Extended Low-intensity Anticoagulation for Unprovoked VTE
Extended Low-intensity Anticoagulation for Unprovoked VTE
Presenter: Clive Kearon, MB, PhD (McMaster University, Hamilton, Ontario, Canada)
A substudy of the Extended Low-intensity Anticoagulation for Unprovoked Venous ThromboEmbolism (ELATE) trial has shown that thrombophilia does not appear to increase the risk of recurrent venous thromboembolism (VTE) during warfarin therapy. Laboratory "abnormalities" associated with VTE (thrombophilia) are present in about 50% of patients who have had an unprovoked episode of VTE and are of clear pathophysiologic and epidemiologic importance, although of uncertain clinical importance for patients with VTE. It was suggested that if the abnormalities predict a substantial increase in recurrent VTE during treatment, these patients might require higher intensity of anticoagulant treatment or different treatment from those without thrombophilia.
The ELATE substudy reported by Dr. Kearon examined whether the risk of recurrent VTE during anticoagulant therapy is increased by the presence of factor V Leiden, the prothrombin gene mutation, antiphospholipid antibody (lupus anticoagulants [LAC] and/or anticardiolipin antibodies [ACLA]), antithrombin deficiency (< 0.79 U/mL), elevated levels of factor VIII (> 90%, > 2.59 U/mL) or factor XI (> 90%, > 1.93 U/mL), elevated homocysteine (> 90%, 15.4 Umol/L), or combinations of these abnormalities.
In the main ELATE study, a multicenter, randomized, double-blind trial that was completed in 2002, a total of 738 patients with ≥ 1 unprovoked episodes of VTE were randomly allocated to extended treatment with either low-intensity warfarin (INR, 1.5-1.9) or conventional-intensity warfarin (INR, 2.0-3.0). All patients had previously completed ≥ 3 months of initial conventional-intensity therapy. Patients were on treatment for a total of 1600 patient-years, during which time 14 patients had a recurrent VTE (0.9% per patient-year) on treatment (11 on low-intensity treatment and 3 on conventional-intensity treatment). There were no differences in major or total bleeding between the 2 groups.
About 650 (88%) of the ELATE patients were tested for the presence of thrombophilia, and Cox proportional modeling was used to determine whether single or multiple thrombophilic states were associated with recurrent VTE during anticoagulant therapy. On-treatment analysis of the rate of recurrent VTE among these patients was consistent with, but with more marked effect than, the original study, with fewer in the conventional-intensity treatment group (HR, 3.8; 95% CI, 1.1,14).
None of seven thrombophilic states investigated could be shown to be a risk factor for VTE during warfarin therapy (Table).
Table. ELATE: Prevalence of Thrombophilic States and Hazards for Venous Thomboembolism
This study also showed that recurrent VTE is very uncommon in patients with unprovoked VTE and thrombophilia who are treated with warfarin. In Dr. Kearon's opinion, these results, together with those of other, similar studies, suggest that it is unnecessary to test for thrombophilia in such patients, a view that received some support in subsequent discussion with the audience.
References
Presenter: Clive Kearon, MB, PhD (McMaster University, Hamilton, Ontario, Canada)
A substudy of the Extended Low-intensity Anticoagulation for Unprovoked Venous ThromboEmbolism (ELATE) trial has shown that thrombophilia does not appear to increase the risk of recurrent venous thromboembolism (VTE) during warfarin therapy. Laboratory "abnormalities" associated with VTE (thrombophilia) are present in about 50% of patients who have had an unprovoked episode of VTE and are of clear pathophysiologic and epidemiologic importance, although of uncertain clinical importance for patients with VTE. It was suggested that if the abnormalities predict a substantial increase in recurrent VTE during treatment, these patients might require higher intensity of anticoagulant treatment or different treatment from those without thrombophilia.
The ELATE substudy reported by Dr. Kearon examined whether the risk of recurrent VTE during anticoagulant therapy is increased by the presence of factor V Leiden, the prothrombin gene mutation, antiphospholipid antibody (lupus anticoagulants [LAC] and/or anticardiolipin antibodies [ACLA]), antithrombin deficiency (< 0.79 U/mL), elevated levels of factor VIII (> 90%, > 2.59 U/mL) or factor XI (> 90%, > 1.93 U/mL), elevated homocysteine (> 90%, 15.4 Umol/L), or combinations of these abnormalities.
In the main ELATE study, a multicenter, randomized, double-blind trial that was completed in 2002, a total of 738 patients with ≥ 1 unprovoked episodes of VTE were randomly allocated to extended treatment with either low-intensity warfarin (INR, 1.5-1.9) or conventional-intensity warfarin (INR, 2.0-3.0). All patients had previously completed ≥ 3 months of initial conventional-intensity therapy. Patients were on treatment for a total of 1600 patient-years, during which time 14 patients had a recurrent VTE (0.9% per patient-year) on treatment (11 on low-intensity treatment and 3 on conventional-intensity treatment). There were no differences in major or total bleeding between the 2 groups.
About 650 (88%) of the ELATE patients were tested for the presence of thrombophilia, and Cox proportional modeling was used to determine whether single or multiple thrombophilic states were associated with recurrent VTE during anticoagulant therapy. On-treatment analysis of the rate of recurrent VTE among these patients was consistent with, but with more marked effect than, the original study, with fewer in the conventional-intensity treatment group (HR, 3.8; 95% CI, 1.1,14).
None of seven thrombophilic states investigated could be shown to be a risk factor for VTE during warfarin therapy (Table).
Table. ELATE: Prevalence of Thrombophilic States and Hazards for Venous Thomboembolism
| Specific Abnormalities | Prevalence (%) | Rate of Recurrent VTE | HR (95% CI) |
|---|---|---|---|
| Factor V Leiden | 26 | 3/171 | 0.7 (0.2-2.6) |
| Prothrombin gene mutation | 9 | 0/60 | 0 |
| Antiphospholipid antibody | 8 | 3/54 | 2.9 (0.6-11) |
| Antithrombin deficiency | 4 | 0/23 | 0 |
| Factor VIII elevation | 10 | 1/67 | 0.7 (0.1-5.4) |
| Factor XI elevation | 10 | 1/66 | 0.7 (0.1-5.0) |
| Homocysteine | 10 | 1/64 | 0.7 (0.8-11) |
| ≥ 2 | 17 | 2/111 | 0.8 (0.4-1.7) |
This study also showed that recurrent VTE is very uncommon in patients with unprovoked VTE and thrombophilia who are treated with warfarin. In Dr. Kearon's opinion, these results, together with those of other, similar studies, suggest that it is unnecessary to test for thrombophilia in such patients, a view that received some support in subsequent discussion with the audience.
References
Kearon C, Ginsberg JS, Kovacs M, et al, for the ELATE Investigators. Influence of thrombophilia on efficacy of warfarin for prevention of recurrent venous thromboembolism: results from a randomized trial. Program and abstracts of the XIX Congress of the International Society on Thrombosis and Haemostasis; Birmingham, UK, July 12-18, 2003. Abstract OC002. Available at
http://www.blackwellpublishing.com/ isth2003/abstract.asp?id=7715.
Kearon C, Ginsberg JS, Kovacs M, et al, for the ELATE Investigators. Low-intensity (INR 1.5-1.9) versus conventional-intensity (INR 2.0-3.0) anticoagulation for extended treatment of unprovoked VTE: a randomized double blind trial. The American Society of Hematology 44th Annual Meeting; December 6-10, 2002; Philadelphia, Pennsylvania. Abstract 562.