CH 253: HEART FAILURE: MANAGEMENT !

Conceptually targeting myocardial fibrosis in HFpEF, the large-scale Aldosterone Antagonist

! Distinctive phenotypes of presentation with diverse management targets exemplify the extensive Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) trial has
syndrome of heart failure, ranging from: been completed
○ Chronic heart failure with reduced ejection fraction (HFrEF) ○ Demonstrated no improvement in the primary composite endpoint, but did show a
○ Heart failure with preserved ejection fraction (HFpEF) secondary signal of benefit on HF hospitalizations, counterbalanced, however, by an
○ Acute decompensated heart failure (ADHF) increase in adverse effects, particularly hyperkalemia.
○ Advanced heart failure ! Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-
! Early management evolved from symptom control to disease-modifying therapy in HFrEF with the HFpEF)
advent of RAAS–directed therapy, beta receptor antagonists, mineralocorticoid receptor ○ Was conducted on the premise that nitrates, which are nitric oxide donors, might improve
antagonists, cardiac resynchronization therapy, and implantable cardio-defibrillators preload, coronary perfusion, endothelial function and improved exercise tolerance
! Similar advances have been elusive in the syndromes of HFpEF and ADHF → devoid of convincing ○ Isosorbide mononitrate did not improve QOL or submaximal exercise capacity, and
therapeutic advances to alter their natural history decreased overall activity levels in treated patients
! Advanced heart failure
○ A stage of disease typically encountered in HFrEF CLINICAL PEARLS
○ Patient remains markedly symptomatic with demonstrated refractoriness or inability to ! Even as efforts to control hypertension in HFpEF are critical, evaluation for and correction of
tolerate full-dose neurohormonal antagonism underlying ischemia may be beneficial
○ Often require escalating doses of diuretics ! Appropriate identification and treatment of sleep-disordered breathing should be strongly
○ Exhibit persistent hyponatremia and renal insufficiency with frequent episodes of heart considered
failure decompensation requiring recurrent hospitalizations ! Excessive decrease in preload with vasodilators may lead to underfilling the ventricle and
○ Such individuals are at the highest risk of sudden or progressive pump failure–related subsequent hypotension and syncope
deaths ! It is suggested that the exercise intolerance in HFpEF is a manifestation of chronotropic
! In contrast, early-stage asymptomatic left ventricular dysfunction is amenable to preventive insufficiency
care, and its natural history is modifiable by neurohormonal antagonism ○ Could be corrected with use of rate responsive pacemakers, but this remains an
inadequately investigated contention
HEART FAILURE WITH PRESERVED EJECTION FRACTION
GENERAL PRINCIPLES
! Therapeutic targets in HFpEF include:
○ Control of congestion
○ Stabilization of heart rate and blood pressure
○ Efforts at improving exercise tolerance
! Have been disappointing:
○ Addressing surrogate targets, such as regression of ventricular hypertrophy in
hypertensive heart disease
○ Use of lusitropic agents, such as calcium channel blockers and beta receptor antagonists
! Experience has demonstrated that lowering blood pressure alleviates symptoms more effectively
than targeted therapy with specific agents

CLINICAL TRIALS IN HFpEF

! The Candesartan in Heart Failure—Assessment of Mortality and Morbidity (CHARM) Preserved
study showed a statistically significant reduction in hospitalizations but no difference in all-cause
mortality in patients with HFpEF who were treated with ARB, candesartan
! The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated
no differences in meaningful endpoints in such patients treated with irbesartan
! An earlier analysis of a subset of the Digitalis Investigation Group (DIG) trial found no role for
digoxin in the treatment of HFpEF
! In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors
with Heart Failure (SENIORS) trial of nebivolol, a vasodilating beta blocker, the subgroup of elderly ACUTE DECOMPENSATED HEART FAILURE
patients with prior hospitalization and HFpEF did not appear to benefit in terms of all-cause or GENERAL PRINCIPLES
cardiovascular mortality. ! ADHF is a heterogeneous clinical syndrome most often resulting in need for hospitalization due to
! Much smaller mechanistic studies in the elderly with the angiotensin-converting enzyme inhibitor confluence of interrelated abnormalities of:
(ACEI) enalapril showed no effect on peak exercise oxygen consumption, 6-min walk distance, ○ Decreased cardiac performance
aortic distensibility, left ventricular mass, or peripheral neurohormone expression ○ Renal dysfunction
○ Alterations in vascular compliance
NOVEL TARGETS ! Diagnosis of ADHF is associated with excessive morbidity and mortality
! Small trial: phosphodiesterase-5 inhibitor sildenafil improved filling pressures and RV function in a ○ Nearly half of these patients readmitted for management within 6 months
cohort of HFpEF patients with pulmonary venous hypertension ○ High short-term (5% in-hospital) and long-term cardiovascular mortality (20% at 1 year)
! This finding led to the phase II trial, where HFpEF patients (left ventricular ejection fraction [LVEF] ○ Long-term aggregate outcomes remain poor → combined incidence of cardiovascular
>50%) with NYHA functional class II or III symptoms received sildenafil at 20 mg three times daily deaths, heart failure hospitalizations, myocardial infarction, strokes, or sudden death
for 3 months, followed by 60 mg three times daily for another 3 months, compared with a placebo reaching 50% at 12 months after hospitalization.
! There was no improvement in functional capacity, quality of life (QOL), or other clinical and surrogate ! Management of these patients has remained difficult and principally revolves around
parameters ○ Volume control and decrease of vascular impedance
○ Maintaining attention to end-organ perfusion (coronary and renal)

