to increased exposure (Steffel et al. 2018a; Parasrampuria et al. 2016).
Metronidazole is known for having a major interaction with VKAs and dose
reductions are often necessary to maintain INR in range. There are not any direct
evidences with DOACs but metronidazole has been reported to increase plasma
concentration and toxicities in a number of CYP3A4 substrates (Hashikata et al.
2015). It has been suggested that metronidazole, among other drugs, is a CYP3A4
inhibitor and concomitant administrations of certain CYP3A4 substrates should be
avoided. On the contrary, a pharmacokinetics study provides evidence that metroni-
dazole does not act as an inhibitor of P-gp-mediated disposition in humans. Given
that probably CYP3A4 may account for the major part of metronidazole interac-
tions, we expect that a major DDI between DOACs and metronidazole is unlikely;
nonetheless, caution and a careful monitoring of the patient should be applied in this
situation.
Rifampin is one of the most potent inducers of CYP3A4/5 and P-gp. Concomitant
use of rifampin may lead to a decrease in edoxaban and DOACs exposure due to
induction of P-gp and CYP3A4/CYP2J2. The effect of rifampin on edoxaban expo-
sure has been evaluated in a specific pharmacokinetic study of multiple doses of the
antibiotics on a single dose of edoxaban and its active metabolites M4 and M6
(Mendell et al. 2015). Rifampin determined an approximate 34% decrease in total
exposure to edoxaban (AUC), when compared with administration of edoxaban
alone, and unlike other DOACs, a concomitant compensatory five- and fourfold
increase of Cmax values of metabolites M4 and M6, respectively (Mendell et al.
2015). These results suggest that the effect of rifampin on edoxaban was not only to
reduce oral bioavailability and increase excretion through potential induction of
P-gp, but also to increase its metabolism to form the metabolite M6 through
CYP3A4/5. The increase in M4 is likely due to the inhibitory effect of rifampin on
OATP1B1 (Vavricka et al. 2002), which is involved in the transport of the active
metabolite, as well as potential induction of CES-1 through upregulation. These
results demonstrate a drug interaction of edoxaban and its metabolites with rifampin.
However, the compensatory increase of the active metabolite M4 led to the sugges-
tion that the co-administration of the two drugs is possible (LIXIANA 2018).
Edoxaban is the only DOAC that can be used with rifampicin. Nevertheless, since
not tested prospectively, the EHRA indicated that this combination should be used
with caution, and avoided when possible (Steffel et al. 2018a). Apart from edoxa-
ban, other DOACs are contraindicated with rifampin.
Considering quinolones pharmacokinetics, levofloxacin is a CYP1A2 inhibitor
while ciprofloxacin is a strong inhibitor of CYP1A2 (Di Minno et al. 2017).
Considering that NOACs are minimally involved in CYP1A2, no relevant interac-
tions are predicted. Carbapenem antibiotics such as meropenem are administered
intravenously and are not predicted to have inhibitory or induction activity on intes-
tinal P-gp. In vitro assessments have reported an inhibitory effect on CYP3A4 and
CYP2C19 enzymes (Branchetti et al. 2013). On this premise, it can be predicted
that edoxaban levels should not be significantly altered by the presence of carbape-
nem antibiotics.
DDI with Antacid Drugs
The prevalence of gastro-esophageal reflux disease is significant worldwide and

evidence indicate, especially in the western countries, an increase in its incidence
(El-Serag et al. 2014). This suggests that an increasingly higher portion of the popu-
lation is using antacid medication.
Theoretically, antacid medications are not devoid of risk of DDI with DOACs.
Especially considering gastric acidity might play a role in DOAC absorption. From
a pharmacological point of view, a small reduction of dabigatran bioavailability has
been observed with concomitant proton-pump inhibitors (PPIs) or H2-blockers,
while no effect has been observed with other DOACs (Steffel et al. 2018a). The
administration of pantoprazole 40 mg bid decreases by 20–30% and by 45% dabi-
gatran AUC and Cmax, respectively, suggesting that an elevated gastric pH may influ-
ence dabigatran oral absorption. Due to dabigatran flat dose-response curve, this
reduction in the dabigatran plasma concentration was not considered clinically rel-
evant (Steffel et al. 2018a). In NVAF patients, PPIs decrease dabigatran AUC by
12.5%. Ranitidine treatment showed no clinically relevant effects on dabigatran
absorption.
PPIs can also have an influence on cytochrome P450 metabolism, especially
CYP2C19 and some PPIs like omeprazole and pantoprazole can also have an inhibi-
tory influence on P-gp. In a pharmacological study, esomeprazole was shown to
have no significant effect on the peak and total exposure of edoxaban during concur-
rent dosing (Parasrampuria and Truitt 2016). Aluminum-magnesium hydroxide tab-
lets have no influence on P-gp or CYP isoenzymes, but they might alter the
absorption of drugs that are concomitantly administered if taken within 1 h.
DDI with Antineoplastic and Immune-Modulating Agents
Cancer patients are at higher risk for thromboembolic events due to the presence of
comorbidities, surgical interventions, and chemotherapy. Data on the use of DOACs
in cancer patients is very limited and few clinical information is available when
considering the effect that specific antineoplastic drugs might have on DOAC expo-
sure. However, the results of the Hokusai VTE Cancer and Caravaggio trials clearly
demonstrated that treatment with edoxaban or apixaban is not inferior to treatment
with subcutaneous dalteparin with respect to the composite outcome of recurrent
venous thromboembolism or major bleeding in patients predominantly with
advanced cancer and acute symptomatic or incidental venous thromboembolism
(Raskob et al. 2018; Agnelli et al. 2018).
Patients treated with edoxaban and apixaban were exposed to many different
classes of anticancer drugs, such as antimetabolites, platinum-based chemotherapy,
c, topoisomerase inhibitors, alkylating agents, anthracyclines, vinca alkaloids,
kinase inhibitors, and antitumor antibiotics. These agents might have significant
influence on CYP3A4 and/or P-gp metabolism, thus altering DOAC exposure.
Although there are no pharmacokinetic and clinical studies assessing the interac-
tion between DOACs and specific anticancer agents, it is possible to predict a criti-
cal outcome for those with a well-defined effect on P-gp and CYP3A4 (Table 4.7).
In particular, the vinca alkaloid vinblastine, the antitumor antibiotic doxorubicin,
and the kinase inhibitors vandetanib and sunitinib are strong inducers of P-gp, and
for this reason their combination with edoxaban, as well as all DOACs should be
avoided (Steffel et al. 2018a). In addition, the Bruton’s tyrosine kinase ibrutinib
significantly increases risk of NVAF, with an estimated cumulative incidence of
5.9% at 6 months and increasing to 10.3% by 2 years of treatment. The management
of NVAF induced by ibrutinib is complicated by the fact that this drug is also a P-gp
inhibitor, thereby increasing exposure to substrates such as DOACs.
Similar situation can be envisioned for other chemotherapeutic drugs inducing
NVAF, such as alkylating agents (e.g., cisplatin, melphalan, and cyclophosphamide
(CTX)), anthracycline agents (e.g., doxorubicin), and cancer targeted therapies
(e.g., sorafenib and sunitinib).
DDI with Antiepileptic Drugs
Seizures are seen in up to 10% patients after stroke and previous stroke and accounts
for 30–40% of all cases of epilepsy in the elderly. Most of these patients require
long-term antiepileptic drug treatment. Furthermore, the same drugs are also pre-
scribed for neuropathic pain, migraine, headaches, or psychiatric disorders. Thus, it
is conceivable to conclude that a considerable number of patients under treatment
with DOACs would be on concomitant therapy with antiepileptic drugs (Table 4.8).
Few clinical evidences exist regarding interactions between antiepileptic drugs
and DOACs. There are evidences that a number of these drugs induce CYP3A4 and
P-gp leading to reduced DOAC exposure.
Human, animals, and in vitro evidence have demonstrated that carbamazepine,
levetiracetam, phenobarbital, and phenytoin are potent inducers of P-gp, and there-
fore may lead to reduced DOACs plasma concentrations and clinical efficacy.
According to the EHRA practical guide, the use of carbamazepine, phenobarbital,
Table 4.7 Predicted effects of antineoplastic drugs on DOACs exposure

Concomitant Drug Effect on DOACs concentration
Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

Antimitotic agents
CYP
Paclitaxel Moderate CYP3A4

induction; CYP3A4/P No significant effect on AUC predicted
-gp competition
Strong P-gp induction;

Vinblastine CYP3A4/P-gp Significant decrease in AUC predicted
competition
Mild CYP3A4
Docetaxel, Vncristine induction; CYP3A4/P No significant effect on AUC predicted
-gp compeitiont
Mild CYP3A4
Vinorelbine induction; CYP3A4/P No significant effect on AUC predicted
-gp competition

Antimetabolites
CYP
P-gp compeittion; no
Metotrexate relevant interaction No significant effect on AUC predicted
anticipated
Pemetrexed, Purine
No relevant
analogs, Pyrimidine
interaction anticipated No significant effect on AUC predicted
analogs
Topoisomerase Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

inhibitors CYP
No relevant
Topotecan No significant effect on AUC predicted
interaction anticipated
CYP3A4/P-gp
competition; no
Irinotecan No significant effect on AUC predicted
relevant
Mild CYP3A4
Etoposide induction; CYP3A4/P No significant effect on AUC predicted
-gp compeittion
Anthracyclines/ Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

CYP
Anthraceneidones
Strong P-gp induction;

Mild CYP3A4
Doxorubicin inhibi tion; Significant decrease in AUC predicted
CYP3A4/P-gp
compeittion
Mild CYP3A4
Idarubicin inhibition; P- No significant effect on AUC predicted
compeittion
P-gp compeittion; no
Daunorubicin relevant interaction No significant effect on AUC predicted
anticipated
no relevant interaction
Mitoxantrone anticipated No significant effect on AUC predicted

Alkylating agents
CYP
Table 4.7 (continued)
Mild CYP3A4
Ifosfamide inhibition; CYP3A4 No significant effect on AUC predicted
competition
Mild CYP3A4
Ciclophosphamide inhibition; No significant effect on AUC predicted
CYP3A4 competition
Lomustine Mild CYP3A4 No significant effect on AUC predicted

inhibition;
CYP3A4 competition;
Busulfan No relevant interactions No significant effect on AUC predicted
anticipated
P-gp competition; no
Bendamustine relevant interaction No significant effect on AUC predicted
anticipated
Chlorambucil,
Melphalan,
Carmustine, No relevant effect
Procarbazine, anticipated No significant effect on AUC predicted
Dacarbazine,
Temozolomide
Platinum-based Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

agents CYP
Cisplatin, Carboplatin, No relevant effect

Oxaliplatin No significant effect on AUC predicted
anticipated
Dabigatran Rivaroxaban Apixaban Edoxaban

Intercalating agents Effect on P-gp and
CYP
Bleomycin, No relevant effect

anticipated No significant effect on AUC predicted
Dactinomycin
No relevant
Mitomycin C No significant effect on AUC predicted
Tyrosine kinase Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

inhibitors CYP
Strong P-gp
inhib ition; Moderate
Imatinib, Crizotinib CYP3A4 inhibition; Significant increase in AUC predicted
CYP3A4/P-gp
competition
Moderate-to-strong P-
gp inhibition; mild
Nilotinib, Lapatinib CYP3A4 inhibition; Possible increase in AUC predicted
CYP3A4/P-gp
competition
Moderate CYP3A4
Vemurafenib induction; CYP3A4/ No significant effect on AUC predicted
P-gp competition
Mild CYP3A4
inhibition;
Dasatinib No significant effect on AUC predicted
CYP3A4/P-gp
competition
Vandetanib, Strong P-gp inhibitor; Significant increase in AUC predicted

CYP3A4 competition
Sunitinib
Erlotinib, Gefatinib CYP3A4 competition No significant effect on AUC predicted
no relevant interaction
anticipated
(continued)
P-gp inhibitor;
Ibrutinib Possible increase in AUC predicted
CYP3A4 competition
Monoclonal Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

antibodies CYP
CYP3A4 competition;
No relevant
Brentuximab interactions No significant effect on AUC predicted
anticipated
Rituximab,
Alemtuzumab,
No relevanteffect
Cetuximab, No significant effect on AUC predicted
assumed
Trastuzumab,
Bevacizumab
Hormonal agents Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

CYP
Moderate CYP3A4
inhibition; Strong P-
Abiraterone gp inhibition; Significantincrease in AUC predicted
CYP3A4/P-gp
competition
Strong CYP3A4
induction; Strong P-gp
Enzalutamide inhibition; Significant increase in AUC predicted
CYP3A4/P-gp
competition
Moderate CYP3A4
Bicalutamide No significant effect on AUC predicted
inhibition
Strong P-gp
inhibition; Mild
Tamoxifen Possible increase in AUC predicted
CYP3A4 inhibition
CYP3A4 competition
Mild CYP3A4
Anastrozole No significant effect on AUC predicted
inhibition
CYP3A4 competition
No relevant
Flutamide interactions No significant effect on AUC predicted
anticipated
CYP3A4 competition
Letrozole, Fulvestrant
No relevant No significant effect on AUC predicted
interactions
anticipated
Raloxifene, No relevant
No significant effect on AUC predicted
Leuprolide, Mitotane interactions
anticipated
Immune-modulating Effect on P-gp and Dabigatran Rivaroxaban Apixaban Edoxaban

agents- CYP
Strong to moderate P-
gp inhibition,
moderate CYP3A4 Strong increase of Possible increasein Possible increase in
Cyclosporine inhibition; +73% AUC
AUC predicted AUC predicted AUC predicted
CYP3A4/P-gp
competition
Strong CYP3A4/P-gp
induction;
Dexamethasone CYP3A4/P-gp Significant decrease in AUC predicted
competition
Strong to moderate P-
gp inhibition, mild
Tacrolimus CYP3A4 inhibition; Significant increase in AUC predicted
CYP3A4/P-gp
competition
Moderate CYP3A4
Prednisone induction; CYP3A4 No significant effect on AUC predicted
competition
Temsirolimus, mild CYP3A4

inhibition; No significant effect on AUC predicted
Sirolimus CYP3A4/P-gp
competition
CYP3A4 competition;
No relevant
Everolimus interactions No significant effect on AUC predicted
anticipated
AUC area under the curve, CYP Cytochrome P450, P-gp P-glycoprotein. Yellow: consider dose
adjustment or different DOAC if 2 or more “yellow” factors are present. Orange: consider dose
adjustment or different DOAC. Red: contraindicated/not recommended
and phenytoin is only possible with edoxaban and apixaban. In this case, the con-
comitant use should be made with caution if cannot be avoided, because there still
is a decreased absorption that might lead to minor efficacy of these DOACs (Steffel
et al. 2018a).
A more stringent indication was deserved for valproic acid and levetiracetam,
whose co-administration with DOACs is contraindicated (Steffel et al. 2018a),
probably due to their more potent effect on P-gp. However, additional data reported
that levetiracetam does not induce P-gp and thus can be utilized with DOACs
(Mathy et al. 2019). On the contrary, other antiepileptic drugs, that do not affect
P-gp function, such as ethosuximide, gabapentin, lamotrigine, pregabalin, and
zonisamide, are not predicted to interact with DOACs (Steffel et al. 2018a). Finally,
the use of oxcarbazepine and topiramate is possible without relevant DDIs only
with edoxaban and dabigatran due to absence of CYP3A4 metabolism. Unfortunately,
the clinical relevance of these drug interactions is largely unknown since mainly
data from in vitro and animal studies are available.
Although all DOACs are considered to interact with P-gp inducers (Steffel et al.
2018a), the influence of these drugs on edoxaban can be considered less problematic
due to the compensatory increase of the active metabolite M4. In addition, the inter-
individual variability of drug plasma concentrations, lower for apixaban and edoxa-
ban and higher for rivaroxaban and dabigatran, is a determining factor for triggering a
clinically significant DDIs. Indeed, in the EHRA guidelines, differently from dabiga-
tran and rivaroxaban, the use of carbamazepine, phenobarbital, and phenytoin is not
contraindicated with edoxaban and apixaban (Steffel et al. 2018a). It can be hypoth-
esized that antiepileptic drugs that do not have an effect on CYP3A4 and P-gp, such
as ethosuximide, gabapentin, lamotrigine, pregabalin, and zonisamide can be used
with all DOACs without relevant pharmacological interaction (Mathy et al. 2019).
Table 4.8 Predicted effects of antiepileptic drugs on DOACs exposure

Drug
Antiepileptic Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
drugs gp and CYP
Carbamazepine Strong Strong Strong -50% AUC -35% AUC
CYP3A4/P-gp reduction of reduction of
induction; AUC AUC
CYP3A4
competition
Ethosuximide CYP3A4 No significant effect on AUC predicted
competition;
No relevant
interaction
known/assumed
Gabapentin No relevant No significant effect on AUC predicted

interactions
known/assumed
Lamotri gine P-gp No significant effect on AUC predicted

competition;
No relevant
interaction
known/assumed
L evetirac etam P-gp No significant effect on AUC predicted

induction; P-
gp competition
Oxcarbazepine CYP3A4 No significant effect on AUC predicted
induction; P-
gp competition
Phenobarbital Strong Decrease in Decrease in Decrease in Decrease in
CYP3A4/P-gp AUC AUC AUC AUC
induction; P-
gp competition
Phenytoin Strong Decrease in Decrease in Decrease in Decrease in
CYP3A4/P-gp AUC AUC AUC AUC
induction; P-
gp competition
Pregabalin No relevant No significant effect on AUC predicted
interactions
known/assumed
Topi ramate CYP3A4 No significant effect on AUC predicted

induction;
CYP3A4
competition
Valproic acid CYP3A4/P-gp Significant decrease in AUC predicted
induction
Zonisamide CYP3A4 No significant effect on AUC predicted
compet ition;
No relevant
intera ctions
known/assumed
AUC area under the curve, CYP Cytochrome P450, P-gp P-glycoprotein. Orange: use with caution
or avoid. Red: contraindicated/not recommended
DIs with Anti-Human Immunodeficiency (HIV)

D
and Anti-Hepatitis C Virus (HCV) Drugs
Several combinations of agents belonging to at least two drug families are recom-
mended for treating HIV. Integrase inhibitors (e.g., dolutegravir or raltegravir) and
non-nucleoside analog polymerase inhibitors (e.g., rilpivirine) are currently the pre-
ferred third agents used along with a two nucleos(t)ide analog backbone, either
abacavir/lamivudine or tenofovir/emtricitabine. The use of HIV protease inhibitors
has progressively been deferred, due to increased potential for DDI and metabolic
complications. Darunavir boosted with ritonavir or cobicistat is the only protease
inhibitor still recommended as first-line HIV therapy. With the exception of tiprana-
vir, all HIV protease inhibitors are inhibitors of CYP3A4, with ritonavir being the
most potent and saquinavir is the least. Ritonavir is also a strong P-gp inhibitor
interfering with many drugs, and it may be expected to increase edoxaban exposure.
Therefore, its co-administration with DOACs is not recommended (Steffel et al.
2018a) (Table 4.9). Similarly, the pharmacoenhancer cobicistat, in addition to be a
potent inhibitor of cytochrome CYP3A4, also inhibits P-gp and BCRP transporters,
and it is predicted to increase DOACs bioavailability.
Among the HCV protease inhibitor, simeprevir is a substrate and inhibitor of
CYP3A4 and P-gp enzymes and through this action may increase the exposure of
substrates for P-gp, such as edoxaban (Table 4.10). Paritaprevir is an HCV protease
inhibitor that is boosted with ritonavir and thus this combination is predicted to
increase the exposure of edoxaban. Grazoprevir is not a P-gp inhibitor based on
in vitro data, and thus it is not expected to interact with edoxaban.
Nonstructural protein 5AB (NS5B) polymerase inhibitors, sofosbuvir depicts an
excellent pharmacokinetic profile, without significant interactions with other drugs
because its metabolism does not involve the CYP450 pathway although it is a P-gp
substrate.
Daclatasvir was the first-in-class developed HCV nonstructural protein 5A
(NS5A) replication complex inhibitor. Daclatasvir is a substrate for CYP3A4 and
P-gp and moderately inhibits P-gp and OATP1B1. Its interaction with DOACs has
not been evaluated; however, daclatasvir increases rosuvastatin exposure, thus
Table 4.9 Predicted effects of anti-HIV therapies on DOACs exposure

Drug
Anti-HIV Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
gp and CYP
DTG + No inhibition No significant effect predicted
ABC/TDF +
3TC
DTG + No inhibition No significant effect predicted
TDF/TAF +
FTC
RAL + No inhibition No significant effect predicted
TDF/TAF +
FTC
EVGc + Cobicistat is a Possible increased exposure
TAF/TDF + potent
FTC CYP3A4 and
P-gp inhibitor
DRVc + ABC Cobicistat is a Possible increased exposure
+ 3TC potent
CYP3A4 and
P-gp inhibitor
and d arunavir
is a CYP3A4
inhibition
DRVc + Cobicistat is a Possible increased exposure
TDF/TAF + potent
FTC CYP3A4 and
P-gp inhibitor
and d arunavir
is a CYP3A4
inhibition
ATVc Cobicistat is a Possible increased exposure
+TDF/TAF + potent
FTC CYP3A4 and
P-gp inhibitor
DRVr + Ritonavir is a Possible increased exposure
TDF/TAF + potent
FTC CYP3A4 and
P-gp inhibitor
DRVr + ABC Ritonavir is a Possible increased exposure
+ 3TC potent
CYP3A4 and
P-gp inhibitor
EFV + Inhibition of Possibleincreased exposure
TDF/TAF + CYP3A4 and
FTC P-gp
RPV + Inhibition of Possible increased exposure
TDF/TAF + CYP3A4 and
FTC P-gp
AZT + 3TC + Inhibition of Possible increased exposure
EFV CYP3A4 and
P-gp
TDF + Inhibition of Possible increased exposure
3TC/FTC + CYP3A4 and
EFV P-gp
TDF + Inhibition of Possible increased exposure
3TC/FTC + CYP3A4 and
NVP P-gp
3TC lamivudine, ABC abacavir, ATVc atazanavir + cobicistat, CYP Cytochrome P450, DRVc
darunavir + cobicistat, DRVr darunavir + ritonavir, DTG dolutegravir, EFV efavirenz, EVG elvite-
gravir, FTC emtricitabine, P-gp P-glycoprotein, RAL raltegravir, RPV rilpivirine, TAF tenofovir
alafenamide, TDF tenofovir disoproxil fumarate. Yellow: consider dose adjustment or different
DOAC if 2 or more “yellow” factors are present. Modified from West et al. (2017)
Table 4.10 Predicted effects of anti-HCV drugs on DOACs exposure

Drug
Anti-HCV Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
gp and CYP
Substrate and
inhi bitor of
Simeprevir Possible increase in AUC predicted
CYP3A4 and
P-gp
No relevant
Grazoprevir interactions No significant effect on AUC predicted
predicted
NS5B Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
polymerase gp and CYP
inhibitors
Sofosbuvir P-gp substrate No significant effect on AUC predicted
P-gp/BCRP
Ledipasvir substrate and Possible increase in AUC predicted
inhi bitor
NS5A Effect on P- Dabigatran Rivaroxaban Apixaban Edoxaban
replication gp and CYP
complex
inhibitor
CYP3A4 and
P-gp substrate,
P-gp and
Daclatasvir Possible increase in AUC predicted
OATP1B1
moderate
inhibition
*Expert opinion, AUC area under the curve, BCRP breast cancer resistance protein, CYP
Cytochrome P450, P-gp P-glycoprotein. Yellow: consider dose adjustment or different DOAC if 2
or more “yellow” factors are present
similar effect with the OATP and/or BCRP substrates are predicted. Similar effect
has been observed with ledipasvir, a substrate and inhibitor of P-gp/BCRP.
DDIs with Monoclonal Antibodies and Interleukin 6 (IL6)
The clearance of therapeutic monoclonal antibodies (mAbs) typically does not

involve CYP450-mediated metabolism or interaction with P-gp, therefore their
pharmacokinetic interactions with small molecule drugs are limited (Ferri et al.
2016). However, mAbs directed against circulating cytokines, such as interleukin
(IL)-6, IL-1β, or TNF-α, for the treatment of immunologic disorders like rheuma-
toid arthritis, celiac disease, and Crohn’s disease may have a significant impact on
drug metabolism. Specific studies have, indeed, demonstrated that IL-6 reduces the
CYP3A4, 2B6, and 2C8 mRNA expression. Even more relevant for DOAC disposi-
tion, is the observation that IL-6-treated mice displayed a 70% reduction in protein
expression of all P-gp isoforms.
On these bases, it is possible that tocilizumab, a monoclonal antibody anti IL-6,
may induce P-gp and reduce DOAC intestinal absorption. A case report of possible
DDI between tocilizumab and dabigatran has been described. The authors claim
that the co-administration of tocilizumab with dabigatran had induced a progres-
sively decreased anticoagulant effect of dabigatran, favoring mesenteric arterial
thrombosis. A possible interaction can also be predicted for the other DOACs.
Similar effect can be hypothesized with the monoclonal antibody dupilumab that
inhibits IL-4 and IL-13 signaling. An open-label drug–drug interaction study was
performed to assess whether a possible interaction of dupilumab with the pharma-
cokinetics of drugs metabolized by cytochrome P450 (CYP450) enzymes, includ-
ing warfarin. The results clearly show no significant DDI of drugs metabolized by
CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6 after IL-4/IL-13 signaling
inhibition by dupilumab.
Conclusions
DDIs have received a great deal of recent attention from the regulatory, scientific,
and health care communities worldwide. A large number of drugs are introduced
every year, and new interactions between medications are increasingly reported.
The co-administration of multiple therapies (polypharmacy) in patients with con-
comitant comorbidities may determine a significant and clinically relevant modifi-
cation of drug’s absorption, distribution, metabolism, and excretion phases.
The different pharmacokinetic properties of each DOACs may significantly
influence the potential DDIs, although exists some similitudes. For instance, all
DOACs are substrate of the P-gp and their bioavailability may be influenced from
the presence of inducers or inhibitors of this drug transporter. For this reason, the
inter-individual variability of drug plasma concentrations, lower for apixaban and
edoxaban and higher for rivaroxaban and dabigatran, is a determining factor for
triggering clinically significant DDIs.
The DDIs of DOACs can also be affected by inducers or inhibitors of CYP3A4.

Edoxaban involvement in cytochrome catalyzed elimination is negligible, thus less
prone to interaction with inducers or inhibitors of CYP3A4 compared to other anti-
Xa inhibitors. Furthermore, edoxaban metabolism produces, through hydrolysis,
the active metabolite M4. For this reason, the reduction of edoxaban exposure by
strong inducers of drug-metabolizing enzymes, i.e., rifampin, may be partially com-
pensated by the formation of M4, an effect that is not observed with other DOACs.
In response to anticipated DDIs, possible strategies, including dosage reduction
or different time of administrations, are recommended. In particular, in order to
avoid the DDIs, it is possible to administer DOACs 2 h before the interacting drug
or after 6 h the use of P-gp inhibitors. For instance, as per the dabigatran SmPC, it
is suggested the administration of the loading dose of ticagrelor 2 h after the
DOAC. In addition, the use of an immediate-release preparation of verapamil is
predicted to avoid the interaction with DOAC when taken at least 2 h before.
The introduction of DOACs in the clinical practice has certainly facilitated the
use of anticoagulant therapies in patients under polypharmacy, with significantly
lower incidence of clinically relevant DDIs as compared to warfarin. However,
additional studies and/or sub-analysis will be necessary to ascertain the DDIs,
which are currently mainly derived from hypothetical conclusions.
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Direct Oral Anticoagulant Reversal
for Management of Bleeding 5
and Emergent Surgery
Sanela Music, John Eikelboom, and Thao Huynh
Introduction
During the last decade, direct oral anticoagulants (DOACs, also referred to as new/
novel/non-vitamin K oral anticoagulants [NOACs] and target-specific OACs) have
become widely used within various clinical contexts for which vitamin K antago-
nists (VKAs, warfarin) were previously indicated. Dabigatran, apixaban, rivaroxa-
ban, edoxaban, and betrixaban are currently approved for stroke and systemic
embolism prevention in non-valvular atrial fibrillation (NVAF), acute venous
thromboembolism (VTE) treatment, secondary prevention of VTE, VTE prevention
after knee or hip replacement surgery (except edoxaban), and stable coronary dis-
ease or peripheral artery disease (rivaroxaban) (SAVAYSA 2020; Sinnaeve et al.
2016; Xarelto 2018; Pradaxa 2018; Anand et al. 2018; Connolly et al. 2009;
Eikelboom et al. 2017; Giugliano et al. 2013; Granger et al. 2011; Patel et al. 2011).
DOACs are replacing VKAs in most of the above indications (Connolly et al.
2009; Giugliano et al. 2013; Granger et al. 2011; Patel et al. 2011). The reasons for
this global paradigm shift in preference of DOACs include their rapid onset of anti-
coagulant effect, lack of need for routine anticoagulation monitoring, and low pro-
pensity for drug and food interactions. Most importantly, the rates of life-threatening
bleeding were decreased compared to usual anticoagulants and for some indications
this was accompanied by a mortality benefit. A meta-analysis by Ruff et al. of the
four major phase 3, randomized trials for DOACs, reviewing efficacy and safety in
71,683 patients treated for NVAF (42,411 on DOAC; 29,272 on warfarin) showed
S. Music · T. Huynh (*)

Division of Cardiology, Department of Medicine, McGill University Health Centre,
Montreal, QC, Canada
J. Eikelboom
Division of Hematology and Thromboembolism, Department of Medicine, McMaster
University, Hamilton, ON, Canada

72 S. Music et al.
that DOACs compared with warfarin significantly reduced risk of haemorrhagic

stroke (RR 0.49, 95% CI 0.38–0.64; p < 0.0001), intracranial hemorrhage (0.48,
0.39–0.59; p < 0.0001), and all-cause mortality (0.90, 0.86–0.95; p = 0.0003) (Ruff
et al. 2014). In a meta-analysis of 10 trials enrolling 35,029 patients treated for
VTE, Gómez-Outes et al. showed that the rates of major bleedings were reduced
compared to conventional therapy (parenteral anticoagulant for ≥5 days followed
by VKA for ≥3 months; 1.8% per year vs. 3.1% per year, p = 0.003), fatal bleeding
(0.1% per year vs. 0.3% per year, p = 0.02), and adjusted case fatality rates of major
bleeding (6% vs. 10%, p = 0.18), respectively (Gómez-Outes et al. 2015). Reduced
risk of intracranial (ICH) and extracranial hemorrhages were also noted with
DOACs compared to warfarin in this meta-analysis (Gómez-Outes et al. 2015).
Nevertheless, bleeding complications, which can be life-threatening, persist with
any anticoagulant including DOACs. In the case of DOACs, crucial consideration
needs to be given to optimal dosing or discontinuation in patients with severe renal
insufficiency as well as hepatic dysfunction, and concerns have been raised about
timely DOAC reversal in the emergent setting (Levi 2016; Bauer 2013).
In the last few years, specific antidotes have been approved for commercial use:
idarucizumab (Praxbindc, Boehringer Ingelheim) for the reversal of the direct
thrombin inhibitor, dabigatran, and andexanet alfa (Andexxa®, Portola), for the
reversal of factor Xa inhibitors, rivaroxaban and apixaban (evaluation pending for
edoxaban and betrixaban) (Praxbind 2015; Andexxa 2018). Andexanet alfa is only
approved in the USA and Europe at this time. We will address in the following
chapter the challenges in management of bleeding associated with DOACs and an
overview of assessment strategies, available reversal agents, and future
perspectives.
Indications for Reversal
When considering DOAC reversal in a patient with an active or imminent high risk
of bleeding, clinicians should undertake a careful risk stratification regarding poten-
tial bleeding severity, status of anticoagulation, and its indication. The decision to
pursue reversal of DOACs must take into account the thrombotic risk of the under-
lying condition as well as possible risks associated with the reversal agents (Andexxa
2018; Dentali et al. 2011).
Emergency Surgery and Urgent Procedures
Considering the short half-lives of DOACs, it is usually feasible to coordinate the

timing of the required intervention to allow for spontaneous clearance of DOACs in
patients with normal renal or hepatic functions (SAVAYSA 2020; Sinnaeve et al.
2016; Xarelto 2018; Pradaxa 2018). However, in cases of major trauma, emergency
surgery, and other urgent clinical situations (such as acute ischemic stroke in a patient
who qualifies for thrombolysis or thrombectomy), time is limited and active reversal
5 Direct Oral Anticoagulant Reversal for Management of Bleeding and Emergent… 73
strategies are required to mitigate bleeding prior to and during the intervention
(Connolly et al. 2016, 2019; Pollack et al. 2015, 2017). The bleeding risk and urgency
of the intervention must be assessed in a team approach in consultation with the
appropriate specialists (neurologist, neurosurgeon, gastroenterologist, surgeon).
Life-Threatening and Uncontrolled Bleeding
To select the optimal strategies for anticoagulation reversal in the case of bleeding,
severity must be assessed accounting for site, amount, and rate of blood loss. This
entails a clinical evaluation including thorough history, physical examination, serial
blood tests, close monitoring, and targeted imaging studies if indicated. Bleedings
that may initially appear significant but are generally self-limited (for example, epi-
staxis or hemorrhoidal bleed) may be managed conservatively, without exposing the
patient to potential risks of thrombosis associated with anticoagulation withdrawal
and reversal. The opposite can also be true; an occult bleed can mask a potentially
life-threatening condition (such as retroperitoneal bleeding). Bleedings requiring
more aggressive interventions include bleeding with substantial blood loss or requir-
ing transfusion (fall in hemoglobin of ≥20 g/L or leading to transfusion of ≥2 units
of red cells), symptomatic bleeding in a critical organ (intracranial, intraspinal,
intraocular, retroperitoneal, intraarticular, pericardial or intramuscularly with com-
partment syndrome), and bleeding that is life-threatening (Schulman and Kearon
2005). Bleedings that require therapeutic interventions such as surgery, radiology-
guided embolization, or endoscopic therapy may also need reversal agents.
General Approach
Assessment of Anticoagulation Status
Upon initial assessment of a bleeding patient on DOAC, clinicians should determine:
• the anticoagulant the patient is taking,

• the timing of the last dose of DOAC,
• intake of any other medications that increase bleeding such as antiplatelets and
nonsteroidal anti-inflammatory drugs, as well as herbal supplements,
• whether an overdose—intentional or unintentional—might be in question,
• the presence of any other comorbidity which may exacerbate bleeding either
intrinsically or through decreased anticoagulant clearance, most importantly kid-
ney and liver diseases.
Keeping the pharmacology of DOACs in mind, anticoagulation can be deemed

negligible beyond five half-lives after the last administration of DOACs in patients
with preserved renal and hepatic functions (see Table 5.1) (Connolly et al. 2009;
Giugliano et al. 2013; Granger et al. 2011; Patel et al. 2011). In the context of renal
74 S. Music et al.
Table 5.1 Clearance of DOACs (SAVAYSA 2020; Sinnaeve et al. 2016; Xarelto 2018; Pradaxa
2018; Connolly et al. 2009; Giugliano et al. 2013; Granger et al. 2011; Patel et al. 2011; Khadzhynov
et al. 2013; Scaglione 2013)
Edoxaban
Rivaroxaban Apixaban (Lixiana®,
Dabigatran (Pradaxa®) (Xarelto®) (Eliquis®) Savaysa®)
Onset Rapid Rapid Rapid Rapid
Tmax (h) 2 2.5–4 1–3 1–2
Half-life 12–17 5–9; elderly: 8–15 10–14
(h) 2.5–3.5 days 11–13 1.5–3 days 1.3–2 days
Five 1–2 days
half-lives
Renal ~80–85% Dialyzable ~36% ~25% ~50%
clearance (Khadzhynov et al. 2013) Non-dialyzable Non-dialyzable Non-dialyzable
Hepatic ~15% ~30% ~25% ~4% (remainder
clearance Safe in moderate hepatic Not Not biliary/
impairment (Child-Pugh recommended in recommended intestinal)
B) (Stangier et al. 2008); moderate-severe in severe Not
Contraindicated if ALT/ hepatic hepatic recommended in
AST >2× ULN impairment impairment moderate-severe
(Connolly et al. 2009) (Child-Pugh (Child-Pugh C) hepatic
B/C) impairment
(Child-Pugh
B/C)
ALT alanine aminotransferase, AST aspartate aminotransferase, ULN upper limit of normal, Tmax
time taken to reach the maximum concentration
impairment, offset of anticoagulation is delayed, particularly for dabigatran, which

can potentially be dialyzed as hemodialysis removes ~57% over 4 h (Khadzhynov
et al. 2013; Getta et al. 2015). Hepatic impairment affects offset of anticoagulation,
particularly for apixaban, edoxaban, and rivaroxaban. Severe hepatic dysfunction
may result in accumulation of these drugs. Drug interactions should also be care-
fully reviewed, chiefly those undergoing P-glycoprotein and cytochrome P450 34A
(CYP34A) metabolism, such as chemotherapeutic agents, antiviral, anti-seizure
medications, anti-rejection therapies, and azole antifungals (SAVAYSA 2020;
Sinnaeve et al. 2016; Xarelto 2018; Pradaxa 2018; Scaglione 2013). Dabigatran and
edoxaban have interactions with strong P-glycoprotein inhibitors and inducers,
while rivaroxaban and apixaban may have interactions with both P-glycoprotein
and CYP34A inhibitors and inducers (SAVAYSA 2020; Xarelto 2018; Pradaxa
2018; Eliquis 2018).
Laboratory assessment of the anticoagulant activity of DOACs is challenging.
Standard anticoagulation testing with prothrombin time/international normalized
ratio (PT/INR); activated partial thromboplastin (aPTT) can be helpful, especially
normalization of aPTT for dabigatran. However, caution is required since they are
not sufficiently accurate to provide a reliable evaluation of the anticoagulant status
for guidance of reversal.
Dilute thrombin time (TT) assays and ecarin clotting time (ECT) are linearly
correlated with the concentration of dabigatran (r2 = 0.67–0.99) (van Ryn et al.
2010). Anti-Xa assays are also correlated across a wide range of drug concentra-
tions of rivaroxaban, apixaban, and edoxaban (r2 = 0.78–1.00) (Samuelson et al.
2017). If these tests are not available, TT or aPTT is recommended over PT/INR
for assessment of dabigatran, and PT/INR is recommended over aPTT for detec-
tion of factor Xa inhibitors (see Table 5.2). As stated above, a clinical estimation
of the residual anticoagulation effect considering time since last administration,
renal and hepatic function and drug interactions, may be of use when an accurate
and precise test for DOACs effect is unavailable. A normal standard coagulation
profile does not exclude therapeutic anticoagulant effect for which an intervention
may be indicated (Samuelson et al. 2017). It is also important to keep in mind the
differential diagnosis of abnormal coagulation tests in a bleeding patient, which
should include disseminated intravascular coagulation (DIC) (due to trauma or
sepsis). The possibility of DIC should require additional testing with fibrinogen
and d-dimer levels.
Table 5.2 Results of Standard Coagulation Assays for DOACs (van Ryn et al. 2010; Samuelson
et al. 2017; Cuker et al. 2014)
Coagulation essay/ Edoxaban
clinically relevant drug Dabigatran Rivaroxaban Apixaban (Lixiana®,
levels (no/yes)a (Pradaxa®) (Xarelto®) (Eliquis®) Savaysa®)
PT/INR
No N N N N
Yes N or ↑ N or ↑ N (rarely ↑) N or ↑
aPTT
No N or ↑ N N N
Yes ↑ N or ↑ N (rarely ↑) N or ↑
TT
No ↑ N/A N/A N/A
Yes ↑ or out of
range
Dilute TT
No N or ↑ N/A N/A N/A
Yes ↑
Anti-Xa
No N/A N or ↑ N or ↑ N or ↑
Yes ↑ ↑ ↑
PT/INR prothrombin time/international normalized ratio, aPTT activated partial thromboplastin,
TT thrombin time, N normal, N/A not applicable (insufficient evidence)
a
Minimum DOAC level that can contribute to bleeding is poorly defined. The International Society
on Thrombosis and Hemostasis recommends considering anticoagulation reversal in serious bleed-
ing with a DOAC level >50 ng/mL, and in invasive procedures with high bleeding risk with a
DOAC level >30 ng/mL (Schulman et al. 2010)
76 S. Music et al.
Specific and Nonspecific Agents
Once it has been determined that a patient is experiencing a serious or life-

threatening bleed requiring reversal of anticoagulation, an arsenal of strategies is
available, although randomized trial data to guide their uses remains limited.
General management for patients with serious or life-threatening major bleed-
ings should include admission and monitoring in a critical care setting with ade-
quate hemodynamic support. The cornerstone of management is continuous
assessment of bleeding severity and hemodynamics with prompt establishment of
large-bore intravenous access, airway protection and transfusions as required, as
well optimization of acid-base and electrolyte balance (including calcium in the
context of possible massive transfusion protocols). Involvement of appropriate spe-
cialists should be timely for consideration of a hemostatic intervention, which may
include surgery (general or neurosurgery), interventional radiology, and gastroen-
terology (for endoscopy).
Management of bleeding on DOAC can be undertaken with hemostatic agents
such as prothrombin complex concentrates (PCCs), antifibrinolytic agents, desmo-
pressin (DDAVP) and drug removal via oral activated charcoal for recently ingested
anticoagulants (potentially hemodialysis for dabigatran). However, during the
recent years, we have seen the development of specific reversal agents which will be
reviewed in further detail below: idarucizumab (Praxbind®) for the reversal of dabi-
gatran and andexanet alfa (Andexxa®) for the reversal of factor Xa inhibitors, rivar-
oxaban and apixaban.
Dabigatran Reversal: Idarucizumab (Praxbind®)
Clinical Pharmacology
Idarucizumab is a humanized monoclonal antibody fragment (Fab) with high affin-

ity for dabigatran (~350 times higher vs. thrombin) as well as its acyl glucuronide
metabolites (see Fig. 5.1) (Praxbind 2015). It is therefore able to bind free and
thrombin-bound dabigatran, resulting in neutralization of its anticoagulant effect
within minutes (van Ryn et al. 2010; Schiele et al. 2013). In a mouse model, despite
structural similarities to thrombin in mode of dabigatran binding, idarucizumab did
not bind to thrombin substrates and did not alter coagulation and platelet aggrega-
tion testing (Schiele et al. 2013). Consequently, it should not have any intrinsic
prothrombotic effect.
Idarucizumab was originally tested in healthy volunteer subjects (men aged 18 to
45) where its administration reduced plasma concentrations of unbound dabigatran
to below detectable thresholds and returned coagulation parameters (dTT, ECT,
aPTT, TT, and ACT) to baseline levels (Glund et al. 2015a, b). This normalization
a b
Dabigatran Factor Xa
inhibitor
Factor Andexanet
IIa alfa
Ala419
Factor
II Ser419
Factor Va Factor Xa
Cell membane Gla
Idarucizumab
c Ciraparantag
Drug Binding sites NH NH NH2

Apixaban H2N
HN N O
Dabigatran
Edoxaban
O N NH
Fondaparinux
NH2
Rivaroxaban H2N HN HN
UFH or LMWH
Fig. 5.1 Reversal agents for direct oral anticoagulants. (a) Idarucizumab, an antibody antigen-
binding fragment (Fab) that binds to dabigatran with an affinity >350 times that of thrombin. (b)
Andexanet alfa, a modified recombinant coagulation factor Xa that competitively binds factor Xa
inhibitors (apixaban, betrixaban, edoxaban, and rivaroxaban). Modified to include amino acid sub-
stitutions and deletion of the γ-carboxyglutamic acid (Gla)-rich membrane-binding domain to pre-
vent assembly of factor Xa and factor Va and creation of the prothrombinase complex. (c)
Ciraparantag, a synthetic inorganic molecule that binds multiple anticoagulation agents through
noncovalent hydrogen bonding and charge–charge interactions. LMWH low-molecular-weight
heparin, UFH unfractionated heparin. (Reprinted with permission from Levy et al. Copyright ©
Springer Nature)
persisted for at least 24 h. Additional investigations in middle-aged and elderly pop-
ulations (up to 80 years of age), and in volunteers with mild or moderate renal
impairment showed similar findings (Glund et al. 2014, 2017). The half-life of ida-
rucizumab approximates 45 min (Glund et al. 2017).
Following an interim report of the RE-VERSE AD study (Reversal Effects of
Idarucizumab on Active Dabigatran), this drug was approved by the United States
Food and Drug Administration (US FDA) in 2015 (Europe in 2015, Canada in 2016)
(Pollack et al. 2015; Food and Drug Administration 2015).
78 S. Music et al.
Dosage and Administration
The recommended dose of idarucizumab is 5 g, intravenously, to be administered in

two separate vials of 2.5 g (50 mL) each, no more than 15 min apart (Praxbind
2015). They can be given as two consecutive infusions or bolus injections via
syringe. This dose reversed the total body load of dabigatran associated with the
99th percentile of the dabigatran levels measured in the Randomized Evaluation of
Long-Term Anticoagulation Therapy (RE-LY) trial (Connolly et al. 2009). Currently,
there is limited evidence for administration of additional doses.
Efficacy and Safety
The RE-VERSE AD trial (final report published in 2017) is a phase 3, multicenter,

prospective, open-label study (n = 503, median age of 78 years) which evaluated the
performance of idarucizumab for dabigatran reversal in patients who had uncon-
trolled bleeding (301 patients with gastrointestinal bleeding, intracranial hemor-
rhage, and trauma) or who required an urgent intervention (202 patients). The
maximum percentage reversal of dabigatran was assessed within 4 h after the
administration of idarucizumab (via diluted TT or ECT), and the median was found
to be 100%, i.e., complete reversal was achieved within 15 min in most patients. The
reversal effect was maintained for 24 h in most patients (Pollack et al. 2017).
Restoration of hemostasis was assessed as a secondary endpoint (Pollack
et al. 2017):
• Among patients treated for bleeding, 203 out of 301 patients could be evaluated
and the median time to cessation of bleeding was 2.5 h, with 134 patients (68%)
achieving documented hemostasis within 24 h.
• In patients undergoing an urgent procedure (median initiation time of 1.6 h), 197
out of 202 patients were evaluated and 184 patients (~93%) had normal peripro-
cedural hemostasis.
The following safety outcomes were reported (Pollack et al. 2017):
• Thrombotic events assessed over a period of 90 days: rate of occurrence was
6.3% and 7.4% in patients treated for bleeding and those treated prior to urgent
procedures, respectively. Events recorded included pulmonary embolism, deep
venous thrombosis, ischemic stroke, and myocardial infarction. Antithrombotic
therapy (prophylactic or therapeutic anticoagulation, or antiplatelet) was reintro-
duced in most patients within ~4–13 days after idarucizumab administration.
Considering the half-life of idarucizumab, this delay in reinitiation of therapy for
patients having achieved hemostasis may have contributed to thrombotic events.
The rates of thrombotic events were comparable to those reported with 4-factor
PCCs for VKA reversal in major surgical procedures or uncontrolled bleeding
(Sarode et al. 2013; Goldstein et al. 2015).
• Mortality at 30 days approximated 13% in both groups, with an estimated 90-day

mortality rate of 19%. This was mainly attributed to the index event severity and
underlying comorbidities leading to multiorgan failure.
• Serious adverse events occurred within 5 days in 23% of patients and most events
were related to worsening of the index event or the underlying condition. The
most frequent events were delirium (2.3%) in patients treated for bleeding, and
cardiac arrest (3.5%) and septic shock (3%) in patients treated for urgent proce-
dures. There was no consistent pattern of adverse effect that could be directly
linked to idarucizumab. There were no hypersensitivity reactions or immunoge-
nicity which may affect the efficacy of reversal. In healthy volunteers, the most
common adverse reactions were headache, constipation, and nausea (all ~5%)
(Glund et al. 2014, 2015a, b, 2017).
In summary, idarucizumab can effectively and rapidly reverse the anticoagulant

effect of dabigatran in most patients with uncontrolled bleeding or requiring urgent
invasive intervention. However, the FDA has included a “black box” warning
regarding the risk of venous and arterial thromboembolic events in the package
insert (Praxbind 2015). Resumption of anticoagulation is recommended as soon as
medically permissible. An important limitation of this landmark trial is the single-
arm design (lack of a control group). However, this was justified as there was no
established standard of care for reversing dabigatran and giving placebo to patients
with uncontrolled bleeding may be deemed unethical.
Use in Clinical Practice
Since idarucizumab’s approval, there are some post-marketing “real-life” use. For
instance, RE-VECTO was a cross-sectional surveillance program of idarucizumab’s
use, spanning from August 2016 to June 2018, at 61 institutions and involved 359
patients in North America, Europe, and Asia Pacific (Fanikos et al. 2020). Clinical
indications of use and population were largely consistent with data collected from
trial settings, with minimal off-label prescribing. Most patients were elderly (75%
over 70 years of age). Life-threatening or uncontrolled bleeding was the most com-
mon indication for idarucizumab (chiefly gastrointestinal and intracranial), fol-
lowed by emergency surgery/urgent procedure (majority gastrointestinal/
abdominal). The recommended 5 g dosing regimen was correctly used in >98% of
dabigatran-treated patients
Kermer et al. (2017) reviewed idarucizumab administration for patients with
intracranial hemorrhage or ischemic stroke eligible for fibrinolysis or at 22 German
hospitals from January to August 2016 (Kermer et al. 2017). Of the 31 patients who
presented with stroke, 19 had ischemic stroke. Following rt-PA, 79% had a positive
outcome with a median 5-point improvement in National Institutes of Health Stroke
Scale (NIHSS). Out of the 12 patients treated for hemorrhagic stroke, two had
increases in the size of the cerebral bleeds, but their overall outcomes were favor-
able with a median NIHSS improvement of 5.5 points (Kermer et al. 2017). In a
80 S. Music et al.
smaller case series where idarucizumab was used for various emergencies including
strokes: the three patients who underwent reversal followed by fibrinolysis had par-
tial (NIHSS 3–5 points) to full neurological recovery (Vosko et al. 2017).
Another specific population in which idarucizumab was evaluated was in patients
undergoing urgent heart transplantation. A case series of 10 patients at the University
Hospitals Leuven showed sustained and complete dabigatran reversal without
thrombotic complications and without interference in heparinization required for
cardiopulmonary bypass (Van Keer et al. 2019). Therefore, dabigatran may be the
anticoagulant of choice for heart failure patients awaiting transplantation (without
ventricular assistance device). Further real-world data and post-marketing analysis
is needed to better assess the generalizability and effectiveness of idarucizumab use,
as well as additional safety outcomes.
actor Xa Inhibitor (Rivaroxaban and Apixaban) Reversal:

