Restarting antiplatelet therapy after intracerebral haemorrhage
Authors: Wendy C Ziai, Alexander Tsiskaridze
Journal: The Lancet (2019)

Antithrombotic therapy is a cornerstone of primary and secondary prevention of ischaemic coronary artery disease and stroke; up to 44% of patients who present with spontaneous intracerebral haemorrhage are taking antithrombotics.1Antithrombotic Trialists' CollaborationCollaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.Br Med J. 2002; 324: 71-86Crossref PubMed Google Scholar, 2Pasquini M Charidimou A van Asch CJ et al.Variation in restarting antithrombotic drugs at hospital discharge after intracerebral haemorrhage.Stroke. 2014; 45: 2643-2648Crossref PubMed Scopus (48) Google Scholar Clinicians commonly face the challenging decision of whether to restart antithrombotic therapy and, if so, when because of a perceived increased risk of recurrent intracerebral haemorrhage.2Pasquini M Charidimou A van Asch CJ et al.Variation in restarting antithrombotic drugs at hospital discharge after intracerebral haemorrhage.Stroke. 2014; 45: 2643-2648Crossref PubMed Scopus (48) Google Scholar, 3Khan NI Siddiqui FM Goldstein JN et al.Association between previous use of antiplatelet therapy and intracerebral haemorrhage outcomes.Stroke. 2017; 48: 1810-1817Crossref PubMed Scopus (38) Google Scholar Nevertheless, we know that survivors face a major ongoing risk of death in the decade after an event.4Hansen BM Nilsson OG Anderson H Norrving B Säveland H Lindgren A Long term (13 years) prognosis after primary intracerebral haemorrhage: a prospective population based study of long term mortality, prognostic factors and causes of death.J Neurol Neurosurg Psychiatry. 2013; 84: 1150-1155Crossref PubMed Scopus (52) Google Scholar Observational studies report decreased incidence of ischaemic cardiovascular events in patients with intracerebral haemorrhage who started antiplatelet therapy after the event, with no increased risk of recurrent intracerebral haemorrhage and no worse functional outcomes.5Ottosen TP Grijota M Hansen ML et al.Use of antithrombotic therapy and longterm clinical outcome among patients surviving intracerebral haemorrhage.Stroke. 2016; 47: 1837-1843Crossref PubMed Scopus (46) Google Scholar, 6Flynn RW MacDonald TM Murray GD MacWalter RS Doney AS Prescribing antiplatelet medicine and subsequent events after intracerebral haemorrhage.Stroke. 2010; 41: 2606-2611Crossref PubMed Scopus (66) Google Scholar, 7Teo KC Lau GKK Mak RHY et al.Antiplatelet resumption after antiplatelet-related intracerebral haemorrhage: a retrospective hospital-based study.World Neurosurg. 2017; 106: 85-91Crossref PubMed Scopus (18) Google Scholar, 8Chen CJ Ding D Buell TJ et al.Restarting antiplatelet therapy after spontaneous intracerebral haemorrhage: Functional outcomes.Neurology. 2018; 91: e26-e36Crossref PubMed Scopus (12) Google Scholar These data are compromised from event misclassification, ascertainment bias, and, most substantially, confounding by indication. Controversy also remains as to whether recurrent intracerebral haemorrhage or ischaemic stroke represents the higher risk for the patient (both estimated at 2–3% per year).9Poon MT Fonville AF Al-Shahi Salman R Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis.J Neurol Neurosurg Psychiatry. 2014; 85: 660-667Crossref PubMed Scopus (368) Google Scholar, 10Bailey RD Hart RG Benavente O Pearce LA Recurrent brain haemorrhage is more frequent than ischemic stroke after intracranial haemorrhage.Neurology. 2001; 56: 773-777Crossref PubMed Scopus (185) Google Scholar In The Lancet, Rustam Al-Shahi Salman and colleagues11RESTART CollaborationEffects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a prospective, randomised, open-label trial.Lancet. 