The combination of genotype data with such clinical factors as age, gender, height, weight, interacting medications, and concurrent disease, accounts for approximately 50-60% of the variability observed among individual warfarin response. Algorithms are being developed to assist physicians in adjusting warfarin dose based on genetic and clinical factors1-3.
See warfarindosing.org for a web-based warfarin dose calculator and additional information about incorporating genotype information into your warfarin management decisions.
The figure below shows the impact of various genotype combinations on the predicted therapeutic warfarin dose for a standard patient as calculated by warfarindosing.org.
| VKORC1 Genotype | |||
| CYP2C9 Genotype | G/G (Normal) | A/G | A/A |
| *1/*1 (Normal) | 7.6 mg/day | 5.5 mg/day |
4.0 mg/day |
| *1/*2 | 6. 2 mg/day |
4.5 mg/day |
3.2 mg/day |
| *1/*3 | 5.1 mg/day |
3.7 mg/day |
2.7 mg/day |
| *2/*2 | 5.0 mg/day |
3.6 mg/day |
2.6 mg/day |
| *2/*3 | 4.1 mg/day |
3.0 mg/day |
2.2 mg/day |
| *3/*3 | 3.4 mg/day |
2.5 mg/day |
1.8 mg/day |
Standardized patient clinical information used in calculations: 50 year old, 6'0" tall, 200 pound, non-Hispanic Caucasian male with a history of myocardial infarction and no previous warfarin therapy. No history of liver disease, smoking, or interacting medications.
Much of what is known about the impact of these variants on warfarin maintenance dose and bleeding event risk is based on retrospective studies of dose and complication frequency by genotype. While studies are underway, there currently exists little prospective data to show improved clinical outcomes when warfarin management is guided by genotype information. This likely contributed to the FDA simply advising that these genetic variants may impact warfarin response, while not yet recommending or requiring genetic testing before warfarin initiation4. It is certainly the expectation that adjusting warfarin dose based on genotype will improve warfarin management, and the FDA recommendations may change as additional data becomes available.
References:
1. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-33.
2. Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005;93:700-5.
3. Millican E, Jacobsen PA, Milligan PE, Grosso L, Eby C, Deych E, Grice G, Clohisy JC, Barrack RL, Burnett RS, Voora D, Gatchel S, Tiemeier A, Gage B. Genetic-Based Dosing in Orthopedic Patients Beginning Warfarin Therapy. Blood 2007.
4. American Medical Association. Genetics and Warfarin Dosing: revision to warfarin labeling. Updated August 23, 2007. Available at: http://www.ama-assn.org/ama/pub/category/17951.html . Accessed December 2, 2007.