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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.


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.

Béjot  Y , Cordonnier  C , Durier  J , Aboa-Eboulé  C , Rouaud  O , Giroud  M .  Intracerebral haemorrhage profiles are changing: results from the Dijon population-based study.   Brain. 2013;136(pt 2):658-664. doi:10.1093/brain/aws349 PubMedGoogle Scholar
O’Donnell  MJ , Chin  SL , Rangarajan  S ,  et al; INTERSTROKE investigators.  Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.   Lancet. 2016;388(10046):761-775. doi:10.1016/S0140-6736(16)30506-2 PubMedGoogle ScholarCrossref
Murthy  SB , Zhang  C , Diaz  I ,  et al.  Association between intracerebral hemorrhage and subsequent arterial ischemic events in participants from 4 population-based cohort studies.   JAMA Neurol. 2021;78(7):809-816. doi:10.1001/jamaneurol.2021.0925 PubMedGoogle ScholarCrossref
Murthy  SB , Diaz  I , Wu  X ,  et al.  Risk of arterial ischemic events after intracerebral hemorrhage.   Stroke. 2020;51(1):137-142. doi:10.1161/STROKEAHA.119.026207 PubMedGoogle ScholarCrossref
Li  L , Poon  MTC , Samarasekera  NE ,  et al.  Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies.   Lancet Neurol. 2021;20(6):437-447. doi:10.1016/S1474-4422(21)00075-2 PubMedGoogle ScholarCrossref
van Nieuwenhuizen  KM , Vaartjes  I , Verhoeven  JI ,  et al.  Long-term prognosis after intracerebral haemorrhage.   Eur Stroke J. 2020;5(4):336-344. doi:10.1177/2396987320953394 PubMedGoogle ScholarCrossref
Chen  Y , Wright  N , Guo  Y ,  et al; China Kadoorie Biobank Collaborative Group.  Mortality and recurrent vascular events after first incident stroke: a 9-year community-based study of 0·5 million Chinese adults.   Lancet Glob Health. 2020;8(4):e580-e590. doi:10.1016/S2214-109X(20)30069-3 PubMedGoogle ScholarCrossref
Baigent  C , Blackwell  L , Collins  R ,  et al; Antithrombotic Trialists’ (ATT) Collaboration.  Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.   Lancet. 2009;373(9678):1849-1860. doi:10.1016/S0140-6736(09)60503-1 PubMedGoogle Scholar
Hart  RG , Pearce  LA , Aguilar  MI .  Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.   Ann Intern Med. 2007;146(12):857-867. doi:10.7326/0003-4819-146-12-200706190-00007 PubMedGoogle ScholarCrossref
Perry  LA , Berge  E , Bowditch  J ,  et al.  Antithrombotic treatment after stroke due to intracerebral haemorrhage.   Cochrane Database Syst Rev. 2017;5:CD012144. doi:10.1002/14651858.CD012144.pub2 PubMedGoogle Scholar
Al-Shahi Salman  R , Murray  GD , Dennis  MS ,  et al.  The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: statistical analysis plan for a randomised controlled trial.   Trials. 2019;20(1):183. doi:10.1186/s13063-019-3270-2 PubMedGoogle ScholarCrossref
Al-Shahi Salman  R , Dennis  MS , Murray  GD ,  et al; RESTART collaborators.  The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial.   Trials. 2018;19(1):162. doi:10.1186/s13063-018-2542-6 PubMedGoogle ScholarCrossref
Al-Shahi Salman  R , Dennis  MS .  Antiplatelet therapy may be continued after intracerebral hemorrhage.   Stroke. 2014;45(10):3149-3150. doi:10.1161/STROKEAHA.114.005786 PubMedGoogle ScholarCrossref
RESTART Collaboration.  Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial.   Lancet. 2019;393(10191):2613-2623. doi:10.1016/S0140-6736(19)30840-2 PubMedGoogle ScholarCrossref
Al-Shahi Salman  R , Minks  DP , Mitra  D ,  et al; RESTART Collaboration.  Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial.   Lancet Neurol. 2019;18(7):643-652. doi:10.1016/S1474-4422(19)30184-X PubMedGoogle ScholarCrossref
RESTART Trial. Accessed August 17, 2021. http://www.RESTARTtrial.org
Bruno  A , Akinwuntan  AE , Lin  C ,  et al.  Simplified modified Rankin scale questionnaire: reproducibility over the telephone and validation with quality of life.   Stroke. 2011;42(8):2276-2279. doi:10.1161/STROKEAHA.111.613273 PubMedGoogle ScholarCrossref
Dennis  M , Mead  G , Doubal  F , Graham  C .  Determining the modified Rankin score after stroke by postal and telephone questionnaires.   Stroke. 2012;43(3):851-853. doi:10.1161/STROKEAHA.111.639708 PubMedGoogle ScholarCrossref
Hicks  KA , Mahaffey  KW , Mehran  R ,  et al; Standardized Data Collection for Cardiovascular Trials Initiative (SCTI).  2017 Cardiovascular and stroke endpoint definitions for clinical trials.   Circulation. 2018;137(9):961-972. doi:10.1161/CIRCULATIONAHA.117.033502 PubMedGoogle ScholarCrossref
Mehran  R , Rao  SV , Bhatt  DL ,  et al.  Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.   Circulation. 2011;123(23):2736-2747. doi:10.1161/CIRCULATIONAHA.110.009449 PubMedGoogle ScholarCrossref
Poon  MT , Fonville  AF , Al-Shahi Salman  R .  Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis.   J Neurol Neurosurg Psychiatry. 2014;85(6):660-667. doi:10.1136/jnnp-2013-306476 PubMedGoogle ScholarCrossref
