Ischemic and bleeding risk in atrial fibrillation with and without peripheral artery disease and efficacy and safety of full and half-dose Edoxaban vs. Warfarin: insights from ENGAGE AF-TIMI 48

Abstract

Abstract Aims In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher-dose edoxaban (60/30mg) and lower-dose edoxaban (30/15) were non-inferior to warfarin for stroke/systemic embolism (SEE) and significantly reduced major bleeding in AF patients in the ENGAGE-AF TIMI 48 trial. Whether the efficacy and safety of these dosing strategies versus warfarin are consistent in patients with AF and PAD has not been described. Methods and Results Of 21,105 patients with AF randomized to warfarin, edoxaban 60/30mg or edoxaban 30/15mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACE), SSE, and major bleeding. Patients with PAD had higher risk of MACE (HRadj 1.33, 95% CI 1.12–1.57, p = 0.001) and CV death (HRadj 1.49, 95%CI 1.21–1.83, p<0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42–3.20; no-PAD 0.86, 95% CI 0.74–1.02, p-interaction 0.57) as was major bleeding (PAD 0.96 95% CI 0.54–1.70; no-PAD 0.80. 95% CI 0.70–0.91, p-interaction 0.54). Edoxaban 30/15mg was inferior for SSE with significant heterogeneity when stratified by PAD status (p-interaction 0.039). Conclusion Patients with AF and PAD are at heightened risk of MACE and CV death versus those without PAD. The efficacy and safety of edoxaban 60/30mg versus warfarin in AF is consistent regardless of PAD; however, edoxaban 30/15mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT00781391