Prof. Mateja Kaja Jezovnik
Prof. Pavel Poredos,
Beyond arterial thrombosis risk reduction, the use of statins may reduce the risk of venous thrombembolic disease. This independent benefit of statin use appears not related to statins lipid-lowering action but more to its pleiotropic effect, with a positive impact on vascular inflammation and endothelial function.
Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) is one of the most frequent and serious vascular diseases, and is associated with high morbidity and mortality. Although major risk factors of venous thrombosis such as surgery, older age, and cancer are well recognised, VTE often develops in subjects without any obvious precipitating factor. Indeed, as many as 26 – 47% of all VTE events are currently classified as idiopathic (1).
Recent evidence suggests there is a link between arterial and venous thrombosis, particularly in patients with idiopathic VTE. Atherosclerosis (clinical and preclinical) is also expected to be more prevalent in patients with spontaneous VTE than in healthy subjects (2, 3). Lastly, the incidence of fatal or non-fatal symptomatic atherosclerotic disease is almost twice that in patients with VTE (4). Therefore, in patients without any obvious precipitating risk factors for VTE, other factors, particularly the ones for atherosclerosis, may play a role in the development of the disease. Both diseases (VTE and atherosclerosis) are thought to be interrelated through similar precipitating factors. Lastly, common pathophysiological mechanisms of venous and arterial thrombosis associated with endothelial dysfunction and vascular inflammation are observed in both conditions.
Furthermore, a positive association has been reported between venous thrombosis and diabetes, hypertension and dyslipidemia (5). Kawasaki and colleagues were the first to demonstrate the association between hypercholesterolemia and objectively verified deep venous thrombosis. The risk of DVT was greatest in the presence of elevated total serum cholesterol, whether with or without concomitant hypertriglyceridemia (6). Subsequent studies showed an elevated risk of VTE in the presence of elevated Lp(a) (7).
Circulating lipids have been shown to have both prothrombotic and endothelium-deteriorating properties (8). Studies suggest a greater generation of thrombin and a higher platelet activation rate in hyperlipidemic blood (9). Dyslipidemia appears to cause venous endothelial dysfunction and transient changes in factor VII coagulant activity in humans (10). Further, Lp(a) is also structurally and functionally homologous to plasminogen, leading to potentially competitive binding of fibrin and hence to impaired fibrinolysis.
A compelling body of evidence for benefits of statin therapy in primary and secondary prevention of atherosclerotic cardiovascular disease is readily available. However, data on the efficacy of statins in prophylaxis of VTE are scarce. The Heart and Estrogens/Progestin Replacement Study (HERS) was first to indicate the relationship between statin use and reduction in VTE risk, showing a 50% risk reduction among statin users compared with non-users (11). Later, several observational studies reported reduced risk of deep venous thrombosis and pulmonary embolism in patients taking statins. Two prospective observational studies and four case control studies found that statins reduces the risk of VTE by 20% to 60%. Nevertheless, retrospective studies published between 2002 in 2009 found no statistically significant reduction in the incidence of VTE in statin users (12). Most recently, the "Justification for the use of the statins in prevention" (JUPITER) trial evaluated the effects of rosuvastatin in normolipidemic subjects with elevated C-reactive protein levels. It suggested that statins may be able to reduce the incidence of VTE. In this first randomised trial, rosuvastatin use was associated with a 43% reduction in VTE compared with placebo. This risk reduction was an independent benefit of statin use, beyond the reduction in the risk of arterial thrombosis (13). Recently, in 2010, two meta-analyses were published on the efficacy of statins in prevention of VTE. The meta-analysis of Agarwal and co-workers included one randomised controlled study (JUPITER) and 9 observational studies. In total, the meta-analysis evaluated 971.307 patients (14). Statin use was associated with a statistically significant reduction in the odds ratio of developing VTE (AOR 0.68, 95% CI 0.54 – 0.86), DVT (AOR 0.59, 95% CI 0.43 – 0.82), and PE (AOR 0.70, 95% CI 0.53-0.94). Therefore, they concluded that statin use is associated with a significantly reduced risk of developing VTE, DVT, or PE by 32%, 41%, and 30% respectively. A meta-analysis conducted by Squizzato also evaluated the effect of lipid-lowering drugs, in particular statins and fibrates (15). Three randomised controlled trials, three cohort and eight case-control studies were included in systemic review with a total of 836.805 patients. Statin use significantly reduced VTE risk (AOR 0.81, 95% CI 0.66-0.99) while the use of fibrates, on the other hand, was associated with significant increase in risk of VTE.
