Statins May Prevent Thromboembolism
Abstract & commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Observational studies have suggested statins may not only reduce arterial cardiovascular events but also venous thromboembolism. In a study assessing the cardiovascular benefits of statin therapy, Glynn et al randomized 17,802 adults with normal lipid levels but elevated C-reactive protein to rosuvastatin or placebo. Symptomatic VTE rates per 100 person-years were 0.18 for statin treatment compared to 0.32 for placebo (HR: 0.57, 95% CI 0.37-0.86, p = 0.007). VTE not associated with hospitalization or other precipitating factors, but was reduced significantly with rosuvastatin (p = 0.09). Statin therapy may reduce rates of VTE, warranting further study.
Source: Glynn R, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Eng J Med. 2009;360:1851-1861.
Drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, also known as statins, are primarily used to prevent arterial cardiovascular events. Several observational studies have suggested this class of drugs may also reduce the risk of venous thromboembolism (VTE),1,2 although others have not confirmed this association.3,4 Glynn et al evaluated data from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) which explored rosuvastatin compared to placebo to prevent first cardiovascular events. Glynn et al now report a protocol-specific endpoint of VTE which included pulmonary embolus or deep venous thrombosis.
This international study randomized 17,802 subjects to placebo or rosuvastatin. Eligibility requirements included men ≥ 50 years of age and women ≥ 60 years of age without known cardiovascular disease. Further, the low density lipoprotein had to be < 130 mg/dL and C-reactive protein level > 2.0 g/L to identify subjects who did not meet standard criteria for lipid-lowering therapy but who had higher levels of inflammation (i.e., CRP), suggesting a heightened risk of cardiovascular events. Subjects could not have a history of VTE, postmenopausal hormonal therapy, or cancer within five years. The trial was terminated early because of a significant reduction in cardiovascular events in the treatment arm.
The rosuvastatin group experienced 60 episodes of VTE compared to 34 episodes in the placebo group. VTE rates per 100 person years were 0.18 for rosuvastatin, compared to 0.32 for placebo (HR 0.57, p = 0.007). One subject in each treatment group who developed a VTE was taking anticoagulation (presumably for atrial fibrillation) upon study enrollment. Provoked VTE, defined as occurring within three months before or after the time of hospitalization, trauma, or cancer, was found in 44 (47%) subjects. The risk of VTE reduction by rosuvastatin was similar for both provoked (HR = 0.52, p = 0.03) and unprovoked VTE (HR = 0.61, p = 0.09). The hazard ratio remained the same for rosuvastatin compared to placebo when considering VTE as events preceding cardiovascular events (HR = 0.57, p = 0.009). Bleeding events did not differ between subgroups.
Commentary
Previous observational studies have suggested that lipid-lowering therapy using a statin may also reduce the risk of VTE.1,2 In this analysis, Glynn et al evaluated the incidence of VTE in a large, randomized study of over 17,000 subjects randomized to rosuvastatin or placebo for primary prevention of cardiovascular events. Glynn et al previously reported the benefits of rosuvastatin in reducing arterial thrombosis in the form of primary cardiovascular events. The incidence of VTE in subjects randomized to rosuvastatin was 0.18 per 100 per years compared to 0.32 for placebo (p = 0.007). One would first suspect that a greater rate of VTE was a consequence of more cardiac events in the placebo group, which lead to hospitalization and more VTE. However, the benefit of rosuvastatin was present for VTE preceding cardiac events and for unprovoked VTE. Further, the treatment effect was independent of beneficial effects on arterial events.
Baseline variables of age, weight, and other factors did not alter the treatment effect. It would be of tremendous interest to know if subjects who developed VTE had unrecognized genetic risk factors for VTE.
This study provides substantial evidence that statins reduce the risk of an initial VTE, as well as primary arterial events. Even though VTE event rates were a secondary endpoint, studies assessing VTE as a primary endpoint for statin treatment in patients with risk factors for VTE will be needed. It would be of enormous importance, however, if statin therapy to prevent cardiovascular events also concomitantly reduces VTE. For now, the data cannot be translated immediately into clinical practice. However, they certainly raise intriguing possibilities about potential roles for statin therapy in patients at high risk for VTE. Venous thromboembolism remains a relatively common disorder associated with substantial morbidity. Primary prevention is typically targeted to high-risk situations such as surgery and hospitalization. However, many patients present with VTE who were not considered at heightened risk. Secondary prophylaxis also remains a challenging population, as there is a substantial risk of VTE recurrence when discontinuing anticoagulation after an initial event. Statins could be studied as adjunctive therapy, or possibly as maintenance therapy, after discontinuing anticoagulation.
The mechanism by which statins mediate reduced VTE has been explored. Ironically, lipid lowering is an unlikely candidate to explain an effect on VTE, as non-statin therapies do not appear to reduce VTE, and VTE rates in placebo-treated subjects in this study were not related to lipid levels. Several anticoagulant properties of statins have been proposed based on preclinical data.
In short, statin therapy to reduce arterial cardiovascular events also may reduce the risk of new venous thromboembolism. Future studies will be needed to confirm these results and to delineate specific patient subsets where statin therapy may be clinically beneficial in reducing VTE.
References
1. Ray JG, et al. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med. 2001;161:1405-1410.
2. Grady D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000;132:689-696.
3. Yang CC, et al. Statins and the risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 2002;53:101-105.
4. Smeeth L, et al. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol. 2009;67:99-109.
Observational studies have suggested statins may not only reduce arterial cardiovascular events but also venous thromboembolism.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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