Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Abstract

Summary Background Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation These 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. Funding British Heart Foundation.

Long-term prognosis after intracerebral haemorrhage

“…Recently, results of RESTART showed that in patients with ICH while on antithrombotic treatment, the risk of recurrent ICH with antiplatelet therapy, on average assigned 76 days after the ICH, is probably small and not exceeding the established benefits of antiplatelets for secondary prevention. 40 In this study, there was no evidence of heterogeneity of the effect of antiplatelet therapy on the risk of recurrent ICH among pre-specified subgroups, including lobar versus non-lobar location of the ICH. A large observational study of the risk of death, stroke or functional outcome in patients with ICH while on anticoagulant treatment for atrial fibrillation suggested a benefit of restarting oral anticoagulants both in patients with non-lobar and in patients with lobar ICH.…”

STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage: Protocol for a randomised controlled trial

“…Recently, the RESTART randomised controlled trial of 537 patients investigated effects of antiplatelet treatment after ICH. 39 During a median follow-up period of two years, RESTART did not show an increase in the rate of recurrent ICH from antiplatelet drugs, but on the contrary a non-significant reduction in the risk of recurrent ICH (adjusted hazard ratio 0.51, 95% CI 0.25–1.03; p = 0.060). The RESTART results are reassuring for antiplatelet treatment but need to be confirmed by other randomised trials.…”

Longer term stroke risk in intracerebral haemorrhage survivors

“…An individual patient data meta-analysis 2 of 1012 patients who resumed treatment with oral anticoagulant therapy following spontaneous ICH found that resumption was associated with reduced mortality and all-cause stroke incidence, as well as more favourable outcomes, at 1 year. RESTART 3 were randomised to either restart or discontinue antiplatelet medications following their ICH. RESTART did not find significant changes in either ICH or major vaso-occlusive events with antiplatelet treatment, even in subgroup analyses where these events were considered by index ICH location.…”