F
Andexanet Alfa (Andexxa®; Ondexxya®)
Clinical Pharmacology
Andexanet alfa (Andexxa®) is a recombinant inactivated modified human coagula-

tion factor Xa. It is devoid of coagulant activity, but able to bind factor Xa inhibitors
with high affinity (see Fig. 5.1) (Andexxa 2018). By binding the inhibitors, andex-
anet alfa restores endogenous factor Xa activity (Lu et al. 2013). Of note, andexanet
also reverses indirect factor Xa inhibitor activity by binding to heparins (unfraction-
ated and low-molecular-weight) and to pentasaccharide-activated antithrombin III
(ATIII).
Several phase two studies were conducted in healthy volunteers who received
factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). Intravenous administration
of andexanet reversed anticoagulation effect in a dose-dependent manner, as dem-
onstrated by reduction of anti-Xa activity, unbound factor Xa inhibitor concentra-
tion, and recovery of thrombin generation (Crowther et al. 2013, 2014a, b; Mark
et al. 2013). In these studies, the pharmacodynamic half-life of andexanet was short
and approximated 1 h. Therefore, it was administered as a bolus followed by an
infusion (1–2 h), which reliably prolonged its activity for the duration of infusion.
Subsequently, a double-blind, placebo-controlled phase three trial evaluated
andexanet in non-bleeding healthy older volunteers (50–75 years of age) receiving
apixaban or rivaroxaban (ANNEXA-A, ANNEXA-R; differing andexanet doses
based on stoichiometric ratios established in phase two studies) (Siegal et al. 2015).
Andexanet was given as a bolus or a bolus followed by a 2-h infusion, with monitor-
ing of mean percent change in anti-Xa activity. In both apixaban- and rivaroxaban-
treated participants, anti-Xa activity was reduced within minutes by 92–94% after
an andexanet bolus (vs. 18–21%, p < 0.001 in the placebo groups) and thrombin
generation was fully restored in 96–100% of participants (vs. 7–11%, p < 0.001 in
the placebo groups), with sustained effect when an infusion of andexanet followed.
A subgroup of patients showed transient increases in D-dimer and prothrombin
fragment 1 and 2 levels, resolving within 24–72 h. Although this raised a theoretical
concern of prothrombotic effect, there were no serious adverse events reported over
a follow-up period of 6 weeks.
Finally, a preliminary report of the pivotal trial ANNEXA-4 (Andexanet Alfa a
Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) indicated a positive
outcome for reversal of factor Xa inhibitors (mostly rivaroxaban and apixaban) in
patients presenting with acute major bleeding (Connolly et al. 2016). In 2018,
andexanet received approval by the FDA for the reversal of rivaroxaban and apixa-
ban in patients with uncontrolled or life-threatening bleeding (Andexxa 2018).
Dosage and Administration
The recommended dosing regimens for andexanet alfa include low and high dose
regimens, each with a bolus followed by a 2-h continuous infusion to achieve ongo-
ing sequestration of factor Xa inhibitors (Andexxa 2018):
• Low dose: 400 mg IV bolus at a target rate of 30 mg/min, followed by a continu-

ous infusion of 4 mg/min for up to 120 min.
• High dose: 800 mg IV bolus at a target rate of 30 mg/min, followed by a continu-
ous infusion of 8 mg/min for up to 120 min.
The appropriate regimen is determined by differing stoichiometric ratios required

for binding of specific factor Xa inhibitors, their doses, and the time since their last
administration. It is summarized below in Table 5.3. Andexanet is commercially
available in 100 mg and 200 mg vials.
Efficacy and Safety
The ANNEXA-4 trial was a multicenter, prospective, open-label, single-arm study

evaluating andexanet in 352 patients (a mean age of 77 years) receiving a factor Xa
inhibitor for NVAF (80% of the cohort) or VTE with acute major bleeding and last
dose of DOAC taken within 18 h (Connolly et al. 2019). The co-primary outcomes
were the percent of change in anti-Xa activity and the proportion of patients
Table 5.3 Andexanet alfa dosing according to DOAC regimen (Andexxa 2018)
Factor Xa Inhibitor <8 h or unknown time
Dosage since last dose >8 h since last dose (<18 h)
Rivaroxaban
≤ 10 mg Low dose Low dose
>10 mg or unknown High dose
Apixaban
≤ 5 mg Low dose Low dose
>5 mg or unknown High dose
82 S. Music et al.
achieving good or excellent hemostasis at 12 h. The efficacy of andexanet was eval-
uated in a subgroup of patients with confirmed major bleeding and pre-hoc defined
threshold of anti-Xa activity considered to represent higher bleeding risk (at least
75 ng/mL; or ≥0.25 IU/mL for patients on enoxaparin). Most patients were taking
rivaroxaban and apixaban, and bleeding was predominantly intracranial (64%) or
gastrointestinal (26%).
The following results were observed (Connolly et al. 2019):
• Median anti-Xa activity was reduced by 92% for rivaroxaban (95% confidence
intervals (CI): 88–94) and apixaban (95% CI: 91–93), and by 75% (95% CI:
66–79) for enoxaparin. A very small number of patients received edoxaban (3%,
n = 10 patients). Extension of the study is underway in Japan and is expected to
yield additional data regarding edoxaban’s reversal.
• Excellent hemostasis was achieved in 171 of 249 evaluated patients (69%), and
good in 33 of 249 patients (13%): total of 82% of patients (204 of 249). Subgroup
analysis showed good to excellent hemostasis for 85% of patients with gastroin-
testinal bleeding and 80% of intracranial bleeding. The majority of patients could
resume anticoagulation after resolution of bleeding.
• Anti-Xa activity was increased at 4 and 8 h after administration of andexanet,
albeit it remained relatively low (~60–70% reduced). Reduction of anti-Xa activ-
ity was not found to be predictive of hemostasis overall, except for a possible
correlation in patients with intracranial hemorrhage whereby the hematoma’s
size and volumes were tracked serially. Consequently, the clinical response to
andexanet cannot be reliably predicted with anti-Xa measurement.
The safety outcomes studied (Connolly et al. 2019) were:
• Thrombotic events occurred in 10% of 353 patients (n = 34) within 30 days of

follow-up. Three percent of the thromboses occurred within 5 days of andexanet.
It is unclear whether these events are related to the underlying thrombotic risk of
the patients or whether there is a contribution from sustained effects of andexanet
alfa. The thromboses included pulmonary embolism, deep venous thrombosis,
ischemic stroke, and myocardial infarction.
• Thirty-day mortality was 14%, which is similar to the all-cause mortality rates
reported in other studies of major anticoagulant-associated bleeding.
• Most common adverse reactions (≥5%) included urinary tract infections and
pneumonia without biological plausibility, as well as infusion-related reactions
(≥3%) in healthy volunteers (Andexxa 2018; Siegal et al. 2015). There were no
major hypersensitivity reactions or neutralizing antibody development reported
in ANNEXA-4.
ANNEXA-4 showed that andexanet reduced anti-Xa activity level as well as

provided good or excellent hemostasis in 82% of patients with factor Xa
inhibitor-associated acute major bleeding. Further studies are needed to deter-
mine if there is a reduction in mortality compared to the reported rates in
anticoagulation-associated bleeding without reversal. Similar to the RE-VERSE

AD, the main limitation of ANNEXA-4 was the single-arm design with the lack
of a control group. The lack of control group was deemed ethically acceptable,
in the setting of bleeding patients and the lack of approved effective reversal
strategies for DOACs. In summary, andexanet is a safe and effective option for
patients with uncontrolled or life-threatening bleeding associated with rivar-
oxaban and apixaban. Use of andexanet for edoxaban- or betrixaban-associated
bleeding is currently off-label (Cuker et al. 2019). It is also not approved in the
case of emergency surgeries and invasive procedures as use in that population
was not studied in ANNEXA-4. As for idarucizumab, the FDA has issued a
black box warning regarding the risk of venous and arterial thromboembolic
events (Andexxa 2018).
Use in Clinical Practice
Since its approval in 2018, there has been limited published data about andexanet in
real-life setting. Generalizability of andexanet’s safety and efficacy remains to be
established outside clinical trial settings. For instance, the ANNEXA-4 investiga-
tors included only patients with a Glasgow coma scale >7 and an estimated hema-
toma volume <60 mL of intracranial hemorrhage (Connolly et al. 2019). Andexanet’s
effectiveness is particularly relevant for anti-Xa-associated intracranial hemorrhage
which is associated with high mortality and morbidity (Purrucker et al. 2016).
Additionally, the ANNEXA-4 investigators also excluded patients who required an
invasive intervention within 12 h (Connolly et al. 2019). There is an ongoing ran-
domized, controlled clinical trial evaluating the efficacy and safety of andexanet
versus usual standard of care in patients with intracranial hemorrhage and receiving
a factor Xa inhibitor (NCT03661528) (Karam et al. 2013).
The Mayo Clinic published their experience with andexanet use from July 2018
to April 2019 (Brown et al. 2019). Of 25 patients evaluated, 13 received andexanet
for intracranial hemorrhage. Eleven patients had follow-up cerebral imaging show-
ing stability in ~91% of these patients. Additionally, three patients had effective
hemostasis, and nine patients received therapy for other major bleeding (four gas-
trointestinal). No thrombotic events were recorded, and 30-day mortality was 24%.
Most treated patients in this series would have been excluded from the ANNEXA-4
trial. Larger post-marketing studies are needed to clarify the optimal use of andex-
anet alfa in clinical practice.
Other Pro-Hemostatic Therapies
Prior to the approval of idarucizumab and andexanet alfa, off-label use of nonspe-
cific pro-hemostatic products for the management of bleeding in patients on DOAC
therapy was endorsed on the basis of studies of animals, healthy volunteers, and
expert consensus as detailed below.
84 S. Music et al.
Clotting Factor Products
Available products with inactivated or activated coagulation factors include pro-

thrombin complex concentrate (PCC; 3-factor, 4-factor inactivated [Kcentra®/
Beriplex®/Octaplex®], 4-factor activated [FEIBA®]), recombinant activated factor
VII (rFVIIa) and plasma products (such as fresh frozen plasma, FFP). Data regard-
ing their efficacy in patients with DOAC-associated bleeding is sparse (Ageno et al.
2012; Arellano-Rodrigo et al. 2015; Cheung et al. 2015; Dibu et al. 2016; Eerenberg
et al. 2011; Honickel et al. 2016; Lambourne et al. 2012; Marlu et al. 2012; Perzborn
et al. 2013; Piran et al. 2019; Pragst et al. 2012; Schulman et al. 2018).
In the case of warfarin, clotting factor products restore hemostasis with a sustain-
able effect when vitamin K is given. As they inhibit exogenous clotting factors,
DOACs are unlikely to have their effect reliably countered by FFP. Indeed, FFP use
is not recommended in this context as their risks may outweigh the potential bene-
fits. Nevertheless, FFP may be appropriate for dilutional coagulopathy associated
with massive transfusion (Ageno et al. 2012).
Recombinant activated factor VII has been recommended for patients presenting
with bleeding associated with dabigatran and apixaban according to the FDA
(Sinnaeve et al. 2016; Pradaxa 2018). Evidence for the efficacy of recombinant
activated factor VII in reversal of the above DOACs is lacking, aside from in vitro
measurement of coagulation (Lambourne et al. 2012) and an inconclusive ex vivo
study in healthy volunteers (Arellano-Rodrigo et al. 2015).
PCCs contain high levels of factors II, IV, and X (plus VII, protein C and S in
4-factor PCC), i.e., vitamin K-dependent coagulation factors. PCCs were developed
and primarily studied for reversal of warfarin anticoagulation. There were some
observational studies of inactivated PCCs for DOAC-associated bleeding (animal
models and healthy volunteers) (Cheung et al. 2015; Eerenberg et al. 2011;
Lambourne et al. 2012; Marlu et al. 2012; Perzborn et al. 2013; Pragst et al. 2012).
In a systemic review, Piran et al. reviewed the use of inactivated PCC for factor Xa
inhibitor-associated major bleeding (primarily rivaroxaban and apixaban) in ten
studies enrolling 340 patients (Piran et al. 2019). The reported proportion of patients
with successful bleeding management varied from 69% (95% CI: 61%–76%) to
77% (95% CI: 63%–92%), depending on the criteria used to define hemostasis. The
mortality rate was 16% (95% CI: 7%–26%) and the rate of thrombotic events was
4% (95% CI: 1%–8%). Essentially, it was uncertain whether PCC administration
was more effective than conservative measures alone in DOAC-related major bleed-
ing. Use in ICH had been less well studied, but more recently, a multicenter, retro-
spective, observational cohort study by Panos et al. reviewed patients with
apixaban- or rivaroxaban-related ICH who received PCCs from January 2015 to
March 2019 (Panos et al. 2020). Of 663 patients included, 433 were evaluated for
hemostatic efficacy, of which 354 patients (81.8%, 95% CI: 77.9–85.2) had excel-
lent or good hemostasis (using modified Sarode criteria). In addition, 25 (3.8%)
patients had 26 thrombotic events, most of which occurred in the first 14 days after
PCC administration. The overall in-hospital mortality of the cohort was 19%.
Therefore, in the context of life-threatening or uncontrolled bleeding, unavailability
of specific reversal agents, or cost effectiveness concerns, it may be reasonable to

administer inactivated PCC as a one-time dose of 50 U/kg IV or 2000 units (more
evidence for four-factor formulation) (Schulman et al. 2018). Similar to idaruci-
zumab and andexanet alfa, PCC has a theoretical and poorly quantified prothrom-
botic risk. Hence, it must be used with caution in carefully selected patients.
There is limited evidence of the potential benefit of activated PCC (aPCC,
FEIBA®) in DOAC-associated bleeding. A prospective study including six patients
with DOAC-associated intracranial hemorrhage who underwent reversal with aPCC
showed no intracranial hemorrhage expansion or any thrombotic complications
(Dibu et al. 2016). In a pig polytrauma model with dabigatran administration, aPCC
prevented fatal bleeding compared to placebo (Honickel et al. 2016). In rats and
primates treated with rivaroxaban, aPCC corrected the bleeding time (Perzborn
et al. 2013). A study in ten non-bleeding volunteers also showed that aPCC restored
thrombin generation impaired by rivaroxaban (Marlu et al. 2012).
Other
Additional pro-hemostatic therapies available for use include antifibrinolytic agents,

such as tranexamic acid, and desmopressin (DDAVP), which may correct impaired
platelet function in uremic patients or with antiplatelets therapy. Again, there is
sparsity of data concerning these agents in DOAC-associated bleeding. Nonetheless,
considering their low risk of thrombosis and widespread availability, these agents
may be appropriate for life-threatening bleeding.
To summarize all available therapeutic options for reversal of DOAC’s effects,
we described a potential management approach to the reversal of DOACs in Fig. 5.2.
These recommendations are in line with the recently published expert consensus
decision pathway on management of bleeding in patients on oral anticoagulants by
the American College of Cardiology (Tomaselli et al. 2020).
The Search of a Universal Antidote
In addition to the development of class and drug-specific reversal agents, the recent
years have seen efforts to find antidotes which can reverse the effects of multiple
anticoagulants. The idea of a so-called “universal” antidote is appealing for its prac-
ticality and wider clinical applicability.
Ciraparantag
Ciraparantag (previously called PER977, Amag Pharmaceuticals) was synthetically

developed to bind to unfractionated heparin, low-molecular-weight heparin,
fondaparinux, and DOACs including dabigatran, rivaroxaban, apixaban, and edoxa-
ban (see Fig. 5.1) (Laulicht et al. 2013; Sullivan Jr et al. 2015; Ansell et al. 2014,
86 S. Music et al.
Uncontrolled or life-threatening bleeding

• ↓Hg of ≥20 g/L /transfusion of
≥2 units of PRBC–refractory to
management
Emergent surgery / procedure • Bleeding in a critical closed
with high risk of bleeding space (e.g. intracranial, retroperi-
toneal, compartment syndrome)
Assess anticoagulant status and degree

• History
• Rx and chart review
• Renal and hepatic dysfunction
• Time since last dose
• Coagulation testing
Dabigatran Factor Xa Inhibitor (Rivaroxaban, Apixa-ban)
↑ TT (dTT) / ECT ↑ antiXa

± ↑aPTT ± ↑PT/INR
Idarucizumab Andexanet alfa

5 g (2x 2.5 g) Low / High dose protocol with 2h infusion
according to DOAC type and dose
Not Available
Prothrombic Complex Concentrate

(inactivated; activated)
General supportive management (apply per localpolicies):

• Cessation of anticoagulation
• Hemodynamic support with fluid resuscitation ± vasopressors
• Airway support if clinically warranted
• Enhanced elimination: oral activated charcoal (if last dose last 2 hours); hemodialysis for
dabigatran
• Transfusionsf iappropriate
• Consider antifibrinolytic agent (eg, tranexamic acid)
• Targeted bleeding site interventions (endoscopic, radiologic, surgical) if appropriate
Fig. 5.2 Approach to direct oral anticoagulant reversal PRBC packed red blood cells, TT thrombin
time (dTT diluted thrombin time), ECT ecarin clotting time, PT/INR prothrombin time/interna-
tional normalized ratio, aPTT activated partial thromboplastin
2017). With noncovalent hydrogen binding of these anticoagulants, ciraparantag

prevents their attachment to factor IIa and Xa target sites. There was no demon-
strable prothrombotic effect and cross-reactivity of this molecule with other coagu-
lation factors (Sullivan Jr et al. 2015).
In healthy volunteers, ciraparantag reduced safely and effectively whole blood
clotting time after exposure to enoxaparin (Costin et al. 2015) and edoxaban
(Schulman et al. 2018; Panos et al. 2020). There was no subsequent prothrom-
botic effect, and no major safety concerns have emerged, except for mild
infusion reactions. In light of the above findings, ciraparantag has been granted
fast track designation by the FDA to facilitate its development (Wong 2013).
There are currently two phase 2 trials in the recruitment phase, for reversal of
rivaroxaban and apixaban by ciraparantag (NCT03172910 and NCT03288454,
respectively).
FXaI16L
FXaI16L was developed as a mutant form of factor Xa with introduction of an amino

acid substitution and is being studied as a “universal” bypass agent for several anti-
coagulants (Thalji et al. 2016). It works by circulating in an inactive state and exhib-
its resistance to active site inhibitors. Upon encounter with factor Va on damaged
cellular surfaces, FXaI16L activated and restore hemostasis at the bleeding site. It
successfully restored hemostasis in mouses exposed to rivaroxaban. FXaI16L also
reversed rivaroxaban- or dabigatran-mediated anticoagulant effect in humans.
Conclusions
During the last decade, DOACs have replaced VKAs for most indications. Although
DOACs are associated with less bleeding and in particular less intracranial hemor-
rhage, uncontrolled or life-threatening bleeding still can occur with DOACs. Patients
anticoagulated with DOAC can also develop acute conditions or endure trauma that
call for emergent surgery.
Supportive management can be offered in the form of transfusions as appropri-
ate, maintenance of fluid balance, interruption of anticoagulation and nonspecific
pro-hemostatic therapies that have limited evidence. In cases of life-threatening
bleeding in closed critical organs (e.g., intracranial), refractory hemorrhage on stan-
dard therapies, and emergency interventions in patients at high bleeding risk, spe-
cific reversal agents should be the treatment of choice when available.
Idarucizumab can provide rapid and sustained reversal of dabigatran for bleeding
patients and those undergoing surgery. Andexanet alfa is a factor Xa inhibitor
approved for reversal of rivaroxaban and apixaban-associated hemorrhage.
Ciraparantag is being studied as a “universal” antidote. It has promising preclinical
data and may be effective for counteracting anticoagulant effect of unfractionated
heparin, low-molecular-weight heparin, fondaparinux, and DOACs including dabi-
gatran, rivaroxaban, apixaban, and edoxaban.
The landscape of anticoagulation has changed drastically in the last few years,
and one of the main concerns from clinicians and patients has been the sparsity of
therapeutic options for treatment of DOAC-associated bleeding. This is changing as
well, and future research should yield more information about clinical applicability,
for instance in patients with ischemic stroke for thrombolysis or thrombectomy can-
didacy, presurgical patients, and moderate bleedings failing usual supportive
therapies.
88 S. Music et al.
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Risk Stratification For and Use of DOAC
Therapies for Stroke Prevention 6
in Patient with Atrial Fibrillation
Alfredo Caturano, Raffaele Galiero, Serenella Spiezia,

and Pia Clara Pafundi
Introduction
Atrial fibrillation (AF) is the most common arrhythmia, with an incidence ranging
from 0.1% in patients <55 years to >9% in octogenarian patients (Caturano et al.
2019). The most important AF complication is represented by a fivefold increased
risk of ischemic stroke, due to a high prevalence of left atrial thrombosis (Fadhlullah
et al. 2016; Bertaglia et al. 2017; AlTurki et al. 2019), hence the major role of anti-
coagulation is in thromboembolism prevention.
Vitamin K antagonists (VKAs) have been widely used for decades. However,
currently, with the marketing of direct oral anticoagulants (DOACs), the therapeutic
scenario has changed. The four available DOAC molecules (dabigatran, apixaban,
rivaroxaban, and edoxaban) have shown a comparable efficacy, with a lower risk of
intracerebral bleeding as compared to well-managed VKAs, as well as an improved
expectancy and quality of life (Caturano et al. 2019; Russo et al. 2020a). These find-
ings were further confirmed by real-world data, also including AF patients with
clinical characteristics excluded from RCTs (Russo et al. 2016, 2018a, 2019a, b,
2020b; Rago et al. 2019a, b; Stabile et al. 2015; Melillo et al. 2020).
The risk of stroke, though common in the AF setting, is extremely variable.
Indeed, diverse risk factors can contribute in different ways to its occurrence. Thus,
a risk stratification algorithm would be mandatory to aid therapeutic decision-
making for thromboprophylaxis.
Framingham score was among the first point-based algorithms, a weighted score
was assigned to each detected risk factor: age (0–10), female sex (6), systolic hyper-
tension (0–4), diabetes mellitus (5), and prior stroke or transient ischemic attack
A. Caturano (*) · R. Galiero · S. Spiezia · P. C. Pafundi

Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi
Vanvitelli”, Naples, Italy

94 A. Caturano et al.
(TIA) (6) (Schnabel et al. 2009). A total score ≥8 was suggestive of introducing oral
anticoagulant therapy (OAC) (Fang et al. 2008).
Over time, we have witnessed both a refinement and improvement of risk strati-
fication. In 1994, a pooled analysis of five randomized controlled trials by the Atrial
Fibrillation Investigators (AFI) has attempted to detect patients’ features prognostic
of either a high or low risk of stroke (Risk Factors for Stroke and Efficacy 1994). It
emerged that AF patients ≤65 years without a history of hypertension, previous
stroke/transient ischemic attack, or diabetes were at very low risk of stroke, even in
the case thromboembolic prophylaxis was not performed. In 1995, the Stroke
Prevention in Atrial Fibrillation (SPAF) also underlined the role of recent onset
congestive heart failure (CHF), history of hypertension (systolic blood pressure
>160 mmHg), and previous arterial thromboembolism as independent risk factors
(Stroke Prevention in Atrial Fibrillation Investigators 1995; The Atrial Fibrillation
Investigators 1997).
Over the years, new scores have been developed to stratify both embolic and
bleeding risk in AF patients, which are currently used in the clinical practice.
Risk Stratification: An Overview
The most common risk stratification system is represented by the CHA2DS2VASc

score, introduced by the Guidelines of the European Society of Cardiology (ESC)
in 2010 (Camm et al. 2012). CHA2DS2VASc allows to classify each patient accord-
ing to a definite risk scale: (1) mild risk (if CHA2DS2VASc = 0), (2) moderate risk
(if CHA2DS2VASc = 1–2 in women and = 1 in men), (3) high risk (if CHA2DS2VASc
≥3 in women and ≥2 in men). Usually anticoagulant therapy, recommended in high
risk patients, over the years, has been proven to remarkably reduce the risk of events
of about two-thirds. Different is the scenario in the case of mild/moderate stroke
risk, for which the anticoagulant treatment should be carefully assessed balancing
embolic and bleeding risk factors (Kirchhof et al. 2016a). In fact, in some cases,
patients could be predisposed to a higher bleeding risk, which can be in turn esti-
mated by diverse scores, among which the most used is the HAS-BLED.
Embolic Risk Stratification
CHADS2
In 2001, Gage et al. merged AFI and SPAF scoring system to establish the new
CHADS2 score, which includes the following risk factors for stroke: cardiac failure,
hypertension, age, diabetes, stroke. The relative impact of each risk factor on the
incidence of stroke has been assigned a specific score, as follows: 2 points to a pre-
vious stroke/TIA event, while all other variables received 1 point.
CHADS2 predictive value, i.e., its validation as risk stratification system, has
been assessed in about 1700 patients, aged 65 to 95, with non-valve atrial
6 Risk Stratification For and Use of DOAC Therapies for Stroke Prevention in Patient… 95
fibrillation (NVAF), assisted by Medicare, to whom warfarin was not prescribed at

discharge. Few patients collected the lowest (0) and highest (5–6) score values. A
score of 0 was associated with a stroke rate per year of 1.9%, while if equal to 6, the
stroke rate arose till the 12.5–18.2% (Gage et al. 2001).
According to the CHADS2 score, patients can be classified in three categories of
risk: (a) low, if the score is equal to 0, (b) intermediate or intermediate/high, if the
score was equal to 1–2, and (c) high to all those with a score ≥3 (Fuster et al. 2011).
Hence, a past history of a previous stroke would have assigned the patient to a mod-
erate risk category, even though it is considered the major risk factor for recurrence.
In 2010, ESC Guidelines modified this classification scale, assigning a moderate
risk with a CHADS2 equal to 1 and high risk with CHADS2 ≥2 in men (Camm
et al. 2012).
The discovery of other risk factors not previously validated and the reduced reli-
ability of the algorithm in low risk patients, with a stroke year incidence of 3.2%,
have stressed the need for further and better risk stratification algorithms (Cove
et al. 2014).
CHA2DS2VASc
CHADS2 bias was overcome by the spread of another risk stratification system:
CHA2DS2VASc (Lip et al. 2010), which has been firstly included in 2010 ESC
Guidelines (Camm et al. 2012) and later confirmed by current ESC guidelines as the
preferred risk stratification algorithm (Kirchhof et al. 2016a). This novel algorithm,
unlike CHADS2, covers additional risk factors (female gender, age 65–74 years, and
vascular disease) and enhances the importance of the major ones. CHA2DS2VASc
ranges from 0 to 9, assigned as follows: 2 points for previous stroke and age
≥75 years, 1 point to vascular disease (myocardial infarction, aortic plaque, and
peripheral vascular disease), systolic heart failure, hypertension, diabetes and age
65–74 years.
CHA2DS2VASc score was validated in the Euro Heart Survey for AF, a real-
world study conducted on a cohort of over 1000 patients (Lip et al. 2010). Benefits
from using the new algorithm were remarkable especially in those referred to low
risk group (CHA2DS2VASc score equal to 0 in males and 1 in females), with an
annual stroke incidence <1%, later confirmed also by other studies in larger cohorts
of patients (Olesen and Torp-Pedersen 2015; Aspberg et al. 2016; Van Staa et al.
2011; Zhu et al. 2015a). Anticoagulation should be started with a CHA2DS2VASc
score ≥1 for men and ≥2 for women (Kirchhof et al. 2016a).
Role of female sex either alone or associated to another risk factor did not con-
sistently increase stroke risk. Thus, recently, the National Heart Foundation of
Australia and the Cardiac Society of Australia and New Zealand, to avoid different
gender thresholds for anticoagulation, have proposed a revision of CHA2DS2Vasc
score excluding sex (NHFA CSANZ Atrial Fibrillation Guideline Working Group
et al. 2018). Currently, complete CHA2DS2VASc represents the most common risk
stratification scheme.
R2CHADS2 Score
Kidney impairment plays a major role in the prognosis of stroke. In fact, subjects
with an acute stroke and reduced estimated glomerular filtration rate (eGFR) have a
higher mortality both in the short-term follow-up and over a 2 years period
(Mostofsky et al. 2009; Guo et al. 2013; Fu et al. 2017). A sub-analysis of the
ROCKET-AF trial, in a highly selected population of over 14,000 individuals with
eGFR>30 mL/min, disclosed impaired renal function as a potent predictor of both
stroke and systemic embolism. Hence, kidney impairment was further added to
CHADS2 classification, assigning a score of 2, thus introducing the R2CHADS2.
Conversely, several studies have shown no added value from renal impairment
inclusion either to CHADS2 or CHA2DS2VASc (Abumuaileq et al. 2015; Roldan
et al. 2013; Friberg et al. 2015).
tria Stroke Score

A
In 2013, a derivation from the “AnTicoagulation and Risk factors In AF” (ATRIA)
cohort, counting about 11,000 non-valvular AF patients, validated the ATRIA risk
score with an improvement of severe events detection (Singer et al. 2013). The nov-
elty of this risk stratification system is the distinction according to patients in pri-
mary or secondary stroke prevention, assigning a score between 0 and 12 in primary
prevention and between 7 and 15 in secondary. Moreover, many other risk factors
were added to the old ones (gender, history of congestive heart failure, hyperten-
sion, diabetes, and stroke). Age classes, presence of proteinuria and eGFR<45 mL/
min or end-stage renal disease (ESRD) were furtherly included. In primary preven-
tion, patients are considered at low risk if the score is ≤5, thus receiving no antico-
agulation. In contrast, all patients in secondary prevention are considered at high
risk and anticoagulated.
All these features render the ATRIA score system not of immediate use in clini-
cal practice. In addition, several studies have proven a higher efficacy of
CHA2DS2VASc than ATRIA in stroke risk prediction (Macle et al. 2015; Hippisley-
Cox et al. 2013; Chao et al. 2015; Lip et al. 2014). In a cohort of over 150,000
Swedish AF patients naïve to anticoagulation also during follow-up, CHADS2,
CHA2DS2VASC, and ATRIA scores were compared to each other. At first, ATRIA
seemed to perform better; however, when categorical scores were optimized for
local population incidence of stroke, no longer advantage emerged (Aspberg
et al. 2016).
QStroke Score
In the view of a more tailored risk stratification of stroke in the general population
without history of previous TIA/stroke, a new algorithm was proposed, the
QSTROKE (Hippisley-Cox et al. 2013). Considered risk factors were: age, ethnic-
ity, gender, smoking habit, diagnosis of diabetes and type, AF, treated hypertension,
kidney disease, rheumatoid arthritis, angina, coronary heart disease, congestive car-
diac failure, valvular heart disease, total serum cholesterol to high density lipopro-
tein cholesterol ratio, body mass index, as well as family history of coronary heart
disease in first-degree relatives <60 years. This score was validated in a cohort of
approximately 1.9 million individuals from England and Wales, aged between 25

and 84 years and without a positive anamnesis either for TIA or stroke. The stroke
event occurred in about 38,000 cases throughout the follow-up period. Among AF
patients QSTROKE performed better than both CHADS2 and CHA2DS2VASc score,
though not easy in clinical practice.
Garfield AF
The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD
AF study) proposed a web-based tool aimed to better stratify lower risk classes (Fox
et al. 2017). This model successfully managed to predict all-cause mortality, stroke/
systemic embolism and major bleeding, including hemorrhagic stroke, with a higher
accuracy than both CHA2DS2VASc for stroke and HAS-BLED for bleeding, in the
general population, as well as in low stroke risk patients (Fox et al. 2017; Dalgaard
et al. 2019).
Factors included in this algorithm are: age, diastolic blood pressure, history of
bleeding, kidney disease, smoking habit, carotid occlusive disease, weight, ethnic-
ity, history of heart failure or left ventricular heart failure (ejection fraction, EF
<40%), history of coronary artery disease or peripheral vascular disease, dementia,
pulse rate, gender, history of stroke, diabetes, current use of antiplatelet drugs. As
mentioned for QSTROKE, either in this case its complexity may represent a limit
for its application in the clinical practice.
BC Stroke Risk Score

A
The ABC stroke score (age, biomarkers, and clinical history) is a simple risk strati-
fication system in AF patients. ABC score was validated in a large cohort of almost
15,000 AF patients with a median follow-up of 1.9 years (Hijazi et al. 2016a), and
includes: age, troponin and NT-proBNP, history of TIA/stroke. The ABC stroke
score showed a higher accuracy than CHA2DS2VASc in predicting stroke risk. This
finding was further confirmed by another recent study on about 8700 AF patients
(Berg et al. 2019).
Conclusions Though both GARFIELD AF and ABC stroke scores are promising,
their knowledge on the long term is still poor; thus further studies are needed.
In addition, note that the role of anticoagulant agents is not risk-free, though also
burdened by bleeding risk. Therefore, only an optimal risk-to-benefit ratio between
hemorrhagic and stroke risk would represent the key-point to guide us in a better
clinical decision-making.
Bleeding Risk Assessment
In patients with a moderate embolic risk (i.e., CHA2DS2VASc = 1 for men, and = 2
for women), some authors reported a potential risk reduction from the use of OACs
(Steffel et al. 2018; Kirchhof et al. 2016b). Beyond the assessments of embolic risk,
European guidelines also include bleeding risk evaluation (Steffel et al. 2018).
Hence, careful attention must be focused on the risk-to-benefit ratio of anticoagu-

lants due to the adverse effects related to major and minor bleeding (Ding et al. 2020).
Hereinafter we will consider the most important scores for hemorrhagic risk
stratification.
In clinical practice, diverse stratification models are available for hemorrhagic
risk assessment. Considered parameters are: advanced age, previous major bleeding
events, previous stroke, recent myocardial infarction, creatinine >1.5 mg/dL, hema-
tocrit <30%, and diabetes. It appears evident that several of the aforementioned risk
factors are common to those for stroke, hence the proposal of the term “shared risk
factors” to underline this aspect.
Over the years, various models have been proposed for bleeding risk stratifica-
tion in patients taking OACs, although few have been validated in AF and many are
not easily applicable, as they either require complex mathematical formulas or
include parameters not measurable in routine clinical practice (Lip et al. 2011a,
2012). For example, the HEMOR2RHAGES-14 score (liver/kidney disease, abuse
of ethanol, neoplasms, old age [>75 years], recurrence of bleeding, thrombocytope-
nia, uncontrolled hypertension, anemia, genetic factors, risk of falls, and stroke) is
characterized by an overlap between bleeding and stroke risk factors, hence creating
burdens in the decision on most appropriate antithrombotic therapy (Gage et al.
2006). A further bleeding risk stratification model, validated with a good predictive
effectiveness, is represented by the ATRIA score (Anticoagulation and Risk Factors
in Atrial Fibrillation), which allows to classify patients into high, medium, and low
risk (Fang et al. 2011). The ORBIT score was instead derived from a cohort of
almost 7500 patients on warfarin therapy, in which a bleeding incidence of 4%
patient-years was reported. In this cohort, age >75 years, a history of anemia or
previous bleeding, renal failure or use of ASA were predictive with a c-score of 0.67
(O'Brien et al. 2015). A recently introduced score is the ABC-bleeding (or “Age,
Biomarkers, Clinical history”), which was developed within the ARISTOTLE study
and validated in the same ARISTOTLE (approximately 14,500 patients) and in the
RE-LY study (approximately 8500 patients). The ABC score is interesting because
it also associates with bio-humoral parameters (GDF-15, troponin T, and hemoglo-
bin) and it is calculated using continuous quantitative data rather than dichotomiz-
ing them into qualitative variables. This score reaches a predictive validity of 0.68,
higher both than the ORBIT (0.65) (Hijazi et al. 2016b), and the most used HAS-
BLED score (c-score = 0.59) (Lip et al. 2018).
As the latest ESC guidelines recommend using HAS-BLED for risk stratification
of AF patients (Kirchhof et al. 2016b; Pisters et al. 2010), we will further focus in
depth on this score.
he HAS-BLED Score
T
HAS-BLED takes the name from the considered parameters: H “hypertension”
(systolic blood pressure >160 mmHg), A “abnormal liver/renal function,” S “stroke,”
B “bleeding history/predisposition,” L “labile international normalized ratio (INR),”
E “elderly” (i.e., age >65 years) and D “concomitant drugs/alcohol.” The HAS-
BLED score allows to classify patients into low-to-moderate risk (if the score is
0–2) and high risk (with a score ≥3). Pisters et al. validated in 2010 this practical
and easy to use score, which is able to estimate the risk of major bleeding at 1 year,
in a real-life cohort of AF patients: the EuroHeart Survey population (Pisters et al.
2010). Of note, the HAS-BLED score has also been validated among non-AF sub-
jects, which renders it applicable at all stages of the patient management pathway
(Kooiman et al. 2015; Omran et al. 2012; Smith et al. 2012).
Validation was based on the predictive ability of the score, measured by c-statistic
of 0.72, higher in the case of concomitant antiplatelet therapy (c-stat = 0.91), and
was later performed also on warfarin-naïve patients, on subjects under non-warfarin
anticoagulants and in those receiving both warfarin and aspirin (Lip et al. 2011b).
HAS-BLED score has proven to be better than the HEMOR2RHAGES and with
a good predictive accuracy. Furthermore, unlike some risk factors within the
HEMOR2RHAGES, all HAS-BLED risk factors are easily recoverable either from
the patient’s medical history or from the routine tests (Pisters et al. 2010; Lip et al.
2011b). Of note, HAS-BLED includes the assessment of anticoagulation quality
control by considering as a criterion the “labile INR,” relevant most of all for VKAs
users (Proietti et al. 2016). The superiority of HAS-BLED against both
HEMORR2HAGES and ATRIA in bleeding risk prediction was furtherly confirmed
by two systematic reviews and meta-analyses by Zhu et al. (2015b) and Caldeira
et al. (2014a).
Thus, the usefulness of such a simple and effective bleeding risk stratification
model appears evident, especially in view of the recent introduction of new DOACs.
As an example, patients considered at a higher bleeding risk according to the HAS-
BLED score, could benefit from the lower dose (110 mg × 2) of the direct oral
thrombin inhibitor, dabigatran, while to subjects at lower bleeding risk may be
administered the higher dose (150 mg × 2) of the drug, which offers a higher effi-
cacy, though a bleeding risk similar to that of warfarin (Steffel et al. 2018).
However, the presence of factors associated with both an increased risk of
embolic and hemorrhagic thrombus suggests taking individual decisions based on
the net clinical benefit of the patients (Steffel et al. 2018; Kirchhof et al. 2016b).
Direct Oral Anticoagulants in AF: General Outline
Current International guidelines suggest administering DOACs as an alternative to

warfarin, in non-valvular AF (NVAF). In fact, DOACs demonstrated an efficacy
equal to Vitamin K Antagonists (VKAs) in the prevention of both stroke and major
embolic events, net of a lower bleeding risk. Moreover, patients taking DOACs do
not need a continuous INR monitoring to control the dosage (Russo et al. 2017a;
Proietti et al. 2015).
Up to date, marketed DOACs are four: Dabigatran, a thrombin direct inhibitor
and three Xa factor inhibitors (rivaroxaban, apixaban, and edoxaban). All most
important registration trials have compared both efficacy and safety of each single
drug with those of warfarin, except for apixaban, for which also a comparative trial
with aspirin has been led.
DOACs and Risk Stratification
According to the most recent guidelines, risk stratification does not change, still
referring to the CHA2DS2VASc Score. From the sub-analyses of both main clinical
trials and post-marketing phase IV studies, further evidence has been provided as
regards both efficacy and safety of DOACs in definite subpopulations.
OACs Efficacy and Safety in Patients with AF and Diabetes

D
Diabetes and AF are strongly related. Diabetic patients, as compared to healthy
subjects, present almost a double risk of experiencing AF. In addition, diverse stud-
ies have shown that in these subjects with hypertension, age >65 years, and AF the
risk of stroke is double (Ding et al. 2020). As compared with warfarin, all DOACs
have shown an equal efficacy in terms of relative risk reduction for stroke (Hijazi
et al. 2016a; Zachary and Richter 2018; Prídavková et al. 2019; Brambatti et al.
2015; Ezekowitz et al. 2015). Currently, in the absence of long-term studies on
DOACs in the diabetic population, no evidence has affirmed the superiority of one
over the others. Their use must also be accompanied by a careful monitoring of the
renal function to avoid an over-dosage (Cosentino et al. 2020), as the altered kinet-
ics due to diabetic kidney disease seems the only interaction observed with DOACs
(Hernandez et al. 2019; Russo et al. 2020c).
OACs and Heart Failure

D
Heart Failure (HF) represents a further indication to the use of anticoagulant therapy
in AF patients. The therapeutic approach with DOACs in this specific subpopulation
does not differ from that in the general population treated with warfarin. Moreover,
no interaction has been found between drugs and HF degree. A recent observational
retrospective study of 2019, on about 60,000 patients with both AF and HF, assessed
safety and efficacy of DOACs as compared to warfarin. Consistently with the main
trials (ARISTOTLE, ROCKET-AF, and RE-LY) and with previous meta-analyses,
an equal efficacy of DOACs was observed (Amin et al. 2019; Savarese et al. 2016;
Xiong et al. 2015).
DOACs and Age ≥75

A recent meta-analysis on approximately 430,000 subjects aged ≥75 years has
shown a similar efficacy of DOACs as compared to warfarin and a lower risk of
intracranial hemorrhage, while the risk of gastrointestinal bleeding was higher
(Russo et al. 2019c, d, 2020d; Mitchell et al. 2019). Hence, dosage modifica-
tions are performed according to each individual’s age (Russo et al. 2020e). In
particular, for dabigatran a reduction should be assessed on a case by case evalu-
ation for patients aged ≥75 years, while it is always recommended if age
>80 years, as well as for apixaban. Conversely, for rivaroxaban and edoxaban no
dose adjustments are needed. These changes are due to the presence of an altered
metabolism in this specific subpopulation, which could trigger an increased
coagulating effect.
DOACs and Hypertension
As known, hypertension represents both a stroke and bleeding risk factor when
using anticoagulants. Due to this reason, an appropriate blood pressure monitoring
is mandatory to minimize the risk of bleeding (Kirchhof et al. 2016a). DOACs are
recommended in hypertensive patients and have no particular metabolic interaction
with this status, hence dose adjustments are not scheduled (Zachary and Richter
2018). However, even in this case, kidney function should be periodically monitored.
OACs and Previous Stroke/TIA

D
Evidence of the use of DOACs in patients with a previous stroke/TIA is poor, mostly
due to the small sample size of the various studies in the literature. Nevertheless,
evidence from previous epidemiological studies reports that these subjects have a
high risk of experiencing a new event, although under anticoagulant treatment.
Findings from the diverse registration trials and meta-analyses, even in this sub-
population, did not show any difference in terms of both efficacy and safety as
compared to warfarin (Coleman et al. 2017; Larsen et al. 2014).
OAC Efficacy and Safety in Female Patients with AF

D
To date, there is no established sex-related difference in terms of both efficacy and
safety between DOACs and warfarin. In addition, no metabolic interaction with the
female gender has been observed (Zachary and Richter 2018; Fang et al. 2005; Poli
et al. 2009).
OACs and Kidney Disease

D
Kidney disease represents a risk factor for both bleeding and embolic events. In
patients with chronic kidney disease (CKD) and AF, even with a CHA2DS2VASc of
0, the stroke risk is fivefold higher than in the general population, while if
CHA2DS2VASc ≥2, it can exceed 7 per 100 person-years. Consistently with these
data, some meta-analyses have proven eGFR as an independent risk factor for stroke
and systemic embolism. The reasons for this state of hypercoagulability in CKD
have been not established yet. Stasis of the left atrium, impaired endothelial func-
tion, and increased platelet activity might explain this correlation (Zachary and
Richter 2018).
In addition, in the general population, CKD may increase AF risk through sev-
eral mechanisms (Alonso et al. 2011). Renal and pulmonary diseases were among
the factors more significantly associated with all-cause mortality. Patients with
stage 3 CKD have been shown a 25% increase in the risk of death associated with a
10-mL/min decrease in creatinine clearance (van Zyl et al. 2020). Considering this
evidence, some authors suggest using anticoagulant therapy in ESRD patients and
hope eGFR would become part of the embolic risk stratification scales.
As reported in the most recent guidelines and preclinical phase trials, use in
severe renal impairment is not recommended for apixaban and rivaroxaban if eGFR
<15 mL/min, while for dabigatran already if eGFR <30 mL/min. In fact, the reduced
excretory and metabolic capacity can increase the concentration of the drug, thus
enhancing its anticoagulant effect and bleeding risk.
However, all main comparative registration trials (ARISTOTLE, RE-LY,

ROCKET) demonstrate a higher efficacy of DOACs in preventing the risk of stroke,
as compared to warfarin, even in the case of renal failure and either mild or moder-
ate eGFR reduction. As well, also safety has been demonstrated as non-inferior to
that of warfarin. Edoxaban administration is recommended only for eGFR values
not exceeding 95 mL/min. In addition, usually in dialysis DOACs are not recom-
mended, though a single study has demonstrated both a good tolerance and safety
of rivaroxaban, apixaban and edoxaban in this sub-setting (Zachary and Richter
2018). However, further studies would be worthy to modify DOACs contraindica-
tions in both dialysis and ESRD patients.
DOACs and Cirrhosis
Only few papers have compared both efficacy and safety of DOACs with heparin
and warfarin in subjects with liver cirrhosis. These patients are usually considered
not eligible due to the potential drug related liver damage and enhanced anticoagu-
lant effect. However, more in depth, while rivaroxaban is contraindicated in the case
of CHILD B and C, CHILD PUGH B subjects do not disclose any alteration due to
the exposure to either apixaban or dabigatran. This might suggest their possible use
also in this sub-setting (Pokorney et al. 2016; Sakuma et al. 2019).
Although the small sample size, DOACs-treated populations have shown an
equal efficacy for stroke with an either lower or equal incidence of bleeding events
as compared to warfarin and heparin. Some authors confirmed DOACs efficacy,
though disclosing a higher rate of bleeding events, primarily gastrointestinal. Thus,
they suggest caution and an endoscopic exam of the gastric and esophagus tract
before undertaking DOACs therapy (Cosentino et al. 2020; Coleman et al. 2017;
Ruff et al. 2014; Lip et al. 2016; Jacobs et al. 2016).
As most of cirrhotic patients enrolled generally have either a CHILD PUGH A or B
(Elhosseiny et al. 2019; Intagliata et al. 2016; Hum et al. 2017; Caldeira et al. 2014b),
it would be useful to acquire new data to prove both efficacy and safety of DOACs in
this sub-setting, especially for what concerns CHILD PUGH C stage cirrhosis.
A brief mention deserves NAFLD and NASH patients. In such conditions,
DOACs have shown an efficacy at least comparable to that of warfarin and a higher
safety. Hence, they represent a good therapeutic option for the treatment of both AF
and VTE in patients with liver disease. In addition, up to date, management of
bleeding complications in these patients can benefit from specific antidotes cur-
rently available for all DOACs (Ballestri et al. 2020).
Anticoagulant Selection
DOACs Registration Trials

