Duration of anticoagulation for venous thromboembolismBMJ 2011; 342 doi: http://dx.doi.org/10.1136/bmj.d2758 (Published 24 May 2011) Cite this as: BMJ 2011;342:d2758
- Saskia Middeldorp, professor of medicine
Venous thromboembolism affects 2-3 per 1000 men and women annually, with a case fatality rate of around 10%, and it results in post-thrombotic syndrome in about a quarter of patients. After anticoagulant treatment is stopped, venous thromboembolism often recurs, with reported cumulative incidences ranging from 19% to 30% in cohorts followed for two to eight years.1 2 Vitamin K antagonists reduce the risk of recurrent venous thromboembolism by more than 80% but also cause major bleeding in a substantial number of patients on long term treatment.3 Thus, the optimum duration of anticoagulant treatment after an episode of venous thromboembolism remains uncertain, despite many trials that have compared different lengths of treatment⇑.
In the linked meta-analysis of individual participants’ data (doi:10.1136/bmj.d3036), Boutitie and colleagues compare outcomes after different lengths of anticoagulant treatment.4 An advantage of this individual patients’ data approach over meta-analysis on a study level is that it is a more sensitive way to identify prognostic factors that are associated with a high or a low risk of recurrence in relation to a specific length of treatment. The main finding of the analysis is that there is no benefit of continuing to treat for more than three months if the intention is to stop eventually, regardless of the initial location of venous thromboembolism and the presence of provoking risk factors. However, an anticoagulant course shorter than three months increases the risk of recurrent venous thromboembolism by 50% (hazard ratio 1.52, 95% confidence interval 1.14 to 2.02).4
A potential disadvantage of the method is that studies are selectively included on the basis of the willingness of investigators to make their crude data available. However, the included studies represent most contemporary trials, and the results do not differ importantly from those of other meta-analyses that were performed at a study level.3 Cohort studies have also consistently found a lower risk of recurrent venous thromboembolism after thrombosis that was provoked by a temporary risk factor than for unprovoked thrombosis (0.55, 0.41 to 0.71).1 The rapid decrease in recurrence rate over time after stopping anticoagulant treatment has also been shown in a previous meta-analysis.5 Finally, a lower risk of recurrence after distal deep vein thrombosis—below the trifurcation of the popliteal veins (0.49, 0.34 to 0.71)—has been described previously.6
Does the current meta-analysis answer the difficult question of how long patients with venous thromboembolism should be given anticoagulants. The guidelines of the American College of Chest Physicians (ACCP), which were written by a subset of the authors of the meta-analysis, recommend at least a three month course for all patients with an unprovoked episode of venous thromboembolism, and indefinite anticoagulant treatment for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism and a low risk of bleeding when this concurs with the patient’s preference.6 This recommendation is based on the absolute risk of recurrence of about 10 per 100 patient years that is seen in these patients, both in trials and cohorts.
The problem with anticoagulant treatment is the associated risk of bleeding. A meta-analysis of 33 trials and prospective cohort studies showed that the case fatality rate of major bleeding was 13.4% (9.4% to 17.4%) and the rate of intracranial bleeding was 1.15 (1.14 to 16) per 100 patient years.7 For patients who received anticoagulants for more than three months—that is, those patients who might be considered for lifelong treatment according to the ACCP guidelines—the case fatality rate of major bleeding remained high at 9.1% (2.5% to 21.7%), and the rate of intracranial bleeding was 0.65 (0.63 to 0.68) per 100 patient years.
Given that the case fatality rate of recurrent venous thromboembolism decreases over time,8 whereas the risk of major bleeding increases with age, the optimum length of anticoagulant treatment after an episode of venous thromboembolism remains uncertain. In accordance with this, many clinicians are not ready to prescribe indefinite treatment in all patients with an unprovoked proximal deep vein thrombosis or pulmonary embolism.9 Unfortunately, the current patient level meta-analysis has been unable to answer important questions in the search for better risk stratification of patients by simple prognostic characteristics including sex,10 presence of intermediate risk factors such as oestrogen use,11 and indicators of an ongoing prothrombotic state.12 Such analyses are urgently needed to determine which patients with unprovoked venous thromboembolism have a high enough risk of recurrence to justify the use of harmful drugs indefinitely.
Cite this as: BMJ 2011;342:d2758
Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.