Statins and venous thromboembolism: a novel effect of statins?

ABSTRACT

Statins play a key role in the management of hypercholesterolemia and other dyslipidemias. However, statins exert several other actions, often referred to as ‘pleiotropic’. This Editorial looks at the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), examining, in particular, the occurrence of venous thromboembolism in the rosuvastatin and placebo groups, and discussing these findings in the context of the current literature. The authors conclude that statin use could perhaps be associated with reductions in the risk of venous thromboembolism, and call for further appropriately designed studies.

Keywords: :

• Rosuvastatin
• Statin
• Venous thromboembolism

In 2008, The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported the comparison of rosuvastatin with placebo on the occurrence of first major cardiovascular events1. JUPITER was a randomised, double-blind, placebo-controlled, multicentre trial that recruited 17,802 apparently healthy men ≥50 years and women ≥60 years with low-density lipoprotein (LDL) cholesterol levels <130 mg/dl (<3.4 mmol/l) and high-sensitivity C-reactive protein (hsCRP) levels ≥2.0 mg/l1. Participants were assigned to rosuvastatin 20 mg/day or placebo. The combined primary end-point was myocardial infarction, stroke, arterial revascularisation, hospitalisation for unstable angina or death from cardiovascular causes. After a median follow-up of 1.9 years, rosuvastatin was associated with a 44% reduction in the rates of the primary end point (0.77 vs.1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively; hazard ratio [HR] for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46–0.69; p < 0.00001)1. Consistent effects were observed in all subgroups evaluated, namely a 54% reduction in myocardial infarctions (0.17 vs. 0.37 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively; HR, 0.46; 95% CI, 0.30–0.70; p = 0.0002), a 48% reduction in strokes (0.18 vs. 0.34 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively; HR, 0.52; 95% CI, 0.34–0.79; p = 0.002), a 47% reduction in revascularisation or unstable angina (HR, 0.53; 95% CI, 0.40–0.70; p < 0.00001), a 47% reduction in the rates of the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (0.45 vs. 0.85 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively; HR, 0.53; 95% CI, 0.40–0.69; p < 0.00001) and a 20% reduction in deaths from any cause (1.00 vs. 1.25 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively; HR, 0.80; 95% CI, 0.67–0.97; p = 0.02)1.

Recently, JUPITER reported on the occurrence of venous thromboembolism2. This was a protocol-specified secondary end point2. Deep vein thrombosis (DVT) or pulmonary embolism (PE) was classified as unprovoked if it occurred in the absence of any recent trauma, hospitalisation or surgery (occurring within 3 months before the event) and in the absence of a malignancy diagnosed before or up to 3 months after the event.

Symptomatic PE or DVT occurred in 94 participants (34 in the rosuvastatin group and 60 in the placebo group)2. Statin therapy was associated with a 43% reduction in the risk of venous thromboembolism compared with placebo (0.18 vs. 0.32 event per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively; HR for the rosuvastatin group, 0.57; 95% CI, 0.37–0.86; p = 0.007)2. This risk reduction was an independent benefit of statin use, beyond the reduction in the risk of arterial thrombosis2. Among the 94 cases of symptomatic PE or DVT, 44 occurred in patients with cancer or recent trauma, hospitalisation, or surgery (i.e., provoked events), whereas a proximate cause was not identified in 50 cases (i.e., unprovoked events). The observed reductions in risk were similar for unprovoked or provoked events (HR for unprovoked events in the rosuvastatin group, 0.61; 95% CI, 0.35–1.09; p = 0.09; HR for provoked events, 0.52; 95% CI, 0.28–0.96; p = 0.03)2.

Statins play a key role in the management of hypercholesterolaemia and other dyslipidemias3,4. However, statins exert several other actions, often referred to as ‘pleiotropic’5–9. These effects include enhancing the stability of atherosclerotic plaques, improving endothelial function, inhibiting the thrombogenic response in addition to decreasing oxidative stress and vascular inflammation5–9. Statins have become an essential component of the treatment of the ‘arterial’ patient, since they reduce events10–14.

A beneficial role for statin therapy in venous thromboembolism is not a novel concept. In a prospective observational study performed almost a decade ago, the Heart and Estrogen/Progestin Replacement Study, statin use (but not the use of other lipid-lowering drugs) was associated with a 50% reduction in the risk of venous thromboembolism compared with non-use (multivariate relative hazard, 0.5; 95% CI, 0.2–0.9; p-value not mentioned)15. Similarly, in a retrospective cohort study from Canada, statin use was associated with a 22% decreased risk of DVT compared with thyroid replacement therapy (adjusted HR, 0.78; 95% CI, 0.69–0.87; p-value not mentioned) among 125 862 patients ≥65 years old16. The statin-induced reduction in the risk of venous thrombosis was also documented in other trials17–19.

Statins may prevent venous thromboembolism by influencing haemostatic factors, nitric oxide bioavailability and endothelial function20–23. JUPITER selected subjects with ‘raised’ hsCRP levels1. It follows that there is a need to consider any link between inflammation (specifically, hsCRP) and venous thromboembolism. Such an association remains controversial20,24–26 possibly because venous thromboembolism does not always have the same causation. On a more speculative note, less inflammation may play a role in the ‘extension’ of venous thromboembolism20,24–26. In this context, it may be relevant that JUPITER recorded symptomatic venous events1.

In conclusion, statin use seems to be associated with a significant reduction in the risk of venous thromboembolism in apparently healthy subjects. This is another potential indication for these drugs. Whether such an effect will be useful for patients with genetic defects or conditions (e.g., cancer or flight-associated DVT) that predispose to venous thromboembolism remains to be established. This speculation should be investigated within the JUPITER trial2. If a ‘venous’ effect is consistent with all statins, these drugs will become more cost-effective because those at risk of either arterial or venous disease could benefit1,2,27. Further basic science studies and appropriately designed clinical trials are needed to confirm the JUPITER results. Retrospective analysis of statin trials may also prove useful.

Transparency

Declaration of funding

This Editorial was written independently. No company or institution supported it financially.

Declaration of financial/other relationships

D.P.M. has disclosed that he has received honoraria for attending international meetings on behalf of Merck Sharpe and Dohme and AstraZeneca, and that he is on the Speaker's Bureau for Merck Sharpe and Dohme, Solvay and AstraZeneca. K.I.P., N.B. and T.P.P. have disclosed that they have no relevant financial relationships.

All peer reviewers receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she is a consultant for Sanofi-Aventis and Pfizer, and that he/she is on the Speaker's Bureau for Sanofi-Aventis. Peer Reviewer 2 has disclosed that he/she has no relevant financial relationships.

Acknowledgement

Following formal submission to CMRO, the contents of this article were shared with AstraZeneca. The authors are grateful for the feedback received, but declare that they were under no obligation to amend the article. AstraZeneca were in no way involved with the concept, drafting, editing or preparation of this article, and the authors retain full responsibility.