Continuing anticoagulants for recurrent venous thromboembolism was better than 6-month anticoagulant therapy

ACP J Club. 1997 Jul-Aug;127:5. doi:10.7326/ACPJC-1997-127-1-005

Source Citation

Schulman S, Granqvist S, Holmström M, et al., and the Duration of Anticoagulation Trial Study Group. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997 Feb 6;336:393-8.

Abstract

Objective

To compare 6 months of anticoagulant therapy with an indefinite treatment period in patients with second episodes of venous thromboembolism.

Design

Randomized controlled trial with 4-year follow-up.

Setting

16 medical centers in Sweden.

Patients

227 patients (mean age 64 y, 61% men) who were ≥ 15 years of age and had had second episodes of acute pulmonary embolism or deep venous thrombosis in the leg, iliac veins, or both. Diagnoses were confirmed by venography, angiography, or the combination of chest radiography and ventilation-perfusion lung scanning.

Intervention

Patients were allocated to anticoagulant therapy for 6 months (n = 111) or to anticoagulation for an indefinite period (n = 116). Initial treatment was unfractionated or low-molecular-weight heparin given for ≥ 5 days; anticoagulation with warfarin sodium or dicumarol was usually started at the same time as heparin therapy. The target international normalized ratio (INR) was 2.0 to 2.85.

Main outcome measures

Recurrent venous thromboembolism, major hemorrhage, and death.

Main results

Analysis was by intention to treat. Patients who received anticoagulant therapy had a lower rate of recurrent venous thromboembolic events than patients who received therapy for 6 months (P < 0.001) (Table). A trend toward a greater rate of major hemorrhage existed in patients who received anticoagulant therapy indefinitely (8.6% vs 2.7%, P = 0.08; {CI for the 5.9% absolute risk increase -12.8% to 0.15%}*). The groups did not differ for death (8.6% vs 14.4%, P = 0.2; {CI for the 5.8% absolute risk reduction -2.6% to 14.6%}*).

Conclusion

In patients with second episodes of venous thromboembolism, the risk for recurrent thromboembolic events was reduced when anticoagulant therapy was continued indefinitely compared with 6-month administration, but this was accompanied by a trend toward increased major hemorrhage.

Sources of funding: Swedish Heart Lung Foundation; Swedish Society of Medicine; Karolinska Institute; Skandia; Trygg-Hansa; Triolab; Nycomed; Stago.

For article reprint: Dr. S. Schulman, Department of Internal Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden. FAX 46-8-317303.

Table. Indefinite vs 6-month anticoagulation†

Outcome	Indefinite EER	6-month CER	RRR (95% CI)	ARR \|CER - EER\|	NNT (CI)
Recurrent venous thromboembolism	2.6%	20.7%	88% (63 to 96)	18.1%	6 (4 to 10)

†Abbreviations defined in Glossary; RRR, ARR, NNT, and CI calculated from data in article.

Commentary

This study by Schulman and colleagues supports the hypothesis that some patients with recurrent venous thromboembolism are at increased risk for further recurrence when anticoagulation is stopped. Risk factors for recurrence include the factor V-Leiden mutation (1), deficiencies of antithrombin III and protein C or S, cancer, and prolonged immobilization (2).

In this study, the incidence of recurrent venous thromboembolism was decreased by 18% in patients who received indefinite treatment with warfarin targeted to an INR of 2 to 2.85. An important finding in this study and in a recent study of patients with the factor V-Leiden mutation (1) is that thromboembolism often recurs 1 to 4 years after the initial episode. The incidence of recurrent thromboembolism in high-risk patients may approach 20% during long-term follow-up (1). Although recurrent thromboembolism was not invariably fatal in this study, the relatively modest risk for bleeding (5% to 7% annually) with the INR targeted to this range has been argued to be cost-effective compared with shorter-term anticoagulant treatment (2).

This study combined patients with temporary and permanent risk factors. Whether indefinite anticoagulant therapy should be considered in patients with thromboembolism and permanent risk factors, including idiopathic venous thromboembolism, is unknown, but studies in this area are currently being done. For the present, clinicians may consider indefinite anticoagulant therapy in high-risk patients with a second episode of venous thromboembolism.

Paul R. Eisenberg, MD
Washington University School of MedicineSt. Louis, Missouri, USA

Paul R. Eisenberg, MD
Washington University School of Medicine
St. Louis, Missouri, USA

References

1. Ridker PM, Miletich JP, Stampfer MJ, et al. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation. 1995;92:2800-2.

2. Hyers TM, Hull RD, Weg JG. Anti-thrombotic therapy for venous thromboembolic disease. Chest. 1995;108:335S-51S.