Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation

Background: Warfarin sodium therapy is highly effective in preventing throm boembolism. Its major toxic effect is hemorrhage, the risk of which increas es with the international normalized ratio (INR). Data on the rate of major hemorrhage and the rate of INR decay after an episode of excessive anticoa gulation therapy would help guide management of elevated INRs in the outpat ient setting. Methods: We prospectively followed up outpatients in an anticoagulant thera py unit from April 24, 1995, through March 1, 1996. Study patients had to b e taking warfarin for longer than 1 month and have an INR target range of 2 .0 to 3.0. Consecutive outpatients with an INR greater than 6.0 were identi fied and compared with a randomly selected concurrent set of patients whose INR was in the target range. Major hemorrhage was defined as fatal, intrac ranial, or requiring hospitalization and transfusion of at least 2 U of blo od. Results: One hundred fourteen patients with INRs greater than 6.0 were iden tified and compared with 268 patients with INRs in the target range. None o f the patients had clinically apparent bleeding at the time of the INR meas urement, and none received phytonadione (vitamin KI). Patients did not diff er significantly in age, sex, indication, or duration of warfarin therapy. Ten patients with an INR greater than 6.0 (8.8%; 95% confidence interval, 4 .3%-15.5%) sought medical attention for abnormal bleeding, and 5 of these e xperienced a major hemorrhage during 14-day follow-up (4.4%; 95% confidence interval, 1.4%-9.9%) compared with none of the patients with an in-range I NR(P<.001). Thirty-three percent of patients with INRs greater than 6.0 had INRs less than 4.0 within 24 hours, 55% within 48 hours, 73% within 72 hou rs, and nearly 90% within 96 hours of temporary discontinuation of warfarin therapy. Conclusions: Outpatients with INRs seater than 6.0 face a significant short -term risk of major hemorrhage. Randomized trials are needed to determine t he net benefit of preventive treatment with phytonadione.