Regular Article
Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: Role of drug induced homocysteinemia?

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Abstract

Background

Previous studies reported that statin use was associated with a decreased risk of venous thromboembolism (VTE), whereas no association was found between fibrate use and VTE. This report aims to test the hypothesis that part of these contrasting associations is related to total homocysteine level (tHcy).

Materials and methods

This report from a case-control study included 677 cases hospitalised with confirmed VTE and no major acquired risk factor of VTE and their 677 controls. Statin and fibrate exposure was defined as a current use of drugs at admission. Fasting serum tHcy was measured in all patients.

Results

The estimated odds ratio for VTE related to statin use was 0.53 (CI 95% 0.37–0.78), whereas it was 1.88 (CI 95% 1.29–2.74) for fibrate use. No difference was found for tHcy levels between patients who were current users of statin compared to non users (17.7 μmol/L ± 7.3 in users vs 18.4 μmol/L ± 8.4 in non users, p = 0.50). In contrast, fibrate users had a significant higher mean level of tHcy than non users (23.2 μmol/L ± 8.7 in users vs 18.4 μmol/L ± 8.4 in non users, p < 0.0001). Nevertheless, adjustment on tHcy level did not alter significance and strength of the association between fibrates and VTE (1.66, CI 95% 1.07–2.59).

Conclusions

Statin use was associated with a significant decreased risk of VTE, whereas fibrate use was associated with a significant increased risk of VTE. This last association was independent of tHcy levels.

Introduction

Previous studies reported that the use of statins was associated with a reduced risk for venous thromboembolism (VTE) [1], [2], [3], [4]. Fibrates, other effective lipid-lowering agents, were not found to be associated with VTE [1], [2], [3], [4]. Moreover, one study reported an increased risk for venous thromboembolic disease associated with fenofibrate treatment [5]. The difference between statins and fibrates as regards the risk of VTE and the underlying mechanisms are still questioned.

VTE is a multifactorial disease with acquired and inherited risk factors. Mild hyperhomocysteinemia has been identified as a risk factor for VTE [6]. Many studies have shown that fibrates increased homocysteine levels [7], [8], [9], [10], [11], whereas statins seemed to have a neutral effect [7], [9], [10], [11]. Therefore, we hypothesized that the contrasting associations previously observed between statins, fibrates and VTE could be due, in part, to this differential effect on total homocysteine (tHcy) levels.

This report aims 1) to add further evidence for a differential association between statin or fibrate use and VTE, and 2) to test the hypothesis that part of this association is related to tHcy level.

Section snippets

Population

Participants in this report were part of an ongoing hospital-based case-control study (called EDITH) designed to evaluate interactions between acquired and inherited risk factors of VTE [12]. The protocol was approved by our hospitals scientific and ethics board. All participants gave written informed consent.

Cases were patients aged over 18 years, hospitalised in Brest University Hospital between May 2000 and December 2004 with an objectively confirmed symptomatic VTE. For this report, we

Results

From May 2000 until December 2004, 677 cases with a venous thromboembolic event not related to a major acquired risk factor were included in the EDITH database.

Baseline characteristics of the 677 cases and 677 matched controls are shown in Table 1.

The mean age of included patients was 68 years. Among the 677 cases, 121 had an isolated pulmonary embolism (PE), 303 an isolated deep venous thrombosis (DVT) and 253 a DVT associated with PE. Cases had a significantly higher body mass index (BMI)

Discussion

In this hospital-based case-control study, statin use was associated with a significant decreased risk of VTE, whereas fibrate use was associated with a significant increased risk of VTE, and thus independently of atherothrombosis or aspirin use. We found no difference on tHcy levels between statin users and non users. In contrast, we found that fibrate users had higher levels of tHcy than non users. However, the increase of tHcy levels with fibrates did not appear as a mechanism involved in

Acknowledgments

Funding

The study was supported by grants from the INSERM (Contrat de Recherche Stratégique 2001, CRES N° 4CR05G), from Région Bretagne (Programme 1044-04013235 n°1440) and the Programme Hospitalier de Recherche Clinique 2000. The Centre Hospitalier Régional et Universitaire de Brest promoted the study. The funders of this study had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the

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