RESEARCH

Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet

reactivity in patients with minor stroke or transient ischaemic

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­attack: open label, blinded endpoint, randomised controlled
phase II trial
Yilong Wang,1,2,3,4 Weiqi Chen,1,2,3,4 Yi Lin,5 Xia Meng,1,2,3,4 Guohua Chen,6 Zhimin Wang,7
Jialing Wu,8 Dali Wang,9 Jianhua Li,10 Yibin Cao,11 Yuming Xu,12 Guohua Zhang,13
Xiaobo Li,14 Yuesong Pan,1,2,3,4 Hao Li,1,2,3,4 Xingquan Zhao,1,2,3,4 Liping Liu,1,2,3,4 Jinxi Lin,1,2,3,4
Kehui Dong,1,2,3,4 Jing Jing,1,2,3,4 S Claiborne Johnston,15 David Wang,16 Yongjun Wang1,2,3,4

For numbered affiliations see ABSTRACT MAIN OUTCOME MEASURES

end of the article. OBJECTIVE Primary outcome was the proportion of patients
Correspondence to: Yilong Wang To test the hypothesis that ticagrelor plus aspirin with high platelet reactivity at 90 days. High platelet
[email protected] is safe and superior to clopidogrel plus aspirin for reactivity was defined as P2Y12 reaction units of
(ORCID 0000-0003-2725-2788)
Yongjun Wang reducing high platelet reactivity at 90 days and more than 208. Secondary outcomes included high
[email protected] stroke recurrence in patients with minor stroke or platelet reactivity at 90 days (7 days either way) in
(ORCID 0000-0002-9976-2341) transient ischaemic attack, particularly in carriers of patients carrying genetic variants that would affect
Cite this as: BMJ 2019;365:l2211 the CYP2C19 loss-of-function allele and patients with clopidogrel metabolism, and any stroke (ischaemic
http://dx.doi.org/10.1136/bmj.l2211
large artery atherosclerosis. or haemorrhagic) recurrence at 90 days (7 days either
Accepted: 19 April 2019 way), six months, and one year.
DESIGN
Open label, blinded endpoint, randomised controlled RESULTS
phase II trial. At 90 days, high platelet reactivity occurred in 35
SETTING (12.5%) of 280 patients in the ticagrelor/aspirin group
Prospective studies conducted at 26 centres in China, and 86 (29.7%) of 290 patients in the clopidogrel/
August 2015 to March 2017. aspirin group (risk ratio 0.40; 95% confidence interval
0.28 to 0.56; P<0.001), and in 10.8% versus 35.4%
PARTICIPANTS
(0.31; 0.18 to 0.49; P<0.001) of patients carrying
675 patients with acute minor stroke or transient
CYP2C19 loss-of-function alleles. Stroke occurred in 21
ischaemic attack.
(6.3%) of 336 patients in the ticagrelor/aspirin group
INTERVENTION and 30 (8.8%) of 339 patients in the clopidogrel/
Ticagrelor (180 mg loading dose, 90 mg twice daily aspirin group (hazard ratio 0.70; 95% confidence
thereafter) or clopidogrel (300 mg loading dose, interval 0.40 to 1.22; P=0.20). Patients with large artery
75 mg daily thereafter) on a background of aspirin atherosclerosis in the ticagrelor/aspirin group had a
(100 mg daily for the first 21 days) within 24 hours of lower stroke recurrence at 90 days than those in the
symptom onset. clopidogrel/aspirin group (6.0% v 13.1%; hazard ratio
0.45, 95% confidence interval 0.20 to 0.98; P=0.04).
No difference was seen in the rates of major or minor
WHAT IS ALREADY KNOWN ON THIS TOPIC haemorrhagic events between the ticagrelor/aspirin and
clopidogrel/aspirin groups (4.8% v 3.5%; P=0.42).
Studies have shown that patients who are carriers of the cytochrome P450 (CYP)
CONCLUSION
2C19*2 and *3 loss-of-function alleles do not benefit from dual antiplatelet
Patients with minor stroke or transient ischaemic
therapy (aspirin combined with clopidogrel), compared with aspirin alone
attack who are treated with ticagrelor plus aspirin
Ticagrelor combined with aspirin has been shown to be more efficacious than have a lower proportion of high platelet reactivity than
clopidogrel combined with aspirin for acute coronary syndromes, regardless of those who are treated with clopidogrel plus aspirin,
CYP2C19 genotypes particularly for those who are carriers of the CYP2C19
However, the safety and efficacy of ticagrelor/aspirin versus clopidogrel/aspirin loss-of-function allele. The results of this study should
has not been evaluated in patients with minor stroke or transient ischaemic be evaluated further in large scale, phase III trials and
attack in different populations.

WHAT THIS STUDY ADDS TRIAL REGISTRATION

Clinicaltrials.gov NCT02506140.
This study suggests the efficacy of ticagrelor/aspirin in reducing high platelet
reactivity compared with clopidogrel/aspirin, especially in patients with
CYP2C19 loss-of-function alleles at 90 days after symptoms onset Introduction
The rate of major or minor haemorrhagic events did not differ between the two Patients with acute minor ischaemic stroke and
groups transient ischaemic attack are at high risk of recurrent
stroke and cardiovascular events.1 The Clopidogrel
As a phase II trial, these results would need to be replicated and investigated
in High-risk patients with Acute Non-disabling
further in larger studies and in different populations in the future
Cerebrovascular Events (CHANCE) trial indicated

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 RESEARCH

that combined clopidogrel and aspirin treatment conducted in accordance with the Declaration of
is superior to aspirin alone in reducing the risk of Helsinki.17 The trial was a prospective, multicentre,
stroke,2 but could increase the risk of non-intracranial randomised, open label, active controlled, blinded

