Elsevier

The Lancet Haematology

Volume 4, Issue 2, February 2017, Pages e83-e93
The Lancet Haematology

Articles
Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis

https://doi.org/10.1016/S2352-3026(16)30184-3Get rights and content

Summary

Background

Statins have been suggested to have a protective effect on venous thromboembolism (which includes deep vein thrombosis and pulmonary embolism), but the evidence is uncertain. We sought to evaluate the extent to which statins are associated with first venous thromboembolism events.

Methods

We did a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs). Relevant studies that reported associations between statins and first venous thromboembolism outcomes were identified from MEDLINE, Embase, Web of Science, Cochrane Library, and a manual search of bibliographies for studies published up until July 18, 2016, and from email correspondence with investigators. Observational cohorts that assessed the association of statin use with venous thromboembolism, deep vein thrombosis, or pulmonary embolism in adults were included, as were intervention studies that assessed the effects of statin therapy compared with a placebo or no treatment and collected data on venous thromboembolism, deep vein thrombosis, or pulmonary embolism outcomes. Studies that compared statins with another statin or lipid-lowering agent were excluded. Study specific relative risks (RRs) were aggregated using random-effects models and were grouped by study-level characteristics. The review has been registered with PROSPERO, number CRD42016035622.

Findings

36 eligible studies (13 cohort studies comprising 3 148 259 participants and 23 RCTs of statins vs placebo or no treatment comprising 118 464 participants) were included. In observational studies, the pooled RR for venous thromboembolism was 0·75 (95% CI 0·65–0·87; p<0·0001) when statin use was compared with no statin use. This association remained consistent when grouped by various study-level characteristics. In RCTs, the RR for venous thromboembolism was 0·85 (0·73–0·99; p=0·038) when statin therapy was compared with placebo or no treatment. Subgroup analyses suggested significant differences in the effect of statins by type of statin, with rosuvastatin having the lowest risk on venous thromboembolism compared with other statins 0·57 (0·42–0·75; p=0·015). There was no evidence of an effect of statin use on pulmonary embolism. Statin use was associated with a significant reduction in risk of the specific endpoint of deep vein thrombosis compared with no statin use (RR 0·77, 95% CI 0·69–0·86; p<0·0001).

Interpretation

Available evidence from observational and intervention studies suggest a beneficial effect of statin use on venous thromboembolism. In intervention studies, therapy with rosuvastatin significantly reduced venous thromboembolism compared with other statins. Further evidence is however needed to validate these findings.

Funding

None.

Introduction

Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is a public health problem. Although pharmacological thromboprophylaxis agents (such as unfractionated heparin, low-molecular weight heparin, warfarin, and novel oral anticoagulants) are effective, they remain underused, because they are associated with increased risk of bleeding.1 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (commonly known as statins) are known for their lipid-lowering properties and are well established for the primary and secondary prevention of cardiovascular disease,2, 3, 4 especially coronary heart disease.5 Statins are also known to have pleiotropic effects on coagulation and inflammation, and do not increase the risk of bleeding.6, 7 Emerging evidence suggests that statins might be effective in reducing the incidence of venous thromboembolism through these pleiotropic effects. Since the publication of the Heart and Estrogen/progestin Replacement Study (HERS),8 which reported an approximately 50% risk reduction in venous thromboembolism in a non-randomised comparison of statin versus non-statin users, several observational studies have evaluated this relationship and reported conflicting results.9, 10, 11, 12, 13 In the first randomised controlled trial (RCT) of statins for the prevention of venous thromboembolism, investigators of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial14 of 17 802 participants, showed that rosuvastatin significantly reduced the occurrence of all cases of venous thromboembolism. These results were based on few venous thromboembolism events suggesting a statistical play of chance and thus triggered calls for further studies to replicate these results.15 After the publication of these studies, there have been efforts to aggregate these data over the past decade, which have resulted in several published reviews on the topic with inconsistent results.16, 17, 18, 19 In an analysis of eight case-control studies and three cohort studies, Squizzato and colleagues17 found no evidence of a significant reduction in venous thromboembolism with statin use when the results were pooled by study design. However, pooled analysis of all studies (including the JUPITER trial) showed a significant reduction in risk of venous thromboembolism. In a meta-analysis of 29 RCTs published in 2012, Rahimi and colleagues19 found no significant reduction in venous thromboembolism events with statin therapy.