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 ! The first principle of management of these patients → identify and tackle known precipitants ! It is generally advisable to continue diuresis until euvolemia has been achieved.
of decompensation ○ Physical examination findings, specifically the jugular venous pressure coupled with
○ Identification and management of medication nonadherence and use of prescribed biomarker trends, are useful in timing discharge planning
medicines such as NSAIDs, cold and flu preparations with cardiac stimulants, and herbal
preparations (licorice, ginseng, and herbal forms of ephedrine) are required The Cardiorenal Syndrome
○ Active infection and overt or covert pulmonary thromboembolism should be sought, ! The cardiorenal syndrome is being recognized increasingly as a complication of ADHF
identified, and treated when clinical clues suggest such direction ! At its simplest, it reflects the interplay between abnormalities of heart and kidney function, with
○ When possible, arrhythmias should be corrected by: deteriorating function of one organ while therapy is administered to preserve the other
■ Controlling heart rate or restoring sinus rhythm in patients with poorly ! Approximately 30% of patients hospitalized with ADHF exhibit abnormal renal function at baseline
tolerated rapid atrial fibrillation → associated with longer hospitalizations and increased mortality
■ Correcting ongoing ischemia with coronary revascularization ! However, studies have been unable to find correlation between deterioration in renal function,
■ Correcting offenders such as ongoing bleeding in demand-related ischemia cardiac output, left-sided filling pressures, and reduced renal perfusion
! A parallel step in management involves stabilization of hemodynamics in those with instability ○ Most patients with cardiorenal syndrome demonstrate a preserved cardiac output
○ The routine use of a pulmonary artery catheter is not recommended and should be ! It is hypothesized that in patients with established heart failure, this syndrome represents a complex
restricted to those who: interplay of neurohormonal factors, potentially exacerbated by “backward failure” resulting from
■ Respond poorly to diuresis, or increased intraabdominal pressure and impairment in return of renal venous blood flow
■ Experience hypotension or signs and symptoms suggestive of a low cardiac ! Continued use of diuretic therapy may be associated with a reduction in GFR and a worsening of
output where therapeutic targets are unclear the cardiorenal syndrome when right-sided filling pressures remain elevated
○ Parameters associated with worse outcomes: ! In patients in the late stages of disease characterized by profound low cardiac output state, inotropic
■ BUN >43 mg/dL (to convert to mmol/L, multiply by 0.357) therapy or mechanical circulatory support has been shown to preserve or improve renal function in
■ SBP <115 mmHg selected individuals in the short term until more definitive therapy such as assisted circulation or
■ Serum creatinine level >2.75 mg/dL (to convert to μmol/L, multiply by 88.4) cardiac transplantation is implemented
■ Elevated troponin I level
Ultrafiltration
! Ultrafiltration (UF) is an invasive fluid removal technique that may supplement the need for diuretic
therapy
! Proposed benefits of UF include:
○ Controlled rates of fluid removal
○ Neutral effects on serum electrolytes
○ Decreased neurohormonal activity
! This technique has also been referred to as aquapheresis in recognition of its electrolyte depletion–
sparing effects
! In a study evaluating UF versus conventional therapy
○ Fluid removal was improved and subsequent heart failure hospitalizations and urgent
clinic visits were reduced with UF
○ No improvement in renal function and no subjective differences in dyspnea scores or
adverse outcomes
! In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, 188
patients with ADHF and worsening renal failure were randomized to stepped pharmacologic care or
UF
○ Similar weight loss occurred in both groups (~5.5 kg), but there was worsening in
creatinine in the UF group
○ Deaths and hospitalizations for heart failure were the same between groups
○ There were more adverse events in the UF group, mainly due to kidney failure, bleeding
complications, and intravenous catheter-related complications
○ This investigation argues against using UF as a primary strategy in patients with ADHF
who are nonetheless responsive to diuretics
! Whether UF is useful in states of diuretic unresponsiveness remains an open question, and this
strategy continues to be employed judiciously in such situations
VOLUME MANAGEMENT
Intravenous Diuretic Agents VASCULAR THERAPY
! Intravenous diuretic agents rapidly and effectively relieve symptoms of congestion and are essential ! Vasodilators including intravenous nitrates, nitroprusside, and nesiritide (a recombinant brain-type
when oral drug absorption is impaired natriuretic peptide) have been advocated for upstream therapy in an effort to stabilize ADHF
! When high doses of diuretic agents are required or when the effect is suboptimal, a continuous ! Nesiritide
infusion may be needed to reduce toxicity and maintain stable serum drug levels ○ Was introduced due to more rapid and greater reduction in pulmonary capillary wedge
! Randomized clinical trials of high- vs. low-dose or bolus vs. continuous infusion diuresis have not pressure compared to other nitrates
provided clear justification for the best diuretic strategy in ADHF → the use of diuretic regimens ○ Enthusiasm for nesiritide waned due to concerns of development of renal insufficiency
remains an art rather than science and an increase in mortality
! Addition of a thiazide diuretic agent such as metolazone in combination provides a synergistic ○ Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure
effect and is often required in patients receiving long-term therapy with loop diuretic agents (ASCEND-HF) study → nesiritide was not associated with an increase or a decrease in
! Change in weight is often used as a surrogate for adequate diuresis, but this objective measure of the rates of death and rehospitalization and had a clinically insignificant benefit on
volume status may be surprisingly difficult to interpret, and weight loss during hospitalization does dyspnea
not necessarily correlate closely with outcomes ○ Renal function did not worsen, but increased rates of hypotension were noted
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 ○ Safety has been established, but the routine use cannot be advocated due to lack of
significant efficacy
! Recombinant human relaxin-2 or serelaxin
○ A peptide upregulated in pregnancy and examined in ADHF patients with a normal or
elevated blood pressure
○ In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin improved dyspnea,
reduced signs and symptoms of congestion, and was associated with less early
worsening of HF
! Recently, the natriuretic peptide urodilatin was tested in a large trial (TRUE-AHF) in ADHF
patients
○ Evidence for decongestion was forthcoming along with a reduction in net endogenous
expression of natriuretic peptides
○ No improvement in clinical outcomes at 6 months
○ Associated with a higher rate of hypotension and worsening serum creatinine