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haemorrhage.1 3 Additionally, about 50% patients with endpoint trial. All participants or their representatives
acute ischaemic stroke had a risk of intracranial large provided written consent before study enrolment.
artery atherosclerosis (LAA) in Asia, and patients with
intracranial arterial stenosis and minor stroke (or a Study design and participants
high risk of transient ischaemic attack) had a higher From August 2015 to March 2017 in 26 study centres
rate of recurrent stroke than those without.4 5 The in China, the PRINCE trial enrolled patients aged 40-
CHANCE genetic substudy showed that patients who 80 years who had had an acute minor ischaemic stroke
were carriers of the cytochrome P450 (CYP) 2C19*2 (National Institutes of Health Stroke Scale score of ≤3
and *3 loss-of-function alleles benefitted more from at the time of randomisation) or those with a moderate
using aspirin alone than from using dual antiplatelet to high risk of transient ischaemic attack (ABCD2 stroke
therapy.6 risk score of ≥4 at the time of randomisation or ≥50%
The metabolism of ticagrelor is primarily via the stenosis of cervical or intracranial vessels that could
CYP3A4 enzyme and does not involve CYP2C19, account for the presentation) who could be treated
unlike clopidogrel.7 A genetic substudy of the with the study drug within 24 hours of symptom onset.
Platelet Inhibition and Patient Outcomes (PLATO) Patients were excluded from the trial if they had a
trial indicated that ticagrelor is more efficacious than diagnosis intracranial haemorrhage, acute coronary
clopidogrel for acute coronary syndromes, regardless syndrome, or other pathology that could account for
of CYP2C19 genotype, but was associated with an the neurological symptoms; had a modified Rankin
increased risk of haemorrhage in patients with a history scale score of more than 2 at randomisation; or had a
of stroke.8 The Acute Stroke or Transient Ischaemic contraindication to ticagrelor, clopidogrel, or aspirin.
Attack Treated With Aspirin or Ticagrelor and Patient The trial included six visits: randomisation
Outcomes (SOCRATES) trial revealed a trend towards (baseline), seven to nine days, 21 days (two days either
better efficacy in reducing the risk of vascular events in way), 90 days (seven days either way), six months (14
the ticagrelor treated group than in the aspirin group days either way), and one year (14 days either way).
in an Asian subpopulation. However, limited data Additional visits at two and 24 hours after the first dose
are available on the safety and efficacy of ticagrelor was administered were optional. All visits involved
for the treatment of stroke, compared with data for face-to-face interviews, with the exception of the six
clopidogrel on a background of aspirin in patients with month follow-up, which was conducted by telephone,
acute stroke.4 9 10 with data collected on electronic case report forms.
High platelet reactivity is defined as resistance The general schedule of the trial and the collection
or non-responsiveness to antiplatelet agents and times for blood and urine samples are listed in the
is a known marker for recurrent ischaemic events supplementary appendix (blood and urine samples
in patients with acute coronary syndrome or those collecting schedule).
patients with percutaneous coronary intervention.11 12
Several studies have shown the predictive value of Randomisation and procedures
high platelet reactivity for ischaemic and bleeding Immediately after signing the written informed consent
events after percutaneous coronary intervention or form, eligible patients were assigned to receive the
in patients with acute coronary syndrome. Multiple following within one hour of randomisation, in a 1:1
factors can contribute to the variability in platelet ratio:
function testing results, thus defining the high platelet
• Intervention (ticagrelor/aspirin): aspirin (a loa­
reactivity status. High platelet reactivity is associated
ding dose of 100-300 mg given as one to three
with poor cerebrovascular outcomes, and might be of
100 mg tablets on day 1, followed by 100 mg once
clinical value for the evaluation of recurrent events in
daily until day 21) combined with ticagrelor (180
patients with stroke.13-16
mg loading dose given as two 90 mg tablets on
We conducted the Platelet Reactivity in Acute Stroke
day 1, followed by 90 mg twice daily until day 90)
or Transient Ischaemic Attack (PRINCE) trial as a phase
• Control (clopidogrel/aspirin): aspirin (a loading
II study to compare the efficacy of ticagrelor plus aspirin
dose of 100-300 mg given as one to three 100 mg
with clopidogrel plus aspirin in reducing high platelet
tablets on day 1, followed by 100 mg once daily
reactivity at 90 days in patients with minor stroke or
until day 21) combined with clopidogrel (300 mg
transient ischaemic attack.17 We also compared the
loading dose given as four 75 mg tablets on day 1,
clinical outcomes in terms of efficacy and safety before
followed by 75 mg once daily until day 90).
a large scale, phase III study.
Patients were allocated via a block randomisation
Methods process by investigators at the clinical centres. The
The PRINCE study protocol (NCT02506140) and data block randomisation sequence was provided by an
collection were approved by the ethics committee of independent statistician using computer generated
Beijing Tiantan Hospital (ethical approval number random numbers with a block size of four. The block
KY2014-048-03) and all of the study centres, and size was not listed in the Chinese version of the protocol

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 RESEARCH

(which was provided to the investigators) in order to of-function allele carriers,” and those with at least
prevent the investigators from speculating about the one loss-of-function allele (*2 or *3) were classified
group assignment. The loading and maintenance doses as “loss-of-function allele carriers.”20 Patients who

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of ticagrelor were administered as in the SOCRATES carried at least one *17 allele (*1/*17 or *17/*17)
and PLATO studies.10 18 were classified as “ultra-metabolisers,” those without
VerifyNow testing was conducted in each study any *2, *3, or *17 allele (*1/*1) were classified as
centre by qualified personnel who were blinded to the “extensive metabolisers,” those with one *2 or *3
treatment allocation. The platelet reaction units were allele (*1/*2 or *1/*3) were classified as “intermediate
measured in each study centre by specially trained metabolisers,” and those with at least two *2 or *3
and qualified personnel according to a standardised alleles (*2/*2, *2/*3, or *3/*3) were classified as “poor
procedure manual. To ensure the validity and repro­ metabolisers.”20 Patients with one *17 and a loss-of-
ducibility of the assay, we held two separate training function allele (*2/*17 or *3/*17) were classified as
course for all the testing personnel from each centre. “unknown metabolisers,” because the clinical effect of
Both the investigators and the patients were aware of these alleles is uncertain.21 22
the study drug assignment, but were blinded to the Based on our preplanned aims, we compared the
platelet reactivity data until the end of the trial. recurrence of stroke in patients whose stroke subtype
was intracranial large artery atherosclerosis (LAA)
Outcomes with those whose stroke subtype was non-LAA based
The primary outcome of the PRINCE trial was the on the stroke subtype of SSS-TOAST (Stop Stroke Study
proportion of patients with high platelet reactivity Trial of Org 10172 in Acute Stroke Treatment stroke
at 90 days. High platelet reactivity was defined as a aetiology classification; supplementary appendix,
P2Y12 reaction unit of more than 208 measured using SSS-TOAST classification criteria). Non-LAA included
the VerifyNow P2Y12 assay. Prespecified secondary cardioaortic embolism, small artery occlusion, other
outcomes included high platelet reactivity at 90 days causes, and undetermined causes.
(seven days either way) in patients carrying genetic
variants that would affect clopidogrel metabolism; any Statistical analysis
stroke (ischaemic or haemorrhagic); and composite An interim analysis was preplanned in the published
clinical vascular events (ischaemic/haemorrhagic protocol.17 We calculated that 952 patients (estimated
stroke, transient ischaemic attack, myocardial 10% dropout rate) would be required to achieve 90%
infarction, or vascular death) at 90 days (seven days power with a two sided α=0.05 to detect a relative
either way), six months, and one year. Each reported reduction of 24% in the proportion of the primary
composite clinical vascular event and safety outcome outcome in the ticagrelor/aspirin group compared with
was independently adjudicated by two members that in the clopidogrel/aspirin group. The data safety
(KD and Jimei Li) of the clinical event adjudication monitoring board opted to terminate the study after
committee, who were blinded to the treatment group the interim analysis based on 476 patients (50% of the
assignments. All discrepancies were reviewed by all five projected necessary sample size) who completed 90
members of the committee and resolved by consensus. days of follow-up, based on achieving a prespecified
The primary safety outcome was major bleeding, which threshold for efficacy (P<0.005). At the time of this
was defined as that in the PLATO study classification decision, an additional 199 patients had already been
of haemorrhagic events: fatal or life threatening bleed, recruited and randomised into the trial, and these
major bleed, and other (supplementary appendix, patients were also followed up to study completion.
PLATO bleeding classification). Secondary safety Therefore, a total of 675 patients were included in the
outcomes included the incidence of intracranial intention-to-treat analyses.
bleeding; dyspnoea events; and mortality at 90 days Proportions were presented for categorical variables,
(seven days either way), six months, and one year. and medians with interquartile ranges or means
(standard deviation) were presented for continuous
Genotyping variables. We compared the proportion of high
The prespecified analysis included the single platelet reactivity at the 90 day follow-up (the primary
nucleotide polymorphisms (SNPs) CYP2C19*2 (681G outcome) between the two study groups using genmod
>A, rs4244285), CYP2C19*3 (636G >A, rs4986893), models adjusted by the high platelet reactivity status at
and CYP2C19*17 (−806C >T, rs12248560), which baseline, reported as a risk ratio with 95% confidence
were genotyped in all participants with adequate intervals. To evaluate the influence of missing data
blood samples. Most genotyping of the three SNPs for the primary outcome, we did sensitivity analyses
was performed by the Sequenom MassARRAY iPLEX assuming that all the missing data were high platelet
platform (Sequenom, San Diego, CA, USA). We used reactivity or not.
Sanger sequencing (ABI 3500 Genetic Analyzer, Applied The differences in the rates of stroke, composite
Biosystems) if the results were otherwise inconclusive. outcome, death, and bleeding events during the
We used star allele nomenclature to categorise 90 day follow-up were assessed by use of Cox
patients by the CYP2C19 metaboliser status, based on proportional hazards regression, and were reported
*2, *3, and *17 genotypes.19 Patients with at least one as hazard ratios with 95% confidence intervals. The
gain-of-function allele (*17) were classified as “gain- proportional hazard assumption for the Cox models

