25th August 2011
A pooled analysis of data from seven randomised controlled trials (RCTs) suggests that three months of anticoagulant treatment is generally sufficient following a venous thromboembolism (VTE) unless there is a high risk of recurrence. Unprovoked proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) have a high risk of recurrence and may require a longer or indefinite anticoagulation, whereas a shorter duration of treatment may be appropriate for isolated distal DVT.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
This study reinforces the recommendations given in the Scottish Intercollegiate Guidelines Network (SIGN) guideline for the prevention and management of VTE and the British Committee for Standards in Haematology (BCSH) guideline for anticoagulation treatment in the management of VTE. Under normal circumstances at least three months of anticoagulant therapy should be given, although this can be shortened or lengthened in certain circumstances, depending on an assessment of the risks and likely benefits from treatment for an individual patient and taking into account their preferences.
What is the background to this?
The current practice for treating VTE (which encompasses DVT and PE) is anticoagulation. There is wide variation in practice, but patients are usually given a brief course of heparin treatment while they start on a 3 to 6 month course of warfarin. Patients who have recurrent VTE are often given life-long treatment with anticoagulants.
There have been several studies that have compared different durations of treatment, although no optimal length of treatment has been established. By pooling individual patient data from seven individual studies, the authors were able to evaluate a range of treatment durations in an attempt to identify the optimal duration of anticoagulant treatment. By increasing the numbers of patients included in the analysis, the authors also investigated how the risk of recurrence varied in defined subgroups (e.g. type of VTE, whether the VTE was unprovoked or provoked by risk factors, such as recent surgery, etc.)
What does this study claim?
The authors found that three months of anticoagulant treatment was associated with a similar risk of recurrent VTE as longer courses of treatment. Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (HR 1.19, 95%CI 0.86 to 1.65).
In addition the study found that the risk of recurrent VTE was approximately doubled for a proximal DVT or PE compared with an isolated distal DVT, and it was also approximately doubled if the thrombosis was unprovoked rather than provoked by a temporary risk factor.
SIGN guideline for prevention and management of VTE (December 2010) states that after a first episode of proximal limb DVT or PE, treatment with a vitamin K antagonist (e.g. warfarin) should be continued for at least three months. However, uninterrupted long term continuation may be appropriate in some patients and can be based on individual assessment, including:
- an unprovoked first event
- the site and severity of the first event
- the presence of persistent comorbidities, e.g. cancer
- the presence of persistent antiphospholipid antibodies
- male sex
- bleeding risk on anticoagulant treatment
- patient compliance and preference.
The BCSH guidelines on oral anticoagulation with warfarin (4th Edition 2011) recommends that proximal DVT or PE should be treated for at least three months. Where an isolated calf vein DVT is diagnosed, treatment can be restricted to six weeks.
Both SIGN and BCSH guidelines recommend treatment with low molecular weight heparin, and not warfarin, for cancer associated VTE.
The decision to continue anticoagulant treatment beyond the first few months is based on a balanced judgement of the potential benefits (e.g. reduced risk of recurrence) and harms of treatment (e.g. increased risk of bleeding) and on the preference of the patient. The study results suggest that for patients who have a VTE, and for whom indefinite anticoagulant treatment is not indicated, anticoagulant treatment could generally stop at three months. Based on subgroup analyses, the study also suggests that for patients with an isolated distal DVT, who need to stop before three months of treatment, the risk is not excessive. This is consistent with the shorter duration recommended for this in the BCSH guideline. However, patients with unprovoked VTE or PE, who have a higher risk of recurrence, may benefit from longer, possibly indefinite, durations of treatment. Although consistent with the guideline recommendations, the findings of these subgroup analyses are not definitive, and further studies are required for confirmation.
Boutitie F, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. BMJ 2011; 342:d3036
Pooled analysis of individual participants’ data from seven RCTs.
2925 patients (mean age 60.5, 52% male) with a first VTE (20% distal DVT, 52% proximal DVT, 29% PE) who did not have cancer. The mean follow up was 1.4 years per patient.
Intervention and comparison
The risk of recurrent VTEs was evaluated and compared for anticoagulant treatments given for different durations (1 or 1.5 months, 3 months, 6 months, 12 or 27 months). The effect of baseline factors was investigated with a Cox proportional hazards model; adjustments were made for age and sex.
Outcomes and results
Recurrence of VTE was lower after isolated distal DVT than after proximal DVT (HR 0.49, 95%CI 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (HR 1.19, 95%CI 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (HR 0.55, 95%CI 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (HR 1.52, 95%CI 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (HR 1.19, 95%CI 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment.
This study was supported by a grant from the French Ministry of Health. The corresponding author was supported by the Heart and Stroke Foundation of Ontario and by a Canadian Institutes of Health Research Team grant.
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