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

• Published in: The Lancet (British edition) 2015-06, Vol.385 (9984), p.2280-2287
• Main Authors: Mega, Jessica L, Dr, Walker, Joseph R, PharmD, Ruff, Christian T, MD, Vandell, Alexander G, PhD, Nordio, Francesco, PhD, Deenadayalu, Naveen, MPH, Murphy, Sabina A, MPH, Lee, James, PhD, Mercuri, Michele F, MD, Giugliano, Robert P, MD, Antman, Elliott M, Prof, Braunwald, Eugene, Prof, Sabatine, Marc S, Dr Prof
• Format: Article
• Language: English
• Subjects: Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - adverse effects; Anticoagulants - therapeutic use; Atrial Fibrillation - complications; Atrial Fibrillation - drug therapy; Atrial Fibrillation - genetics; Cytochrome P-450 CYP2C9 - genetics; Double-Blind Method; Drug dosages; Factor Xa Inhibitors - administration & dosage; Factor Xa Inhibitors - therapeutic use; Genetic variance; Genetic Variation; Genetics; Genotype; Genotype & phenotype; Genotypes; Hemorrhage - chemically induced; Humans; Internal Medicine; International Normalized Ratio; Medical treatment; Patients; Pharmacogenetics; Pyridines - administration & dosage; Pyridines - therapeutic use; Risk Assessment; Sensitivity analysis; Stroke - prevention & control; Thiazoles - administration & dosage; Thiazoles - therapeutic use; Vitamin K Epoxide Reductases - genetics; Warfarin - administration & dosage; Warfarin - adverse effects; Warfarin - therapeutic use
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(14)61994-2

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 are at increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin. Methods ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2·0–3·0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1 . The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov , number NCT00781391. Findings 14 348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2·2%, IQR 0–20·2; 8·4%, 0–25·8; and 18·3%, 0–32·6; ptrend