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RESEARCH

was examined by including a time dependent covariate treatment effect in reducing stroke recurrence differed
with interaction of treatment group, and a logarithmic between patients with LAA and those without LAA by
function of survival time in the model. testing the treatment-by-stroke subtype interaction

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We assessed whether the treatment effect differed in effect in a genmod model. The models also included
certain genotype categories by testing the treatment-by- the main effects of treatment group and genotype or
genotype interaction effect in genmod models for the stroke subtype. All statistical analyses were two sided,
primary outcome and Cox models for other outcomes, and differences with a P value of less than 0.05 were
as described earlier. We also tested whether the considered to be statistically significant. Analyses were

Table 1 | Baseline characteristics of patients in the PRINCE trial

Trial group
Characteristic Ticagrelor/aspirin (n=336) Clopidogrel/aspirin (n=339)
Age (years)
  Mean (standard deviation) 61.1 (8.5) 60.5 (9.0)
  Median (interquartile range) 62.0 (55.0-67.0) 61.0 (54.0-67.0)
Female sex (No (%)) 91 (27.1) 90 (26.5)
Systolic blood pressure (mm Hg)
  Mean (standard deviation) 152.3 (22.5) 154.9 (21.2)
  Median (interquartile range) 150.0 (137.5-168.0) 154.0 (140.0-170.0)
Diastolic blood pressure (mm Hg)
  Mean (standard deviation) 87.7 (13.0) 89.4 (12.8)
  Median (interquartile range) 87.5 (80.0-96.0) 88.0 (80.0-97.0)
Body mass index*
  Mean (standard deviation) 25.0 (3.8) 25.0 (3.8)
  Median (interquartile range) 24.6 (22.6-27.0) 24.8 (22.7-27.3)
Pulse rate (beat/min; mean (SD)) 75.1 (10.1) 76.3 (11.5)
Medical history (No (%))
 Hypertension 203 (60.4) 208 (61.4)
 Dyslipidaemia 20 (6.0) 21 (6.2)
  Diabetes mellitus 79 (23.5) 85 (25.1)
  Ischaemic stroke 59 (17.6) 62 (18.3)
  Transient ischaemic attack 8 (2.4) 10 (2.9)
  Coronary artery disease 26 (7.7) 25 (7.4)
  Known atrial fibrillation 0 (0.0) 4 (1.2)
  Flutter valvular heart disease 1 (0.3) 0 (0.0)
  Pulmonary embolism 0 (0.0) 0 (0.0)
Smoking status (No (%))
 Non-smoker 150 (44.6) 155 (45.7)
  Current smoker 160 (47.6) 159 (46.9)
 Ex-smoker 26 (7.7) 25 (7.4)
Drug use before randomisation (No (%))
  Proton pump inhibitor 2 (0.6) 3 (0.9)
 Statin 36 (10.7) 30 (8.8)
 Aspirin 77 (22.9) 69 (20.4)
 Clopidogrel 5 (1.5) 10 (2.9)
 Ticagrelor 0 (0.0) 0 (0.0)
Time to randomisation after onset of symptoms (h; mean (range)) 14.0 (8.3-20.6) 13.8 (8.0-20.8)
Time to randomisation after onset of symptoms (No (%))
  <12 h 139 (41.4) 144 (42.5)
  ≥12 h 197 (58.6) 195 (57.5)
Qualifying event (No (%))
  Minor stroke 275 (81.8) 289 (85.3)
  Transient ischaemic attack 61 (18.2) 50 (14.7)
Baseline ABCD2 score among patients with transient ischaemic attack
5.0 (4.0-5.0) 4.5 (4.0-5.0)
as the qualifying event (median (interquartile range))†
SSS-TOAST stroke subtype (No (%))‡
  Large artery atherosclerosis 151 (54.9) 153 (52.9)
  Cardioaortic embolism 8 (2.9) 5 (1.7)
  Small artery occlusion 104 (37.8) 109 (37.7)
  Other causes 7 (2.5) 9 (3.1)
  Undetermined causes 5 (1.8) 13 (4.5)
 Unknown 2 (0.7) 7 (2.4)
 Unclassified 3 (1.1) 6 (2.1)
*Body mass index is the weight in kilograms divided by the square of the height in metres.
†ABCD2 stroke risk scores range from 0 to 7, with higher scores indicating higher risk; data provided in the table are only for the group of 111 patients
whose qualifying event was transient ischaemic attack for inclusion in the trial.
‡SSS-TOAST stroke subtype=Stop Stroke Study Trial of Org 10172 in Acute Stroke Treatment stroke aetiology classification (supplementary appendix,
SSS-TOAST classification criteria); data provided in the table are only for the group of 564 patients whose qualifying event was minor stroke for inclusion
in the trial.

