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The Lancet

Volume 376, Issue 9745, 18–24 September 2010, Pages 975-983
The Lancet

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Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial

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Summary

Background

Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0–3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population.

Methods

In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0–3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600.

Findings

The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1–65·5%, 65·5–72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR.

Interpretation

The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.

Funding

Boehringer Ingelheim.

Introduction

Vitamin K antagonists, such as warfarin, can reduce risk of stroke in patients with atrial fibrillation, but the benefits are seen only over a narrow therapeutic range. Treatment with vitamin K antagonists needs regular laboratory-guided adjustments of the dose because response to treatment is affected by interactions with food and drugs.1, 2, 3 The lowest risk of stroke and bleeding is reached by maximising the time in the optimum therapeutic range (TTR), with an international normalised ratio (INR) of 2·0–3·0.4, 5, 6, 7, 8, 9 However, there are large variations in TTR between indivi-duals, sites, and countries, all of which affect patient outcomes.10, 11, 12

Dabigatran etexilate is an oral direct thrombin inhibitor that provides stable anticoagulation at a fixed dose without any need for laboratory control. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial,13 in patients who had atrial fibrillation and at least one additional risk factor for stroke 150 mg dabigatran twice daily reduced both stroke and intracranial and life-threatening bleeding without any significant change in overall major bleeding compared with warfarin, whereas 110 mg dabigatran twice daily was non-inferior at reducing risk of stroke, but reduced intracranial, life-threatening, and major bleeding.14 The mean TTR of 64% in the warfarin group is similar to that in other prospective randomised trials10, 12 and a meta-analysis.15 Although this value might seem low, observational data from usual clinical practice often show even lower means.11, 16 Therefore, the overall standards of anticoagulation in the warfarin group of RE-LY correspond well to contemporary standards for such treatment. As in previous multicentre multinational trials of anticoagulation, there were wide variations in INR control between countries and sites, which have led to questions of the relevance of the overall findings for countries and sites with better mean INR control. We therefore did a prespecified assessment of the primary and secondary outcomes of the RE-LY trial in relation to the quality of INR control. In the absence of any indicator of anticoagulation status in the dabigatran groups, the average TTR each centre achieved in its patients treated with warfarin was used as an approximation of quality of INR control for all its patients (centre's mean TTR [cTTR]) receiving warfarin.10 The objective was therefore to assess the effects of centre-based INR control on these outcomes.13

Section snippets

Patients

The detailed design and primary results of RE-LY have been published.14 18 113 patients were recruited from 951 clinical centres in 44 countries. Inclusion criteria were documented atrial fibrillation and at least one of the following: previous stroke or transient ischaemic attack; congestive heart failure or reduced left ventricular ejection fraction (<40%); at least 75 years of age; or at least 65 years of age with diabetes mellitus, hypertension, or coronary artery disease. Exclusion

Results

18 024 patients from 906 sites were included in the investigations of relations to cTTR by applying cTTR as a proxy in all patients in each centre. The cTTR could not be estimated in 45 of the 951 participating sites because serial INR values were not available for any patients on warfarin maintenance treatment.

On the basis of observations in 5791 patients who were randomly assigned to receive warfarin, the quartiles of iTTR were: less than 53·6%, 53·6–67·2%, 67·2–78·4%, and more than 78·4%. In

Discussion

In this analysis of the RE-LY trial we have shown fewer ischaemic strokes but not fewer occurrences of intracranial bleeding with increasing cTTR in the warfarin group. Accordingly, there were no significant interactions between cTTR control and total stroke with either dose of dabigatran compared with warfarin. Thus, these findings support the superiority of 150 mg dabigatran twice daily and the non-inferiority of 110 mg dabigatran twice daily versus warfarin for protection against stroke in

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