The DVT Limbo Rock: How Low Can You Go?

Abstract & Commentary

Synopsis: Keeping the INR in the range of 1.5 to 2.0 is safe and effective.

Source: Ridker PM, et al. N Engl J Med. 2003;348:1425-1434.

Warfarin use in deep-vein thrombosis (DVT) is the prototypical "rock and a hard place" don’t use it, and you risk a recurrence of DVT. Use it, and you risk major and minor bleeding. Current guidelines recommend periodic monitoring of the patient’s international normalized ratio (INR) with the goal of keeping it between 2.0 and 3.0 (moderate intensity). The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was designed to determine if long-term, low-intensity therapy with a target INR of 1.5 to 2.0 could reduce the risk of recurrent DVT. This would be desirable because, intuitively, a lower INR would be associated with a reduced risk of major hemorrhage. Eligible patients were older than 30 years; had an idiopathic DVT; had already completed 3 months of moderate-intensity warfarin; had no history of metastatic cancer, major gastrointestinal hemorrhage, or hemorrhagic stroke; had a life expectancy greater than 3 years (to accommodate study follow-up); were not taking dipyridamole, ticlopidine, clopidogrel, heparin, more than 325 mg of aspirin or any other drug known to affect prothrombin time; and did not have known lupus anticoagulant or antiphospholipid antibodies.

This study randomized 578 patients to placebo or warfarin. The randomization was double blinded. All patients were seen every 2 months for office visits at which time an INR was drawn and the warfarin dose adjusted; placebo patients had sham dose adjusting. The placebo group (253) and the warfarin group (255) were similarly composed. The average age was 53 years; 47% were female. The racial make-up was comparable, predominantly non-Hispanic white with African Americans and Hispanics represented. Average body-mass index was 29.9. There were equivalent numbers of diabetics. More than a quarter of patients in both groups were positive for Factor V Leiden or a prothrombin mutation. The patients were followed for an average of 2.1 years with the longest follow-up at 4.3 years. Patients in the warfarin group took a median dose of 4 mg and had a median INR of 1.7. The primary end points were recurrent DVT, pulmonary embolism, and major hemorrhage (a bleeding event that resulted in hospitalization or transfusion). Strokes and a composite end point of recurrent DVT, major hemorrhage, and death were also followed. The independent data and safety monitoring board terminated the study when it became apparent that patients on low-dose warfarin enjoyed a "large and statistically extreme benefit." In the placebo group there were 37 recurrent DVTs (7.2 per 100 person-years). In the warfarin group there were 14 (2.6 per 100 person-years). Patients with Factor V Leiden or a prothrombin mutation derived similar benefit, 8.6 vs 2.2 DVTs per 100 person-years. Two patients in the placebo group had a major hemorrhage vs 5 patients in the warfarin group, a nonsignificant difference. There were 8 deaths and 2 strokes in the placebo group vs 4 deaths and 1 stroke in the warfarin group (not statistically significant).

Comment by Allan J. Wilke, MD

Moderate-dose warfarin (INR, 2.0 to 3.0) is effective in preventing DVT,1 but at a cost: risk of bleeding, frequent blood tests, and dose tweaking. Duration of therapy has received the most attention recently. Current recommendations, based on the circumstances of the DVT, are 3 months (DVT occurring in someone with a reversible cause [eg, immobility]), 6 months (first idiopathic DVT), and 12 months (recurrent idiopathic DVT). The current study indicates that we may be able to have our cake and eat it, too. The inclusion/exclusion criteria are not overly stringent, but applying the results to someone with lupus anticoagulant or antiphospholipid antibodies should be done with caution; these patients generally need a higher INR (2.5-3.5). It is important to remember, too, that all patients received moderate-dose warfarin for 3 months before randomization. An editorialist notes that a study in press that compares low-intensity to moderate-intensity warfarin shows that moderate-intensity warfarin performed significantly better than low-intensity warfarin with no increase in adverse effects.2 Perhaps we will need a study of placebo vs low-intensity warfarin vs moderate-intensity warfarin to sort it all out.

Dr. Wilke is Assistant Professor of Family Medicine, Medical College of Ohio, Toledo, OH.

References

1. Geerts WH, et al. Chest. 2001;119(Suppl):132S-175S.

2. Schafer AI. N Engl J Med. 2003;348:1478-1480.