Pharmacogenomics is the study of how an individual's genetic makeup, or genotype, affects the body's response to drugs. It is an examination of the inherited components and variations in genes that dictate drug or medication response. Pharmacogenomics explores the ways these variations can be used to try to predict whether a patient will have a good response to a drug, a bad response to a drug, or no response at all.

There has been considerable public interest in the use of pharmacogenomic testing to predict the patient's response to warfarin, an orally administered anticoagulant drug that is marketed most commonly as Coumadin. Anticoagulant drugs are sometimes referred to as "blood thinners" by the lay public. Warfarin affects the vitamin K-dependent clotting factors II, VII, IX and X. The anticoagulant effect of warfarin is assessed with the prothrombin time (PT) and the International Normalized Ratio (INR). In this method, the ratio of the patient's PT to the mean PT for a group of normal individuals is calculated.

The most common and generally agreed upon indications for warfarin therapy are in patients with mechanical heart valves and, to a lesser extent, those patients with atrial fibrillation who are post-cerebrovascular accident or transient ischemic attack. Other indications include atrial fibrillation with thromboembolic risk factors including age over 65 years, diabetes, hypertension, as well as congestive heart failure.

The duration of anticoagulation therapy varies with the underlying indication and with the patient's response to therapy. Some conditions require anticoagulation for only a period of a few months, while other conditions require long-term and possibly life-long anticoagulation.

Since October 4, 2006, the FDA approved labeling for Coumadin® has included the following boxed warning.

WARNING: BLEEDING RISK
Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age >65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS) and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients).

The FDA approved label notes many factors that can influence the anticoagulant effect of warfarin, including dietary intake of green leafy vegetables and cranberry juice, alcohol consumption, age, Asian ethnicity and liver function. Many other drugs affect warfarin metabolism. A very small sample includes analgesics, antibiotics, anticonvulsants, antineoplastics, beta adrenergic blockers, antifungals, hormone preparations and vitamins. The current label lists approximately 130 specific drugs reported to interact with coumadin.

Warfarin is eliminated by metabolic conversion to inactive metabolites by cytochrome P450 enzymes in the liver. It is claimed that genetic variability in the CYP2C9 and/or VKORC1 genes, in combination with many other factors, may partially predict a patient's response to warfarin.

The label also notes several small clinical trials that associate genomic factors with warfarin dose. The trial investigators suggest that pharmacogenomic testing may contribute to the identification of patients who may be more likely to over- or under-respond to warfarin. The dosing information in the label does not require or explicitly recommend pharmacogenomic testing prior to the initiation of warfarin therapy.

Clearly, an individual patient's initial response to warfarin therapy may be influenced by a multitude of factors well beyond genetic variation. We are concerned by the paucity of evidence available to determine what effect on overall health outcomes, if any, can be confidently attributed to treatment strategies that include pharmacogenomic testing in the determination of dosing.

CMS is internally opening this National Coverage Analysis (NCA) to complete a thorough review of the evidence to determine if the use of pharmacogenomic testing for warfarin is reasonable and necessary under the Medicare program.