2019; (published online May 22.)http://dx.doi.prg/10.1016/S0140-6736(19)30840-2Google Scholar report results of the RESTART trial, the first multicentre randomised trial investigating the safety of starting antiplatelet therapy in the subacute phase after intracerebral haemorrhage in patients taking antithrombotic drugs before the event. This open-label, blinded endpoint trial recruited 537 adults (69–82 years, 33% women) with spontaneous intracerebral haemorrhage, and tested whether restarting antiplatelet therapy, in comparison with avoidance, was associated with differences in the frequency of recurrent intracerebral haemorrhage and occlusive vascular events. The results showed a lower point estimate of risk for recurrent spontaneous intracerebral haemorrhage (primary outcome) for patients on antiplatelet therapy compared with those who did not receive this therapy, although this result was not significant (adjusted hazard ratio [HR] 0·51 [95% CI 0·25–1·03]; p=0·06). Most composite secondary endpoints combining haemorrhagic and vascular occlusive events were similar between groups. Only serious vascular events, as defined in the trial protocol (composite of myocardial infarction, stroke, or death from a vascular cause), were significantly reduced in the group on antiplatelet therapy (adjusted HR 0·65 [95% CI 0·44–0·95]; p=0·025). These results are much anticipated, given exclusion of patients with intracerebral haemorrhage in previous studies evaluating benefits and risks of antiplatelet therapy for secondary prevention. Al-Shahi Salman and colleagues should be congratulated on doing a high-quality pragmatic trial. The study, however, did not achieve the required sample size of 720 subjects with at least 2 years of follow-up. Therefore, exposure to the planned sample of different individuals with intracerebral haemorrhage did not occur. Rather, the investigators randomised 537 subjects and extended follow-up to 5 years, achieving 1064 person-years of follow-up (99·3% completion). Expanding follow-up on a smaller cohort might be inconsequential had there not been an apparent stabilisation of the intracerebral haemorrhage risk without occurrence of primary outcome (recurrent intracerebral haemorrhage) among 243 participants with more than 2 years of follow-up. The absence of events after 2 years is hardly plausible and probably reflects underpowering for the outcome event, with low survival rates at longer follow-up or possibly problems with adherence. Importantly, further follow-up of both the primary outcome and adherence is planned. Although we do not know if the eligible recruited and non-recruited patients are systematically different, some lack of clinical equipoise burdened the recruitment process, resulting in the possibility of selection bias caused by screening failure (randomisation of only one patient from every 12 eligible ones). This point seems especially important for two exclusion reasons: 26% of eligible participants were not assigned to treatment because the physician was certain about whether or not to use antiplatelet therapy and 30% because of other reasons.12Maxwell AE MacLeod MJ Joyson A et al.Reasons for non-recruitment of eligible patients to a randomised controlled trial of secondary prevention after intracerebral haemorrhage: observational study.Trials. 2017; 18: 162Crossref PubMed Scopus (7) Google Scholar Therefore, some selection bias might have been introduced in the study. Randomisation was permitted at any time beyond 24 h after intracerebral haemorrhage and was minimised for time from intracerebral haemorrhage onset to randomisation with a median of 76 days. Unfortunately, this study does not provide substantial numbers of early and late treatment events. Although similar treatment effect estimates for the primary outcome in the pre-median and postmedian periods after intracerebral haemorrhage symptom onset do not suggest that the risk is higher in the first 2 months, optimal timing of starting antiplatelet therapy after intracerebral haemorrhage remains unclear. Future studies would benefit from earlier onset of antiplatelet on the basis of the results from RESTART because they suggest that the risk of intracerebral haemorrhage recurrence with antiplatelet therapy is potentially low. Finally, the primary outcome is in part driven by a low proportion of non-lobar haemorrhage in patients on antiplatelet therapy (3·9% vs 11·8% in those avoiding antiplatelet therapy). Again, a very high rate of screening failure and a small sample of intracerebral haemorrhage survivors might have a role in limiting the number of observed events because of the exclusion of patients at perceived higher risk. It is reassuring, however, that in the imaging subgroup analysis, all, but very modest harm, is excluded for patients with cerebral microbleeds.13Al-Shahi Salman A-S Minks DP Mitra D et al.