Lack of Residual Vein Thrombosis Predicts for Low Risk of Recurrent DVT
September 1, 2008
Lack of Residual Vein Thrombosis Predicts for Low Risk of Recurrent DVT
Abstract & Commentary
By Andrew Artz, MD, Division of Hematology/Oncology, University of Chicago, Chicago. Dr. Artz reports no financial relationship to this field of study.
Synopsis: The optimal duration of oral anticoagulation therapy after an initial symptomatic deep venous thrombosis remains unknown. Siragusa and investigators assessed patients by ultrasonography for the presence of residual vein thrombosis (RVT) after 3 months of anticoagulation for a DVT. Those with RVT were randomized to 9 additional months of anticoagulation versus discontinuation. Among the 70% with RVT, prolonged anticoagulation showed only a non-significant trend for reducing recurrent DVT. For the 30% without RVT, all of whom stopped anticoagulation after 3 months, only 1 of 78 patients (1.3%) developed a recurrent DVT. For select patients, the lack of RVT after initial anticoagulation identifies patients where anticoagulation may be safely discontinued. The optimal duration of anticoagulation for higher risk patients, including those with RVT, remains undefined.
Source: Siragusa S, et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood. 2008;vol.112: 511-515.
Venous thrombo-embolism, a problem encompassing both pulmonary embolus and deep venous thrombosis, accounts for considerable morbidity and mortality. Immediate anticoagulant therapy significantly reduces complications such as pulmonary embolus and post-phlebetic syndrome. After initial therapy with intravenous heparin or low molecular weight heparin, most patients are safely transitioned to maintenance oral anticoagulation therapy (OAT) using warfarin.
A first episode of deep venous thrombosis (DVT) of the lower limbs associated with a reversible risk factor such as surgery leads to a recommendation of 3 months of anticoagulation. Six months or greater of OAT will generally be advised for an idiopathic DVT.1
Recurrent thrombosis is dramatically reduced by maintenance OAT.2 Unfortunately, after discontinuation of OAT therapy, recurrent DVT persists as a major risk, even after prolonged anticoagulation. Further, prolonged OAT exposes patients to the danger of serious bleeding as well as the expense and effort of monitoring therapy.3 Thus, the optimal duration of anticoagulation remains unknown.
Risk stratification tools, such as D-dimer levels4 and residual vein thrombosis (RVT)5,6, are being developed to select which patients are at higher risk of recurrences to determine who may or may not benefit from prolonged OAT.
In this study, Siragusa and colleagues performed a multi-center study of DVT patients addressing the impact of RVT as well as the benefit of prolonged anticoagulation for those found to have RVT.
Patients completing 3 months of OAT with a target INR between 2-3 for an idiopathic or provoked symptomatic DVT were eligible. However, patients with a high risk of recurrence were excluded, such as active cancer, antiphospholipid antibody syndrome, protein C or S deficiency, or homozygosity for factor V Leidin and/or the prothrombin gene mutation. Compression ultrasonography was performed on the affected leg after 3 months of oral anticoagulation therapy. A residual vein thrombosis (RVT) was defined as the presence of 40% or more of the vein not compressed compared to non-compression in at least 1 of the 2 segments examined. Patients with RVT were randomized to 9 additional months of OAT (1 year total) or discontinuation. OAT was also discontinued in those without RVT. Patients were followed for a total of 2 years from diagnosis.
Of the 312 patients enrolled, 54 were excluded because of lack of informed consent or because long-term OAT was indicated. The study was stopped early at 258 evaluable patients because not giving prolonged OAT to those with RVT was considered harmful. RVT was present in 70% of patients at the end of 3 months of OAT. Among them, 92 were randomized to 9 more months OAT and 88 were randomized to discontinue OAT. Not surprisingly, a higher proportion of idiopathic DVT (around 75 to 78%) vs provoked DVT (22-25%) had RVT compared to no RVT. The 78 (30%) without RVT discontinued OAT.
