Data compare dabigatran etexilate to dose-adjusted warfarin across RE-LY trial centers

Boehringer Ingelheim announced Aug. 29 that results from a pre-specified, retrospective, unblinded subanalysis of the RE-LY trial - the largest atrial fibrillation outcomes trial ever conducted - were published in The Lancet. The subanalysis evaluated the primary outcomes of RE-LY in relation to each center’s average time in therapeutic range (cTTR) (INR 2.0–3.0) for patients taking warfarin (Coumadin, Bristol-Myers Squibb).

Study centers were placed into 1 of 4 groups based on cTTR (<57.1%, 57.1% –  65.5%, 65.5% – 72.6%, and >72.6%). Primary outcomes were assessed across the 3 treatment arms (dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily, and warfarin) and demonstrated:

* There was no significant interaction between cTTR and stroke and systemic embolism for either dabigatran etexilate 110 mg twice daily or dabigatran etexilate 150 mg twice daily compared with warfarin (interaction P=.89 and .20).

* There was no significant interaction between cTTR and major bleeding with dabigatran etexilate 110 mg twice daily (interaction P=.50). However, there was a significant interaction when comparing dabigatran etexilate 150 mg twice daily to warfarin (interaction P=.03), with lower rates at centers where INR control was low, and similar rates at centers where control was higher.

* There was no significant interaction between cTTR and intracranial bleeding for either dabigatran etexilate 110 mg twice daily or dabigatran etexilate 150 mg twice daily compared with warfarin (interaction P=.71 and .89).

“Well-controlled warfarin is very effective for the prevention of stroke in patients with atrial fibrillation,” said Dr. Michael Ezekowitz, MB, ChB, DPhil, professor and vice president of clinical research for Lankenau Institute of Wynnewood, Pa. “However, we know in clinical practice there can be large variations in the level of control. The results of this subanalysis suggest the level of control achieved across RE-LY trial centers did not influence the effects of dabigatran etexilate compared with warfarin for stroke prevention.”

The individual time in therapeutic range (iTTR) during the trial was calculated using the Rosendaal method for 5,791 patients randomized to warfarin, excluding INRs from the first week and after discontinuation of study drug. For patients who temporarily discontinued warfarin, the time interval between temporary discontinuation and restart of medication was also not counted.

Each center’s time in therapeutic range was calculated based on the average iTTR in the group of patients randomized to warfarin. Among the 951 centers, cTTR could not be appropriately estimated at 45 centers because too few patients with serial INR values were available. Accordingly, 18,024 patients from 906 sites were included in the analysis.