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Am Fam Physician. 2004;69(5):1272

Because conventional warfarin therapy (a target International Normalized Ratio [INR] of 2.0 to 3.0) has been shown to virtually eliminate the risk of recurrent venous thromboembolism, interest has developed in attempting low-intensity anticoagulation. The latter technique still may be effective in preventing blood clots but may decrease the risk of serious bleeding that sometimes occurs with standard warfarin administration. Kearon and colleagues designed a trial of low-intensity versus conventional-intensity anticoagulation in patients with a history of deep venous thrombosis or pulmonary embolism.

The investigators screened 1,455 consecutive patients with unprovoked venous thromboembolism and enrolled 738 patients in the study. The most common causes for exclusion were declined consent, an additional indication for warfarin use beyond prophylaxis of recurrent blood clots (e.g., atrial fibrillation), or a life expectancy of less than two years. All patients had completed at least three months of standard, full-dose anticoagulation therapy before study entry. Patients were randomized to continuation of conventional-intensity anticoagulation or low-intensity warfarin use (target INR of 1.5 to 1.9) and were followed for a mean duration of 2.4 years. A total of 142 patients withdrew from the study. Randomization equalized the prevalence in the two treatment groups of most risk factors for recurrent clotting (i.e., advanced age, inherited hypercoagulability [e.g., factor V Leiden], duration of previous full-dose anticoagulation) but unexpectedly left significantly more patients with a history of more than one clot in the low-intensity group (13 patients) than in the conventional-intensity group (two patients).

Recurrent venous thromboembolism was significantly more common in patients taking low-intensity warfarin (16 episodes) than in those taking standard anticoagulation (six episodes). Fatal pulmonary embolism occurred in one low-intensity patient and two conventional-intensity patients. The incidence of major bleeding was not significantly different between patients taking low-intensity treatment (nine episodes) and patients taking full-dose warfarin (eight episodes). No fatal or intracranial bleeding episodes occurred in either treatment group.

The authors conclude that low-intensity warfarin anticoagulation is not as effective as conventional-intensity anticoagulation in preventing recurrent venous thromboembolism and does not improve the rate of major bleeding complications.

editor's note: This study is best considered in concert with another recently published trial1 of low-intensity anticoagulation that showed favorable conclusions. This other trial compared low-intensity warfarin with placebo and showed that the risk of recurrent blood clots was cut by two thirds without any significant increase in bleeding. The reader also will want to consider a number of factors in the first study that may have skewed the findings. Despite randomization, one half of the initially screened patients were enrolled, almost 20 percent failed to complete the assigned treatment, and there were more patients in the low-intensity treatment group with a history of more than one clot.—b.z.

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