Elsevier

The Lancet Neurology

Volume 9, Issue 12, December 2010, Pages 1157-1163
The Lancet Neurology

Fast track — Articles
Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial

https://doi.org/10.1016/S1474-4422(10)70274-XGet rights and content

Summary

Background

In the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran reduced occurrence of both stroke and haemorrhage compared with warfarin in patients who had atrial fibrillation and were at increased risk of stroke. We aimed to assess the effects of dabigatran compared with warfarin in the subgroup of patients with previous stroke or transient ischaemic attack.

Methods

In the RE-LY trial, 18 113 patients from 967 centres in 44 countries were randomly assigned to 110 mg or 150 mg dabigatran twice daily or to warfarin dose adjusted to international normalised ratio 2·0 to 3·0. Median follow-up was 2·0 years (IQR 1·14–2·86), and the primary outcome was stroke or systemic embolism. The primary safety outcome was major haemorrhage. Patients and investigators were aware of whether patients received warfarin or dabigatran, but not of dabigatran dose, and event adjudicators were masked to treatment. In a predefined analysis, we investigated the outcomes of the RE-LY trial in subgroups of patients with or without previous stroke or transient ischaemic attack. RE-LY is registered with ClinicalTrials.gov, NCT00262600.

Findings

Within the subgroup of patients with previous stroke or transient ischaemic attack, 1195 patients were from the 110 mg dabigatran group, 1233 from the 150 mg dabigatran group, and 1195 from the warfarin group. Stroke or systemic embolism occurred in 65 patients (2·78% per year) on warfarin compared with 55 (2·32% per year) on 110 mg dabigatran (relative risk 0·84, 95% CI 0·58–1·20) and 51 (2·07% per year) on 150 mg dabigatran (0·75, 0·52–1·08). The rate of major bleeding was significantly lower in patients on 110 mg dabigatran (RR 0·66, 95% CI 0·48–0·90) and similar in those on 150 mg dabigatran (RR 1·01; 95% CI 0·77–1·34) compared with those on warfarin. The effects of both doses of dabigatran compared with warfarin were not significantly different between patients with previous stroke or transient ischaemic attack and those without for any of the outcomes from RE-LY apart from vascular death (110 mg group compared with warfarin group, interaction p=0·038).

Interpretation

The effects of 110 mg dabigatran and 150 mg dabigatran twice daily in patients with previous stroke or transient ischaemic attack are consistent with those of other patients in RE-LY, for whom, compared with warfarin, 150 mg dabigatran reduced stroke or systemic embolism and 110 mg dabigatran was non-inferior.

Funding

Boehringer Ingelheim.

Introduction

Patients with atrial fibrillation are at a high risk of stroke, particularly if they have already had a transient ischaemic attack or an ischaemic stroke.1, 2 Oral anticoagulation with adjusted-dose warfarin is effective for the prevention of stroke in these patients.3 Dabigatran is an oral reversible direct thrombin inhibitor that can be given in fixed daily doses independent of age or bodyweight;4 it has a bioavailability of 6·5%, and about 80% of the dose is excreted by the kidney.5 By contrast with oral vitamin K antagonists, dabigatran does not require routine coagulation monitoring.5

Twice daily treatment with 110 mg or 150 mg dabigatran has been compared with adjusted-dose warfarin in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, a non-inferiority study in 18 113 patients who had atrial fibrillation and were at increased risk of stroke.6 The number of patients who had a stroke or systemic embolism was similar in the 110 mg dabigatran twice daily group but was lower in the 150 mg dabigatran twice daily group compared with the warfarin group. Compared with warfarin, 110 mg dabigatran twice daily was associated with lower rates of major haemorrhage and 150 mg dabigatran twice daily with similar rates. Intracranial haemorrhage was significantly reduced with both doses of dabigatran compared with warfarin.

In this prespecified subgroup analysis of RE-LY, we aimed to investigate whether the effects of dabigatran on secondary prevention of stroke in the subgroup of patients with previous transient ischaemic attack or ischaemic stroke—who are at high risk of recurrent stroke2 and are more susceptible to adverse events from anticoagulation, in particular cerebral haemorrhage3, 7—are consistent with the results in the entire study population.

Section snippets

Patients

The RE-LY trial, a PROBE (prospective randomised, open-label, blinded endpoint) study, was designed to establish the non-inferiority of two masked doses of dabigatran compared with adjusted warfarin in patients with atrial fibrillation who had an increased risk of stroke.8 18 113 patients from 967 centres in 44 countries were enrolled between December, 2005, and December, 2007. The trial had a median follow-up of 2·0 years (IQR 1·14–2·86).

Patients were eligible if they had atrial fibrillation

Results

In the RE-LY trial, 18 113 patients were enrolled, of whom 3623 (20·0%) had previously had a transient ischaemic attack or stroke (table 1): 2273 (12·5%) previously had a stroke, 1663 (9·2%) a transient ischaemic attack, and 313 (1·7%) both. One patient in the 110 mg dabigatran group did not provide information on history of stroke or transient ischaemic attack and so was excluded from the analyses. A CHADS2 score (a measure of the risk of stroke in which congestive heart failure, hypertension,

Discussion

In this subanalysis of the RE-LY study, we report a higher annual rate of stroke in patients with atrial fibrillation if they had already had a stroke or a transient ischaemic attack (panel). The stroke rates in the warfarin group of RE-LY (1·58% per year)6 were lower than reported in the European Atrial Fibrillation Trial (4% per year).3 In the Studio Italiano Fibrillazione Atrial study,10 which compared warfarin (INR 2·0–3·5) with indobufen in 916 patients with atrial fibrillation and recent

References (13)

  • Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials

    Arch Intern Med

    (1994)
  • PA Wolf et al.

    Atrial fibrillation as an independent risk factor for stroke: The Framingham Study

    Stroke

    (1991)
  • Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke

    Lancet

    (1993)
  • AG Turpie

    New oral anticoagulants in atrial fibrillation

    Eur Heart J

    (2008)
  • J Stangier et al.

    The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects

    Br J Clin Pharmacol

    (2007)
  • SJ Connolly et al.

    Dabigatran versus warfarin in patients with atrial fibrillation

    N Engl J Med

    (2009)
There are more references available in the full text version of this article.

Cited by (413)

  • Comparison of primary and secondary stroke prevention in patients with nonvalvular atrial fibrillation: Results from the RAFFINE registry

    2022, Journal of Stroke and Cerebrovascular Diseases
    Citation Excerpt :

    Direct oral anticoagulant (DOAC) therapy does not require regular monitoring of coagulation and has equivalent efficacy for stroke prevention and a better safety profile, such as a lower rate of intracranial hemorrhage, compared with warfarin in patients with nonvalvular (NV) AF in randomized, controlled trials (RCTs).9-12 Subgroup analyses of these trials have shown that the effects of DOACs were consistent in patients with and without prior stroke or transient ischemic attack (TIA).13-16 DOACs have been available from 2010 in clinical practice in Japan and may have impacted anticoagulation therapy for stroke prevention in patients with NVAF.

View all citing articles on Scopus

Members listed in webappendix

View full text