Fewer venous thromboembolism recurrences occurred with 6 months than with 6 weeks of anticoagulant therapy
ACP J Club. 1996 Jan-Feb;124:9. doi:10.7326/ACPJC-1996-124-1-009
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• Correction: Fewer venous thromboembolism recurrences occurred with 6 months than with 6 weeks of anticoagulant therapy
Schulman S, Rhedin AS, Lindmarker P, et al. and the Duration of Anticoagulation Trial Study Group. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995 Jun 22;332:1661-5. [PubMed ID: 7760866]
To compare 6 weeks with 6 months of oral anticoagulant therapy in patients who have had a first episode of deep venous thrombosis (DVT) or pulmonary embolism (PE).
Randomized controlled trial with 2-year follow-up.
16 centers in Sweden.
897 patients (mean age 61 y, 56% men) who were ≥ 15 years of age with a first episode of DVT confirmed by venography or PE confirmed by angiography or by chest radiography and perfusion-ventilation lung scanning. Exclusion criteria were pregnancy; allergy to warfarin or dicumarol; indication for continuous oral anticoagulation; paralysis of the affected leg; contraindication to compression stocking use; current or previous venous ulcer; cancer; ≥ 1 previous thromboembolic event; or congenital deficiency of antithrombin, protein C, or protein S. Follow-up was complete.
Patients were assigned to oral anticoagulation with warfarin sodium or dicumarol, targeted to an INR of 2.0 to 2.85 for 6 weeks (n = 443) or 6 months (n = 454).
Main Outcome Measures
Recurrent venous thromboembolism, major hemorrhage during oral anticoagulation, or death during the 2-year study period.
Analysis was by intention to treat. Six months of anticoagulation led to fewer recurrences of venous thromboembolism at 2 years than did 6 weeks of anticoagulation (9.5% vs 18.1%, P < 0.001) (Table). 53% of the recurrences in the 6-week group occurred within 6 months of cessation of therapy. From 6 months on, the rate of recurrence in the 2 groups was similar. Patients receiving oral anticoagulant therapy for 6 weeks compared with those receiving it for 6 months did not differ for major hemorrhage (1 [0.2%] vs 5 patients [1.1%], P = 0.23) or death (22 patients [5.0%] vs 17 patients [3.7%], P = 0.46).
In patients with a first episode of deep venous thrombosis or pulmonary embolism, fewer recurrences of venous thromboembolism occurred in patients receiving 6 months of oral anticoagulant therapy compared with those receiving 6 weeks of therapy.
Sources of funding: Swedish Heart Lung Foundation; Swedish Society of Medicine; Karolinska Institute; Skandia; Trygg-Hansa; Triolab; Karolinska Hospital; Nycomed; Stago.
For article reprint: Dr. S. Schulman, Coagulation Unit, Karolineska Hospital, S-17176 Stockholm, Sweden FAX 468-517-75084.
Table. Long-term (6-mo) vs short-term (6-wk) of anticoagulant therapy to prevent recurrence of deep venous thrombosis or pulmonary embolism*
|Outcomes at 24 y||Long-term||Short-term||RRR (95% CI)||NNT (CI)|
|Recurrence of venous thromboembolism||9.5%||18.1%||48% (23 to 63)||12 (8 to 24)|
|Death||3.7%||5.0%||25% (-39 to 59)||Not significant|
*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
The study by Schulman and colleagues is the largest of 6 randomized trials that have addressed treatment duration in patients with DVT or PE (1). Although the interventions were not blinded, bias was reduced by using objective diagnoses for both the qualifying thromboembolic events and for the recurrences, and by blinding outcome adjudication.
Only 1% of patients had recurrent thromboembolic events while receiving anticoagulants, and only 1% of patients who were anticoagulated for 6 months had major bleeding. Even after 6 months of therapy, a constant rate of recurrence of approximately 5.4%/y was observed. The additional events observed in patients treated for 6 weeks were clustered in the 4 months after cessation of anticoagulation.
When data from this trial are considered with findings from other treatment studies, a clearer picture of the optimal duration of oral anticoagulation emerges (1-3). Duration of treatment should be individualized based on the extent of thrombosis (calf or proximal) and on the patient's competing risks for recurrence and major bleeding (2-4). In this trial, the reduction in relative risk with 6 months compared with 6 weeks of therapy was about 50% in all subgroups. The risk for recurrence was 8.6% in patients with a temporary risk factor who had 6 weeks of therapy and 24.4% for those with a permanent or unknown risk factor. This means that 26 patients with reversible risk factors and 8 patients without reversible risk factors would need to be treated for 6 months rather than 6 weeks to prevent a recurrence. Therefore, for patients at average risk for bleeding and with a reversible risk factor, we would be preventing at least 4 recurrences for every bleed we caused, and for the high-risk patients without reversible risk factors we would be preventing at least 12 recurrences. This suggests that we should treat patients for 6 months if they are at low risk for bleeding. In patients at higher risk for bleeding, clinicians must carefully consider the trade-off between recurrences prevented and bleeding caused.
William H. Geerts, MD
Sunnybrook Health Science CentreToronto, Ontario, Canada
Since the publication of the study by Schulman and colleagues, several relevant studies and reviews have been published (1-3). The recommended duration of anticoagulation should be individualized, based on the benefit-risk ratio for each patient taking into account the risk for recurrence if therapies are discontinued and the risk for bleeding if anticoagulation is continued.
The following factors affect the risk for recurrence: proximal DVT or PE, persistent risk factor, idiopathic VTE, molecular hypercoagulability, active cancer, and multiple episodes of VTE.
Factors that decrease the risk for recurrence are calf DVT and transient, reversed risk factor.
The following are lists of factors that affect the risk for bleeding: elderly, being a woman, early after the start of anticoagulant therapy, personal physician monitoring, previous GI bleeding or stroke, chronic renal failure, cancer, concomitant use of antiplatelet drugs, high INR values, and unstable INR values.
Factors that decrease the risk for bleeding are: young, being a man, later after the start of anticoagulant therapy, and being monitored at an anticoagulant clinic.