Statins in the prevention of venous thromboembolism: A meta-analysis of observational studies

doi:10.1016/j.thromres.2011.05.012

Thrombosis Research

Volume 128, Issue 5, November 2011, Pages 422-430

https://doi.org/10.1016/j.thromres.2011.05.012 Get rights and content

Abstract

Introduction

Studies have established a relationship between inflammation and venous thromboembolism (VTE). Though statins modulate inflammation, it is uncertain if they prevent VTE in heterogeneous populations. A recent randomized trial demonstrated that statins prevent VTE in healthy older adults, yet this has not been well established in other groups, including younger individuals and individuals with comorbidities. The objective of this meta-analysis was to estimate the effect of statins on VTE in a heterogeneous group of adults.

Methods

We systematically reviewed the effect of statins in preventing VTE in adult inpatients and outpatients. We systematically searched MEDLINE (1966-Jan 2010), EMBASE (1980-Jan 2010), Google Scholar, Cochrane Library, PapersFirst, ProceedingsFirst, and ISI Web of Science, manually reviewed references, and contacted experts. Observational studies that compared any dose of statin to no statin or placebo, examined inpatients or outpatients, and assessed VTE, pulmonary embolism, and/or deep vein thrombosis were included. Study selection, data abstraction and study quality evaluation (using the Newcastle-Ottawa Scale) were independently conducted in duplicate.

Results

Four cohort studies and four case-control studies met criteria. Comparing statins to control, the odds ratio for VTE was 0.67 (95% confidence interval 0.53, 0.84), and for deep vein thrombosis was 0.53 (95% confidence interval 0.22, 1.29). The association was attenuated in lower-quality studies and studies enrolling older individuals.

Conclusions

Further well-designed trials are needed to evaluate the risks and benefits of statins in preventing VTE in heterogenous populations of adults, identify high-risk subgroups, and analyze cost-effectiveness of statin use for this indication.

Section snippets

Study identification and selection

We searched for all published and unpublished observational studies, irrespective of language, that examined the effect of statins on VTE. We conducted a detailed electronic search of MEDLINE (1966 to January 2010, week 1) and EMBASE (1980 to January 2010, week 1) databases, using OvidSP Version UI02.03.01_H11_2.10. The search strategy combined terms for statins with terms for venous thrombosis and used search filters for observational studies (see Supplemental Table 1). We also manually

Study selection

Our search identified 58 published studies (see Fig. 1). We excluded 52 studies after title and abstract screening. The remaining 6 studies were retrieved for more detailed evaluation. We identified 8 additional potentially relevant studies through manual review, consultation with experts, and searches of unpublished work, abstracts, and conference proceedings. Of the 14 studies retrieved for full text screening, 6 studies were excluded, 5 because they were duplicates of other studies, and 1

Discussion

In this meta-analysis, we found that statin use was associated with lower rates of VTE and DVT than no statin use. The OR was significant for VTE (OR 0.67; 95% CI 0.53, 0.84), but not for DVT, as its confidence interval crossed 1 (OR 0.53; 95% CI 0.22, 1.29). The latter odds ratio's lack of statistical significance is likely the result of a small sample size. There were insufficient data to calculate a pooled estimate of the effect of statins on PE, and none of the studies included mortality as

Conflict of interest statement

None.

Acknowledgements

This study received no external funding, and the authors declare no financial or personal conflicts of interest. Dr. Pai holds a fellowship from the Canadian Hemophilia Society and a Hamilton Health Sciences New Investigator Grant. Dr. Evans is supported by K12-HL083690 from the National Heart Lung and Blood Institute. Dr. Cook holds a Canada Research Chair of the Canadian Critical Care Trials Group. Dr. Crowther holds a Career Investigator Award from the Heart and Stroke Foundation of Canada

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Cited by (53)

