No Increase in Recurrent DVT Despite Thrombophilic Risk Factors

Abstract & Commentary

By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.

Synopsis: The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism and bleeding in patients receiving long-term anticoagulation remains unclear.

Source: Wahlander K, et al. Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long-term secondary prevention of venous thromboembolism. Br J Haematol. 2006;133:68-77.

This study represents a reanalysis of a large randomized trial comparing ximelagatran to placebo to reduce recurrence of venous thromboembolism (VTE) following 6 months of standard anticoagulation following after an initial VTE. Six common prothrombotic risk factors were ascertained by laboratory testing (factor V Leiden, prothrombin gene mutation, protein C, protein S, antithrombin, and anticardiolipin antibodies). At least one risk factor was identified in 41% of patients and 2 or more in 8% (21% of all subjects showed a factor V Leiden mutation). The reanalysis continued to show fewer VTE recurrences with extended anticoagulation using ximelagatran. However, prothrombotic risk factors had no impact on recurrence or bleeding in either arm compared to those without these risk factors. Thus, the common laboratory identified prothrombotic risk factors for VTE did not indicate subgroups for the risks or benefits of therapy might differ. Further research is warranted to better stratify recurrence risk after a standard course of 6 months of anticoagulation for VTE.

VTE is a common disorder with significant morbidity. At least one third will harbor a thrombophilic defect on routine laboratory testing. Anticoagulation remains standard therapy but the efficacy of prolonged anticoagulation compared to standard duration anticoagulation (usually 6 months), raises the question of optimal anticoagulation duration.1,2 Previously, the authors reported the Thrombin Inhibitor in Venous Thromboembolism (THRIVE) III trial showing increased efficacy of an additional 18 months of ximelagatran, an oral direct thrombin inhibitor, compared to placebo for reducing recurrent VTE after a 6-month course of standard anticoagulation (P < 0.001).3 In this study, the authors explore whether the presence of a laboratory identified thrombophilic risk factors increases VTE recurrence over those without risk factors from the THRIVE III trial.

In this updated analysis, they identified prothrombotic risk factors (eg, heterozygosity for factor V Leiden or prothrombin gene G20210A mutation, deficiencies of protein C, S or anti-thrombin, presence of anticardiolipin antibodies). Among the 1223 patients across 142 centers, 559 were in the ximelagatran arm and 540 in the placebo arm. Prothrombotic risk factors occurred in 41% of patients, among whom 8% had 2 or more risk factors, equally distributed between treatment arms. Factor V Leiden and prothrombin gene mutations occurred in 21% and 5% of patients, respectively. Investigators were not made aware of the thrombophilia screening results.

The updated analysis continued to show prolonged anticoagulation with ximelagatran reduced VTE recurrence over placebo and was not impacted by prothrombotic risk factors. Within the placebo group, VTE recurrence was not impacted prothrombotic risk factors. Similar results were seen in the treatment arm except for a small subset with low protein C where an VTE recurrence occurred more often. Bleeding risk was not altered by the presence of a prothrombotic risk factor (one might hypothesize a lower bleeding risk in the presence of a prothrombotic risk factor) in either the treatment or placebo group.

Commentary

Determining the optimal duration of anticoagulation after a VTE remains elusive. While randomized studies have shown fewer recurrences with prolonged anticoagulation, the inconvenience, costs, and risks of prolonged therapy can not be minimized, especially absent improved overall survival. Identifying patients at higher risk of VTE recurrence who might derive a larger relative risk reduction from prolonged anticoagulation would have enormous clinical value and also help guide clinical testing.

The findings of this study are consistent with most other data that the common laboratory defined prothrombotic risk factors may not appreciable impact recurrence risk. Despite the general notion that common mutations such as factor V Leiden or the prothrombin gene mutation place patients at very high risk of thrombosis, this study again supports the concept that heterozygosity for factor V Leiden or the prothrombin gene mutation did not increase recurrence risk over patients without a risk factor. Considering multiple effects, both genetic and environmental alike, probably combine to predispose to VTE, finding a single defect that accurately predicts recurrence risk for the majority of patients seems improbable. It is important to note that inferences are limited among subgroups of patients often considered at very high risk, such as antiphospholipid antibody syndrome (only anticardiolipin antibodies on a single test were performed) or homozygous factor V Leiden (small number).

In summary, common prothrombotic risk factors do not strongly influence VTE recurrence over patients without laboratory evidence of a risk factor. Future studies designed at better defining subsets with different VTE recurrence risks are sorely needed to tailor therapy towards individual risk.

References

1. Ridker PM, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434.

2. Schulman S, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997;336:393-398.

3. Schulman S, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003;349:1713-1721.