FDA encourages pharmacogenetic test for warfarin

24 August 2007

The US Food and Drug Agency (FDA) has announced the approval of an updated label for Coumarin, a branded version of the blood-thinning drug warfarin. The new label will explain that genetic variation in two specific genes influences how patients respond to the drug, including a statement that “lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes”. Larry Lesko, a director at the FDA’s Center for Drug Evaluation, has described the new label as bringing “personalized medicine to the mainstream”.

Warfarin is the most widely used anti-coagulant medication in the world, prescribed to over 2 million people a year to prevent blood clots, heart attacks and strokes. Patients can display markedly different responses to the drug, so doses vary enormously between individuals in order to reduce the risk of bleeding complications during treatment. Despite this awareness, it is estimated that complications from warfarin treatment send more than 43,000 emergencies to hospital each year in the US, which is more than any other drug except insulin.

Although a variety of behavioural factors influence a patient’s response to warfarin – including diet, alcohol intake and body mass – two genes have been identified that account for much of the variation. One gene, CYP2C9, produces a cytochrome P450 oxidase enzyme that helps the body metabolize warfarin and other medicines. Patients with various mutations in this gene process warfarin more slowly (see previous Journal Club article) and therefore need a smaller dose. A second gene, VKORC1, produces a vitamin K-dependent blood-clotting protein that is blocked by warfarin. Patients with mutations in this gene also need a smaller dose of warfarin as they produce less of the target protein. Indeed, some patients with a rare missense mutation in VKORC1 have complete warfarin resistance and therefore need a different anticoagulant altogether.

FDA economists estimate that by formally integrating genetic testing into routine warfarin therapy, the US alone would avoid 85,000 serious bleeding events and 17,000 strokes annually (see Associated Press article). Despite this fact, the FDA stopped short of recommending that physicians order genetic testing for all patients taking warfarin, saying that further studies are needed to establish its utility and cost-effectiveness. However, with a number of warfarin sensitivity tests already available, the new label is likely to persuade both patients and physicians to seek genetic reassurance before starting warfarin treatment.