Recurrent thrombotic events occurred in only 1.3% of those without RVT during the 2 year course of the study. In contrast, a highly significant recurrence risk of 23% was found among those with RVT. For those with RVT, the recurrence risk of 10.1% for those randomized to prolonged OAT was not statistically different from the incidence of 15.2 for those who discontinued OAT (P = 0.421 for the difference). Interestingly, around 20% of recurrences were in the contra-lateral leg from the RVT. Major bleeding was rare, occurring in only 3 patients in the entire study cohort.
Commentary
Deep venous thrombosis (DVT) persists as one of the most common challenges. Although the question asked often centers on the appropriate evaluation to exclude contributing factors, the true therapeutic question for which testing is focused relates to the duration of anticoagulation. Despite numerous randomized studies, the optimal duration of anticoagulation often remains unclear.
This study suggests that assessing for residual vein thrombosis (RVT) by compression ultrasonography may have a clinical role in identifying patients who may safely discontinue anticoagulation after 3 months. Specifically, in those without RVT, only one of the 78 patients had a recurrent DVT. In contrast, for those with RVT after 3 months of OAT, a considerable fraction had recurrences, either with 9 additional months of anticoagulation (19%) or without (27%).
Unfortunately, for those with RVT, prolonged OAT did not significantly reduce recurrence risk because recurrence frequently occurred at the conclusion of OAT. Other studies have reported similar findings; recurrences tend to occur after completing OAT and do not seem mitigated by longer initial OAT.7 The authors argue the study results support even longer anticoagulation than 9 additional months in the study. A contrasting view is that most (70 to 80%) patients do not recur, and we should avoid exposing everyone to continued OAT. Irrespective, once patients stop anticoagulation, particularly if they have RVT, very close monitoring and patient education is warranted.
Elevations of D-dimer have also been studied as a marker of an increased risk of DVT recurrence, although the data are limited in that D-dimer assessment occurred one month after stopping OAT.4 Since DVT recurrences often manifest shortly after stopping OAT, studies performed before discontinuation hold greater promise. Further investigation will be required to compare RVT and D-dimer levels.
The authors confirm previous reports addressing RVT; DVT recurrence is not restricted to the affected leg 5,6 as 20% occurred in the contra-lateral leg from the initial DVT and finding of RVT. These data support the hypothesis that such patients are systemically predisposed to DVT. The fact that prolonged OAT delayed but did not mitigate subsequent DVT recurrences, further buttresses the concept of RVT being a marker for a procoagulant state.
Important limitations to the study warrant discussion. The study excluded patients known to have a high risk recurrence such as those with cancer and thrombophilias with a high recurrence risk (eg, antiphospholipid antibody syndrome). Thus, these data apply to select patients. Most difficult is that RVT is non-specific; the majority of patients had RVT but most of these did not recur, either with or without prolonged OAT. Whether the finding of RVT really changes clinical practice can be argued since most patients without RVT had a provoked DVT. Stopping anticoagulation therapy would be the standard of care without a second ultrasound at 3 months. Similarly, the majority of patients with RVT had idiopathic DVT's and normally would undergo a longer duration of OAT.
In summary, the finding of residual vein thrombosis after 3 months of anticoagulation for a symptomatic DVT in select patients appears to identify a subset that may be considered for discontinuing anticoagulation therapy. For those having RVT, prolonged OAT or very close monitoring for recurrence are necessary.
References
1. Pinede L, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation. 2001;103:2453-60.
2. Hull R, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979;301:855-858.
3. Linkins LA, et al. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med. 2003;139:893-900.
4. Palareti G, et al. D-dimer testing to determine the duration of anticoagulation therapy. NEJM. 2006;355:1780-1789.
5. Piovella F, et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica. 2002;87:515-522.
6. Prandoni P, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002;137:955-960.
7. Agnelli G, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. NEJM. 2001;345:165-169.
The optimal duration of oral anticoagulation therapy after an initial symptomatic deep venous thrombosis remains unknown.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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