As cholesterol is recognised to be one of the most important risk factors, statins are widely prescribed as cholesterol lowering drugs. However, beneficial clinical effect of statins most probably extend beyond the lipid lowering actions and is importantly associated with a positive impact of pathogenetic mechanisms of thrombosis that include endothelial dysfunction and vascular inflammation. In the prospective, randomised, double-blind Pravastatin Inflammation/CRP Evaluation (PRINCE) study, pravastatin significantly reduced CRP levels in an LDL-independent manner (16), and in JUPITER, rosuvastatin effect was related to CRP levels (17).
Endothelial dysfunction most probably contributes to the development, not only of arterial atherothrombotic disease, but probably also to the risk of VTE (18). The ability of statins to improve endothelial function and nitric-oxide production is well recognised (19).
Additionally, antithrombotic effects of statins may be mediated by their anti-inflammatory properties. Statins may also facilitate the prevention of thrombembolic events through their antiplatelet and anticoagulation properties. Indeed, statins have been shown to exert direct inhibitory effects on platelet function, independently from cholesterol levels(20). Another mechanism may involve peroxisome proliferator-activated receptors (PPARs), that are involved in inflammation responses (21). The antithrombotic properties of statins may also be attributable to their ability to inhibit production of tissue factor, an activator of extrinsic coagulation path (22). Furthermore, the "Atorvastatin and Thrombogenicity of Carotid Atherosclerotic Plaque" (ATROCAP) study showed that statins reduce tissue factor activity as well as macrophage infiltration of human vessels, whereby consequently reducing cell-mediated thrombin generation (23). Most of the described mechanisms of action of statins are not related to cholesterol levels, and are perhaps associated with their pleiotropic properties.
It seems that the preventive effects on VTE is related only to statins and not to other lipid lowering drugs (24).
Currently, it is unknown whether VTE prevention is a class-effect of statins or statins differ in their antithrombotic efficacy. One of the studies suggested that simvastatin but not pravastatin provided prevention of VTE (25). However, a study by Ramcharan and colleagues showed a trend of greater risk reduction of VTE in subjects treated with pravastatin than simvastatin (24). Moreover, it is also unknown if a statin benefit is dose-dependent.
The study investigating niacin failed to demonstrate an effect on the risk of VTE, and the use of fibrates was found to increase the risk of VTE (26).
Recent studies have shown a possible association between hyperlipidemia and venous thrombembolism. Therefore, a preventive effect of lipid lowering drugs, particularly statins, is expected. Current evidence suggests that statins significantly reduce the risk of VTE. Results of trials suggest that statins most probably decrease the risk of VTE independently from cholesterol lowering but through mechanisms related to the pleiotropic effects of these drugs. Future trials should clarify the role of statins in the prevention of VTE and the underlying mechanisms of the effects of lipid lowering drugs on haemostasis. Widespread use of statins for prophylaxis of VTE cannot be generally recommended at this stage. Future studies are needed to identify those patients who can maximally benefit from treatment with statins for prevention of VTE as well as to elucidate a therapeutic role for statins in patients with existing venous thrombosis.