The introduction of DOACs in clinical practice has opened new scenarios both in
the prevention and treatment of thromboembolism (Wigle et al. 2019; López-López
et al. 2017). Overall, DOACs disclose a more favorable risk-to-benefit ratio than
that of vitamin K antagonists (VKAs) therapy (Czuprynska et al. 2017; Raschi et al.
2016; Almutairi et al. 2017). However, the balance between thrombotic and hemor-
rhagic risk still remains a fragile clinical junction in the choice of the best oral
anticoagulant (OAC) therapy. Evidence about both efficacy and safety of new
DOACs thus represents a crucial element.
DOACs share common characteristics. They are all direct inhibitors of factors
involved in the common path of coagulation, they have a relatively short half-life
(8–15 h) and a rapid absorption (1.5–4 h).
Primary efficacy objective of all registration trials was the prevalence of stroke,
either ischemic or hemorrhagic, plus systemic embolism; while the primary safety
outcome was instead the prevalence of both major and non-major, but clinically
relevant bleeding events (Schulman et al. 2005). Hemorrhagic strokes were included
in both the primary outcome and among the adverse safety events. Outcomes were
assessed after a median follow-up time of 2 years. As first, non-inferiority was
assessed and, subsequently, the potential superiority.
The first DOAC introduced in the marketing was dabigatran. The RE-LY
(“Randomized Evaluation of Long-term anticoagulation theraphY”) study is a pro-
spective, randomized, “open-label” phase III study, part of the “RE-VOLUTION”
clinical study program aimed at evaluating efficacy and safety of dabigatran com-
pared to standard therapy (warfarin) in the prevention of ischemic and hemorrhagic
stroke in AF patients (Connolly et al. 2009).
In this open-label study, 18,113 patients were enrolled, divided into two treat-
ment arms based on the dosage of the drug, respectively 110 mg × 2 (n = 6.015) and
150 mg × 2 (n = 6.076) and a control arm of patients taking warfarin (n = 6.022) at
the dose necessary to keep INR between 2 and 3. The study population had a mean
age of 71 years, for the 60% males. All patients had NVAF and at least one of the
following risk factors: history of stroke/TIA, either EF <40% or clinical signs of
heart failure in NYHA class II, III, or IV in the last 6 months prior to enrollment,
age >75 years (between 65 and 75 years in the presence of T2DM, hypertension, or
coronary artery disease). In other words, all enrolled subjects had a CHADS2VASC
score ≥1. Of note, about the 40% was also under aspirin therapy and only the 50%
was naïve for warfarin. The RE-LY study proved non-inferiority of dabigatran at a
dosage of 110 mg bid with respect to warfarin in the reduction of stroke and sys-
temic embolisms, expressed by a Relative Risk (RR) of 0.91 (95% CI 0.74–1.11).
Conversely, no advantages over warfarin emerged for secondary efficacy outcomes:
stroke, cardiovascular (CV) mortality, and all-cause death. Indeed, at the higher
dosage, even superiority of dabigatran as compared to warfarin was demonstrated
(RR 0.66; 95% CI 0.53–0.82), a lower rate of both stroke and CV deaths, while
myocardial infarctions (MI) were more frequent. As regards adverse events, preva-
lence of minor bleeding was significantly lower, while no difference emerged for
major bleeding events. Finally, gastrointestinal bleeding was more frequent as com-
pared to warfarin. In 2014, mortality outcomes were furtherly reassessed, though
not substantially modifying the previous findings (Connolly et al. 2014).
The ROCKET-AF study (“Rivaroxaban Once-daily oral direct factor Xa inhibi-
tion Compared with vitamin K antagonist for prevention of stroke and Embolism
Trial in Atrial Fibrillation”) focused on the assessment of rivaroxaban for the
prevention of ischemic strokes in AF patients (Patel et al. 2011). ROCKET-AF is a

double-blind study on about 14,000 patients comparing rivaroxaban at the dosage of
20 mg/day (dropped to 15 mg/die in the case of glomerular filtrate (GFR) between
30 and 9 mL/min) with a control arm taking warfarin at the dose necessary to main-
tain INR between 2 and 3. Unlike the RE-LY study, enrolled patients had to present
a CHADS2VASC ≥2 (i.e., a NVAF associated with previous stroke/TIA/systemic
embolism or at least 2 of the following risk factors: heart failure/EF <30%, hyper-
tension, age >75 years, T2DM). A severe kidney failure and high bleeding risk were
instead considered exclusion criteria.
The study revealed non-inferiority of rivaroxaban 20 mg as compared to warfarin
for the primary efficacy outcome, with a HR of 0.79 (95% CI 0.66–0.96), though
not reaching the superiority. Non-inferiority was also proven for the secondary out-
come of all-cause death. Similar findings also emerged in assessment of the primary
safety outcome (frequency of clinically relevant major and minor bleedings) (HR
1.03; 95% CI 0.96–1.11).
A similar study design was applied in the assessment of apixaban. The
ARISTOTLE study (“Apixaban for Reduction in Stroke and Other ThromboemboLic
Events in atrial fibrillation”) is a prospective double-blind randomized clinical trial
led on about 18,000 patients. Apixaban at the oral dose of 5 mg bid (dropped at
2.5 mg bid in patients aged >80 years, with a body weight <60 kg and creatinine
>1.5 mg/dL) was compared with warfarin (with a dosage appropriate to the INR
target value between 2 and 3) in AF patients with at least one other additional risk
factor for stroke or systemic embolism (Granger et al. 2011). Enrollment criteria
were instead similar to RE-LY, hence a CHADS2VASc ≥1. Patients with mechani-
cal valve prostheses, severe renal failure and under double antiplatelet therapy were
instead excluded. Remarkably, as compared to other molecules, apixaban proved
superior to warfarin in reducing the risk of stroke and systemic embolism (HR 0.79;
95% CI 0.66–0.95), as well as all-cause mortality in the study population. Further,
the analysis of safety outcome revealed a significant reduction also for what con-
cerned major bleedings.
Likewise, the ENGAGE AF-TIMI 48 study (Effective aNticoaGulation with fac-
tor XA next GEneration in Atrial Fibrillation) is a double-blind randomized clinical
trial on 21,105 patients, aimed at comparing edoxaban either at the dosage of 60 mg/
day (n = 7.035) or 30 mg/day (n = 7.034) with warfarin at the dosage needed to keep
INR between 2 and 3 (n = 7.036) (Giugliano et al. 2013). Of note, edoxaban dosages
were halved in the case of eGFR between 30 and 49 mL/min, body weight <60 kg
or concomitant use of verapamil. In addition, similarly to the ROCKET-AF study,
enrolled patients had to have a CHADS2VASc ≥2. The ENGAGE-AF TIMI 48
proved non-inferiority of edoxaban as compared to warfarin in reducing the risk of
stroke at both dosages, while superiority was not demonstrated for the primary out-
come. Edoxaban revealed instead superior to warfarin for what concerns safety, i.e.,
in reducing major bleeding events, while the annual incidence of gastrointestinal
hemorrhages was significantly lower than warfarin only at the dosage of 30 mg/day.
Later, in a pre-specified analysis of the ENGAGE AF-TIMI 48 study, the clinical
outcome was compared by stratifying patients into 3 groups based on age (<65,
65–74, and ≥75 years). The older group included almost 8500 patients (mainly
females, with a lower body weight and reduced GFR, hence requiring lower dosage
of edoxaban). No significant differences against warfarin emerged in terms of effi-
cacy and safety, despite the frequently reduced dosage, while major bleeding was
significantly lower (HR 0.83, 95% CI 0.70–0.99). This pre-specified analysis once
again confirms the close relationship between age and both thromboembolic and
hemorrhagic risk in AF patients, even after adjustment for any confounding factors
(Kato et al. 2016; O’Donoghue et al. 2015).
Apixaban is the only DOAC proven as superior over warfarin in terms of both
efficacy and safety for a single dosage, demonstrating a decrease of major bleeding
from 3% (warfarin) to 2% patients/year, as well as a reduction in all-cause mortality.
In addition, apixaban is the only drug, at full dose, not significantly affecting the
rate of major gastrointestinal bleeding. ARISTOTLE efficacy and safety outcomes
are generalizable to all CHADS2VASC and HAS-BLED categories. Furthermore,
the reduction of the dosage for apixaban is indicated in a small minority of patients
(Pelliccia et al. 2016).
Over recent years, efforts have been made to find which DOAC had the most
favorable risk-to-benefit profile according to the recommendations for which they
were registered. Due to the lack of comparative studies between the different
DOACs, but only vs. warfarin, diverse meta-analyses and systematic reviews
attempted to indirectly compare the four DOACs (Ruff et al. 2014; Adam et al.
2012; Dentali et al. 2012).
Real-World Evidence (RWE) studies may provide additional information to that
of registration trials and meta-analyses, proposing a picture closer to daily clinical
practice (Camm et al. 2018; Garrison et al. 2007; Russo et al. 2015, 2017b, 2018b,
2019e; Verdecchia et al. 2019). Prospective non-interventional studies (Larsen et al.
2013; Maura et al. 2015), such as the XANTUS phase IV study, instead provide
highly reliable efficacy and safety information, since they allow to acquire knowl-
edge in real time in different kind of populations. Particularly, the XANTUS study
showed that the enrollment of patients with characteristics similar to RE-LY and
ARISTOTLE studies was associated with a safety profile of rivaroxaban higher than
that observed in the registration study (Camm et al. 2016).
Oral Anticoagulant Selection
Only in few specific conditions warfarin is preferable to DOACs, as follows:
(a) In patients with either mechanical heart valves of any type or with severe mitral
stenosis from any cause (January et al. 2019).
(b) In patients with severe end-stage renal disease (ESRD) or in hemodialysis; even
though apixaban has also been approved in this condition in the United States
(January et al. 2019).
(c) In patients already on warfarin treatment, who are used to INR monitoring, and
whose INR is within the therapeutic time range (TTR) for an interval >65%
(January et al. 2019; McAlister et al. 2018).
(d) In patients with a scarce adherence in taking the appropriate pharmacological
dose of DOAC, thus requiring a closer monitoring of the compliance to the
OAC therapy (Garkina et al. 2016).
(e) In subjects taking antiepileptic drugs (particularly phenytoin, carbamazepine,
phenobarbital, and valproate) and in patients with human immunodeficiency
virus (HIV) infection on antiretroviral therapy based on protease inhibitors
(Wigle et al. 2019; Galgani et al. 2018).
A brief consideration deserves patients with COVID-19 receiving antiretroviral

therapy in whom, due to their important procoagulant status, anticoagulant strate-
gies alternative to DOACs should be considered, given the diverse pharmacological
interactions (Marietta et al. 2020).
Thus, we can conclude that most DOACs represent an advance in the therapeutic
safety as compared to warfarin, for the prevention of thromboembolism in AF patients.
OACs unlike VKAs do not exactly exhibit the same indications and availability
in all countries. In fact, local factors such as formal committees and costs of therapy
may affect their availability (Heidbuchel et al. 2015; Russo et al. 2018c).
Other studies report a more favorable outcome of dabigatran as compared to
warfarin in AF ablation (RE-CIRCUIT Trial) (Calkins et al. 2017). As well, over the
years, both dabigatran and rivaroxaban have been associated with lower risks of
adverse renal outcomes than warfarin in AF patients (Yao et al. 2017). Moreover, for
what concerns the elderly AF patients taking OAC therapy, dabigatran has been
associated with a lower risk of osteoporotic fracture as compared to warfarin (Lau
et al. 2017).
In addition, further data on pharmacologic interactions with DOACs have also
been emerging, even though their interpretation must carefully evaluate the trial
design, including factors such as the lack of control groups, incomplete laboratory
and history data, as well as of data for some drugs (in particular edoxaban) and the
variability of DOACs dosage (some doses approved in the United States differ from
those in Europe). Hence, prospective RCT focused on DOACs comparison would
be worthy to better evaluate the comparative bleeding risk and efficacy (January
et al. 2019).
New Scenarios in the Risk Stratification Panorama
Although CHA2DS2-VASc is currently the most used score, as well as the most
recommended by all international guidelines, several studies have disclosed the
presence of other new risk factors, both clinical and laboratory, which could be
independently associated with the occurrence of stroke. These might be comple-
mentary to the CHA2DS2VASc risk scale and increase its discriminatory power.
Besides this, new risk scores have been proposed in the last few years, which could
either replace or support CHA2DS2VASc.
New Clinical Risk Factors
BMI
From an analysis of the Japanese registers on about 12,000 NVAF patients assessing
the predictive power of the single risk factors for stroke, a statistically significant
positive association both with a low body weight (≤50 kg) and low BMI (<18.5 kg/
m2) emerged (HR 1.55; 95% CI: 1.05–2.29; p = 0.030). This finding was consistent
with two previous studies. However, the same authors observe that, rather than a
risk factor, BMI could represent a risk modifier. In fact, the study population also
included patients with a BMI <18.5 kg/m2 not reaching the outcome. Hence, due to
the inconsistency with other studies and the small sample size, up to now BMI has
been yet considered neither a risk factor nor a modifier. If these findings were con-
firmed by larger studies, BMI could be included in the most part of risk assessment
scales (Yao et al. 2017; Lau et al. 2017; Okumura et al. 2020; Lee et al. 2019; Zhu
et al. 2016).
Echocardiography
According to 2016 ESC guidelines for AF, the role of transthoracic echocardiogra-
phy is currently limited to an assessment of overall cardiac function, hence useful to
exclude the presence of thrombi in the atrium in order to practice AF cardioversion
and diagnose structural pathologies more likely associated. However, also thanks to
the presence of new software and echocardiographic parameters (e.g., strain), some
authors suggest that echocardiography might play an important role in identifying
new risk factors for stroke in AF. In a recent study, Galderisi and colleagues argued
that the function of left atrium assessed by means of strain functionality and its
enlargement could represent a stroke risk factor in AF patients (Tufano and Galderisi
2020). Consistent with these findings, another study on about 3000 patients, with a
3-year follow-up, showed that some factors, including the left atrial diameter, were
independently associated with either stroke or systemic embolism. Among these, a
high Relative Wall Thickness (RWT higher than the median) was significantly asso-
ciated with stroke/SE. Thus, the authors suggested that RWT could be associated
with CHA2DS2VASc to improve its discriminatory power (Tezuka et al. 2020).
Recently, Olsen et al. in a study led on patients with paroxysmal AF, the SURPRISE
echo sub-study, observed that the left atrial reservoir strain was altered in patients
suffering from cryptogenic stroke (Olsen et al. 2020).
Despite the evidence, these findings are still divergent and there are still few
studies in the literature to establish with a good certainty whether and which of the
echocardiographic parameters may be associated with CHA2DS2VASc. Therefore,
even in the case of echocardiographic parameters, further studies are needed to
ascertain their validity as risk factors.
Biomarkers
Several biomarkers have been tested in AF patients to find a correlation between

their concentration level and the stroke event. Among them, diverse studies showed
an association between high BNP/NT-proBNP levels and an increased risk of
thromboembolic events (Tezuka et al. 2020; Hayashi et al. 2018; Roldan et al.
2014). Moreover, the sub-analysis of two of the main registration trials of DOACs
(ARISTOTLE and RE-LY) confirmed this finding (Hijazi et al. 2012, 2013). In
addition, in a study aimed at evaluating the association of some biomarkers with
stroke in AF patients, only high NT-proBNP levels (≥300 pg/mL) have been
reported as an independent predictor, indeed positively associated with the inci-
dence of stroke (Shin et al. 2019).
Besides proBNP, T-troponin concentrations have also been assessed as potential
biomarkers suggestive of stroke risk. Consistently with RE-LY sub-analyses,
another study confirmed this significant association (aHR 2.35; 95% CI: 1.26–4.36;
p = 0.007) (Vafaie et al. 2019).
Another biomarker proposed as useful to improve the predictive value of
CHA2DS2VASc is endothelin. In a population of about 200 patients, this emerged as
significantly associated with high CHADS2/CHA2DS2VASc scores and an increase
in the volume of the left atrium (Zheng et al. 2019).
In the most recent years also other biomarkers, such as hemostatic (d-dimer, von
Willebrand factor (vWF), soluble E-selectin, and P-selectin) and inflammatory
(interleukin-6 (IL-6) and C-reactive protein (CRP)) have been assessed. However,
findings were divergent. Moreover, there is still little evidence in favor of their use
and sample sizes are too small to include one of these in the current stroke risk scales.
Other authors also observe how the concentration of these markers is extremely vari-
able, as well as too high within the same subject to be able to standardize a range
usable in risk stratification. Even the laboratory costs of these exams are too high to
be subjected to a routine evaluation. These are some of the reasons why, up to now,
the use of such biomarkers may only be justified from scientific research purposes,
whilst their potential use at a routine clinical level still seems far away.
New Scores
New scores have been proposed, not to replace, though rather to accompany
CHA2DS2VASc. Among these, the Intermountain Mortality Risk Scores (IMRSs),
which is based on a score calculated from both blood count and biochemical param-
eters. In the past, it has been used to stratify the risk of mortality and cardiovascular
pathologies (myocardial infarction, heart failure, coronary artery disease, etc.). A
recent study assessed the power of the IMRSs in the stratification of stroke risk in
AF patients, both independently of CHA2DS2VASc, and complementarily, to
increase its discriminating power (c-statistic). Individually, the two scores showed a
similar predictive power, while overall IMRSs can further differentiate high and low
risk patients into the groups identified by the CHA2DS2VASc. Thus, such a score
could be useful to identify patients at high risk of stroke among those borderlines at
the CHA2DS2VASc (Horne et al. 2010; Graves et al. 2018), hence improving and
enhancing its performance.
Some authors also observe that a liver dysfunction due to the presence of liver
diseases such as HCV related hepatopathy, NAFLD, and cirrhosis is predisposing to
the development of various cardiac diseases, including FA. In fact, it seems that an
autonomic cardiac dysfunction might be related to the inflammatory status typical
of liver disease. Some authors suggest that liver injury indices may be functional for
stratifying the risk of both cardiovascular diseases and embolic events. A study on
about 3000 AF patients with liver disease has shown that FIB4, a score suggestive
of the degree of fibrosis and liver damage, if combined with the CHA2DS2VASc,
could increase its predictive power for cardiovascular events. As a result, the associ-
ated FIB4/CHA2DS2VASc improved its c-statistic, bringing it from 0.61 to 0.64
(respectively alone and associated with the FIB4 index) (Saito et al. 2020; Sato et al.
2017; Käräjämäki et al. 2015).
Up to now, the list of risk factors and scores valid for stroke risk stratification
cannot be improved. Available evidence is poor, and findings are still divergent.
Thus, hopefully, future larger studies will enhance the stratification capacity of the
CHA2DS2VASc and, perhaps, novel risk factors closely related to the embolic event
will be discovered.
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Use of DOAC in Patients with Kidney
Disease 7
Riccardo Vio, Riccardo Proietti, and Lorenzo Calo’
Introduction
Atrial fibrillation and chronic kidney disease are on the rise worldwide. Both disorders
are strictly related to aging population and may coexist in the same patient. Chronic
kidney disease affects 15% of adults, who in turn will suffer from atrial fibrillation in
up to 30% of cases depending on the severity of the renal impairment (Tonelli et al.
2012; Wizemann et al. 2012). The factors predisposing to atrial fibrillation in chronic
kidney disease patients include hypertension, heart failure, and autonomic imbalance,
leading to structural and electrical remodeling of the atria (Kumar et al. 2019).
Moreover, thromboembolic complications typical of atrial fibrillation are ampli-
fied in patients with renal dysfunction, who may have a hypercoagulable state due
to increased platelet activity, activation of the renin-angiotensin-aldosterone sys-
tem, altered vessel wall contractility and vascular endothelium changes, resulting in
a ≈50% increase of stroke or systemic thromboembolism (Olesen et al. 2012;
Providência et al. 2014; Bansal et al. 2013; Proietti et al. 2018).
Oral anticoagulation therapy, nowadays preferably with direct oral anticoagulants
(DOACs), represents the cornerstone for stroke thromboprophylaxis in high-risk
patients with atrial fibrillation according to CHA2DS2VASc score (Hindricks et al.
2021). The impaired renal function which defines chronic kidney disease directly
R. Vio (*)
Department of Cardiac, Thoracic, Vascular and Public Health Sciences, University of Padova,
Padova, Italy
R. Proietti
Cardiac Rehabilitation Unit Ospedale, Sacra Famiglia Fatebenefratelli, Erba, Italy
L. Calo’
Department of Medicine, Nephrology, Dialysis and Transplantation Unit, University of
Padova, Padova, Italy
122 R. Vio et al.
impacts on the anticoagulation regimen, since all four available DOACs are elimi-
nated at least partially by the kidneys. Dabigatran has the highest renal elimination
(80%), whereas edoxaban, rivaroxaban, and apixaban have lower values (50%, 35%,
and 27%, respectively) (Steffel et al. 2018). Cockcroft–Gault formula is commonly
used to calculate, on the basis of serum creatinine levels, the creatinine clearance
(CrCl, expressed in mL/min), that is an estimation of the glomerular filtration rate
(GFR). Other equations express the GFR in mL/min/1.73 m2, such as CKD-EPI,
which is used to classify the severity of chronic kidney disease (Inker et al. 2014). For
the sake of dosing the DOACs on the basis of kidney function (see below), CrCl cal-
culated with Cockcroft–Gault formula should be used as a reference, since it was
adopted by all the randomized controlled trials that led to their commercialization
(Connolly et al. 2009; Patel et al. 2011; Granger et al. 2011; Giugliano et al. 2013).
A correct prescription is fundamental because adverse events due to suprathera-
peutic levels include major bleeding such as hemorrhagic stroke. The alterations of
hemostatic system in chronic kidney disease include not only the possible afore-
mentioned pro-thrombotic state, but also hemorrhagic diathesis led by platelet dys-
function, compromised platelet aggregation, and intercurrent anemia (Hedges et al.
2007). Regular calculation of CrCl during follow-up is required and European
experts recommend monitoring renal function at least yearly, or more often if base-
line CrCl is reduced (i.e., <60 mL/min). The proposed formula for calculating the
rechecking interval in months of the renal function during DOAC therapy is CrCl/10
(e.g., for CrCl 40 mL/min the rechecking interval is 4 months) (Steffel et al. 2018).
Atrial fibrillation favors the progression of chronic kidney disease: in a large study
of patients with moderate to severe loss of renal function, incident atrial fibrillation
was independently associated with a 67% higher rate of progression to the end-stage
phase (Bansal et al. 2013; Winkelmayer 2013). Periodic reassessment of renal func-
tion helps to timely identify further CrCl decline, avoiding DOACs accumulation at
supratherapeutic plasma levels that may cause major bleedings.
In this chapter, we review the current evidence regarding efficacy and safety
profiles of DOACs according to different clinical setting (non-end-stage and end-
stage kidney disease). International recommendations (European and American) are
presented throughout the text and reassumed in Fig. 7.1.
Non-End-Stage Kidney Disease
In the past decades, warfarin was the preferred anticoagulant used for stroke preven-
tion in patients with atrial fibrillation. The limitations related to warfarin therapy
(i.e., slow onset of action, variable pharmacologic effects, several food and drug
interactions) were overcome by the advent of DOACs, that in turn demonstrated a
similar efficacy and better safety profile. All DOACs show a predictable pharmaco-
kinetic and do not require regular monitoring of the coagulation to optimize their
clinical management. Warfarin is metabolized by the liver and so it is routinely used
even in patients with end-stage kidney disease. Conversely, DOACs are eliminated
by the kidneys to some extent and their use in patients with impaired renal function
raises some concerns: the RE-LY, ROCKET AF, and ENGAGE AF-TIMI 48 trials,
7 Use of DOAC in Patients with Kidney Disease 123
Fig. 7.1 Recommendations for DOACs dosing on the basis of renal function according to
European and American guidelines. European and American recommendations are based on the
latest 2018 EHRA and 2019 AHA/ACC/HRS documents (Steffel et al. 2018; January et al. 2019).
BID bis in die, OD omne in die, EU Europe, US United States
that respectively tested efficacy and safety of dabigatran, rivaroxaban, and edoxa-
ban, excluded patients with severe chronic kidney disease (i.e., CrCl <30 mL/min)
(Connolly et al. 2009; Patel et al. 2011; Giugliano et al. 2013). The inclusion criteria
in the ARISTOTELE trial were slightly less stringent since apixaban has the lowest
renal elimination and patients with CrCl >25 mL/min were enrolled (Granger et al.
2011). Numerous post-hoc analysis of these studies investigated whether or not
DOACs efficacy and safety were confirmed in patients with mild to moderate
chronic kidney disease compared to those with normal renal function.
In the study by Hijazi et al., the efficacy and safety of dabigatran compared to
warfarin were analyzed in relation to baseline renal function (Hijazi et al. 2014).
After estimating the GFR with CKD-EPI formula instead of Cockcroft–Gault equa-
tion used in the trial, he found significant interactions between treatment and renal
function: both dabigatran dosages (150 and 110 mg bis in die - BID) displayed
lower rates of major bleeding in patients with GFR >80 mL/min, while their effi-
cacy was consistent with the overall trial regardless of renal function (Hijazi et al.
2014). In patients with severe renal dysfunction (GFR 15–29 mL/min),
124 R. Vio et al.
pharmacological projections suggested a reduced dose of dabigatran 75 mg BID:

US Food and Drug Administration allows the administration of such regimen in this
case, but dabigatran remain contraindicated in Europe when GFR is <30 mL/min
because of safety concerns (Steffel et al. 2018; Lehr et al. 2012; January et al. 2019).
For rivaroxaban, other pharmacokinetics analysis demonstrated that maximal
serum concentrations were 25–30% higher in patients with moderate chronic kid-
ney disease (CrCl 30–49 mL/min) (Kubitza et al. 2010). This evidence triggered the
reduction of rivaroxaban dosage from 20 mg omne in die (OD) to 15 mg OD in
moderate renal insufficiency in the ROCKET AF trial, that involved a sizeable pro-
portion of the study population (one in five study patients) (Patel et al. 2011). The
overall study demonstrated a benefit in stroke reduction and systemic embolism
comparable to warfarin, with fewer fatal hemorrhages. A post-hoc analysis demon-
strated that rivaroxaban 15 mg in moderate renal impairment yielded the same
results of the standard 20 mg in preserved kidney function, excluding a heterogene-
ity in treatment effect across dosing groups (Fox et al. 2011). The administration of
rivaroxaban 15 mg OD is permitted both in Europe and in the US even in case of
severe renal impairment (GFR 15–29 mL/min), despite this condition represented
an exclusion criterion for the trial (Steffel et al. 2018; January et al. 2019).
Another DOAC approved in case of GFR >15 mL/min is edoxaban (Steffel et al.
2018; January et al. 2019). The clearance of edoxaban depends for half percent on
renal elimination, and total drug exposure increases by 32 to 72% in patients with
mild to severe renal dysfunction (Parasrampuria and Truitt 2016). Therefore, in the
ENGAGE AF-TIMI 48 trial the edoxaban dose was reduced from 60 to 30 mg OD
in patients with moderate renal insufficiency (CrCl 30–49 mL/min); patients with
severe reduction of renal function (CrCl<30 mL/min) were excluded (Giugliano
et al. 2013). Other criteria for dose reduction were weight ≤60 kg or administration
of a strong P-glycoprotein inhibitor. Compared to warfarin, edoxaban had a compa-
rable efficacy for stroke prevention, carrying a reduced risk for bleeding and cardio-
vascular death (Giugliano et al. 2013). Bleeding rates were lower at all levels of
CrCl, as later assessed by Bohula et al. (2016). A further post-hoc analysis added
useful evidence that in patients who developed severe chronic impairment during
follow-up (CrCl <30 mL/min) stroke and major bleeding rates were similar between
those treated with edoxaban compared to those on warfarin (Chan et al. 2016). On
the other hand, edoxaban 60 mg may be less effective for stroke prevention in
patients with “supranormal” renal function (CrCl >95 mL/min) and in such cases it
is contraindicated in the US, whereas European recommendations indicate a cau-
tionary use (Steffel et al. 2018; Giugliano et al. 2013; January et al. 2019; Bohula
et al. 2016).
Apixaban has the minimal renal excretion compared to the other DOACs, only
27% (Steffel et al. 2018). It is commercialized in two dosages, 5 mg or 2.5 mg
BID. Criteria for dose reduction include not only creatinine values (≥1.5 mg/dL),
but also weight ≤60 kg and age ≥80 years: when at least two out of three criteria are
met 2.5 mg BID should be prescribed (Steffel et al. 2018; January et al. 2019).
Hohnloser et al. analyzed data of ARISTOTELE trial and found that apixaban com-
pared to warfarin reduced the rate of stroke, death, and major bleeding irrespective
of renal function (Hohnloser et al. 2012). Of note, the patients who benefited the
most from reduction of serious bleeding events were those having at least a moder-
ate renal impairment (CrCl <50 mL/min). Corroborative evidence was provided by
a recent post-hoc analysis focusing on the enrolled patients with the lowest CrCl
(25–30 mL/min): in such patients with severe renal impairment apixaban treatment
was associated with a greater reduction in bleedings compared to those having a
CrCl >30 mL/min (Stanifer et al. 2020). In severe kidney disease (CrCl 15–30 mL/
min), apixaban is approved in the US with the same aforementioned criteria for
moderate renal impairment, whether in Europe is permitted at the lowest dosage
(2.5 mg BID) irrespective of age and weight (Steffel et al. 2018; January et al. 2019).
End-Stage Kidney Disease
End-stage kidney disease is classified under stage 5 of chronic kidney disease,

together with persons with a GFR <15 mL/min/1.73 m2 (Inker et al. 2014). It is
defined as permanent loss of kidney function that invariably leads to death unless
dialysis or transplantation is pursued.
Herein are described evidence and current practice regarding oral anticoagula-
tion in these two different clinical scenarios.
Patients on Dialysis
Patients with chronic kidney disease on dialysis have almost a double risk of stroke
compared to non-end-stage counterparts (USRDS 2006). In addition, all nephro-
pathic patients show some degree of platelet dysfunction and impaired platelet
aggregation, that are even more pronounced in end-stage renal disease; the so-called
“uremic platelet dysfunction” further augments the bleeding risk (Seliger et al.
2003; Suzuki et al. 2007).
In this clinical scenario, the side effects of anticoagulation therapy might offset
the desired benefit. Available evidence showed that warfarin increased the rate of
bleeding events without any impact on stroke prevention or death (Harel et al.
2017). A recent meta-analysis gathered all the literature in the field and confirmed
warfarin inefficacy for ischemic stroke prevention among patients on dialysis; hem-
orrhagic strokes were significantly higher in those receiving treatment, but mortality
was comparable between groups (Randhawa et al. 2020). Factors that can explain
these observations include the routine administration of heparin during dialysis and
the interference of uremic state with the metabolisms of warfarin, making difficult
to maintain the international normalized ratio in therapeutic range (Chan et al. 2009;
Marinigh et al. 2011; Leblond et al. 2001; Yang et al. 2017). Apart from growing
concern in the trade-off between harm and benefit, warfarin seems to accelerate the
worsening of renal function either by favoring parenchymal microbleeds or by pro-
moting vascular calcifications (Brodsky et al. 2011; Tantisattamo et al. 2015). All
the above-mentioned considerations raised the urgent need for new therapeutic
126 R. Vio et al.
approaches, looking at DOACs as appealing alternatives to warfarin in this medi-

cally complex population.
European recommendations contraindicate the use of all DOACs in patients with
CrCl <15 mL/min or on dialysis, whether US Food and Drug Administration allows
only apixaban in these cases (Steffel et al. 2018; January et al. 2019). Following this
labeling the use of apixaban has grown in American patients with atrial fibrillation
on dialysis, accounting for approximately one out of four new anticoagulants pre-
scribed in this population (Siontis et al. 2018). In a recent study, Siontis and col-
leagues retrospectively compared the rate of stroke/systemic embolism, major
bleedings, and death between patients on dialysis treated with apixaban versus war-
farin (Siontis et al. 2018). The researchers concluded that both standard and reduced
dose of apixaban (5 mg and 2.5 mg BID, respectively) were associated with a lower
risk of major bleedings, but only the standard dose significantly reduced thrombo-
embolic events and death compared to warfarin. However, they described also high
rates of intracerebral bleedings and drug discontinuations, casting doubts on the real
progress in the management of these complex patients.
Despite being contraindicated, Chan et al. found that prescription of dabigatran
and rivaroxaban was occurring among patients on dialysis in the US (Chan et al.
2015). The authors reported that either drugs were associated with a higher rate of
hospitalization for bleedings and hemorrhagic death, supporting the current labeling
of dabigatran and rivaroxaban. More recent evidence showed that a reduced dose of
rivaroxaban (10 mg OD) may lower severe bleeding complications compared to
warfarin in hemodialysis patients (de Vriese et al. 2020).
New randomized clinical trials are under way and will shed some lights on the
outcome of DOACs for stroke prevention in patients with atrial fibrillation on hemo-
dialysis. The RENAL-AF trial (Renal Hemodialysis Patients Allocated Apixaban
Versus Warfarin in Atrial Fibrillation trial; ClinicalTrials.gov identifier
NCT02942407) was prematurely stopped for failure to enroll a sufficient number of
patients (Pokorney 2019). Other ongoing studies are similarly attempting to com-
pare the efficacy and safety of apixaban versus vitamin-K antagonists for stroke
prevention in patients with atrial fibrillation and end-stage kidney disease. These
studies include the SAFE-HD trial (Strategies for the Management of Atrial
Fibrillation in Patients Receiving Hemodialysis; ClinicalTrials.gov identifier
NCT03987711) and the AXADIA trial (Compare Apixaban and Vitamin-K
Antagonists in Patients with Atrial Fibrillation and End-Stage Kidney Disease;
ClinicalTrials.gov identifier NCT02933697). The design of the SAFE-HD trial pro-
vided for a control arm of patients without anticoagulation, since previous studies
pointed out the ineffectiveness and potential harm of oral anticoagulation with war-
farin in patients receiving dialysis (Randhawa et al. 2020).
Kidney Transplant Recipients
Atrial fibrillation occurs in over 7% of kidney transplant recipients in the first

3 years after transplantation and is higher in the peri-transplant period (Malyszko
et al. 2018). New onset of atrial fibrillation in kidney transplant recipients confers a
worse prognosis and is associated with a reduced graft and patient survival
(Malyszko et al. 2018). In high-risk patients according to CHA2DS2VASc score,
the start of oral anticoagulation therapy is indicated (Hindricks et al. 2021). Since
recent years, vitamin-K antagonists have been the only oral anticoagulant agents
available. An analysis performed on a US registry of patients with end-stage kidney
disease failed to show a significant reduction of a composite endpoint of mortality
and stroke in patients who underwent renal transplant and were treated with warfa-
rin for new onset AF (Lenihan et al. 2015). Accordingly, the authors reported that in
the overall population with AF and renal transplant warfarin was underprescribed
possibly due to lack of evidence for a clinical benefit and a perceived increased risk
of bleeding in hemodialyzed patients (Lenihan et al. 2015).
Direct oral anticoagulants provide a potentially safer option in patients who have
had renal transplant. However, they have at least a partial renal excretion and so
exposure can increase in patients with chronic kidney disease, including those who
received kidney transplant. Ischemia-induced injury to the kidney both during the
procurement period and transplant surgery can lead to temporary reduced graft
function in the immediate post-transplant period, with delayed or slow graft func-
tion that require hemodialysis in 25% of deceased-donor recipient and 3–5% of
living donor recipient (Salerno et al. 2017). At the moment, no clinical trial data is
available for DOACs use in patients post renal transplant, a population with a unique
challenge: maintenance of an effective immunosuppression.
Calcineurin inhibitors, tacrolimus and ciclosporin, are among the most com-
monly used immunosuppressants; the use of these drugs is not straightforward.
Both have a narrow therapeutic index and blood concentrations vary considerably
between individuals. A narrow therapeutic index indicates that the blood concentra-
tion range between safe and subtherapeutic values is small. In transplant recipients,
both supratherapeutic and subtherapeutic drug concentrations can have devastating
results. Subtherapeutic levels increase the risk of transplant rejection and suprath-
erapeutic levels (over-immunosuppression) can lead to infection and/or drug-
specific side effects (Lenihan et al. 2015). Vanhove et al. assessed the effect of
DOACs on the disposition of calcineurin inhibitors in patients underwent renal
transplant (Vanhove et al. 2017). The study included 39 kidney recipients (29 on
rivaroxaban and 10 on apixaban). The authors reported an increase (<20%) in calci-
neurin inhibitors through concentration, which was not clinically relevant. A recent
statement of European Heart Association on the basis of known pathways of calci-
neurin inhibitors metabolism, involving CYP3A and efflux pump P-glycoprotein
suggests that apixaban may be used in association with tacrolimus and cyclosporin
with close monitoring and dose adjustment (Steffel et al. 2018). More recently, a
study of drug interaction between apixaban and calcineurin inhibitors has been car-
ried out in a small cohort of healthy volunteers which has shown that the fluctuation
of drug levels is within those observed during the development program of the drug
(Bashir et al. 2018). Therefore, no dose adjustment of the drug was needed during
co-administration of apixaban with calcineurin inhibitors in healthy volunteers
(Bashir et al. 2018).
128 R. Vio et al.
Conclusions
In summary, the use of DOACs in patients with non-end stage kidney disease and
atrial fibrillation is effective for ischemic stroke prevention similarly to warfarin,
showing an overall better safety profile. European and American recommendations
slightly differ with regard to DOACs labeling, particularly in case of severe renal
impairment.
The observational data regarding the use of warfarin in atrial fibrillation patients
on dialysis warrant caution. Available evidence shows that these patients have no
benefit from warfarin treatment in the prevention of ischemic stroke or in the overall
mortality. Conversely, they are exposed to a significant higher risk of hemorrhagic
stroke. Some retrospective data demonstrated promising results with apixaban, but
years will be needed for the conclusion of the ongoing randomized clinical trials. In
the meantime, the management of stroke risk among patients with atrial fibrillation
on dialysis will remain challenging. Patients who underwent kidney transplant may
benefit as well from the use of DOACs but possible interactions with lifesaving
immunosuppressants raise some concerns.
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Anticoagulation in Elderly Patients
with Atrial Fibrillation Authors 8
Andreina Carbone, Roberta Bottino, Antonello D’Andrea,
Introduction
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, and age is
one of the strongest predictors for ischemic stroke in AF (Krishnamurthi et al. 2013;
Go et al. 2001; Lin et al. 1996; Miyasaka et al. 2006; AlTurki et al. 2019). Elderly
patients are at higher risk of both ischemic and bleeding events compared to younger
patients, and age is an overlapping factor in both the CHA2DS2-VASc score for stroke
(Lip et al. 2010) and the HASBLED score for bleeding risk assessment (Pisters et al.
2010). Over the age of 80 years, the annual risk of stroke increases to up to 23.5%
(Chatap et al. 2002; Fuster et al. 2001). Vitamin K antagonists (VKAs) reduce the risk
of ischemic stroke in patients with AF, especially in the elderly, but increase the bleed-
ing risk and require frequent international normalized ratio monitoring (Perera et al.
2009; Zimetbaum et al. 2010). Furthermore, VKAs have multiple drug and food inter-
actions (Kirchhof et al. 2016). For these reasons, despite the higher risk of ischemic
events, anticoagulants are underused in elderly patients (Hylek et al. 2006; Tulner et al.
2010). Elderly may present with multiple comorbidities including dementia, a ten-
dency to falls, chronic kidney disease, anemia, hypertension, diabetes, and cognitive
dysfunction (Tulner et al. 2010). Such conditions may limit quality of life, and hepatic
and kidney dysfunction, with multiple simultaneous medications, makes drug interac-
tions and adverse drug reactions more likely (Tulner et al. 2010). Integrated AF man-
agement and careful adaptation of drug dosing seem reasonable to reduce the
complications of AF therapy in such patients (Andreotti et al. 2015). Direct oral
A. Carbone · R. Bottino · P. Golino · G. Nigro · V. Russo (*)

Division of Cardiology, University of Campania “Luigi Vanvitelli,” Monaldi Hospital,
Naples, Italy
A. D’Andrea
Department of Cardiology, University of Campania “Luigi Vanvitelli”, Naples, Italy
Department of Cardiology, Umberto I hospital, Nocera Inferiore, Salerno, Italy

132 A. Carbone et al.
anticoagulants (DOACs) have emerged as alternatives to VKAs and are gradually

increasing their popularity because of their fewer interactions and ease of use. Their
effectiveness and safety have been well-established in the general population, but the
benefit in the elderly is still unclear. Data about the safety and the effectiveness in
patients >75 years old are available, but the management of the DOACs therapy in
octogenarians and in frail patients is more challenging. This chapter will focus in detail
on patients ≥75 years of age treated for stroke prevention in AF.
Indications for Stroke Prevention in Elderly
The risk scores and the oral anticoagulant (OAC) indications for stroke prevention in
elderly with AF are the same as in younger patients. Both the European Society of
Cardiology (ESC) and National Institute for Health and Care Excellence (NICE)
guidelines (UK) recommend assessment of stroke risk using the CHA2DS2-VASc
score considering OAC prescription for scores of ≥1 in males and ≥ 2 in females
(Hindricks et al. 2020; National Institute for Health and Care Excellence 2014). The
American College of Cardiology/American Heart Association/Heart Rhythm Society
(ACC/AHA/HRS) guidelines differ slightly with OAC being recommended for higher
CHA2DS2-VASc scores of ≥2 and ≥ 3 in men and women, respectively (January
et al. 2014). For scores of 1, management options include withholding OAC, or treat-
ment either with an OAC or aspirin (January et al. 2014). Therefore, the age ≥ 75 years
gives 2 score points and female sex 1 score point, and all patients ≥75 years of age,
with AF, are recommended to receive OAC with a class Ia recommendation irrespec-
tive of the presence or absence of additional risk factors (Hindricks et al. 2020).
ntithrombotic Strategies in Elderly with AF: Anticoagulant Vs.

A
Antiplatelet Therapy
Antiplatelet monotherapy is not recommended for stroke prevention in AF patients,

regardless of stroke risk (Hindricks et al. 2020). In the Birmingham Atrial Fibrillation
Treatment of the Aged Study, patients ≥75 years of age on acetylsalicylic acid did
not show a lower rate of major bleedings compared with VKA, but VKA was supe-
rior to acetylsalicylic acid regarding stroke prevention (Mant et al. 2007). In this
study, even very elderly patients had a 50% risk reduction for embolic/ischemic
events on VKA with a similar bleeding risk as on acetylsalicylic acid, with well-
controlled time in therapeutic range of 67% in the VKAs group (Mant et al. 2007).
In the AVERROES trial comparing acetylsalicylic acid and apixaban, bleeding rates
in elderly AF patients were similarly increased in the two groups, and for patients
≥85 years, annual rates for stroke or systemic embolism increased to 6.5%, for
major bleedings to 4.7%, and for intracranial hemorrhage to 2.9% on acetylsalicylic
acid, but anticoagulation with apixaban showed significantly lower rates of stroke or
systemic embolism with safety comparable to acetylsalicylic acid (Ng et al. 2016).
Double antiplatelet therapy (DAPT) , for stroke prevention in AF, was studied in
two RCTs compared with VKAs. In the ACTIVE W (Atrial Fibrillation Clopidogrel
8 Anticoagulation in Elderly Patients with Atrial Fibrillation Authors 133
Trial with Irbesartan for Prevention of Vascular Events) trial (Investigators AWGotA
et al. 2006), DAPT with aspirin and clopidogrel was less effective than warfarin for
prevention of stroke, systemic embolism, myocardial infarction, and vascular death
(the annual risk of events was 5.6% vs. 3.9%, =0.0003; mean age 70.2 ± 9.4 years
old), with a similar rate of major bleeding (Investigators AWGotA et al. 2006). Also,
in the ACTIVE-A trial (Investigators et al. 2009), patients unsuitable for anticoagu-
lation had a lower rate of thromboembolic complications when clopidogrel was
added to aspirin compared with aspirin alone, but with a significant increase in
major bleeding (Investigators et al. 2009).
In conclusion, antiplatelet monotherapy was ineffective for stroke prevention and
was associated with a higher risk of ischemic stroke and major hemorrhages in
elderly patients with AF (Mant et al. 2007; Sjalander et al. 2014; Lip 2011), whereas
DAPT is associated with a bleeding risk similar to OAC therapy (Investigators
AWGotA et al. 2006; Investigators et al. 2009). In consequence, antiplatelet therapy
should not be used for stroke prevention in AF patients (Hindricks et al. 2020).
DOACs in Elderly Patients: Current Evidences
DOACs have been shown to be more effective and safe than VKAs for long-term
stroke prevention in patients with non-valvular AF, either in trial (Granger et al.
2011; Patel et al. 2011; Connolly et al. 2011; Giugliano et al. 2013) or in real-life
setting (Bando et al. 2018; Deitelzweig et al. 2017; Yao et al. 2016; Shinohara et al.
2018; Kwon et al. 2016; Russo et al. 2015, 2017a, b). In a meta-analysis of random-
ized controlled trials comparing DOACs (rivaroxaban, apixaban, and dabigatran;
insufficient data was available for edoxaban) with VKAs therapy in patients aged
≥75 years, DOACs were associated with equal or greater efficacy than conventional
therapy, without causing excessive bleeding (Sardar et al. 2014). Four different ran-
domized controlled trials have evaluated DOACs compared with VKA for stroke
prevention in AF with different inclusion and exclusion criteria, and consequently,
the DOACs cannot be compared directly (Table 8.1).
Dabigatran
The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial

compared the direct thrombin-inhibitor dabigatran to warfarin (Connolly et al.
2009). The study included 3027 patients ≥80 years (16.7%) at baseline (Connolly
et al. 2009). In patients ≥75 years of age, the combined risk of stroke or systemic
embolism and major bleeding was similar between VKA and both dosages of dabi-
gatran (Eikelboom et al. 2011), with intracranial bleeding risk lower but extracra-
nial bleeding risk similar or higher with both doses of dabigatran compared with
warfarin (Eikelboom et al. 2011).
A post hoc simulation of dabigatran usage based on RE-LY trial dataset indicates
that “EU label simulated dabigatran treatment” (dabigatran 110 mg bid in one of the
following situations: age ≥80 years; increased risk of bleeding or concomitant
Table 8.1 Tabella capitolo Russo trial
134
RE-LY (Connolly
et al. 2009) ROCKET-AF (Halperin et al. 2014) ARISTOTLE (Granger et al. 2011) ENGAGE (Kato et al. 2016)
Drug (vs. VKA) Dabigatran Rivaroxaban Apixaban Edoxaban
Reduced dose 150 mg bid 20 mg qd 5 mg bid 60 mg qd
110 mg bid 15 mg qd 2.5 mg bid 30 mg qd
Patients (N) 18,113 14,264 18,201 14,071
Age (mean in years) 72 73 70 72
Patients ≥75 years, 7258 (40) 6229 (44) 5678 (31) 5668 (40)
N (%)
Creatinine clearance • ≥80 mL/min: Creatinine clearance, median • >80 mL/min: 10.5% • >80 mL/min: 12%
in ≥75 years at 12% 55 mL/min (IQR 44, 68) • 51–80 mL/min: 51.5% • 51–80 mL/min: 52%
baseline • 50–79 mL/min: • 31–50 mL/min: 33.6% • ≤ 50 mL/min: 37%
57% • ≤30 mL/min: 3.9%
• <50 mL/min:
26%
Primary safety Major bleeding Composite of major and nonmajor clinically relevant (NMCR) Major bleeding defined by ISTH Major bleeding defined by ISTH
endpoint defined as a bleeding: criteria: criteria:
reduction in the • Major bleeding was defined as clinically overt bleeding • Fatal bleeding • Fatal bleeding
hemoglobin level associated with any of the following: fatal outcome, • Symptomatic bleeding in a • Symptomatic bleeding in a critical
of at least 2 g/dL, involvement of a critical anatomic site (intracranial, spinal, critical area or organs such as area or organ such as intracranial,
transfusion of at ocular, pericardial, articular, retroperitoneal, or intramuscular intracranial, intraspinal, intraspinal, intraocular,
least 2 units of with compartment syndrome), fall in hemoglobin intraocular, retroperitoneal, retroperitoneal, intra-articular or
blood or requiring concentration >2 g/dL, transfusion of >2 units of whole intra-articular or pericardial, or pericardial, or intramuscular with
inotropic agents, blood or packed red blood cells, or permanent disability intramuscular with compartment compartment syndrome
symptomatic • NMCR bleeding was defined as overt bleeding not meeting syndrome • Bleeding causing a fall in
bleeding in a criteria for major bleeding but requiring medical • Bleeding causing a fall in hemoglobin level ≥2 g/dL or
critical area or intervention, unscheduled contact (visit or telephone) with a hemoglobin level ≥2 g/dL or leading to transfusion ≥2 units of
organ physician, temporary interruption of study drug (i.e., delayed leading to transfusion ≥2 units of whole blood or red cells
dosing), pain, or impairment of daily activities whole blood or red cells
A. Carbone et al.
Event rates (DOAC 1.9 (110 mg bid) 2.3 vs. 2.9 1.6 vs. 2.2 1.9 vs. 2.3
vs. VKA %/years) vs. 2.1 0.80 (0.63–1.02) 0.71 (0.53–0.95) 0.83 (0.67–1.04)
and hazard ratios 1.4 (150 mg bid)
(or relative risk for vs. 2.1
Dabigatran) for 0.88 (0.66–1.17)
stroke or systemic (110 bid)
embolism in 0.67 (0.49–0.90)
patients ≥75 years. (150 bid)
HR (OR RR) 95%
CI
vs. VKA %/years) vs. 4.4 1.11 (0.92–1.34) 0.64 (0.52–0.79) 0.83 (0.70–0.89)
major bleedings in (110 bid)
patients ≥75 years. 1.18 (0.98–1.42)
HR (OR RR) 95% (150 bid)
CI
vs. VKA %/years) vs. 1.6 1.69 (1.19–2.39) 0.99 (0.69–1.42) 1.32 (1.01–1.72)
gastrointestinal (110 bid)
bleedings in patients 1.79 (1.35–2.37)
8 Anticoagulation in Elderly Patients with Atrial Fibrillation Authors
≥75 years. HR (OR (150 bid)

RR) 95% CI
vs. VKA %/years) vs. 1 0.80 (0.50–1.28) 0.34 (0.20–0.57) 0.40 (0.26–0.62)
(or relative risk for vs. 1
intracranial bleeding (110 bid)
in patients 0.42 (0.25–0.70)
≥75 years. HR (OR (150 bid)
135
RR) 95% CI
verapamil use) may be associated with superior efficacy and safety compared to
warfarin, presenting a significant reduction in thromboembolic events (HR: 0.74)
and major bleedings (HR 0.85), but not gastrointestinal major bleeding (HR: 1.23)
(Lip et al. 2014).
A recent subgroup analysis for age of RE-LY trial by Lauw et al. (2017) showed
that both doses of dabigatran provide highly consistent protection against stroke and
systemic embolism and much lower rates of intracranial bleeding compared with
warfarin irrespective of ages. In particular, the effects of dabigatran versus warfarin
regarding the stroke/systemic embolism prevention were consistent in patients
≥80 years [dabigatran 110 mg bid (HR = 0.75) and 150 mg bid (HR = 0.67)]
and ≥ 85 years [dabigatran 110 mg bid (HR = 0.52) and 150 mg bid (HR = 0.70)]
(Sardar et al. 2014). Regarding the intracranial bleeding, there was a lower rate in
both patients aged ≥80 years [Dabigatran 110 mg bid (HR = 0.30) and 150 mg bid
(HR = 0.55)] and ≥ 85 years [Dabigatran 110 mg bid (HR = 0.13) and 150 mg bid
(HR = 0.61)] (Lauw et al. 2017).
A propensity score-matched analysis of 134,414 elderly AF patients (43% aged
75–84 years and 16% aged ≥85 years) enrolled in FDA Medicare study, who initi-
ated anticoagulant treatment with dabigatran, showed the dabigatran use was asso-
ciated with a significant reduced risk of ischemic stroke (HR 0.80), intracranial
hemorrhage (HR 0.34), and mortality (HR 0.86); with a significant increased risk of
major gastrointestinal bleeding (HR: 1.28) (Graham et al. 2015). The subgroup
analyses stratified by age and gender showed and increased risk of major gastroin-
testinal bleeding with dabigatran for women aged 75 years and older (HR 1.50) and
for men aged 85 years and older (HR 1.55) compared with warfarin. Below these
ages, gastrointestinal bleeding risk was comparable for both anticoagulants (Graham
et al. 2015). No beneficial effect of dabigatran on mortality was present in women
aged 85 years and older (Graham et al. 2015), where there was a trend for a higher
risk of death with dabigatran compared with warfarin (HR 1.24) (Graham et al.
2015). This shift in hazard ratio between younger and older aged women repre-
sented a statistically significant interaction and suggests that the benefit-risk profile
of dabigatran may be less favorable in women aged 85 years and older than in other
age-gender groups (Graham et al. 2015).
Rivaroxaban
The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with
Vitamin K Antagonism for Prevention of Stroke and Embolism trial in Atrial
Fibrillation (ROCKET-AF) study compared the factor Xa-inhibitor rivaroxaban to
warfarin (Halperin et al. 2014). The trial included 6229 patients ≥75 years (44%)
and 2595 patients (18%) ≥80 years at baseline. A sub-analysis of ROCKET-AF has
shown that elderly patients (≥ 75 years old; n = 6229) are a particularly high-risk
group for thromboembolic events (2.57% versus 2.05%/100 patient-years;
P = 0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P < 0.0001)
respect to younger; however, the effects of rivaroxaban versus warfarin did not
differ with age. Anticoagulation with rivaroxaban was as effective as warfarin in

reducing stroke and systemic embolism (95% CI, HR = 0.88 [0.67–1.16]) in older
patients and was associated with less intracranial bleeding (95% CI, HR = 0.80
[0.50–1.28]) (Halperin et al. 2014). Rivaroxaban was associated with a higher risk
of this combined bleeding endpoint in elderly patients compared with patients ran-
domized to warfarin, due mainly to more frequent nonmajor bleeding (95% CI, HR
0.70 [0.39–1.25]). This interaction was restricted to extracranial bleeding and driven
primarily by gastrointestinal bleeding, which was more frequent among elderly
patients in the rivaroxaban group than in the warfarin group (2.81% versus
1.66%/100 patient-years; P = 0.0002) (Halperin et al. 2014). Rates of major bleed-
ing were not significantly different between the rivaroxaban and warfarin groups in
elderly (4.86% versus 4.40%/100 patient-years; P = 0.336). Data about the clinical
performance of rivaroxaban in octogenarians enrolled in ROCKET-AF trial are not
available.
The Shikoku Rivaroxaban Registry Trial (SRRT) is a retrospective survey of the
use of rivaroxaban for stroke prevention in elderly Japanese patients which enrolled
1339 patients divided into control group (886 patients aged <80 years) and extreme
elderly group (453 patients aged ≥80 years) (Bando et al. 2018). The incidence of
cerebral infarction (0.94%/person-year; HR 1.66; 95% CI 0.45–2.94; p = 0.450) and
cerebral hemorrhage (0.89%/person-year; HR 2.32; 95% CI 0.51–4.13; p = 0.274)
did not differ in the extreme elderly group and the control group (Bando et al. 2018).
Real-life data about the clinical profile of rivaroxaban in octogenarians Caucasian
patients are lacking.
Apixaban
The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial
Fibrillation (ARISTOTLE) trial compared the factor Xa-inhibitor apixaban to war-
farin (Granger et al. 2011). The study included 5642 patients ≥75 years (31%) and
2436 patients (18%) ≥80 years at baseline (Granger et al. 2011). The absolute clini-
cal benefits of apixaban were greater in the older population; in particular, in patients
≥80 years a significant reduction of stroke or systemic embolism (HR 0.81), major
bleeding (HR: 0.66), and intracranial hemorrhage (HR 0.36) was showed with apix-
aban compared to warfarin (Granger et al. 2011).
In a sub-analysis of Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in
Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K
Antagonist Treatment (AVERROES) trial, apixaban was more effective than aspirin
for stroke prevention in patients with >85 years old compared to those aged
≥75 years (HR 0.50) (Ng et al. 2016).
In a propensity score-matching short-term observational study, including 7107
AF elderly patients (mean age 78.1 years) in each cohort (apixaban versus warfa-
rin), Deitelzweig et al. (2017) demonstrated that apixaban treatment was associated
with a significant lower risk for stroke/systemic embolism (HR: 0.65, P < 0.001),
ischemic stroke (HR: 0.63, P < 0.001), any major bleeding (HR: 0.53, P < 0.001),
gastrointestinal major bleeding (HR: 0.53, P < 0.001), and other major bleedings
(HR: 0.48, P < 0.001) respect to VKAs therapy (Deitelzweig et al. 2017). These
findings are also consistent with a recent retrospective cohort study conducted by
Yao et al., who reported that treatment with apixaban versus warfarin was associ-
ated with a 33% lower risk for stroke/systemic embolism (HR = 0.67, P = 0.04) and
55% lower risk for major bleeding (HR 0.45, P < 0.001) among AF elderly patients
(median age: 73 years old) (Yao et al. 2016).
Edoxaban
The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–

Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial compared
the factor Xa-inhibitor edoxaban to warfarin (Kato et al. 2016). It included 8474
patients ≥75 years of age (40.2%) and 1440 patients ≥80 years of age (17%). The
rates of stroke/systemic embolic event in patients aged ≥75 years were similar with
edoxaban versus warfarin (1.50% per year in warfarin group; 1.18% per year in
edoxaban group; hazard ratio vs. warfarin, HR 0.79; P < 0.001 for noninferiority,
P = 0.02 for superiority), while major bleeding was significantly lower with edoxa-
ban (3.43% per year in warfarin group and 2.75% per year in edoxaban group)
(Kato et al. 2016). The absolute risk reduction in major bleeding (HR = 0.83) and in
intracranial hemorrhage (HR = 0.40) was greater for edoxaban than warfarin as age
increased, resulting in a better net clinical benefit with age increase. These benefits
relative to warfarin were maintained in patients aged ≥80 and ≥85 years old (Kato
et al. 2016; Russo et al. 2019a, 2020a, b), demonstrating the robustness of the find-
ings with edoxaban in octogenarians with AF.
The ELDERCARE-AF (Edoxaban Low-Dose for EldeR CARE AF patients)
study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group,
multicenter study that will compare the safety and efficacy of once-daily edoxaban
15 mg versus placebo in Japanese patients with non-valvular AF ≥80 years of age
who are considered ineligible for standard oral anticoagulant therapy (Okumura
et al. 2017; Okumura et al. 2020). They showed that once-daily 15-mg dose of
edoxaban was superior to placebo in preventing stroke or systemic embolism and
did not result in a significantly higher incidence of major bleeding than placebo
(Okumura et al. 2020). The results of ELDERCARE-AF may provide clarity as to
the efficacy and safety of reduced doses of edoxaban for the prevention of stroke in
the Japanese very elderly patients, but data are needed also for the Caucasian
population.
VKA Versus DOACs in Elderly
Many studies have compared warfarin vs. DOACs in elderly patients (Russo et al.
2019b, 2020c; Verdecchia et al. 2019). A retrospective analysis of Taiwan National
Health Insurance Research Database (NHIRD), including 15,756 AF patients
≥90 years, showed that the risk of ischemic stroke was similar between elderly
patients treated with warfarin or DOACs (4.07%/y versus 4.59%/y; HR: 1.16;
P = 0.654) but the risk of intracranial hemorrhage (ICH) was substantially lower
with DOACs (0.42%/year versus 1.63%/year; HR 0.32; P = 0.044) (Chao et al. 2018).
Furthermore, Shinohara et al. enrolled 346 AF patients >80 years; 266 (76.9%)
received direct DOACs and 80 (23.1%) received warfarin (Shinohara et al. 2018).
Low body mass index (BMI) (<18.5 kg/m2) was demonstrated the most significant
factor associated with the bleeding in frail octogenarians with AF who were newly
initiated on OACs (Shinohara et al. 2018). The type of OACs was not a risk factor
for the development of bleeding whether its dose was appropriately adjusted or not,
and the rate of the incidence of bleeding events did not differ significantly between
the DOACs and warfarin groups (Shinohara et al. 2018). These findings suggest that
DOAC use in non-severe frail octogenarians with AF may be as safe as warfarin
therapy (Shinohara et al. 2018). Other data suggest the safety and efficacy use of
DOACs in patients aged >80 with low body weight, justified by a reduction in over-
all mortality over VKAs (Russo et al. 2020d).
A retrospective Asian study analyzed 293 consecutive patients aged ≥80 years
with non-valvular AF who had taken either DOACs (148 cases, 50.5%) or warfarin
(145 cases, 49.5%) (Shinohara et al. 2018). The incidence of stroke/systemic
embolic events were low in both groups with no significant differences (1.16% for
DOACs vs. 2.98% for warfarin per 100 patient-years, P = 0.46) (Shinohara et al.
2018). However, major bleeding occurred in a significant number of patients with
both DOACs (8.96 per 100 patient-years) and warfarin (12.46 per 100 patient-years)
treatments, which was not significantly different between the two groups (P = 0.29)
(Kwon et al. 2016).
Data are needed to identify the difference between the DOACs in terms of safety
and benefits and to recognize, “the best anticoagulation” in elderly patients.
Anticoagulation in Frail Elderly
“Frailty” is a clinical condition with an increased vulnerability to pathogens and

various types of stress and can lead to addiction and/or death. Fragility can be
related to different causes and is mainly observed in the over 80 years old (Clegg
et al. 2013). It is more prevalent in those who are >65 years and in females. The
prevalence varies from 9% in patients with 75–79 years old to 26% in patients
≥85 years old (Collard et al. 2012).
Frailty represents a condition of high instability that negatively affects both pre-
scription and maintenance of anticoagulation therapy, for many factors such as
comorbid conditions (heart failure, dementia, chronic obstructive pulmonary dis-
ease, diabetes, chronic kidney disease, etc.), risk of falls, malnutrition, and poly-
pharmacy (Annoni and Mazzola 2016). Older and frail people are less likely to
receive OAC despite sufficient evidence supporting the use of OAC in this popula-
tion (Graham et al. 2015; Biteker et al. 2017; Singh et al. 2011). Frailty, comorbidi-
ties, and increased risk of falls do not outweigh the benefits of OAC given the small
absolute risk of bleeding in anticoagulated elderly patients. Evidence from RCTs

(Mant et al. 2007; Rash et al. 2007), meta-analyses (Sardar et al. 2014; Ruff et al.
2014), and large registries (Graham et al. 2015; Chao et al. 2018; Lip et al. 2015;
Siu and Tse 2014) support the use of OAC in this group. Antiplatelets are neither
more effective nor safer than warfarin and may even be harmful (Chao et al. 2018),
whereas DOACs appear to have a better overall risk benefit profile compared with
warfarin (Mant et al. 2007; Sardar et al. 2014; Chao et al. 2018; Ruff et al. 2014;
Mozaffarian et al. 2015; Alnsasra et al. 2019; Dietzel et al. 2018). Prescribing a
reduced dose of OAC is less effective in preventing AF adverse outcomes (Steinberg
et al. 2013; Gage et al. 2000; Dillinger et al. 2018; Nieuwlaat et al. 2007).
In the ORBIT-AF register, frailty was the third cause of non-prescription of OAC
for the high risk and history of bleeding or for the refusal of treatment by the patient
(O'Brien et al. 2014). In a small Australian study, only 20% of OAC was prescribed
for frail elderly people with AF (Perera et al. 2009). Steinberg et al. (2013) reported
that physical frailty represents a barrier to the prescription also for DOACs.
Oqab et al. conducted a systematic review in frail AF patients (Oqab et al. 2018).
They found that approximately 40% of adults with AF over the age of 80, admitted
in hospital, were diagnosed as frail, and the rate of OAC prescription was lower in
frail elderly as compared to non-frail (OR 0.49, 95% CI 0.32–0.74) (Oqab et al.
2018). Geriatric characteristics such as cognitive impairment, malnutrition risk,
depression, and falls are frequently cited reasons for under-prescription of oral anti-
coagulants (Oqab et al. 2018).
In historical studies, the OAC prescription rates were of 35–65%, compared to
rate of 70% observed in the FRAIL-AF study (Lefebvre et al. 2016) as it suggested
a more judicious use of OAC in older patients, particularly as a significant propor-
tion in the study had diagnoses such as dementia. However, the authors noted that
non-frail to moderately frail patients were 3.5 times more likely to receive OAC
than severely frail patients, irrespective of their thromboembolic and bleeding risk,
highlighting that the impression of severe frailty significantly influenced OAC pre-
scription decisions (Lefebvre et al. 2016).
Studies on which international guidelines was based did not explicitly assess
frailty (Granger et al. 2011; Patel et al. 2011; Giugliano et al. 2013; Connolly et al.
2009). Assessment and modification of bleeding risk factors using the HAS-BLED
score is recommended, but there may be additional considerations in a population
with frailty such as a higher risk of bleeding and falls. The optimal treatment strat-
egy for people with AF and frailty is therefore unclear, and the generalizability of
trial evidence across the spectrum of older people may be limited as they excluded
people anticipated to be in the last 1–2 years of life and those with several
comorbidities.
Fall risk is an important parameter of frailty. In a sub-analysis of the ARISTOTLE
trial, a history of fall(s) was associated with an increased intracranial hemorrhage
risk (HR 1.96 [95% CI: 1.06–3.61]) (Rao et al. 2018). However, in the ENGAGE
AF-TIMI 48 trial and in the Loire Valley AF Project, the presence or absence of fall
risk or a history of falls did not increase the incidence of intracranial hemorrhage
(Banerjee et al. 2014; Steffel et al. 2016). The reason for these contradictory results
is uncertain.
To evaluate the OAC-associated bleeding risk in AF patients who were at risk of
developing falls, Man-Son-Hing et al. (1999) have showed, in analysis of older
individuals with an average annual stroke risk of 6% and falls risk of 33%, warfarin
was associated with the highest quality-adjusted life expectancy compared to aspi-
rin or no treatment. The study also estimated that an older patient taking warfarin
would need to fall 295 times a year to offset the benefits of OAC. Also, for both
edoxaban and apixaban, the relative safety and efficacy profile compared with war-
farin were consistent in high fall risk patients (Rao et al. 2018; Steffel et al. 2016).
Thus, falls or risk of it alone should not be absolute contraindications to OAC (Man-
Son-Hing et al. 1999; Steffel et al. 2018).
Dementia is another reason for OAC non-prescription in AF (Bahri et al. 2015;
Proietti et al. 2020). However, like falling, dementia should not be a general contra-
indication for OAC (Steffel et al. 2018; Russo et al. 2020e). Anticoagulation in
dementia can be challenging, as therapy adherence and a patients’ ability to make
decisions are often suboptimal (Steffel et al. 2018). Nonetheless, OAC treatment is
correlated with lower ischemic stroke and all-cause mortality rates in these patients
(Subic et al. 2018). Moreover, AF is linked to dementia and cognitive decline, and
OAC in AF has been associated with a lower risk of dementia (Alonso and Arenas
de Larriva 2016; Friberg and Rosenqvist 2018). Anticoagulation treatment is there-
fore encouraged, but attention to therapy adherence is important.
Practical Choice of DOACs in Older Patients
On the basis of current evidence, it is not possible to recommend one DOAC over
another in elderly patients with AF. In general, there are some recommendations to
take into consideration. All DOACs are contraindicated in patients with AF and
hepatic insufficiency Child-Pugh category C; dabigatran, apixaban, and edoxaban
may be used with attention in patients in category B (Steffel et al. 2018). DOACs
are associated with lower incidence of major bleeding compared with VKAs in
patients with liver disease (Pastori et al. 2018; Lee et al. 2019).
In elderly patients with kidney impairment, apixaban is a reasonable choice
(Diener et al. 2017). Dabigatran and rivaroxaban may be used with caution in AF
patients aged ≥75 years for the high risk of gastrointestinal bleeding (By the
American Geriatrics Society Beers Criteria Update Expert P 2019).
Apixaban seems to be the drug with the most favorable risk/benefit ratio in older
patients (Kuhn-Thiel et al. 2014; Pazan et al. 2016).
Furthermore, AF patients should be assessed for DOAC-specific dose-reduction
criteria (such as age >80 years, low body weight <60 kg, reduced renal function)
and for other factors with potential effect on DOACs plasma level (nonsteroidal
anti-inflammatory drugs, drugs interactions with antifungal drugs, quinidine, clar-
ithromycin, erythromycin, verapamil) (Steffel et al. 2018).
Conclusions
The anticoagulant treatment in elderly patients represents a tricky issue in the stroke
prevention. Data currently available in literature showed that the better profile of
clinical efficacy and safety of DOACs in preventing thromboembolic events, versus
VKAs, in AF patients is conserved also in elderly (≥75 year). DOACs showed a
particularly high net benefit versus warfarin but, on the basis of current evidence, it
is not possible to recommend one DOAC over another, considering only the age.
Treatment of elderly patients presents numerous challenges, and an individualized
approach should be taken, taking into consideration the risk of bleeding, other
comorbidities, and the different characteristics of the individual DOACs.
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The “Obesity Paradox” and the Use
of NOAC 9
Introduction
The World Health Organization defines obesity as a condition of increased adipose

tissue up to a body mass index (BMI) > 30 kg/m2 which affects the state of health
(Hales 2017). In the last 40 years, obesity has constantly increased its incidence all
over the world (Abarca-Gómez et al. 2017), with a current prevalence of 39.8% of
US adults, affecting over 90 million people irrespective of gender, age, or ethnicity
(Hales 2017). Obesity, mainly in its abdominal form, is an important cardiovascular
(CV) risk factor known to be responsible for increased CV morbidity and mortality
(Jensen et al. 2014; Berrington de Gonzalez et al. 2010), including increased rates
of venous thromboembolism (VTE) (Ageno et al. 2008; Yang et al. 2012) and atrial
fibrillation (AF) (Boriani and Proietti 2018; Lavie et al. 2017) for which oral anti-
coagulation (OAC) is needed (Hindricks et al. 2020; Konstantinides et al. 2020). To
date, for treatment and prevention in non-valvular AF (NVAF) and in VTE patients,
major guidelines suggest the use of non-vitamin K anticoagulants (NOACs) over
vitamin K oral antagonists (VKAs) (Hindricks et al. 2020; Konstantinides et al.
2020). OAC therapy with NOACs in obese patients can be particularly challenging
in consideration of the pharmacokinetic alterations that occur in such subjects
(mainly drugs volume distribution and elimination) (Polso et al. 2014; Jain et al.
2011; Morrish et al. 2011; Wurtz et al. 1997). Due to clinical, pharmacokinetic, and
pharmacodynamic evidences suggesting drug exposure differences with increased
weight and BMI, the International Society on Thrombosis and Haemostasis (ISTH)
discourage NOACs use in morbidly obese patients (BMI > 40 kg/m2 or
R. Bottino · A. Carbone · P. Golino · G. Nigro · V. Russo (*)

Cardiology, Department of Translational Medical Sciences, University of Campania “Luigi
Vanvitelli”, Monaldi Hospital, Naples, Italy
B. Liccardo
Department of Cardiology, Monaldi Hospital, Naples, Italy

150 R. Bottino et al.
weight > 120 kg) (Martin et al. 2016). Interestingly, in addition to the above, it is

important to take into account that evidences in literature support the hypothesis of
an inverse relationship between obesity/overweight and CV outcomes which is
given the name of “obesity paradox” (Elagizi et al. 2018; Lavie et al. 2009), a phe-
nomenon described in patients with hypertension (Uretsky et al. 2007; Stamler et al.
1991; Tuomilehto 1991; Wassertheil-Smoller et al. 2000), heart failure (Horwich
and Fonarow 2002; Fonarow et al. 2007; Powell-Wiley et al. 2018), coronary artery
disease (Gruberg et al. 2002; Romero-Corral et al. 2006; Hastie et al. 2010;
Oreopoulos et al. 2009), and other CV conditions, including AF (Lavie et al. 2009,
2017) and VTE (Bauer 2019; El-Menyar et al. 2018; Karabay et al. 2019). This
chapter aims to review the available evidences of an obesity paradox in NVAF and
VTE to examine the current state of the art of the use of NOACs in obese patients
suffering from these conditions.
Obesity Paradox in NVAF Patients
Since 2010, several studies focused on the association between NVAF and the obe-
sity paradox.
Three systematic reviews of the literature, of which the most recent published in
2020 (Zhou et al. 2020), investigate the association between obesity and NVAF
outcomes (Zhou et al. 2020; Zhu et al. 2016; Proietti et al. 2017).
The study by Zhu and colleagues included nine studies (Sandhu et al. 2016;
Proietti et al. 2016; Kwon et al. 2017; Inoue et al. 2016; Wang et al. 2015; Pandey
et al. 2016; Overvad et al. 2013; Hamatani et al. 2015; Ardestani et al. 2010) with
49,364 participants and found that the relative risks (RR) of overweight and obese
patients were lower than those of normal weight patients for stroke/systemic embo-
lism (S/SE), all-cause death, and CV death (Zhu et al. 2016) (Table 9.1).
Proietti et al. in a systematic review of 13 studies (5 subgroup analysis of RCTs
(Sandhu et al. 2016; Proietti et al. 2016; Ardestani et al. 2010; Badkeha et al. 2010;
Senoo and Lip 2016) and 8 observational studies (Kwon et al. 2017; Inoue et al.
2016; Wang et al. 2015; Pandey et al. 2016; Overvad et al. 2013; Bunch et al. 2016;
Yanagisawa et al. 2016; Wang et al. 2014)) found an obesity paradox in the overall
results of subgroup analysis of RCTs (Table 9.3) but not in observational studies
after statistical adjustment (Proietti et al. 2017).
Finally, in 2020, Zhou and coworkers in a systematic review and metanalysis of
nine studies (one phase III RCT (Connolly et al. 2009), six post hoc analyses of
randomized clinical trials (RCTs) (Sandhu et al. 2016; Proietti et al. 2016; Pandey
et al. 2016; Boriani et al. 2019; Balla et al. 2017; Hohnloser et al. 2019), and two
retrospective cohort studies (Park et al. 2017; Lee et al. 2019)) confirmed an obesity
paradox in overweight and obese anticoagulated AF patients when compared to
underweight patients for S/SE (overweight: relative risk [RR] 0.81, 95% CI
0.71–0.91; obesity: RR 0.69, 95% CI 0.61–0.78) and all-cause death (overweight:
RR 0.73, 95% CI 0.64–0.83; obesity: RR 0.72, 95% CI 0.66–0.79), while no differ-
ences between BMI groups were found for major bleeding (MB) (Table 9.1).
9 The “Obesity Paradox” and the Use of NOAC 151
Obesity Paradox in VTE Patients
The concept of obesity paradox can be applied to VTE patients too with controver-
sial results available in literature.
In 2008, Barba et al. investigated the association between BMI and mortality in
VTE patients based on the “Registro Informatizado Enfermedad TromboEmbólica”
(RIETE) registry data (Barba et al. 2008), an ongoing, international, multicenter,
prospective registry of consecutive patients presenting with symptomatic acute VTE
confirmed by objective tests (RIETE Registry 2020). At the time, the study included
Table 9.1 Main research on obesity paradox in NVAF patients

Total Obese
patients patients
References Study design (n) (n%) Outcomes
Zhu et al. Meta-analysis and 49,364 N/A S/SE
(2016) systematic review RR (95% CI)
(9 studies) Underweight 1.67
Underweight, (1.12–2.49)
overweight, and P = 0.01
obese vs. normal Overweight 0.91
weight patients (0.80–1.04)
P = 0.18
Obese 0.84
(0.72–0.98)
P = 0.02
All-cause death
RR (95% CI)
Underweight 2.61
(2.21–3.09)
P < 0.00001
Overweight 0.78
(0.62–0.96)
P = 0.02
Obese 0.84
(0.64–1.10)
P = 0.21
CV death
RR (95% CI)
Underweight 2.49
(1.38–4.50)
P = 0.003
Overweight 0.79
(0.58–1.08)
P = 0.14
Obese 0.99
(0.79–1.24)
P = 0.93
(continued)
Total Obese
patients patients
References Study design (n) (n%) Outcomes
Zhou et al. Meta-analysis and N/A N/A S/SE
(2020; Balla systematic review RR (95% CI)
et al. 2017) Underweight 1.98
(1.19–3.28)
P = 0.008
Overweight 0.81
(0.71–0.91)
P = 0.0005
Obese 0.69
(0.61–0.78)
P < 0.00001
All-cause death
RR (95% CI)
Underweight 4.34 (0.57–
32.83) P = 0.15
Overweight 0.73
(0.64–0.83)
P < 0.00001
Obese 0.72 (0.66–
0.79)
P < 0.0001
MB
RR (95% CI)
Underweight 2.1 (0.89–4.92)
P = 0.09
Overweight 0.93
(0.79–1.08)
P = 0.33
Obese 1.04
(0.91–1.18)
P = 0.59
NVAF non-valvular atrial fibrillation, HR hazard ratio, OR odds ratio, RR relative risk, CI confiden-
tial interval, N/A not applicable, S/SE stroke/systemic embolism, CV cardiovascular, MB major
bleeding, RR are expressed with normal weight as reference category, except where explicitly
reported
10,114 patients divided into BMI category with 43% of patients being overweight
(BMI 25–30 kg/m2) and 27% of patients being obese (BMI >30 kg/m2). Study
results showed that obese patients with acute VTE have less than half the mortality
rate when compared with normal BMI patients (Barba et al. 2008). Moreover, over-
weight and obese patients demonstrated lower risk of fatal pulmonary embolism
(PE). These results were recently confirmed and demonstrated separately for cancer
and noncancer VTE patients in extreme obese patients (Giorgi-Pierfranceschi
et al. 2020).
The association between mortality and BMI was also the field of investigation of
Stein and coworkers (Stein et al. 2011). From the Nationwide Inpatient Sample, the
researchers selected obese and nonobese patients diagnosed with PE from short-
stay hospitals throughout the United States from 1998 to 2008 (Stein et al. 2011).
Final results showed that overall mortality was statistically significantly lower in
obese patients with PE compared with nonobese PE patients (4.3% vs. 9.5%,
RR = 0.45, P < 0.0001).
Conversely, in a retrospective analysis of 345,831 in-hospital PE patients strati-
fied for BMI, Keller and colleagues showed that in-hospital mortality was lower for
obesity class I and II patients while underweight and class III obese patients had
higher mortality rate when compared to the reference group (normal weight/over-
weight patients) (Keller et al. 2019) (Table 9.2).
Also, in a retrospective cohort study by El-Menyar and coworkers of 662 DVT
patients (49% obese), BMI >30 kg/m2 was found to be a predictor of survival but
recurrent DVT was higher in obese class I patients (P < 0.01) (El-Menyar et al.
2018). After statistical adjustment for age, sex, PE, and duration of warfarin treat-
ment, authors found that patients with BMI >40 kg/m2 had better survival (El-
Menyar et al. 2018). See Table 9.2 for details.
Table 9.2 Main research on obesity paradox in VTE patients

Total Obese
patients patients
References Study design (n) (%) Outcomes
Barba et al. Retrospective 10,114 2752 Death
(2008) analysis of (27) RR (95% CI)
prospective registry Underweight 2.1(1.5–
Underweight, 2.7)
overweight, and P < 0.001
obese vs. normal Overweight 0.6
weight patients (0.5–0.7)
P < 0.001
Obese 0.5
(0.4–0.6)
P < 0.001
MB
OR (95% CI)
Underweight 2.7
(1.4–5.1)
P < 0.01
Fatal PE
OR (95% CI)
Overweight 0.6
(0.4–0.8)
P < 0.01
Obese 0.4
(0.2–0.6)
P < 0.01
(continued)
Total Obese
patients patients
References Study design (n) (%) Outcomes
Giorgi- Retrospective 16,490 1642 Death
Pierfranceschi analysis of (11.1) HR (95% CI)
et al. (2020) prospective registry Obese 0.67
Obese NC and WC NC (0.49–0.96)
patients vs. P < 0.05
nonobese patients Obese 0.68
WC (0.50–0.94)
P < 0.05
MB
HR (95% CI)
Obese 0.67
NC (0.57–1.58)
P > 0.05
Obese 0.99
WC (0.51–1.93)
P > 0.05
Stein et al. Retrospective 17,979,200 203,500 All-cause death
(2011) cohort study (1) RR (95% CI)
PE/obese vs. PE/ 0.45 (0.44–0.46)
nonobese P < 0.0001
Keller et al. Retrospective 345,831 29,741 Mortality
(2019) cohort study of PE (8.6) OR (95% CI)
patients Underweight 1.15
Obese, (1.00–1.31)
underweight, vs. P = 0.04
normal weight/ Obesity I 0.56
overweight (0.52–0.60)
P < 0.001
Obese II 0.63
(0.58–0.69)
P < 0.001
Obese III 1.18
(1.10–1.27)
P < 0.001
El-Menyar et al. Retrospective 662 324 Predictors of survival
(2018) cohort study (49) (95% CI)
Association BMI ≥ 30 OR 0.52
between obesity and (0.29–0.92)
DVT P = 0.03
BMI ≥ 40 HR 0.18
(0.05–0.69)
P = 0.02
VTE venous thromboembolism, HR hazard ratio, OR odds ratio, RR relative risk, CI confidential
interval, NC noncancer, WC with cancer, PE pulmonary embolism, MB major bleeding, BMI body
mass index in kg/m2. HR, OR, RR are expressed with normal weight as reference category, except
where explicitly reported
ody Weight and Use of NOACS:

B
Pharmacological Considerations
Obesity affects the pharmacokinetics of drugs, including the volume of distribution

as well as drug clearance. Indeed, renal blood flow and clearance have been shown
to be increased in obesity and could increase elimination of NOACs (Chagnac et al.
2000). Several studies have investigated the pharmacological profile of NOACs
depending on changes in body weight.
It has been demonstrated that BMI influences the apparent volume of distribution
of dabigatran but without impact on the concentration time profiles and overall
exposure (Liesenfeld et al. 2011). Also, evidences from the Dabigatran versus
Warfarin in Patients with Atrial Fibrillation (RE-LY) trial show that weight is not an
independent risk factor for bleeding and thrombotic outcomes even in patients with
weight > 100 kg (Reilly et al. 2014).
In the randomized, single-blind, placebo-controlled, parallel-group study of
Kubitza et al., rivaroxaban 10 mg in extreme body weight patients (≤50 and
>120 kg) was well tolerated, showing no significant changes on its pharmacokinetic
and pharmacodynamic profile (Kubitza et al. 2007). Similarly, Barsam and col-
leagues found that the most important covariate impacting rivaroxaban pharmacoki-
netics is creatinine clearance, and the weight alone has little effect (Barsam et al.
2017). However, extremely obese patients were poorly represented (BMI >40 kg/
m2: n = 6).
The open-label, parallel-group study of Upreti et al. (2013) investigated the
effect of extremes of body weight on apixaban pharmacokinetics, pharmacodynam-
ics, safety, and tolerability. Following administration of a single oral dose of 10 mg
apixaban, high body weight group (>120 kg) had approximately 31% (90% CI:
18–41%) and 23% (90% CI: 9–35%) lower apixaban Cmax and AUC(0,∞), respec-
tively, showing a modest change in apixaban exposure in these patients.
No studies directly designed to investigate the pharmacological profile of edoxa-
ban in extremely obese patients are yet available. However, it has been demon-
strated that renal function is the most important intrinsic determinant of total
edoxaban exposure and that nonrenal clearance values decrease in subjects with
lower body weight (Yin et al. 2014).
Finally, a recent study by Piran et al. examined peak plasma concentration of
dabigatran, apixaban, and rivaroxaban in 38 extreme obese patients (BMI > 40 kg/
m2 or weight > 120 kg) (Piran et al. 2018). The study reported that 95% of the study
population had peak plasma levels of NOACs higher than the median trough level
for each of the three NOACs, 79% (95% CI: 63–89%) of patients had levels within
the usual on-therapy range, and 21% (95% CI: 11–37%) of patients had a peak
NOAC concentration below the expected range (i.e., below the fifth percentile for
apixaban and rivaroxaban and below the tenth percentile for dabigatran), which
could be interpreted as indicating suboptimal drug exposure (Piran et al. 2018).
OACs Versus Warfarin Across BMI Groups: Current

N
Clinical Evidences
NVAF Patients
Dabigatran
In a weight-based analysis of the RE-LY trial, BMI subgroups were categorized into
an upper 10% (BMI of >36 kg/m2), a middle 80% (BMI of 22.5 to ≤36 kg/m2), and
a bottom 10% (BMI of ≤22.5 kg/m2) to compare efficacy (S/SE) and safety (MB)
outcomes at 1 year, in relation to BMI and according to treatment assignment (dabi-
gatran 150 mg, 110 mg, or warfarin) (The use of dabigatran according to body mass
index 2020). An obesity paradox was confirmed: 1-year bleeding and S/SE rates
were higher in patients with the bottom 10% BMI values compared to middle and
upper BMI subgroups (all P-values <0.001). One-year S/SE rate was significantly
lower in the dabigatran 150 mg group in the middle and upper BMI category while
bleeding was significantly lower with dabigatran 110 mg in the same BMI groups.
These findings suggest that dabigatran preserves results of the RE-LY trial irre-
spective of BMI category (Table 9.3).
Rivaroxaban
Peterson and colleagues compared the risks of S/SE and MB in 3563 matched pairs
of morbidly obese AF patients (BMI >40 kg/m2 or >120 kg) treated with rivaroxa-
ban or warfarin recruited from two different US databases (Peterson et al. 2019).
Outcomes analyzed were the incidence of S/SE and MB. Final results showed that
outcomes were similar for rivaroxaban and warfarin users (S/SE: 1.5% vs. 1.7%;
P = 0.50; MB: 2.2% vs. 2.7%; P = 0.14) but rivaroxaban administration was associ-
ated with a lower healthcare resource utilization and costs (Peterson et al. 2019).
Later, in a larger cohort study of 35,613 NVAF patients with BMI >30 kg/m2 on
rivaroxaban 1:1 propensity matched with a same number of warfarin patients, Costa
and colleagues could find that compared to warfarin, rivaroxaban was associated
with a reduced risk of S/SE and MB. Subanalysis by BMI groups found no statisti-
cally significant interaction across BMI categories for S/SE (P-interaction = 0.58)
or MB (P-interaction = 0.44) outcomes (Costa et al. 2020a). However, BMI >40 kg/
m2 accounted for 25% of the total rivaroxaban cohort with the majority of patients
having a BMI between 30 and 34.1 kg/m2.
These findings suggest that rivaroxaban can be at least as effective and safe as
warfarin in obese patients (Table 9.3).
Apixaban
Recently, Hohnloser et al. conducted a weight-based post hoc analysis of the
“Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial
Fibrillation (ARISTOTLE)” trial to compare efficacy and safety of apixaban versus
warfarin across three different body weight group (≤60, >60–120, >120 kg)
(Hohnloser et al. 2019). Final cohort study included 18,139 patients of which 1985
(10.9%) were in the low-weight group (≤60 kg), 15,172 (83.6%) were in the
Table 9.3 NOACs in NVAF obese patients
Patients
References Study design NOAC (n) Obese patients (%) Outcomes
Ezekowitz et al., 2014 (The Post hoc analysis of the Rivaroxaban 18,113 N/A One Year S/SE rates
use of dabigatran according RE-LY trial (95% Confidence Interval)
to body mass index 2020) Upper BMI (>36) vs. Dabigatran BMI bottom
middle BMI (22.5–36) vs. 110 mg 2% (0.9–3.1)
bottom BMI (≤22.5) and BMI middle
dabigatran 110/150 mg vs. 1.5% (1.2–1.9)
BMI upper
warfarin across BMI
1.2% (0.3–2.0)
groups Dabigatran 150 mg BMI bottom
1% (0.2–1.8)
BMI middle
1.2% (0.9–1.5)
BMI upper
0.9% (0.1–1.6)
Warfarin BMI bottom
2.9% (1.6–4.2)
BMI middle
1.6% (1.2–1.9)
BMI upper
9 The “Obesity Paradox” and the Use of NOAC
1.3% (0.4–2.3)
One Year Major Bleeding Rates
(95% CI)
Dabigatran BMI bottom
110 mg 4.1% (2.5–5.6)
BMI middle
3% (2.5–3.5)
BMI upper
3% (1.6–4.4)
Dabigatran BMI bottom
150 mg 4.7% (3.0–6.4)
BMI middle
3.9% (3.4–4.5)
BMI upper
3.7% (2.2–5.2)
Warfarin BMI bottom
5.1% (3.3–6.7)
BMI middle
3.8% (3.3–4.4)
157
BMI upper
3.7% (2.2–5.2)
(continued)
158
Patients
Petearson et al. (2019) Retrospective propensity Rivaroxaban 3563 3563 S/SE
score match cohort study matched pairs (100) OR (95% CI)
Rivaroxaban vs. warfarin in matched pairs 0.88 (0.60–1.28)
obese patients P = 0.50
MB
OR (95% CI)
0.80 (0.59–1.08)
P = 0.14
Costa et al. (2020a) Retrospective propensity Rivaroxaban 35,613 matched 35,613 S/SE
score match cohort study pairs (100) matched pairs HR (95% CI)
Rivaroxaban vs. warfarin in 0.83 (0.73–0.94)
obese patients P = N/A
MB
HR (95% CI)
0.82 (0.75–0.89)
P = N/A
Balla et al. (2017) Post hoc analysis of the Rivaroxaban 14,030 5206 S
ROCKET AF trial (37.1) HR (95% CI)
Overweight and obese vs. Obese patients (BMI ≥ 35) on 0.62 (0.40–0.96)
normal weight patients rivaroxaban P = 0.033
Obese patients (BMI ≥ 35) on 0.48 (0.31–0.74)
warfarin P < 0.001
Hohnloser et al. (2019) Post hoc weight-based Apixaban 18,139 982 S/SE
analysis of the >120 kg HR (95% CI)
ARISTOTLE trial (5.4%) ≤60 kg 0.63 (0.41–0.96)
61–120 kg 0.85 (0.70–1.05)
Apixaban >120 kg 0.39 (0.12–1.22)
vs. warfarin Interaction P = 0.64
All-cause death
HR (95% CI)
≤60 kg 1.10 (0.85–1.43)
61–120 kg 0.84 (0.74–0.95)
>120 kg 1.19 (0.69–2.04)
Interaction P = 0.36
MB
HR (95% CI)
≤60 kg 0.55 (0.36–0.82)
61–120 kg 0.71 (0.61–0.83)
>120 kg 0.74 (0.37–1.50)
Interaction P = 0.02
R. Bottino et al.
Patients
Authors, year, reference Study design NOAC (n) Obese patients (%) Outcomes
Proietti et al. 2017 (2017) Metanalysis Dabigatran 50,031 18,632 (37.2%) NOACs across BMI groups
(3 out of 13 studies included in Rivaroxaban S/SE
the original systematic review) Apixaban OR (95% CI)
Overweight 0.75 (0.66–0.84)
Efficacy and safety of NOACs P < 0.00001
across BMI groups and vs. Obese 0.62(0.54–0.70)
warfarin P < 0.00001
Overweight vs. 0.83(0.73–0.94)
Obese P < 0.003
MB
OR (95% CI)
Overweight 0.84 (0.7–1.01)
P = 0.06
Obese 0.84 (0.72–0.98)
P = 0.03
Overweight vs. (0.92–1.10)
Obese P = 0.95
NOACs vs. warfarin
S/SE
OR (95% CI)
Normal weight 0.65 (0.53–0.79)
P < 0.00001
Overweight 0.88 (0.74–1.05)

P = 0.14
Obese 0.84 (0.70–1.03)
P = 0.09
MB
OR (95% CI)
P = 0.04
Overweight 0.89 (0.73–1.08)
P = 0.22
Obese 1.03(0.9–1.18)
P = 0.7
(continued)
159
160
Patients
Kido and Ngorsuraches Retrospective cohort study Dabigatran 128 128 (100%) S/TIA
(2019) NOACs vs. warfarin in Rivaroxaban (64 for each treatment RR (95% CI)
extremely obese patients Apixaban group) 0.84 (0.23–3.14)
P = 0.80
MB
RR (95% CI)
0.44 (0.15–1.25)
P = 0.11
Zhou et al. (2020) Systematic review and Dabigatran N/A N/A S/SE
meta-analysis Rivaroxaban RR (95% CI)
(9 studies) Apixaban Underweight 0.61 (0.46–0.80)
Efficacy and safety of NOACs Edoxaban P = 0.0004
vs. warfarin across BMI groups
P = 0.006
Overweight 0.87 (0.76–0.99)
P = 0.04
Obese 0.87 (0.73–1.04)
P = 0.12
MB
Risk Ratio (95% CI)
Underweight 0.67 (0.55–0.81)
P < 0.0001
P = 0.004
Overweight 0.83 (0.71–0.96)
P = 0.01
Obese 0.90 (0.81–1.01)
P = 0.08
NOACs non-vitamin K oral anticoagulants, NVAF non-valvular atrial fibrillation, HR hazard ratio, OR odds ratio, RR relative risk, CI confidential interval, N/A not applicable, S/SE
stroke/systemic embolism, MB major bleeding, S stroke, TIA transient ischemic attack, BMI body mass index in kg/m2. HR, OR, RR are expressed with normal weight or warfarin
as reference category, except where explicitly reported
R. Bottino et al.
midrange weight group (>60–120 kg), and 982 (5.4%) were in the high-weight
group (>120 kg). Efficacy outcomes were S/SE, all-cause death, and myocardial
infarction, while safety outcomes included MB, clinically relevant nonmajor bleed-
ing (CRNMB), intracranial bleeding, gastrointestinal bleeding, and any bleeding at
2 years of follow-up. Treatment with apixaban results in lower rate of efficacy and
safety outcome; however, no interaction between body weight, efficacy outcome,
and randomization treatment (apixaban vs. warfarin) was found (interaction
P > 0.05) with the exception of MB, suggesting that warfarin was associated with a
higher risk of MB in the lower weight range group when compared with the higher
weight categories; this was not seen with apixaban use.
These findings suggest that efficacy and safety of apixaban are not affected by
BMI and weight. Table 9.3 shows details on results for S/SE, all-cause death, and MB.
Edoxaban
Data on edoxaban in obese AF patients are presented in a post hoc analysis of The
Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–
Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial (Boriani
et al. 2019). In this analysis, higher BMI was independently associated with lower
adjusted risk of S/SE (hazard ratio (HR) 0.88, P = 0.0001) and death (HR 0.91,
P < 0.0001) in those treated with edoxaban or warfarin, and no significant interac-
tion was observed between BMI analyzed as a categorical variable and the out-
comes of S/SE, all-cause mortality, MB, CRNMB, or the net clinical outcome (P for
interaction >0.16 for each outcome). However, increasing BMI was independently
associated with a greater risk of MB (HR 1.06, 95% CI 1.01–1.12, P = 0.025) and
of CRNMB (HR 1.05, 95% CI 1.02–1.08, P = 0.0007). The effects of edoxaban vs.
warfarin on S/SE, MB, and net clinical outcome were similar across BMI groups.
These findings suggest that edoxaban has comparable clinical profile when com-
pared to warfarin in obese patients with safety characteristics worsening in this
subset of patients.
OACs Overview in NVAF Obese Patients

N
In the abovementioned systematic review of Proietti et al. (2017), it was also con-
ducted a metanalysis of NOACs safety and efficacy in the subgroup analysis of
RCTs. Results showed that overweight and obese patients have a significantly lower
risk of S/SE when compared to normal weight patients, with obese patients being at
lower risk even when compared to overweight patients. MB was statistically signifi-
cantly lower when comparing obese patients to normal weight ones with lower risk
for obese patients. No significant difference for S/SE and MB between NOACs and
warfarin was found across BMI groups with exception of normal weight patients as
expected (Table 9.3).
Recently, Kido et al. conducted a retrospective, single-center cohort study in AF
patients and extreme body weight (BMI > 40 kg/m2 or weight > 120 kg), treated
with warfarin or NOACs (i.e., dabigatran, rivaroxaban, or apixaban). The primary
efficacy outcome was the incidence of S or transient ischemic attack (TIA), whereas
the primary safety outcome was the incidence of MB. A total of 128 patients were
included in the study with half of them taking a NOAC (dabigatran: 31.3, apixaban:
29.7%, and rivaroxaban: 39.1%). Results show that the incidence rate of S or TIA
was 1.75%/year in the NOAC group compared with 2.07%/year in the warfarin
group (P = 0.80). The incidence rate of MB was 2.18%/year in the NOAC group,
compared with 4.97%/year in the warfarin group (P = 0.11). Interestingly, com-
pared with apixaban and rivaroxaban, use of dabigatran showed a highest number of
ischemic events (dabigatran: 3, rivaroxaban: 1, apixaban: 0). MB rate was numeri-
cally lowest in the dabigatran group (dabigatran vs. rivaroxaban vs. apixaban:
1.34% vs. 2.13% vs. 2.82% per year), but there were two events of life-threatening
bleeding in the dabigatran group and no such events with rivaroxaban and apixaban.
The authors concluded that while apixaban and rivaroxaban seem to be effective and
safe in morbidly obese patients, caution is needed with dabigatran in this subset of
patients (Kido and Ngorsuraches 2019) (Table 9.3).
In the metanalysis of Zhou and colleagues, use of NOACs was associated to bet-
ter efficacy and safety outcomes (S/SE and MB) in underweight, normal weight,
and overweight patients compared to warfarin (S/SE; underweight: RR 0.61, 95%
CI 0.46–0.80; normal weight: RR 0.72, 95% CI 0.58–0.91; overweight: RR 0.87,
95% CI 0.76–0.99; MB; underweight: RR 0.67, 95% CI 0.55–0.81; normal weight:
RR 0.72, 95% CI 0.58–0.90; overweight: RR 0.83, 95% CI 0.71–0.96) while in
obese patients, NOACs and warfarin demonstrated similar efficacy and safety pro-
file with no statistically significant differences between treatment groups for S/SE
and MB (Table 9.3) (Zhou et al. 2020).
VTE Obese Patients
abigatran, Apixaban, and Edoxaban

D
Even if major RCTs comparing dabigatran vs. warfarin for the treatment of VTE
included more obese patients than later landmark trials, they were still underpow-
ered to truly evaluate the safety and efficacy of dabigatran in this population. None
of the studies reported outcomes in patients with a BMI of ≥40 kg/m2 (Schulman
et al. 2009, 2011, 2013).
The Oral Apixaban for the Treatment of Acute Venous Thromboembolism
(AMPLIFY) trial (Agnelli et al. 2015), which demonstrated the noninferior efficacy
of apixaban compared to standard therapy as well as its more favorable safety pro-
file in VTE patients, completed a subgroup analysis by BMI and body weight but
the study was underpowered for this analysis. In fact, only 19.4% of patients in the
apixaban group weighed 100 kg or more, and only 13% had a BMI >30 kg/m2.
Regarding edoxaban, no high-quality data on its clinical and pharmacological
profile are available for VTE treatment in obese and extremely obese patients.
Rivaroxaban
Spyropoulos and colleagues conducted a retrospective 1:1 propensity score matched
cohort study addressed to obese VTE patients started with rivaroxaban or warfarin
and followed for 3 months after recruitment. Two thousand eight hundred ninety
matched pairs of morbidly obese VTE patients initiating rivaroxaban or warfarin

were identified from 2 US claims databases. Results showed that morbidly obese
VTE patients receiving rivaroxaban had similar risks of recurrent VTE (odds ratio
[OR]: 0.99; 95% CI: 0.85–1.14) and MB (OR: 0.75; 95% CI: 0.47–1.19) versus
warfarin (Spyropoulos et al. 2019) (Table 9.4).
Very recently Costa and coworkers published a retrospective cohort study includ-
ing 6755 rivaroxaban matched with 6755 warfarin users with BMI ≥ 30 kg/m2 and
incident VTE. Rivaroxaban was associated with a reduced hazard of recurrent VTE
compared to warfarin (HR 0.61, 95% CI: 0.51–0.72; HR 0.65, 95% CI: 0.55–0.77;
HR 0.63, 95% CI: 0.54–0.74) with no difference in MB (HR 0.99, 95% CI: 0.68–1.44;
HR 0.90, 95% CI: 0.64–1.26; HR 1.00, 95% CI: 0.73–1.36). No statistical difference
was found across BMI categories (30–34.9; 35–39.9; ≥40 kg/m2) for either recur-
rent VTE (P-interaction ≥0.43) or MB (P-interaction ≥0.58) at any time point (3, 6,
and 12 months) (Costa et al. 2020b) (Table 9.4).
These findings suggest that rivaroxaban could be at least as effective and safe as
warfarin in the treatment of VTE in extreme obese patients.
OACs Overview in VTE Patients

N
Apixaban, rivaroxaban, and dabigatran were compared to warfarin in a retrospective
study by Coons et al. including 632 patients receiving a NOAC and 1208 patients
receiving warfarin for an acute VTE admission and a body weight at the time of
inclusion between 100 and 300 kg. No statistically significant differences were
found between groups in the primary outcome of VTE (P = 0.93), PE (P = 0.94),
and DVT (P = 0.56). Within 12 months of the index event, bleeding occurred in 11
(1.7%) NOAC patients and 14 (1.2%) warfarin patients (P = 0.31). The most com-
mon types of bleeding in both groups were gastrointestinal and genitourinary
(Coons et al. 2020) (Table 9.4).
A systematic review and metanalysis of the literature recently explored the effi-
cacy and safety of NOACs (dabigatran, apixaban, and rivaroxaban) compared to
warfarin in VTE treatment in morbidly obese patients (bodyweight of >120 kg or
BMI > 40 kg/m2). The study included five observational studies (Spyropoulos et al.
2019; Kushnir et al. 2019; Sa et al. 2019; Quan et al. 2020; Perales et al. 2020) find-
ing that NOACs are noninferior to warfarin for efficacy (recurrence of VTE) and
safety outcome (MB) (Elshafei et al. 2020) (Table 9.4).
NVAF and VTE Obese Patients: Overview of NOACS Use
Several retrospective studies aimed to investigate the role of NOACs in obese

patients in both NVAF and VTE.
The Dresden NOAC Registry enrolled 3432 patients on dabigatran (n = 348,
10.1%), rivaroxaban (n = 2104, 61.3%), apixaban (n = 685, 20%), or edoxaban
(n = 285, 8.6%) treatment both for NVAF and VTE. Of the all cohort, 731 had a
BMI of 30.0–34.9 kg/m2 and 346 had a BMI of ≥35 kg/m2. Authors found that
Table 9.4 NOACs in VTE obese patients
164
Patients Obese patients

References Study design NOAC (n) (%) Outcomes
Spyropoulos et al. Retrospective matched cohort study Rivaroxaban 2890 2890 Recurrent VTE
(2019) Rivaroxaban vs. warfarin in obese matched pair matched pair OR (95% CI)
patients (100%) 0.99 (0.85–1.14)
P = 0.84
MB
OR (95% CI)
0.75 (0.47–1.19)
P = 0.22
Costa et al. Retrospective matched cohort study Rivaroxaban 6755 6755 Recurrent VTE
(2020b) Rivaroxaban matched matched pairs HR (95% CI)
vs. warfarin in obese patients pairs (100%) 3 months 0.61 (0.51–0.72)
P = 0.43
6 months 0.65 (0.55–0.77)
P = 0.59
12 months 0.63 (0.54–0.74)
P = 0.61
MB
HR (95% CI)
3 months 0.99 (0.68–1.44)
P = 0.71
6 months 0.90(0.64–1.26)
P = 0.72
12 months 1.00 (0.73–1.36)
P = 0.58
R. Bottino et al.
Coons et al. Retrospective 2:1 propensity score Dabigatran 1840 1840 Recurrent VTE
(2020) match cohort study Rivaroxaban (100%) HR (95% CI)
NOACs vs. warfarin in obese patients Apixaban 1.03 (0.71–1.50)
(100–300 kg) Bleeding
NOACs 11 (1.7%) of 632
Warfarin 14 (1.2%) of 1208
P = 0.31
Elshafei et al. Systematic review and metanalysis Rivaroxaban 6585 6585 Recurrent VTE
(2020) (5 studies) (100%) OR (95% CI)
NOACs vs. warfarin in extreme obese 1.07 (0.93–1.23)
patients P = 0.69
MB
OR (95% CI)
0.80 (0.54–1.17)
P = 0.98
NOACs non-vitamin K oral anticoagulants, VTE venous thromboembolism, HR hazard ratio, OR odds ratio, CI confidential interval, MB major bleeding, HR
and OR are expressed with warfarin as reference category, except where explicitly reported
165
on-treatment rates of clinical outcomes (S/SE, TIA, VTE, MB) were lowest in over-
weight and obese patients (Tittl et al. 2018) (Table 9.5).
The retrospective, single-center analysis of Duperreault et al. (2020) compared
new or recurrent VTE, stroke, and TIA (major outcomes) and incidence of major or
minor bleeding events (minor outcome) between morbidly obese and nonobese
patients prescribed apixaban or rivaroxaban for NVAF or VTE. Obese patients with
BMI from 30.1 to 39.9 kg/m2 were excluded to specifically compare nonobese
patients with extreme obese ones. The cohort included 291 patients, 153 of whom
were morbidly obese and 138 of whom were nonobese. No differences between
groups were observed for major outcomes (P = 0.67) but MB occurred less fre-
quently in morbidly obese patients (P = 0.02).
Choi and colleagues collected data on 390 obese patients (BMI >40 kg/m2) on
OAC treatment for NVAF or prior VTE (Choi et al. 2017). In the final cohort of the
182 apixaban-treated patients, 124 had AF and 58 a prior VTE while of the 212
warfarin-treated patients, 124 had AF and 88 a prior VTE. Authors could not dem-
onstrate a statistically significant difference in the rate of recurrent VTE or in the
rate of stroke in the apixaban group compared to warfarin group (recurrent VTE:
1.7% vs. 1.1%, OR 1.53, P = 0.76; rate of stroke: 0.8% vs. 2.4%, OR 0.33, P = 0.3)
because of the small population size. Regarding bleeding events rate, no statistically
significant difference was found between groups (apixaban group: 8.3% vs. warfa-
rin 12.0%, OR 0.67, P = 0.23), but MB was significantly less common in patients on
apixaban (0.6% vs. 4.3%, OR 0.12, P = 0.02) (Choi et al. 2017).
Kushnir and coworkers conducted a single-center, retrospective analysis on 795
patients with a BMI of at least 40 kg/m2 who were prescribed apixaban (150), riva-
roxaban (326), or warfarin (319) for VTE (n = 366) or NVAF (n = 429) to compare
incidence of recurrence of VTE, stroke, and bleeding between groups. In VTE
patients, no significant differences were found between treatment groups in the inci-
dence of recurrent VTE or for bleeding event. In NVAF patients, while incidence of
stroke was similar between treatment groups, MB occurred more often in warfarin-
treated patients: 3/103 patients on apixaban (29%, 95% CI: 0–6.2), 5/174 on rivar-
oxaban (29%, 0.4–5.4), and 12/152 on warfarin (79%, 3.6–12.2); P = 0.063 (Kushnir
et al. 2019).
Similar results emerged in the retrospective study of 90 obese patients prescribed
apixaban (n = 41, 52%), rivaroxaban (n = 33, 37%), dabigatran (n = 11, 12%), or
warfarin for NVAF or VTE conducted by Kalani et al. No statistical difference
between NOACs and warfarin was found for S/SE (OR 1.11, 95% confidence inter-
val [CI] 0.45–2.78; P = 0.82) and MB events (P = 0.065) (Kalani et al. 2019).
Table 9.5 summarize results from these studies.
Table 9.5 NOACs in both NVAF and VTE obese patients
Tittl et al. (2018) Retrospective analysis of Dabigatran 3432 1077 Combined Endpoint
prospective registry Rivaroxaban (31.4%) On treatment rate events (%)
Efficacy and safety of Apixaban VTE (BMI ≤ 30) 24/770 (3.1)
NOACs in obese patients Edoxaban VTE (BMI ≥ 30) 6/285(2.1)
NVAF(BMI ≤ 30) 74/1556(4.8)
NVAF(BMI ≥ 30) 33/778(4.2)
MB
On treatment rate events (%)
VTE (BMI ≤ 30) 24/770 (3.1)
VTE (BMI ≥ 30) 9/285 (3.2)
NVAF(BMI ≤ 30) 104/1556(6.7)
NVAF(BMI ≥ 30) 44/778(5.7)
Duperreault et al. Retrospective matched Rivaroxaban 291 153 Thrombotic events

