Pharmacogenetics Strikes Again, This Time with Warfarin

Dosing of warfarin is one of the most challenging problems in clinical practice today. This drug has a narrow therapeutic index, and achieving therapeutic objectives can be very cumbersome for both patient and physician. Various algorithms have been devised to solve this problem.It is well established that variations in two genes, one in the cytochrome P450 family (CYP2C9) and the other in the vitamin K epoxide reductase complex (VKORC1) play important roles in the variable dose requirements that different patients have for warfarin.A study recently published in the NEJM (http://content.nejm.org/cgi/content/abstract/360/8/753) demonstrated that a pharmacogenetic algorithm incorporating clinical information and information on these two genetic mutations performed better than an algorithm based solely on clinical factors or a fixed dose of 5 mg per day in predicting the correct dose requirement for warfarin.

I think the most interesting outcome of this retrospective study is the demonstration that significant percentages of patients had requirements well below and above the fixed dose of 5 mg per day. 33.9% of patients required 21 mg or less per week (<3>7 mg or more per day). It was in these outlier groups that the pharmacogenetic algorithm performed better than the clinical algorithm.

Does this mean that everyone should be tested for CYP2C9 or VKORC1?

No--not yet. As pointed out in the accompanying editorial (http://content.nejm.org/cgi/content/full/360/8/811), warfarin dosing is and always will be empiric, since "the pharmacodynamic end point is the entire basis of warfarin dosage." As yet, there is no randomized prospective trial demonstrating that pharmacogenetic testing and algorithmic dosing provides a clinical benefit. This study however could be the precursor to such a study.

From a clinical standpoint, it is important to remember that when a patient requires what seems like an unusually high or low dose of warfarin to obtain a therapeutic INR, it is most likely related to polymorphisms of either one of these genes, and one should not necessarily doubt the veracity of the INR test result.