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 RESEARCH

performed by use of SAS software, version 9.4 (SAS the results published through email or telephone. The
Institute, Cary, NC, USA). results of the research will be broadcasted to all the
participants and general public through internet news,

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Patient and public involvement popular science articles, newspapers, and social media.
The design, outcome measurement, recruiting plans, or
implementation of the study were independent of any Results
patient. The gene and platelet reactivity testing results Between August 2015 and March 2017, 5644 patients
of every patient will be delivered to the patient himself with stroke or transient ischaemic attack were
or his appointed relatives after the primary results of screened at 26 hospitals, and 675 patients (mean age

5644
Patients with stroke or TIA screened

4969
Patients excluded
1176 Delay beyond 24 hour time window
671 Moderate and major ischaemic stroke
9 ICH/SAH
327 TIA with lower risk (ABCD2<4)
196 Contraindication for study drug or
indicate to prohibited concomitant
drugs or therapy
26 Symptoms limited to isolated
numbness, isolated visual changes,
or isolated dizziness/vertigo
8 Inability to swallow drug
1437 Refused consent
792 Other reasons
23 Contraindication for MRI
304 Intervention or thrombolytic therapy

675
Randomised

336 339
Received ticagrelor and aspirin Received clopidogrel and aspirin
(analysis by intention to treat) (analysis by intention to treat)

All participants All participants

14 Enrolled inappropriately 9 Enrolled inappropriately
3 >24 hours from onset 4 >24 hours from onset
3 Severe hepatic insufficiency 0 Severe hepatic insufficiency
2 Hct <30% 0 Hct <30%
4 Intracranial haemorrhage on CT scan 1 Intracranial haemorrhage on CT scan
1 Vascular malfunctions 1 Vascular malfunctions
2 Bradyarrhythmia and atrial fibrillation 2 Bradyarrhythmia and atrial fibrillation
0 Hypersensitivity to clopidogrel 1 Hypersensitivity to clopidogrel
2 Intracranial metastatic tumour 0 Intracranial metastatic tumour
69 Had permanent drug discontinuation 47 Had permanent drug discontinuation
11 Were non-adherent to study protocol 10 Were non-adherent to study protocol
36 Had adverse events or severe 18 Had adverse events or severe
adverse events adverse events
0 Needing of anticoagulation therapy 2 Needing of anticoagulation therapy
1 Had surgery 0 Had surgery
4 Had other reasons 0 Had other reasons
12 Decided to stop treatment 9 Decided to stop treatment
6 Lost to follow-up for clinical events 6 Lost to follow-up for clinical events
at 90 days at 90 days
9 Enrolment errors 5 Enrolment errors
56 VerifyNow P2Y12 not obtained 49 VerifyNow P2Y12 not obtained
at 90 days at 90 days
15 Genotype: at least one of the three 10 Genotype: at least one of the three
CYP2C19 alleles not obtained CYP2C19 alleles not obtained

280 321 290 329

Included in Included in Included in Included in
primary outcome analysis genetic substudy primary outcome analysis genetic substudy

Fig 1 | Trial profile. TIA=transient ischaemic attack; MRI=magnetic resonance imaging; ICH/SAH=intracerebral
haemorrhage/subarachnoid haemorrhage; Hct=haematocrit; CT=computed tomography; VerifyNow P2Y12=VerifyNow
P2Y12 platelet reactivity assay

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RESEARCH

Ticagrelor/aspirin (supplementary tables B, C, and D show details of

Clopidogrel/aspirin the baseline characteristics of patients enrolled in
350 the genetic substudy). Of the 650 participants, 374
Mean PRU

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(57.5%) were classified as CYP2C19 loss-of-function
300 carriers.
P<0.001 P<0.001 We obtained valid measurements in 627 (92.9%)
250 and 570 (84.4%) patients for the VerifyNow P2Y12
assay at the seven day and 90 day follow-up periods,
200
respectively. The P2Y12 reaction units before receiving
the study drugs were similar in the ticagrelor/aspirin
150
and clopidogrel/aspirin groups (mean 256.4 (standard
deviation 61.3) v 246.9 (53.7), P=0.13). The ticagrelor/
100
aspirin group had significantly fewer P2Y12 reaction
units than the clopidogrel/aspirin group (69.3 (87.0)
50
v 173.5 (67.6); P<0.001) at 90 day follow-up (fig 2).
0
The primary outcome (high platelet reactivity) was
observed in 35 of 280 patients (12.5%) in the ticagrelor/
90
aspirin group, and in 86 of the 290 patients (29.7%)
Proportion of HOPR (%)