(2020) cohort study Apixaban (52.6) Number of events (%)
Rivaroxaban and apixaban in Nonobese 3(1.2)
morbidly obese vs. nonobese Morbidly obese 2(2.2)
P = 0.67
MB
Number of events (%)
Nonobese 7 (5.1)
Morbidly obese 1 (0.7)
P = 0.02
(continued)
167
168

Choi et al. (2017) Retrospective cohort study Apixaban 390 1840 Recurrent VTE
Apixaban vs. warfarin in (100%) Apixaban 1.7%
morbidly obese patients Warfarin 1.1
OR 1.53, P = 0.76
Stroke
Apixaban 0.8%
Warfarin 2.4%
OR 0.33 P = 0.31
MB
Apixaban 0.6%
Warfarin 4.3%
OR 0.12, P = 0.02
R. Bottino et al.
Kushnir et al. Retrospective cohort study Rivaroxaban 795 6585 Recurrent VTE
(2019) NOACs vs. warfarin in Apixaban (100%) Incidence rate (95% CI)
morbidly obese patients Apixaban 2.1% (0.0–6.3)
Rivaroxaban 2.0% (0.0–4.2)
Warfarin vs. NOACs 1.2% (0.0–2.9)
P = 0.74
MB (VTE patients)
Incidence rate (95% CI)
Apixaban 2.1% (0.0–6.3)
Warfarin vs. NOACs 2.4 (0.1–4.7)
P = 0.77
Stroke (NVAF patients)
Apixaban 1.0% (0.0–2.9)

Warfarin vs. NOACs 1.3% (0·0–3.1)
P = 0.71
MB (NVAF patients)
Apixaban 2.9% (0.0–6.2)
Rivaroxaban 2∙9% (0.4–5.4)
Warfarin vs. NOACs 7∙9% (3.6–12.2)
P = 0.063
(continued)
169
170

Kalani et al. Retrospective cohort study Dabigatran 180 S/SE
(2019) NOACs vs. warfarin in Rivaroxaban OR (95% CI)
morbidly obese patients Apixaban 1.11 (0.45–2.78)
P = 0.82
MB
OR (95% CI)
0.66 (0.11–4.04)
P = 0.65
NOACs non-vitamin K oral anticoagulants, NVAF non-valvular atrial fibrillation, VTE venous thromboembolism, OR odds ratio, CI confidential interval, S/SE
stroke/systemic embolism, MB major bleeding, BMI body mass index in kg/m2. OR are expressed warfarin as reference category, except where explicitly
reported
R. Bottino et al.
Discussion
Obesity is clearly related to a higher risk of morbidity and mortality in general

population (Aune et al. 2016; Di Angelantonio et al. 2016). However, in several
CVD (coronary artery disease, hypertension, heart failure), it has been demonstrated
an obesity paradox using BMI as an obesity parameter (Uretsky et al. 2007; Fonarow
et al. 2007; Gruberg et al. 2002; Oreopoulos et al. 2009). In VTE and NVAF patients
and more in NOACs use in obese patients, results from the literature are very
controversial.
Although quick and easy to establish, BMI do not take into account the differ-
ence in mass composition (fat versus lean) and fat distribution (Nuttall 2015) so that
results from available data can be confounded by the use of this parameter to define
obesity. To fully understand the association between obesity and CV outcomes, it
could be necessary to use other obesity indexes as waist circumference (WC), waist-
to-hip ratio (WHR), waist-to-height ratio (WHtR), and waist-to-hip-to-height ratio
(WHHR), all of them predictors of all-cause and CV mortality (Coutinho et al.
2011, 2013; Sahakyan et al. 2015). Moreover, obesity paradox demonstrated
through BMI has been predominantly observed in overweight an obese I patients,
with morbidly obese patients generally poorly represented (Antonopoulos
et al. 2016).
Due to these controversial evidences, it is reasonable to hypothesize that a sub-
group of obese patients who have a better fitness status (not meeting metabolic
syndrome criteria and performing a better exercise test) can show a CV prognosis
similar to that of normal weight patients (Ortega et al. 2013).
Even if several studies tried to highlight an obesity paradox in NVAF and VTE,
the percentage of extremely obese patients in such studies is generally small and
only a few are directly targeted to study this population (El-Menyar et al. 2018;
Kubitza et al. 2007; Upreti et al. 2013; Piran et al. 2018; Tittl et al. 2018; Duperreault
et al. 2020). Use of NOACs in extremely obese patients is a major concern in clini-
cal practice, and evidences supporting their use are lacking and controversial. On
the other hand, NOACs have demonstrated to be as effective and safe as VKAs in
several particular settings in which no RCTs are available (Russo et al. 2018a; b,
2019a, b, c; Melillo et al. 2020; Rago et al. 2019) so that even in the obesity field it
might be a possibility.
Moreover, NOACs in real-life experiences tend to show good outcomes, main-
taining the efficacy and safety profile demonstrated in the main RCTs (Russo et al.
2015, 2017a, b, 2020a; ). Anyway, in real-world data too, there are sparse and con-
troversial evidences regarding obese population. In fact, while some real-world reg-
istries (ETNA-VTE Europe 2020), subgroup analysis (Deitelzweig et al. 2019), and
case report (Russo et al. 2020b, c) found that NOACs have comparable risk of S/SE
compared to VKAs, some others report treatment failure in this subset of patients
(Breuer et al. 2013; Safouris et al. 2014).
Overall, the available presented data seems to suggest that NOACs are effective
and safe used in high-weight/BMI patients especially when compared to low body
weight patients who are generally more associated with a poor prognosis (Russo
et al. 2020d). Even so, it is important to note that all studies we have reported are
retrospective and the majority relatively small with obvious limits related to their
final conclusions.
Conclusion
Obesity paradox is a challenging and new concept in CVD. It can be applied to

NVAF and VTE and in anticoagulated patients with NOACs. Emerging data sug-
gests that obese patients on NOACs have similar CV outcomes compared to VKAs
users but more extensive and RCTs are necessary to confirm these preliminary
observations.
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Direct Oral Anticoagulation in Cancer
Patients 10
Antonello D’Andrea, Paolo Golino, Gerardo Nigro,
and Vincenzo Russo
Introduction
Thrombosis is the second leading cause of mortality in cancer patients (Prandoni

et al. 2005; Noble and Noble 2006). Venous thromboembolism (VTE) , arterial
thromboembolism, and disseminated intravascular coagulation are all possible
manifestations of cancer-mediated thrombosis (Levi 2014; Eichinger 2016). Atrial
fibrillation (AF) and VTE are two common thromboembolic cardiovascular disease
(CVD) largely represented in cancer patients. Several studies showed an increased
risk of AF after cancer first diagnosis (O’Neal et al. 2015; Hu et al. 2013; Guzzetti
et al. 2002) and VTE is estimated to occur in approximately 20% of cases (Blom
et al. 2005; Khorana and Francis 2018; Walker et al. 2013) being one of the leading
causes of death in cancer patients receiving chemotherapy (Khorana et al. 2007).
Anticoagulation is the main prophylactic and treatment regimen in patients suffer-
ing thromboembolic events. A number of risk factors (Mandala et al. 2011) and
pathogenetic mechanisms (Falanga et al. 2015) are involved in cancer-mediated
thrombosis. Anticoagulation exposes cancer patients to an increased risk of bleed-
ing, especially when compared to anticoagulated non-cancer patients (Hull et al.
2006; Hutten et al. 2000; Meyer et al. 2002; Schulman et al. 2013; Prandoni et al.
2002; Palareti et al. 2000). Therefore, the prophylaxis and treatment management of
Roberta Bottino and Andreina Carbone contributed equally with all other contributors.
R. Bottino · A. Carbone · P. Golino · G. Nigro · V. Russo (*)

Division of Cardiology, University of Campania “Luigi Vanvitelli,” Monaldi Hospital,
Naples, Italy
B. Liccardo
Department of Cardiology, Monaldi Hospital, Naples, Italy
A. D’Andrea
Department of Cardiology, Umberto I° Hospital Nocera Inferiore, Campania, Italy

thromboembolic events is challenging in this subset of patients. In general popula-

tion direct acting oral anticoagulants (DOACs) are preferred over Vitamin K antago-
nists (VKAs) for treatment of VTE and stroke prevention in AF (Hindricks et al.
2020; Konstantinides et al. 2020). Little is still known about use of DOACs in can-
cer patients with AF with evidences only available from retrospective, observational
and subgroup analysis of randomized clinical trial (RCTs) and no available specific
guidelines (Russo et al. 2019a; Deng et al. 2019; Yang et al. 2020). More data are
available for treatment with DOACs in VTE cancer patients. However, major guide-
lines still recommend low molecular weight heparin (LMWH) for VTE treatment in
this subgroup of patients (Farge et al. 2016; Kearon et al. 2016; Lyman et al. 2015)
with the exception of rivaroxaban and edoxaban who were directly compared with
LMWH (Khorana et al. 2018). Due to the more favorable pharmacological profile
of DOACs over VKAs and LMWH, deepening the knowledge in this field is manda-
tory. For this reason, we aim to review the available data on the use of DOACs in AF
cancer patients for stroke prevention and for treatment of cancer-mediated
thrombosis.
Use of DOACs in AF Cancer Patients
Literature data for the use of DOACs in AF cancer patients are generally lacking.
The main RCTs of DOACs have included a small number of patients with cancer
due to reduced life expectancy or an excessively high risk of bleeding in patients
with malignancies (Connolly et al. 2009; Granger et al. 2011; Patel et al. 2011;
Giugliano et al. 2013).
Recently several studies have explored the role of DOACs in this subgroup of
patients (Russo et al. 2019a; Deng et al. 2019; Yang et al. 2020).
From the observational and metanalytical results obtained, it was possible to
conclude that DOACs could be a valid alternative to VKAs for stroke prevention in
AF cancer patients (Russo et al. 2019a; Deng et al. 2019; Yang et al. 2020).
From the systematic review including six studies by Russo (Russo et al. 2019a)
and colleagues emerged that efficacy and safety profile of DOACs in AF cancer
patients are maintained when compared to that of general population. Specifically,
some interesting results emerge from this descriptive analysis: (a) the annual inci-
dence of bleedings, ischemic stroke, and thromboembolic events in AF cancer
patients on DOAC therapy is generally small compared with VKAs (range for
bleedings:1.2–4.4% (Melloni et al. 2017; Laube et al. 2017); range for ischemic
stroke and thromboembolic events: 0–4.9% (Ording et al. 2017; Russo et al. 2018));
(b) the risk of thromboembolic and bleeding events in AF cancer patients is similar
to that of non-cancer patients, irrespective of the treatment they are prescribed
(DOACs vs VKAs) (Ording et al. 2017); (c) in DOACs patients, the risk of stroke,
thromboembolic, and bleeding complications is similar between cancer and non-
cancer patients (Melloni et al. 2017; Ording et al. 2017); and (d) when gastrointes-
tinal bleedings occur, clinical characteristics are similar between those occurring on
dabigatran and those on warfarin (hospitalization rate, mean nights in hospital,
10 Direct Oral Anticoagulation in Cancer Patients 181
intensive care unit requirement, transfusion requirement, the need for endoscopic,
and surgical intervention) (Russo et al. 2019a; Flack et al. 2017). Details of the stud-
ies included in Russo et al. analysis are available in Table 10.1.
Deng and Yang’s working groups separately conducted a meta-analysis of five
studies (Deng et al. 2019; Yang et al. 2020) [three post hoc analyses from three
RCTs (Melloni et al. 2017; Fanola et al. 2018; Chen et al. 2019), one retrospective
propensity score-matched study (Shah et al. 2018), and one retrospective population-
based observational data study (Kim et al. 2018)].
The pooled analysis from the three post hoc analyses of the Apixaban Versus
Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial (Melloni et al.
2017), Rivaroxaban Versus Warfarin in Non-valvular Atrial Fibrillation
(ROCKET-AF) trial (Chen et al. 2019), and the Edoxaban Versus Warfarin in
Table 10.1 Principal characteristics and results of the studies included in Russo et al. system-
atic review
Cancer patients
on DOACs Outcomes
References Study design n (%) HR (95% CI)
Ording et al. Restrospective cohort 1809 TE eventsa,b VKA
(2017) study (15.2%) n/N Cancer vs. cancer
free
628/10,046 vs.
2734/49,057
(6.5% vs. 5.8%)
HR, 1.0 (0.93–1.1)
DOACs
Cancer vs. cancer
free
65/1809 vs.
290/7207
(4.9% vs. 5.1%)
HR, 0.80 (0.61–1.1)
MBa,c VKA
n/N Cancer vs. cancer
free
513/10,046 vs.
2025/49,057
(5.4% vs. 4.2%)
HR, 1.1 (1.0–1.2)
DOACs
Cancer vs. cancer
free
60/10,046 vs.
166/49,057
(4.4% vs. 3.1%)
HR, 1.2 (0.92–1.7)
(continued)
Cancer patients
on DOACs Outcomes
Flack et al. RE-LY 34 MGIBd Overall
(2017) Post hoc analysis (77.2%) related to GI (N = 546)
cancers Dabigatran vs.
(N = 44) warfarin
n/N 34/398 vs. W:10/148
(8.5% vs. 6.8%)
P = 0.6
Colorectal cancer
N = 35/44 (79.5%)
Dabigatran vs.
Warfarin
30/34 vs. 5/10
(88.2% vs. 50.0%)
P = 0.02
Gastric cancer
N = 6
Dabigatran vs.
warfarin
1/34 vs. 5/10
(2.9% vs. 50%)
Melloni et al. ARISTOTLE 615 S/SEa Cancer
(2017) Post hoc analysis (49.8%) n/N Apixaban vs.
warfarin
15/615 vs. 14/621
(1.4% vs. 1.2%)
HR, 1.09
(0.53–2.26)
Cancer free
Apixaban vs.
warfarin
196/8493 vs.
251/8454
(1.3% vs. 1.6%)
HR, 0.77
(0.64–0.93)
MBa Cancer
n/N Apixaban vs.
warfarin
24/615 vs. 32/621
(2.4% vs. 3.2%),
HR, 0.76
(0.45–1.29)
Cancer free
Apixaban vs.
warfarin
303/8493 vs.
430/8454
(2.1% vs. 3.1%)
HR, 0.69
(0.59–0.80)
Cancer patients
on DOACs Outcomes
Laube et al. Retrospective cohort 163 Stroke 1 year cumulative
(2017) study (100%) incidence
(vs. ROCKET-Trial)
1.4% (vs. 1.7%)
(0–3.4%)
MBd 1 year cumulative
incidence
(vs. ROCKET-Trial)
1.2% (vs. 3.6%)
(0–2.9)
Russo et al. Retrospective cohort 76 TE eventse 0
(2018) study (100%) MBd Cumulative
incidence
3.9%
Annual incidence
1.4%
Iannotto et al. Case–control study 25 TE eventsf NOACs vs. LDA
(2017) (3.3%) Incidence rate n, (%)
1 vs. 2
(4–8%)
MBd NOACs vs. LDA
Incidence rate n, (%)
3 vs. 3
(12% vs. 12%)
DOACs direct oral anticoagulants, VKA vitamin K antagonists, HR hazard ratio, CI confidential
interval, TE thromboembolic event, MB major bleeding, MGIB major gastrointestinal bleeding, GI
gastrointestinal, S/SE stroke/systemic embolism, LDA low-dose aspirin
a
Annual incidence
b
Recurrence of ischemic stroke, VTE, other arterial embolism, or myocardial infarction
c
Diagnosis of hemorrhagic stroke or GI, lung, or urinary hemorrhage
d
According to the International Society of Thrombosis and Hemostasis criteria
e
Ischemic stroke, transient ischemic attack, or systemic embolism
f
Any documented thrombosis
Patients with Atrial Fibrillation (ENGAGE-TIMI 48) trial (Fanola et al. 2018) in
Deng’s metanalysis showed that cancer and non-cancer patients have similar effi-
cacy and safety outcome (all P > 0.05) (Deng et al. 2019). Moreover, results from
the analysis of all studies included showed that cancer patients on DOACs had sig-
nificantly lower risk of stroke/systemic embolism (S/SE) (P = 0.04) and VTE
(P < 0.0001) with a trend toward a lower rate of ischemic stroke (P = 0.05). No
significant differences were found in risk of myocardial infarction (P = 0.26), all-
cause death (P = 0.39), and CV death (P = 0.13). About safety outcomes, use of
DOACs was associated with a decreased risk of intracranial or gastrointestinal
bleeding (P = 0.04) and a tendency toward statistical significance for a reduced risk
of major bleeding (MB) compared with warfarin (RR = 0.73; 95% CI: 0.53–1.00;
P = 0.05). Risks of major or clinically relevant nonmajor bleeding (CRNMB) and

any bleeding were similar between treatment groups (P = 0.96 and P = 0.39, respec-
tively) (Deng et al. 2019).
Yang et al. conducted a network meta-analysis (NMA) on the same five studies
(Yang et al. 2020; Laube et al. 2017; Fanola et al. 2018; Chen et al. 2019; Shah et al.
2018; Kim et al. 2018) to evaluate and rank anticoagulant strategies in AF cancer
patients. The rank score used was the surface under the cumulative ranking area
(SUCRA) probabilities: the larger the value, the higher the probability of the end-
point event. The NMA showed no significant differences between DOACs regard-
ing outcome (primary efficacy outcome: S/SE; secondary efficacy outcome:
all-cause death; incidental VTE was described too), with all DOACs achieving a
better efficacy profile compared with warfarin. Rivaroxaban followed by apixaban
ranked the first and second best in lowering risk of S/SE followed by dabigatran and
edoxaban and finally warfarin (SUCRAs: 25.2%, 29.3%, 52.3%, 55.8%, 87.4%,
respectively) (Yang et al. 2020). In addition, apixaban and dabigatran were associ-
ated with the lower probability and the better ranking for VTE occurrence (Yang
et al. 2020). Regarding safety outcomes (MB according to the International Society
on Hemostasis and Thrombosis (ISTH) criteria (Schulman et al. 2010)), no statisti-
cally significant differences were found between treatment groups with the excep-
tion of apixaban which was found safer than warfarin (OR 0.39, 95% CI: 0.18–0.79,
SUCRA:4.9%) (Yang et al. 2020) .
Table 10.2 shows principal characteristics and results of the five studies included
in the abovementioned metanalyses while Table 10.3 summarizes results of Deng
and Yang’s studies.
Table 10.2 Results on S/SE and MB of the studies included in Deng and Yeng meta-analysis
Cancer patients/DOACs
users with cancer Outcomes
References Study design DOAC studied HR, (95%CI)
Chen et al. Rocket-AF 640/309 S/SE History of cancer
(2019) Post hoc analysis Rivaroxaban n/N Rivaroxaban vs.
warfarin
8/307 vs. 16/329
(1.36 vs. 2.71)a
HR, 0.52 (0.22–1.21)
MB History of cancer
n/N Rivaroxaban vs.
warfarin
97/309 vs. 96/331
(23.63 vs. 21.59)
HR, 1.09 (0.82–1.44)
Shah et al. Retrospective 16,096/6075 Ischemic Dabigatran vs.
(2018) cohort study Dabigatran stroke warfarin
(2189) n/N 26/2189 vs. 127/8339
Rivaroxaban HR, 0.89 (0.56–1.42)
(2808) P = 0.63
Apixaban Rivaroxaban vs.
(1078) warfarin
16/2808 vs. 59/5673
HR, 0.74 (0.40–1.39)
P = 0.35
Apixaban vs. warfarin
4/1078 vs. 18/2775
HR, 0.71 (0.19–2.60)
P = 0.6
Dabigatran vs.
rivaroxaban
9/859 vs. 3/922
7.61 (1.52–38.12)
P = 0.01
Apixaban vs.
rivaroxaban
3/1126 vs. 13/2016
HR, 0.52 (0.13–2.17)
P = 0.37
SBb Dabigatran vs.
n/N warfarin
70/2189 vs. 329/8339
HR, 0.96 (0.72–1.27)
P = 0.75
Rivaroxaban vs.
warfarin
68/2808 vs. 181/5673
HR, 1.09 (0.79–1.50)
P = 0.59
10/1078 vs. 84/2775
HR, 0.37 (0.17–0.79)
P = 0.01
Dabigatran vs.
rivaroxaban
22/859 vs. 22/922
HR, 1.07 (0.50–2.32)
P = 0.86
Apixaban vs.
rivaroxaban
10/1126 vs. 43/2016
HR, 0.29 (0.13–0.65)
P = 0.002
(continued)
Fanola et al. ENGAGE 1153/395 S/SE Cancer
(2018) AF-TIMI 48 Edoxaban Edoxaban vs. warfarin
Post hoc analysis 14/390 vs. 24/395
c
(1.43 vs. 2.38)
HR, 0.60 (0.31–1.15)
No Cancer
Edoxaban vs. warfarin
282/6645 vs. 313/664
c
(1.58 vs 1.77)
HR, 0.89 (0.76–1.05)
P-interaction = 0.25
MB Cancer
56/390 vs. 63/395
c
(7.92 vs. 8.18)
HR, 0.98 (0.68–1.4)
No cancer
388/6645 vs. 494/6641
c
(2.62 vs. 3.34)
HR, 0.98 (0.68–1.4)
P-interaction = 0.31
Melloni ARISTOTLE 1236/615 S/SE Cancer
et al. (2017) Post hoc analysis Apixaban n/N Apixaban vs. warfarin
15/615 vs. 14/621
(1.4% vs. 1.2%)
HR, 1.09 (0.53–2.26)
Cancer free
196/8493 vs. 251/8454
(1.3% vs. 1.6%)
HR, 0.77 (0.64–0.93)
MB Cancer
n/N Apixaban vs. warfarin
24 /615 vs. 32/621
(2.4% vs. 3.2%),
HR, 0.76 (0.45–1.29)
Cancer free
303/8493 vs. 430/8454
(2.1% vs. 3.1%)
HR, 0.69, (0.59–0.80)
Kim et al. Retrospective 1651/388d S/SE NOACs vs. warfarin
(2018) cohort study Dabigatran n/N 9/388 vs. 40/388
(140) (1.3 vs. 5.5)a
Apixaban P = <0.001
(138) MB NOACs vs. warfarin
Rivaroxaban n/N 8/388 vs. 36/388
(110)
(1.2 vs. 5.1)a
P = <0.001
DOAC direct oral anticoagulants, MB major bleeding, S/SE stroke/systemic embolism, SB severe
bleeding, CI confidential interval
a
Events per 100-patient years
b
Subarachnoid hemorrhage, intracerebral hemorrhage, gastrointestinal bleeding requiring transfu-
sion and not trauma related
c
Annualized event rate (100-patient/year)
d
Propensity scored matched with 388 warfarin users
Table 10.3 Principal results of the metanalysis exploring safety and efficacy of DOACs versus
warfarin in cancer patients with AF
Studies included Outcomes
References (n, reference) a
RR/OR, (95% CI)
Deng et al. (2019) Efficacy S/SE
outcome RR, 0.52 (0.28–0.98)
Ischemic stroke
RR, 0.63 (0.4–1.0)
VTE
RR, 0.37 (0.22–0.63)
MI
RR, 0.75 (0.45–1.25)
All-cause death
RR, 0.81 (0.49–1.32)
CV death
RR, 0.71 (0.45–1.1)
Safety MB
outcome RR, 0.73 (0.53–1.0)
MB or CRNMB
RR, 1.00 (0.86–1.17)
Intracranial or gastrointestinal bleeding
RR, 0.65 (0.42–0.98)
Any bleeding
RR, 0.93 (0.78–1.10)
(continued)
References (n, reference) a
RR/OR, (95% CI)
Yang et al. (2020) Efficacy S/SE Dabigatran
outcome 0.6 (0.18–1.80)
Apixaban
0.48 (0.17–1.30)
Rivaroxaban
0.47 (0.18–1.2)
Edoxaban
0.71 (0.11–4.5)
VTE Dabigatran
0.24 (0.07–1.00)
Apixaban
0.12 (0.05–0.52)
Rivaroxaban
0.56 (0.25–2.0)
All-cause death Dabigatran
0.43 (0.10–1.8)
Apixaban
0.72 (0.24–2.00)
Rivaroxaban
0.62 (0.21–1.80)
Edoxaban
1.1 (0.24–4.8)
Safety MB Dabigatran
outcome 0.64 (0.25–1.4)
Apixaban
0.39 (0.18–0.79)
Rivaroxaban
0.65 (0.30–1.20)
Edoxaban
0.78 (0.21–2.9)
SUCRAb S/SE Rivaroxaban
25.2%
Apixaban
29.3%
Dabigatran
52.3%
Edoxaban
55.8%
Warfarin
87.4%
VTE Apixaban
0.1%
Dabigatran
33.3%
Rivaroxaban
66.7%
Warfarin
100%
MB Apixaban
4.9%
Rivaroxaban
47.1%
Dabigatran
47.3%
Edoxaban
62.4%
Warfarin
88.4%
References (n, reference) RR/OR, (95% CI)
a
DOAC direct oral anticoagulant, AF atrial fibrillation, S/SE stroke systemic embolism, VTE venous
thromboembolism, MB major bleeding, CRNMB clinically relevant non major bleeding, CV car-
diovascular, MI myocardial infarction, SUCRA surface under the cumulative ranking area, CI con-
fidential interval
a
RR in Deng’s results, OR in Yeng results
b
NOACs are listed near the corresponding outcome from the better SUCRA to the worst
VTE in Cancer Patients: Are the DOACs Always the Best Choice?
VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a
common complication of cancer, and its prevention and treatment is a challenge
because of the drug interactions and varieties of coexisting comorbidities (Khorana
2010). According to a large observational cohort study, the incidence of VTE in
active cancer patients is 5.8 per 100 person-years (Cohen et al. 2017). Cancer
patients are usually in a state of hypercoagulability that results from various factors,
including the type of malignancy, extent of disease, patient age, antitumor treat-
ment, and the presence of coexisting diseases (Zwicker et al. 2007). The highest rate
of VTE was observed among patients receiving systemic cancer therapy for tumors
of the pancreas, stomach, or lung (Khorana et al. 2007; Blom et al. 2006; Chew
et al. 2006; Lyman et al. 2013). VTE is an important cause of death in cancer patients
as it is second only to tumor progression (Khorana et al. 2007). VTE can lead to a
series of comorbidities, such as longer hospitalization, higher risk of bleeding, and
delay or discontinuation of chemotherapy, which may affect patients’ quality of life
and prognosis (Carrier and Lee 2014). For these reasons, the choice of the best anti-
coagulation therapy is mandatory for this group of patients.
Primary Prevention of VTE in Cancer Patients
Pharmacological prophylaxis can reduce VTE incidence, but it may also increase
the risk of bleeding (Agnelli et al. 2009; Khorana et al. 2017). According to existing
research, the most commonly used anticoagulant drugs are LWMH and warfarin.
Many large RCTs have demonstrated the efficacy and safety of anticoagulants to
reduce the incidence of VTE events in ambulatory cancer patients. The PROTECHT
study, involving 1150 patients, has shown that nadroparin reduces the incidence of
VTE events without significantly increasing bleeding risks (Agnelli et al. 2009).
The SAVE ONCO study involving 3212 patients has shown similar results using the
ultra-LMWH semuloparin (Agnelli et al. 2012). However, current guidelines do not
recommend the routine thromboprophylaxis in patients receiving chemotherapy
(Lyman et al. 2015; https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf)
. A systematic review published in the Cochrane Library has indicated some posi-
tive results for thromboprophylaxis, but routine thromboprophylaxis is not
indicated in ambulatory cancer patients, and the evaluation of the risks and benefits
is necessary before its prescription in high-risk patients (Di Nisio et al. 2016). The
risk differs among cancer patients, and the Khorana risk score allows for identifica-
tion of patients with cancer at increased risk for VTE (Khorana et al. 2008).
In recent years, DOACs have played an increasingly important role in clinical
practice (Russo et al. 2015, 2019a, b; Russo et al. 2020a, b, c, d). DOACs have
been shown to be safe, effective, and well tolerated for VTE among non-cancer
patients (Agnelli et al. 2013; Prins et al. 2013). RCTs comparing DOACs with
placebo have been performed for primary prophylaxis in cancer patients with
inconstant results for the incidence of VTE events and bleeding complications
(Khorana et al. 2019; Carrier et al. 2019). Studies of thromboprophylaxis with
LMWH in ambulatory patients with cancer have demonstrated that anticoagula-
tion is associated with a significant relative risk reduction in VTE, but current
clinical guidelines do not recommend routine outpatient VTE prophylaxis (except
for multiple myeloma and select high-risk solid tumors), because the overall ben-
efit-to-risk profile in an unselected patient population is uncertain (Khorana et al.
2019; Carrier et al. 2019). CASSINI trial (Khorana et al. 2020) is a randomized
clinical study that compares the efficacy and safety of rivaroxaban with placebo in
the prevention of VTE in high-risk ambulatory patients with cancer receiving sys-
temic cancer therapy, as determined by the validated Khorana risk score. This
study confirms the benefit of rivaroxaban in thromboprophylaxis, but only after
determining the risk/benefit of anticoagulation in high-risk patients with cancer
(Khorana et al. 2020).
Also, apixaban was tested in this setting in the AVERT trial (Carrier et al. 2019).
Apixaban therapy resulted in a significantly lower rate of VTE than placebo among
intermediate-to-high-risk ambulatory patients with cancer who were starting che-
motherapy. The rate of MB episodes was higher with apixaban than with placebo
(Carrier et al. 2019).
High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting
a new systemic chemotherapy regimen) may be offered thromboprophylaxis with
apixaban, rivaroxaban, or LMWH provided there are no significant risk factors for
bleeding and no drug interactions (Lyman et al. 2015). Consideration of such ther-
apy should be accompanied by a discussion with the patient about the relative ben-
efits and harms (Lyman et al. 2015).
At present, no anticoagulant is approved for routinely primary thromboprophy-
laxis in outpatients with cancer.
Treatment of VTE in Cancer Patients
In the general population, the efficacy and safety of DOACs in the long-term ther-
apy of VTE were demonstrated in six large randomized trials (RECOVER I-II;
EINSTEIN-TVP, EINSTEIN-TEP; AMPLIPHY; HOKUSAI TEV). Post hoc analy-
sis and meta-analysis suggested efficacy and safety of DOACs in patients with
cancer, but these patients were underrepresented, not well identified for the type of
oncological diagnosis and treatment, and finally the definition of “active cancer”
varied greatly from one study to another.
Recent randomized trials have investigated the efficacy of DOACs among cancer
patients with VTE (Agnelli et al. 2020; Raskob et al. 2018; Young et al. 2018;
McBane et al. 2020). These trials have some limitations: one was a pilot trial (Young
et al. 2018), whereas another small trial was prematurely terminated (McBane et al.
2020). Moreover, the two large studies were noninferiority trials and not powered to
evaluate the safety of DOACs in this setting (Agnelli et al. 2020; Raskob et al.
2018). The Table 10.4 summarizes the most important characteristics of these
studies.
Furthermore, a sub-analysis of the HOKUSAI-VTE cancer study has evaluated
the occurrence of the composite outcome, recurrent VTE, or MB in subgroups based
on adjudicated cancer diagnoses, including those with gastrointestinal, lung, uro-
genital, breast, hematological, and gynecological cancer. In the gastrointestinal can-
cer group, the benefit–risk trade-off requires careful evaluation because edoxaban
was associated with an absolute 9.2% increase in MB compared with dalteparin.
The absolute risk of recurrent VTE was 3.9% numerically lower with edoxaban.
Oral edoxaban is an attractive alternative to subcutaneous dalteparin for the treat-
ment of the majority of patients with cancer-associated VTE, including those with
urogenital, lung, breast, hematological, and gynecological cancer (Mulder
et al. 2020).
Based on the currently available evidence, the guidelines of European Society of
Cardiology and of American Society of Clinical Oncology (Konstantinides et al.
2020; Lyman et al. 2015) recommend that patients with VTE and cancer, particu-
larly those with gastrointestinal cancer, should be encouraged to continue LMWH
for 3–6 months. This also applies to patients in whom oral treatment is unfeasible
due to problems of intake or absorption, and to those with severe renal disease. In
all other cases, the choice between LMWH and edoxaban or rivaroxaban (the pub-
lication of the CARAVAGGIO trial on apixaban in this setting is subsequent to the
guidelines) is left to the discretion of the physician and the patient’s preference.
Owing to the high risk for recurrence, patients with cancer should receive indefinite
anticoagulation after a first episode of VTE. Renal function and drug–drug interac-
tion should be checked prior to using a DOAC.
Discussion
Compared to warfarin , DOACs have a more predictable anticoagulant effect with a

more favorable pharmacological profile, so that they are the first-line anticoagulant
treatment proposed in the general population affected by AF and VTE (Hindricks
et al. 2020; Konstantinides et al. 2020). Cancer patients are a subgroup of patients
with a delicate balance between hemorrhagic and thrombotic risk, so it is essential
to choose the right anticoagulation and the time to start it; on the other hand,
192
Table 10.4 Principal characteristics of the most important RCTs about the treatment of venous thromboembolism (deep venous thrombosis and pulmonary embolism)
in cancer patients
Mean age, Recurrent VTE (events) Major bleeding (events)
n years Male% Metastasis
Prior VTE
(DOAC/ (DOAC/ (DOAC/ (DOAC/ (DOAC/ Risk
LMWH LMWH LMWH LMWH LMWH Risk ratio ratio
groups) groups) groups) Type of tumor groups) groups) DOAC group Control group DOAC LMWH (95% CI) DOAC LMWH (95% CI)
Young et al. 203/203 67/67 57/48 Colorectal, lung, 58/58 NR Rivaroxaban Dalteparin 8/203 18/203 0.44 11/203 6/203 1.83
(Meyer et al. (median) breast cancer 15 mg BID for (CLOT (0.20–1.00) (0.69–
2002) 3 weeks, followed protocol) for 4.86)
SELECT-D by 20 mg QD for 6 months.
TRIAL 6 months.
Raskob et al. 522/524 64.3/63.7 53.1/50.2 Colorectal, lung, 52.5/53.4 9.4/12 Edoxaban 60 mg Dalteparin 41/522 59/524 0.70 36/522 21/524 1.72
(Hutten et al. breast, QD (for (CLOT (0.48–1.02) (1.02–
2000) gynecologic and 6 months) after at protocol) for 2.91)
HOKUSAI- hematologic least 5 days of 6 months.
VTE CANCER malignancies concomitant
STUDY Dalteparin
McBane et al. 150/150 64.4/64.0 72/73 Colorectal, lung, 65.3/66.0 5.4/8.1 Apixaban 10 mg Dalteparin 1/145 9/142 0.11 0/145 2/142 0.20
(Schulman et al. pancreatic and BID for 7 days (CLOT (0.01–0.85) (0.01–
2013) hepatobiliary followed 5 mg protocol) for 4.04)
BID for 6 months 6 months.
Agnelli et al. 576/579 67.2/67.2 50.7/47.7 Lung, breast, 67.5/68.4 7.8/10.5 Apixaban 10 mg Dalteparin 32/576 46/579 0.70 22/576 23/579 0.96
(Hull et al. genitourinary BID for 7 days (CLOT (0.45–1.08) (0.54–
2006) followed 5 mg protocol) for 1.71)
CARAVAGGIO BID for 6 months 6 months.
TRIAL
RCT randomized controlled trial, DOAC direct oral anticoagulants, LMWH low molecular weight heparin, VTE venous thromboembolism, CI confidence interval, CLOT
Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer trial
R. Bottino et al.
particular attention is needed for the greater risk of bleeding of the cancer patients
during anticoagulant treatment compared to the general population (Hull et al.
2006; Hutten et al. 2000; Meyer et al. 2002; Schulman et al. 2013; Prandoni et al.
2002; Palareti et al. 2000; Hindricks et al. 2020). Especially for AF cancer patients,
evidences are rare and sparse. There are no RCTs available that directly compare
DOACs to warfarin in this subgroup of patients and results emerge only from retro-
spective analysis of RCTs (Melloni et al. 2017; Flack et al. 2017; Fanola et al. 2018;
Chen et al. 2019) and from very small studies (Russo et al. 2018, 2019a; Deng et al.
2019; Yang et al. 2020; Laube et al. 2017; Shah et al. 2018; Kim et al. 2018; Ianotto
et al. 2017). However, in August 2019, the ISTH guidelines recommended the use
of DOAC over VKAs and LMWH in cancer patients receiving chemotherapy with
newly diagnosed NVAF (Delluc et al. 2019) with the exception of patients with
gastrointestinal cancer or the presence of gastrointestinal abnormalities that can
lead to gastrointestinal bleeding events. More evidence is currently available on the
use of DOACs in VTE cancer patients. Rivaroxaban, edoxaban, and recently apixa-
ban were compared directly with LMWH for the treatment of VTE in cancer
patients, demonstrating noninferiority in lowering the rate of VTE recurrence but
with some concern for bleeding events (Khorana et al. 2019; Carrier et al. 2019;
Raskob et al. 2018). Indeed, a higher risk of CRNMB mainly driven by gastrointes-
tinal bleeding events was evidenced with DOAC in cancer patients and VTE, but
such events were almost entirely referable to gastrointestinal cancer patients, which
is why guidelines still suggest the use of LMWH in patients with gastrointestinal
tumors or gastrointestinal abnormalities that may increase the risk of bleed-
ing events.
Conclusion
DOACs are a revolutionary anticoagulation treatment. Several preliminary evi-

dences suggest their effectiveness and safety in AF cancer patients but RCTs should
improve these findings. Currently it is better defined their role in VTE cancer
patients even if some concern still remains for their safety profile especially in gas-
trointestinal malignancies and above all for thromboprophylaxis for which no
defined recommendations are available due to the paucity of targeted evidences.
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DOACs and Dementia in Patients
with Atrial Fibrillation 11
Ahmed AlTurki, Hasan AlTurki, Riccardo Proietti,
and T. Jared Bunch
Introduction
Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical

practice, affecting more than 37 million people worldwide in 2017, and has been
increasing in both incidence and prevalence with an aging population (Disease et al.
2018; Chugh et al. 2014). AF is associated with increased morbidity and mortality,
including stroke, systemic and venous thromboembolism, heart failure, and myo-
cardial infarction (Wolf et al. 1991; Wang et al. 2003; Violi et al. 2016; Holst et al.
2010; Benjamin et al. 1998). Dementia is another disorder of aging, affecting over
35 million people in 2010 and also increasing worldwide with an aging population
(Licher et al. 2019; Wortmann 2012). Dementia is a neurological disorder involving
loss of cognition to a degree which affects function, and which also commonly
affects memory (Arvanitakis et al. 2019). Alzheimer’s dementia is the most com-
mon form of dementia and is responsible for up to 75% of cases (Silva et al. 2019).
Direct oral anticoagulants (DOACs) have recently become the standard of care
for most patients with non-valvular AF for the prevention of thromboembolic dis-
ease (January et al. 2019). In this chapter, we will review the association between
A. AlTurki (*)
H. AlTurki
University of British Columbia, Vancouver, BC, Canada
R. Proietti
T. J. Bunch
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah
School of Medicine, Salt Lake City, UT, USA

200 A. AlTurki et al.
AF and dementia, as well as the effects of oral anticoagulants (OACs) and specifi-
cally DOACs on the risk of dementia in patients with AF.
Atrial Fibrillation and Dementia
The association between AF and dementia has been documented by several large
observational studies. Ott and colleagues analyzed data from the Rotterdam study,
which included 6584 participants aged between 55 and 106 years. The authors
found a significant association of AF with dementia (OR: 2.3, 95% CI: 1.4–3.7) and
cognitive impairment (OR: 1.7, 95% CI: 1.2–2.5) (Ott et al. 1997). This association
was stronger in women, more pronounced in the young elderly, and independent of
a prior history of strokes, which was rigorously adjudicated (Ott et al. 1997). Mielke
et al. examined data from a cohort study of 135 elderly patients with incident
Alzheimer’s disease who were followed for a mean of 3 years with cognitive assess-
ments by clinical dementia rating and mini-mental state examinations scores. The
authors reported that participants with AF had a more rapid decline in cognition
compared to patients without AF (Mielke et al. 2007). Bunch and colleagues
explored the relationship between AF and dementia in a study of 37,025 patients
from a large prospective population-based study in Utah, USA using ICD-9 codes
to define dementia (Bunch et al. 2010). Participants had no history of dementia and
at least 5 years of follow-up data. To provide greater rigor on the diagnosis of
dementia, only ICD 9 codes entered by neurology were used. In an age-based analy-
sis, AF independently was significantly associated with all types of dementia with
the highest risk was in participants <70 years of age. Interestingly, these younger
participants (<70 years) with AF had the highest relative risk of developing
Alzheimer’s dementia (OR 2.3, P < 0.001) suggesting that the observed association
went beyond an epiphenomenon due to the common risk factor of advancing age
(Bunch et al. 2010). After dementia diagnosis, the presence of AF was associated
with a marked increased risk of mortality, around 40%, in all subtypes of dementia.
AF has been identified as an independent risk factor for dementia, including
Alzheimer’s, vascular, and senile dementia, both in patients with and without a his-
tory of stroke (Bunch et al. 2010; Kalantarian et al. 2013; Marzona et al. 2012;
Kwok et al. 2011; Santangeli et al. 2012; de Bruijn et al. 2015; Satizabal et al. 2016;
Dublin et al. 2011; Singh-Manoux et al. 2017; Saglietto et al. 2019a; Proietti et al.
2020). One meta-analysis, which included eight population-based studies with
77,668 patients, found that in patients without baseline cognitive impairment or his-
tory of stroke, AF was associated with increased risk of incident dementia (HR 1.42,
95% CI: 1.17–1.72) (Santangeli et al. 2012). Of the patients included, 15% had AF
at baseline; the mean follow-up was 7.7 ± 9.1 years (range 1.8–30 years), and the
incidence of dementia was 6.5%. A systematic review by Kalantarian and col-
leagues, which included 21 studies, demonstrated an increase in relative risk of
cognitive impairment in patients with AF and history of stroke (RR 2.7, 95% CI:
1.82–4.00) and independent of stroke history (RR 1.34, 95% CI: 1.13–1.58)
(Kalantarian et al. 2013). Kwok et al. performed a meta-analysis of 15 studies which
included 46,637 participants with a mean age 71.7 years. This showed that AF was
11 DOACs and Dementia in Patients with Atrial Fibrillation 201
associated with significant increase in dementia overall (OR 2.0, 95% CI: 1.4–2.7,
P < 0.0001) (Kwok et al. 2011). Interestingly, one of the included studies showed
that conversion of mild cognitive impairment to dementia had a significant associa-
tion with AF (OR 4.6, 95% CI: 1.7–12.5).
otential Mechanisms in the Association Between AF

P
and Dementia
The association between AF and dementia is likely multifactorial with numerous

possible contributing mechanisms, including stroke, subclinical cerebral infarcts,
microvascular bleeds, and cerebral hypoperfusion (Alonso and Arenas de Larriva
2016). These mechanisms are summarized in Fig. 11.1 (Gallinoro et al. 2019).
Patients with AF can develop micro thromboembolisms leading to silent infarcts,
with about a third of patients with AF being found to have evidence of such on MRI
imaging (Hara et al. 1995). Repeated subclinical infarcts are likely the cause of
increased risk of vascular dementia in patients with AF.
Over the last 30 years, the incidence of dementia has been declining. (Satizabal
et al. 2016) This may be partly attributable to the increased use of anticoagulation in
patients with AF. This is supported by a study of patients on long-term warfarin which
showed that those with AF were more likely to develop dementia than those on warfa-
rin for other indications (HR 2.42, 95% CI: 1.85–3.18, P < 0.0001) and that higher time
spent in therapeutic range was associated with reduced risk of developing dementia
regardless of AF status (Bunch et al. 2016). However while anticoagulation reduces the
Sinus rhythm
Cognitive
Dysfunction
Cognitive
Impairment
Dementia
Genetic Factors
Reduced Cerebral Blood Flow
Aging
Reduced Cerebral Mass
Anticoagulation
Microbleeds
Blood Stasis
Silent Cerebral Infarct

Atrial Fibrillation
Embolic stroke
Prothrombotic state
Neuroinflammation
Fig. 11.1 Mechanisms involved in cognitive dysfunction in patients affected by atrial fibrillation.
Gallinoro E, D’Elia S, Prozzo D, Lioncino M, Natale F, Golino P, et al. Cognitive Function
and Atrial Fibrillation: From the Strength of Relationship to the Dark Side of Prevention. Is
There a Contribution from Sinus Rhythm Restoration and Maintenance? Medicina
(Kaunas). 2019;55(9)
risk of stroke in patients with AF, it also carries the risk of microvascular brain bleeds
which may increase the risk of cognitive impairment (Saito et al. 2014). In a study of
patients with AF on both warfarin and an antiplatelet agent, patients who had an INR
over 3 for more than 25% of the time were 2.40 times more likely to develop dementia
(P = 0.04), with no difference in risk seen in those who spent less than 25% of the time
with an INR over 3. This supports the hypothesis that microvascular bleeds leading to
chronic cerebral injury play a role in the association between AF and dementia (Jacobs
et al. 2015a). Additionally, in patients on warfarin, the risk of dementia increased with
increasing CHADS2 scores, and AF was associated with increased risk of dementia
across all CHADS2 score strata. This suggests that the risk of dementia attributed to AF
is not solely secondary to OAC use (Graves et al. 2017).
Another possible mechanism relates to AF associated cerebral hypoperfusion
(Petersen et al. 1989; Lavy et al. 1980; Anselmino et al. 2016). Gardarsdottir and
colleagues assessed the blood flow in the cervical arteries, which was measured
with phase contrast MRI and brain perfusion, in 2291 participants who were divided
into three groups: persistent AF, paroxysmal AF but were in sinus rhythm at the time
of imaging AF, and no history of AF (Gardarsdottir et al. 2017). Those in the persis-
tent AF group had significantly lower total cerebral blood flow, both when com-
pared with the paroxysmal AF group (P < 0.05) and the no AF group (P < 0.001).
Brain perfusion was lowest in the persistent AF group compared with the paroxys-
mal AF group (P < 0.05) and those with no AF (P < 0.001) (Gardarsdottir et al.
2017). There is evidence to suggest that higher ventricular rates during AF is associ-
ated with higher rates of cerebral hypoperfusion events in a computational model
(Saglietto et al. 2019b). One study has shown that AF associated cerebral hypoper-
fusion is more pronounced in patients under 50, compared to those over 65 (Lavy
et al. 1980). This may partly explain the age-dependent risk of developing dementia
in patients with AF, as one study showed that incident AF was associated with
increased risk of dementia in those aged less than 67 but not in those aged 67 over,
with a strong association between the duration of exposure to AF in the younger age
group (de Bruijn et al. 2015). It has also been observed that patients with AF who
underwent catheter ablation had significantly lower rates of dementia than those
with AF who did not undergo ablation and were comparable to the dementia rates in
patients without AF (Bunch et al. 2011).
Oral Anticoagulation and Dementia Risk
There have been several observational studies demonstrating that OAC is associated
with reduced incidence of dementia in patients with AF. One retrospective study
showed that in patients with AF and without dementia at baseline, OAC was associ-
ated with a 29% lower risk of dementia (HR 0.71, 95%CI: 0.68–0.74) (Friberg and
Rosenqvist 2018). In another analysis using data from the same registry, in patients
with AF, low stroke risk (CHADSVASC 1 or 0), and no baseline dementia, OAC
was associated with a 38% lower risk of CI (HR 0.62, 95% CI: 0.48–0.81) (Friberg
et al. 2019). In a UK registry, OAC was associated with lower risk of dementia when
compared to no treatment (HR 0.90, 95% CI: 0.85–0.95, P < 0.001) or antiplatelet

therapy alone (HR 0.84, 95% CI: 0.79–0.90, P < 0.001). However, in patients on
both an OAC and an antiplatelet agent, the risk of dementia was higher than with no
treatment (HR 1.17, 95% CI: 1.05–1.31, P = 0.006) (Mongkhon et al. 2020). This
may be due to an increased risk of cerebral microbleeds.
The association between OAC therapy and a reduction in dementia has been
shown in different populations globally. A longitudinal Swedish-based study dem-
onstrated that AF was a risk factor for developing dementia and that use of an OAC
in patients with AF was associated with a reduced risk of developing dementia (HR
0.40, 95% CI: 0.18–0.92) (Ding et al. 2018). A Korean-based study showed similar
results with AF being associated with increased risk of dementia and those on OAC
having lower risk of developing dementia (HR 0.61, 95% CI: 0.54–0.68, P < 0.001).
The study also showed an increase in the incidence of dementia with increasing
CHADSVASc scores independent of AF status (Kim et al. 2019).
The quality of anticoagulation is also important; when using warfarin, this can be
assessed via measures such as time in therapeutic range. In a study of patients with
AF and no baseline cognitive impairment who were receiving warfarin, longer
times spent out of the therapeutic range were associated with increased risk of
developing cognitive impairment. Patients who were in the therapeutic range
51–75% of the time had a two-and-a-half-fold increase in risk of cognitive impair-
ment (hazard ratio 2.57, P = 0.001), those in therapeutic range between 26% and
50% of the time had a fourfold increase in risk of cognitive impairment (hazard ratio
4.10, P = 0.001), and those who were at therapeutic range < 25% of the time had a
fivefold increase (hazard ratio 5.34, P = 0.001) (Jacobs et al. 2014). This matches
the findings of another observational study which showed that both a 10% reduction
in time spent in subtherapeutic range (HR 0.71, 95% CI: 0.64–0.79) and time spent
in supra therapeutic range (HR 0.67, 95% CI: 0.57–0.79) reduced risk of dementia
(Madhavan et al. 2018). Mechanistically, this potentially reflects a reduction in the
risk of micro thromboembolisms and microvascular bleeds, respectively. In a recent
study, Petroni and colleagues also found similar results: there was a higher risk of
dementia in patients who spend less than 60% of time in therapeutic range (OR
21.71, 95% CI: 4.35–108, P < 0.001). In addition, the authors found that use of
aspirin instead of an OAC (OR 24.74, 95% CI: 1.27–482.12, P = 0.034) and the
presence of an average daily heart rate over 100 or under 60 (OR 6.04, 95% CI:
1.09–33.29, P = 0.039) were independent risk factors for dementia (Petroni
et al. 2020).
These findings were confirmed by meta-analyses. One meta-analysis, consisting
of one randomized controlled trial and five observational studies found that patients
with AF on OAC had reduced risk of developing dementia (RR 0.79, 95% CI:
0.67–0.93) and that the benefit was greatest in those with a high percentage of time
spent in therapeutic range (Mongkhon et al. 2019). In another meta-analysis,
patients with AF on OAC were 29% less likely to develop dementia (HR 0.71, 95%
CI: 0.69–0.74, P < 0.00001) (Cheng et al. 2018).
Patient age at the time of initiating anticoagulation may also be an important fac-
tor. In one RCT of patients aged 75 and over with AF, warfarin did not show any
significant benefit in reducing dementia compared to aspirin, although the study was
limited by the follow-up period of 33 months (Mavaddat et al. 2014).
DOACs and Dementia
As previously mentioned, DOACs are superior or at least noninferior in reducing

the risk of stroke compared to warfarin, and all DOACs are also associated with a
reduced risk of bleeding. This has been shown in landmark trials of DOACs in
patients with non-valvular AF (Ruff et al. 2014). Given the proposed mechanisms
for dementia in patients with AF, it is possible that DOACs may be superior to war-
farin in preventing dementia. Figure 11.2 depicts the spectrum of cerebral injury
which may be reduced by DOAC therapy (Jacobs et al. 2015b).
The current data comparing DOACs to warfarin has been conflicting. In a retro-
spective analysis of data from a Swedish registry, there appeared to be a lower risk
of dementia with DOAC (HR 0.48, 95% CI: 0.40–0.58) than with warfarin (HR
0.62, 95% CI: 0.60–0.64) when compared to no treatment. However, a direct
Spectrum of Cerebral Injuries from Atrial