1. Goldhaber SZ. Venous thromboembolism prophylaxis: quality, location (hospital vs. home), and duration. Thromb Haemost 2009; 102(1):1-2. 2. Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lensing AW, Prins MH, Girolami A. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348(15):1435-1441. 3. Jezovnik MK, Poredos P, Lusa L. Idiopathic venous thrombosis is associated with preclinical atherosclerosis. J Atheroscler Thromb; 17(3):304-311. 4. Prandoni P, Ghirarduzzi A, Prins MH, Pengo V, Davidson BL, Sorensen H, Pesavento R, Iotti M, Casiglia E, Iliceto S, Pagnan A, Lensing AW. Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis. J Thromb Haemost 2006; 4(9):1891-1896. 5. Ageno W, Dentali F.Venous thromboembolism and arterial thromboembolism. Many similarities, far beyond thrombosis per se. Thromb Haemost 2008; 100(2):181-183. 6. Kawasaki T, Kambayashi J, Ariyoshi H, Sakon M, Suehisa E, Monden M. Hypercholesterolemia as a risk factor for deep-vein thrombosis. Thromb Res 1997; 88(1):67-73. 7. von Depka M, Nowak-Gottl U, Eisert R, Dieterich C, Barthels M, Scharrer I, Ganser A, Ehrenforth S. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000; 96(10):3364-3368. 8. Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and vascular endothelial dysfunction. Atherosclerosis 1998; 138(2):229-235. 9. Cignarella A, Mussoni L, Mannucci L, Ferioli E, Puglisi L, Tremoli E. Platelet activation supports the development of venous thrombosis in hyperlipidemic rats. Blood Coagul Fibrinolysis 1998; 9(1):47-53. 10. Bladbjerg EM, Marckmann P, Sandstrom B, Jespersen J. Non-fasting factor VII coagulant activity (FVII:C) increased by high-fat diet. Thromb Haemost 1994; 71(6):755-758. 11. Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, Bittner V, Schrott HG, Blumenthal RS, Levy R. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002; 105(25):2962-2967. 12. Perez A, Bartholomew JR. Interpreting the JUPITER trial: statins can prevent VTE, but more study is needed. Cleve Clin J Med; 77(3):191-194. 13. Paraskevas KI, Bessias N, Perdikides TP, Mikhailidis DP. Statins and venous thromboembolism: a novel effect of statins? Curr Med Res Opin 2009; 25(7):1807-1809. 14. Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract; 64(10):1375-1383. 15. Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, Venco A, Ageno W. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J; 31(10):1248-1256. 16. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286(1):64-70. 17. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21):2195-2207. 18. Kaja Jezovnik M, Poredos P, Stalc M. Impairment of the Vasodilatation Capability of the Brachial Artery in Patients with Idiopathic Venous Thrombosis. J Atheroscler Thromb. 19. Spring S, Simon R, van der Loo B, Kovacevic T, Brockes C, Rousson V, Amann-Vesti B, Koppensteiner R. High-dose atorvastatin in peripheral arterial disease (PAD): effect on endothelial function, intima-media-thickness and local progression of PAD. An open randomized controlled pilot trial. Thromb Haemost 2008; 99(1):182-189. 20. Ali FY, Armstrong PC, Dhanji AR, Tucker AT, Paul-Clark MJ, Mitchell JA, Warner TD. Antiplatelet actions of statins and fibrates are mediated by PPARs. Arterioscler Thromb Vasc Biol 2009; 29(5):706-711. 21. Kroger N, Shimoni A, Zagrivnaja M, Ayuk F, Lioznov M, Schieder H, Renges H, Fehse B, Zabelina T, Nagler A, Zander AR. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood 2004; 104(10):3361-3363. 22. Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103(18):2248-2253. 23. Cortellaro M, Cofrancesco E, Arbustini E, Rossi F, Negri A, Tremoli E, Gabrielli L, Camera M. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 2002; 88(1):41-47. 24. Ramcharan AS, Van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJM. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis. Journal of Thrombosis and Haemostasis 2009; 7(4):514-520. 25. Doggen CJ, Lemaitre RN, Smith NL, Heckbert SR, Psaty BM. HMG CoA reductase inhibitors and the risk of venous thrombosis among postmenopausal women. J Thromb Haemost 2004; 2(5):700-701. 26. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenofibrate therapyon cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366(9500):1849-1861.
Our mission: To reduce the burden of cardiovascular disease
© 2018 European Society of Cardiology. All rights reserved