A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

• Published in: Circulation (New York, N.Y.) Vol. 125; no. 16; pp. 1997 - 2005
• Main Authors: ANDERSON, Jeffrey L, HOME, Benjamin D, HUNTINGHOUSE, John A, ROLLO, Jeffrey S, SILER, Dustin, BAIR, Tami L, KNIGHT, Stacey, MUHLESTEIN, Joseph B, CARLQUIST, John F, STEVENS, Scott M, WOLLER, Scott C, SAMUELSON, Kent M, MANSFIELD, Justin W, ROBINSON, Michelle, BARTON, Stephanie, BRUNISHOLZ, Kim, MOWER, Chrissa P
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 24.04.2012
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Anticoagulants - administration & dosage; 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; Female; Humans; International Normalized Ratio; Male; Medical sciences; Middle Aged; Mixed Function Oxygenases - genetics; Pharmacogenetics; Pharmacology. Drug treatments; Treatment Outcome; Vasodilator agents. Cerebral vasodilators; Vitamin K Epoxide Reductases; Warfarin - administration & dosage; Young Adult; clinical trial; Antivitamin K; Pharmacogenetics; Warfarin; genetics; Coumarine derivatives; anticoagulants; Cardiovascular disease; Anticoagulant
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.111.070920

Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ≤1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.