Fibrillation and Atrial Fibrillation Management
a b c
Micro Micro
Macro Emboli Micro Emboli
Emboli Bleed
Fig. 11.2 Three separate cranial images with the mechanisms that impact cognition that may be
reduced with direct acting oral anticoagulants: (a) diffusion-weighted axial magnetic resonance
images showing large ischemic injury in the left posterior parietal lobe. Multiple emboli are also
seen; (b) axial magnetic resonance image in which the ventricles and cortical sulci demonstrate
generalized atrophy and resultant enlargement in cerebral spinal fluid spaces as well as white mat-
ter disease; (c) non-contrast computed tomographic scan showing a subdural hematoma as well as
intraparenchymal hemorrhage. Used with permission from Jacobs et al. (2015b). Jacobs V, Cutler
MJ, Day JD, Bunch TJ. Atrial fibrillation and dementia. Trends in Cardiovascular Medicine.
2015;25(1):44–51
comparison between DOAC and warfarin showed no difference in dementia risk

(HR 0.97, 95% CI: 0.67–1.40) (Friberg and Rosenqvist 2018). In another retrospec-
tive study, from a UK registry, there was no significant difference in dementia risk
for DOACs compared to warfarin (HR 0.89, 95% CI: 0.70–1.14, P = 0.373)
(Mongkhon et al. 2020). A retrospective study which looked at 39,160 patients on
an OAC (with 7.5% using a DOAC) compared patients using a propensity score
matching procedure which generated two cohorts with 2528 patients each. Patients
on a DOAC had lower incidence of the composite endpoint when compared to war-
farin (0.42, CI: 0.19–0.93 compared to 0.74, CI: 0.55–1.00 per 100 years at risk)
(Friberg et al. 2019). An observational study of 5254 patients on OAC, over 90% of
which had AF, showed that dementia was more likely to occur in those taking war-
farin (0.7–0.3%, P = 0.03) compared to DOACs with no difference when individual
DOACs were compared to each other (Jacobs et al. 2016). Another observational
study comparing individual DOACs to warfarin showed that patients on DOACs
were less likely to develop dementia, specifically with dabigatran (HR 0.85, 95%
CI: 0.71–1.01), rivaroxaban (HR 0.85, 95% CI: 0.76–0.94), and apixaban (HR 0.80,
95% CI: 0.65–0.97). There were no observed differences in dementia rates when
comparing DOAC agents to each other (Chen et al. 2018). In a meta-analysis of
eight studies that included 471,057 patients with AF, those on DOACs were less
likely to develop dementia compared to those on warfarin (HR 0.51, 95% CI:
0.37–0.71, P < 0.00001) (Cheng et al. 2018).
Future Directions
There are several pending RCTs which aim to evaluate the efficacy of a DOAC
when compared to warfarin for dementia prevention in patients with AF. The
Cognitive Decline and Dementia in Atrial Fibrillation Patients (CAF) trial
(NCT03061006) is an ongoing clinical trial designed to evaluate whether patients
on dabigatran will be less likely to develop dementia when compared to patients on
dose-adjusted warfarin (target INR 2.0–3.0). The trial will also examine the effects
in serial cognition scores. The study population includes patients with non-valvular
AF and a CHADS2 or CHADSVASC score of 2 or more, who were being initiated
on OAC. Those with a history of moderate to severe cognitive impairment were
excluded (Bunch et al. 2019). Several biomarkers of cerebral neurologic injury have
been found to be elevated in patients with AF. These include circulating Tau,
GDF15, and GFAP, and these will also be evaluated in the CAF trial to look for cor-
relation with cognition (Galenko et al. 2019). The Anticoagulants and Cognition
(ACCOG) trial (NCT04073316) is a randomized controlled trial which aims to
compare cognitive performance in patients aged 70 years and older with non-
valvular AF, and without baseline dementia, randomized to receive either rivaroxa-
ban or warfarin. The primary outcome will be change in global cognitive performance
at 6 months to 1 year. The Trial of Apixaban vs. Warfarin in Reducing Rate of
Cognitive Decline, Silent Cerebral Infarcts and Cerebral Microbleeds in Patients
with Atrial Fibrillation (ARISTA) (NCT03839355) is a randomized controlled trial
which aims to compare apixaban and warfarin in patients with non-valvular AF,
aged 60 and older, and with CHADSVAS 2 and above. The primary outcomes
include a standardized neurocognitive function score as well as the incidence of
silent cerebral infarcts and microbleed detected by MRI. The Cognitive Impairment
Related to Atrial Fibrillation Prevention trial (GIRAF) (NCT01994265) will com-
pare warfarin to dabigatran in patients aged 70 and older with non-valvular AF and
CHADSVAS 1 or more in reducing risk of cognitive decline. The Blinded
Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive
Impairment in AF (BRAIN-AF) (NCT02387229) is an upcoming randomized con-
trolled trial that will enroll 3250 participants aged 30–62 with non-valvular AF and
low risk of stroke (CHADS 0). Participants will be randomized to rivaroxaban,
when compared to standard of care, with neurocognitive decline as part of a com-
posite primary endpoint, which includes stroke and transient ischemic attack, as
well as a secondary endpoint (Rivard et al. 2019).
Conclusions
AF is an independent predictor of dementia in populations with or without a history

of stroke. AF is associated with vascular dementia but also Alzheimer’s dementia
and senile dementia. DOACs may lead to a lower risk of dementia by decreasing the
risk of both thromboembolism and microbleeds.
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Non-vitamin K Antagonists and Cardiac
Implantable Electronic Devices 12
Introduction
Cardiac implantable electrophysiological device (CIED) surgeries, which include

pacemaker (PM) and implantable cardioverter defibrillator (ICD) implantation, are
commonly performed worldwide with approximately 1.5 million procedures per
year (Mond and Proclemer 2011). Of patients who undergo such procedures, up to
35% are receiving long-term anticoagulation at the time of implantation (AlTurki
et al. 2016). Patients receiving oral anticoagulation require careful perioperative
management to avoid the potential significant adverse events of pocket hematoma
and pocket infection (Bernard et al. 2012). In addition, the widespread use of CIEDs
has led to the recognition of subclinical atrial fibrillation (SCAF); this has been
found in a considerable proportion of patients with CIEDs (Healey et al. 2012).
Understanding the prevalence of SCAF, associated risk of stroke, and efficacy and
safety of oral anticoagulation is imperative in the management of SCAF (AlTurki
et al. 2019). The main decision point is whether to start anticoagulation and at what
burden of SCAF or in which patient subgroups. In this chapter, we will review the
strategies and evidence for the perioperative management of NOACs in patients
undergoing CIED surgery. In addition, the management of device detected SCAF
will also be reviewed.
A. AlTurki (*) · V. Essebag

R. Proietti

Pocket Hematomas
Device pocket hematomas are an important major adverse event complicating CIED
surgery. The incidence of pocket hematomas ranges from 1.2% when no anticoagu-
lant is present, 2.3–6.5% on continued-warfarin therapy, and 7–16% during heparin
bridging (Birnie et al. 2013; Sant’anna et al. 2015). Pocket hematomas may lead to
significant morbidity, prolong hospitalization, and may require reoperation for
evacuation (Birnie et al. 2013; Sridhar et al. 2015; Sticherling et al. 2015). Most
importantly, pocket hematomas are associated with a significantly increased risk of
device infection (Essebag et al. 2016). A clinically significant hematoma (CSH),
which has been defined as a hematoma that required reoperation or resulted in pro-
longation of hospitalization or required interruption of oral anticoagulation, was
associated with an >sevenfold increase in the subsequent risk of serious device
infection in BRUISE CONTROL (Bridge or Continue Coumadin for Device Surgery
Randomized Controlled Trial) (Essebag et al. 2016). Therefore, it is crucial to pre-
vent the occurrence of pocket hematomas, and perioperative antithrombotic man-
agement is an integral component of this management.
Vitamin K Antagonists
Vitamin K antagonists (VKAs) were the main therapeutic option for oral anticoagu-
lation prior to the introduction of NOACs. Krahn and colleagues showed that the
periprocedural management of VKA anticoagulation varied among electrophysiolo-
gists in Canada (Krahn et al. 2009). Most clinicians chose to withhold oral antico-
agulation without initiating heparin bridging in those at low risk of thromboembolism
and to use a form of heparin bridging in those at medium to high risk of thrombo-
embolism. Observational studies suggested that continued anticoagulation with
warfarin was associated with 70% lower odds of a pocket hematoma with a similar
risk of thromboembolic events (Sant’anna et al. 2015). The BRUISE CONTROL
trial was conducted to resolve the debate whether continued VKA was superior to
heparin bridging with regard to CSH in those at moderate or greater risk of throm-
boembolism (Birnie et al. 2013). This trial randomized 681 patients, with moderate
to severe risk of thromboembolism (estimated annual risk of 5% or greater) to either
continued-warfarin treatment or bridging therapy with heparin. CSH occurred in
3.5% in the continued-warfarin group, compared to 16.0% in the heparin-bridging
group (relative risk, 0.19; 95% confidence interval, 0.10–0.36; P < 0.001).
Thromboembolic complications were rare and similar in both groups (Healey et al.
2012). Furthermore, continued-warfarin therapy was found to be cost effective com-
pared with bridging-heparin therapy in patients at high risk of thromboembolic
events undergoing device surgery, with a cost savings of approximately $1800 per
patient treated (Coyle et al. 2015). The BRUISE CONTROL trial led to a change in
guideline recommendations and clinical practice (Birnie et al. 2014).
12 Non-vitamin K Antagonists and Cardiac Implantable Electronic Devices 213
Non-vitamin K Oral Antagonists
The introduction of NOACs, starting in 2009, has transformed the landscape of oral
anticoagulation including its perioperative management. The perioperative manage-
ment of NOACs involves one of the two following approaches: (1) appropriate tim-
ing of the cessation and reinitiation of the drug based on the predicted clearance,
mainly taking into account patients’ renal function; (2) continued anticoagulation
based on low patient and surgical risk of bleeding (AlTurki et al. 2016). However,
given their relatively recent use, there has been limited data on outcomes in patients
undergoing CIED surgery who are receiving NOACs. Prior to the publication of
relevant studies on this matter, in a Canadian survey involving 22 centers, which
performed approximately 14,971 device implants of which around 10% involved
NOACs at the time, NOAC were discontinued in anticipation of device implantation
in 82% of centers with 73% of these centers not utilizing heparin bridging
(Nascimento et al. 2014). In the Outcomes Registry for Better Informed Treatment
of Atrial Fibrillation (ORBIT-AF) registry, among 9129 AF patients, 416 (5%)
underwent CIED surgery during a median follow-up of 30 months. Oral anticoagu-
lation therapy was commonly interrupted for CIED surgery in 64% of warfarin
patients and 65% of NOAC patients. A substantial proportion of patients, 18% on
interrupted warfarin and 10% on interrupted NOAC, received intravenous bridging
anticoagulation. Major bleeding or stroke was a very rare occurrence in either group
of this analysis (Black-Maier et al. 2017).
The best observational data was derived from secondary analyses of the large
landmark randomized trials that compared NOACs to VKAs in patients with non-
valvular AF. A sub-analysis of the RELY trial, which compared dabigatran to war-
farin, that included 611 patients who underwent CIED surgery offers was the first to
be reported (Essebag et al. 2017). Warfarin was interrupted for a median of 144 h
with 18.4% of patients undergoing heparin bridging. On the other hand, the duration
of dabigatran interruption was a median of 96 h. Pocket hematomas occurred in
2.2% of patients on dabigatran and 4.0% patients on warfarin (P = 0.218). Pocket
hematoma incidence was lower in those who received dabigatran compared to those
who received warfarin with heparin bridging but not when compared with warfarin
without bridging. Thromboembolic events were similar between the two groups
(Essebag et al. 2017). In data from Rivaroxaban Once Daily Oral Direct Factor Xa
Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation (ROCKET AF), during a median follow-up of
2.2 years, 453 patients underwent CIED surgery (Leef et al. 2017). Most patients
had the study drug interrupted for the procedure without intravenous bridging anti-
coagulation. The rate of adverse events was low in both groups: 11 patients (4.6%)
in the rivaroxaban group experienced bleeding complications compared with 15
(7.1%) in the warfarin group, and thromboembolic complications occurred in 3
patients (1.3%) in the rivaroxaban group and 1 (0.5%) in the warfarin group (Leef
et al. 2017). In the Effective Anticoagulation with Factor Xa Next Generation in
Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AFTIMI
48) trial that compared edoxaban and warfarin, CIED surgeries were performed in
943 patients who were receiving study drug; in the majority (n = 728, 74%), study
drug was interrupted >3 days (median 5 days, interquartile range 0–11 days) (Steffel
et al. 2019). Again, the event rates were very low: six strokes/systemic embolic
events (three each in the lower dose edoxaban arm and warfarin arm) and one major
bleeding event (in the lower dose edoxaban arm) occurred; two of the six strokes
and the major bleeding event occurred in patients in whom procedures performed
with <3 days periprocedural interruption of study drug (Steffel et al. 2019).
The BRUISE CONTROL 2 trial randomized 662 patients with AF and risk of
thromboembolism (CHA2DS2-VASc score ≥ 2), to continued vs. interrupted
NOAC (Birnie et al. 2018). For the interrupted NOAC approach, rivaroxaban or
apixaban was discontinued after the last dose taken 2 days before surgery, while
dabigatran was discontinued drug based on a time interval dependent on glomerular
filtration rate. All three drugs were resumed at the next regular dose timing ≥24 h
after surgery. The median time between pre- and postoperative NOAC doses was
12 h in the continued NOAC arm compared to 72 h in the interrupted NOAC arm.
The trial was terminated early due to futility. CSH occurred in 2.1% of patients in
the continued NOAC arm and 2.1% of patients in the interrupted NOAC arm
(P = 0.97) (Birnie et al. 2018); the incidence of thromboembolic events was also
very low with one stroke occurring in each arm. Therefore, either approach is rea-
sonable with the choice dependent on the clinical scenario. This was subsequently
confirmed in a systematic review of two trials and three observational studies that
showed similar findings: continuing DOAC for device implantation compared to
interrupting DOAC resulted in no significant difference in CSH (2.1% vs. 1.8%; RR
1.15; 95%CI: 0.44–3.05) or thromboembolism (0.03% vs. 0.03%; RR 1.02; 95%CI:
0.06–16.21) (Mendoza et al. 2020).
NOAC Interruption for CIED Surgery
The general principle is that CIED surgery is considered a low bleeding risk proce-
dure (AlTurki et al. 2016). Due to the predictable waning anticoagulant effects of
NOACs, bridging anticoagulation is not required and has been shown to increase the
risk of bleeding in all surgeries (Douketis et al. 2015) as well as CIED surgery spe-
cifically (Birnie et al. 2013). Therefore, NOAC interruption involves timing the ces-
sation and reinitiation of the drug based on the predicted clearance, which takes
renal function into account (AlTurki et al. 2016; Spinler and Shafir 2012). In patients
with normal renal function undergoing a low bleeding risk procedure, the usual
practice is to discontinue the NOAC 24 h prior to the procedure and to reinstate the
drug 24 h after, provided no significant bleeding has occurred (Sticherling et al.
2015). Figure 12.1 shows the timeframe for NOAC interruption in those undergoing
CIED surgery. The specific information for each specific NOAC is provided below
(AlTurki et al. 2016; Sticherling et al. 2015; Birnie et al. 2014):
1. Dabigatran
(a) Twice-daily drug with a half-life of 14 h.
Resume DOAC
24-48 hours
Hold 1day before the
CrCI ≥ 50 postoperatively
surgery
(if no significant
bleeding)
Hold 2 days before

surgery (for Dabigatran) Resume DOAC
Patient on
DOAC 24-48 hours
scheduled for CrCI 30-50 postoperatively
Hold 1 day before (if no significant
PM/ICD
surgery (for bleeding)
insertion
Rivaroxaban/Apixaban/
Edoxaban*)
Patient should not be on

DOAC but if on
CrCI ≤ 30 Apixaban/Rivaroxaban/Edo
xaban* then hold for at
least 36 hours
Fig. 12.1 Strategy for NOAC interruption in patients undergoing CIED surgery. AlTurki A,
Proietti R, Birnie DH, et al. Management of antithrombotic therapy during cardiac implant-
able device surgery. J Arrhythm. 2016; 32:163–169
(b) When CrCl is >50 mL/min, hold the day before surgery, i.e., missing 2 doses
before the day of surgery (12–25% residual anticoagulant effect at the time
of surgery).
(c) When CrCl is between 30 and 50 mL/min (half-life of 15–18 h), hold 2 days
before surgery, i.e., 4 missed doses to give the same residual anticoagulant
effect (12–25%).
(d) Should not be used in patients with a CrCl of ˂30 mL/min.
(e) Resume 24 h postoperatively.
2 . Rivaroxaban
(a) Once-daily drug with a half-life of 9 h.
(b) Hold the day before surgery, i.e., missing one dose before the day of surgery
(12–25% residual anticoagulant effect at the time of surgery).
(c) Should not be used in patients with a CrCl less than 30 mL/min.
(d) If used in patients with a CrCl between 15 and 30 mL/min, at least 36 h of
drug interruption is advised.
(e) Use of the drug should be resumed 24–48 h postoperatively.
3. Apixaban
(a) Twice-daily drug with half-life of 9 h.
(b) Hold the day before surgery and resume 24–48 h postoperatively, if renal
function is >30 mL/min.
(c) If apixaban is used in patients with a CrCl between 15 and 30 mL/min, then
at least 36 h of drug interruption is advised.
4. Edoxaban
(a) Once-daily drug with a half-life of 10–14 h.
(b) Hold the day before surgery and resume 24–48 h postoperatively, if renal
function is >30 mL/min (Ferretto et al. 2020; Wong et al. 2018).
(c) Should not be used in patients with a CrCl ˂ 30 mL/min.
Concomitant Antiplatelet Therapy
With a substantial proportion of patients receiving antiplatelet therapy in addition to

anticoagulation, an understanding of the impact of combined therapy on hematoma
development after CIED surgery is important. In a pooled analysis using patient
level data from the BRUISE CONTROL trials, antiplatelet use was associated with
CSH in 9.8% versus 4.3% of patients (P < 0.001) who did not receive concomitant
antiplatelet therapy. Furthermore, antiplatelet therapy was a strong independent pre-
dictor of CSH after multivariable adjustment (odds ratio, 1.965; 95% CI:
1.202–3.213; P = 0.0071) (Essebag et al. 2019a). Unscheduled outpatient visits for
wound assessment (15.4% versus 7.5%, P < 0.001) also increased if the patient was
on an antiplatelet at the time of device surgery. Interestingly, applying current
guidelines regarding combination antithrombotic therapy, concomitant antiplatelet
therapy is potentially inappropriate or interruptible, and this should be assessed
prior to intervention. Of the 681 patients enrolled in the BRUISE CONTROL trial,
280 (41%) received concomitant antiplatelet therapy during CIED surgery. Of the
280 patients receiving antiplatelet therapy, 97 (34.6%) had no indication for con-
comitant antiplatelet therapy according to current guidelines, and an additional 146
(52.1%) were on antiplatelet therapy that could potentially have been interrupted
around CIED surgery (Essebag et al. 2019b).
Predictors of Pocket Hematoma
In patients receiving NOACs, it is important to assess for risk factors that increase
the risk of CSH. The presence of these factors should lead to consideration of inter-
ruption of NOAC therapy or a greater duration of interruption. Bridging anticoagu-
lation and concomitant antiplatelet therapy have already been discussed. Device
type and left ventricular ejection fraction <30% have been shown to be strong pre-
dictors of pocket hematoma in single-center studies (Ferretto et al. 2020;
Notaristefano et al. 2020). Implantable cardioverter defibrillator implantation car-
ries an increased risk of CSH. In an analysis of the SIMPLE trial which included
2500 patients who received a defibrillator, CSH occurred in 2.2% of patients, of
whom 10.7% developed a device-related infection (Masiero et al. 2016). Independent
predictors of wound hematoma on multivariable analysis included subpectoral loca-
tion of the device, older age, previous stroke, and an upgrade from a previous
pacemaker.
Anticoagulation of Patients with Subclinical Atrial Fibrillation
Subclinical atrial fibrillation (SCAF) refers to the detection of AF by CIEDs in

asymptomatic patients not known to have AF (AlTurki et al. 2019). The
Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and
the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) was a landmark
study designed to assess the association between SCAF and stroke and systemic
embolism. The trial enrolled 2580 patients who had received a CIED for sinus or
atrioventricular nodal dysfunction in the preceding 2 months, had a risk factor for
stroke, and were not known to have any history of AF or atrial flutter or require oral
anticoagulation for any indication (Healey et al. 2012). After 3 months of monitor-
ing, patients were divided into two groups based on the presence of SCAF and fol-
lowed for a mean of 30 months. SCAF was associated with a fivefold increased risk
of clinical AF (HR 5.56; 95% CI: 3.78–8.17; P < 0.001) and a 2.5-fold increased
risk of stroke or systemic embolism (HR 2.49; 95% CI: 1.28–4.85; P = 0.007).
Interestingly, the stroke risk was not as high as that seen with clinical AF, which is
fivefold greater than the general population, but is still substantial at two to two-
and-a-half times the risk (AlTurki et al. 2019). Two questions remained after the
results of ASSERT: which patients with SCAF are at the highest risk of stroke and
are anticoagulation beneficial in this population.
Burden of SCAF
The burden of SCAF (i.e., longer and more frequent episodes) is thought to be an
important predictor of stroke. Proietti and colleagues assessed this relationship in a
systematic review and meta-analysis (Proietti et al. 2016). The analysis was limited
by a small number of studies that reported such data and the varying cutoff points
used in the studies. The authors concluded that a direct correlation between burden
of asymptomatic AF and HR for stroke cannot be confirmed (Proietti et al. 2016).
Van Gelder et al. performed an important sub-analysis of the ASSERT study and
found that SCAF episodes lasting 24 h and longer were associated with an increased
risk of ischemic stroke or systemic embolism (Van Gelder et al. 2017). Patients
were divided into one of the following groups on the basis of the duration of the
single longest episode of SCAF: >6 min to 6 h (19%), >6 to 24 h (7%), and >24 h
(11%), while those who had no SCAF or SCAF for <6 min were excluded from this
analysis. There was a threefold increase in the associated risk of stroke (adjusted
HR 3.24, 95% CI: 1.51–6.95, P = 0.003) in those with episodes of 24 h or more with
an absolute stroke risk of around 5% which approximates the risk of stroke seen in
clinical AF (AlTurki et al. 2019). In contrast, in those with SCAF between 6 min
and 24 h, the risk of stroke was not significantly different from patients without
SCAF (Van Gelder et al. 2017). Similar results were reported in another registry;
those with SCAF episodes of 24 h or longer had a significantly increased risk of
stroke (OR 3.1, 95% CI: 1.1–10.5, P = 0.044) (Capucci et al. 2005). While these
studies clearly identified a high-risk group, it remains unclear whether those with
episodes lasting between 6 min and 24 h have a significantly increased risk of stroke
and in particular those with episodes longer than 6 h (AlTurki et al. 2019).
Progression of SCAF
Another predictor of stroke may be the presence of progression to longer episodes

of SCAF. De novo AF with a SCAF burden of ≥5 min was detected in 2244 patients
(34%) during a follow-up period of 2.4 ± 1.7 years in a large multicenter registry.
Among those with SCAF, 49.8% transitioned to a higher SCAF burden threshold
during follow-up, including 24% of patients who transitioned from a lower thresh-
old to a daily SCAF burden of ≥23 h (Boriani et al. 2018). Male gender and a
CHADS2 score of 2 or greater predicted the transition to a greater SCAF burden on
multivariate analysis (Boriani et al. 2018). In another sub-study of ASSERT, patients
in whom the longest SCAF episode was >6 min but <24 h during the first year were
included (Wong et al. 2018). The authors assessed the association between progres-
sion to SCAF >24 h or the development of clinical AF and heart failure hospitaliza-
tions. During a mean follow-up of 2 years, 15.7% of patients progressed and the rate
of heart failure hospitalization among patients with SCAF progression was 8.9%
per year compared with 2.5% per year for those without progression (Wong et al.
2018). This is consistent with the relationship seen between clinical AF and heart
failure in which a vicious cycle can develop (Glotzer 2018); the development of
heart failure is another risk factor for stroke.
Predictors of SCAF
Through several studies, predictors of SCAF have been identified. A high propor-
tion of right ventricular pacing predicted SCAF in those with sinus node dysfunc-
tion and hypertension predicted SCAF in those with pacemakers for atrioventricular
block (Cheung et al. 2006). In ASSERT, sinus node dysfunction and a lower resting
heart rate predicted SCAF (Healey et al. 2012). In another study, older age and dia-
stolic blood pressure predicted SCAF (Glotzer et al. 2009). In addition, prior HF,
sinus node disease, and increased left atrial volume index independently predicted
SCAF (Kim et al. 2016). In a meta-analysis of ten studies, only heart failure reliably
predicted SCAF (Belkin et al. 2018). In patients older than 65 years of age with at
least two stroke risk factors who received an implantable loop recorder, independent
predictors of AF included increased age and increased left atrial size (Healey
et al. 2017).
Anticoagulation for SCAF
The treatment of SCAF presents several challenges due to the aforementioned

issues, and there are various factors to keep in mind when considering the treatment
of SCAF. In clinical AF, oral anticoagulation is recommended regardless of AF sub-
type and depending on the presence of clinical factors (age, hypertension, diabetes
mellitus, heart failure, and stroke) which have consistently been shown to increase
stroke risk (Andrade et al. 2018). Given that oral anticoagulation has been shown to
significantly decrease stroke risk in clinical AF, this risk reduction should theoreti-
cally translate to SCAF. However, in SCAF, the increased risk is of a lower magni-
tude (2–2.5 times) compared to clinical AF (5 times), and this may reduce the net
clinical benefit observed with anticoagulation in SCAF. Patients with SCAF >24 h
have an absolute risk profile that is similar to that observed in clinical AF and are the
subgroup of SCAF most likely to derive benefit from oral anticoagulation (AlTurki
et al. 2019). This is consistent with current guidelines, and NOACs are used prefer-
entially to warfarin similar to the treatment of clinical AF. An algorithm for the
management of SCAF is shown in Fig. 12.2. Current guidelines suggest that patients
with SCAF greater than 24 h as well as at least one risk factor for stroke should
receive oral anticoagulation. In addition, the guidelines also suggest that patients
with shorter durations of SCAF but who are at high risk, such as those with crypto-
genic stroke, ought to be considered for oral anticoagulation (AlTurki et al. 2019;
Macle et al. 2016). Due to the absence of well-defined cutoffs of AF burden in
which oral anticoagulation is indicated, a substantial variation in physician attitudes
and practice patterns exists (Noseworthy et al. 2019). This is best illustrated in a
cohort study that included 10,212 patients who received CIEDs in 2011–2014; 45%,
39%, 32%, and 24% of patients had SCAF lasting ≥6 min, >1 h, >6 h, and >24 h,
respectively (Perino et al. 2019). The proportion of patients who were prescribed
oral anticoagulation within 90 days of SCAF was relatively low with small incre-
ments as the AF burden increased (≥6 min, 13%; >1 h, 16%; >6 h, 21%; >24 h,
27%) (Perino et al. 2019). Clearly, more data is needed to provide clinicians guid-
ance on how to manage SCAF of intermediate duration. Two ongoing trials will
hopefully shed some much-needed light.
Ongoing Trials
ARTESIA is a prospective, multicenter, double-blind, randomized controlled trial,

enrolling patients with SCAF detected by a CIED who have additional risk factors
for stroke (Lopes et al. 2017). Inclusion criteria include: (1) least one episode of
SCAF ≥6 min in duration; (2) 55 years of age or older; and (3) have risk factors for
stroke. Exclusion criteria are: (1) documented AF on a 12-lead electrocardiogram
and (2) an indication for oral anticoagulant therapy. Participants will be randomized
to apixaban or aspirin 81 mg daily with appropriate placebo pills accordingly. The
primary outcome is the composite of stroke, transient ischemic attack with imaging
confirmation, and systemic embolism. The trial is aiming to recruit 4000 patients
Fig. 12.2 Management
algorithm for subclinical Atrial high rate episodes detected on device
atrial fibrillation. AlTurki
A, Marafi M, Russo V,
et al. Subclinical Atrial
Fibrillation and Risk of
Stroke: Past, Present and
Future. Medicina
(Kaunas). 2019;55
Confirm AF on
electrogram If not then continue
or episodes longer to monitor
than 6 minutes
If confirmed, initiate
Attempt to document
anticoagulation if patient
on 12-
has a risk
lead electrocardiogram
factor for stroke*
If confirmed, consider
Any episodes lasting anticoagulation if patient
for ≥ 24 hours has a risk
factor for stroke**
Any episodes lasting Close follow-up of the

patient as high risk to transition
for ≥ 6 hours and in
to an episode 24 hours (if has a
particular ≥12
risk factor for stroke), Consider
hours discussing the pros
and cons of anticoagulation
including the lack of evidence
pending the results of
ARTESIA and
NOAF-AFNET 6***
Continue to
monitor***
from 230 international clinical sites and is expected to have 36 months of follow-up
until 248 adjudicated primary outcome events have occurred (Lopes et al. 2017).
NOAH-AFNET 6 is an investigator-driven, prospective, randomized trial
(Kirchhof et al. 2017). The trial enrolled patients with SCAF and one or more risk
factors for stroke. Inclusion criteria include: (1) SCAF; (2) age ≥65 years; and (3)
at least one other stroke risk factor. Exclusion criteria include: (1) documented AF
or (2) an indication for oral anticoagulation. Broad inclusion/exclusion criteria used
to replicate clinical practice. NOAH-AFNET 6 will randomize 3400 patients to
edoxaban or no anticoagulation in a superiority trial; aspirin may be used depending
on the clinical indication. The primary efficacy outcome is stroke or cardiovascular
death, and the primary safety outcome will be major bleeding and all patients will
have follow-up until the intended 222 target primary outcomes are reached. Patients
who develop AF will be censored and offered open-label anticoagulation instead
(Kirchhof et al. 2017).
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Direct Oral Anticoagulants and Atrial
Fibrillation Ablation 13
Introduction
Catheter ablation (CA) for atrial fibrillation (AF) is increasingly used as a strategy
for rhythm control due to expanding indications (AlTurki et al. 2020). Improvements
in operator experience, techniques, and equipment have resulted in greater efficacy
and safety (Calkins et al. 2017a). The incidence of major adverse events due to CA
is low (Samuel et al. 2017); however, thromboembolism remains a major concern
with targeted strategies to mitigate that risk. The periprocedural management of
anticoagulation is of great import as it impacts the incidence of major bleeding and
has a central role in preventing thromboembolism.
In the aftermath of CA, the decision to continue anticoagulation has important
implications in the short and longer term. Patients often desire an end to oral antico-
agulation. Data from the AFFIRM trial suggested that discontinuing anticoagula-
tion in those receiving rhythm control with an antiarrhythmic drug is ill-advised
with a notable increase in the risk of thromboembolism (Sherman et al. 2005). CA
is much more efficacious at establishing rhythm control and lowering the burden of
AF than AADs (Calkins et al. 2017a; AlTurki et al. 2019a). A lower burden of AF
has been suggested to decrease thromboembolism risk (AlTurki et al. 2019b).
In this chapter, we will review the evidence for the periprocedural management
of anticoagulation in patients undergoing CA as well as the short and long-term
postprocedural management. We will focus on the role of direct acting oral antico-
agulants in these contexts.
A. AlTurki (*) · V. Essebag

R. Proietti

Risk of Thromboembolism with AF Ablation
AF ablation increases the risk of thromboembolism during and in the aftermath of

the procedure (Page et al. 2014); the mechanisms for this increased risk are through
all the components of Virchow’s triad. Firstly, endothelial injury caused by the
introductions of sheaths and catheters into the left atrium and ablation energy appli-
cation onto the endothelial surface. In addition, the sheaths and catheters may dis-
lodge any preformed thrombus and can serve as a nidus for thrombus formation.
Secondly, hypercoagulability induced by the interaction of ablation hardware with
blood as well as thrombogenic debris, which is generated at the site of ablation; and
finally, blood flow stasis post conversion of AF into sinus rhythm. This is due to left
atrial stunning as well as left atrial dilatation. The fundamental goal of anticoagula-
tion is to minimize the risk of thromboembolism without excessively increasing the
risk of clinically significant bleeding, which may involve vascular access complica-
tions, the most common complication, and pericardial effusion and tamponade, the
most serious complication.
Pre-ablation Anticoagulation Strategies
Many of those who undergo an AF ablation have an elevated risk of thromboembo-

lism, best assessed by using the CHADSVASc score. The presence of even one risk
factor, excluding female sex and vascular disease, is enough to indicate chronic oral
anticoagulation. Given the risk of thromboembolism associated with the procedure,
especially if the patient is in AF at the time, most electrophysiologists would anti-
coagulate the patient for 3 weeks prior to the scheduled ablation. There are two
broad strategies for managing oral anticoagulation in the days prior to the proce-
dure: uninterrupted oral anticoagulation and interrupted oral anticoagulation. In an
interrupted strategy, patients have their oral anticoagulant stopped before the CA,
with or without bridging with another anticoagulant; while in an uninterrupted strat-
egy, there is continuation of oral anticoagulation throughout the periproce-
dural period.
Warfarin Management Periprocedurally
Warfarin had been the mainstay for stroke prevention AF. Initially, the standard
practice was to interrupt warfarin 5 days prior to the procedure and then bridge
patients with low molecular weight heparin. The rationale for this approach was the
notion that an uninterrupted anticoagulation strategy would lead to an increased risk
of major bleeding especially pericardial tamponade. However, in a prospective mul-
ticenter, Di Biase et al. showed that uninterrupted anticoagulation with warfarin
periprocedurally was associated with a lower risk of periprocedural stroke (0% vs.
0.9%; P < 0.05) (Biase et al. 2010). In addition, there was no observed increase in
the risk of bleeding complications. This study was seminal to the concept that an
13 Direct Oral Anticoagulants and Atrial Fibrillation Ablation 227
uninterrupted anticoagulation strategy may be the optimal approach. The results

were subsequently corroborated in a large meta-analysis, which included nine stud-
ies and 27,402 patients (Santangeli et al. 2012). Uninterrupted warfarin was associ-
ated with a decrease of thromboembolic complications (OR, 0.10; 95% CI:
0.05–0.23; P < 0.001) and minor bleeding complications (OR, 0.38; 95% CI:
0.21–0.71; P = 0.002) compared with interrupted warfarin. Importantly, uninter-
rupted warfarin was not associated with an increase in the risk of major bleeding
(OR, 0.67; 95% CI: 0.31–1.43; P = 0.30), including cardiac tamponade (OR, 0.69;
95% CI: 0.19–2.47; P = 0.57). A randomized controlled trial, COMPARE, was con-
ducted to more definitively identify the optimal anticoagulation strategy (Biase
et al. 2014). The study enrolled 1584 patients: 790 assigned to discontinue warfarin
and 794 assigned to continuous warfarin. The primary endpoint of the study was
incidence of thromboembolic events in the 48 h after ablation. There were 29 strokes
(3.7%) in those who discontinued warfarin compared to only two strokes (0.3%) in
those receiving continuous warfarin (P < 0.001). Warfarin discontinuation was an
important predictor of periprocedural thromboembolism (odds ratio, 13; 95% con-
fidence interval: 3.1–55.6; P < 0.001). The incidence of major bleeding did not dif-
fer between the two groups (P = 0.31) but there was a higher incidence of minor
bleeding in the interrupted warfarin group (22.0% vs. 4.1%, P < 0.001). On the
basis of these results, the current standard of care has become an uninterrupted war-
farin strategy.
DOAC Management Periprocedurally
The introduction of DOACs in 2010 has changed the anticoagulant management of

patients with AF. Due to a superior safety profile and possible better efficacy com-
pared to warfarin, DOACs have become first-line therapy for anticoagulation of AF
and are used in preference to warfarin. The increased use of DOACs has led to a
need to identify the optimal anticoagulation strategy in patients undergoing AF
ablation.
Rivaroxaban is an oral factor Xa inhibitor that was shown to be noninferior to
warfarin in the ROCKET-AF trial (Patel et al. 2011). Piccini and colleagues per-
formed a post hoc analysis of the ROCKET-AF trial that examined patients who
underwent AF ablation and found that the incidences of stroke or systemic embo-
lism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-
treated and warfarin-treated groups (Piccini et al. 2013). In a cohort study, 272
patients receiving uninterrupted periprocedural rivaroxaban before an AF catheter
ablation procedure were matched by age, sex, and type of rhythm disorder with 272
patients who received uninterrupted phenprocoumon, a vitamin K antagonist
(Dillier et al. 2014). No thromboembolic events occurred in either group and there
were no deaths. The incidence of major bleeding was low and similar in both groups
with one tamponade in the rivaroxaban group and one hematoma requiring transfu-
sion in the phenprocoumon group (Dillier et al. 2014). Similar results were found in
a multicenter, observational, prospective study of a registry of patients undergoing
AF ablation in which patients receiving uninterrupted rivaroxaban were matched by

age, sex, and AF type to those receiving uninterrupted warfarin (Lakkireddy et al.
2014). No differences were observed in the incidence of major bleeding (1.6% vs.
1.9%, P = 0.772), minor bleeding (5.0% vs. 5.9%, P = 0.602), or thromboembolic
complications (0.3% vs. 0.3%, P = 1.0) between the rivaroxaban and warfarin
groups, respectively, in the first 30 days (Lakkireddy et al. 2014). In a meta-analysis
of seven observational studies involving 3575 patients, thromboembolic events
occurred in 0.4% and 0.4% (RR 0.71, 95% CI 0.26–1.96; P = 0.51) and major
bleeding events occurred in 1.2% and 2.3% (RR 0.49, 95% CI 0.24–1.02; P = 0.06)
of those receiving rivaroxaban and warfarin, respectively (Aryal et al. 2014).
VENTURE-AF (active-controlled multicenter study with blind-adjudication
designed to evaluate the safety of uninterrupted rivaroxaban and uninterrupted vita-
min K antagonists in subjects undergoing catheter ablation for non-valvular atrial
fibrillation) was randomized, open-label trial of patients with AF undergoing cath-
eter ablation (Cappato et al. 2015). The incidences of major bleeding and thrombo-
embolic events were similarly low in both treatment arms; no events in the
rivaroxaban arm and one major bleeding as well as two thromboembolic events in
the vitamin K arm (0.8%; one ischemic stroke and one vascular death). This high-
lights the safety of an uninterrupted oral anticoagulation strategy.
Dabigatran is a direct thrombin inhibitor and was the initial DOAC approved for
stroke prevention in AF. In an analysis of data from a prospectively collected regis-
try that included 999 patients who received either dabigatran that was minimally
interrupted or uninterrupted warfarin, there was no difference in thromboembolic
(0.3% vs. 0.2%; P = 0.78) or major bleeding (1.1% vs. 1.6%; P = 0.48) events in the
two groups (Bassiouny et al. 2013). However, observational data also suggested an
increased risk of bleeding with dabigatran compared to warfarin. In a prospective
registry of 290 patients who received either uninterrupted dabigatran or uninter-
rupted warfarin, there was no difference in thromboembolic events (2.1% vs. 0%;
P = 0.25). Those who received dabigatran had a significantly higher risk of major
bleeding (6.0% vs. 1.0%; P = 0.019), and dabigatran use was an independent pre-
dictor of bleeding (Lakkireddy et al. 2012). Meta-analyses on the subject produced
conflicting results. Abdulhak and colleagues, in an analysis of nine studies that
included 3036 patients, found no difference in thromboembolic events (OR 2.15,
95% CI: 0.58–7.98; P = 0.54) or bleeding (Bin Abdulhak et al. 2013). In contrast,
Sardar et al. in a meta-analysis of 18 studies that included 5513 patients found that
the risk of stroke or transient ischemic attack (OR 5.54, 95% CI: 1.94–10.08), and
all thromboembolic events (OR 2.81, 95% CI: 1.23–6.45) were higher in those who
received dabigatran (Sardar et al. 2014). There was no difference in the risk of major
bleeding between the two groups, and dabigatran use was associated with a lower
risk of minor bleeding (OR 0.60, 95% CI: 0.41–0.87). These conflicting results and
the need for more definitive data led to the Randomized Evaluation of Dabigatran
Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an
Uninterrupted Periprocedural Anticoagulation Strategy (RECIRCUIT) trial (Calkins
et al. 2017b). This was a randomized, open-label trial with blinded adjudicated end-
points in which 635 patients who were undergoing AF catheter-based ablation
received either uninterrupted dabigatran or uninterrupted warfarin for 4–8 weeks

prior to the procedure and 8 weeks after. The primary endpoint, which was the inci-
dence of major bleeding events during and up to 8 weeks after ablation, was lower
with dabigatran than with warfarin (1.6% vs. 6.9%; P < 0.001). In addition, dabiga-
tran was associated with fewer periprocedural pericardial tamponades and groin
hematomas than warfarin. Thromboembolic events were also assessed as a key sec-
ondary endpoint and had a very low incidence with only one event occurring in the
warfarin group (Calkins et al. 2017b).
Apixaban is an oral factor Xa inhibitor and in patients with AF, apixaban was
shown to be superior to warfarin with regard to stroke prevention, major bleeding,
and all-cause mortality (Granger et al. 2011). In a prospective multicenter registry,
Di Biase and colleagues assessed the feasibility of an interrupted apixaban strategy
in patients undergoing AF ablation; these patients were matched for age, gender,
and type of AF, for an equal number of patients undergoing AF ablation on uninter-
rupted warfarin (Di Biase et al. 2015). There were no differences in major complica-
tions (1% vs. 0.5%, P = or total bleeding complications (4.5% vs. 3%, P = 0.43)
between the two groups, and there were no symptomatic thromboembolic compli-
cations. Another matched cohort study by Kaess et al. and an observational study by
Shah et al. showed similar results (Kaess et al. 2015; Shah et al. 2017). In a meta-
analysis of six studies with 1691 patients comparing uninterrupted apixaban and
uninterrupted warfarin, there was no difference in thromboembolic events
(OR = 1.10, 95% CI: 0.24–5.16), major bleedings (OR = 1.56, 95% CI: 0.59–4.13),
cardiac tamponade (OR 1.69, 95% CI: 0.52–5.54), minor bleedings (OR 0.96, 95%
CI: 0.58–1.59), and the composite endpoint of death, thromboembolic events, and
bleedings (OR 1.03, 95% CI: 0.65–1.64) between the two groups (Blandino et al.
2016). Randomized controlled trials were performed to ascertain whether uninter-
rupted apixaban is similar to uninterrupted warfarin, the standard of care as well as
to compare uninterrupted to minimally interrupted apixaban. In an exploratory
open-label randomized trial in Japan that randomized 200 patients, those who
received uninterrupted apixaban required administration of more heparin to main-
tain an activated clotting time >300 s than those who received uninterrupted warfa-
rin (apixaban, 14,000 ± 4000 units; warfarin, 9000 ± 3000 units) (Kuwahara et al.
2016). There was no difference in thromboembolic events including silent infarcts
as well as major or minor bleeding between the two groups. In the Apixaban
Evaluation of Interrupted Or Uninterrupted Anticoagulation for Ablation of Atrial
Fibrillation (AEIOU) trial, 300 patients were randomized to uninterrupted versus
minimally interrupted (holding one dose) periprocedural apixaban (Reynolds et al.
2018). Clinically significant bleeding did not significantly differ between the two
groups, occurring in 11.3% of patients on uninterrupted apixaban and 9.7% patients
on interrupted apixaban, and neither did major bleeding with incidence rates of
1.3% with uninterrupted apixaban and 2.1% with interrupted apixaban; there were
no thromboembolic events. The Atrial Fibrillation catheter Ablation compared to
VKA therapy (AXAFA—AFNET 5) trial was an investigator-initiated, randomized,
blinded outcome assessment study comparing continuous apixaban therapy to con-
tinuous vitamin K antagonist therapy (Kirchhof et al. 2018). The primary outcome
of death, stroke, or major bleeding was observed in 6.9% patients randomized to

apixaban, and in 7.3% randomized to VKA which met the margin for noninferiority.
There was no significant difference in major bleeding (6.2% vs. 7.9%), tamponade
(0.6% vs. 1.6%), quality of life, or cognitive function between the two groups
(Kirchhof et al. 2018).
Edoxaban is also an oral factor Xa inhibitor and was shown to be noninferior to
warfarin with respect to the prevention of stroke or systemic embolism and was
associated with significantly lower rates of bleeding in patients with non-valvular
AF (Giugliano et al. 2013). In an analysis from this trial of patients who underwent
AF ablation while receiving edoxaban, with a greater than 3-day interruption of
edoxaban in the majority of patients, treatment there associated was a low risk of
ischemic (0%) and bleeding (1.3%) events during the first 30 days post ablation
(Steffel et al. 2017). Data from small observational studies showed the feasibility of
an uninterrupted edoxaban strategy compared to an uninterrupted vitamin K antago-
nist strategy (Kottmaier et al. 2018; Naito et al. 2020). In a prospective multicenter
study in Japan that included 513 patients who received uninterrupted edoxaban for
at least 4 weeks prior to AF ablation and at least three after the ablation, no throm-
boembolism and one major bleeding event (0.2%, cardiac tamponade) were
observed (Takahashi et al. 2019). However, this study was limited by the lack of a
comparative group. To investigate the efficacy and safety of uninterrupted edoxaban
versus warfarin in 553 patients undergoing AF catheter-based ablation, the
ELIMINATE-AF trial (a Prospective, Randomized, Open-Label, Blinded Endpoint
Evaluation Parallel Group Study Comparing Edoxaban versus VKA in Subjects
Undergoing Catheter Ablation of Non-valvular Atrial Fibrillation) was conducted
(Hohnloser et al. 2019). There was no difference in major bleeding (2.5% vs. 1.5%),
thromboembolic events (0.2% vs. 0%), or death (none) in those who received edox-
aban or warfarin, respectively.
Therefore, current guidelines now recommend uninterrupted DOAC therapy as a
standard of care for patients undergoing AF catheter ablation (Calkins et al. 2017a).
In addition, it is reasonable to hold one to two doses of DOAC therapy prior to AF
ablation with reinitiation post ablation. Interestingly, while the individual trials did
not show superiority of DOAC compared to warfarin, Romero and colleagues per-
formed a meta-analysis of randomized trials comparing DOAC to warfarin and
found that DOAC use was associated with a reduced risk of major bleeding (RR:
0.45; 95% CI: 0.20–0.099 p = 0.05) (Romero et al. 2019) (Fig. 13.1).
Intraprocedural Anticoagulation
Intraprocedural anticoagulation with unfractionated heparin is an integral and well-

established component of catheter ablation of atrial fibrillation (Calkins et al.
2017a). As mentioned, this is to reduce the effect of endothelial injury, hypercoagu-
lability, and stasis induced by instrumentation of the left atrium. Heparin should be
administered prior to transeptal puncture, and this practice has been shown to reduce
the incidence of thromboembolism (Di Biase et al. 2014). Current guidelines
DOACs VKA Risk Ratio Risk Ratio

Study or subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
ASCERTAIN 2 64 1 63 9.1% 1.97 [0.18, 21.17]
AXAFA 20 318 25 315 39.9% 0.79 [0.45, 1.40]
ELIMINATE-AF 1 316 2 101 9.0% 0.16 [0.01, 1.74]
Kuwahara 2016 1 100 3 100 10.0% 0.33 [0.04, 3.15]
RE-CIRCUIT 4 317 21 318 26.5% 0.19 0.07, 0.55]
VENTURE-AF 0 123 1 121 5.5% 0.33 [0.01, 7.97]
Total (95% CI) 1238 1018 100.0% 0.45 [0.20, 0.99]

