Fast track — ArticlesEfficacy 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
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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