SAFETY AND EFFICACY OF NON-VITAMIN K ORAL ANTICOAGULANTS (NOAC) VERSUS WARFARIN ACROSS VARIOUS TIME IN THERAPEUTIC RANGE (TTR) STRATA AMONG PATIENTS WITH ATRIAL FIBRILLATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Among atrial fibrillation (AF) patients, non-vitamin K oral anticoagulants (NOAC) were shown to be at least as efficacious and safe as warfarin in terms of stroke prevention and bleeding. We evaluated the risks and benefits of NOAC agents relative to warfarin among AF patients with various degrees of international normalized ratio (INR) control, as reflected by their times in therapeutic range (TTR). Using MEDLINE, EMBASE, www.clinicatrials.gov, and web-based searches of publicly accessible documents from the FDA and the European Medicines Agency, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) which compared the therapeutic effect of NOAC vs. warfarin in adult AF patients according to their centre-based TTR. For trials which studied various NOAC doses, we included results involving the higher-dose arms. Using random effects models, we report pooled hazard ratios (HR) of stroke or systemic embolism (SSE) and major bleeding with 95% confidence intervals (CI). Effect modification between the lowest and highest TTR subgroups was assessed with a test for interaction. From 1,904 citations, six studies from four RCTs (71,681 patients) were included. Patients were divided into tertiles according to their centre-based TTR (low, intermediate, high) (Figure). NOAC-treated patients demonstrated significant reductions in the risk of SSE compared to patients treated with warfarin (HR 0.81; 95% CI: 0.71-0.91, p=0.0005). Across all TTR strata, NOAC-treated patients had lower risk of SSE vs. those treated with warfarin (low TTR: HR 0.73; 95% CI: 0.61-0.88, p=0.0007; intermediate TTR: HR 0.76; 95% CI: 0.59-0.98, p=0.03; high TTR: HR 0.78; 95% CI: 0.63-0.96, p=0.02). No statistically significant interaction was noted across various TTR strata. Overall, there was a trend toward lower risk of major bleeding among NOAC-treated patients relative to warfarin-treated patients (HR 0.86; 95% CI: 0.72-1.02, p=0.08); this was most pronounced in the low TTR group (HR 0.68, 95% CI 0.55-0.84, p=0.0003). The risk of major bleeding between NOAC- and warfarin-treated patients were comparable in the high TTR group (HR 1.0, 95% CI 0.80-1.26, p=0.97). A statistically significant interaction was observed between the lowest and highest TTR groups (Pinteraction=0.01), suggesting that the impact of NOAC (vs. warfarin) on major bleeding differed according to INR control. (Figure) NOAC agents were consistently more efficacious than warfarin in preventing stroke and systemic embolism, regardless of the TTR. The greatest relative and absolute safety benefit of NOAC agents was observed when compared to warfarin-treated patients with low TTR.