Research in context

Evidence before this study

The lipid-lowering properties of statins and their effectiveness for the primary and secondary prevention of cardiovascular disease are well established. Statins are currently only approved for lipid lowering in the primary and secondary prevention of cardiovascular disease. We searched for relevant prospective cohort studies done in general populations and randomised controlled trials (RCTs) reporting on associations between statins and venous thromboembolism (including deep vein thrombosis and pulmonary embolism) in MEDLINE, Embase, Web of Science, and Cochrane Library, with particular emphasis on systematic reviews and meta-analyses. We used the search terms “statin”, “hydroxymethylglutaryl-CoA reductase inhibitors”, “venous thromboembolism”, “deep vein thrombosis”, and “pulmonary embolism”. Several observational studies were found to have investigated the relationship, but the results were conflicting. Some RCTs showed that statins reduced the occurrence of venous thromboembolism, but these results were based on few venous thromboembolism events, which suggested a statistical play of chance. Previous reviews on the topic have also reported inconsistent results. Statins might have a protective effect on the incidence of venous thromboembolism; however, the overall evidence is uncertain.

Added value of this study

This meta-analysis of observational and intervention studies suggests a beneficial effect of statin therapy on venous thromboembolism. In observational studies, the protective effect of statins on risk of venous thromboembolism remained consistent when grouped by various study-level characteristics. In intervention studies, rosuvastatin therapy substantially and significantly reduced the risk of venous thromboembolism risk, with no benefit seen with other statins.

Implications of all the available evidence

Based on both observational and clinical trial evidence, these findings underscore a potential beneficial role of statin therapy on venous thromboembolism in addition to its established role in cardiovascular disease prevention. The results also suggest that this effect of statins might be attributed to rosuvastatin. Prevention of venous thromboembolism could be another potential indication of statins; however, before any guideline recommendations can be made, further research is needed to unequivocally establish this potential true protective effect.

Existing evidence shows that uncertainty about the effect of statins on venous thromboembolism outcomes remains. Additionally, several features of previous reviews limited the generalisability and validity of the findings. First, most of the previous reviews (except for the study by Rahimi and colleagues19) pooled a small number of studies, which did not provide adequate power to assess the associations. Second, several reviews pooled results of different study designs making interpretation of the findings difficult. Third, the reviews did not explore in detail potential sources of heterogeneity among the contributing studies using formal tests such as subgroup analyses and meta-regression techniques. Statin use is under considerable debate and of clinical interest as more people are being prescribed statin therapy. In view of the newer studies published since the last relevant meta-analysis on the topic, further work is needed to address the persisting uncertainty of the role of statins in venous thromboembolism outcomes. We aimed to summarise the available observational and interventional evidence in one updated systematic review and meta-analysis. Our objectives were to establish the associations of statin use with risk of first venous thromboembolism outcomes in observational cohort studies, to quantify the effects of statin use given alone compared with placebo (or no treatment) for the primary prevention of venous thromboembolism outcomes in RCTs, and to examine all associations under a wide range of relevant study-level characteristics.

Section snippets

Search strategy and selection criteria

We did this systematic review and meta-analysis using a predefined protocol in accordance with PRISMA20 and MOOSE21 guidelines (appendix pp 2–5). Two authors (SKK and SS) independently searched MEDLINE, Embase, Web of Science, and the Cochrane electronic databases for studies published before July 18, 2016, with particular emphasis on systematic reviews and meta-analyses. The computer-based searches combined terms related to statins (eg, statin, hydroxymethylglutaryl-CoA reductase inhibitors,

Results

Our initial search of relevant databases and manual searches of reference lists identified 1125 potentially relevant citations. After screening based on titles and abstracts, 54 articles remained for full-text assessment. After detailed assessments, 18 articles were excluded (appendix pp 7–8). 36 studies met our inclusion criteria and were included in the meta-analysis (figure 1; appendix pp 9–16). Summary characteristics of relevant observational cohort studies and RCTs included in the

Discussion

The findings of this systematic review and meta-analysis suggest a role for statins in the primary prevention of venous thromboembolism in both observational cohort and intervention studies. The inverse association of statin use and venous thromboembolism shown in observational studies remained consistent across several study-level subgroups. In RCTs, there was suggestion of effect modification in stratified analyses by type of statin. Rosuvastatin therapy substantially and significantly

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