Randomized Trial of Warfarin Nomograms

TO THE EDITOR:

In their randomized, double-blind trial, Kovacs and colleagues (1) concluded that loading doses of warfarin (10 mg on 2 consecutive days) are more effective than standard dosing (5 mg on 2 consecutive days) in achieving therapeutic INR values among outpatients with deep venous thrombosis who were receiving at least 5 days of therapy with low-molecular-weight heparin. However, the authors have not adequately established the safety of this approach, particularly with respect to avoiding prothrombotic complications of warfarin. Among their study's end points, the authors did not list 2 such sequelae: warfarin-induced skin necrosis and warfarin-induced venous limb gangrene. These complications typically occur when patients receive loading doses of warfarin and have special predisposing circumstances, such as hereditary abnormalities in the protein C anticoagulant pathway (for example, protein C or protein S deficiency) or certain acquired hypercoagulability states (for example, heparin-induced thrombocytopenia or cancer-associated disseminated intravascular coagulation) (2, 3). Kovacs and colleagues did not determine whether any of their patients had such coexisting abnormalities. An important reason to avoid loading doses of warfarin—even when it may be safe in most patients—is because it is unsafe in the minority of patients who have one of these risk factors for warfarin-induced necrosis, and the presence of these risk factors is generally unknown when warfarin therapy is started. Finally, before physicians decide whether to use loading doses on the basis of Kovacs and colleagues' report, they should also be aware of the advice of Bristol-Myers Squibb, the manufacturer of Coumadin: “It is recommended that COUMADIN therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT [prothrombin time]/INR determinations” (4). To use a loading dose nowadays invites the specific criticism that the manufacturer's recommendations—which are aimed at maximizing patient safety—have been ignored.