Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: open label, blinded endpoint, randomised controlled phase II trial

Abstract

Objective: To test the hypothesis that ticagrelor plus aspirin is safe and superior to clopidogrel plus aspirin for reducing high platelet reactivity at 90 days and stroke recurrence in patients with minor stroke or transient ischaemic attack, particularly in carriers of the CYP2C19 loss-of-function allele and patients with large artery atherosclerosis.

Design: Open label, blinded endpoint, randomised controlled phase II trial.

Setting: Prospective studies conducted at 26 centres in China, August 2015 to March 2017.

Participants: 675 patients with acute minor stroke or transient ischaemic attack.

Intervention: Ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 mg loading dose, 75 mg daily thereafter) on a background of aspirin (100 mg daily for the first 21 days) within 24 hours of symptom onset.

Main outcome measures: Primary outcome was the proportion of patients with high platelet reactivity at 90 days. High platelet reactivity was defined as P2Y12 reaction units of more than 208. Secondary outcomes included high platelet reactivity at 90 days (7 days either way) in patients carrying genetic variants that would affect clopidogrel metabolism, and any stroke (ischaemic or haemorrhagic) recurrence at 90 days (7 days either way), six months, and one year.

Results: At 90 days, high platelet reactivity occurred in 35 (12.5%) of 280 patients in the ticagrelor/aspirin group and 86 (29.7%) of 290 patients in the clopidogrel/aspirin group (risk ratio 0.40; 95% confidence interval 0.28 to 0.56; P<0.001), and in 10.8% versus 35.4% (0.31; 0.18 to 0.49; P<0.001) of patients carrying CYP2C19 loss-of-function alleles. Stroke occurred in 21 (6.3%) of 336 patients in the ticagrelor/aspirin group and 30 (8.8%) of 339 patients in the clopidogrel/aspirin group (hazard ratio 0.70; 95% confidence interval 0.40 to 1.22; P=0.20). Patients with large artery atherosclerosis in the ticagrelor/aspirin group had a lower stroke recurrence at 90 days than those in the 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 haemorrhagic events between the ticagrelor/aspirin and clopidogrel/aspirin groups (4.8% v 3.5%; P=0.42).

Conclusion: Patients with minor stroke or transient ischaemic attack who are treated with ticagrelor plus aspirin have a lower proportion of high platelet reactivity than those who are treated with clopidogrel plus aspirin, particularly for those who are carriers of the CYP2C19 loss-of-function allele. The results of this study should be evaluated further in large scale, phase III trials and in different populations.

Trial registration: Clinicaltrials.gov NCT02506140.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Beijing Municipal Science and Technology Commission, Beijing Municipal Commission of Health and Family Planning, and National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

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

Fig 2

Platelet reactivity in trial groups at baseline and follow-up, showing P2Y12 reaction units (PRU; mean (standard deviation)) and proportion (%; 95% confidence intervals) of patients with high platelet reactivity (HOPR; PRU >208 as measured by the VerifyNow P2Y12 assay). A total of 333, 306, and 280 patients in the ticagrelor/aspirin group and 336, 321, and 290 patients in the clopidogrel/aspirin group were included in the 0, 7, and 90 day analyses, respectively

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

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)