Possible requiem: trial-and-error warfarin

Integration of rapid turnaround generic testing with clinical information may revolutionize the way we dose warfarin.

The orthopedic surgical community has embraced venous thromboembolism prophylaxis, and has achieved a successful reduction in deep vein thrombosis and pulmonary embolism. I remember the days when symptomatic venous thromboembolism and fatal pulmonary embolism used to be frequent complications of total hip and total knee replacement. Now, they are uncommon. Orthopedic surgeons have available a variety of thromboprophylaxis strategies from which to choose: low-molecular-weight heparin, fondaparinux, or warfarin. In the United States, at least half of all orthopedic surgeons routinely utilize warfarin. They embrace variable-dose warfarin because it appears to have fewer bleeding complications than low fixed doses of low-molecular-weight heparin or fondaparinux, although there are more frequent episodes of (usually asymptomatic) deep vein thrombosis. The major practical problem with warfarin is selecting the proper dose to achieve the desired international normalized ratio (INR). Because warfarin thromboprophylaxis is recommended for at most 4 weeks, it is important to get the dose right as quickly as possible.

I am certain that medical historians will be incredulous when they study the way we have dosed warfarin since it was first marketed in the 1950s. The standard approach to warfarin dosing is taking an educated guess, based upon the patient's age, nutritional status, drug-drug interactions, and comorbidities such as liver disease. The INR result 3 to 4 days after dosing provides guidance on whether to continue the same warfarin dose, increase the dose if the INR is too low, or decrease the dose if the INR is too high. Under the best of circumstances, a therapeutic target INR is achieved only about 60% of the time. The issue at hand is whether contemporary integration of genetics and clinical medicine will compose the requiem for warfarin dosing by trial and error.

No reliable nomogram exists for warfarin dosing. We have recently learned that genetic mutations account for at least one third of warfarin dose variance. The challenge for us in the anticoagulation community is to translate the polymorphisms in the cytochrome P450 2C9 and vitamin K epoxide reductase genes into practical daily use when we initiate warfarin dosing. An algorithm that combines genetic and clinical information to predict a warfarin maintenance dose when we initiate warfarin will provide a major advance in our use of this tricky anticoagulant.

In this issue of Blood, Millican and colleagues have made an important contribution. They have painstakingly devised and refined an algorithm for orthopedic surgical patients that combines genetic and clinical information. They found a close correlation between the warfarin dose predicted by their nomogram and the therapeutic dose that was eventually required to achieve the target INR. Although it is a cohort study and not a randomized trial, this publication opens the door to possible integration of clinical and genetic information in a way that can be translated into everyday application.

Millican and colleagues have also posted a warfarin dosing algorithm on their free website, www.WarfarinDosing.org. This provides clinicians with a starting point for estimating the warfarin dose based upon clinical information as well as genetic information (if available) rather than reverting to the weary trial and error method. This dosing algorithm is preliminary and requires confirmation.

There remains much controversy about whether the clinical nomogram or clinical plus genetic nomogram yields better outcomes than the usual method of warfarin dosing using an educated guess. To explore this issue further, the National Heart, Lung, and Blood Institute will sponsor a randomized trial of about 2000 patients allocated to 1 of 3 groups: trial and error dosing, clinical algorithm dosing, and clinical plus genetic algorithm dosing (http://www.fbo.gov/spg/HHS/NIH/NHLBI/NHLBI%2DHV%2D08%2D03/Attachments.html). Until the results of this trial are available, there will be heated debate about whether the costs and inconvenience of rapid-turnaround genetic testing are worth the effort. If trial and error warfarin dosing proves to yield the least favorable results, the requiem for this old-fashioned approach will be broadcast worldwide.