Statins and venous thromboembolism

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).

1 - VTE and atherosclerosis

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).

2 - Lipids and venous thrombosis

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.

3 - Statins and VTE

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.

4 - Statins and venous thrombosis

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).

Conclusion:

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.