INOTROPIC THERAPY
! Impairment of myocardial contractility often accompanies ADHF
! Pharmacologic agents that increase intracellular concentration of cAMP via direct or indirect
pathways, such as sympathomimetic amines (dobutamine) and phosphodiesterase-3 inhibitors
(milrinone), respectively, serve as positive inotropic agents
○ Their activity leads to an increase in cytoplasmic calcium
! Inotropic therapy in those with a low-output state…
○ Augments cardiac output
○ Improves perfusion
○ Relieves congestion acutely
! Milrinone and dobutamine have similar hemodynamic profiles
! Milrinone
○ Slower acting and is renally excreted → thus requires dose adjustments in the setting of
kidney dysfunction
○ Acts downstream from the β1-adrenergic receptor → may provide an advantage in
patients receiving beta blockers when admitted to the hospital
! Studies are in universal agreement that long-term inotropic therapy increases mortality NEUROHORMONAL ANTAGONISTS
○ However, the short-term use of inotropic agents in ADHF is also associated with ! Other trials testing unique agents have yielded disappointing results in the situation of ADHF
increased arrhythmia, hypotension, and no beneficial effects on hard outcomes ! In patients who fail to respond adequately to medical therapy, mechanical assist devices may be
! Inotropic agents are currently indicated as: required (covered in more detail in Chap. 255)
○ Bridge therapy (to either left ventricular assist device support or to transplant)
○ Selectively applied palliation in end-stage heart failure HEART FAILURE WITH REDUCED EJECTION FRACTION
! Novel inotropic agents that leverage the concept of myofilament calcium sensitization rather than ! The treatment of symptomatic heart failure that evolved from a renocentric (diuretics) and
increasing intracellular calcium levels have been introduced hemodynamic therapy model (digoxin, inotropic therapy) ushered in the era of disease-modifying
! Levosimendan therapy with neurohormonal antagonism
○ A calcium sensitizer that provides inotropic activity, but also possesses ! RAAS blockers and beta blockers → form the cornerstone of pharmacotherapy → lead to
phosphodiesterase-3 inhibition properties that are vasodilators in action attenuation of decline and improvement in cardiac structure and function with consequent reduction
○ Makes the drug unsuitable in states of low output in the setting of hypotension in symptoms, improvement in QOL, decreased burden of hospitalizations, and a decline in mortality
! Omecamtiv mecarbil from both pump failure and arrhythmic deaths
○ Another drug that functions as a selective myosin activator
○ Prolongs the ejection period and increases fractional shortening
○ The force of contraction is not increased → as such, this agent does not increase
myocardial oxygen demand
! Other inotropic agents that increase myocardial calcium sensitivity through mechanisms that reduce
cTnI phosphorylation or inhibit protein kinase A are being developed.