Total events 28 53
Heterogeneity: Tau2 = 0.33; Chi2 = 7.99, df = 5 (P = 0.16); l2 = 37%
Test for overall effect: Z = 1.99 (P = 0.05) 0.01 0.1 1 10 100
Favors DOACs Favors VKA
Fig. 13.1 Forest plot comparing the risk of major bleeding with an uninterrupted direct oral anti-
coagulant strategy versus an uninterrupted vitamin K antagonist strategy. Used with permission
from Romero et al. (Elsevier) (Romero et al. 2019)
recommended heparin dosing should be adjusted to achieve and maintain a target

activated clotting time of 300 s or greater based upon body weight and preproce-
dural coagulation profile. However, when using an uninterrupted DOAC strategy as
opposed to warfarin, data suggests that higher doses of heparin are required to
achieve the targeted clotting time, and the operating electrophysiologist should be
aware of this.
Postprocedural Anticoagulation
AF ablation has clearly been shown to improve rhythm control of AF and results in
a lower burden of disease (AlTurki et al. 2020). In a recently published trial with
2789 patients that compared early rhythm control including AF ablation to usual
care, early rhythm control led to a reduction in the primary endpoint which was a
composite of death from cardiovascular causes, stroke, or hospitalization with wors-
ening of heart failure or acute coronary syndrome (hazard ratio, 0.79; 96% CI:
0.66–0.94; P = 0.005); there was also a significant reduction in stroke (hazard ratio
0.65; 95% CI: 0.44–0.97) (Kirchhof et al. 2020). The optimal long-term anticoagu-
lation strategy in those who undergo AF ablation is unclear and is an area that is
lacking in high-quality data. The current standard of care is to provide at least 8–12
weeks of oral anticoagulation post ablation and then decide on longer term antico-
agulation based on the patient’s overall stroke risk; this is in keeping with current
international AF ablation guidelines (Calkins et al. 2017a). Bunch et al. showed that
in select patients with low stroke risk (CHADS2 = 0–1) who undergo AF ablation
using an aggressive anticoagulation strategy with heparin as well as an open-
irrigated tip catheter scores have a low risk of thromboembolism when discharged
on aspirin alone compared to warfarin (Bunch et al. 2009). Saad and colleagues
examined a cohort of 327 patients, the majority of whom had a CHADS2 score of
2–3, who underwent AF ablation and discontinued oral anticoagulation 6–12
months post ablation and were then followed up for 46 ± 17 months. There were no
symptomatic ischemic cerebrovascular events despite 91% of patients not receiving
anticoagulation (Saad et al. 2011). In a large multicenter observational study of
3355 patients that compared those who discontinued anticoagulation versus those
who continued, there was a very low risk of thromboembolism in both groups
(0.07% off anticoagulation vs. 0.45% on anticoagulation) that was not statistically
significant (P = 0.06) (Themistoclakis et al. 2010). A major hemorrhage was
observed in 0.04% of those off anticoagulation compared to those on anticoagula-
tion (2%; P < 0.0001). Proietti et al. performed a meta-analysis of 16 studies that
included 25,177 patients (Proietti et al. 2019). There was no significant difference
in the incidence of thromboembolic events between patients on and off oral antico-
agulants AF ablation (RR 0.66; 95% CI: 0.38–1.15). The Optimal Anti-Coagulation
for Enhanced-Risk Patients Post–Catheter Ablation for Atrial Fibrillation (OCEAN)
trial is an ongoing study that aims to assess whether using a DOAC (rivaroxaban) is
superior to acetylsalicylic acid in reducing the risk of clinically overt stroke, sys-
temic embolism, or covert stroke (primary composite outcome) in patients who
have not had an apparent recurrent atrial arrhythmias for a minimum of 1 year after
AF ablation (Verma et al. 2018). Major bleeding including intracranial hemorrhage
will also be assessed. This trial may help identify the optimal long-term anticoagu-
lation strategy after AF ablation.
Conclusions
Uninterrupted DOAC is the current standard of care for patients undergoing AF

catheter-based ablation. Higher doses of heparin are required intra-procedure to
maintain activated clotting times at target when using DOAC compared to warfarin.
DOAC use must be maintained for at least 8 weeks post ablation, and long-term use
depends on overall thromboembolic risk. Observational data suggests that thrombo-
embolic risk is low in patients with low overall risk who undergo ablation. An ongo-
ing trial will evaluate whether cessation of DOAC is safe post ablation.
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DOAC Therapy in Patients Post Left Atrial
Appendage Occlusion or Isolation 14
T. Jared Bunch
Atrial fibrillation (AF) is the most common encountered sustained arrhythmia in

clinical practice. In a cohort of 5201 adults, in people over the age of 65 years, the
arrhythmia had an incidence of 19.2 per 1000 patient-years (Psaty et al. 1997). This
AF incidence is increasing both in developed and underdeveloped countries as tra-
ditional risk factors in these community increase as well as from unknown factors
(Go et al. 2001).
Approximately 1 of 6 embolic strokes are associated with AF, and their impact is
significant with higher rates of disability, healthcare costs, stroke recurrences, and
mortality compared to strokes from other sources (Wolf et al. 1991). Overall, the
mechanisms of stroke in patients with AF are multifactorial and represent both
embolic and non-embolic sources. In addition, atherosclerotic carotid and cerebral
macro- and microvascular diseases are common in patients with AF and enhance
stroke risk (Lodder et al. 1990; Chesebro et al. 1990; Bunch et al. 2020).
The left atrial appendage (LAA) has been commonly cited as the source of most
embolic events in patients with AF. Most citations refer to a study by Blackshear
and Odell(1996), which examined the location of clots in patients with AF com-
pared by the presence or absence of rheumatic heart disease. In 1288 patients with
AF, 222 patients were found to have an intra-atrial source, and among these patients,
201 (91%), the intra-atrial source was the LAA. The study promotes two founda-
tional principles; first, that in the vast majority patients with AF, we currently do not
know the source of the embolic event, and strategies to prevent stroke must take into
consideration this uncertainty. Second, when we do know the location of the source,
it is most likely the LAA, and as such, in a minority of patients, LAA therapies are
an important consideration to reduce stroke risk.
T. J. Bunch (*)
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah
School of Medicine, Salt Lake City, UT, USA

236 T. J. Bunch
Stroke Reduction in Patients with Atrial Fibrillation
Anticoagulation for systemic disease–based risk in patients with AF remains the

cornerstone of stroke prevention therapies. Vitamin K antagonists are highly effec-
tive in decreasing stroke risk and have been used for nearly seven decades for this
purpose (Lip et al. 2012; Ruff et al. 2014). The narrow therapeutic index, need for
frequent monitoring, and multiple dietary and drug interactions have resulted in
underutilization of these drugs and the need to seek better pharmacologic solutions
(Ruff et al. 2014). Direct oral anticoagulants (DOAC) have been widely adopted
into contemporary practice with fewer drug and dietary interactions, no need for
routine monitoring of drug levels, and equal to superior efficacy and safety com-
pared to vitamin K antagonists (Connolly et al. 2009, 2011; Patel et al. 2011;
Giugliano et al. 2013).
Despite the potential ease-of-use advantages with DOAC therapies, compliance
rates remain suboptimal. In a large meta-analysis of real-world adherence involving
594,784 unique patients, the pooled proportion of patients with good adherence was
71% for apixaban, 60% for dabigatran, and 70% for rivaroxaban. Adherence with
DOAC therapy was superior to that observed with vitamin K antagonists (odds
ratio, 1.44 [95% CI: 1.12–0.86). Lack of adherence with DOAC therapies was asso-
ciated with an increased risk of stroke (hazard ratio (HR), 1.39 [95% CI: 1.06–1.81])
(Ozaki et al. 2020). A persistent challenge with DOAC therapy use is the cost of
these medications that impact access and used in both developed and underdevel-
oped countries.
These limitations with prior and contemporary therapies have provided a very
attractive substrate for the development of alternative approaches to reduce stroke
rates in patients with AF.
Left Atrial Appendage Occlusion
Multiple technologies for LAA occlusion are available, but for this chapter the
focus will be primarily on the Watchman device (Boston Scientific. Marlborough,
MA) as the data to date comprise the largest enrolled LAA occlusion populations
with the longest follow-up durations.
The PROTECT AF (Watchman Left Atrial Appendage System for Embolic
Protection in Patients With Atrial Fibrillation) trial included 542 patients and an
additional 460 in a continued access protocol registry that underwent attempted
LAA occlusion. In 91% of patients, the device was successfully implanted.
Procedure- or device-related safety events within 7 days were commonly initially
(7.7%) and declined with experience (3.7%), including procedure-related stroke
(0.9% and 0%, respectively) (Reddy et al. 2011). The LAA occlusion device com-
pared favorably to warfarin in regard to incident strokes (1.8 versus 4.3 events per
100 patient-years).
In a second randomized trial, PREVAIL AF (Evaluation of the Watchman LAA
Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin
14 DOAC Therapy in Patients Post Left Atrial Appendage Occlusion or Isolation 237
Therapy), periprocedural complication rates remained low, and at 18 months, the

rate of the composite of stroke, systemic embolism, and cardiovascular/unexplained
death) was 0.064 in the device group versus 0.063 in the control group, which did
not achieve the prespecified criteria noninferiority (Holmes et al. 2014).
At 5 years of follow-up, a meta-analysis of these studies showed that ischemic
stroke/systemic embolism rate was higher with LAA closure, but did not reach sta-
tistical significance (HR: 1.71; p = 0.080). Differences in hemorrhagic stroke, dis-
abling/fatal stroke, cardiovascular/unexplained death, all-cause death, and
post-procedure bleeding favored LAA closure (HR: 0.20; p = 0.0022; HR: 0.45;
p = 0.03; HR: 0.59; p = 0.027; HR: 0.73; p = 0.035; HR: 0.48; p = 0.0003, respec-
tively) (Reddy et al. 2017).
Even when successfully implanted, LAA closure device performance over time
has been suboptimal. Device endothelialization has been slower than anticipated
and can be incomplete years after implantation, and risk factor-driven device-related
thrombus can develop in up to 3.8% of patients. These risk factors elevate stroke
risk by four to fivefold (Sivasambu et al. 2019; Alkhouli et al. 2018). Risk factors
for device-related thrombus include many of those associated with general stroke
risk on patients with AF and include transient ischemic attack or stroke (OR: 2.31;
95% CI: 1.26–4.25; P = 0.007), permanent atrial fibrillation (OR, 2.24; 95% CI:
1.19–4.20; P = 0.012), vascular disease (OR, 2.06; 95% CI: 1.08–3.91; P = 0.028),
left atrial appendage diameter (OR, 1.06 per mm increase; 95% CI: 1.01–1.12;
P = 0.019), and left ventricular ejection fraction (OR, 0.96 per 1% increase; 95%
CI: 0.94–0.99; P = 0.009) (Dukkipati et al. 2018).
In addition, residual LAA leaks after implantation are common with small leaks
present in up to 32% of patients and larger leaks in approximately 1–12% (Saw
et al. 2017; Viles-Gonzalez et al. 2012). Leak is more common in patients with a
large landing zone diameter, persistent/permanent AF, and an off axis device loca-
tion (Nguyen et al. 2019). The presence of leaks is associated with stroke and major
adverse event rates, but should improve with procedural experience and technology
advances.
The persistent long-term stroke events compared to warfarin, which has per-
formed poorly historically, and those event rates observed with DOAC therapies
suggest that post-procedure antithrombotic strategies will likely play a key role in
the long-term utility observed after LAA closure (Table 14.1).
ntithrombotic Therapy After Percutaneous Left Atrial

A
Appendage Occlusion
Although most patients who receive LAA occlusion have an absolute or relative
contraindication to anticoagulation, antithrombotic therapy post-procedure is rec-
ommended for a specified period of time to prevent device-associated thrombus.
However, the type of therapy, duration of therapy, and in what combination to use
are not well defined. In addition, all of these questions may differ as individualized
approaches based upon actual or perceived risk are required for long-term
management.
238
Table 14.1 Comparison of clinical data from the PROTECT AF and PREVAIL AF and DOAC trials
PROTECT AF PREVAIL AF PROTECT AF Apixaban Rivaroxaban Edoxaban Dabigatran
LAA closure LAA closure Warfarin (ARISTOTLE) (ROCKET AF) (ENGAGE AF) (RELY)
Age, years 72 74 73 70 73 72 72
CHADS2 2.2 2.6 2.3 2.1 3.5 2.8 2.1
Major or minor – – – 18.1 14.9 16.9 16.4
bleeding (%)
Major bleeding (%) 3.5 – 4.1 2.1 3.6 2.8 3.1
Stroke/systemic 2.3 2.3 2.7 1.3 1.7 1.6 1.1
embolism (%)
T. J. Bunch
Different antithrombotic strategies studied after Watchman device implantation

include vitamin K oral anticoagulants, DOACs, dual antiplatelet therapies, aspirin
monotherapy across different time duration as well as no additional therapy (Reddy
et al. 2017, 2013; Boersma et al. 2017; Bergmann et al. 2017).
For example, in the PREVAIL and the PROTECT AF trials that are widely used
for guidance, patients were treated with warfarin for 45 days (INR 2–3) after device
placement to allow healing and potential endothelialization . Warfarin was discon-
tinued if transesophageal echocardiography showed complete closure or near clo-
sure. After that, patients received aspirin and clopidogrel for 6 months, and then
long-term aspirin (Reddy et al. 2017).
In the real-life registry, EWOLUTION (Watchman Outcomes in Real-Life
Utilization), strategies were variable and reflected individualized practices.
Following LAA closure, patients received dual antiplatelet therapy, vitamin K
antagonists, DOAC, single antiplatelet, or no therapy (60.3%, 15.4%, 10.9%, 7%,
and 6.5%, respectively). Device thrombus (2.6%), stroke (0.4%), and major bleed-
ing SAE (2.6%) rates were low in general at 3 months and did not vary by postim-
plantation antithrombotic medication strategy (Bergmann et al. 2017).
In the ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial
Appendage Closure Technology) trial, which was a multicenter, prospective, non-
randomized study of the WATCHMAN device in warfarin ineligible patients post-
device treatment included dual antiplatelet therapy for 6 months followed by aspirin
indefinitely. Serious procedure- or device-related safety events occurred in 8.7% of
patients (13 of 150 patients). All-cause stroke or systemic embolism incidence was
2.3% per year and ischemic stroke incidence (1.7% per year) (Reddy et al. 2013).
Other strategies have been advocated for different LAA closure systems, but the
general themes of diversity based upon expert opinion of risk and benefits prevail in
these studies.
Recently, PRAGUE-17 (Left Atrial Appendage Closure vs. Novel Anticoagulation
Agents) was published. Patients were randomized 1:1 to DOAC therapy versus
LAA closure. After LAA closure, the recommended antithrombotic regimen was
aspirin 100 mg/day plus clopidogrel 75 mg/day for 3 months. If a transesophageal
echocardiogram then showed no device-related thrombus or leak of >5 mm, clopi-
dogrel was withdrawn, and aspirin was continued indefinitely. In patients with a
very high thrombotic risk, alternative regimens included DOAC substitution for
DAPT for up to 3 months or DOACs for 6 weeks followed by dual antiplatelet
therapy for 6 weeks. The primary outcomes of stroke, transient ischemic attack,
systemic embolism, cardiovascular death, major or nonmajor relevant bleed, or
procedural-related complications were similar at a median follow-up of 19.9 months
(10.9% LAA closure group versus 13.4% DOAC group, p = 0.0004 for noninferior-
ity) (Osmancik et al. 2020). In the subgroup of high-risk AF patients in which
DOAC therapy could be used in the early post LAA closure period, there were also
no differences in long-term safety or efficacy outcomes.
The European Heart Rhythm Association/European Association of Percutaneous
Cardiovascular Interventions expert consensus statement has issued
240 T. J. Bunch
Table 14.2 Antithrombotic therapy before and after LAA closure

Clinical situation and therapeutic concept (Adapted from Consensus Statement) (Glikson et al.
2020)
“Should do this”—Green Heart Recommendation
• After WATCHMAN implantation, warfarin (INR 2–3) should be given for 45 days,
followed by clopidogrel for 6 months after the procedure in low bleeding risk group of
patients; while in high bleeding risk group, oral anticoagulation should not be applied
“May do this”—Yellow Heart Recommendation
• DOAC is a possible alternative to warfarin after WATCHMAN implantation
• After WATCHMAN implantation in patients not suitable for oral anticoagulation, dual
antiplatelet therapy including clopidogrel 75 mg/day for 1–6 months after the procedure
(load 300–600 mg prior to procedure if not previously on clopidogrel)
• After AMPLATZER Cardiac Plug or Amulet implantation, dual anticoagulation therapy
including clopidogrel 75 mg/day for 1–6 months after the procedure (load 300–600 mg
prior to procedure if not previously on clopidogrel)
• Other options that may be considered on a case-by-case basis include a single antiplatelet
therapy (acetylsalicylic acid or clopidogrel) for short periods of time, as long as approved
by a team consensus
recommendations for antithrombotic treatment approach after left atrial appendage

closure (Table 14.2) that reflect many of the trials and their post closure manage-
ment approaches (Glikson et al. 2020).
Left Atrial Appendage Isolation
Pulmonary vein isolation is the cornerstone of ablation strategies for patients with
atrial fibrillation (Calkins et al. 2017). However, in some patients, particularly those
with advanced AF subtypes, the left atrial appendage can serve as a trigger for
recurrent arrhythmias. The BELIEF trial was a randomized trial in longstanding
persistent AF patients between a standard “extensive” ablation versus standard abla-
tion with LAA isolation. At 12-month follow-up, 48 (56%) patients in LAA isola-
tion group vs. 25 (28%) in extensive ablation alone group were recurrence free of
atrial arrhythmias after a single procedure (HR1.92; 95% CI: 1.3–2.9; p = 0.001)
(Di Biase et al. 2016).
Despite a potential value in rhythm control with LAA isolation, the mechanisms
surrounding thrombus formation in the LAA, hemostasis, hypercoagulability, and
endothelial injury are augmented in patients that undergo persistent electrical isola-
tion of the LAA with mechanical uncoupling. As such it was not surprising to find
patients such as the one illustrated in Fig. 14.1 that presented with stroke, despite
adequate anticoagulation. In a registry study of 50 patients that underwent LAA
isolation, transesophageal echocardiography was performed during follow-up in
47/50 (94%) patients independent of symptoms. LAA thrombus was identified on
transesophageal echocardiography in 10 (21%) patients (on oral anticoagula-
tion = 9; no oral anticoagulation = 1) (Rillig et al. 2016). Among these nine patients,
three were on vitamin K antagonists, one on dabigatran (200 mg/day), four on
INR Values (Goal: 2-3)

4
3.5
3
2.5
2
1.5
1
0.5
0
30-Jul
6-Aug
13-Aug
20-Aug
27-Aug
3-Sep
10-Sep
17-Sep
24-Sep
1-Oct
8-Oct
15-Oct
22-Oct
29-Oct
5-Nov
12-Nov
19-Nov
26-Nov
Fig. 14.1 The figure shows the CT images at the time of admission for an acute stroke. The INR
findings show the values recorded 4 months prior to admission. The case is of 56-year-old female
with hypertension, grade ¾ diastolic dysfunction, two prior ablations, the second with extensive
substrate modification for non-PV triggers (4 months prior) with left atrial appendage isolation
rivaroxaban (20 mg/day), and one on apixaban (10 mg/day). If a thrombus was
found on DOAC therapy, these patients were transitioned to a vitamin K antagonist
with a goal INR of 2.5–3.5. Among the 50 patients that underwent LAA isolation,
three (6%) suffered a stroke.
A second larger study examined the impact of post LAA isolation occlusion or
long-term oral anticoagulation on risk of LAA thrombus at 6 months post LAA
isolation (Di Biase et al. 2019). In this study, 1854 consecutive post-LAA isolation
patients with follow-up transesophageal echocardiography (TEE) performed in
sinus rhythm at 6 months to assess LAA function was included. In the post-ablation
period, 336 patients with preserved LAA function were off oral anticoagulation
with very low stroke events. In the 1518 patients with abnormal LAA contractility,
1086 remained on oral anticoagulation with incident stroke/transient ischemic
attack rate of 1.7% versus 16.7% in those off oral anticoagulation (p < 0.001). In 81
patients with impaired LAA function, an LAA closure device was placed with stan-
dard post device anticoagulation with no observed strokes.
This second study highlights the significant iatrogenic stroke risk with LAA iso-
lation that results in impaired LAA function. In the group without impaired LAA
function, it is unclear if there was durable isolation, if the flow measurements were
reproducible, or if there was some benefit to the enhanced mechanical atrial func-
tion. What is very concerning about the observed strokes in this population is that
they often occurred rapidly, within 1–10 days, of a held or missed dosed of antico-
agulation, highlighting the potential challenges with long-term anticoagulation use
in patients that undergo LAA isolation and the likely value of LAA occlusion
despite the limitations discussed previously.
uture Directions with Left Atrial Appendage Closure

F
and Anticoagulation
There are a number of trials actively recruiting in this space that will provide addi-
tional clarity regarding the role of LAA occlusion in patients with AF compared to
DOACs, but there are none to compare postimplantation anticoagulation strategies.
242 T. J. Bunch
The Left Atrial Appendage Occlusion versus Novel Oral Anticoagulation for
Stroke Prevention in Atrial Fibrillation (Occlusion-AF, ClinicalTrials.gov:
NCT03642509) is a randomized (1:1) trial of 750 patients that will compare out-
comes between the Amulet or Watchman devices and DOACs. The primary out-
come is a composite of stroke (hemorrhagic or ischemic), systemic embolism,
major bleeding, or all-cause mortality assessed after at least 2 years follow-up for
the last enrolled patient.
Comparison of Anticoagulation with Left Atrial Appendage Closure After AF
Ablation (OPTION, ClinicalTrials.gov Identifier: NCT03795298) is a randomized
(1:1) trial of 1600 patients that will compare outcomes post atrial fibrillation
between patients treated with the Watchman FLX device sequential or planned at
the time of ablation and DOACs. The primary endpoints are noninferiority for
stroke, all-cause death, and systemic embolism and then for superiority for non-
procedural bleeding over 36 months of follow-up.
Left Atrial Appendage Closure in Patients with Atrial Fibrillation Compared to
Medical Therapy (CLOSURE-AF, ClinicalTrials.gov: NCT03463317) is a random-
ized trial of 1512 patient to CE-mark–approved LAA closure devices followed by
post-procedure treatment (antiplatelet therapy with acetylsalicylic acid and clopido-
grel) versus DOAC or vitamin K antagonist therapies. The primary endpoints are
sought at 24 months, but the trial is designed to be an event driven with a noninferi-
ority test, if significant, followed by superiority test. The primary endpoint is a com-
posite of stroke, systemic embolism, major bleeding, and cardiovascular or
unexplained death.
Amplatzer Amulet LAAO vs. NOAC (CATALYST, ClinicalTrials.gov:
NCT04226547) randomized trial (1:1) of 2650 patients randomized to the Amplatzer
Amulet LAA Occluder versus DOAC therapy with follow-up of 2 years. The end-
points are that the device will be noninferior for the composite of ischemic stroke,
systemic embolism, or cardiovascular mortality and superior for major bleeding or
clinically relevant nonmajor bleeding.
In consideration of these trials, most are anticipating low stroke event rates and
are focused on a noninferior design to show noninferiority to anticoagulation
approaches. The follow-up periods when considering the score and duration of man-
agement of a patient with AF are brief. However, many of these trials are designed
not to answer the way to manage patients with AF long term, but to try to answer the
prevalent question can LAA closure approach the benefit shown by DOAC therapies
alone in a scientifically acceptable manner for therapy adoption into practice.
Next, the field of electrophysiology remains plagued by the continued use of
clinical stroke, often with disability, as the primary endpoint for brain health. This
endpoint provides a myopic understanding of the actual impact of atrial fibrillation
on brain health and function and relies for the most part on a clinical presentation of
a frequently clinically silent event, whose true impact may become apparent
years later.
Finally, there remains a critical need to explore the role of different long-term
antithrombotic strategies in patients that receive an LAA closure device. The reli-
ance on long-term antiplatelet strategies is not supported by quality data, and these
agents are far from benign for both macro- and micro-brain injuries.
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Use of Direct Oral Anticoagulants After
Transcatheter Aortic Valve Replacement 15
Andrea Scotti, Mauro Massussi, Antonio Landi,
and George Besis
Introduction
Transcatheter aortic valve replacement (TAVR) has emerged as the standard of care
for patients with symptomatic severe, aortic stenosis (Nishimura et al. 2021;
Baumgartner et al. 2017). Since the completion of large randomized clinical trials
on low-risk patients treated with transfemoral TAVR, a number of approximately
270,000 candidates may benefit from this procedure in European Union and North
America annually (Durko et al. 2018). Similarly to percutaneous coronary interven-
tion (PCI), a balance between bleeding and thrombotic complications has to be
taken into consideration. The optimal antithrombotic therapy is determined by pro-
cedural and clinical considerations. Current evidence and the future perspectives on
the use of anticoagulants after TAVR will be presented.
Technical Aspects of Transcatheter Bioprosthetic Heart Valves
The available transcatheter bioprosthetic heart valves (BHVs) consist of three leaf-
lets of bovine or porcine pericardium attached to a stent frame. Despite some com-
mon features, BHVs differ from their surgical counterparts due to some unique
features that must be considered for appropriate selection of antithrombotic therapy.
The stents are uncoated and are directly exposed to blood flow. Comparisons
among different materials are not available but, extrapolating knowledge from coro-
nary stent research, nitinol frames (self-expandable BHVs) might offer better hemo-
compatibility and lower thrombogenicity potential compared to stainless steel
A. Scotti (*) · M. Massussi · A. Landi

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua
Medical School, Padua, Italy
G. Besis
Department of Cardiology, Fondazione Policlinico A. Gemelli, Rome, Italy

248 A. Scotti et al.
(Mangieri et al. 2019). Various grades of endothelization have been reported in
struts in direct contact with native endocardium. On the contrary, some concerns
have been raised regarding thrombus development on bare-metal structures in
ascending aorta lumen (van Kesteren et al. 2017).
In the absence of outcome studies on bovine and porcine leaflets in transcatheter
BHVs, the experience derived from cardiac surgery suggests that no significant dif-
ferences should be expected between these two types of leaflet tissues (Hickey et al.
2015). Animal models demonstrated how crimping forces can lead to structural
changes (e.g., leaflet tears) which can represent the primum movens of thrombosis
(Kiefer et al. 2011).
Finally, the implanted BHVs are responsible of altered hemodynamic conditions
in the space between the valve leaflets and the sinus of Valsalva (Ducci et al. 2016).
The decreased turbulence, flow velocity, and shear rate found in this region might
account for increased thrombogenicity after TAVR leading to hypoattenuating leaf-
let thickening (HALT) development and reduced motion.
Thrombotic vs. Bleeding Risk
Antithrombotic therapy in TAVR is particularly challenging because of the risk of

both ischemic and bleeding events (Saito et al. 2020). These complications are asso-
ciated with conspicuous high mortality rates (Saito et al. 2020). Therefore, a correct
balance between these opposing adverse outcomes is fundamental in the choice of
antithrombotic therapy and may vary depending on the clinical context.
Recent Percutaneous Coronary Intervention
In case of recent percutaneous coronary intervention (PCI), management of medical

therapy is mainly driven by the need for dual antiplatelet therapy (DAPT). The clini-
cal syndrome (stable coronary artery disease vs. acute coronary syndrome), rather
than the stent type, determines the duration of such therapy. Therefore, for obvious
reasons, in the absence of preexisting indications, there is no room for anticoagula-
tion in this setting.
Atrial Fibrillation
Atrial fibrillation (AF) is the most common rhythm disorder associated with severe
aortic stenosis; the STS/ACC TVT Registry reported a prevalence of 40% in
patients undergoing TAVR (Holmes et al. 2015). An additional 10% of new onset
AF cases has been detected (Mojoli et al. 2017). Therefore, up to half of the patients
undergoing TAVR potentially need oral anticoagulation (OAC) as part of the anti-
thrombotic therapy. A recent study investigated the impact of OAC type on 1-year
clinical outcome after TAVR (Jochheim et al. 2019). Although bleeding risk was
15 Use of Direct Oral Anticoagulants After Transcatheter Aortic Valve Replacement 249
comparable, a higher ischemic event rate was found among patients taking non-
vitamin K OAC (NOAC) compared to those on vitamin K antagonists (VKAs);
composite outcome of all-cause mortality, myocardial infarction, and cerebrovascu-
lar event at 1-year was 21.2% with NOAC vs. 15.0% with VKAs (hazard ratio [HR]
1.44, p = 0.050). Opposite results emerged from an analysis of the PARTNER
(Placement of AoRTic TraNscathetER Valve) II registries where patients discharged
on NOAC did not differ from those on VKAs in the following outcomes: overall
death 21% vs. 27.6%, stroke or TIA 11.6% vs. 8.8%, bleeding 23.1% vs. 22.4%, in
NOAC vs. VKAs, respectively (Kosmidou et al. 2019). However, when OAC was
added to a minimum 6 months regime of DAPT, a significant reduction in strokes
was observed. This finding was maintained after analyzing only acute/subacute
(procedure related) and late events (diffuse inflammatory and atherosclerotic pro-
cess). For this reason, Kosmidou et al. (2019) suggest the use of OAC (regardless of
type) in conjunction with APT for at least 6 months in patients with AF undergoing
TAVR. The absence of a significant difference between NOAC and VKAs in term of
bleeding could be attributed to the aetiology of post-TAVR hemorrhages that are
mostly mechanically provoked. Another possible explanation may be found in the
advanced age of patients undergoing TAVR. The reduction of major bleeds with
NOAC becomes nonsignificant when analyzing patients with AF and ≥75 years old
(Ruff et al. 2014).
Cerebrovascular Complications
Stroke is the most feared complication after TAVR. In the first year, it can occur in
up to 7% of intermediate or high-risk patients, similarly to what is observed in the
surgical counterpart (Vranckx et al. 2017). This 1-year time window can be further
divided into three parts, classifying stroke occurrence as acute, subacute, or late.
Acute stroke (on the first day) results from the mechanical deployment of the device
which interacts with the calcified aorta and degenerated valve. The consequence of
the embolization of tissue-derived debris is the finding of new cerebral emboli on
neuroimaging. This phenomenon has been observed in two-thirds of the patients but
does not correlate with clinical events (Giustino et al. 2016). A careful advancement
of the TAVR system and the use of embolic protection devices can attenuate this
complication. After the procedure and up to 30 days, we can define stroke occur-
rence as subacute. It is mainly caused by new-onset AF, which, as previously men-
tioned, can be detected in up to 10% of the patients (Mojoli et al. 2017). Finally, late
strokes are those reported in the 30 days–1 year period after the procedure. These
events are mainly related to systemic atherosclerosis with peripheral arterial disease
and preexisting AF. In some series, the role of anticoagulants in protecting from late
strokes caused by AF has been reported (Chopard et al. 2015).
Subclinical Leaflet Thrombosis
Subclinical leaflet thrombosis is a phenomenon already described in surgical bio-

prosthetic valves. It has been recently investigated in TAVR where its occurrence
has been found to be higher compared to the surgical counterpart (101 of 752 [13%]
vs. 5 of 138 [4%], TAVR vs. SAVR, respectively; P = 0.001) (Chakravarty et al.
2017). The diagnosis can be made identifying hypoattenuating lesions with the use
of four-dimensional multidetector computed tomography angiography. These
lesions have been associated with increased stroke risk and trans valvular gradients
1–9 months after TAVR and can potentially result in decreased long-term valve
durability (Hansson et al. 2016). The PARTNER 3 Cardiac Computed Tomography
(CT) sub-study described the dynamic nature of subclinical leaflet thrombosis:
spontaneous resolution (50%), new appearance (20%), and increased frequency
with time (24% at 1 year) (Makkar et al. 2020). Given these findings, the authors
question the utility of routine CT scanning at a single time point; a clinic-guided CT
imaging would be more prudent. Both DOACs and VKAs were associated with
lower rates of subclinical leaflet thrombosis compared to placebo, single, or DAPT
(4% vs. 15%, 16%, and 15%, respectively; all p < 0.0001) (Chakravarty et al. 2017).
A short-term (90 days) duration of anticoagulation led to resolution of leaflet throm-
bosis and improved function, while OAC discontinuation was associated with 50%
risk of recurrence (Hansson et al. 2016). An anticoagulation treatment strategy in
patients without an established indication for oral anticoagulation after successful
TAVR has not yet proven to be of clinical benefit. The extension of TAVR to younger
and low-risk patients, whose frequency of subclinical leaflet thrombosis reaches
1 in 4 patients, represents a strong argument for further clinical trials. Indeed, this
type of patient could benefit most from an oral anticoagulant therapy; the healthier
status could lead to a more favorable risk–benefit ratio for anticoagulation, and the
longer life expectancy makes valve durability even more relevant.
Current Evidence and Future Perspectives
Current guideline recommendations are largely derived from expert consensus

extrapolating experience from PCI and open-heart aortic valve replacement and are
summarized in Table 15.1.
Intraprocedural antithrombotic treatment is mainly based on the use of paren-
teral anticoagulation with unfractioned heparin (UFH) at doses of 50–70 IU/kg with
a target activated clotting time between 250 and 300 s. This practice is favored in
order to address the risk of thrombotic complications due to catheter manipulations,
guidewire insertion, balloon aortic valvuloplasty, and valve implantation and to
avoid bleedings from vascular access sites. Bivalirudin can be considered as a valid
alternative in case of contraindications to UFH .
After TAVR, until recently it was widely prescribed a DAPT with aspirin and
clopidogrel for 3–6 months, followed by aspirin alone lifelong. However, these indi-
cations are not well supported by current evidence and may be applied only in
Table 15.1 Current society guidelines for antithrombotic therapy after transcatheter aortic valve
replacement
Indication for OAC
Society guidelines Timing NO YES
ACC/AHA 2020 Short – DAPT for 3–6 months – VKAs in new-onset (≤ 3
term (IIb/B) if low bleeding risk months) AF (IIa/B)
– VKAs (INR 2.5) for 3
months (IIb/B-NR) if low
bleeding risk
– Rivaroxaban (10 mg daily)
plus aspirin (75–100 mg) is
contraindicated (III/B)
Long Aspirin 75/100 mg (IIa/B) – NOAC or VKAs after
term 3 months (I/A)
ESC/EACTS 2017 Short – DAPT for 3–6 months – OAC + aspirin/
term (IIa/C) thienopyridine for 3
– SAPT if high bleeding risk months (IIa/C)
(IIb/C) – OAC if high bleeding risk
(I/C)
Long Aspirin/thienopyridine OAC (I/C)
term (IIb/C)
OAC oral anticoagulation, ACC/AHA American College of Cardiology/American Heart
Association, NOAC non-vitamin K OAC, DAPT dual antiplatelet therapy, VKAs vitamin K antago-
nists, INR international normalized ratio, ESC/EACTS European Society of Cardiology/European
Association of Cardio-Thoracic Surgery, SAPT single antiplatelet therapy
patients with low-bleeding risk. In fact, a recent randomized clinical trial demon-
strated an advantage of single antiplatelet therapy (SAPT) over DAPT in reducing
the risk for major or life-threatening events while not increasing the risk for myo-
cardial infarction or stroke (Rodés-Cabau et al. 2017). Therefore, provided that
larger studies support this approach, a single antiplatelet agent could be a safer
alternative to DAPT in patients without an indication to OAC.
The issue of bleeding complications was not addressed by clinical trials on trans-
catheter procedures until the REPLACE-2 (Randomized Evaluation in PCI Linking
Angiomax to Reduced Clinical Events 2) trial. Bleeding was found to be a predictor
of death at 1 year that was as powerful as myocardial infarction (Feit et al. 2007).
This strong evidence impacted all subsequent studies that considered this complica-
tion worthy of being a primary outcome. The Global Study Comparing a
rivAroxaban-based Antithrombotic Strategy to an antiplatelet-based Strategy after
Transcatheter aortic vaLve rEplacement to Optimize Clinical Outcome (Galileo,
n = 1520) study randomized TAVR patients who did not have indications for OAC
in receiving 10 mg of rivaroxaban up to 25 months plus low-dose aspirin during the
first 3 months vs. 3 months DAPT followed by aspirin alone (NCT02556203).
Addition of OAC was found to be associated with increased risk of death, thrombo-
embolic as well as bleeding complications and resulted in premature termination of
the study (Dangas et al. 2020). The Anti-Thrombotic Strategy after Trans-Aortic
Valve Implantation for Aortic Stenosis (ATLANTIS, n = 1509) trial will provide
more data on the use of NOAC comparing the standard of care (DAPT or VKAs)
with an anticoagulant-based strategy with apixaban 5 mg bid, stratifying for the
need or not for OAC other than TAVI (NCT02664649).
In the setting of preexisting OAC indication, The Antiplatelet Therapy for Patients
Undergoing Transcatheter Aortic Valve Implantation (POPular TAVI, n = 1000) trial
was designed to provide randomized data on OAC vs. OAC plus clopidogrel for 3
months (NCT02247128). The investigators of this study reported a lower incidence
of serious bleeding over a period of 1 month or 1 year with OAC alone than with
OAC plus clopidogrel (Nijenhuis et al. 2020). In the same context of OAC indica-
tion but with the use of different NOAC, the Aortic Valve Replacement Versus
Conservative Treatment in Asymptomatic Severe Aortic Stenosis (AVATAR) trial
will report on the net clinical benefit of OAC alone (VKAs or Apixaban/Edoxaban)
vs. OAC plus aspirin at 1 year (NCT02735902).
While the use of OAC is undisputed among patients with AF, the need to add an
antiplatelet agent is still debatable. As previously mentioned, conflicting evidence
complicate the final selection. Therefore, the choice of appropriate therapy needs to be
characterized by an approach that will favor OAC alone in case of enhanced bleeding
risk and, on the contrary, will suggest OAC plus aspirin if the thrombotic risk prevails.
Triple antithrombotic therapy (OAC plus DAPT) is not addressed by current guide-
lines and should be considered only in special situations (e.g., recent PCI and con-
comitant AF). In addition to the previously mentioned ATLANTIS trial, the Edoxaban
Compared to Standard Care after Heart Valve Replacement Using a Catheter in
Patients with Atrial Fibrillation (ENVISAGE-TAVI AF; NCT02943785; n = 1400)
and the Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet
Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement
(ADAPT-TAVR; NCT03284827; n = 220) trial will provide more evidence on the
efficacy and safety of NOAC (edoxaban) vs. VKAs or vs. DAPT, respectively.
At the moment, subclinical leaflet thrombosis is not addressed by current guide-
lines. Particular attention must be paid to this complication which can be effectively
treated with the use of anticoagulation therapy.
To conclude, we can affirm that, to date, there are several gaps that need to be
filled. In the absence of risk prediction models, a careful clinical judgement has to
guide the choice of the appropriate antithrombotic therapy. Ongoing studies will
provide better knowledge and more robust recommendations.
Conflict of Interest The authors have no conflicts of interest to declare.
Disclaimer None.
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Use of Direct Oral Anticoagulants After
Percutaneous Coronary Intervention 16
Antonio Landi, Mauro Massussi, Andrea Scotti,
and George Besis
Introduction
Atrial fibrillation (AF) is the most common cardiac rhythm disorder with an esti-
mated prevalence of 1.5–2% in the general population (Moti et al. 2015). The bur-
den of this emerging arrhythmia is predicted to further expand in the next years due
to growing ageing population, with a major increase in healthcare cost (Virani et al.
2020). The cornerstone of AF-related thromboembolic prevention is represented by
oral anticoagulation (OAC) with vitamin K antagonists (VKA) and more recently
with direct oral anticoagulants (DOAC) (Steffel et al. 2018). In this setting, OAC is
essential for preventing cerebral and systemic embolization arising from left atrial
appendage thrombus, where blood stasis and low shear-stress promote formation of
less platelet-rich thrombi.
However, about 30% of AF patients present with concomitant coronary artery
disease (CAD), often requiring percutaneous coronary intervention (PCI)
(Michniewicz et al. 2018; Nieuwlaat et al. 2005). Moreover, indications for lifelong
OAC occur in up to 10% of patients undergoing coronary angiography (Michniewicz
et al. 2018). In this context, dual antiplatelet therapy (DAPT) is needed to prevent
stent thrombosis (ST) and coronary events due to platelet-rich thrombi in high
shear-stress regions.
A sizeable proportion of patients presents with multiple comorbidities, which
may require the combination of OAC and DAPT, a treatment also known as triple
antithrombotic therapy (TAT). On one hand, this regimen is “theoretically” required
in order to prevent ischemic complications with different pathophysiological mech-
anisms (systemic, cerebral, and coronary ischemic events); on the other hand, the
A. Landi (*) · M. Massussi · A. Scotti

G. Besis

256 A. Landi et al.
risk of major and fatal bleedings is markedly increased in patients on TAT, in par-
ticular in those patients with high bleeding risk at baseline. The growing interest of
the scientific community has led to several randomized controlled trials (RCTs),
evaluating different strategies of combining OAC and antiplatelet therapy. However,
the optimal management of AF patients requiring PCI is still debated, and ongoing
studies and meta-analyses will probably change the landscape in the near future
(Capodanno and Angiolillo 2014; Capodanno et al. 2019).
In this chapter, we summarize current evidence coming from large RCTs and
recent recommendations about management of antithrombotic therapy in AF
patients undergoing PCI. We also discuss the pivotal role of personalized ischemic
and bleeding risk assessment in order to offer a tailor-made treatment for those
patients. Finally, we will present emerging interventional strategies in high bleeding
risk patients, such as left atrial appendage occlusion (LAAO) and newer generation
drug-eluting stents (DES).
In the Middle of Ischemic and Bleeding Risk
The advent of DOAC in clinical practice and evidences from landmark trials has
brought about a paradigm shift in the optimal treatment strategies in AF patients
undergoing PCI.
An antithrombotic regimen consisting of OAC, aspirin, and P2Y12 inhibitors
(TAT) has been initially endorsed by international guidelines to ensure a compre-
hensive protection against ischemic events (thromboembolism and coronary throm-
bosis). However, TAT is associated with a higher risk of bleeding, particularly in
protracted administration. Sørensen et al. have clearly outlined that TAT fourfold
increases the risk of fatal and nonfatal bleedings in patients with myocardial infarc-
tion (MI) when compared to treatment with aspirin alone (Sørensen et al. 2009).
Moreover, it is important to emphasize that high bleeding risk (HBR) patients are
excluded or underrepresented in clinical trials, and the reported rates of major and
minor bleeding represent only the tip of the iceberg. Indeed, in major DAPT trials,
1-year major bleeding rates range from 0.3 to 2.8% (Fig. 16.1). Thus, the recogni-
tion of HBR patients is of paramount importance in daily clinical practice as well as
its impact on prognosis, which is emerging as a major issue. Data from ARISTOTLE
(Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial
Fibrillation) trial demonstrated that major bleedings occurrence 12-fold increases
the risk of death, stroke, and MI within 30 days (Held et al. 2014).
This increased bleeding risk associated with TAT and its impact on clinical out-
comes has generated great interest in this complex clinical scenario, and main
research initiatives aim to identify alternative antithrombotic strategies and deter-
mine their optimal duration. Indeed, antithrombotic treatment and its duration
should take into account the dynamic nature of ischemic hazard (thromboembolism
and coronary thrombosis) and the individualized stratification of ischemic and
bleeding risk.
16 Use of Direct Oral Anticoagulants After Percutaneous Coronary Intervention 257
4
1-year bleeding (%)
3 2.8
2.7
2.0 1.9
2
1.5
1.2
0.9 1.0
1 0.7
0.3
0
Y
T
ET
T
Y
IG
ER L
C
TE T
PT P
PT ISE
N
AD BA
P
IT
DA AR
DA TO
TI
S
LE
D
ES
DA
R
C
O
DA EC
LE LO
SM
EL
U
AR
PR
PR
G
C
SE
EX
BARC 3-5 TIMI GUSTO STEEPLE
major/minor
Fig. 16.1 One-year bleeding rates in dual antiplatelet therapy (DAPT) trials according to different
bleeding scores. As we can see from the bar chart, high bleeding risk patients are excluded or
underrepresented in DAPT trials. Bleeding events were evaluated according to different risk
scores. BARC Bleeding Academic Research Consortium, TIMI thrombolysis in myocardial infarc-
tion, GUSTO Global Use of Strategies to Open Occluded Arteries, STEEPLE Safety and Efficacy
of Enoxaparin in PCI Patients, an International Randomized Evaluation
Temporal evolution of ischemic risk represents a key point and different trends,
and pathophysiological mechanisms are recognized in the context of thromboem-
bolic and coronary events. Indeed, in AF patients requiring OAC, it has been well
established that stroke risk continues to increase over time. This continuous increase
may be related to structural remodeling of left atrium, which undergoes progressive
enlargement and loss of contractile function, with consequent increase of AF bur-
den, blood stasis, and thromboembolic risk. On the other hand, pathophysiological
mechanisms of ST are quite different and its risk seems to follow a more predictable
temporal pattern. Indeed, the majority of ST events occurs in the early phases after
coronary stenting, a temporal window of high thrombotic hazard in which a more
aggressive antiplatelet therapy is needed. Following this vulnerable period, lower-
ing the intensity of antiplatelet treatment has been demonstrated to be a safe option
in patients at high bleeding risk.
Current guidelines and consensus documents underline the importance of indi-
vidual stratification of ischemic and bleeding hazard (Angiolillo et al. 2018;
Neumann et al. 2018; Valgimigli et al. 2017). In recent years, several scores have
been proposed to predict the risk of ischemic or bleeding events in AF patients or
those undergoing PCI. For instance, in AF patients, CHADS2 and CHA2DS2-Vasc
258 A. Landi et al.
are well-established scores for ischemic risk assessment, while HAS-BLED, ABC,
and ATRIA are used for bleeding risk stratification. On the other hand, in patients
undergoing PCI, DAPT and PRECISE-DAPT scores have been proposed for isch-
emic and bleeding risk stratification, respectively (Saito and Kobayashi 2019).
However, no scoring system has been validated in AF patients undergoing PCI and
tested in RCT. Moreover, some of these scores are limited by considerable overlap
among risk factors for ischemic and bleeding events. Initial evidence seems to sup-
port the predictive ability of CHA2DS2-Vasc (with cutoff value of 5) and HAS-
BLED scores towards ischemic and bleeding events, respectively, in anticoagulated
patients undergoing PCI (Fauchier et al. 2016; Yoshida et al. 2019).
Currently, antithrombotic therapy, its composition and duration, is left to clini-
cian’s discretion and should take into consideration not only scoring systems and
clinical factors but also anatomical and PCI features (Giustino et al. 2016). Further
studies are warranted to develop or validate novel scoring systems, aiming to guide
antithrombotic therapy in AF patients undergoing PCI.
Lessons from Randomized Clinical Trials
VKA in Triple Versus Dual Antithrombotic Therapy
Two randomized trials attempted to explore novel antithrombotic strategies to

improve safety of TAT by withdrawing aspirin (WOEST trial [What is the Optimal
antiplatelet & Anticoagulant Therapy in Patients with Oral Anticoagulation and
Coronary StenTing] (Dewilde et al. 2013)) or reducing its duration (ISAR-TRIPLE
trial [Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent
Implantation] (Fiedler et al. 2015)).
The WOEST trial was the first RCT enrolling 573 patients (28% with acute coro-
nary syndromes [ACS]) treated with PCI and randomized to TAT (VKA, aspirin and
clopidogrel) versus dual antithrombotic therapy (DAT) (VKA and clopidogrel)
(Dewilde et al. 2013). The primary endpoint was 1-year minor and major bleedings.
The study demonstrated a 64% relative reduction of bleeding in patients random-
ized to DAT versus TAT (19.4% versus 44.4%, hazard ratio [HR] 0.36; 95% CI:
0.26–0.5, p < 0.0001), driven by a reduction in minor bleedings. Although throm-
botic events were also reduced in DAT group, the study was underpowered for effi-
cacy endpoints. Prolonged duration of TAT, the low sample size, and proportion of
ACS patients represent the main limitations of this study, which however paved the
way to several aspirin-free trials.
The ISAR TRIPLE trial enrolled 614 PCI patients (one-third with ACS) with any
indications for OAC and randomized to 6 weeks versus 6 months of DAPT (Fiedler
et al. 2015). The primary endpoint, a composite of death, MI, definite ST, stroke, or
TIMI major bleeding at 9-month, did not differ between the two groups. Of note, a
landmark analysis of events between 6 weeks and 6 months showed an increased
risk of bleeding in patients randomized to TAT versus DAT. Despite the low sample
size and lack of power to detect significant differences in ischemic endpoints,
WOEST and ISAR TRIPLE trials outlined that TAT should be as short as possible,
and a less intensive antithrombotic regimen is a safe option in patient requiring
OAC and antiplatelet therapy.
DOAC in Triple Versus Dual Antithrombotic Therapy
The introduction of DOACs represented a major breakthrough in antithrombotic

management of AF patients, on the basis of evidence coming from four pivotal stud-
ies: RE-LY (Connolly et al. 2009), ROCKET-AF (Patel et al. 2011), ARISTOTLE
(Granger et al. 2011), and ENGAGE AF-TIMI 48 trials (Giugliano et al. 2013).
Although post hoc analysis of these trials demonstrated the relative safety and effi-
cacy of DOAC in AF patients undergoing PCI, definite conclusions could not be
drawn due to low proportion of patients treated with concomitant antiplatelet ther-
apy; moreover, patients on DAPT were mostly excluded from these studies
(Fig. 16.2).
Thus, four large RCTs have been conducted to investigate the safety and efficacy
of different DOACs in AF patients undergoing PCI (Table 16.1): PIONEER AF-PCI
(Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment
Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist
Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous
Coronary Intervention) (Gibson et al. 2016), RE-DUAL PCI (Randomized
Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy
with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing
Percutaneous Coronary Intervention) (Cannon et al. 2017), AUGUSTUS (An Open-
label, 2 × 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety
of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients
With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous
Coronary Intervention) (Lopes et al. 2019a), and ENTRUST-AF PCI (Edoxaban-
based Versus Vitamin K Antagonist-based Antithrombotic Regimen After Successful
Coronary Stenting in Patients with Atrial Fibrillation) (Vranckx et al. 2019).
ENGAGE
RE-LY ROCKET-AF ARISTOTLE
AF-TIMI 48
Dabigatran Rivaroxaban Apixaban
Edoxaban
Concomitant
ASA 32% 37% 24% 29%
Concomitant
2% <2% 2% 2%
Clopidogrel
Concomitant
5% Excluded Excluded Excluded
DAPT
Fig. 16.2 Antiplatelet therapy in direct oral anticoagulants (DOAC) trials. In DOAC trials,
patients receiving P2Y12 inhibitors or DAPT are excluded or underrepresented. ASA acetylsalicylic
acid, DAPT dual antiplatelet therapy
Table 16.1 Study design and key outcomes of trials investigating DOAC in atrial fibrillation (AF) patients undergoing percutaneous coronary interven-
260
tion (PCI)
PIONEER AF-PCI RE-DUAL PCI (Cannon et al. ENTRUST-AF PCI
(Gibson et al. 2016) 2017) AUGUSTUS (Lopes et al. 2019b) (Vranckx et al. 2019)
Year 2016 2017 2019 2019
Design Open label RCT Open label RCT RCT, 2 × 2 factorial design Open label RCT
Size (no. of patients) 2.124 2.725 4.614 1.506
Time to randomization ≤3 ≤5 ≤14 ≤5
(days)
ACS (%) 52 51 61 52
DOAC dose • Low-dose Both doses of APIXABAN 5 mg bid; 2.5 mg bid EDOXABAN 60 mg od;
RIVAROXABAN (15 mg DABIGATRAN approved with ≥2 of the following criteria: 30 mg if one or more
od) for thromboembolic factors:
prevention in AF • Age ≥ 80 years • Creatinine clearance
15–50 mL/min
• Very-low-dose • Weight ≤ 60 kg • Body weight ≤ 60 kg
RIVAROXABAN (2.5 mg • Creatinine ≥ 1.5 mg/dL • Concomitant use of
bid) specific potent P-GPI
Comparison 1. Low-dose 1. DABIGATRAN 1. APIXABAN + P2Y12i + placebo 1. EDOXABAN + P2Y12i
RIVAROXABAN + P2Y12i 110 mg + P2Y12i
2. Very-low-dose 2. DABIGATRAN 2. VKA +P2Y12i + placebo
RIVAROXABAN + DAPT 150 mg + P2Y12i
3. VKA + DAPT 3. VKA + DAPT 3. APIXABAN + P2Y12i + ASA 2. VKA + P2Y12i + ASA
4. VKA + P2Y12i + ASA
Primary End-point Major or minor TIMI Major or clinically relevant Major or clinically relevant minor Major or clinically
bleeding or bleeding minor bleeding bleeding relevant non-major
requiring medical attention bleeding
A. Landi et al.
Duration of DAPT in 1, 6 or 12 months 1 month after BMS 3 6 months 1–12 months
the triple therapy months after DES
group
Follow-up duration 12 months >12 months 6 months 12 months
RCT randomized controlled trial, ACS acute coronary syndrome, VKA vitamin K antagonist, P-GPI P-glycoprotein inhibitors, od once daily, bid twice daily,
BMS bare metal stent, DES drug-eluted stent; other abbreviations as in Figs. 16.1 and 16.2
16 Use of Direct Oral Anticoagulants After Percutaneous Coronary Intervention
261
262 A. Landi et al.
PIONEER AF-PCI Trial

