Elsevier

The Lancet

Volume 368, Issue 9533, 29 July–4 August 2006, Pages 371-378
The Lancet

Articles
Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis

https://doi.org/10.1016/S0140-6736(06)69110-1Get rights and content

Summary

Background

Individual risk of recurrent venous thromboembolism affects patient management and might differ between men and women. We did a meta-analysis to assess from available evidence whether men and women have the same risk of recurrent venous thromboembolism after stopping anticoagulant treatment.

Methods

Eligible articles were identified by searches of MEDLINE (source PubMed, 1966 to February 2005), EMBase (1980 to February 2005), and the Cochrane database 2005, issue 1. Prospective cohort studies and randomised trials were eligible if they included patients with objectively diagnosed venous thromboembolism treated for a minimum of 1 month and followed up for recurrence after anticoagulant treatment was stopped. Data were extracted for study design, study quality, and the number, sex, and age of enrolled patients, risk factors for venous thromboembolism, treatment given, duration of follow-up, and the number of episodes of recurrent venous thrombosis.

Findings

15 studies (nine randomised controlled trials and six prospective observational studies) enrolling a total of 5416 individuals (2729 men), of whom 816 (523 men) had recurrent venous thromboembolism after stopping treatment, were eligible for inclusion. The pooled estimate of the relative risk (RR) of recurrent venous thromboembolism for men compared with for women was 1·6 (95% CI 1·2–2·0). Significant heterogeneity was shown among individual study findings; however, the higher risk of recurrent venous thromboembolism in men than in women was consistent across predefined subgroups. The relative risk for recurrence in men from randomised trials (RR 1·3; 95% CI 1·0–1·8) was lower than that from observational studies (2·1; 1·5–2·9). The lower risk of recurrent venous thromboembolism in women did not seem to be accounted for by a reduced rate of recurrence after venous thromboembolism associated with oestrogen treatment or pregnancy.

Interpretation

Men seem to have a 50% higher risk than women of recurrent venous thromboembolism after stopping anticoagulant treatment. If confirmed by further prospective studies, this difference in risk of recurrence should be considered when duration of anticoagulant treatment is determined in individual patients.

Introduction

Venous thromboembolism, consisting of deep-vein thrombosis and pulmonary embolism, is a potentially fatal disorder with an estimated annual incidence of 0·1% in white populations.1 After stopping anticoagulant treatment, individuals who have had a first episode of venous thromboembolism are at long-term increased risk of further events. In two prospective cohort studies of consecutive patients with deep-vein thrombosis who stopped taking anticoagulants after a minimum of 3 months of treatment, the cumulative incidence of recurrent venous thromboembolism was approximately 25% after 5 years.2, 3 About 5% of recurrent episodes are fatal,4 recurrent deep-vein thrombosis substantially increases the risk of the post-thrombotic syndrome,5 and recurrent pulmonary embolism predisposes to chronic pulmonary hypertension.6

Oral anticoagulant treatment with a vitamin K antagonist is highly effective at preventing recurrent venous thromboembolism.7, 8, 9 However, oral anticoagulant treatment is associated with an increased risk of bleeding, which can be fatal10 and is inconvenient. The decision to continue treatment is affected by the balance between the heightened risk of recurrent venous thromboembolism if treatment is stopped and the raised risk of bleeding if treatment is continued. Identification of risk factors for recurrent venous thromboembolism in individual patients can help to identify those who will benefit from long-term anticoagulation. The presence of a temporary risk factor, such as recent surgery, is associated with a lower risk of recurrence than is unprovoked thrombosis or a continuing risk factor.8, 11, 12, 13, 14, 15 Patients with proximal deep-vein thrombosis or pulmonary embolism have a two-fold increase in recurrence compared with patients with isolated distal deep-vein thrombosis,12 as do individuals with more than one previous thrombotic episode compared with those with only a single event.16, 17 Malignancy increases the risk of recurrence by about three-fold,2, 16, 18 as does the presence of antiphospholipid antibodies.12

Two studies suggested that after stopping anticoagulant treatment men have a significantly higher risk of recurrent venous thromboembolism than do women,19, 20 whereas analysis of data from two randomised trials did not show such an association.21 To establish if there is a higher risk of recurrent venous thromboembolism in men than in women we did a meta-analysis of all relevant available evidence. A secondary objective of this analysis was to look for potential explanations for any observed difference in risk between men and women.

Section snippets

Methods

We prospectively developed a protocol that defined specific objectives, the strategy for study identification, criteria for study selection, methods to be used for assessing study quality, how data would be extracted, study outcomes, and statistical methodology.

Results

Using the predefined search strategy we identified 1733 potentially eligible articles (figure 1). 15 studies were eligible for inclusion in the meta-analysis.7, 8, 12, 13, 17, 19, 20, 21, 24, 25, 26, 27, 28, 29, 30 Initial agreement between the two reviewers on whether a study was eligible for inclusion occurred in 84/89 manuscripts (94%; κ=0·88); initial disagreement was resolved by discussion in the other five studies (three were included8, 24, 25 and two were excluded3, 31). Details of the

Discussion

Our analysis showed that men have about a 50% higher risk than women of recurrent thrombosis and that this increase is consistent across different subgroups of patients with venous thromboembolism. The cause of this heightened risk in male patients is unclear. The lower risk of recurrent venous thromboembolism in women has been suggested to be associated with a higher prevalence in women than in men of distal deep-vein thrombosis, which is associated with a lower risk of recurrent venous

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