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NEUROHORMONAL ANTAGONISM ! In symptomatic patients (NYHA class II–IV), an aldosterone antagonist should be strongly
! Meta-analyses suggest a 23% reduction in mortality and a 35% reduction in the combination considered, but four-drug therapy should be avoided
endpoint of mortality and hospitalizations for heart failure in patients treated with ACEIs ! A recent trial called the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) tested a
! Patients treated with beta blockers provide a further 35% reduction in mortality on top of the benefit direct renin inhibitor, aliskiren
provided by ACEIs alone ○ No significant difference in cardiovascular death or hospitalization at 6 or 12 months was
! Experience has demonstrated the safety of ACEIs in treating patients with mild renal insufficiency noted
and the tolerability of beta blockers in patients with moderately controlled diabetes, asthma, and ○ Aliskiren was associated with a reduction in circulating natriuretic peptides, but any
obstructive lung disease disease-modifying effect was overcome by excessive adverse events including
! The benefits of ACEIs and beta blockers extend to advanced symptoms of disease (NYHA class hyperkalemia, hypotension, and renal dysfunction
IIIb–IV) ○ These studies point to the limits achieved with RAAS modulation in this clinical syndrome
○ However, a number of patients with advanced heart failure may not be able to achieve
optimal doses of neurohormonal inhibitors and require cautious reduction in dose ARTERIOVENOUS VASODILATION
exposure to maintain clinical stability ! The combination of hydralazine and nitrates has been demonstrated to improve survival in HFrEF
○ Such individuals with lower exposure to ACEIs and beta blockers represent a high-risk ○ Hydralazine reduces systemic vascular resistance and induces arterial vasodilatation by
cohort with poor prognosis. affecting intracellular calcium kinetics
○ Nitrates are transformed in smooth muscle cells into nitric oxide → stimulates cyclic
Class Effect and Sequence of Administration guanosine monophosphate production and consequent arterial-venous vasodilation
! ACEIs exert their beneficial effects in HFrEF as a class ! This combination improves survival, but not to the magnitude evidenced by ACEIs or ARBs
! The beneficial effects of beta blockers are thought to be limited to specific drugs ! However, in individuals with HFrEF unable to tolerate RAAS-based therapy for reasons (ex. renal
○ Beta blockers with intrinsic sympathomimetic activity (xamoterol) and other agents, insufficiency or hyperkalemia) this combination is preferred as a disease-modifying approach
including bucindolol, have not demonstrated a survival benefit
○ Beta blocker use in HFrEF should ideally be restricted to carvedilol, bisoprolol, and NOVEL NEUROHORMONAL ANTAGONISM
metoprolol succinate ! Targeting neurohormonal pathways beyond the RAAS and sympathetic nervous system with
! Cardiac Insufficiency Bisoprolol Study (CIBIS) III → outcomes did not vary when either agent (ACEIs incremental blockade has been largely unsuccessful
or beta blockers) was initiated first ! Endothelin antagonist bosentan is associated with worsening heart failure in HFrEF despite
! Thus, it matters little which agent is initiated first; what does matter is that optimally titrated doses of demonstrating benefits in right-sided heart failure due to pulmonary arterial hypertension
both ACEIs and beta blockers be established in a timely manner. ! Similarly, the centrally acting sympatholytic agent moxonidine worsens outcomes in left heart failure
! The combined drug omapatrilat
Dose and Outcome ○ Hybridizes an ACEI with a neutral endopeptidase inhibitor
! A trial has indicated that higher tolerated doses of ACEIs achieve greater reduction in ○ Was tested in the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing
hospitalizations without materially improving survival Events (OVERTURE) trial
! Beta blockers demonstrate a dose-dependent improvement in cardiac function and reductions in ■ Did not favorably influence the primary outcome measure of the combined
mortality and hospitalizations risk of death or hospitalization for heart failure requiring intravenous
! Clinical experience suggests that, in the absence of symptoms to suggest hypotension (fatigue and treatment
dizziness), pharmacotherapy may be up-titrated every 2 weeks in stable ambulatory patients as ■ Risk of angioedema was notably higher with omapatrilat than ACEIs alone
tolerated ! More recently, the introduction of LCZ696, an ARB (valsartan) with an endopeptidase inhibitor
(sacubitril), has shown a survival benefit in a large trial versus ARB alone
MINERALOCORTICOID ANTAGONISTS ○ The drug, referred to as an angiotensin receptor–neprilysin inhibitor (ARNI) (and
! Aldosterone antagonism is associated with a reduction in mortality in all stages of symptomatic denoted Entrezto) demonstrated an incremental improvement in survival when
NYHA class II to IV HFrEF compared to ACEI alone
! Elevated aldosterone levels in HFrEF: ○ Most guidelines now advocate switching ACEI to this drug as a standard in patients
○ Promote sodium retention, electrolyte imbalance, and endothelial dysfunction with mild-moderate systolic heart failure when they remain symptomatic despite fully
○ May directly contribute to myocardial fibrosis tolerated doses of conventional therapy
! The selective agent eplerenone (tested in NYHA class II and post–MI heart failure) and the
nonselective antagonist spironolactone (tested in NYHA class III and IV heart failure) reduce
mortality and hospitalizations, with significant reductions in sudden cardiac death (SCD)
! Hyperkalemia and worsening renal function are concerns, especially in patients with underlying
chronic kidney disease
○ Renal function and serum potassium levels must be closely monitored.

RAAS THERAPY AND NEUROHORMONAL “ESCAPE”

! Neurohormonal “escape”
○ Witnessed in patients with HFrEF by the finding that circulating levels of angiotensin II
return to pretreatment levels with long-term ACEI therapy
○ ARBs blunt this phenomenon by binding competitively to the AT1 receptor.
! The Valsartan Heart Failure Trial (Val-HeFT) suggested that addition of valsartan in patients already
receiving treatment with ACEIs and beta blockers was associated with a trend toward worse
outcomes
! Initial clinical strategy should be to use a two-drug combination first
○ ACEI and beta blocker
○ If beta blocker intolerant, then ACEI and ARB
○ If ACEI intolerant, then ARB and beta blocker)

