Prevention or Procrastination? The Effect of Coumadin on Long-Term Risk of Thrombosis
Prevention or Procrastination? The Effect of Coumadin on Long-Term Risk of Thrombosis
Abstract & commentary
Synopsis: The benefits of long-term anticoagulation for idiopathic DVT dissipate after stopping coumadin.
Source: Agnelli G, et al. N Engl J Med. 2001;345:165-169.
The warfarin optimal duration italian trial was a multicenter, nonblinded, randomized, controlled trial of 268 patients with an indiopathic deep vein thrombosis (DVT).1 All patients received 3 months of coumadin and were then randomized either to discontinue coumadin or to continue coumadin for an additional 9 months. All patients were then followed for a minimum of 2 years (mean follow-up 37 months) for the primary end points of recurrence of a thrombosis, pulmonary embolism, major bleeding, and death. Patients with a known history of cancer, hyper-coagulopathy, venous stasis, or injury were excluded from the study.
At the 1-year mark, patients treated with 12 months of coumadin had less DVT recurrence than patients treated with 3 months of coumadin (RR = 0.36; 95% CI, 0.12-1.11). At the conclusion of 2 years of follow-up, however, there was no difference in the recurrence of DVT (RR = 0.99; 95% CI, 0.57-1.73). Twenty-eight patients (21%) in the control group and 31 patients in the treatment group had complications. There was no difference in mortality.
Comment by Jeff Wiese, MD
The trial is consistent with previous studies that have established that 6 months of coumadin following an idiopathic DVT is superior to 3 months of therapy in reducing the recurrence of DVT.2,3 This study asks the important question: what happens to those patients treated with 6 months of coumadin after the drug is stopped? Do they continue to enjoy protection from DVT, or has coumadin only delayed the inevitable rethrombosis?
Patients treated with 12 months of coumadin had a reduced risk of recurrence than those treated with only 3 months of therapy (RR = 0.36; 95% CI, 0.12-1.11). However, this difference had evaporated at 24 months of follow-up. Patients who had been protected from thrombosis while on coumadin experienced thrombosis when the drug was stopped. At the conclusion of 2 years of follow-up, 21 (16%) patients in both groups had experienced a recurrent DVT. Furthermore, there was no benefit in prevention of mortality or pulmonary embolism with the additional 9 months of coumadin. This suggests that coumadin had only delayed the inevitable thrombosis, and the delay offered no benefit to the patient.
Further study will be required to change the current standard of care that suggests that patients should receive 6 months of coumadin following an idiopathic DVT. This study may ultimately change that standard, however. Because coumadin carries a 4% per year bleeding risk, most patients are assigned a stop date for the coumadin.3 If an additional 9 months of coumadin only delays the inevitable thrombosis, then it stands to offer only the complications of bleeding during those 9 months. A shorter dose of coumadin may be preferable.
This study may have been underpowered to detect a difference between the 2 groups at the 2-year point. The difference in gender between the 2 groups (55% men in the control group vs 61% in the treatment group) also raises questions about the success of the randomization. It is possible that the intervention group was assigned a disproportionate number of patients with Factor V Leiden or antithrombin, variables not assessed in this study population.
Physicians should be aware that a certain subgroup (15%) of patients is likely to have recurrent DVT even after coumadin is stopped. The duration of coumadin therapy does not seem to alter this risk.
References
1. Kearon C, et al. N Engl J Med. 1999;340:901-907.
2. Schulman S, et al. N Engl J Med. 1995;332:1661-1665.
Dr. Wiese is Chief of Medicine, Charity, and University Hospitals, Associate Chairman of Medicine, Tulane Health Sciences Center, New Orleans, La.
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