Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation

• Published in: Circulation (New York, N.Y.) Vol. 116; no. 22; pp. 2563 - 2570
• Main Authors: ANDERSON, Jeffrey L, HORNE, Benjamin D, CARLQUIST, John F, STEVENS, Scott M, GROVE, Amanda S, BARTON, Stephanie, NICHOLAS, Zachery P, KAHN, Samera F. S, MAY, Heidi T, SAMUELSON, Kent M, MUHLESTEIN, Joseph B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 27.11.2007
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Anticoagulants - therapeutic use; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Cytochrome P-450 CYP2C9; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Dosage Calculations; Drug Monitoring - methods; Female; Genotype; Humans; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Pharmacogenetics - methods; Pharmacology. Drug treatments; Treatment Outcome; Vascular wall; Vasodilator agents. Cerebral vasodilators; Vitamin K Epoxide Reductases; Warfarin - administration & dosage; Human; clinical trial; Warfarin; Coumarine derivatives; Oral administration; anticoagulation; Genotype; Cardiovascular disease; Anticoagulant; Antivitamin K; genetics; Comparative study; pharmacogenetics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.107.737312

Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials. Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic = 30.7%, standard = 33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic = 29%, standard = 39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of > or = 4 (P=0.03). An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.