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RESTART

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

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Year of Publication: 2019

Authors: RESTART Collaboration

Journal: The Lancet

Citation: Lancet 2019; 393: 2613-23

Link: http://dx.doi.org/10.1016/S0140-6736(19)30840-2

PDF: https://www.thelancet.com/action/showPdf...%2819%2930840-2

Clinical Question

In patients who survive an intracerebral hemorrhage (ICH) that occurred while they were taking antithrombotic therapy, what are the effects of restarting versus avoiding antiplatelet therapy on the risk of recurrent ICH and other major vascular events?

Study Overview

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.

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) — adjusted 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 (trial operational definition) were similar between groups (15% start vs 14% avoid, HR 1.02) — restarting antiplatelets did not demonstrably reduce the high rate of ischemic events.
In the ATT Collaboration-defined composite of major vascular events (non-fatal MI, non-fatal stroke, or vascular death), antiplatelet therapy was associated with a significant reduction (HR 0.65, 95% CI 0.44–0.95, P=0.025).
Predominantly lobar ICH population (62%) — the subset at highest risk for CAA-related recurrence — yet restarting appeared safe even in this concerning subgroup.
Underpowered — recruited only 537 of the planned 720 patients (75% of target); the primary outcome did not reach conventional statistical significance (P=0.060).
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.
At the time of publication, the authors identified no completed RCTs on this question and highlighted ongoing trials (RESTART-Fr [NCT02966119] and STATICH [NCT03186729]) that would be needed to confirm the findings; the paper also noted that no guidelines with strong recommendations about long-term antiplatelet therapy after ICH were available.

      

Design

Study Type: Prospective, randomised, open-label, blinded endpoint, parallel-group trial.

Randomization: 1

Blinding: Open-label for participants and clinicians, but outcome events were adjudicated by a committee blinded to treatment allocation.

Enrollment Period: May 22, 2013, to May 31, 2018.

Follow-up Duration: Median of 2.0 years.

Centers: 122

Countries: United Kingdom

Sample Size: 537

Analysis: Intention-to-treat analysis using Cox proportional hazards regression.

Inclusion Criteria

Adults (≥18 years) who survived at least 24 hours after a spontaneous intracerebral haemorrhage.
Patients were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease at the onset of the ICH.
Antithrombotic therapy was discontinued after the ICH.

Exclusion Criteria

ICH attributable to preceding head injury, haemorrhagic transformation of an ischaemic stroke, or intracranial haemorrhage without parenchymal component.
Patients still taking antithrombotic therapy at the time of providing consent (i.e., after ICH).
Pregnant, breastfeeding, or of childbearing age and not using contraception.
Patient (or their carer) unable to understand spoken or written English.

Baseline Characteristics

Characteristic	Control	Active
Age (median [IQR])	76 (69-82)	77 (69-82)
Male	187 (70%)	173 (65%)
White Ethnicity	242 (90%)	251 (94%)
Indication for prior antithrombotic (At least one occlusive vascular disease)	239 (89%)	236 (88%)
History of prior intracranial or extracranial haemorrhage	25 (9%)	22 (8%)
Location of ICH (Lobar supratentorial)	166 (62%)	166 (62%)
Time since ICH onset (median [IQR])	71 (29-144) days	80 (30-149) days
Context of enrolment (Hospital outpatient)	173 (64%)	181 (68%)

Arms

Field	Control	Start antiplatelet therapy
Intervention	Participants were allocated to a policy of avoiding antiplatelet therapy.	Participants were allocated to start antiplatelet therapy (one or more of aspirin, dipyridamole, or clopidogrel), with the specific drug and dose determined by the responsible consultant.
Duration	Median of 2.0 years.	Median of 2.0 years.

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Recurrent symptomatic spontaneous intracerebral haemorrhage.	Primary	9% (23/268)	4% (12/268)	0.51	0.060
All major haemorrhagic events	Secondary	25 events	18 events	adjusted HR 0.71 (95% CI 0.39-1.30)	0.27
All major occlusive vascular events (trial operational definition: ischaemic stroke, MI, mesenteric ischaemia, PAO, DVT, PE, or revascularisation procedures)	Secondary	38 events	39 events	adjusted HR 1.02 (95% CI 0.65-1.60)	0.92
All major haemorrhagic or occlusive vascular events (combined composite)	Secondary	61 events	54 events	adjusted HR 0.86 (95% CI 0.60-1.24)	0.43
Major occlusive vascular events (as defined in the trial protocol)	Secondary	52 events	45 events	adjusted HR 0.84 (95% CI 0.56-1.25)	0.39
Major vascular events (as defined by the Antithrombotic Trialists' Collaboration: non-fatal MI, non-fatal stroke [ischaemic, haemorrhagic, or uncertain cause], or vascular death)	Secondary	65 events	45 events	adjusted HR 0.65 (95% CI 0.44-0.95)	0.025
Major haemorrhagic events	Adverse	9% (25/268)	7% (18/268)	adjusted HR 0.71 (95% CI 0.39-1.30)	0.27
Serious adverse events (not outcomes or expected stroke complications)	Adverse	Total: 11

Criticisms

Underpowered — only 537 of planned 720 patients recruited (75% of target); the primary outcome did not reach conventional statistical significance (P=0.060).
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.
Limited data on some concomitant medications during follow-up (e.g., statin use); however, blood-pressure lowering drug use and BP control were documented and showed good balance between groups (median SBP 130 mm Hg).
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.

Funding

British Heart Foundation

Based on: RESTART (The Lancet, 2019)