The Warfarin Pharmacogenomics Risk-Benefit Analysis Case Study
 

One component of the project described above is applying RBA methods to assess the clinical benefits, harms, and uncertainty associated with using genetic testing to determine dose levels for patients receiving therapy with the anticoagulant drug warfarin.  Warfarin is an effective drug for reducing the risk of clotting events in patients with artificial heart valves and conditions such as atrial fibrillation and deep venous thromboembolism. However, warfarin dosing is complicated by the fact that there is considerable variation in the required therapeutic dose both between and within patients. Consequently, patients are required to undergo frequent measurement of anticoagulation status (using the “International Normalized Ratio” [INR]) and subsequent dosage adjustments. If warfarin dose levels are too low, and INR values are below the patient’s targeted range, there is increased risk of clotting events. If warfarin dose levels are too high, and INR values are above the patient’s targeted range, there is increased risk of bleeding events. Due to this relationship, and ongoing anticoagulation measurement and dose adjustment, warfarin is one of the most common causes of serious adverse drug events leading to hospitalization. (1)

Warfarin Pharmacogenomics Research to Date

Recent studies have demonstrated an association between two specific genetic variants and required warfarin dose. (2,3,4) These studies found that patients who have variants of the genes CYP2C9 and VKORC1 require a lower dose of the drug to achieve values within the targeted INR range. Additionally, studies have demonstrated that patient’s genotype status may impact the relative proportion of time spent above, within, and below their targeted INR range, which may in turn influence risk of bleeding and clotting events. (5,6) However, no study to date has definitively demonstrated that using genetic information to determine warfarin dose improves patient outcomes. (7)

Motivation for Developing a Warfarin Pharmacogenomics Risk-Benefit Analysis Model

The uncertainty surrounding the current level of evidence for genotype-guided warfarin dosing, lack of consensus on what constitutes clinically significant outcome improvement based on genetic testing, and a lack of a formalized process to evaluate these factors, highlight the need for additional tools to aid stakeholders in making decisions about warfarin pharmacogenomics. The linked excel-based warfarin pharmacogenomics risk-benefit analysis model seeks to serve this important function.

Warfarin Risk-Benefit Analysis Interactive Model


[1] Gurwitz JH, Field TS, Judge J, et al. The incidence of adverse drug events in two large academic long-term care facilities. Am J Med. Mar 2005;118(3):251-258.
[2] Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. Jun 2 2005;352(22):2285-2293.
[3] Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of pharmacogenetics and clinical factors to predict the
maintenance dose of warfarin. Thromb Haemost. Jan 2004;91(1):87-94.
[4] Hillman MA, Wilke RA, Caldwell MD, Berg RL, Glurich I, Burmester JK. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics. Aug 2004;14(8):539-547.
[5] Limdi NA, McGwin G, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 1173C/T Genotype on the Risk of Hemorrhagic
Complications in African-American and European-American Patients on Warfarin. Clin Pharmacol Ther. Jul 25 2007.
[6] Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. Unpublished data; 2007.
[7] Anderson JL, Horne BD, Stevens SM, et al. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Circulation. November 7, 2007. 

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