Effects of statins in primary and secondary prevention for venous thromboembolism events: A meta analysis
2022, Vascular Pharmacology
The associations between statins use and incidence or recurrence of venous thromboembolism (VTE) are controversial. We aimed to conduct a meta-analysis to reconcile the conflicting results.
We searched PubMed, Embase and Cochrane Library for studies published from database inception until May 31, 2021. Cohort studies and Randomized Controlled Trials that reported incidence or recurrence of VTE using statins compared with placebo or non-statins were included for meta-analysis.
A total of 43 studies comprising over 8.6 million participants were included for analysis. The median follow-up duration was 38.1 months. Compared with no statins treatment, statins appeared to have a protective effect in primary prevention of VTE (RR 0.78, 95% CI 0.72–0.85), but significant heterogeneity was found among included studies (I² = 81%). Statins was also associated with a 26% reduced risk of recurrent VTE (RR 0.74, 95% CI 0.70–0.78), even in patients receiving anticoagulant therapy (RR 0.77, 95% CI 0.65–0.92). In patients with a history of VTE, statins was associated with a reduced risk of bleeding and all cause mortality. The NNT of statins to prevent one case of VTE in the cancer population, and one case of recurrent VTE in patients with a history of VTE was 103.1 and 90.7 person-years respectively.
In high-risk patients, statins treatment may reduce the incidence of VTE. Statins can also reduce the risk of recurrent VTE and all-cause mortality in patients with a history of VTE.
Protective role of statins during anticoagulation for venous thromboembolism: beyond their lipid lowering effect?
2020, European Journal of Internal Medicine
Initiation of statins and risk of venous thromboembolism: Population-based matched cohort study
2019, Thrombosis Research
Citation Excerpt :
Statins are effective lipid-lowering drugs used in the prevention of arterial thromboses [8]. However, statins also possess anti-inflammatory and anti-thrombotic effects [9], making them potentially suitable to prevent VTE [10–15]. The JUPITER trial–the only randomized controlled trial (RCT) to test the hypothesis that statins protect against VTE– reported a 43% risk reduction among 17,802 individuals randomized to receive either rosuvastatin 20 mg daily or placebo [10].
The effects of statins in prevention of venous thromboembolism (VTE) is not well established.
To examine the risks of first-time VTE in a cohort of patients initiating statin treatment and in a matched general population comparison cohort.
We conducted a nationwide, population-based, matched cohort study based on data from Danish health registries. The study period was 1 January 2005–31 December 2015. We identified statin initiators (without VTE, myocardial infarction, or ischemic stroke) and sex-, age-, and calendar year-matched (1,3) individuals from the general population (without statin use, VTE, myocardial infarction, or ischemic stroke). We computed cumulative risks and comorbidity-adjusted hazard ratios (HRs) of VTE, myocardial infarction, and ischemic stroke.
Among 601,011 statin initiators and 1,803,033 matched population cohort members during 2005–2015, the cumulative risk after 11 years was 2.8% for VTE (both cohorts), 4.7% vs. 2.9% for myocardial infarction, and 7.1% vs. 5.2 for ischemic stroke. After adjustment, statin use was associated with a slightly decreased risk of VTE (adjusted HR: 0.95 [95% CI: 0.92–0.97]), driven by a reduced risk of unprovoked VTE (adjusted HR: 0.92 [95% CI: 0.89–0.95]). The reduced risks of VTE were more pronounced among patients who had an imaging examination performed. The adjusted HRs were elevated for myocardial infarction and ischemic stroke.
Statin initiation was associated with a reduced risk of VTE, with no indication of a healthy-user effect. Based on available evidence, statins have weak thromboprophylactic effects.
Statin and all-cause mortality in patients receiving anticoagulant therapy for venous thromboembolism. Data from the RIETE registry
2019, European Journal of Internal Medicine
The clinical outcomes during the course of anticoagulation in patients with venous thromboembolism (VTE) using statins remain controversial.
We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the risk for VTE recurrences, major bleeding or death during anticoagulation, according to the use of statins at baseline. We used propensity score-matching (PSM) to adjust for confounding variables.
From February 2009 to January 2018, 32,062 VTE patients were included. Of these, 7,085 (22%) were using statins. Statin users were 10 years older (73±11 vs. 63±19 years, respectively) and more likely to have comorbidities or to be using antiplatelets or corticosteroids at baseline than non-users. During the course of anticoagulation (median, 177 days), 694 patients developed VTE recurrences, 848 bled and 3,169 died (fatal pulmonary embolism 176, fatal bleeding 121). Statin users had a similar rate of VTE recurrences (hazard ratio [HR]: 0.98; 95%CI: 0.82–1.17), a higher rate of major bleeding (HR: 1.29; 95%CI: 1.11–1.50) and a similar mortality rate (HR: 1.01; 95%CI: 0.93–1.10) than non-users. On PSM analysis, statin users had a significantly lower risk for death (HR: 0.62; 95%CI: 0.48–0.79) and a similar risk for VTE recurrences (HR: 0.98; 95%CI: 0.61–1.57) or major bleeding (HR: 0.85; 95%CI: 0.59–1.21) than non-users.
During anticoagulation for VTE, patients using statins at baseline had a lower risk to die than non-users.
Usefulness of Statins for Prevention of Venous Thromboembolism
2018, American Journal of Cardiology
Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is common with an annual incidence of 1 to 5 per 1,000, resulting in major morbidity, mortality, and increased health care costs. It is more common in the elderly, obese, those with cancer, those undergoing surgery, and those with previous VTE. Strategy to reduce its occurrence has important public health implications. Pleotropic effects of statins may have beneficial effects on a number of potential targets associated with VTE. Statins have excellent safety profile and seem to be associated with beneficial effects in VTE in case-control studies, large observational studies, meta-analyses, and a randomized trial. In conclusion, after critically reviewing the clinical data supporting statin use in the prevention of VTE, we presented clinical recommendations for the use of statins in reducing VTE occurrence, especially in high-risk situations.
Preinjury statin use and thromboembolic events in trauma: a 10-year retrospective evaluation
2018, Journal of Surgical Research
Citation Excerpt :
Therefore, we hypothesized that trauma patients who were on statins before injury would have a lower rate of VTE development. The protective effects of statins against VTE have been demonstrated in two recent meta-analyses, where Pai et al.9 show statin use associated with significantly reduced odds of developing VTEs (odds ratio [OR] = 0.67), whereas Agarwal et al.8 show statin use to be associated with lower rates of VTE (by 32%). While the strongest evidence to date is derived from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial published by Glynn et al.,7 here we also see a decreased efficacy with increased age.
Traumatic injury is well known to increase the risk of venous thromboembolic events (VTEs), occurring in up to 58% of trauma patients. Statin medications have significant anti-inflammatory properties and have been shown to reduce the risk of VTE. We hypothesized that trauma patients who received statin medication before injury would have a lower incidence of VTE after injury.
A 10-y retrospective review identified all patients admitted to our trauma service with an injury severity score >9 and an intensive care unit stay of >3 d. This population was categorized as either “statin recipient” (SR) or “statin naïve,” with subsequent categorical division by occurrence of VTE. Our primary outcome measure was the occurrence of documented VTE in both statin naïve and SR subjects.
A total of 2519 trauma patients were included with 97 (3.8%) developing VTE. Pretrauma statin use in males remained as an independent predictor of VTE (odds ratio = 2.25, 95% confidence interval = 1.25-4.04, P < 0.01). The median time to VTE onset was 3 d longer in SRs (10.0 d; confidence interval = 7.3-12.7, P < 0.05).
Pretrauma statin use does not appear to have a protective benefit of VTE prevention in trauma patients, as we have shown pretrauma SR male trauma patients to have a twofold increased incidence of VTE. However, when considering the 3 d longer median time to VTE onset found in SRs, we consider the protective benefit of statin use reported in the current literature as likely attributable to this observed delayed onset.