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HEART RATE MODIFICATION STATINS
! Ivabradine ! Potent lipid-altering and pleiotropic effects of statins reduce major cardiovascular events and
○ An inhibitor of the If current in the sinoatrial node improve survival in non–heart failure populations
○ Slows the heart rate without a negative inotropic effect ! Once heart failure is well established → this therapy may not be as beneficial and theoretically could
○ The Systolic Heart Failure Treatment with Ivabradine Compared with Placebo Trial even be detrimental by depleting ubiquinone in the electron transport chain
(SHIFT) was conducted in patients with class II or III HFrEF, a heart rate >70 beats/min, ! Two trials have tested low-dose rosuvastatin in patients with HFrEF and demonstrated no
and history of hospitalization for heart failure during the previous year improvement in aggregate clinical outcomes
■ Ivabradine reduced hospitalizations and the combined endpoint of ! If statins are required to treat progressive coronary artery disease in the background setting of heart
cardiovascular-related death and heart failure hospitalization failure, then they should be employed
○ In the 2012 European Society of Cardiology guidelines for the treatment of heart failure, ! However, no rationale appears to exist for routine statin therapy in nonischemic heart failure.
clinically, Ivabradine should be considered in patients who remain symptomatic after
guideline-based ACEIs, beta blockers, and mineralocorticoid receptor antagonists and ANTICOAGULATION AND ANTIPLATELET THERAPY
with residual heart rate >70 beats/min ! HFrEF is accompanied by a hypercoagulable state and therefore a high risk of thromboembolic
○ Another group in whom potential benefit may be expected includes those unable to events, including stroke, pulmonary embolism, and peripheral arterial embolism
tolerate beta blockers. ! Long-term oral anticoagulation is established in certain groups, including patients with atrial
fibrillation, but data are insufficient to support the use of warfarin in patients in normal sinus rhythm
DIGOXIN without a history of thromboembolic events or echocardiographic evidence of left ventricular
! Digitalis glycosides exert a mild inotropic effect, attenuate carotid sinus baroreceptor activity, and thrombus
are sympatho-inhibitory ! In the large Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, full-dose
! These effects decrease serum norepinephrine levels, plasma renin levels, and possibly aldosterone aspirin or INR– controlled warfarin was tested
levels ○ Among patients with reduced LVEF in sinus rhythm, there was no significant overall
! The DIG trial demonstrated a reduction in heart failure hospitalizations in the treatment group difference in the primary outcome between treatment with warfarin and treatment with
(patients with heart failure and sinus rhythm) but no reduction in mortality or improvement in QOL aspirin
! Treatment with digoxin resulted in a higher mortality rate and hospitalizations in women than men ○ Warfarin: A reduced risk of ischemic stroke, but offset by an increased risk of major
! Low doses of digoxin are sufficient to achieve any potentially beneficial outcomes, and higher doses hemorrhage
breach the therapeutic safety index ! Aspirin blunts ACEI-mediated prostaglandin synthesis (clinical importance of this finding remains
! Although digoxin levels should be checked to minimize toxicity and although dose reductions are unclear)
indicated for higher levels, no adjustment is made for low levels ! Current guidelines support the use of aspirin in patients with ischemic cardiomyopathy
! Generally, digoxin is now relegated as therapy for patients who remain profoundly symptomatic
despite optimal neurohormonal blockade and adequate volume control FISH OIL
! Treatment with long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been shown to be
ORAL DIURETICS associated with modestly improved clinical outcomes in patients with HFrEF
! Neurohormonal activation results in avid salt and water retention ! GISSI-HF trial: 3-month treatment with ω-3 PUFAs enriched circulating eicosapentaenoic acid (EPA)
! Loop diuretic agents and docosahexaenoic acid (DHA)
○ Often required because of their increased potency ! Low EPA levels are inversely related to total mortality in patients with HFrEF.
○ Frequent dose adjustments may be necessary because of variable oral absorption and
fluctuations in renal function MICRONUTRIENTS
○ From trials: no data suggest that these agents improve survival → thus, diuretic agents ! Evidence suggests an association between heart failure and micronutrient status
should ideally be used in tailored dosing schedules to avoid excessive exposure ! Reversible heart failure has been described as a consequence of severe thiamine and selenium
! Indeed, diuretics are essential at the outset to achieve volume control before neurohormonal deficiency
therapy is likely to be well tolerated or titrated. ○ Thiamine deficiency has received attention in heart failure because malnutrition and
diuretics are prime risk factors for thiamine loss
CALCIUM CHANNEL ANTAGONISTS ○ Small studies have suggested a benefit of supplementation of thiamine in HFrEF with
! Amlodipine and felodipine, second-generation calcium channel–blocking agents, safely and evidence of improved cardiac function
effectively reduce blood pressure in HFrEF but do not affect morbidity, mortality, or QOL ○ This finding is restricted to chronic heart failure states and does not appear to be
! The first-generation agents (including verapamil and diltiazem) beneficial in the ADHF phenotype
○ May exert negative inotropic effects and destabilize previously asymptomatic patients ○ Due to the exploratory nature of the evidence, no recommendations for routine
○ Their use should be discouraged supplementation or testing for thiamine deficiency can be made

INFLAMMATION ENHANCED EXTERNAL COUNTERPULSATION (EECP)