Flynn  RW , MacDonald  TM , Murray  GD , MacWalter  RS , Doney  AS .  Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage.   Stroke. 2010;41(11):2606-2611. doi:10.1161/STROKEAHA.110.589143 PubMedGoogle ScholarCrossref
Biffi  A , Halpin  A , Towfighi  A ,  et al.  Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy.   Neurology. 2010;75(8):693-698. doi:10.1212/WNL.0b013e3181eee40f PubMedGoogle ScholarCrossref
Chong  BH , Chan  KH , Pong  V ,  et al.  Use of aspirin in Chinese after recovery from primary intracranial haemorrhage.   Thromb Haemost. 2012;107(2):241-247. doi:10.1160/TH11-06-0439 PubMedGoogle ScholarCrossref
Clark  TG , Altman  DG , De Stavola  BL .  Quantification of the completeness of follow-up.   Lancet. 2002;359(9314):1309-1310. doi:10.1016/S0140-6736(02)08272-7 PubMedGoogle ScholarCrossref
Hróbjartsson  A , Thomsen  AS , Emanuelsson  F ,  et al.  Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors.   BMJ. 2012;344:e1119. doi:10.1136/bmj.e1119 PubMedGoogle Scholar
Strong  B , Pudar  J , Thrift  AG ,  et al.  Sex disparities in enrollment in recent randomized clinical trials of acute stroke: a meta-analysis.   JAMA Neurol. 2021;78(6):666-677. doi:10.1001/jamaneurol.2021.0873 PubMedGoogle ScholarCrossref
Wood  L , Egger  M , Gluud  LL ,  et al.  Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study.   BMJ. 2008;336(7644):601-605. doi:10.1136/bmj.39465.451748.AD PubMedGoogle ScholarCrossref
Mackman  N , Bergmeier  W , Stouffer  GA , Weitz  JI .  Therapeutic strategies for thrombosis: new targets and approaches.   Nat Rev Drug Discov. 2020;19(5):333-352. doi:10.1038/s41573-020-0061-0 PubMedGoogle ScholarCrossref
Ding  X , Liu  X , Tan  C ,  et al.  Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: a meta-analysis of cohort studies.   J Neurol Sci. 2018;384:133-138. doi:10.1016/j.jns.2017.11.009 PubMedGoogle ScholarCrossref
Teo  KC , Lau  GKK , Mak  RHY ,  et al.  Antiplatelet resumption after antiplatelet-related intracerebral hemorrhage: a retrospective hospital-based study.   World Neurosurg. 2017;106:85-91. doi:10.1016/j.wneu.2017.06.015 PubMedGoogle ScholarCrossref
González-Pérez  A , Gaist  D , de Abajo  FJ , Sáez  ME , García Rodríguez  LA .  Low-dose aspirin after an episode of haemorrhagic stroke is associated with improved survival.   Thromb Haemost. 2017;117(12):2396-2405. doi:10.1160/TH17-05-0342 PubMedGoogle Scholar
Ma  X , Liu  D , Niu  S ,  et al.  Low-dose antiplatelet therapy survey after intracerebral hemorrhage in China: a retrospective hospital-based study.   Neurosurg Rev. 2021. doi:10.1007/s10143-021-01483-8 PubMedGoogle Scholar
Moon  JY , Lee  JG , Kim  JH .  Antiplatelet therapy after intracerebral hemorrhage and subsequent clinical events: a 12-year South Korean Cohort Study.   Eur Neurol. 2021;84(3):183-191. doi:10.1159/000514552 PubMedGoogle ScholarCrossref
Murthy  SB , Biffi  A , Falcone  GJ ,  et al; VISTA-ICH Steering Committee Collaborators.  Antiplatelet therapy after spontaneous intracerebral hemorrhage and functional outcomes.   Stroke. 2019;50(11):3057-3063. doi:10.1161/STROKEAHA.119.025972 PubMedGoogle ScholarCrossref
Shoamanesh  A , Patrice Lindsay  M , Castellucci  LA ,  et al Canadian stroke best practice recommendations: Management of Spontaneous Intracerebral Hemorrhage, 7th Edition Update 2020. Int J Stroke. 202;16(3):321-341. doi:10.1177/1747493020968424
Ziai  WC , Tsiskaridze  A .  Restarting antiplatelet therapy after intracerebral haemorrhage.   Lancet. 2019;393(10191):2567-2569. doi:10.1016/S0140-6736(19)31094-3 PubMedGoogle ScholarCrossref
Cheng  B , Li  J , Peng  L ,  et al.  Efficacy and safety of restarting antiplatelet therapy for patients with spontaneous intracranial haemorrhage: a systematic review and meta-analysis.   J Clin Pharm Ther. 2021;46(4):957-965. doi:10.1111/jcpt.13377 PubMedGoogle ScholarCrossref
Girotra  T , Feng  W .  Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): are neurologists feeling more comfortable to RESTART antiplatelet?   Ann Transl Med. 2019;7(suppl 6):S214. doi:10.21037/atm.2019.08.84 PubMedGoogle ScholarCrossref
Eun  MY , Jung  JM .  Safety and efficacy of restarting antiplatelet therapy after intracerebral hemorrhage.   Ann Transl Med. 2019;7(suppl 6):S218. doi:10.21037/atm.2019.08.96 PubMedGoogle ScholarCrossref
Li  L , Geraghty  OC , Mehta  Z , Rothwell  PM ; Oxford Vascular Study.  Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study.   Lancet. 2017;390(10093):490-499. doi:10.1016/S0140-6736(17)30770-5 PubMedGoogle ScholarCrossref
Kelly  J .  New horizons: managing antithrombotic dilemmas in patients with cerebral amyloid angiopathy.   Age Ageing. 2021;50(2):347-355. doi:10.1093/ageing/afaa275 PubMedGoogle ScholarCrossref
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