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Altered Warfarin Regimen Benefits Venous Thromboembolism Patients

Kate Traynor

A report slated for publication in the April 10 New England Journal of Medicine (NEJM) suggests that long-term, low-intensity warfarin therapy is safe and effective for preventing recurrent venous thromboembolism (VTE).

By following up the usual three to 12 months of full-strength warfarin therapy with a less-intense regimen that maintained patients' International Normalized Ratio (INR) at 1.5–2.0, clinicians decreased by 64 percent the risk of a new episode of VTE but did not increase the odds of major bleeding beyond what would occur with a placebo, equivalent to the usual treatment.

The benefits to patients in the low-intensity warfarin group were so striking that the study was halted early, after about 40 percent of the clinical trial data were available. An online version of the report was released by the journal's editors today, six and a half weeks early, because of the clinical importance of the study's findings.

Typically, patients who have had an episode of VTE receive up to 10 days' therapy with heparin, then enough warfarin to maintain an INR in the range of 2.0–3.0 for three to 12 months. They then stop anticoagulation therapy completely.

The report in NEJM examined data from 508 adults age 30 years or older who had suffered a VTE episode of unknown cause and underwent at least three uninterrupted months of oral anticoagulation therapy. After enrolling in the study, each patient completed a 28-day period of low-intensity warfarin sodium therapy to confirm that the INR goal of 1.5–2.0 could be readily maintained on a dosage of no more than 10 mg/day.

Patients who successfully completed the initial 28 days of low-intensity anticoagulation proceeded to the portion of the study in which they did not know whether they were taking warfarin tablets or identical-appearing placebos. By the time the independent data and safety monitoring committee decided to stop the study, 255 adults had been receiving low-intensity warfarin therapy, and 253 patients had been taking placebo tablets.

Each patient's INR was monitored and the warfarin dosage adjusted every eight weeks accordingly, or more frequently if the value was outside a predetermined range. Patients in the placebo group underwent sham dosage adjustments and had an INR of about 1.0. On average, the study participants had completed 2.1 years of treatment when the study was halted.

VTE recurred in approximately 6 percent of patients in the warfarin group and 15 percent of those in the placebo group. Thirty-four minor bleeding events occurred in the placebo group and 60 in the warfarin group, a significant difference but one that did not affect whether patients continued with the study.

Two of the patients in the placebo group and five in the warfarin group had a major bleeding event, a difference that was not statistically significant.

In all, 56 patients in the placebo group and 64 in the warfarin group dropped out of the study. According to the report, the main reasons for stopping therapy early were the patient's refusal to continue, minor bruising, a change in the patient's medical condition, and the development of a new indication for anticoagulation therapy.

The accompanying editorial declared that the study's findings make a reasonable case for the use of long-term, low-intensity warfarin therapy for the secondary prevention of VTE. In his editorial, Andrew I. Schafer, chairman of the Department of Medicine at the University of Pennsylvania School of Medicine, mentioned a study described in preliminary form last year that suggested the standard regimen of warfarin, producing an INR of 2.0–3.0, is more effective but not more harmful than low-intensity therapy, with its INR of 1.5–1.9, for preventing recurrent VTE. That study, which appeared as an abstract in the journal Blood, was acknowledged by the authors of the NEJM report, who did not comment further.

Funding for the recent study was provided by the National Heart, Lung, and Blood Institute. Warfarin sodium tablets and matching placebos were provided at no charge by Bristol-Myers Squibb Co., maker of Coumadin.