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Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic AttackA Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials

Educational Objective
To determine the optimal duration of dual antiplatelet therapy for minor ischemic stroke or transient ischemic attack.
1 Credit CME
Key Points

Question  What is the optimal duration of dual antiplatelet therapy for minor ischemic stroke or transient ischemic attack?

Findings  In this pooled analysis of 2 randomized clinical trials, early and short-term clopidogrel-aspirin treatment was associated with a reduction in the risk of major ischemic events without increasing the risk of major hemorrhage in patients with minor stroke or transient ischemic attack. The main net clinical benefit of dual antiplatelet therapy occurred within the first 21 days.

Meaning  This analysis suggests that, in patients with acute minor stroke or transient ischemic attack, dual antiplatelet therapy should be initiated as soon as possible, but preferably within 24 hours after symptom onset, and continued for a duration of 21 days.

Abstract

Importance  Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA.

Objective  To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA.

Design, Setting, and Participants  This analysis pooled individual patient–level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019.

Interventions  In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset.

Main Outcomes and Measures  The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage.

Results  The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant.

Conclusions and Relevance  In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

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Article Information

Accepted for Publication: May 31, 2019.

Corresponding Authors: S. Claiborne Johnston, MD, PhD, Dean’s Office, Dell Medical School, University of Texas at Austin, 1912 Speedway, Ste 564, Austin, TX 78712 (clay.johnston@utexas.edu) and Yongjun Wang, MD, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing, China, 100070 (yongjunwang@ncrcnd.org.cn).

Published Online: August 19, 2019. doi:10.1001/jamaneurol.2019.2531

Correction: This article was corrected on September 30, 2019, to fix an error in Figure 2 . The labels “major ischemic events” (for the black line) and “major hemorrhages” (for the orange line) were missing from Figure 2 and have been added. This article was corrected online.

Author Contributions: Drs Johnston and Yongjun Wang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Pan and Elm contributed equally to this work as co–first authors.

Concept and design: Li, Farrant, Kim, Liu, Yongjun Wang, Johnston.

Acquisition, analysis, or interpretation of data: Pan, Elm, Li, Easton, Yilong Wang, Meng, Kim, Zhao, Meurer, Dietrich, Johnston.

Drafting of the manuscript: Pan, Farrant, Liu, Johnston.

Critical revision of the manuscript for important intellectual content: Elm, Li, Easton, Yilong Wang, Farrant, Meng, Kim, Zhao, Meurer, Dietrich, Yongjun Wang.

Statistical analysis: Pan, Elm.

Obtained funding: Easton, Yongjun Wang, Johnston.

Administrative, technical, or material support: Yilong Wang, Farrant, Meng, Zhao, Johnston.

Supervision: Li, Yilong Wang, Zhao, Liu, Yongjun Wang, Johnston.

Conflict of Interest Disclosures: Dr Elm reports grants from the National Institute of Neurological Disorders and Stroke during the conduct of the study. Dr Easton reports grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, nonfinancial support from Sanofi, and personal fees from Boehringer Ingelheim during the conduct of the study. Dr Kim reports grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke during the conduct of the study, as well as personal fees from Neuravi and grants from SanBio outside the submitted work. Dr Meurer reports grants from the National Institute of Neurological Disorders and Stroke during the conduct of the study. Dr Johnston reports grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, with Sanofi providing drug and matching placebo for 85% of the patients enrolled in the trial, nonfinancial support from Sanofi, and grants from AstraZeneca during the conduct of the study. No other disclosures were reported.

Funding/Support: The study is supported by grants from Ministry of Science and Technology of the People’s Republic of China (grants 2016YFC0901001, 2016YFC0901002, 2017YFC1310901, 2017YFC1310902, 2017YFC1307905, 2018YFC1311700, and 2018YFC1311706), Beijing Municipal Commission of Health and Family Planning (grants 2016-1-2041 and SML20150502), Beijing Municipal Science & Technology Commission (grant D151100002015003), the National Institute of Neurological Disorders and Stroke (grants U01 NS062835, U01 NS056975, and U01NS059041), and Sanofi.

Role of the Funder/Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: This investigator-initiated pooled analysis was supported by Sanofi. The authors, individually and collectively, are responsible for all content and editorial decisions and received no payment from Sanofi directly or indirectly (through a third party) related to the development and presentation of this publication.

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