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QUESTION: In patients who have had a first episode of idiopathic proximal deep venous thrombosis, what is the long term effectiveness of extending to 1 year the initial 3 month course of oral anticoagulant treatment?
10 study centres in Italy.
267 patients (mean age 67 y, 58% men) who had a first episode of symptomatic idiopathic proximal deep venous thrombosis confirmed by compression ultrasonography or venography, and had completed 3 uninterrupted months of oral anticoagulant treatment without a recurrence of thromboembolism or bleeding. Exclusion criteria included anticoagulant treatment for reasons other than venous thromboembolism, major psychiatric disorders, life expectancy < 2 years, and inability to return for follow up. 90% of patients completed the study.
After 3 months of treatment with warfarin (97% of patients) or acenocoumarol, 133 patients were allocated to discontinue (3 mo treatment group) and 133 patients to continue (1 y treatment group) oral anticoagulant treatment for 9 additional months. The dose of the oral anticoagulant was adjusted to maintain an international normalised ratio of 2.0 to 3.0.
Main outcome measures
The primary outcome was recurrent deep venous thrombosis. Secondary outcomes were major bleeding and all-cause mortality.
At ≥ 2 years, intention to treat analyses showed that the groups did not differ for incidence rates of recurrent deep venous thrombosis, major bleeding, and all-cause mortality (table). The study had an 80% power to detect a 50% reduction in the risk of recurrence at the 5% level of significance.
In patients who had a first episode of idiopathic proximal deep venous thrombosis, 3 months was equivalent to 1 year of oral anticoagulant treatment in preventing recurrences at ≥ 2 years.
5 previous, well-designed, randomised trials have compared different durations of anticoagulation for venous thromboembolism (VTE).1–5 3 of these studies tested whether the duration of anticoagulation could be reduced from 31, 3 or 6 months2 to only 4 or 6 weeks in patients who, for the most part, had a first episode of VTE and did not have cancer. All 3 studies found that shortening the duration of treatment resulted in about a 2-fold increase in the rate of recurrent VTE after anticoagulants were stopped, without being associated with a convincing reduction in the rate of bleeding. These studies also found that the risk for recurrent VTE was about 4 times higher for “unprovoked” or “idiopathic” VTE than for thrombosis that was provoked by a transient risk factor, such as recent surgery.
The other 2 trials evaluated an extended duration of anticoagulant treatment in 2 groups of patients with VTE who were thought to have a high risk for recurrence: those with a second episode of VTE4 and those with a first unprovoked episode of VTE.5 Both studies found that extending oral anticoagulant treatment (international normalised ratio of 2.0 to 3.0) was effective for preventing recurrent VTE; however, long term use was associated with a substantial risk for bleeding. Schulman et al4 concluded that after a second episode of thrombosis the risk for recurrent VTE after completing 6 months of treatment (about 6% per year) was not high enough to routinely recommend extended treatment. Our group found that after a first episode of unprovoked thrombosis, the risk for recurrent VTE after completing 3 months of treatment was higher than expected (about 25% during the first year), which justified treatment for longer than 3 months; however, we could not say how much longer than 3 months was required.5
In a mix of patients with provoked and unprovoked VTE, Pinede et al found the risk for recurrent VTE to be similar after completing 3 and 6 months of treatment. In patients with a first episode of unprovoked deep venous thrombosis, Agnelli et al found a similar risk for recurrent VTE after completing 3 months and 12 months of treatment. In the latter study, this risk was only about 5% per year, much lower than the 25% observed after 3 months of treatment in a similarly defined patient population.5
A consistent finding across studies is that 3 months of anticoagulant treatment is adequate for patients with VTE that has been provoked by a major transient risk factor. The subsequent risk for recurrence is low (< 5% per year); however, uncertainty exists when the risk for recurrence after an unprovoked VTE is as low after 3 months of treatment as it is after 6 months. Although the 2 new studies strongly suggest that 3 months of treatment achieves as low a subsequent risk for recurrent VTE as 6 or 12 months of treatment, neither study had the power to establish this definitively. On the basis (mostly) of the results of our own study,5 which is representative of our patient population, I will continue to recommend a minimum of 6 months of anticoagulant treatment for a first unprovoked episode of VTE, provided patients do not have a high risk for bleeding. Current evidence suggests that patients with unprovoked VTE who have been treated for 6 months or longer have a risk for recurrent VTE of about 10% during the year after anticoagulant treatment is stopped. Therefore, once patients have successfully completed 6 months of treatment, I encourage them to remain on long term treatment provided they have a low risk for bleeding and do not find treatment a burden.