Simvastatin (Page 2 of 10)

Clinical Studies in Adults

Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. After six weeks of treatment with simvastatin the median (25th and 75th percentile) changes in LDL-C, TG, and HDL-C were -39% (-46, -31%), -19% (-31, 0%), and 6% (-3, 17%). Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin also significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Furthermore, simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, in this study, 1,021 of the patients were 65 and older. Cholesterol reduction with simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in these elderly patients, compared with younger patients.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method 2 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40-80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing coronary heart disease (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males 65 years of age and older (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; nonfatal myocardial infarctions, stroke, and revascularization procedures (coronary and non-coronary) (see Table 1).

TABLE 1
Summary of Heart Protection Study Results
Endpoint Simvastatin Placebo Risk Reduction (%) p-Value
(N=10,269) n (%)* (N=10,267) n (%)* (95% CI)
*
n = number of patients with indicated event
Primary
Mortality 1,328 (12.9) 1,507 (14.7) 13 p=0.0003
(6-19)
CHD mortality 587 (5.7) 707 (6.9) 18 p=0.0005
(8-26)
Secondary
Non-fatal MI 357 (3.5) 574 (5.6) 38 p<0.0001
(30-46)
Stroke 444 (4.3) 585 (5.7) 25 p<0.0001
(15-34)
Tertiary
Coronary revascularization 513 (5) 725 (7.1) 30 (22-38) p<0.0001
Peripheral and other non-coronary revascularization 450 (4.4) 532 (5.2) 16 (5-26) p=0.006

Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with simvastatin had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Furthermore, treatment with simvastatin produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD.

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