80 in the clopidogrel/aspirin group at 90 days (risk ratio

0.40; 95% confidence interval 0.28 to 0.56; P<0.001;
70
fig 2 and table 2). Similar results were observed for the
60 primary outcome in sensitivity analyses assuming that
all missing data for the primary outcome showed high
50
P<0.001
platelet reactivity or not (supplementary table E).
P<0.001 Stroke, the main secondary outcome, occurred
40
in 21 (6.3%) of the 336 patients in the ticagrelor/
30
aspirin group and 30 (8.8%) of the 339 patients in
20 the clopidogrel/aspirin group (hazard ratio 0.70; 95%
confidence interval 0.40 to 1.22; P=0.20). Composite
10
clinical vascular events occurred in 22 patients
0 (6.5%) in the ticagrelor/aspirin group and 32 patients
0 7 90
Days (9.4%) in the clopidogrel/aspirin group (0.68; 0.40 to
1.18; P=0.17; table 2). All of the proportional hazard
Fig 2 | Platelet reactivity in trial groups at baseline and follow-up, showing P2Y12 assumptions were met (P=0.89 for stroke and P=0.85
reaction units (PRU; mean (standard deviation)) and proportion (%; 95% confidence for composite events).
intervals) of patients with high platelet reactivity (HOPR; PRU >208 as measured by the Among the CYP2C19 loss-of-function carriers, high
VerifyNow P2Y12 assay). A total of 333, 306, and 280 patients in the ticagrelor/aspirin platelet reactivity at 90 days was markedly less frequent
group and 336, 321, and 290 patients in the clopidogrel/aspirin group were included in
in the ticagrelor/aspirin group than in the clopidogrel/
the 0, 7, and 90 day analyses, respectively
aspirin group (10.8% v 35.4%; risk ratio 0.31, 95%
confidence interval 0.18 to 0.49; P<0.001; supplementary
61.1, standard deviation 8.5) were enrolled before table F). The event rates of stroke, composite events, and
the data safety monitoring board opted to terminate haemorrhagic events varied by treatment assignment
the trial after reviewing the results of the interim and phenotype (fig 3). Other primary and secondary
analysis. Thus, 336 patients were randomly assigned outcomes in patients with available genotype data are
to the ticagrelor/aspirin group and 339 patients were listed in supplementary table G.
assigned to the clopidogrel/aspirin group (table 1). Among the patients with LAA, stroke recurrence at
Patients were excluded from the trial mainly because 90 days was markedly lower in the ticagrelor/aspirin
of a delay beyond the 24 hour time window and group than in the clopidogrel/aspirin group (6.0% v
because they refused consent (fig 1). The average age 13.1%; hazard ratio 0.45, 95% confidence interval
was 60.8 (standard deviation 8.7), and 26.8% (n=181) 0.20 to 0.98; P=0.04; table 3 and fig 4). However,
of the patients were women. At 90 days, 12 patients among patients with non-LAA, the risk of stroke
were lost to follow-up owing to clinical events, and the recurrence was similar in the ticagrelor/aspirin group
VerifyNow P2Y12 assay data were not obtained from and clopidogrel/aspirin groups (8.1% v 7.4%; 1.1, 0.46
105 patients (supplementary table A shows details to 2.63; P=0.84; table 3 and fig 4). The proportional
of the baseline characteristics of patients with and hazard assumption was met (P=0.93).
without platelet function data). The primary safety outcome (PLATO major hae­
Among the 675 patients enrolled, 650 (mean morrhagic event) occurred in five patients (1.5%) in
age 60.8 (standard deviation 8.7)) had complete the ticagrelor/aspirin group and four (1.2%) in the
genotype data for all three SNPs, of whom 321 were clopidogrel/aspirin group (hazard ratio 1.27; 95%
randomly assigned to the ticagrelor/aspirin group and confidence interval 0.34 to 4.72; table 2). Three patients
329 were assigned to the clopidogrel/aspirin group (0.9%) in the ticagrelor/aspirin group and two (0.6%)

6 doi: 10.1136/bmj.l2211 | BMJ 2019;365:l2211 | the bmj

 RESEARCH

Table 2 | Effect of ticagrelor/aspirin versus clopidogrel/aspirin on efficacy and safety outcomes in PRINCE trial
Trial participants (No with event/total No (%)) Hazard ratio or risk
Outcomes Ticagrelor/aspirin Clopidogrel/aspirin ratio (95% CI)* P

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Primary efficacy outcomes†
Baseline 268/333 (80.5) 260/336 (77.4) 1.04 (0.96 to 1.13) 0.33
7+2 days 12/306 (3.9) 89/321 (27.7) 0.14 (0.07 to 0.23) <0.001
90±7 days 35/280 (12.5) 86/290 (29.7) 0.40 (0.28 to 0.56) <0.001
Secondary efficacy outcomes
Stroke 21/336 (6.3) 30/339 (8.8) 0.70 (0.40 to 1.22) 0.20
Composite events‡ 22/336 (6.5) 32/339 (9.4) 0.68 (0.40 to 1.18) 0.17
Ischaemic stroke 18/336 (5.4) 28/339 (8.3) 0.64 (0.35 to 1.16) 0.14
Haemorrhagic stroke 3/336 (0.9) 2/339 (0.6) 1.52 (0.25 to 9.08) 0.65
Myocardial infarction 0/336 (0.0) 1/339 (0.3) — —
Death from cardiovascular causes 1/336 (0.3) 2/339 (0.6) 0.50 (0.05 to 5.55) 0.58
Death from any cause 3/336 (0.9) 2/339 (0.6) 1.50 (0.25 to 9.00) 0.65
Transient ischaemic attack 1/336 (0.3) 2/339 (0.6) 0.50 (0.05 to 5.53) 0.57
Primary safety outcomes§
Major bleeding 5/336 (1.5) 4/339 (1.2) 1.27 (0.34 to 4.72) 0.72
Major, fatal, life threatening bleeding 4/336 (1.2) 3/339 (0.9) 1.35 (0.30 to 6.03) 0.69
Fatal bleeding 1/336 (0.3) 1/339 (0.3) 1.01 (0.06 to 16.13) 1.00
Intracranial haemorrhage 3/336 (0.9) 2/339 (0.6) 1.27 (0.34 to 4.72) 0.72
Major, other 1/336 (0.3) 1/339 (0.3) 1.01 (0.06 to 16.18) 0.99
Minor bleeding 11/336 (3.3) 8/339 (2.4) 1.40 (0.56 to 3.47) 0.47
Major or minor bleeding 16/336 (4.8) 12/339 (3.5) 1.36 (0.64 to 2.88) 0.42
Minimal bleeding 64/336 (19.0) 36/339 (10.6) 1.86 (1.24 to 2.80) 0.003
Any bleeding 75/336 (22.3) 48/339 (14.2) 1.65 (1.15 to 2.37) 0.007
Other safety outcomes
Respiratory, thoracic, and mediastinal 22/336 (6.5) 0/339 (0.0) — <0.001
disorders
Dyspnoea 14/336 (4.2) 0/339 (0.0) — <0.001
Epistaxis 6/336 (1.8) 0/339 (0.0) — 0.04
*Risk ratios used for the primary efficacy outcome and hazard ratios used for secondary efficacy outcome.
†Primary outcome indicates high platelet reactivity, which was defined as a P2Y12 reaction unit of more than 208, as measured by a VerifyNow P2Y12
assay.
‡A composite event was defined as a new clinical vascular event, including stroke, transient ischaemic attack, myocardial infarction, or death from
cardiovascular causes.
§Primary safety outcomes were defined according to the PLATO criteria (supplementary appendix, PLATO bleeding classification). All 675 patients were
included in the analysis of safety outcomes. Other safety outcomes included those leading to permanent drug discontinuation.

