Pharmacogenomics of Warfarin: Clinical Implications

Deepak Voora, MD

Disclosures

June 13, 2011

Background

There is currently a wealth of data surrounding genetic polymorphisms in 2 genes, CYP2C9 and VKORC1, and how these specific polymorphisms affect variation in warfarin dose requirements, international normalized ratio (INR) control during warfarin initiation, and, for certain variants, bleeding outcomes in patients treated with warfarin.[1] The strength of this evidence prompted the US Food and Drug Administration (FDA) to update the drug label for warfarin in 2007 and then again in January 2010 with recommendations for initiation dose modifications in carriers of the specific CYP2C9 and VKORC1 variants.

However, despite the strong and consistent association data surrounding these variants and a variety of warfarin-related outcomes, there is a paucity of data demonstrating their benefit in clinical practice. The few studies performed to date were either underpowered or lacked adequate control populations and demonstrated inconsistent results.[2,3] Although larger, appropriately powered, randomized controlled trials are expected to deliver results within the coming years, these trials might not answer all relevant questions, such as how to incorporate novel anticoagulants, how to measure the cost-effectiveness of testing, and how to evaluate the effect of genetic variants on hard clinical endpoints such as bleeding and thrombosis.

What is the practicing clinician to do in the face of convincing pharmacogenetic association data but few clinical data?

As of now, there are no clear guidelines to direct clinical practice on the use of genetic testing to inform warfarin therapy administration. Those that do exist recommend against routine testing, as no prospective clinical trial has yet demonstrated any clinical benefit.[4] Until such data are available, these recommendations are unlikely to change.

Dabigatran, an oral direct thrombin inhibitor that has proven superior to warfarin in lowering the risk for stroke, systemic embolism, and/or hemorrhage,[5] does not seem to have the same pharmacogenetic considerations as warfarin, and thus its use bypasses the need for pharmacogenetic testing. However, dabigatran comes with a significant cost disadvantage and is renally cleared, so warfarin might still be preferred in certain patients. Therefore, there remains a need for guidance on how to use genetic testing to inform warfarin therapy in selected individuals.

When to Consider Genetic Testing

Adding genetic information might inform warfarin therapy in a number of scenarios. First, clinicians routinely assess an individual patient's bleeding risk prior to initiation of warfarin therapy. By taking into account age, functional status, concomitant medications, and comorbid conditions, clinicians weigh the risk-benefit ratio of warfarin therapy and choose either warfarin or alternative therapy. One additional factor to consider in this process is the presence (or absence) of genetic variants that may complicate warfarin therapy. Using a patient's CYP2C9 or VKORC1 genotypes as additional risk factors for bleeding could determine whether to initiate warfarin therapy or to choose an alternative such as dabigatran.

Another common clinical scenario is in patients who require "triple therapy" with aspirin, clopidogrel, and warfarin, such as patients with coronary artery disease, percutaneous coronary intervention, and new-onset atrial fibrillation. If a clinician chooses to add warfarin therapy, genetic testing might help to better predict dose requirements and prevent bleeding complications. Most commercial labs offer genetic testing of the major variants affecting warfarin metabolism, and online dosing calculators (such as www.warfarindosing.org) can aid in the interpretation of test results.

Finally, a third common scenario concerns a patient taking warfarin who has developed bleeding complications or is at risk of developing complications because of out-of-range INR values. Genetic testing in this scenario could be helpful in identifying individuals at risk for continued difficulty with warfarin therapy and may be used to identify patients who might benefit from alternative anticoagulants, such as dabigatran.

We currently exist in an "evidentiary gap" where there are solid and consistent association data for genetic variants and warfarin-related outcomes, but there is little evidence to guide the clinician on how to use these novel biomarkers. Until such data are available, routine use of genetic testing is not recommended. Nevertheless, the scenarios described above are some examples of when genetic testing may be beneficial in selected individuals.

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