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; (published online May 22.)http://dx.doi.org/10.1016/S1474-4422(19)30184-XSummary Full Text Full Text PDF PubMed Scopus (51) Google Scholar Larger trials with robust samples of different intracerebral haemorrhage locations in the brain and different causes are needed to answer these questions. The high frequency of intracerebral haemorrhage worldwide should allow for such studies to be done and, hopefully, replicated. This pilot study does, however, provide useful information for planning future trials and is extremely promising for the idea that restarting antiplatelet therapy in the subacute phase after intracerebral haemorrhage is safe over a 5-year period. This trial, along with previous studies, supports the requirement for even larger future studies given the low survival after intracerebral haemorrhage, small number of subsequent events, and the long-term burden of the disease. Clearly, clinical equipoise remains possible; despite the perception as a relative contraindication, antithrombotic therapy resumption is now reported in up to a third of patients following intracerebral haemorrhage.5Ottosen TP Grijota M Hansen ML et al.Use of antithrombotic therapy and longterm clinical outcome among patients surviving intracerebral haemorrhage.Stroke. 2016; 47: 1837-1843Crossref PubMed Scopus (46) Google Scholar, 6Flynn RW MacDonald TM Murray GD MacWalter RS Doney AS Prescribing antiplatelet medicine and subsequent events after intracerebral haemorrhage.Stroke. 2010; 41: 2606-2611Crossref PubMed Scopus (66) Google Scholar, 7Teo KC Lau GKK Mak RHY et al.Antiplatelet resumption after antiplatelet-related intracerebral haemorrhage: a retrospective hospital-based study.World Neurosurg. 2017; 106: 85-91Crossref PubMed Scopus (18) Google Scholar Moreover, subsequent ischaemic strokes or myocardial infarctions appear to be two to three times more common than recurrent intracerebral haemorrhage.6Flynn RW MacDonald TM Murray GD MacWalter RS Doney AS Prescribing antiplatelet medicine and subsequent events after intracerebral haemorrhage.Stroke. 2010; 41: 2606-2611Crossref PubMed Scopus (66) Google Scholar, 7Teo KC Lau GKK Mak RHY et al.Antiplatelet resumption after antiplatelet-related intracerebral haemorrhage: a retrospective hospital-based study.World Neurosurg. 2017; 106: 85-91Crossref PubMed Scopus (18) Google Scholar Finally, antiplatelet therapy is only one of multiple factors influencing recurrent intracerebral haemorrhage, but also age, hypertension, cerebral amyloid angiopathy, cerebral microbleeds, ethnicity, and apolipoprotein E alleles, thereby requiring ongoing study of potentially important interactions between these factors and antiplatelet therapy.8Chen CJ Ding D Buell TJ et al.Restarting antiplatelet therapy after spontaneous intracerebral haemorrhage: Functional outcomes.Neurology. 2018; 91: e26-e36Crossref PubMed Scopus (12) Google Scholar, 14Biffi A Halpin A Towfighi A et al.Aspirin and recurrent intracerebral haemorrhage in cerebral amyloid angiopathy.Neurology. 2010; 75: 693-698Crossref PubMed Scopus (248) Google Scholar, 15Biffi A Sonni A Anderson CD et al.Variants at APOE influence risk of deep and lobar intracerebral haemorrhage.Ann Neurol. 2010; 68: 934-943Crossref PubMed Scopus (211) Google Scholar We hope that RESTART has started a bigger, more inclusive, and more robust stroke community effort. WCZ is supported by grants from the National Institutes of Neurological Disorders and Stroke for other trials in intracerebral haemorrhage, and receives consulting fees from CR Bard, Inc, both outside of the area of work commented on here. AT has nothing to declare. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trialThese results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. Full-Text PDF Open Access