Regular Article
Sex-specific risk factors for recurrent venous thromboembolism

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Abstract

Background

Men have higher risk of recurrent venous thromboembolism (VTE) than women but this sex difference remains unexplained. In addition, whether men and women share same risk factors for recurrent VTE is unclear.

Methods

In a prospective cohort study, 583 patients (234 men and 349 women) aged 18 to 90, with a first idiopathic VTE, were followed for an average of 28 months. We assessed the association between baseline characteristics and VTE recurrence by gender.

Results

Recurrent VTE occurred in 38 women and 36 men (incidence = 4.6% and 7.5% per year respectively; HR = 1.6; 95% CI, 1.0-2.6). This relation between sex and recurrent VTE was more pronounced in patients younger than 50 years and in the presence of factor V Leiden (FVL) mutation. Multivariate analyses showed that obesity (HR, 2.8 (95% CI, 1.3-6.0)) and aging (HR, 1.3 (95% CI, 1.1-1.4) per 10 years increase) were related to an increased risk of recurrent VTE in women while FVL mutation (HR, 3.5 (95% CI, 1.5-8.1)) was a risk factor of recurrent VTE among men.

Conclusion

Men and women do not share the same risk factors for recurrent VTE. Consequently, gender has to be taken into account to improve the risk stratification and prevention of VTE recurrence.

Introduction

Venous thromboembolism (VTE) is a chronic, multifactorial and potentially fatal disease affecting more than 1 person for 1000 per year [1], [2]. The risk of recurrence is high in the first 2 years after stopping anticoagulation therapy with a cumulative incidence of recurrent VTE of 25% after 5 years [3]. Prolonged anticoagulation treatment can prevent most episodes of recurrence but this must be balanced with the risk of bleeding in particular in persons at low risk of recurrence [4]. Stratification of patients in low or high risk groups appears essential to tailor the duration of the anticoagulation therapy to each patient [3], [5]. Many risk factors for recurrent VTE have been identified [6] and several studies showed that men have about 50% higher risk of recurrent VTE than women after anticoagulation therapy is stopped [7]. This sex difference in the risk of recurrent VTE was so far largely unexplained and different hypothesis have been made. Hormonal exposure of women at the time of their first event has been suggested to partly explain the lower recurrence risk observed in women compared to men [8], [9]. However, some studies showed that the difference in the recurrence risk according to gender persisted after exclusion of women with hormonal factors at first event [10], [11]. Recently, younger age at first event in women has also been considered to explain the difference in the recurrence risk between men and women [9], [12]. By contrast, some studies found that age did not play any role in the VTE recurrence risk neither in men nor in women [13], [14].

All hypotheses that have been proposed to explain the discrepancy between men and women on the risk of recurrent are still under debate. Identification of sex-specific risk factors for recurrent VTE could provide new insight into the understanding of sex-related risk of recurrent VTE.

In this context we set up a prospective cohort study aimed to assess potential sex-specific risk factors for recurrent VTE.

Section snippets

Population and study design

The FARIVE study is a case–control study associated with a pre-specified cohort study of all idiopathic cases performed in 11 centers in France. The detailed methodology of the case–control study has been previously described [15]. The present work is based on the FARIVE cohort study. Since January 2003, all consecutive patients treated as inpatients or outpatients for a first episode of idiopathic proximal Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) who fulfilled all inclusion

Results

Between 2003 and 2009, 990 patients were included in the cohort (Fig. 1). Of these, 407 patients were excluded because of the following conditions: 9 removed their consent to the study, 71 were lost for follow-up, 208 patients did not stop the anticoagulation therapy, no information about the date of discontinuing anticoagulation for 6 patients, 113 had surgery, trauma or pregnancy within the 3 months preceding first event or developed a cancer during the follow-up. A total of 583 patients (234

Discussion

This large prospective cohort study including 583 patients with a first episode of VTE showed that male sex was associated with a higher risk of recurrent VTE. However, this sex-related difference in VTE recurrence risk did not persist after 50 years. This result may be partly explained by the increased risk of recurrent VTE among older women compared with younger men. Recent studies confirmed that older age was associated with an increasing risk of recurrent VTE in women but not in men [5], [9]

Conflicts of interest statement

None to declare.

Acknowledgment

Joseph Emmerich had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial support

The FARIVE study was supported by Fondation pour la Recherche Médicale, Programme Hospitalier de recherche clinique (PHRC), Fondation de France, and the Leducq Foundation (LINAT Leducq International Network Against Thrombosis).

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