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Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral HemorrhageExtended Follow-up of the RESTART Randomized Clinical Trial

Educational Objective
To investigate the long-term effects of antiplatelet therapy after stroke due to intracerebral hemorrhage.
1 Credit CME
Key Points

Question  What are the long-term effects of antiplatelet therapy after stroke caused by intracerebral hemorrhage in patients who were in the pilot phase of the Restart or Stop Antithrombotics Randomized Trial?

Findings  In this randomized clinical trial of 537 participants with extended follow-up for a median total of 3.0 years (interquartile range, 2.0-5.0 years), the proportion of participants with intracerebral hemorrhage recurrence was 8.2% after allocation to start antiplatelet therapy and 9.3% without antiplatelet therapy, a nonsignificant difference. There were nonsignificantly fewer major vascular events among individuals in the group taking antiplatelet therapy vs the group avoiding antiplatelet therapy (26.8% vs 32.5%).

Meaning  After intracerebral hemorrhage associated with antithrombotic drug use, antiplatelet therapy appears to be safe.

Abstract

Importance  The Restart or Stop Antithrombotics Randomized Trial (RESTART) found that antiplatelet therapy appeared to be safe up to 5 years after intracerebral hemorrhage (ICH) that had occurred during antithrombotic (antiplatelet or anticoagulant) therapy.

Objectives  To monitor adherence, increase duration of follow-up, and improve precision of estimates of the effects of antiplatelet therapy on recurrent ICH and major vascular events.

Design, Setting and Participants  From May 22, 2013, through May 31, 2018, this prospective, open, blinded end point, parallel-group randomized clinical trial studied 537 participants at 122 hospitals in the UK. Participants were individuals 18 years or older who had taken antithrombotic therapy for the prevention of occlusive vascular disease when they developed ICH, discontinued antithrombotic therapy, and survived for 24 hours. After initial follow-up ended on November 30, 2018, annual follow-up was extended until November 30, 2020, for a median of 3.0 years (interquartile range [IQR], 2.0-5.0 years) for the trial cohort.

Interventions  Computerized randomization that incorporated minimization allocated participants (1:1) to start or avoid antiplatelet therapy.

Main Outcomes and Measures  Participants were followed up for the primary outcome (recurrent symptomatic ICH) and secondary outcomes (all major vascular events) for up to 7 years. Data from all randomized participants were analyzed using Cox proportional hazards regression, adjusted for minimization covariates.

Results  A total of 537 patients (median age, 76.0 years; IQR, 69.0-82.0 years; 360 [67.0%] male; median time after ICH onset, 76.0 days; IQR, 29.0-146.0 days) were randomly allocated to start (n = 268) or avoid (n = 269 [1 withdrew]) antiplatelet therapy. The primary outcome of recurrent ICH affected 22 of 268 participants (8.2%) allocated to antiplatelet therapy compared with 25 of 268 participants (9.3%) allocated to avoid antiplatelet therapy (adjusted hazard ratio, 0.87; 95% CI, 0.49-1.55; P = .64). A major vascular event affected 72 participants (26.8%) allocated to antiplatelet therapy compared with 87 participants (32.5%) allocated to avoid antiplatelet therapy (hazard ratio, 0.79; 95% CI, 0.58-1.08; P = .14).

Conclusions and Relevance  Among patients with ICH who had previously taken antithrombotic therapy, this study found no statistically significant effect of antiplatelet therapy on recurrent ICH or all major vascular events. These findings provide physicians with some reassurance about the use of antiplatelet therapy after ICH if indicated for secondary prevention of major vascular events.

Trial Registration  isrctn.org Identifier: ISRCTN71907627

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: July 21, 2021.

Published Online: September 3, 2021. doi:10.1001/jamaneurol.2021.2956

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Al-Shahi Salman R et al. JAMA Neurology.

Corresponding Author: Rustam Al-Shahi Salman, PhD, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingom (rustam.al-shahi@ed.ac.uk).

Author Contributions: Dr Al-Shahi Salman and Ms Rodriguez 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.

Concept and design: Al-Shahi Salman, Dennis, Sandercock, Sudlow, Murray, Werring, White.

Acquisition, analysis, or interpretation of data: Al-Shahi Salman, Sandercock, Sudlow, Wardlaw, Whiteley, Murray, Stephen, Rodriguez, Lewis, White.

Drafting of the manuscript: Al-Shahi Salman, Rodriguez.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Murray, Stephen, Rodriguez, Lewis.

Obtained funding: Al-Shahi Salman, Dennis, Sudlow, Whiteley, Murray.

Administrative, technical, or material support: Al-Shahi Salman, Sandercock, Wardlaw, Whiteley, White.

Supervision: Al-Shahi Salman, Dennis, Lewis.

Conflict of Interest Disclosures: Dr Dennis reported receiving grants from the British Heart Foundation during the conduct of the study. Dr Sudlow reported receiving grants from the British Heart Foundation during the conduct of the study. Dr Wardlaw reported receiving grants from the Scottish Funding Council during the conduct of the study and grants from Fondation Leducq, British Heart Foundation, EU H2020, UK Stroke Association, Medical Research Council, and Alzheimer’s Society outside the submitted work. Dr Murray reported receiving grants from the British Heart Foundation during the conduct of the study. Dr Werring reported receiving personal fees from Bayer, Alexion/Portola, Alnylam, and NovoNordisk outside the submitted work. Dr White reported receiving grants from Stryker, Penumbra, Medtronic, and Microvention and personal fees from Microvention outside the submitted work. No other disclosures were reported.

Funding/Support: The study was funded by a special project grant SP/12/2/20422 from the British Heart Foundation. The University of Edinburgh and the Lothian Health Board are cosponsors. This study was also supported by the National Institute for Health Research Clinical Research Network, National Health Service Research Scotland Scottish Stroke Research Network, and National Health Service Research Scotland through grant E131252 from the Edinburgh clinical research facility and National Health Service Lothian Research and Development.

Role of the Funder/Sponsor: The funding sources 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.

Group Information: The members of the RESTART Collaboration are listed in Supplement 3.

Meeting Presentation: This paper was presented at ESOC 2021, the 7th European Stroke Conference; September 3, 2021; virtual conference.

Data Sharing Statement: See Supplement 4.

Additional Contributions: Imaging acquisition, processing, and data collection were performed at the Edinburgh Imaging Facility, University of Edinburgh, which is part of the SINAPSE (Scottish Imaging Network: A Platform for Scientific Excellence) collaboration (funded by the Scottish Funding Council and the Chief Scientist Office).We thank the British Heart Foundation for funding the trial, continuing to support it while recruitment was challenging, and granting a no-cost extension to enable us to acquire an extra 2 years of follow-up. We thank all participants, their relatives or caregivers, and their primary care practitioners, outcome event adjudicators, imaging adjudicators, the trial steering committee, and the data monitoring committee. We thank the Edinburgh Clinical Trials Unit staff for their involvement.

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