Pamela Cheng, DO
What to do after having a spontaneous intracerebral hemorrhage while on blood thinners? Prior to RESTART, there were no published randomized controlled trials testing the safety or benefit of resuming long-term antithrombotic therapy in survivors of intracerebral hemorrhage. Previous secondary stroke prevention trials showed a favorable benefit of antithrombotic therapy, but these trials excluded patients with history of intracerebral hemorrhage. RESTART was thus initiated with the aim of establishing whether starting versus avoiding antiplatelet therapy had any effect on recurrent symptomatic intracerebral hemorrhage and whether this risk of bleeding would exceed the benefit of reduction of vascular events.
RESTART was an investigator-led, pragmatic, multi-center, prospective, randomized, open-label, blinded endpoint, parallel-group trial in 122 hospitals in the United Kingdom. Inclusion criteria were adults older than 18 years of age who had survived at least 24 hours of spontaneous intracerebral hemorrhage while on either anticoagulant or antiplatelet therapy. Exclusion criteria included hemorrhage related to trauma, hemorrhagic transformation of an ischemic stroke, intracranial hemorrhage without intracerebral hemorrhage, or if they were pregnant, breastfeeding, or of childbearing age. Intervention arm was restricted to use of either oral aspirin, dipyridamole, or clopidogrel, begun within 24 hours of randomization.
The primary outcome was fatal or non-fatal radiographically or pathologically proven recurrent symptomatic intracerebral hemorrhage. Secondary outcomes were a composite of all major hemorrhagic events and a composite of all major occlusive vascular events. Between May 22, 2013, and May 31, 2018, 562 patients were enrolled in the study. 268 participants were randomly assigned to start antiplatelet therapy and 269 to avoid antiplatelet therapy. 62% of patients had lobar intracerebral hemorrhage; 88% had one or more previous occlusive vascular disease. Adherence to therapy was good: 99% at discharge, 89% after 2 years, and 82% after 4 years. Few patients (<10%) were on anticoagulant therapy at follow up.
For the primary outcome, 4% of patients who restarted antiplatelet therapy had recurrent intracerebral hemorrhage versus 9% of those who did not restart (HR 0.51, [95% CI 0.25-1.03]; p 0.06). While this finding may be due simply to chance, it suggests that restarting antiplatelet therapy is associated with a modest, if any, increase in the risk of recurrent intracerebral hemorrhage. Furthermore, 30-day mortality was not different between the two groups. While there was no difference in the secondary outcomes of major occlusive events described in this trial, there was a significant reduction of major vascular events as defined by the Antithrombotic Trialists’ Collaboration, (HR 0.65, [95% CI 0.45-0.05], p = 0.027). In conclusion, despite the trial falling short of its intended 720 participants, the authors concluded that the proven benefit of antiplatelet therapy in secondary stroke prevention likely outweighs the risk of restarting antiplatelet therapy following an intracerebral hemorrhage.