Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia

Abstract

The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days 3 and 28, but not platelet beta-thromboglobulin (betaTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas beta TG release was reduced only in the simvastatin group on days 3 and 28. All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.

Systemic blood coagulation activation in acute coronary syndromes

“…Total inactivation of fVa after cleavage at Arg 506 and Arg 306 by APC (fVai 306,506 ) is associated with a 30 kDa fVa-HC fragment (fVa-HC 30 , residues 307 to 506). 7 The generation of this product of APC cleavage is greatly enhanced in AMI, an indication increased expression of the thrombin-thrombomodulin system either because of the enhanced thrombin availability, the enhanced expression of thrombomodulin and/or the endothelial protein C receptor (EPCR) or all of the above.…”

“…In previous studies with this model we have reported the influence of aspirin and statins on thrombin generation [24][25][26][27][28][29] and platelet activation. 28,30 …”

Long-term fenofibrate treatment impairs endothelium-dependent dilation to acetylcholine by altering the cyclooxygenase pathway

“…Furthermore, apart from that effect, fenofibrate has been considered a vascular anti-inflammatory and anti-thromboembolic drug through its decrease of plasma inflammatory cytokines and thromboembolic products, respectively [16,17]. Clinical trials of fenofibrate in patients with diabetes type 2 and with dyslipidemia report an improvement in impaired cardiovascular parameters associated to an improvement of endothelial function [18,19].…”

“…Clinical trials of fenofibrate in patients with diabetes type 2 and with dyslipidemia report an improvement in impaired cardiovascular parameters associated to an improvement of endothelial function [18,19]. This beneficial effect of fenofibrate on endothelial function seems to be mediated by an increase of endothelial NO release and/or bioavailability related to the inhibition of inflammatory pathways in the arterial wall, the antioxidant effect of fenofibrate and the enhancement of endothelial NOS (eNOS) expression and activity [13,16]. Endothelium-derived NO is an important mediator of cardiovascular protection through its regulatory effects on vascular tone, platelet aggregation, oxidative stress, leukocyte adherence and vascular smooth muscle cell proliferation [20].…”

Acceleration of New Biomarkers Development and Discovery in Synergistic Diagnostics of Coronary Artery Disease

“…In empirical reconstruction, simulated maximum thrombin levels (p<0.01) and rates (p<0.01) were 50% higher with ACS while the initiation phases of thrombin generation were shorter than in patients with stable CAD (Brummel-Ziedins et al, 2008). Elevated levels of thrombin derivatives are associated with clinical risk factors for stroke (Lane et al, 1983;Takano et al, 1991 Kłoczko et al, 1996), hyperglycaemia and hypercholesterolemia (Wada et al, 1992;Sanguigni et al, 2005;Undas et al, 2005).…”