! Targeting inflammatory cytokines such as TNF-α by using anticytokine agents such as infliximab ! Peripheral lower extremity therapy
and etanercept → unsuccessful and associated with worsening heart failure ○ Uses graded external pneumatic compression at high pressure
! Use of IVIG therapy in nonischemic etiology of heart failure has not been shown to result in beneficial ○ Administered in 1-h sessions for 35 treatments (7 weeks)
outcomes ○ Has been proposed to reduce angina symptoms and extend time to exercise-induced
! Nonspecific immunomodulation has been tested in the Advanced Chronic Heart Failure Clinical ischemia in patients with coronary artery disease
Assessment of Immune Modulation Therapy (ACCLAIM-HF) trial ! The Prospective Evaluation of Enhanced External Counterpulsation in Congestive Heart Failure
○ Ex-vivo exposure of a blood sample from systolic heart failure patients to controlled (PEECH) study assessed the benefits of enhanced external counterpulsation in the treatment of
oxidative stress was hypothesized to initiate apoptosis of leukocytes → physiologic patients with mild-to-moderate heart failure
response to apoptotic cells results in a reduction in inflammatory cytokine production and ○ Improved exercise tolerance, QOL, and NYHA functional classification but without an
upregulation of anti-inflammatory cytokines accompanying increase in peak oxygen consumption
○ This promising hypothesis was not proven, although certain subgroups (those with no ○ A placebo effect due to the nature of the intervention simply cannot be excluded
history of previous myocardial infarction and those with mild heart failure) showed signals
in favor of immunomodulation
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EXERCISE ○ Catheter ablation and pulmonary vein isolation appear to be safe and effective in this
! The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) high-risk cohort and compare favorably with the more established practice of AV node
study investigated short-term (3-month) and long-term (12-month) effects of a supervised exercise ablation and biventricular pacing
training program in patients with moderate HFrEF. ! Diabetes mellitus
! Exercise was safe, improved patients’ sense of well-being, and correlated with a trend toward ○ Frequent co-morbidity in heart failure
mortality reduction ○ Prior studies using thiazolidinediones (activators of peroxisome proliferator-activated
! Significant improvements in cardiopulmonary exercise time and peak oxygen consumption receptors) have been associated with worsening heart failure
persisting at 12 months ○ Glucagon-like peptide 1 (GLP-1) agonists such as liraglutide have also been tested and
! Therefore, exercise training is recommended as an adjunctive treatment in patients with heart do not lead to greater post-hospitalization clinical stability or worsening in heart failure
failure. ○ Empagloflozin was tested demonstrated a decrease in cardiovascular mortality as well
as hospitalizations for heart failure
MANAGEMENT OF SELECTED COMORBIDITY ■ This drug, a sodium–glucose cotransporter 2 (SGLT2), induces an osmotic
! Sleep-disordered breathing diuresis as well as ketosis
○ Common in HF and particularly in HFrEF ■ This drug class may represent a viable therapeutic avenue in diabetics with
○ A range of presentations exemplified by obstructive sleep apnea, central sleep apnea, heart failure
and its extreme form of Cheyne-Stokes breathing are noted
○ Frequent periods of hypoxia and repeated micro- and macro-arousals trigger adrenergic NEUROMODULATION USING DEVICE THERAPY
surges → can worsen hypertension and impair systolic and diastolic function ! Autonomic dysfunction is common in heart failure and attempts at using devices to modulate the
○ A high index of suspicion is required, especially in patients with difficult-to-control sympathetic and parasympathetic systems have been undertaken
hypertension or with predominant symptoms of fatigue despite reverse remodeling in ! Broadly, devices that achieve vagal nerve stimulation, baroreflex activation, renal sympathetic
response to optimal medical therapy denervation, spinal cord stimulation, or left cardiac sympathetic denervation have been employed
○ Worsening of right heart function with improvement of left ventricular function noted on ! Small preclinical and clinical studies have demonstrated benefits, but large-sized randomized trials,
medical therapy should immediately trigger a search for underlying sleep-disordered when conducted, have failed
breathing or pulmonary complications such as occult embolism or pulmonary ! INOVATE-HF study tested vagal nerve stimulation among individuals with stable HF
hypertension ○ Vagus nerve stimulation did not reduce the rate of death or hospitalization for HF
○ Treatment with nocturnal positive airway pressure improves oxygenation, LVEF, and 6- ○ However, functional capacity and QOL were favorably affected by vagus nerve
min walk distance but no conclusive data exist to support this therapy as a disease- stimulation.
modifying approach with reduction in mortality
! Anemia CARDIAC RESYNCHRONIZATION THERAPY
○ Common in heart failure patients, reduces functional status and QOL, and is associated ! Nonsynchronous contraction between the walls of the left ventricle (intraventricular) or between the
with increased proclivity for hospital admissions and mortality ventricular chambers (interventricular) impairs systolic function, decreases mechanical efficiency of
○ More common in the elderly, in those with advanced stages of HFrEF, in the presence contraction, and adversely affects ventricular filling
of renal insufficiency, and in women and African Americans ! Mechanical dyssynchrony → results in an increase in wall stress and worsens functional mitral
○ Mechanisms include iron deficiency, dysregulation of iron metabolism, and occult regurgitation
gastrointestinal bleeding ! The single most important association of extent of dyssynchrony is a widened QRS interval on the
○ Intravenous iron using either iron sucrose or carboxymaltose has been shown to ECG, particularly in the presence of a left bundle branch block.
correct anemia and improve functional capacity ! With placement of a pacing lead via the coronary sinus to the lateral wall of the ventricle, cardiac
■ CONFIRM-HF demonstrated that use of ferric carboxymaltose in a simplified resynchronization therapy (CRT) enables a more synchronous ventricular contraction by aligning
high dose schedule resulted in improvement in functional capacity, the timing of activation of the opposing walls
