Improves endothelium dependent vasodilation and prothrombotic state and reduces oxidant stress and inflammatory markers in hypercholesterolemic individuals.
Decreases plasma thrombin activatable fibrinolysis inhibitor and improves endothelial function in hypercholesterolemic patients.
Increases t-PA and decreases PAI-1 production in endothelial cells.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) a randomized, double blind study of 12,064 patients revealed using 80 mg daily compared 20 mg daily resulted in a lowered LDL-C decrease of 13 mg/dL in both groups, no difference of primary end point of major coronary events, stroke and revascularization, while 53 patients on the 80 mg dose had myopathy, and only 3 patients with the 20 mg dose developed myopathy.
SEARCH trial was a 6.7 year randomized double-blind trial comparing the efficacy and safety of 80 mg of simvastatin compared to 20 mg of simvastatin, with or without B12 and folate in survivors of acute myocardial infarction, stroke, or arterial revascularization: cardiovascular events occurred in 25.7% of the 20 mg group, 24.5% in the 80 mg group, a 6% reduction in a relative risk of major adverse cardiovascular events consistent with the 13 milligrams per deciliter difference in LDL cholesterol levels.
Myopathy with serum creatine kinase more than 10 times the upper limits of normal, with unexplained muscle weakness or pain developed in 0.9% of patients in the above study in the 80 mg group, but only in .02% of patients in the 20 mg group (SEARCH trial).
A to Z Trial with 4497 patients with acute coronary syndrome randomized to receive 40 mg of simvastatin daily for 1 month followed by 80 mg daily or placebo for 4 months followed by 20 mg of simvastatin daily: follow-up 6-10 months no difference in cardiovascular death, nonfatal myocardial infarction, readmission for acute coronary syndrome and stroke.
A to Z Trial with 4497 patients indicates that myopathy occurred in 9 patients on the simvastatin 80 mg dose and in no patients with lower doses of simvastatin.
80 mg dose should be restricted to patients who have been taking that dose chronically without evidence of muscle toxicity.
Because of drug interactions concomitant use the following drugs is contraindicated-strong CYP3A4 inhibitors such as itraconazole, ketoconazole, protease inhibitors, erythromycin, clarithromycin and nefazodone, gemfibrozil, cyclosporine, and danazol.
Because of drug interactions the dose of simvastatin should not exceed 10 mg way utilizing amiodarone, verapamil or diltiazem, and should not exceed 20 mg amlopidine or ranolazine.