RE-LY Substudy Finds Dabigatran Effective in Secondary Stroke Prevention

A substudy of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial demonstrates that dabigatran is as effective in AF patients for secondary stroke prevention as it is for overall stroke prevention. In their paper in the Lancet Neurology, Hans-Christoph Diener and the RE-LY study group report the results of the trial in the predefined subset of more than 3600 AF patients who had had a previous stroke or TIA.

The rate of stroke or systemic embolism was similar in all three groups (2.78% for warfarin, 2.32% for 110 mg dabigatran, 2.07% for 150 mg dabigatran). Compared to the warfarin group, the rate of major bleeding was lower in the low-dose dabigatran group (RR 0.66) and the same in the high-dose dabigatran group (RR 1.01). Intracranial bleeding was significantly lower in both dabigatran groups when compared to the warfarin group, prompting the authors to raise the possibility that dabigatran doesn’t cross the blood-brain barrier.

Compared to the warfarin group, net clinical benefit (defined as the composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major hemorrhage) was marginally lower in the low-dose dabigatran group (RR 0.81) but not the high-dose dabigatran group (RR 1.01). In an accompanying comment, Deirdre Lane and Gregory Lip write that, based on this analysis, “110 mg dabigatran might be the preferred treatment option in patients who have had a previous stroke or transient ischaemic attack.” They note, however, that the paper does not include head-to-head comparisons of the safety and efficacy of the 2 doses of dabigatran and recommend that physicians talk with their patients “regarding their preferences for treatment dose… to ascertain their threshold for stroke prevention over increased bleeding risk or vice versa.” (It should be noted that the FDA recently approved the 150 mg dose of dabigatran, but not the 110 mg dose.)

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Here is the Lancet press release:


A new anticoagulant drug dabigatran is as effective as warfarin in preventing stroke in patients with atrial fibrillation who have previously had a stroke or transient ischaemic attack, according to an Articlepublished Online First by The Lancet Neurology.

Patients with atrial fibrillation are at a higher risk of stroke or systemic embolism. Last year, the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial found that 110 mg dabigatran twice daily was as effective as warfarin in reducing the occurrence of stroke and that 150 mg dabigatran twice daily was better than warfarin in patients who had atrial fibrillation. The US Food and Drug Administration (FDA) has recently approved dabigatran 150 mg for the prevention of stroke in patients with atrial fibrillation.

3623 (20%) of 18113 patients in the main study had previously had a stroke or transient ischaemic attack, and this factor further increases the risk of recurrent stroke. This subgroup is alsomore susceptible to adverse events from anticoagulation, in particular cerebral haemorrhage. This is pertinent since one of warfarin’s negative side-effects is bleeding.

This new study byHans-Christoph Diener, Department of Neurology, University Hospital Essen, Essen, Germany, and colleagues, is an analysis of this subgroup. They wanted to see whether the results from this subgroup would be consistent with the main study population.

The team found that warfarin and both dosages of dabigatran were equally effective in preventing stroke or systemic embolism in patients with a previous transient ischaemic attack or stroke. Compared with warfarin, the relative risk stroke or systemic embolism with the 150 mg dose of dabigatran was 0·75 (95% CI 0·52–1·08) and for the 110 mg dose was 0·84 (95% CI 0·58–1·20). 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 110 mg dose of dabigatran was also associated with a significant reduction in the rate of vascular death (RR 0·63, 95% CI 0·43–0·92) and all-cause mortality (0·70, 0·53–0·94).

The authors say: “The exact mechanism for the lower rate of intracranial bleeding with dabigatran compared with warfarin, beyond a more stable anticoagulation, is not yet known. One possible explanation is that dabigatran does not cross the blood–brain barrier.”

They conclude: “In choosing the dose of dabigatran, physicians need to trade off the benefits of stroke prevention against the risk of haemorrhage. In general, strokes are more severe than major haemorrhages and have more significant long-term consequences. The dose of 150 mg dabigatran twice daily could be preferred to 110 mg twice daily because it significantly reduces the risk of ischaemic stroke without increasing the risk of haemorrhagic stroke.”

In an accompanying Comment, Dr Deirdre A Lane and Professor Gregory Y H Lip, at theUniversity of Birmingham Centre for Cardiovascular Sciences, UK, say this subgroup analysis is important because“there are very little data on the benefit of oral anticoagulation for secondary stroke prevention, and even less evidence on the safety of oral anticoagulation in this group”.

They conclude: “Because of the necessary trade-off between stroke prevention and bleeding with both doses of dabigatran, consultation with patients regarding their preferences for treatment dose will be even more important to ascertain their threshold for stroke prevention over increased bleeding risk or vice versa.”

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