in the clopidogrel/aspirin group had intracranial 1). Serious adverse events and adverse events leading
haemorrhage. However, the rate of any haemorrhagic to permanent drug discontinuation within 90 days are
events occurring was higher in the ticagrelor/aspirin listed in supplementary table 1.
group (22.3%) than in the clopidogrel/aspirin
group (14.2%; 1.65, 1.15 to 2.37; table 2). All of the Discussion
proportional hazard assumptions were met (P=0.99 Principal findings
for major haemorrhagic event and P=0.82 for any This PRINCE trial results indicated that the proportion
haemorrhagic events). The rate of major bleeding did of high platelet reactivity at 90 days reduced with
not vary significantly between the ticagrelor/aspirin ticagrelor compared with clopidogrel, in patients with
and clopidogrel/aspirin groups amongst the carriers acute minor stroke and those at moderate-to-high risk
of the CYP2C19 loss-of-function allele (rate 0.0% v of transient ischaemic attack treated with aspirin.
1.6%; hazard ratio 0.35, 95% confidence interval This trial was not powered to study clinical events.
0.04 to 3.33; P=0.43) and non-carriers (0.0% v 0.7%; However, we observed fewer strokes and composite
supplementary table G). outcomes at 90 days in patients who were treated
Dyspnoea was more common in the ticagrelor/aspirin with dual antiplatelet therapy using ticagrelor/aspirin
group (n=54, 16.1%) than in the clopidogrel/aspirin compared with clopidogrel/aspirin within 24 hours
group (n=11, 3.2%; supplementary table H). A total of of the onset of minor stroke or transient ischaemic
69 (20.5%) patients in the ticagrelor/aspirin group and attack, without increasing the risk of major, minor, or
47 (13.9%) in the clopidogrel/aspirin group stopped intracranial haemorrhage. Treatment discontinuation
receiving the study drug before 90 days (fig 1); the most was, however, higher with ticagrelor due to an
common reasons were dyspnoea and epistaxis. The increased rate of dyspnoea and minimal haemorrhagic
rate of permanent discontinuation caused by dyspnoea events (that is, epistaxis).
was 4.2% (14/336) in the ticagrelor/aspirin group and
0.0% in the clopidogrel/aspirin group, and the rate of Comparison with other studies
permanent discontinuation caused by epistaxis was The major haemorrhage rate in the present study was
1.8% (n=6) in the ticagrelor/aspirin group and 0.0% lower than that found in the PLATO study (ticagrelor/
in the clopidogrel/aspirin group (supplementary table aspirin group 1.5% v 11.6%; clopidogrel/aspirin group

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RESEARCH

Outcome Ticagrelor/aspirin Clopidogrel/aspirin Hazard ratio or risk ratio Hazard ratio or risk ratio P P for
Phenotype No with event/total No (%) No with event/total No (%) (95% CI) (95% CI) value interaction

HOPR at 90 days

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Poor 4/38 (10.5) 14/33 (42.4) 0.23 (0.07 to 0.55) 0.004
Intermediate 12/113 (10.6) 41/124 (33.1) 0.34 (0.18 to 0.58) <0.001
Extensive 16/117 (13.7) 25/119 (21.0) 0.59 (0.33 to 1.03) 0.07
0.42
Ultra 0/1 (0.0) 2/5 (40.0) NA
Unknown 1/6 (16.7) 2/4 (50.0) 0.33 (0.02 to 2.44) 0.29
Total 33/275 (12.0) 84/285 (29.5) 0.40 (0.27 to 0.56) <0.001
Stroke
Poor 4/39 (10.3) 5/41 (12.2) 0.82 (0.22 to 3.05) 0.77
Intermediate 11/138 (8.0) 16/145 (11.0) 0.71 (0.33 to 1.54) 0.39
Extensive 4/136 (2.9) 8/133 (6.0) 0.48 (0.14 to 1.58) 0.23
0.98
Ultra 0/1 (0.0) 0/6 (0.0) NA
Unknown 0/7 (0.0) 1/4 (25.0) NA
Total 19/321 (5.9) 30/329 (9.1) 0.64 (0.36 to 1.13) 0.13
Composite events
Poor 4/39 (10.3) 6/41 (14.6) 0.68 (0.19 to 2.39) 0.54
Intermediate 12/138 (8.7) 17/145 (11.7) 0.73 (0.35 to 1.54) 0.60
Extensive 4/136 (2.9) 8/133 (6.0) 0.48 (0.14 to 1.58) 0.23
0.99
Ultra 0/1 (0.0) 0/6 (0.0) NA
Unknown 0/7 (0.0) 1/4 (25.0) NA
Total 20/321 (6.2) 32/329 (9.7) 0.63 (0.36 to 1.10) 0.10
Major or minor events
Poor 3/39 (7.7) 2/41 (4.9) 1.61 (0.27 to 9.65) 0.60
Intermediate 3/138 (2.2) 6/145 (4.1) 0.53 (0.13 to 2.11) 0.37
Extensive 6/136 (4.4) 4/133 (3.0) 1.45 (0.41 to 5.15) 0.56
0.97
Ultra 0/1 (0.0) 0/6 (0.0) NA
Unknown 0/7 (0.0) 0/4 (0.0) NA
Total 12/321 (3.7) 12/329 (3.6) 1.03 (0.46 to 2.29) 0.94

0.125 0.25 0.5 1 2 4 8

Fig 3 | Effect of ticagrelor/aspirin versus clopidogrel/aspirin on high platelet reactivity and clinical outcome in PRINCE trial participants at 90 days,
stratified by metaboliser status. A total of 321 patients in the ticagrelor/aspirin group and 329 patients in the clopidogrel/aspirin group were
included in the genetic analysis. Patients with two *2 or *3 alleles (*2/*2, *2/*3, or *3/*3) were classified as having a poor metaboliser phenotype,
those with one *2 or *3 allele (*1/*2 or *1/*3) were classified as having an intermediate metaboliser phenotype, those without a *2, *3, or *17
allele (*1/*1) were classified as having an extensive metaboliser phenotype, and those with a single *17 allele (*1/*17) and *17 homozygotes
were classified as having an ultra-metaboliser phenotype. HOPR=P2Y12 reaction units of more than 208, as measured the VerifyNow P2Y12 assay;
composite event=a new clinical vascular event, including stroke, transient ischaemic attack, myocardial infarction, or death from cardiovascular
causes; NA=not applicable

1.2% v 11.2%).18 This difference could be partly due to occurred more commonly with ticagrelor than with
the short term use of dual antiplatelet therapy in our clopidogrel treatment.10 18
study compared with the PLATO study (21 v 277 days).
By contrast, a slightly higher major haemorrhagic rate Safety of study drug
was found in PRINCE than in the Asian subgroup in the The premature discontinuation of the study drug was
SOCRATES trial (1.5% in the ticagrelor/aspirin group in more frequent in the ticagrelor/aspirin group than
PRINCE v 0.6% in the ticagrelor used as monotherapy in the clopidogrel/aspirin group, although the rate
in SOCRATES).4 This difference could be related to the of serious adverse events did not differ between the
combined use of two drugs in our study. Similar to that two groups. The treating physician or patient had the
reported in the PLATO and SOCRATES trials, dyspnoea option of temporarily or permanently discontinuing

Table 3 | Stroke recurrence at 90 days, by cause

Trial participants (No with event/total No (%)) Hazard ratio
Cause of stroke* Ticagrelor/aspirin (n=336) Clopidogrel/aspirin (n=339) (95% CI)* P P for interaction
Large artery
9/151 (6.0) 20/153 (13.1) 0.45 (0.20 to 0.98) 0.04 0.13
atherosclerosis
Non-large artery
10/124 (8.1) 10/136 (7.4) 1.10 (0.46 to 2.63) 0.84 —
atherosclerosis
*Cause of stroke classified by the SSS-TOAST stroke subtype (SSS-TOAST=Stop Stroke Study Trial of Org 10172 in Acute Stroke Treatment stroke aetiology
classification (supplementary appendix, SSS-TOAST classification criteria)). Non-large artery atherosclerosis included patients with cardioaortic embolism,
small artery occlusion, other causes, and undetermined causes.

