PDF: RESTART
(2019)Objective
Assess the safety of starting antiplatelet therapy in survivors of spontaneous intracerebral hemorrhage (ICH) who were previously on antithrombotic therapy.
Study Summary
• In patients who had an ICH while on antithrombotic therapy, restarting antiplatelet therapy did not increase the risk of recurrent symptomatic ICH and may have reduced it. Although not statistically significant, the findings suggest that the risk of ICH recurrence is likely too small to outweigh the benefits of secondary prevention with antiplatelet therapy.
Intervention
Prospective, open-label, blinded-endpoint, randomized controlled trial in 122 UK hospitals. Adults (≥18 years) with ICH while on antithrombotic therapy were randomized (1:1) to either resume or avoid antiplatelet therapy after surviving at least 24 hours post-ICH. Median time to randomization was 76 days. Primary outcome: recurrent symptomatic ICH. Median follow-up: 2.0 years.
Study Design
Arms: Array
Outcome
• Recurrent symptomatic ICH: 4% (restart) vs. 9% (avoid); adjusted HR 0.51 (95% CI 0.25–1.03); p=0.060
• Major hemorrhagic events: 7% vs. 9%; HR 0.71 (95% CI 0.39–1.30); p=0.27
• Major occlusive vascular events: 15% vs. 14%; HR 1.02 (95% CI 0.65–1.60); p=0.92
• Composite major vascular events (per ATT definition): HR 0.65 (95% CI 0.44–0.95); p=0.025
• No evidence of harm from restarting antiplatelet therapy
• Results consistent across subgroups and sensitivity analyses
• Major hemorrhagic events: 7% vs. 9%; HR 0.71 (95% CI 0.39–1.30); p=0.27
• Major occlusive vascular events: 15% vs. 14%; HR 1.02 (95% CI 0.65–1.60); p=0.92
• Composite major vascular events (per ATT definition): HR 0.65 (95% CI 0.44–0.95); p=0.025
• No evidence of harm from restarting antiplatelet therapy
• Results consistent across subgroups and sensitivity analyses
Bottom Line
In patients who had a previous intracerebral hemorrhage while on antithrombotic therapy, restarting antiplatelet therapy was not associated with a significant increase in the risk of recurrent ICH or major hemorrhagic events compared to avoiding antiplatelet therapy. These findings suggest that the risk of recurrent ICH with antiplatelet therapy is likely small enough that it does not outweigh the known benefits of antiplatelets for preventing occlusive vascular disease.
Major Points
- First and largest RCT to address whether antiplatelets are safe to restart after spontaneous ICH — 537 patients across 122 UK hospitals with median 2.0-year follow-up.
- Recurrent symptomatic ICH occurred in 4% (start antiplatelet) vs 9% (avoid antiplatelet) — HR 0.51 (95% CI 0.25–1.03, P=0.060), not statistically significant but numerically favoring restart.
- The HR of 0.51 suggesting antiplatelets may REDUCE ICH recurrence was unexpected and paradigm-challenging — previously assumed that antiplatelets would increase ICH risk.
- Major occlusive vascular events were similar between groups (15% start vs 14% avoid, HR 1.02) — restarting antiplatelets did not demonstrably reduce the high rate of ischemic events.
- Predominantly lobar ICH population (62%) — the subset at highest risk for CAA-related recurrence — yet restarting appeared safe even in this concerning subgroup.
- Underpowered (537 vs planned 720 patients) — the borderline P=0.060 would likely have reached significance with full enrollment, highlighting the difficulty of post-ICH trial recruitment.
- Only 1 in 12 eligible patients was recruited — severe selection bias limits generalizability; enrolled patients may have had greater clinical equipoise (lower perceived risk).
- The antiplatelet regimen was physician's choice (mostly aspirin monotherapy) — results may not apply to dual antiplatelet therapy or other agents.
- Together with SoSTART (2021, anticoagulant restart) and observational meta-analyses, RESTART established the emerging paradigm that antithrombotic restart after ICH may be safer than previously feared.
- Influenced AHA/ASA and ESO guidelines — restarting antiplatelets after ICH is now considered reasonable in patients with strong occlusive vascular indications (Class IIb, Level B).
Study Design
- Study Type
- Prospective, randomised, open-label, blinded endpoint, parallel-group trial.
- Randomization
- Yes
- Blinding
- Open-label for participants and clinicians, but outcome events were adjudicated by a committee blinded to treatment allocation.
- Sample Size
- 537
- Follow-up
- Median of 2.0 years.
- Centers
- 122
- Countries
- United Kingdom
Primary Outcome
Definition: Recurrent symptomatic spontaneous intracerebral haemorrhage.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 9% (23/268) | 4% (12/268) | 0.51 (0.25-1.03) | 0.060 |
Limitations & Criticisms
- Underpowered — only 537 of planned 720 patients recruited; the borderline P=0.060 suggests the trial may have reached significance with full enrollment.
- Only 1 in 12 eligible patients was recruited — severe selection bias as clinicians only randomized patients with genuine equipoise, likely excluding those at highest or lowest perceived risk.
- Open-label design may bias clinical decision-making — physicians knowing allocation could affect subsequent antithrombotic management, BP targets, and threshold for investigating symptoms.
- Antiplatelet regimens were physician's choice (mostly aspirin monotherapy) — cannot determine whether specific agents or dual antiplatelet therapy carry different risk profiles.
- Predominantly white UK population (90–94%) — results may not generalize to other ethnicities, particularly Asian populations where ICH prevalence and CAA patterns differ.
- 62% lobar ICH but no MRI-based CAA diagnosis (Boston criteria) — unable to distinguish true CAA from other lobar ICH etiologies, which may have different recurrence risks.
- The unexpected finding that antiplatelets may REDUCE ICH recurrence (HR 0.51) lacks a clear biological mechanism and could be a statistical artifact of the underpowered trial.
- No information on concomitant medications, BP control quality, or statin use during follow-up — these factors could confound ICH recurrence risk.
- Median time from ICH to enrollment was ~76 days — results may not apply to very early antiplatelet restart (<2 weeks) when hematoma instability risk is highest.
Citation
Lancet 2019; 393: 2613-23