Anticoagulation in ICH Survivors for Prevention and Recovery (ASPIRE)

Although it is the deadliest stroke subtype and often leads to severe disability, survivors of ICH show substantial recovery during the months and years after the event. Therefore, prevention of further brain injury and worsened disability is a vital consideration in this vulnerable population. A major knowledge gap in how to prevent further brain injury involves prevention of stroke from atrial fibrillation (AF) in this population. Among survivors of ICH, 15-20% of patients have AF. The effectiveness of oral anticoagulant (OAC) use has been firmly established for preventing ischemic stroke in general populations, but its role in ICH survivors has never been investigated in a prospective trial. Several retrospective, observational studies suggest that in ICH patients with AF in whom OAC was not restarted, ischemic events occurred in 10-15% of patients within 1 year of ICH, compared to rates of 5% when OAC was initiated. The high rate of ischemic stroke is consistent with common vascular co-morbidities in an ICH population. Approximately 70%-90% of patients with ICH have a CHA2DS2-VASc score ≥ 2, typically a class I indication for OAC use. Furthermore, 1-year mortality rates were also higher in ICH patients with AF who were not started on OAC (38% and 19%) compared to those who did receive anticoagulation (8% and 10%). The major limitation of these studies are the possibility of selection bias and confounding by indication. Patients with ICH were generally excluded from randomized clinical trials of OAC for stroke prevention. There are no clinical trials testing the effect of non-vitamin K antagonist OACs (NOACs), which have a lower risk of ICH than warfarin, in patients with ICH. As a result, the current AHA/ASA ICH guidelines state that the usefulness of the NOACs in patients with AF and past ICH to decrease the rate of recurrent stroke is uncertain (Class IIb, Level C). We propose a clinical trial to test the hypothesis that apixaban is superior to aspirin for improving functional outcome (assessed by shift towards improved scores on the modified Rankin Scale at 12 months) in patients with atrial fibrillation (AF) and recent non-lobar intracerebral hemorrhage (ICH). Because prospective safety data is quite limited for the lobar ICH population, we believe that this question should first be pursued in patients with deep ICH, where currently, our preliminary data suggests that a minority of ICH survivors start anticoagulation, while the majority of patients start either antiplatelet agents or anticoagulation. By selecting modified Rankin as the primary endpoint for this intervention, we propose a novel endpoint for a stroke prevention trial. Simply measuring recurrent ICH or ischemic stroke as binary outcomes fails to reflect that one stroke event may result in minor dysarthria while another results in complete hemiparesis—both are treated the same in traditional trials. Our use of mRS as the primary outcome will allow us to capture the true burden of stroke events on patients. We believe this trial design will answer an important, common question, and the results in either direction will be important for clinical practice.