symptoms, and QOL ○ Early studies showed improved exercise capacity, reduction in symptoms, and evidence
○ Oral iron supplementation does not appear to be effective in treating iron deficiency in of reverse remodeling
heart failure ! The Cardiac Resynchronization in Heart Failure Study (CARE-HF) trial demonstrated a reduction in
○ Erythropoiesis-regulating agents such as erythropoietin analogues have been studied all-cause mortality with CRT placement in patients with HFrEF on optimal therapy with continued
with disappointing results moderate-to-severe residual symptoms of NYHA class III or IV heart failure
! Depression ! Recent trials have demonstrated disease-modifying properties of CRT in even minimally
○ Common in HFrEF (prevalence of one in five patients) symptomatic patients with HFrEF, including the RAFT and MADIT-CRT, both of which sought to use
○ Is associated with a poor QOL, limited functional status, and increased risk of morbidity CRT in combination with an implantable defibrillator. Most benefit in mildly symptomatic HFrEF
and mortality in this population patients accrues from applying this therapy in those with a QRS width of >149 ms and a left bundle
○ Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART- branch block pattern
CHF) trial, showed that although sertraline was safe, it did not provide greater reduction ! Narrow QRS dyssynchrony has not proven to be a good target for treatment
in depression or improve cardiovascular status among patients with heart failure and ! Uncertainty surrounds the benefits of CRT in those with ADHF, a predominant right bundle branch
depression compared with nurse-driven multidisciplinary management block pattern, atrial fibrillation, and evidence of scar in the lateral wall, which is the precise location
! Atrial arrhythmias where the CRT lead is positioned.
○ Are common, especially atrial fibrillation
○ Serve as a harbinger of worse prognosis in patients with heart failure SUDDEN CARDIAC DEATH PREVENTION IN HEART FAILURE
○ When rate control is inadequate or symptoms persist → pursuing a rhythm control ! SCD due to ventricular arrhythmias is the mode of death in approximately half of patients with
strategy is reasonable heart failure and is particularly proportionally prevalent in HFrEF patients with early stages of the
○ Rhythm control may be achieved via pharmacotherapy or by percutaneous or disease
surgical techniques ! Patients who survive an episode of SCD are considered to be at very high risk and qualify for
○ Referral to practitioners or centers experienced in these modalities is recommended placement of an implantable cardioverterdefibrillator (ICD)
○ Antiarrhythmic drug therapy should be restricted to amiodarone and dofetilide → ! Two single most important risk markers for stratification of need and benefit are:
both have been shown to be safe and effective but do not alter the natural history of the ○ The degree of residual LV dysfunction despite optimal medical therapy (≤35%) to allow
underlying disease. for adequate remodeling
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 ○ Underlying etiology (post–MI or ischemic cardiomyopathy) ○ Other remodeling procedures, such as use of an external mesh-like net attached around
! Currently, appropriate candidates for ICD prophylactic therapy are: the heart to limit further enlargement, have not been shown to provide hard clinical
○ Patients with NYHA class II or III symptoms of heart failure, and benefits
○ An LVEF <35%, irrespective of etiology of heart failure ! Mitral regurgitation (MR)
! In patients with a myocardial infarction and optimal medical therapy with residual LVEF ≤30% (even ○ Occurs with varying degrees in patients with HFrEF and dilated ventricles.
when asymptomatic), placement of an ICD is appropriate ○ Annular dilatation and leaflet noncoaptation in the setting of anatomically normal
! A recent Danish trial suggested that prophylactic ICD implantation in patients with symptomatic papillary muscles, chordal structures, and valve leaflets characterize functional MR
systolic heart failure not caused by coronary artery disease was not associated with a significantly ○ In patients who are not candidates for surgical coronary revascularization, mitral valve
lower long-term rate of death from any cause than was usual clinical care repair remains controversial
○ In this trial, benefits were noted in those aged <60 years ○ Ischemic MR (or infarct-related MR) is typically associated with leaflet tethering and
! In patients with a terminal illness and a predicted life span of <6 months or in those with NYHA class displacement related to abnormal left ventricular wall motion and geometry
IV symptoms who are refractory to medications and who are not candidates for transplant, the risks ○ No evidence to support the use of surgical or percutaneous valve correction for functional
of multiple ICD shocks must be carefully weighed against the survival benefits MR exists as disease-modifying therapy even though MR can be corrected.
! If a patient meets the QRS criteria for CRT, combined CRT with ICD is often employed
CELLULAR AND GENE-BASED THERAPY
! The cardiomyocyte possesses regenerative capacity and such renewal is accelerated under
conditions of stress and injury, such as an ischemic event or heart failure
! Investigations that use either bone marrow–derived precursor cells or autologous cardiac-derived
cells have gained traction but have not generally improved clinical outcomes in a convincing manner
! More promising are cardiac-derived stem cells
○ Small trials demonstrated improvements in left ventricular function but require far more
work to usher in a clinical therapeutic success
○ The appropriate route of administration, the quantity of cells to achieve a minimal
therapeutic threshold, the constitution of these cells (single source or mixed), the
mechanism by which benefit accrues, and short- and long-term safety remain to be
elucidated
! Targeting molecular aberrations using gene transfer therapy, mostly with an adenoviral vector, has
been tested in HFrEF
○ A cellular target includes calcium cycling proteins such as inhibitors of phospholamban
such as SERCA2a which is deficient in patients with HFrEF
○ This target was tested in the CUPID (Efficacy and Safety Study of Genetically Targeted
Enzyme Replacement Therapy for Advanced Heart Failure) trial
■ Initially demonstrated that natriuretic peptides were decreased, reverse
remodeling was noted, and symptomatic improvements were forthcoming
■ However, a confirmatory trial failed to meet its primary efficacy endpoint

