Statins have been used for secondary prevention of CAD with good results. Simvastatin has been evaluated in several studies including the Scandanavian Simvastatin Survival Study (4S) (16), the Simvastatin/ Enalapril Coronary Atherosclerosis Trial (SCAT) (17), and the Multicentre Anti-Atheroma Study (MAAS) (18). In addition to lowering LDL cholesterol levels, simvastatin has been shown to cause angiographic improvement in the coronary vessels, as well as slowing the progression of diffuse and focal atherosclerosis. In addition, the drug is believed to induce positive vascular remodeling, thereby reducing the occurrence of restenosis (19). The 4S study included 4444 patients with documented or symptomatic CAD. This was the first study to unequivocally demonstrate a reduction in the total CAD mortality (34% reduction in treated group with a 51% reduction in of coronary revascularization rate). Risk reduction was evident in multiple subgroups such as women, diabetics, and elderly patients (> 60 years of age). Similar results were seen in the SCAT study that evaluated normo-cholesterolemic patients with CAD, and the MAAS study that demonstrated less angiographic progression of atherosclerosis in the simvastatin treated group compared to the placebo group.
Lovastatin was used in the Canadian Coronary Atherosclerosis Intervention trial (CCAIT) (20-22) and the Monitored Atherosclerosis Repression Study (MARS) (23). The CCAIT study (20) was designed to evaluate whether lovastatin therapy retards the progression or facilitates the regression of coronary atherosclerosis as assessed by serial angiograms. This study concluded that the effect of lovastatin in preventing the formation of new coronary lesions might be more important than its effect on established lesions. Subgroup analysis in women and diabetics concurred with the main analysis. The MARS was the first trial that employed serial coronary angiograms to test the effects of a single drug therapy using lovastatin more than 2 years. The results showed that there was no significant difference in lesions <50% stenosed at baseline, but for lesions >50% stenosed at baseline there was regression.
The Cholesterol and Recurrent Events (CARE) trial (24), the Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) study (25), and the Regression Growth Evaluation Statin study (REGRESS) (26-28) evaluated patients with established CAD given pravastatin. CARE reported a 24% reduction in the incidence of fatal and nonfatal coronary event in the treatment group, with a 23% reduction in the need for PTC A and a 31 % reduction in the incidence of stroke. There were similar findings in the LIPID study that reported a 23% decrease in the incidence of combined fatal and nonfatal coronary events. In the REGRESS study, patients with established CAD treated with pravastatin demonstrated a significant event reduction, regardless of whether they had increased or normal cholesterol levels. These data imply that the non-LDL effects of the statins may also be important for the risk reduction with this class of drugs.
Atorvastatin, one of the most potent statins available, was used in the Atorvastatin Versus Revascularization Treatments (AVERT) study (29). This study randomized 341 patients with CAD to atorvastatin 80 mg/day vs angioplasty plus usual care. The mean LDL cholesterol in the atorvastatin group was 77 mg/dL compared to 119 mg/dL in the angioplasty group. Therapy with atorvastatin was associated with a significantly longer time to first ischemic event, which corresponded to a risk reduction of 36%.
The majority of late coronary events in patients post coronary artery bypass graft (CABG) relate to degeneration of saphenous vein grafts. Lipid lowering after coronary revascularization has been shown to prevent clinical events related to plaque instability, and inhibits progression of saphenous vein graft disease. In the Post Coronary Artery Bypass Graft trial, lovastatin was combined with cholestyramine to lower LDL levels to less than 85 mg/dL (30). Aggressive lowering of LDL showed significantly less progression of graft atherosclerosis compared with moderate lowering of LDL. Subgroup analysis was done to evaluate the treatment effects by age, gender, and selected cardiovascular risk factors such as diabetes, hypertension, high-density lipoprotein (HDL), and triglycerides (TG) levels (31). Aggressive lowering of LDL delayed progression of atherosclerosis irrespective of gender, age, and these risk factors for CAD.
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