Extended anticoagulation prevented recurrence after a first episode of idiopathic venous thromboembolism
ACP J Club. 1999 July-Aug;131:10. doi:10.7326/ACPJC-1999-131-1-010
Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999 Mar 25;340:901-7.
In patients who have had a first episode of idiopathic venous thromboembolism (VTE), will extended prophylaxis with warfarin reduce the rate of recurrence of VTE (deep venous thrombosis [DVT] and pulmonary embolism [PE])?
Randomized, double-blind, placebo-controlled trial.
15 centers in North America.
162 patients (mean age 59 y, 60% men) with a first episode of VTE (confirmed proximal DVT or PE that occurred in the absence of a major thrombogenic risk factor) who had completed a 3-month regimen of oral anticoagulation. Major exclusion criteria were contraindications to long-term anticoagulation, possibility of pregnancy, allergies to contrast media, or inability to complete 2-year follow-up. Follow-up was 100%.
79 patients were allocated to warfarin with dose adjustments to maintain an international normalized ratio (INR) of 2.0 to 3.0, and 83 patients were allocated to placebo with sham dose adjustments.
Main outcome measures
Development of confirmed symptomatic VTE (DVT or PE). Secondary outcomes were major bleeding and death.
The study was stopped early when a highly favorable effect was shown at a planned interim analysis. Patients in the warfarin group had a lower rate of recurrent VTE (P < 0.001), had more total bleeding episodes (P = 0.03), and showed a trend toward more major bleeding episodes (P = 0.09) (Table). The groups did not differ for death (1.2% in the warfarin group vs 4.1% in the placebo group, P = 0.2).
Patients with a first episode of idiopathic venous thromboembolism had a high rate of recurrence after 3 months of anti-coagulation. Continued anticoagulation with warfarin reduced the rate of recurrent venous thromboembolism.
Sources of funding: Dupont Pharma and Medical Research Council of Canada.
For correspondence: Dr. C. Kearon, Hamilton Health Sciences Corporation, Henderson Division, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada. FAX 905-575-7320.
Table. Warfarin vs placebo after 3 months of anticoagulation for idiopathic VTE*
|Outcomes at mean 10 mo||Warfarin||Placebo||RRR (95% CI)||NNT (CI)|
|Recurrent VTE||1.3%||20.5%||94% (65 to 99)||6 (3 to 9)|
|RRI (CI)||NNH (CI)|
|Major bleeding||3.8%||0%||Infinity||Not significant|
|Total bleeding||11.4%||1.2%||845% (61 to 5613)||10 (5 to 30)|
*VTE = venous thromboembolism. Other abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from data in article.
The well-designed and well-monitored study by Kearon and colleagues favors extending the previously recommended duration of anticoagulant treatment in patients with a first episode of idiopathic VTE (1). The population studied, however, raises issues that should be considered before implementation of this regimen. Idiopathic VTE occurred in patients without lower-limb trauma, general anesthesia, hospitalization with confinement to bed, thrombophilia, or a history of cancer. These patients could be divided into 2 groups of unknown proportions. Some patients may have had undiagnosed thrombophilic diseases, such as occult cancer (2), an inflammatory disease, or a hidden blood disorder associated with hyperviscosity. For these patients, the search for an emerging disease during oral anticoagulant therapy might lead to treatment of a thrombophilic disease and then to discontinuation of anticoagulation. The other patients may have had clear idiopathic VTE without any transient or emerging risk factors for VTE. These patients could benefit from long-term anticoagulation, but the 27% incidence of thromboembolic events during the first year without treatment might decrease over the years and become lower than the bleeding risk during treatment (11.5%/y). Because the study was stopped early (follow-up of 10 mo instead of the 24 mo previously planned), this issue remains unresolved.
Another way to manage these patients could have been to monitor D-dimer levels: Prolonged anticoagulation should be considered only for patients with hypercoagulability, which may be assessed by evaluating the persistent elevation of D-dimer levels (3). However, this hypothesis still needs to be confirmed.
Anticoagulation prevents the long-term risk for recurrence that is associated with idiopathic VTE, but an individual strategy remains difficult to specify. Longer treatment is better—but for how long?
Jean-Francois Bergmann, PhD, MD
Hopital Lariboisiere-University Paris VIIParis, France