Should we use pharmacogenetic testing when prescribing warfarin?
The answer is not clear. There is evidence in favor of pharmacogenetic testing, but not yet enough to strongly recommend it. However, we do believe that physicians should consider it when starting patients on warfarin therapy.
WARFARIN HAS A NARROW THERAPEUTIC WINDOW
Although newer drugs are available, warfarin is still the most commonly used oral anticoagulant for preventing and treating thromboembolism.1 It is highly effective but has a narrow therapeutic window and wide interindividual variability in dosage requirements, which poses challenges to achieving adequate anticoagulation.1–3 Inappropriate dosing contributes to a high rate of bleeding events and emergency room visits.4
Warfarin is monitored using the prothrombin time. Because the prothrombin time varies depending on the assay used, the standardized value called the international normalized ratio (INR) is more commonly used.
Clinical factors such as age, body size, and drug interactions affect warfarin dosage requirements and are important to consider,5 even though they account for only 15% to 20% of the variability in warfarin dose.6
Genetic factors also affect warfarin dosage requirements. The combination of genetic and clinical factors accounts for up to 47% of the dose variability.7
GENES THAT AFFECT WARFARIN
Several genes are known to influence warfarin’s pharmacokinetics and pharmacodynamics. Of these, the two most clinically relevant and well studied are CYP2C9 (which codes for cytochrome P450 2C9) and VKORC1 (which codes for vitamin K epoxide reductase).7 These genes are polymorphic, with some variants producing less-active enzymes that allow warfarin to be more active. Therefore, patients who carry these variants need lower doses of this drug (see below).
CYP2C9 variants
The CYP2C9 gene has several variants. Of these, CYP2C9*2 and CYP2C9*3 are associated with the lowest enzyme activity.
Patients with either of these variants require significantly lower warfarin doses to reach therapeutic levels than those with the wild-type gene (ie, CYP2C9*1). CYP2C9*2 reduces warfarin clearance by 40%, and the CYP2C9*3 variant reduces it by 75%.7 Having a *2 or *3 allele increases the risk of bleeding during warfarin therapy and the time needed to achieve a stable dose.8 Other variants associated with lower warfarin dose requirements are *5, *6, and *11.
The prevalence of these variants is significantly higher in people of European ancestry (roughly one-third) than in Asian people and African Americans,7 although no one has recommended not testing in these low-prevalence populations. Limdi et al9 reported that by including the *5, *6, and *11 variants in genetic testing (in addition to *2 and *3), they could identify more African Americans (9.7%) who carried at least one of these abnormal variants than reported previously. Differences among ethnic groups need to be taken into account when interpreting pharmacogenetic studies.
VKORC1 variants
Patients also need lower doses of warfarin if they carry the VKORC1 −1639G>A variant, and they spend more time with an INR above the therapeutic range and have higher overall INR values. However, having this variant does not appear to increase the risk of bleeding.
The −1639G>A variant is the most common variant of VKORC1. Rarer ones have also been described, but most commercially available tests do not detect them.
Racial differences exist in the prevalence rates of the various VKORC1 polymorphisms, with the most sensitive (low-dose) genotype predominating in Asians and the least sensitive (high-dose) genotype predominating in African Americans. Over 50% of people of European ancestry carry the intermediate-sensitivity genotype (typical dose).7
CURRENT RECOMMENDATIONS FOR OR AGAINST TESTING
FDA labeling
In 2007, the US Food and Drug Administration (FDA) required that the warfarin package insert carry information about initial dosing based on CYP2C9 and VKORC1 testing. This recommendation was revised in 2010 to include a table to help clinicians select an initial warfarin dose if CYP2C9 and VKORC1 genotype information is available. However, the FDA does not require pharmacogenetic testing, leaving the decision to the discretion of the clinician.7
American College of Chest Physicians
The American College of Chest Physicians recommends against routine pharmacogenetic testing (grade 1B) because of a lack of evidence that it improves clinical end points or that it is cost-effective.5
WHAT EVIDENCE SUPORTS GENETIC TESTING TO GUIDE WARFARIN THERAPY?
To date, no large randomized, controlled trial has been published that looked at clinical outcomes with warfarin dosing based on pharmacogenetic testing. However, several smaller studies have suggested it is beneficial.
One trial found that when dosing was informed by pharmacogenetic testing, patients had significantly more time in the therapeutic range, a lower percentage of INRs greater than 4 or less than 1.5, and fewer serious adverse events (death, myocardial infarction, stroke, thromboembolism, and clinically significant bleeding events).10 Patients whose dosage was determined using pharmacogenetic algorithms as opposed to traditional clinical algorithms maintained a therapeutic INR more consistently.11
In addition, compared with historical controls, patients whose physician used pharmacogenetic testing to guide warfarin dosing had a rate of hospitalization 31% lower and a rate of hospitalization specifically for bleeding or thromboembolism 28% lower during 6 months of follow-up.12,13
Several studies have attempted to assess the cost-effectiveness and utility of pharmacogenetic testing in warfarin therapy. As yet, the results have been inconclusive.14 Larger prospective trials are under way and are estimated to be completed in late 2013.15 These include:
- COAG (Clarification of Optimal Anticoagulation Through Genetics)
- GIFT (Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis)
- EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin).
We hope these studies will provide greater clarity on the clinical utility and cost-effectiveness of pharmacogenetic testing to guide warfarin dosing.