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0.15

Cumulative probability of stroke

P=0.14 for log rank test

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0.1

0.05
LAA: Ticagrelor + aspirin
LAA: Clopidogrel + aspirin
Non-LAA: Ticagrelor + aspirin
Non-LAA: Clopidogrel + aspirin
0
0 30 60 90
Days since randomisation
No at risk
LAA: ticagrelor + aspirin
151 122 92 62
LAA: clopidogrel + aspirin
153 124 94 64
Non-LAA: ticagrelor + aspirin
124 95 65 35
Non-LAA: clopidogrel + aspirin
136 107 77 47

Fig 4 | Stroke recurrence risk with ticagrelor/aspirin versus clopidogrel/aspirin in PRINCE trial participants at 90 days,
based on cause of stroke. LAA=large-artery atherosclerosis; Non-LAA=non-large-artery atherosclerosis (including
cardioaortic embolism, small artery occlusion, other causes, and undetermined causes)

the drug in case of an adverse event, and could have subtyping analyses, our results were exploratory
taken this opportunity more frequently because of the and hypothesis generating, so future studies are
open label design, when using an unapproved drug needed. We also found a relatively high (7.7%) stroke
(that is, ticagrelor) in this indication. Furthermore, recurrence rate in patients with non-LAA (table 3),
because early discontinuation and non-adherence are compared with studies conducted in other developed
likely to contribute to the increased platelet reactivity countries.9 This might be relevant with the overall
observed at 90 days (compared with that observed at recurrent stroke rate after minor stroke or transient
seven days), the efficacy of ticagrelor on high platelet ischaemic attack also being relatively high, because
reactivity could have been even higher in patients in the recurrent stroke included a new stroke and also
the case of a blinded study design. rapid worsening (National Institutes of Health Stroke
Score ≥4) of an existing focal neurological deficit in our
Clinical efficacy study.
Although we tested the clinical efficacy (recurrent Among patients randomised to clopidogrel, we saw
stroke) between the two groups, the sample size was a dose-response association between the number of
small and this phase II trial was not powered to find a CYP2C19 loss-of-function alleles and the proportion
clinical effect. Our finding of fewer recurrent stroke and of high platelet reactivity, with patients carrying
composite events in patients treated with ticagrelor/ more loss-of-function alleles having a higher propor­
aspirin than in those treated with clopidogrel/aspirin tion of platelet aggregation. A larger benefit with
would need to be replicated, because the current study ticagrelor compared with clopidogrel was observed
provided only a 25.5% power to show a 30% relative in the proportion of high platelet reactivity in patients
risk difference with a two sided test at a 5% significance carrying more loss-of-function alleles. While a similar
level. Given a 90% power and a significance level of trend in clinical outcomes was seen among patients
5% (two sided), a total of 4690 patients would need randomly allocated to clopidogrel, those allocated
to be included in a phase III trial to detect the relative to ticagrelor also had higher rates of clinical events
risk difference between the ticagrelor/aspirin and if they carried a greater number of loss-of-function
clopidogrel/aspirin groups, based on the event rates in allele. However, these results should be interpreted
our study. with caution, owing to the very low number of patients
The stroke recurrence rate in LAA group was higher and events.
than that in the non-LAA group in our study. Patients
with minor stroke or transient ischaemic attack Limitations
with LAA might benefit more from ticagrelor plus This study had several limitations. Firstly, the primary
aspirin than from clopidogrel plus aspirin treatment. outcome used high platelet reactivity as a marker
Considering the large numbers required for the stroke of risk for events but not yet proved as a causal risk

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RESEARCH

factor of thrombotic events. Further studies are needed Funding: The study was supported by grants from the National
Key Technology Research and Development Programme of the
to evaluate the clinical efficacy of dual antiplatelet Ministry of Science and Technology of the People’s Republic of
therapy as the primary endpoint in this target China (2013BAI09B14, 2015BAI12B04, and 2015BAI12B02),