PIONEER AF-PCI trial compared three treatment strategies in 2124 anticoagulated
patients undergoing PCI: low-dose rivaroxaban (15 mg once daily [od]) plus P2Y12
inhibitor (DAT, group 1), very low-dose rivaroxaban (2.5 mg twice daily [bid]) plus
DAPT followed by rivaroxaban 15 mg od at the time of P2Y12 discontinuation
(group 2), and standard triple therapy (VKA plus DAPT, group 3) (Gibson et al.
2016). To put the evidences into perspective, it is important to underline that the
dosage in both rivaroxaban regimens is lower than that approved for thromboembo-
lism prevention in AF patients. Moreover, DAPT duration (1, 6, 12 months) was left
to clinician’s discretion in group 2 and 3, and clopidogrel was chosen in the majority
of patients (93%). The primary endpoint, a composite of TIMI major or minor
bleeding and bleeding requiring medical attention, was significantly higher at 1-year
in the standard TAT arm compared to other two groups, driven by a significant
reduction in bleeding requiring medical attention. There were no differences in
major adverse cardiovascular events (a composite endpoint of cardiovascular death,
MI, or stroke) in line with the results of WOEST and ISAR-TRIPLE trial, even
though they were underpowered for efficacy endpoints.
RE-DUAL PCI Trial

RE-DUAL PCI randomized 2725 PCI patients with AF (51% with ACS) to two dif-
ferent DAT regimens (dabigatran 110 mg or 150 mg bid plus clopidogrel or ticagre-
lor in 12% of patients) versus standard TAT (VKA plus DAPT with clopidogrel or
ticagrelor) (Cannon et al. 2017). In the TAT arm, aspirin was administered for 1
month in patients who received bare metal stents (BMS) and 3 months for patients
with DES. At 14-month follow-up, the rate of major or clinically relevant nonmajor
bleeding was lower for patients in DAT arms for either the two regimens compared
to TAT group (15.4% in the 110 mg DAT group versus 26.9% in the TAT group, HR
0.52, 95% CI: 0.42–0.63, p < 0.001 for both noninferiority and superiority; 20.2%
in the 150 mg DAT group versus 25.7% in the TAT group, HR 0.72, 95% CI:
0.58–0.88, p < 0.001 for noninferiority). There were no statistically significant dif-
ferences in thromboembolic complications between two DAT arms and TAT group.
Of note, patients randomized to the 110 mg dabigatran dose had an increased abso-
lute risk (although nonsignificant) of thromboembolic events or death (11.0% ver-
sus 8.5%, HR 1.30, 95% CI: 0.98–1.73, p = 0.07) and ST (15 versus 8 ST events,
HR 1.86, 95% CI: 0.79–4.40, p = 0.15) when compared with TAT group.
The results of RE-DUAL PCI trial, as well as PIONEER AF-PCI, support the
take-home message arising from WOEST trial, i.e., that DAT is associated to less
bleeding events compared to TAT. However, it has not yet been elucidated if the
lower bleeding risk is related to use of DOAC (instead of VKA) or to early discon-
tinuation of aspirin.
AUGUSTUS Trial
In the AUGUSTUS trial, 4614 patients (61% with ACS, of whom 24% medically
treated) were first randomized (2 × 2 factorial design) to receive apixaban or VKA
(first randomization) and, then, randomized again to receive aspirin or placebo
(second randomization) (Lopes et al. 2019a). The study was designed to compare
safety of apixaban versus VKA and to assess the effect of aspirin withdrawal.
Median time from index event to randomization was 6.6 days. At 6-month follow-
up, the results may be summarized as follows: (1) apixaban was associated with
lower risk of major or clinically relevant nonmajor bleeding events compared to
VKA (HR 0.69; 95% CI: 0.58–0.81; p < 0.001); (2) additional aspirin resulted in
higher risk of bleeding (HR 1.89; 95% CI: 1.59–2.24; p < 0.001); (3) the rate of
death or ischemic events did not significantly differ between placebo and aspirin
group (HR 1.12; 95% CI: 0.9–1.41). Although definite conclusions on efficacy end-
points could not be drawn, AUGUSTUS trial provide interesting insights into the
effect of aspirin removal. It should be noted that in all three previous trials, there is
a temporal window to randomization from 3 to 14 days (Table 16.1), during which
patients were treated with TAT. Thus, it remains debatable if aspirin could be with-
drawn in the early period after PCI, when the risk of coronary events is higher.
ENTRUST-AF PCI Trial

In ENTRUST-AF PCI trial, 1506 AF patients undergoing PCI were randomized to
edoxaban 60 mg (or 30 mg according to labeling indications) plus a P2Y12 inhibitor
for 12 months or VKA in combination with a P2Y12 inhibitor and aspirin (100 mg
once daily, for 1–12 months) (Vranckx et al. 2019). Time to randomization was up
to 5 days (median time 45 h). During 12 months of follow-up, DOAC strategy was
found noninferior to VKA regimen with regard to the primary endpoint, a compos-
ite of major or clinically relevant nonmajor bleeding (17% versus 20%; HR 0.83;
95% CI: 0.65–1.05). No significant differences were detected in ischemic endpoints
between the two strategies, although the study was underpowered to detect signifi-
cant differences in efficacy outcomes.
Meta-analysis
In order to further explore this relevant issue, Lopes et al. conducted a network
meta-analysis involving more than 10,000 patients from four RCTs (WOEST,
PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS) (Lopes et al. 2019b). They
found that DAT (consisting of DOAC and a P2Y12 inhibitor) significantly reduced
bleeding events (odds ratio 0.49; 95% CI: 0.30–0.82) with a similar rate of ischemic
outcomes (odds ratio 1.02; 95% CI: 0.71–1.97).
Another recent meta-analysis pooled aggregate data from four DOAC-based
RCTs (PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI),
showing that DAT and in particular DOAC instead of VKA is associated with less
bleeding events, including minor and intracranial hemorrhages (Gargiulo et al.
2019). However, there was a trend toward increased risk of MI with a statistically
significant increase in ST with DAT.
Finally, evidence coming from RCT and meta-analysis provided interesting
pathophysiological and clinical implications. First, DOAC use should be preferred
over VKA in all AF patients undergoing PCI, since the superior safety profile in
terms of bleeding seems to be a class effect. Second, efficacy profile of DAT for
ischemic outcomes has been evaluated in all RCTs as secondary endpoint, and a
264 A. Landi et al.
careful evaluation of study population is essential in order to apply these findings

into the appropriate clinical setting. Indeed, in RE-DUAL PCI (Cannon et al. 2017)
and AUGUSTUS trial (Lopes et al. 2019a), nearly 60% of patients underwent PCI
for stable angina, positive stress test, or were medically managed ACS. So, ischemic
outcomes—mainly stent-related—should be interpreted and extrapolated to ACS
patients with caution due to the “low-risk” CAD. Of note, only up to 30% of patients
included in these studies were female, an additional risk factor for thromboembo-
lism and bleeding. Thus, further studies are warranted to evaluate ischemic out-
comes in these particular populations. Third, these findings highlight that a
one-size-fits-all strategy cannot be applied, and a tailored approach should guide the
complex management of these patients, in terms of timing and composition of anti-
thrombotic treatments. In other words, an individual ischemic and bleeding risk
assessment should be formulated prior to initiation or early discontinuation TAT.
Current Recommendations
Current guidelines and consensus documents by European and American expert

bodies on antithrombotic management of anticoagulated patients undergoing PCI
do not include recent evidences on DOAC (Angiolillo et al. 2018; Neumann et al.
2018). Both guidelines endorse DOAC use over VKA, unless contraindicated.
However, North American consensus document recommends TAT only during peri-
PCI period, and DAT immediately after hospital discharge should be considered in
most patients (Angiolillo et al. 2018).
On the other hand, current 2018 ESC guidelines on myocardial revascularization
(Neumann et al. 2018) and recent focus update on DAPT (Valgimigli et al. 2017)
recommend TAT for at least 1 month and up to 6 months in patients with high isch-
emic risk due to ACS or other anatomical and procedural features (Table 16.2)
which outweigh the bleeding risk. After this TAT period, dual therapy with OAC
and aspirin or clopidogrel is recommended up to 12 months, followed by OAC
alone. In patients in whom the bleeding risk outweighs the ischemic risk, dual ther-
apy (clopidogrel and an OAC) is an alternative to 1-month TAT. When a DOAC is
used in combination with aspirin and/or clopidogrel, the lowest approved dose
Table 16.2 High ischemic Prior ST on adequate antiplatelet therapy

risk: anatomical and Stenting of the last patent vessel
procedural characteristics
Multivessel disease (DM)
CKD
≥3 implanter stent
≥3 treated lesions
2-Stent bifurcation technique
Total stent length > 60 mm
CTO treatment
ST stent thrombosis, DM diabetes mellitus, CKD chronic
kidney disease, CTO chronic total occlusion
AF patients undergoing PCI
Ischemic and bleeding risk assessment
VERY-HIGH HIGH ISCHEMIC

HIGH BLEEDING
BLEEDING RISK RISK
RISK
ASA
ASA
ASA
Peri-PCI
1-month
OAC (DOAC>VKA)
OAC (DOAC>VKA)
OAC (DOAC>VKA)
CLOPIDOGREL
CLOPIDOGREL
CLOPIDOGREL
3-month
6-month
12-month
Fig. 16.3 Antithrombotic management of AF patients undergoing PCI, according to European

perspective. OAC oral anticoagulation, other abbreviations as in Fig. 16.2 and Table 16.1
effective for stroke prevention should be considered. All the above recommenda-
tions are class IIa with varying level of evidence. When rivaroxaban is used in com-
bination with aspirin and/or clopidogrel, rivaroxaban 15 mg od may be used instead
of rivaroxaban 20 mg od (class IIb, Level of evidence B). Ticagrelor or prasugrel
should be avoided as part of TAT because of lack of data and high bleeding risk
(class III, level of evidence C) (Sarafoff et al. 2013). Figure 16.3 provides a practical
algorithm of antithrombotic management in AF patients undergoing PCI, based on
European recommendations.
In summary, European perspective highlights the importance of: (1) keeping
TAT duration as short as possible and DAT after PCI should be considered as an
option only in very selected patients; (2) ischemic and bleeding risk assessment
using validated risk predictors (e.g., CHA2DS2-VASc, ABC, and HAS-BLED); (3)
considering a target INR in the lower part of the recommended target range when a
VKA is used, in order to avoid bleeding complications; (4) using low-dose aspirin;
and (5) using routinely proton pomp inhibitors.
266 A. Landi et al.
Practical Management of AF Patients Undergoing PCI
Procedural and Peri-PCI Management
Nowadays, PCI has become a safe and well-established procedure, with widely
adopted use of radial access and very low rates of stent-related complications with
contemporary DES, such as ST. Moreover, an appropriate risk and benefit stratifica-
tion and the increasingly standardized management of OAC in patients undergoing
elective or urgent PCI, together with selected use of glycoprotein IIb/IIIa inhibitors
only for bailout indications, have contributed to consistent reduction in bleeding
events in current clinical practice.
According to guidelines and consensus documents (Neumann et al. 2018;
Valgimigli et al. 2017), DAPT duration should be irrespective of stent type, opting
for contemporary DES over BMS. However, as mentioned above, the management
of aspirin removal represents a major issue. Based on ISAR-TRIPLE trial and other
observational studies, many clinically relevant bleeding events occurred during the
early period after PCI due to the use of multiple periprocedural antithrombotic med-
ications (Fiedler et al. 2015). All DOAC trials investigating safety of DAT versus
TAT randomized AF patients undergoing PCI to an aspirin-free strategy with a time
(from index procedure to randomization) of up to 3 days in PIONEER AF-PCI
(Gibson et al. 2016), 5 days in RE-DUAL PCI (Cannon et al. 2017) and ENTRUST
AF-PCI (Vranckx et al. 2019) trials, and 6 days in AUGUSTUS trial (Lopes et al.
2019a). Consequently, North American guidelines suggest DAT as default strategy
(Angiolillo et al. 2018; January et al. 2019), whereas European guidelines recom-
mend DAT (keeping aspirin in the peri-PCI period or until hospital discharge) only
for patients at very-high bleeding risk (Neumann et al. 2018).
Choice and Duration of Antithrombotic Therapy After PCI
European and American guidelines strongly recommend preferring DOAC use over
VKA, due to the lower bleeding risk. Moreover, in case of VKA use, the dose inten-
sity should be carefully modulated with a target INR in the lower part of the target
range aiming for a time in the therapeutic range (TTR)>65–70%. It should be noted
that, in the AUGUSTUS trial, median percentage of time of INR <2 was nearly 25%
and TTR was only 59% (Lopes et al. 2019a).
When a DOAC is used in TAT regimen, the lowest approved dose effective for
stroke prophylaxis should be considered (i.e., dabigatran 110 mg bid, rivaroxaban
15 mg od, according to 2018 ESC guidelines on myocardial revascularization
(Neumann et al. 2018)). After antiplatelets discontinuation, OAC should be contin-
ued at full dosage approved for stroke prophylaxis.
The duration of TAT should be as short as possible and up to 1 month. Indeed,
ISAR-TRIPLE trial showed no significant differences between 6-week and 6-month
TAT in anticoagulated patients undergoing PCI in terms of ischemic and bleeding
complications. Moreover, a landmark analysis of this study has clearly outlined a
40% reduction of clinically relevant bleeding events in patients randomized to

6-week compared to 6-month group (Fiedler et al. 2015). It has been well estab-
lished that DAPT is superior to aspirin plus OAC in terms of reduction of ischemic
complications for a period of 1-month post-PCI (Leon et al. 1998). On the other
hand, recent evidence have demonstrated that adding antiplatelet therapy to OAC
increases bleeding events with no added benefit on ischemic protection in stable
CAD (Lamberts et al. 2014; Hamon et al. 2014). Accordingly, current guidelines
suggest that TAT duration should be up to 1 month, based on individualized bleed-
ing and ischemic risk stratification. Indeed, TAT should be shortened to the peri-PCI
period (until hospital discharge) in patients at very-high bleeding risk or prolonged
up to 6 months in case of high ischemic risk due to ACS or other anatomical/proce-
dural characteristics that outweigh the bleeding risk (Neumann et al. 2018;
Valgimigli et al. 2017).
VKA in Triple Therapy in the DOAC Era: Is There Still Room?
DOAC use should be preferred over VKA in patients treated with TAT. However,
there is still room for VKA in selected patients requiring triple therapy; in particular,
patients with:
–– Moderate to severe mitral stenosis or mechanical prosthetic valves;

–– Cancer-associated thromboembolism or other hypercoagulable states (antiphos-
pholipid syndrome, nephrotic syndrome, and congenital coagulopathies);
–– Drugs interactions;
–– Advanced renal insufficiency, end-stage renal disease, or hepatic dysfunc-
tion; and
–– High body weight and patients with obesity who undergo bariatric surgery.
Other Interventional Strategies
According to current guidelines, among strategies of bleeding prevention, LAAO

may be considered in patients with high stroke risk and contraindications for long-
term OAC (class IIb, Level of evidence B) (Kirchhof et al. 2016). Furthermore,
several clinical trials are ongoing to evaluate shorter duration of antiplatelet therapy
in HBR patients undergoing PCI and will provide further insights into the role of
dual antithrombotic therapy in anticoagulated patients.
Conclusions
The optimal management of AF patients following PCI represents a complex clini-

cal scenario, requiring a challenging balance between ischemic and bleeding risk.
Recent literature data from large RCT demonstrated the safety of dual (DOAC and
268 A. Landi et al.
single antiplatelet agent) versus triple antithrombotic therapy. However, the efficacy
profile of these strategies for reduction of ischemic events has been evaluated as
secondary endpoints and no definite conclusions can be drawn in this regard.
Nevertheless, based on current evidence, the protection against ischemic complica-
tions offered by TAT seems to be outweighed by an increased bleeding rate, sug-
gesting keeping on TAT as short as possible and for no longer than 6 months (in
patients with high ischemic risk). In conclusion, a one-size-fits-all strategy cannot
be applied, and an individualized approach should guide the complex management
of these patients in a fine balance between ischemic and bleeding complications.
Disclaimer None.
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Direct Oral Anticoagulants and Left
Ventricular Thrombosis: The Evidence 17
for a Good Therapeutic Approach
Mauro Massussi, Andrea Scotti, Antonio Landi,

and George Besis
Introduction
The formation of thrombus in the left ventricle represents a serious condition lead-
ing to significant risk of stroke and systemic embolization. In the thrombolytic era,
intraventricular thrombus has been reported in up to 40% of patients after anterior
myocardial infarction (Nihoyannopoulos et al. 1989). Along with the improvement
of the revascularization technique (primary percutaneous coronary intervention
(PCI)) and wide introduction of dual antiplatelet therapy (DAPT), the occurrence of
left ventricular thrombosis (LVT) has substantially decreased. However, a preva-
lence ranging between 4 and 9% after acute myocardial infarction (MI) is still
described (Robinson et al. 2016). A marked prevalence of LVT has also been
recorded among patients affected by heart failure with reduced ejection fraction.
While conspicuous data are available regarding the prevalence of LVT among
patients with ischemic cardiomyopathy, only a few have been published regarding
nonischemic cardiomyopathies (Zabczyk et al. 2019).
Numerous pathophysiological mechanisms contribute to the genesis of LVT and
can be classified among the three components of Virchow’s triad: blood stasis,
hypercoagulability, and tissue injury. While many of these factors have been well-
extensively described, others derive from contradictory studies and need further
investigation.
The management of LVT poses unique challenges; though current recommenda-
tions indicate anticoagulation as the mainstay treatment, in this specific clinical
setting direct oral anticoagulants (DOACs) are not a plausible alternative to warfa-
rin due to the paucity of evidence available, thus more evidence is needed to justify
M. Massussi (*) · A. Scotti · A. Landi

G. Besis

272 M. Massussi et al.
their use in clinical practice. The aim of this chapter is to describe the epidemiology
and the factors exposing to increased risk of LVT along with a review of the current
clinical evidences and the new pharmacological perspectives.
Epidemiology
In clinical practice, the vast majority of left ventricular thrombi are diagnosed after
MI. In older series, LVT was described in almost 30% of patients after acute ante-
rior transmural MI (Johannessen et al. 1984; Lamas et al. 1988; Asinger et al. 1981);
while in the current era of PCI, there still remains a wide distribution of the preva-
lence, ranging from 0.4% reported by Ram et al. (2018) up to 26% recorded by
Meurin et al. (2015) (Fig. 17.1). These epidemiological observations are mostly
explained by patient selection criteria and chosen diagnostic techniques.
LVT in Dilated Cardiomyopathy
Limited evidence are available on the epidemiology of LVT in patients affected by

dilated cardiomyopathy; however, according to a recent retrospective investigation
by McCarthy and colleagues, heart failure with a reduced ejection fraction is the
most common etiology of LVT in the contemporary era (McCarthy et al. 2019).
Hypertrophic cardiomyopathy may associate with LVT, especially if apical aneu-
rysm is present. Also, the acute phase of Takotsubo syndrome can be complicated
by LVT since apical ballooning is a predisposing condition to thrombi development.
Santoro and colleagues reported a 14% rate of LVT in the presence of apical bal-
looning while a large retrospective observational study on 1676 patients from the
International Takotsubo Registry recorded a lower (3.3%) prevalence of left ven-
tricular thrombus and embolism in the acute phase of the disease (Santoro et al.
Fig. 17.1 Incidence of left ventricular thrombus after ST-elevation myocardial infarction. On the
left side of the graph are reported older studies, accomplished during pre-PCI era while on the right
side there are more recent studies
17 Direct Oral Anticoagulants and Left Ventricular Thrombosis: The Evidence… 273
2017). Other phenotypes of Takotsubo syndromes (midventricular and the basal

types) are rarely complicated by LVT.
LVT has been sporadically described in the setting of amyloidosis, hypereosino-
philic syndrome, and Chagas’ disease.
High-Risk Patients
The formation of LVT is mostly influenced by the location and the size of the isch-
emic injury, and patients with the highest risk are those with anterior-apical MI
associated with severe wall motion abnormality (Greaves et al. 1997). There are
extensive evidence pointing out that the main risk factors related with LVT after
AMI are both the presence of an anterior-apical scar and the reduction of systolic
function (Shacham et al. 2013; Gianstefani et al. 2014). According to many authors,
LV dysfunction has the strongest impact on LVT formation, and this finding is sup-
ported by the LVEF, which is significantly lower in the subgroup of LVT patients.
Furthermore, the apex of the left ventricle is largely considered as the region where
more likely thrombi occur. The formation of LVT is strongly associated with apical
LV dysfunction, thus underlining the role of blood stasis due to regional myocardial
dysfunction as an important cause of development of cardiac thrombus (Weinsaft
et al. 2016). In addition to the main clinical predictors of LVT, numerous studies
have emphasized the impact of mitral regurgitation (MR) on the formation of
thrombi within the left heart chambers proposing a protective effect of MR in LVT
formation as a consequence of the decreased blood stasis (Kalaria et al. 1998),
although clinical results are discordant.
Intriguingly researches have explored the link between CHF and pro-
inflammatory and hypercoagulability state (Serebruany et al. 2002).
Diagnostic Modalities
Transthoracic echocardiography (TTE) is widely used to assess post-MI LV func-

tion and structure, as well as to exclude early postinfarction mechanical complica-
tions. LVT presents as an echo-dense mass distinct from the cardiac muscle,
frequently contiguous to an abnormally contracting LV segment or a myocardial
aneurysm (Weinsaft et al. 2016) (Fig. 17.2). Based on their appearance, thrombi can
be categorized; protuberant thrombi have borders which extrude into LV cavity and
may be pedunculated or sessile, while mural thrombi are flat. Protuberant thrombi
are often mobile masses, thus they are associated with a higher risk of isch-
emic stroke.
TTE has reported sensitivity ranging from 21 up to 35% with a specificity greater
than 90% (Weinsaft et al. 2011). The major obstacle to LVT detection by TTE is a
poor TTE acoustic window.
Transesophageal echocardiography (TEE) is rarely applicable for LVT detection
because the left ventricular apex is foreshortened and in the far field. Both TEE and
a b
c d
Fig. 17.2 Left ventricular thrombus with different diagnostic tools. Small-size apical LVT
appears as an echo-dense mass on transthoracic echocardiography (a) and more delineated after
intravenous contrast medium (b). Cardiac magnetic resonance imaging: LVT on delayed-
enhancement image, four-chamber view (c), and turbo inversion recovery magnitude (TIRM)
sequence of the same view on showing high signal in the apical segments of the left ventricle
consistent with myocardial edema and apical thrombus (d)
TTE detection rate of LVT correlate with thrombus size, and overall sensitivity may
vary according to the thrombus size and to the clinical pretest probability.
If the acoustic window is suboptimal, the addition of intravenous contrast
medium improves endocardial border delineation and has a documented higher
diagnostic accuracy for LVT (Weinsaft et al. 2016) (Fig. 17.2).
CMR is considered the gold standard imaging modality for assessing the pres-
ence, size, and location of intracardiac thrombi. LVT is identified as low-signal
intensity intraventricular filling defects, generally sticking to areas of hyper-
enhanced LV myocardial scarring (Fig. 17.2).
Treatment Options
LVT provides a substrate for systemic embolism; however, the true incidence of
embolic events is still to be unequivocally defined. A recent study, aimed at deter-
mining the incidence of systemic embolism linked to LVT, proved that patients had
a 3.7% annual for the composite endpoint of transitory ischemic attack, stroke, and
systemic arterial embolism over a median follow-up of 3 years, four times higher
when compared with matched non-LVT patients (Velangi et al. 2019). Older studies
documented a particularly elevated range of embolic risk up to 22%, proving that
thrombus mobility and thrombus protrusion were the main risk factors for emboli-
zation with a reported sensitivity in predicting embolism of 58% and 88%, respec-
tively (Visser et al. 1985). Of note, studies that included few patients with a relatively
short-term follow-up (<12 months) recorded almost no embolic events (Table 17.1).
Prevention of Embolic Events
All decisions regarding anticoagulant therapy in patients at risk of developing LVT

must consider the concurrent risk of bleeding, which is a particularly important
issue, as many of these patients need to be on DAPT in addition to warfarin therapy.
The role of prophylactic anticoagulation for patients without a definite LVT is still
unclear. The 2012 ESC guidelines for the management of ST-elevation AMI sug-
gested that anticoagulant therapy will also be of benefit to those at high risk for LVT
and low bleeding risk, defined as patients with an LVEF less than 30% or a severe
anteroapical wall motion abnormality with apical aneurysm (Steg et al. 2012). It is
worth to note that the abovementioned recommendation is based on relatively old
trials and is not supported by more recent data (Turpie et al. 1989). Results from
observational retrospective studies do not favor the prophylactic OAC with warfarin
after primary PCI for patients with anteroapical akinesia (Le May et al. 2015;
Table 17.1 Embolic events rate in published studies of LV thrombus detected by late gadolinium
enhancement CMR
Patients with Follow-up, Embolic Annualized rate of
LVT, n years events, n embolism (%)
Weinsaft et al. 55 0.5 3 –
Weir et al. 15 0.5 0 –
Meurin et al. 19 0.7 1 –
Delewi et al. 17 2 0 –
Poss et al. 26 1 1 3.8
Cambronero- 27 3.5 0 –
Cortinas et al.
Merkel et al. 33 In-hospital 3 –
Velangi et al. 155 3.3 19 3.7
Robinson et al. 514 0.9 54 10.9
CMR cardiac magnetic resonance, LVT left ventricular thrombosis
Shavadia et al. 2017). Also, the COMMANDER-HF trial failed to demonstrate the
benefit of low-dose oral anticoagulation in patients with severe HF in sinus rhythm,
but a post hoc analysis of the same trial with an outcome measure more specific for
thromboembolic events supported the hypothesis that low-dose rivaroxaban may
reduce the risk of myocardial infarction, ischemic stroke, sudden death, and symp-
tomatic pulmonary embolism/deep vein thrombosis (Greenberg et al. 2019).
The introduction of potent platelet P2Y12 receptor inhibitors in clinical practice
may have contributed to a reduction of LVT incidence after AMI, as suggested by a
retrospective analysis comparing ticagrelor to clopidogrel (Altıntaş et al. 2019).
Despite being biologically plausible, there is no trial in literature confirming that
DAPT plays a protective role against the formation of LVT and subsequent emboli-
zation, thus antiplatelet therapy cannot be considered as a substitute for anticoagula-
tion to prevent embolization of LV thrombus.
Treatment of Definite LVT
urrent International Guidelines

C
International guidelines agreed on recommend anticoagulation therapy for patient
affected by definite LVT. The 2013 guidelines by the American Heart Association
(ACCF/AHA) and the 2017 ESC guidelines both suggested oral anticoagulation
with vitamin K antagonists as a first-line therapy (O’Gara et al. 2012; Ibanez et al.
2018). The AHA/American Stroke Association 2014 guidelines on stroke preven-
tion considered DOACs (dabigatran, rivaroxaban, or apixaban) as an alternative to
warfarin for post-MI LVT in case of vitamin K antagonists intolerance (Class IIb;
Level of Evidence: C) (Kernan et al. 2014).
Surprisingly, the vast majority of the studies cited by guidelines are dated from
the era before the routine introduction of DOACs in clinical practice, thus empha-
sizing only on the efficacy of parenteral therapy with heparin for the treatment of
LVT patients with high embolic risk (Kernan et al. 2014). Early studies found that
parenteral anticoagulation with heparin, continued for more than 48 h, was effective
in preventing systemic embolization (Vaitkus and Barnathan 1993). However, given
the fact that oral warfarin therapy in appropriate patients is likely to be as effective
and more practical than anticoagulation with heparin, prolonged parenteral therapy
is seldom recommended. There are actually no studies that have evaluated the opti-
mal timing of parenteral anticoagulation in patients being started on warfarin, the
consensus is that oral anticoagulation therapy should start as soon a definite LVT is
identified, and parenteral anticoagulation therapy should be discontinued when
effective anticoagulation with warfarin has been achieved (INR of 2–3) (Massussi
et al. 2021). Since most events occur within the first 3–4 months, patients with
documented LVT should undergo anticoagulant therapy with warfarin starting early
after myocardial infarction for at least 3 months to lower the risk of thrombus for-
mation and embolization.
It is well-known that triple antithrombotic therapy with warfarin is associated
with an increased risk of bleeding, and the result of landmark approval trials
enrolling patients affected by AF confirmed that all DOACs are superior to warfarin
in terms of safety and are not inferior in terms of effectiveness. All the studies evalu-
ating triple therapy with warfarin reported an increased elevated rate of clinically
significant bleeding (major bleedings and clinically relevant nonmajor bleedings).
Even though contemporary trials evaluating triple vs. double antithrombotic regi-
mens (RE-DUAL PCI (Cannon et al. 2017), PIONEER AF (Gibson et al. 2016),
AUGUSTUS (Lopes et al. 2019), and ENTRUST AF PCI (Vranckx et al. 2019))
were not powered to definitively assess these ischemic efficacy endpoints, since it
would require much larger samples followed for prolonged duration, double therapy
was associated with similar rates of composite thromboembolic events (unplanned
revascularization, MI/stent thrombosis, and death) compared with triple therapy.
irect Oral Anticoagulants

D
Limited data are available on the use of DOACs to replace warfarin in patients with
LVT, and high-quality large prospective studies or randomized trials are missing.
Two reviews of published case reports of 36 and 41 patients treated with different
molecules confirmed thrombus resolution in almost all the subjects with a median
treatment duration of 30 days and with no embolic events reported (Leow et al.
2018; Kajy et al. 2019). Recently, the results of three retrospective studies on the
topic were published (Fleddermann et al. 2019; Lattuca et al. 2020; Robinson et al.
2020). Despite not being designed for a direct comparison between VKA and
DOACs, the analysis by Lattuca and colleagues on 159 patients with LVT suggested
a similar rate of LVT resolution with both anticoagulant strategies (Lattuca et al.
2020). A recent multicentric retrospective investigation by Robinson and colleagues
on the risk of stroke and systemic embolism (SSE) with different anticoagulation
regimens evidencing that VKA therapy was associated with a lower SSE risk com-
pared to DOACs treatment (Robinson et al. 2020). Only prospective randomized
trials could provide more lights on the equivalence of DOACs and warfarin for the
treatment of LVT.
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Index
A all-cause mortality, 105

Aluminum-magnesium hydroxide tablets, 54 ARISTOTLE study, 104
Alzheimer’s dementia, 200 bleeding risk stratification (see Bleeding
Anticoagulant therapy, 132, 133 management, risk stratification)
Anticoagulation, 9, 179 CV mortality, 103
antithrombotic strategies, 132, 133 and dementia, 200, 201
apixaban, 137, 138 and DOACs, 204, 205
dabigatran, 133, 136 independent risk factor, 200
DOACs in, 133 oral anticoagulation and risk, 202–204
edoxaban, 138 potential mechanisms in, 201, 202
in frail elderly, 139–141 drug dosage, 103
in older patients, 141 ENGAGE AF-TIMI 48 study, 104, 105
rivaroxaban, 136, 137 hemorrhagic strokes, 103
stroke prevention, indications for, 132 left atrial appendage, 236, 237
VKA vs. DOACs in, 138, 139 non-inferiority, 104
Anti-hepatitis C virus (HCV) drugs, 61, 63, 64 RE-LY study, 103
Anti-human immunodeficiency (HIV) drugs, risk stratification (see Risk stratification)
61, 63, 64 ROCKET-AF study, 103, 104
Antiplatelet monotherapy, 132, 133 RWE studies, 105
Antiplatelet therapy, 132, 133, 256, 257, stroke reduction, 236
259, 267 VKAs therapy, 102
Antithrombin, 5, 132, 133 Atrial fibrillation Investigators (AFI), 94
Anti-Xa therapy, 17 Atrial Fibrillation Reduction Atrial Pacing
Apixaban, 15, 124, 163, 166, 190, 193, 215 Trial (ASSERT), 217
anticoagulation in elderly patients with AUGUSTUS trial, 262, 263
atrial fibrillation, 137, 138
for NVAF patients, 156, 161, 162
for VTE patients, 162 B
Apixaban for Reduction in Stroke and Other Biomarkers, 108
Thromboembolic Events in atrial Bioprosthetic heart valves (BHVs), 247, 248
fibrillation (ARISTOTLE) study, Bleeding management, 256–258
104, 256 anticoagulation
Apixaban versus Warfarin in Patients with ECT, 75
Atrial Fibrillation (ARISTOTLE) initial assessment, 73
trial, 181 laboratory assessment, 74
Asymptomatic Severe Aortic Stenosis renal and hepatic functions, 73, 74
(AVATAR), 252 TT, 75
Atrial fibrillation (AF), 10, 131, 199, 226, 235, complications, 72
248, 249, 255 dabigatran reversal (see Idaracizumab)

https://doi.org/10.1007/978-3-030-74462-5
282 Index
Bleeding management (cont.) Cognitive Impairment Related to Atrial

emergency surgery and urgent Fibrillation Prevention Trial
procedures, 72, 73 (GIRAF), 206
FXa reversal (see Factor Xa inhibitor) Concomitant antiplatelet drugs, 48
life-threatening condition, 73 Coronary artery disease (CAD), 17, 18, 255
pro-hemostatic therapies, 83–86 Cytochrome P450 (CYP450) enzymes, 64
risk stratification
European guidelines, 97
HAS-BLED score, 98, 99 D
parameters, 98 Dabigatran, 163, 215
specific and nonspecific agents, 76 anticoagulation in elderly patients with
uncontrolled bleeding, 73 atrial fibrillation, 133, 136
“universal” antidote NVAF patients, 156
ciraparantag, 85, 87 VTE patients, 162
FXaI16L, 87 Daclatasvir, 61
Blinded Randomized Trial of Anticoagulation Deep venous thrombosis (DVT), 41
to Prevent Ischemic Stroke and Dementia, 141, 199–201
Neurocognitive Impairment in AF and DOACs, 204, 205
(BRAIN-AF), 206 independent risk factor, 200
Blood coagulation cascade oral anticoagulation and risk, 202–204
aberrant activation, 1 potential mechanisms in, 201, 202
cell-based model of Diabetes, 100
activation of zymogens, 2 Digoxin metabolism, 44
contact pathway, 4 Dilute thrombin time (TT), 75
mammalian blood coagulation, 2 Direct oral anticoagulants (DOACs), 5, 41,
membrane anchoring, 2 131, 180, 184–189, 199, 204, 205,
platelet agonists, 2 227–230, 232, 236, 255
TF-FVIIa complex, 3, 5 AF cancer patients, 180, 181, 183, 184
effect of oral anticoagulants, 5–7 in elderly patients, 133, 138, 139
primary and secondary haemostasis, 1 kidney disease, 121, 122
Body mass index (BMI), 107 end-stage kidney disease, 125
dialysis, patients on, 125, 126
kidney transplant recipients, 126, 127
C non-end-stage kidney disease, 122–125
Calcineurin inhibitors, 127 nonvalvular atrial fibrillation, 10–13
Carbapenem antibiotics, 54 in older patients, 141
Cardiac implantable electrophysiological vitamin K antagonists, 9
device (CIED), 211 VTE in cancer patients, 189, 192, 193
atrial fibrillation, 217 primary prevention of, 189, 190
concomitant anti-platelet therapy, 216 treatment of, 190, 191
NOAC interruption, 214–216 Double antiplatelet therapy (DAPT), 132
pocket hematoma, 212, 216 Drug-drug interactions (DDIs)
Cardiovascular (CV) mortality, 103 antacid medication, 54
Catheter ablation (CA), 225, 228, 229 antiarrhythmic drugs, 43–46
Cell-based model, 3 antibiotics and antifungal drugs, 51–54
Cerebral hypoperfusion, 202 antiepileptic drugs, 55, 59, 61
Cerebrovascular complications, 249 antineoplastic and immune-modulating
Chronic kidney disease (CKD), 101, 121 agents, 55, 59
Ciclosporin, 127 antiplatelet and antithrombotic
Cirrhosis, 102 drugs, 46–48
Clarithromycin, 52 CYP3A and P-gp, 43
Cockcroft–Gault equation, 123 edoxaban and apixaban, 42
Cognitive Decline and Dementia in Atrial HCV drugs, 61, 63, 64
Fibrillation Patients (CAF) HIV, 61, 63, 64
Trial, 205 IL-6, 64
Index 283
lipid-modifying agents, 49, 50 invasive intervention, 79

mAbs, 64 restoration of hemostasis, 78
NSAID drugs, 48, 49 RE-VERSE AD trial, 78
oral anticoagulant therapy, 41 safety outcomes, 78, 79
Dual antiplatelet therapy (DAPT), 46, 248, 255 Interleukin (IL)-6, 64
Intermountain Mortality Risk Scores (IMRSs),
108, 109
E Intraprocedural anticoagulation, 230, 231
Ecarin clotting time (ECT), 44, 75
Edoxaban, 15, 59, 124, 155, 180, 191,
193, 216 L
anticoagulation in elderly patients with Left atrial appendage (LAA), 235–237, 241, 242
atrial fibrillation, 138 antithrombotic therapy, 239, 240
for NVAF patients, 161 isolation, 240, 241
for VTE patients, 162 Left atrial appendage antithrombotic
Edoxaban versus Warfarin in Patients with therapy, 237
Atrial Fibrillation (ENGAGE-TIMI Left atrial appendage occlusion (LAAO), 256
48) trial, 181–183 Left ventricular assist device, 22
Embolic stroke, 21 Left ventricular thrombosis (LVT), 18, 19
End-stage kidney disease, 125–127 diagnostic modalities, 273, 274
ENTRUST-AF PCI trial, 263 in dilated cardiomyopathy, 272, 273
Erythromycin, 52 high risk patients, 273
management, 271
prevalence, 272
F treatment options
Factor Xa (FXa) inhibitor, 28, 29 embolic events, 275, 276
clinical pharmacology, 80, 81 international guidelines, 276, 277
in clinical practice, 83 randomized trials, 277
dosage and administration, 81 short-term follow up, 275
efficacy and safety, 81–83 SSE, 277
Fall risk, 140 systemic embolism, 275
Frailty, 139–141 Low molecular weight heparin (LMWH), 180
Free FVIIa, 2
M
G Mechanical valves, 21, 22
Gastro-esophageal reflux disease, 54 Metronidazole, 53
Global Anticoagulant Registry in the Mitral regurgitation (MR), 273
FIELD-Atrial Fibrillation Monoclonal antibodies (mAbs), 64
(GARFIELD AF study), 97 Myocardial infarction (MI), 256, 271, 276
Myocardial injury after non-cardiac
surgery, 19, 20
H
Heart failure (HF), 20, 100
Heparin-induced thrombocytopenia, 19 N
High bleeding risk (HBR), 256 Non-end-stage kidney disease, 122–125
Hypertension, 101 Nonsteroidal anti-inflammatory drugs
Hypoattenuating leaflet thickening (NSAIDs), 48, 49
(HALT), 248 Nonstructural protein 5AB (NS5B)
polymerase inhibitors, 61
Non-valvular AF (NVAF), 149–152,
I 157–163, 166–170
Idaracizumab apixaban, 156, 161
clinical pharmacology, 76, 77 dabigatran, 156
in clinical practice, 79, 80 edoxaban, 161
dosage and administration, 78 rivaroxaban, 156
284 Index
Non-vitamin K anticoagulants (NOACs), 149, bioavailability, 31

171, 213, 214 dabigatran, 30, 31, 33
body weight and, 155 dysphagia, 32, 33
NVAF patients, 157–163, 166–170 edoxaban, 32
apixaban, 156, 161 parameters, 30
dabigatran, 156 P-gp, 33
edoxaban, 161 pH-dependent solubility, 31
rivaroxaban, 156 rivaroxaban, 31, 32
VTE patients, 163–170 excretion, 35–38
dabigatran, apixaban, edoxaban, 162 metabolism, 34, 35
rivaroxaban, 162, 163 plasma protein binding, 33, 34
time to peak concentration (Tmax), 29, 30
volumes of distribution (Vd), 33, 34
O Phosphatidylserine (PS), 2
Obesity, 171 Physico-chemical properties, 27, 28
definition of, 149 PIONEER AF-PCI trial, 262
and NOACs, 155 Pocket hematomas, 212
Obesity paradox Post procedural anticoagulation, 231, 232
in NVAF, 150–152, 157–163, 166–170 Pre-ablation anticoagulation strategies, 226
apixaban, 156, 161 Primary hemostasis, 1
dabigatran, 156 Prophylaxis in Nonmajor Orthopaedic Surgery
edoxaban, 161 (PRONOMOS) trial, 14
rivaroxaban, 156 Proton-pump inhibitors (PPIs), 54
in VTE, 151–154, 163–170
dabigatran, apixaban, edoxaban, 162
rivaroxaban, 162, 163 R
Oral anticoagulation (OAC), 105, 106, 121, Randomized controlled trials (RCT), 256
149, 202–204, 225, 226, 231 Randomized Evaluation of Long-Term
Anticoagulation Therapy (RE-
LY), 10, 103
P Real-world (RWE) studies, 105
Paritaprevir, 61 Renin-angiotensin-aldosterone system, 121
Percutaneous coronary intervention, 248, 255, Rheumatic heart disease, 19
264, 265, 267 Rifampin, 53
antithrombotic therapy, 266, 267 Risk stratification
AUGUSTUS trial, 262, 263 ABC stroke score, 97
bleeding risk, 256–258 ATRIA risk score, 96
DOAC, triple versus dual antithrombotic biomarkers, 108
therapy, 259 BMI, 107
ENTRUST-AF PCI trial, 263 CHA2DS2VASc score, 95
ischemic, 256 CHADS2 score, 94, 95
meta analysis, 263, 264 efficacy and safety
peri-PCI management, 266 age, 100
PIONEER AF-PCI trial, 262 cirrhosis, 102
RE-DUAL PCI, 262 diabetes, 100
VKA, 258, 267 in female patients, 101
P-glycoprotein (P-gp), 33 heart failure, 100
Pharmacodynamics hypertension, 101
apixaban, 29 kidney disease, 101, 102
FXa, 28, 29 stroke/TIA, 101
time to peak concentration (Tmax), 29, 30 GARFIELD AF study, 97
Pharmacokinetics IMRSs, 108, 109
absorption liver diseases, 109
apixaban, 31, 32 oral anticoagulant selection, 105, 106
Index 285
prevention, 99 Transient ischemic attack (TIA), 101

QSTROKE, 96, 97 Triple antithrombotic therapy (TAT), 255, 256,
R2CHADS2, 96 276, 277
risk scale, 94
transthoracic echocardiography, 107
Rivaroxaban, 14, 17, 45, 48, 163, 166, 180, U
184, 191, 193, 215 Unfractioned heparin (UFH), 250
anticoagulation in elderly patients with Uremic platelet dysfunction, 125
atrial fibrillation, 136, 137 Ultra-LMWH semuloparin, 189
for NVAF patients, 156, 162
for VTE patients, 162, 163
Rivaroxaban for Valvular Heart Disease and V
Atrial Fibrillation (RIVER) Venous thromboembolism (VTE), 41, 179
trial, 13 in cancer patients, 189, 192, 193
Rivaroxaban versus Warfarin in Nonvalvular primary prevention of, 189, 190
Atrial Fibrillation (ROCKET-AF) treatment of, 190, 191
trial, 181 chronic thromboembolic pulmonary
hypertension, 13
coronary artery disease, 17, 18
S dabigatran, 15
Shared risk factors, 98 deep venous thrombosis, 16
Shikoku Rivaroxaban Registry Trial edoxaban, 15
(SRRT), 137 embolic stroke, 21
Single antiplatelet therapy (SAPT), 251 enoxaparin- vitamin K antagonist
Stroke, 101 group, 14
Stroke and systemic embolism (SSE), 277 fatal pulmonary embolism, 16
Stroke prevention, indications for, 132 heart failure in sinus rhythm, 20
Subclinical atrial fibrillation (SCAF), 211, 217 heparin-induced thrombocytopenia, 19
anticoagulation, 219 Hokusai VTE Cancer trial, 17
burden, 217 left ventricular assist device, 22
predictors, 218 left ventricular thrombus, 18, 19
progression, 218 mechanical valves, 21, 22
Subclinical leaflet thrombosis, 250 myocardial injury after non-cardiac
Supranormal renal function, 124 surgery, 19, 20
nonfatal pulmonary embolism, 16
obesity paradox in, 151–154, 163–170
T dabigatran, apixaban, edoxaban, 162
Tacrolimus, 127 rivaroxaban, 162, 163
Takotsubo cardiomyopathy, 18 pooled analysis, 12, 15
TF pathway inhibitor (TFPI), 4 post-thrombotic syndrome, 13
Thrombosis, 179 recurrent venous thromboembolism, 16
Thrombotic risk rheumatic heart disease, 19
vs. bleeding risk VTE-related mortality, 13
atrial fibrillation, 248, 249 Vitamin K antagonist (VKA), 6, 41, 102, 131,
cerebrovascular complications, 249 138, 139, 180, 212, 255
percutaneous coronary Vitamin K epoxide reductase complex 1
intervention, 248 (VKORC1), 28
subclinical leaflet thrombosis, 250
safety outcomes, 82
Transcatheter aortic valve replacement, W
247, 251 Warfarin, 28, 124, 166, 180, 187–189, 191,
Transesophageal echocardiography (TEE), 241 203, 205, 226, 227

Direct Oral Anticoagulants From Pharmacology To Clinical Practice

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Direct Oral

Direct Oral Anticoagulants

Nicola Ferri Vincenzo Russo

ISBN 978-3-030-74461-8 ISBN 978-3-030-74462-5 (eBook)

© Springer Nature Switzerland AG 2021

1 The Coagulative Cascade�������������������������������������������������������������������������� 1

11 DOACs and Dementia in Patients with Atrial Fibrillation�������������������� 199

The blood coagulation cascade is an integral part of hemostasis, a biological process

© Springer Nature Switzerland AG 2021 1

The Cell-Based Model of Blood Coagulation

The coagulation cascade consists of an ordered sequence of reactions that lead to

TF/VII/VIIa Initiation phase

Fibrinogen Fibrin Final phase

Fig. 1.1 The cell-based model of the blood coagulation cascade

Extrinsic Xase Intrinsic Xase

stabilization of the platelet plug because of rapid FXa-dependent inactivation of

followed by activation of fibrinogen to fibrin that ultimately leads to generation of a

The Effect of Oral Anticoagulants on the Coagulation Cascade

On the contrary, dabigatran mostly affects the amplification phase of coagula-

The coagulation cascade consists of a cascade of enzyme activation events in which

Anticoagulation is an important therapeutic option to prevent and treat thrombus

© Springer Nature Switzerland AG 2021 9

Nonvalvular Atrial Fibrillation

Oral anticoagulation is one of the mainstays of treatment of patients with atrial

RE-LYs* 134/6076 199/6022 0.66 (0.53-0.82) 0.0001

0.5 1.0 2.0

Favours NOAC Favours warfarin

Favours NOAC Favours warfarin

warfarin (RR 0.81, 95% CI 0.73–0.91; P < 0.0001), including a reduction in hemor-

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary

Rivaroxaban with Enoxaparin (MAGELLAN) was designed to assess the efficacy

20 mg once daily) or standard therapy with enoxaparin followed by an adjusted-­

Coronary Artery Disease

Left Ventricular Thrombus

Another important indication for oral anticoagulation is the development of left

echocardiogram diagnosed left ventricular thrombi, anticoagulation with DOACs

Rheumatic Heart Disease

Myocardial Injury After Noncardiac Surgery

Myocardial injury after noncardiac surgery is due to myocardial ischemia which

at 30 days as well as possible up to 2 years after noncardiac surgery (Devereaux

Heart Failure in Sinus Rhythm

Embolic Stroke of Undetermined Source

Cryptogenic strokes constitute 20 to 30% of ischemic strokes; the majority of cryp-

occurred 4% and 2% in those receiving dabigatran and warfarin, respectively. Due

Left Ventricular Assist Device

Anticoagulation is mandatory in patients with left ventricular assist devices. The

The chemical structure of DOACs currently approved internationally is shown in

© Springer Nature Switzerland AG 2021 27

Warfarin acts by inhibiting vitamin K epoxide reductase complex 1 (VKORC1),

IX IXa VIIa VII

Fig. 3.2 Schematic view of the mechanism of action of DOACs

Table 3.1 Pharmacokinetic and pharmacodynamic characteristics of DOACs

Similar situation is observed for the reversibility of the pharmacological effect,

The pharmacokinetics parameters of DOACs are summarized in Table 3.1.

As shown in Table 3.1, DOACs are characterized by different volumes of distribu-

The variability in the plasma concentration of edoxaban, administrated once

Parasrampuria DA, Truitt KE. Pharmacokinetics and pharmacodynamics of edoxaban, a non-­

© Springer Nature Switzerland AG 2021 41

Table 4.1 Inducers and inhibitors of CYP3A and P-gp

1 The Coagulative Cascade�� 1

11 DOACs and Dementia in Patients with Atrial Fibrillation�� 199

The Cell-Based Model of Blood Coagulation

The Effect of Oral Anticoagulants on the Coagulation Cascade

Nonvalvular Atrial Fibrillation

20 mg once daily) or standard therapy with enoxaparin followed by an adjusted-

Coronary Artery Disease

Left Ventricular Thrombus

Rheumatic Heart Disease

Myocardial Injury After Noncardiac Surgery

Heart Failure in Sinus Rhythm

Embolic Stroke of Undetermined Source

Left Ventricular Assist Device

Parasrampuria DA, Truitt KE. Pharmacokinetics and pharmacodynamics of edoxaban, a non-

DDI with Antiarrhythmic Drugs

DDI with Antiplatelet and Antithrombotic Drugs

DDI with NSAIDs Drugs

DDI with Statins and Lipid-Modifying Agents

DDI with Antibiotics and Antifungal Drugs

DDI with Antacid Drugs

DDI with Antineoplastic and Immune-Modulating Agents

DDI with Antiepileptic Drugs

DIs with Anti-Human Immunodeficiency (HIV)

DDIs with Monoclonal Antibodies and Interleukin 6 (IL6)

Emergency Surgery and Urgent Procedures

Life-Threatening and Uncontrolled Bleeding

Assessment of Anticoagulation Status