DISEASE MANAGEMENT AND SUPPORTIVE CARE

SURGICAL THERAPY IN HEART FAILURE ! Despite stellar outcomes with medical therapy, admission rates following heart failure hospitalization
! Coronary artery bypass grafting (CABG) is considered in patients with ischemic cardiomyopathy remain high, with nearly half of all patients readmitted to hospital within 6 months of discharge
with multivessel coronary artery disease ! Recurrent heart failure and related cardiovascular conditions account for only half of
! The recognition that hibernating myocardium, defined as myocardial tissue with abnormal function readmissions in patients with heart failure, whereas other comorbidity-related conditions account for
but maintained cellular function, could recover after revascularization led to the notion that the rest
revascularization with CABG would be useful in those with living myocardium ! The key to achieving enhanced outcomes must begin with the attention to transitional care at the
! Revascularization is most robustly supported in individuals with ongoing angina and left ventricular index hospitalization with facilitated discharge through comprehensive discharge planning, patient
failure and caregiver education, appropriate use of visiting nurses, and planned follow-up
○ Revascularizing those with left ventricular failure in the absence of angina remains ! Early post-discharge follow-up, whether by telephone or clinic-based, may be critical to ensuring
controversial stability because most heart failure–related readmissions tend to occur within the first 2 weeks
! The Surgical Treatment for Ischemic Heart Failure (STICH) trial in patients with an ejection fraction after discharge
of ≤35% and coronary artery disease amenable to CABG ○ Although routinely advocated, intensive surveillance of weight and vital signs with use of
○ Demonstrated no significant initial benefit compared to medical therapy telemonitoring has not decreased hospitalizations
○ However, patients assigned to CABG had lower rates of death from cardiovascular ! Intrathoracic impedance measurements have been advocated for the identification of early rise in
causes and of death from any cause or hospitalization for cardiovascular causes over filling pressure and worsened hemodynamics so that preemptive management may be employed →
10 years than among those who received medical therapy alone. has not been successful and may worsen outcomes in the short term
! Surgical ventricular restoration (SVR) ! Implantable pressure monitoring systems do tend to provide signals for early decompensation, and
○ A technique characterized by infarct exclusion to remodel the left ventricle by reshaping in patients with moderately advanced symptoms, such systems have been shown to provide
it surgically in patients with ischemic cardiomyopathy and dominant anterior left information that can allow implementation of therapy to avoid hospitalizations by as much as 39%
ventricular dysfunction ! Once heart failure becomes advanced, regularly scheduled review of the disease course and options
○ However, in a trial, the addition of SVR to CABG had no disease modifying effect with the patient and family is recommended including discussions surrounding end-of-life
○ However, left ventricular aneurysm surgery is still advocated in those with: preferences when patients are comfortable in an outpatient setting
■ Refractory heart failure ! As the disease state advances further, integrating care with social workers, pharmacists, and
■ Ventricular arrhythmias community-based nursing may be critical in improving patient satisfaction with the therapy,
■ Thromboembolism arising from an akinetic aneurysmal segment of the enhancing QOL, and avoiding heart failure hospitalizations
ventricle
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 ! Equally important is attention to seasonal influenza vaccinations and periodic pneumococcal
vaccines that may obviate non–heart failure hospitalizations in these ill patients
! When nearing end of life, facilitating a shift in priorities to outpatient and hospice palliation is key, as
are discussions around advanced therapeutics and continued use of ICD prophylaxis, which may
worsen QOL and prolong death.

GLOBAL CONSIDERATIONS
! Substantial differences exist in the practice of heart failure therapeutics and outcomes by geographic
location
! The penetrance of CRT and ICD is higher in the United States than in Europe.
! Variation in the benefits of beta blockers based on world region remains an area of controversy
! In oral pharmacologic therapy trials of HFrEF, patients from southwest Europe have a lower
incidence of ischemic cardiomyopathy and those in North America tend to have more diabetes and
prior coronary revascularization
! There is also regional variation in medication use even after accounting for indication
○ In TOPCAT, the drug spironolactone was effective when used in the US population while
patients recruited from Russia and contiguous territories showed no difference
○ Whether this represents population differences or trial conduct disparity remains to be
investigated
! ADHF, patients in Eastern Europe tend to be younger, with higher ejection fractions and lower
natriuretic peptide levels
! Patients from South America tend to have the lowest rates of comorbidities, revascularization, and
device use
! In contrast, patients from North America have the highest comorbidity burden with high
revascularization and device use rates
! Given geographic differences in baseline characteristics and clinical outcomes, the generalizability
of therapeutic outcomes in patients in the United States and Western Europe may require
verification.

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