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population. Secondly, about 15% of patients were the Advanced Innovation Centre for Human Brain Protection
(117212), the Beijing Municipal Science and Technology
lost to follow-up for the evaluation of high platelet
Commission (D15110700200000, D151100002015001,
reactivity at 90 days. However, similar results were D151100002015002, D151100002015003), and the Beijing
observed after assuming all the missing data were high Municipal Commission of Health and Family Planning. AstraZeneca
provided the study drugs. The funders had no role in design and
platelet reactivity or not. Thirdly, potential selection
analysis of this trial.
bias could exist because we enrolled patients from sites
Competing interests: All authors have completed the ICMJE
that were mostly urban hospitals and that had more uniform disclosure form at www.icmje.org/coi_disclosure.pdf and
experts and medical resources. Fourthly, the cause declare: support from the Beijing Municipal Science and Technology
Commission, Beijing Municipal Commission of Health and Family
of stroke and the genetic differences in the CYP2C19
Planning, and National Key Technology Research and Development
gene differ between Chinese patients with stroke and Program of the Ministry of Science and Technology of the People’s
European patients with stroke. The results of our study Republic of China for the submitted work; no financial relationships
should be evaluated in different populations in the with any organisations that might have an interest in the submitted
work in the previous three years; no other relationships or activities
future. Finally, the open label design could have led to that could appear to have influenced the submitted work.
a placebo effect,23 which might have caused potential Ethical approval: The trial was conducted in accordance with the
bias in adverse events assessment, drug continuation, guiding principles of the Declaration of Helsinki and was approved
and even the physicians’ or patients’ decisions. by the local ethics committees (IRB protocol number V4.0; ethical
approval number KY2014-048-03).
AUTHOR AFFILIATIONS Data sharing: The technical appendix, dataset, and statistical code
1
Department of Neurology, Beijing Tiantan Hospital, Capital Medical are available from the corresponding author at yongjunwang@ncrcnd.
University, No 119 South 4th Ring West Road, Fengtai District, org.cn.
Beijing 100070, China The lead author affirms that this manuscript is an honest, accurate,
2
China National Clinical Research Centre for Neurological Diseases, and transparent account of the study being reported; that no
Beijing, China important aspects of the study have been omitted; and that any
3
Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China discrepancies from the study as planned (and, if relevant, registered)
4
have been explained.
Beijing Key Laboratory of Translational Medicine for
Cerebrovascular Disease, Beijing, China This is an Open Access article distributed in accordance with the
5 Creative Commons Attribution Non Commercial (CC BY-NC 4.0)
Department of Neurology and Institute of Neurology, First Affiliated license, which permits others to distribute, remix, adapt, build upon
Hospital, Fujian Medical University, Fuzhou, China this work non-commercially, and license their derivative works on
6
Department of Neurology, Wuhan No 1 Hospital, Wuhan, China different terms, provided the original work is properly cited and the
7
Department of Neurology, Taizhou First People’s Hospital, use is non-commercial. See: http://creativecommons.org/licenses/
Huangyan Hospital of Wenzhou Medical University, Taizhou, China by-nc/4.0/.
8
Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China 1  Amarenco P, Lavallée PC, Labreuche J, et al, TIAregistry.org
9
Department of Neurology, North China University of Science and Investigators. One-year risk of stroke after transient ischemic attack
Technology Affiliated Hospital, Tangshan, China or minor stroke. N Engl J Med 2016;374:1533-42. doi:10.1056/
10
Department of Neurology, First Hospital of Fangshan District, NEJMoa1412981
2  Wang Y, Wang Y, Zhao X, et al, CHANCE Investigators. Clopidogrel with
Beijing, China
11
aspirin in acute minor stroke or transient ischemic attack. N Engl J
Department of Neurology, Tangshan Gongren Hospital, Tangshan, Med 2013;369:11-9. doi:10.1056/NEJMoa1215340
China 3  Wang D, Gui L, Dong Y, et al. Dual antiplatelet therapy may increase
12
Department of Neurology, First Affiliated Hospital of Zhengzhou the risk of non-intracranial haemorrhage in patients with minor
University, Zhengzhou, China strokes: a subgroup analysis of the CHANCE trial. Stroke Vasc
13 Neurol 2016;1:29-36. doi:10.1136/svn-2016-000008
Department of Neurology, Second Hospital of Hebei Medical 4  Wang Y, Minematsu K, Wong KS, et al, SOCRATES Steering Committee
University, Shijiazhuang, China and Investigators. Ticagrelor in acute stroke or transient ischemic
14
Department of Neurology, Northern Jiangsu People’s Hospital, attack in Asian patients: from the SOCRATES Trial (acute stroke
Clinical Medical School, Yangzhou University, Yangzhou, China or transient ischemic attack treated with aspirin or ticagrelor
15 and patient outcomes). Stroke 2017;48:167-73. doi:10.1161/
Dell Medical School, University of Texas at Austin, Austin, TX, USA
STROKEAHA.116.014891
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INI Stroke Network, OSF Healthcare System, University of Illinois 5  Wang Y, Zhao X, Liu L, et al, CICAS Study Group. Prevalence and
College of Medicine, Peoria, IL, USA outcomes of symptomatic intracranial large artery stenoses and
occlusions in China: the Chinese Intracranial Atherosclerosis
We thank all patients and their families for providing blood, the
(CICAS) Study. Stroke 2014;45:663-9. doi:10.1161/
participating researchers at all study centres, and Tabassome Simon STROKEAHA.113.003508
(from Clinical Pharmacology in the Department of Pharmacology, AP- 6  Liu L, Wong KS, Leng X, et al, CHANCE Investigators. Dual
HP, Saint-Antoine Hospital, Pierre and Marie Curie University (UPMC), antiplatelet therapy in stroke and ICAS: Subgroup analysis
Paris, France) for helping us revising our manuscript and providing all of CHANCE. Neurology 2015;85:1154-62. doi:10.1212/
valuable suggestions for our study. WNL.0000000000001972
Contributors: YiW and WC contributed equally to the manuscript. 7  Brilakis ES, Patel VG, Banerjee S. Medical management after coronary
YiW, WC, XM, and YL contributed to the study design, drafting, and stent implantation: a review. JAMA 2013;310:189-98. doi:10.1001/
revision of the manuscript. YP and HL contributed to study design, jama.2013.7086
implementation of the statistical analysis, and revision of manuscript. 8  Wallentin L, James S, Storey RF, et al, PLATO investigators. Effect
KD contributed to study design and the review of the clinical events of CYP2C19 and ABCB1 single nucleotide polymorphisms on
outcomes of treatment with ticagrelor versus clopidogrel for
that occurred in all patients. YiW, YoW, YL, XZ, LL, SCJ, and DW were
acute coronary syndromes: a genetic substudy of the PLATO trial.
members of the PRINCE trial steering committee. JJ coordinated the
Lancet 2010;376:1320-8. doi:10.1016/S0140-6736(10)61274-3
central magnetic resonance imaging analyses. JinL coordinated the 9  Amarenco P, Albers GW, Denison H, et al, SOCRATES Steering
central blood sample and genetic sequencing. GC, ZW, JW, DW, JiaL, Committee and Investigators. Efficacy and safety of ticagrelor versus
YC, YX, GZ, and XL contributed to the study design, revision of the aspirin in acute stroke or transient ischaemic attack of atherosclerotic
manuscript, and approval of the report. YoW is the guarantor. The origin: a subgroup analysis of SOCRATES, a randomised, double-
corresponding author attests that all listed authors meet authorship blind, controlled trial. Lancet Neurol 2017;16:301-10. doi:10.1016/
criteria and that no others meeting the criteria have been omitted. S1474-4422(17)30038-8

10 doi: 10.1136/bmj.l2211 | BMJ 2019;365:l2211 | the bmj

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10  Johnston SC, Amarenco P, Albers GW, et al, SOCRATES Steering (PRINCE) trial: Rationale and design. Int J Stroke 2017;12:321-5.
Committee and Investigators. Ticagrelor versus aspirin in acute doi:10.1177/1747493017694390
stroke or transient ischemic attack. N Engl J Med 2016;375:35-43. 18  Wallentin L, Becker RC, Budaj A, et al, PLATO Investigators. Ticagrelor
doi:10.1056/NEJMoa1603060 versus clopidogrel in patients with acute coronary syndromes. N Engl

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11  Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients J Med 2009;361:1045-57. doi:10.1056/NEJMoa0904327
and recurrent events post-stenting: results of the PREPARE POST- 19  Scott SA, Sangkuhl K, Stein CM, et al, Clinical Pharmacogenetics
STENTING Study. J Am Coll Cardiol 2005;46:1820-6. doi:10.1016/j. Implementation Consortium. Clinical Pharmacogenetics
jacc.2005.07.041 Implementation Consortium guidelines for CYP2C19 genotype
12  Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet and clopidogrel therapy: 2013 update. Clin Pharmacol
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