Elsevier

The Lancet Neurology

Volume 20, Issue 10, October 2021, Pages 842-853
The Lancet Neurology

Articles
Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial

https://doi.org/10.1016/S1474-4422(21)00264-7Get rights and content

Summary

Background

Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation.

Methods

SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete.

Findings

Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study.

Interpretation

Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials.

Funding

British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.

Introduction

Compared with the general population, survivors of spontaneous (non-traumatic) intracerebral haemorrhage are at higher risk of ischaemic stroke and myocardial infarction, and their risk of all major vascular events is higher still (about 8% per year overall).1, 2, 3 Atrial fibrillation is present in 14–42% of patients with any type of intracranial haemorrhage,4, 5, 6, 7, 8, 9 and more than doubles the risk of major vascular events.3

The oral vitamin K antagonist warfarin provides about a 64% relative reduction in the risk of stroke in atrial fibrillation compared with control or placebo, despite a small increase in the risk of major bleeding.10 Treatment with a direct (ie, non-vitamin K antagonist) oral anticoagulant (DOAC) reduces the risk of stroke, intracranial haemorrhage, and death compared with warfarin for patients with atrial fibrillation.11 However, the randomised controlled trials that confirmed these effects did not include survivors of intracranial haemorrhage who had atrial fibrillation. These patients are at higher risk of intracranial haemorrhage than the general population3, 12 and intracranial haemorrhages are more likely to be fatal when associated with oral anticoagulant use,13 leaving uncertainty about the effects of oral anticoagulation for these patients.

Research in context

Evidence before this study

Randomised controlled trials have shown that oral anticoagulation reduces the high risk of systemic embolism by almost two-thirds for patients with atrial fibrillation despite doubling their low risk of major bleeding. However, these trials excluded patients with intracranial haemorrhage. We searched the Cochrane Central Register of Controlled Trials, MEDLINE Ovid (from 1946), Embase Ovid (from 1974), online registers of clinical trials, and bibliographies of relevant publications on June 11, 2021, with no language restrictions (for search terms see appendix pp 3–5). We found one completed randomised feasibility study involving 30 patients (NASPAF-ICH, NCT02998905) and one completed randomised phase 2 trial involving 101 patients (APACHE-AF, NCT02565693) that compared the effects of oral anticoagulation versus antiplatelet therapy for participants with atrial fibrillation after intracerebral haemorrhage; these trials were inconclusive about clinical outcomes. Meta-analyses of observational studies of patients with atrial fibrillation and intracranial haemorrhage mostly found associations between oral anticoagulation and reduced risks of major ischaemic vascular events, but no significant change in the risk of recurrent major haemorrhagic vascular events.

Added value of this study

The Start or STop Anticoagulants Randomised Trial (SoSTART) is, to our knowledge, the largest randomised controlled trial to date to compare the effects of starting versus avoiding oral anticoagulation for atrial fibrillation after intracranial haemorrhage. Participants allocated to start oral anticoagulation had more intracranial haemorrhage recurrences, but our prespecified margin for declaring non-inferiority was not met (p=0·152). However, non-significant results for our three composite secondary outcomes suggest that starting oral anticoagulation might be superior to avoiding oral anticoagulation for preventing any symptomatic major vascular event.

Implications of all the available evidence

Further randomised trials are justified to investigate the non-inferiority of the effects of oral anticoagulation on major bleeding for patients with atrial fibrillation after intracranial haemorrhage or whether oral anticoagulation might be superior for preventing symptomatic major vascular events (especially those that are fatal or disabling). Clinicians should embed ongoing randomised controlled trials that are addressing this problem in their clinical practice so that these trials and the COCROACH planned individual participant data meta-analysis are adequately powered to provide definitive evidence.

The NOACs for Stroke Prevention in Patients With Atrial Fibrillation and Previous ICH (NASPAF-ICH) randomised feasibility study in 30 patients and the Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With Atrial Fibrillation (APACHE-AF) phase 2 randomised trial in 101 patients have compared the effects of starting oral anticoagulation versus antiplatelet therapy or no antithrombotic therapy for participants with atrial fibrillation after intracerebral haemorrhage, but were inconclusive about safety and efficacy.14, 15, 16 Cohort studies of patients with spontaneous intracranial haemorrhage and atrial fibrillation comparing oral anticoagulation with either antiplatelet agents or no antithrombotic therapy have mostly found associations between oral anticoagulation and lower risks of major ischaemic vascular events, but no significant change in the risk of recurrent major haemorrhagic vascular events, although these studies are susceptible to selection bias.17, 18 Consequently, recent guidelines throughout the world have been unable to make strong recommendations about oral anticoagulation for atrial fibrillation after intracranial haemorrhage, although they tend to recommend a DOAC over a vitamin K antagonist if used, and avoidance of antiplatelet agents.19, 20, 21, 22, 23, 24

We initiated the Start or STop Anticoagulants Randomised Trial (SoSTART) for survivors of spontaneous intracranial haemorrhage who have atrial fibrillation to establish the feasibility of performing a definitive randomised trial in an acceptable timescale and to estimate whether the risk of recurrent symptomatic spontaneous intracranial haemorrhage after oral anticoagulation is sufficiently low (non-inferior) to justify a definitive randomised trial.

Section snippets

Study design

SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot-phase, non-inferiority trial done at 67 hospitals in the UK. The Scotland A Research Ethics Committee approved the trial protocol (version 3.0, Sept 11, 2017). The trial co-sponsors were the University of Edinburgh and NHS Lothian Health Board. The patient reference group for the Research to Understand Stroke due to Haemorrhage (RUSH) programme co-designed the study materials and reviewed progress. The

Results

In the internal feasibility phase, between March 29, 2018, and Dec 27, 2018, 908 patients were screened (appendix p 6), 204 were eligible, and 109 of them were invited to participate. 46 declined, 63 provided consent, and 60 were enrolled. By the time the target recruitment of the feasibility phase was reached, 20 sites had been active for 6 months or longer and their median recruitment rate was 0·25 participants (IQR 0·12–0·47) per site per month; we used this recruitment rate, the trial's

Discussion

In this randomised trial of survivors of intracranial haemorrhage who had atrial fibrillation, we established that it would be feasible for a 6-year definitive main phase trial at 60 sites to recruit 800 participants and follow them for 1 year. We did not find evidence that starting oral anticoagulation was non-inferior to avoiding oral anticoagulation with respect to intracranial haemorrhage. In analyses of three composite secondary outcomes, we found weak evidence that starting oral

Data sharing

A deidentified version of the dataset used for analysis with individual participant data (excluding participants who opted out of data sharing) and a data dictionary, the study protocol, the statistical analysis plan, and the informed consent form will be available online for other researchers to apply for use 1 year after publication. Written proposals will be assessed by members of the SoSTART trial steering committee and a decision made about the appropriateness of the use of data. A data

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