Non-vitamin K antagonist oral anticoagulants compared with warfarin at different levels of INR control in atrial fibrillation: A meta-analysis of randomized trials

BackgroundThe efficacy and safety of warfarin for stroke prevention in atrial fibrillation (AF) depend on the time in the therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. This meta-analysis focused the relative efficacy and safety of non-VKA oral anticoagulants (NOAC) compared with warfarin at different thresholds of centre's TTR (cTTR).MethodsWe searched PubMed, Embase, CENTRAL and websites of regulatory agencies, limiting searches to randomized phase 3 trials. Primary outcomes were stroke or systemic embolism (SSE) and major or non-major clinically relevant (NMCR) bleeding. We used a random-effects model to pool effect on outcomes according to different thresholds of cTTR.ResultsFour TTR sub-studies with a total of 71,222 patients were included. The benefit of NOAC in reducing SSE compared with warfarin was significantly higher in patients at cTTR < 60% (HR 0.79, 95% CI 0.68-0.90) and at 60% to < 70% (0.82, 0.71-0.95) but not at ≥ 70% (1.00, 0.82-1.23) with a significant interaction for cTTR < 70% or ≥ 70% (p = 0.042). The risk of major or NMCR bleeding was significantly lower with NOAC as compared with warfarin in patients at all sub-groups (0.67, 0.54-0.83 for patients at cTTR < 60% and 0.75, 0.63-0.89 at 60% to < 70%) except for cTTR ≥ 70% (HR 0.84, 0.64-1.11), but the interaction for cTTR < 70% or ≥ 70% was not statistically significant (p = 0.271).ConclusionsThe superiority in efficacy of NOAC compared with warfarin for stroke prevention is lost above a cTTR threshold of approximately 70%, but the relative safety appears to be less modified by the centre-based quality of INR control.