Abstract 13016: Anticoagulation Control in Warfarin Treated Patients Undergoing Cardioversion for Atrial Fibrillation: A Pre-specified Ancillary Analysis From the ENSURE-AF Trial

Background: In the ENSURE-AF study (NCT 02072434), the oral factor Xa inhibitor edoxaban was compared to warfarin in 2199 patients undergoing electrical cardioversion of nonvalvular AF. Ideal patient management requires optimization warfarin within a therapeutic range of INR 2.0-3.0. We determined aspects of anticoagulation control in the warfarin arm of this trial. Methods: In this multicenter, PROBE, parallel group Phase 3b clinical trial, we performed a pre-specified analysis of 1104 patients randomized to warfarin. We determined the Time to achieve Therapeutic Range (TtTR), Time in Therapeutic Range (TiTR), their clinical determinants and impact on outcomes. The primary safety endpoint was the composite of major + clinically relevant non-major (CRNM) bleeding from time of first administration of study drug to end of treatment +3 days. Patients were followed for 28 days on study drug after cardioversion + another 30 days to assess safety. Results: Among 1104 patients randomized to enoxaparin/warfarin, 27% were naïve to oral anticoagulants at randomization. Mean age was 64.2±11 years and mean CHA 2 DS 2 -VASc score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching INR 2.0-3.0 on warfarin was 70.8%. In 695 patients with INR <2 prior to first dose and who reached therapeutic range of ≥2, 436 had a SAMe-TT 2 R 2 score ≤2 and 259 a score of >2. Mean TtTR was 7.7 and 7.6 days, respectively. In 974 patients with INR in range of 2-3 post first dose, TiTR was 71.1% vs 70.3% for patients with SAMe-TT 2 R 2 score ≤2 and >2, respectively. On multivariate regression, an independent predictor of extended TtTR was CrCl (P=0.02). Independent predictors of TiTR were prior VKA experience (P<0.01) and low HAS-BLED score (P=0.02). TtTR was marginally related to stroke/SE/MI/CV mortality (P=0.06; OR [odds ratio]=0.23, CI 0.02-1.17) but not to any bleeding (P=0.53; OR=0.72, CI 0.28-1.80). TiTR was related to any bleeding (P=0.02; OR=0.39, CI 0.16-0.88), but not stroke/SE/MI/CV mortality (P=0.31; OR=0.42, CI 0.07-1.98). Conclusion: In this well-managed cohort of warfarin users in a clinical trial setting with a high TiTR (>70%), the SAMe-TT 2 R 2 score did not discriminate between mean TtTR and TiTR. Even in this short term study, TiTR was related to bleeding events.