(Statins) and Fixed-dose Combination Products Containing a Statin

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Final Report Update 5 Drug Effectiveness Review Project reduced low-density lipoprotein by 35%, from 133 mg/dL to 87 mg/dL. By the end of follow-up (about 3.3 years), low-density lipoprotein was 89 mg/dL in the patients still taking atorvastatin compared with 127 mg/dL in the control group. There were 100 primary endpoint events in the atorvastatin group (100/5168, or 1.9%) and 150 events in the placebo group (3%). The event rate in the placebo group corresponded to a 10-year coronary event rate of 9.4%. Over 3.3 years, the number needed to treat to prevent 1 nonfatal myocardial infarction or death from coronary heart disease was 94 (P=0.005). Atorvastatin increased the chance of remaining free of myocardial infarction for 3.3 years from 95% to 97%. For the secondary and tertiary endpoints, strokes were reduced (number needed to treat, 158; P
Final Report Update 5 Drug Effectiveness Review Project to 1.18). PROSPER recruited a select group of elderly subjects. Of 23 770 people who were screened, 16 714 were ineligible or refused to participate. The PREVEND-IT trial 124 was a population-based (N=864), randomized, placebocontrolled trial with a 2 X 2 factorial design. Residents of 1 city in the Netherlands with persistent microalbuminuria were randomized to fosinopril and pravastatin for the prevention of cardiovascular morbidity and mortality. In the pravastatin 10 mg compared with placebo arm, there was no reduction in urinary albumin excretion and no significant reduction in cardiovascular events after an average 46 months of follow-up (hazard ratio, 0.87; 95% CI, 0.49 to 1.57). In a subgroup analysis of 286 patients with the metabolic syndrome (33% of the total group), 180 the unadjusted hazard ratio was non-significant (hazard ratio, 0.48; 95% CI, 0.21 to 1.07). However, when adjusted for age and sex, there was a significant reduction in cardiovascular events in the pravastatin group (hazard ratio, 0.39; 95% CI, 0.17 to 0.89). The ALERT trial established the efficacy and safety of fluvastatin in patients who had undergone renal transplant. Fluvastatin was superior to placebo in reducing cardiac deaths or non-fatal myocardial infarction, 127, 181, 182 but there was no effect on the renal endpoints of graft loss, doubling of serum creatinine, or decline in glomerular filtration rate. 173 The MEGA study 144 enrolled Japanese adults without known coronary disease who had coronary heart disease risk equivalents or other risk factors (21% diabetes, 42% hypertension, 20% smokers). Patients were randomized to lower doses of pravastatin 10-20 mg (typical doses used in Japan) plus diet or diet alone and found 33% relative reduction in the incidence of coronary events with pravastatin over a mean follow-up of 5.3 years (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; rate, 1.7% pravastatin compared with 2.55% diet alone). The primary endpoint was driven by reductions in nonfatal myocardial infarction and the need for revascularizations. Allcause mortality was lower in pravastatin-treated patients, though statistical significance was not achieved (hazard ratio, 0.72; 95% CI, 0.51 to 1.01; P=0.055). Patients with diabetes. There were 8 trials 125, 134, 142, 145, 146, 178, 183, 184 evaluating long-term effectiveness of atorvastatin 10-20 mg, simvastatin 40 mg, and fluvastatin 80 mg in patients with diabetes (Table 10; Evidence Table 2). Of the 8 trials, CARDS (Collaborative Atorvastatin Diabetes Study) was the only study designed to assess primary prevention of cardiovascular disease in patients with type 2 diabetes. Two-thousand eight-hundred thirty eight patients without elevated cholesterol levels (mean lowdensity lipoprotein less than 107 mg/dL), who had no history of cardiovascular disease but at least 1 of the risk factors of retinopathy, albuminuria, current smoking, or hypertension, were randomized to atorvastatin 10 mg or placebo. After 3.9 years of follow-up, there was a significant relative risk reduction of 37% in cardiovascular events but not with all-cause mortality (Table 10). The CARDS trial was stopped 2 years earlier than planned because of significant benefit at the second interim analysis. In addition to CARDS, 3 placebo-controlled trials (HPS, ASCOT-LLA, ASPEN) 142, 178, 184 enrolled patients with type 2 diabetes with and without established cardiovascular disease, and subgroup analyses were performed for those classified as primary prevention. Overall, CARDS, HPS, and ASCOT-LLA 125, 178, 184 found the study statins to be beneficial in reducing coronary events compared with placebo in patients with type 2 diabetes with and without established cardiovascular disease (Table 10; Evidence Table 2). The HPS trial was the largest of these, including 5963 patients with diabetes. There was a 27% reduction in risk of major coronary events (first nonfatal myocardial infarction or coronary death), similar to the reduction in risk in the overall population of high-risk patients with simvastatin 40 mg. Among the 2912 Statins Page 45 of 128
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(Statins) and Fixed-dose Combination Products Containing a Statin

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