Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial

摘要: Summary Background Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who at increased risk of with warfarin and, consequently, those would derive a greater safety benefit direct rather than warfarin. Methods ENGAGE AF-TIMI 48 was randomised, double-blind trial in which atrial fibrillation were assigned to achieve target international normalised ratio 2·0–3·0, or higher-dose (60 mg) lower-dose (30 edoxaban once daily. A subgroup included prespecified analysis and genotyped for CYP2C9 VKORC1 . The results create three genotype functional bins (normal, sensitive, highly sensitive responders warfarin). This registered ClinicalTrials.gov, number NCT00781391. Findings 14 348 analysis. Of 4833 taking warfarin, 2982 (61·7%) classified as normal responders, 1711 (35·4%) 140 (2·9%) responders. Compared spent proportions time over-anticoagulated first 90 days treatment (median 2·2%, IQR 0–20·2; 8·4%, 0–25·8; 18·3%, 0–32·6; p trend interaction =0·0066; =0·0036). After days, reduction versus similarly beneficial across genotypes. Interpretation genotypes more likely experience early from compared Funding Daiichi Sankyo.