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Regular ArticleStatins in the prevention of venous thromboembolism: A meta-analysis of observational studies

Abstract

Introduction

Methods

Results

Conclusions

Section snippets

Study identification and selection

Study selection

Discussion

Conflict of interest statement

Acknowledgements

Thromb Res

J Thromb Haemost

Thromb Res

J Thromb Haemost

Ophthalmology

2009: with special feature on medical technology

Why might statins prevent venous thromboembolism: what needs to be done to know more?

Expert Opin Investig Drugs

An evaluation of candidate genes of inflammation and thrombosis in relation to the risk of venous thromboembolism: The Women's Genome Health Study

Circ Cardiovasc Genet

C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort

Thromb Haemost

The relationship between inflammation and venous thrombosis. A systematic review of clinical studies

Thromb Haemost

Inflammation in patients with lupus anticoagulant and implications for thrombosis

J Rheumatol

Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS)

Circulation

Use of statins and the subsequent development of deep vein thrombosis

Arch Intern Med

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Br J Clin Pharmacol

Statins and the risk of idiopathic venous thromboembolism

Br J Clin Pharmacol

A randomized trial of rosuvastatin in the prevention of venous thromboembolism

N Engl J Med

Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study

Fundam Clin Pharmacol

Regular Article
Statins in the prevention of venous thromboembolism: A meta-analysis of observational studies