Cardiovascular Trials Review Update
Cardiovascular Trials Review Update
Title. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial.
Authors. Heart Protection Study Collaborative Group.
Reference. Lancet 2002;360:7-22.
Disease. Atherosclerosis.
Purpose. To evaluate whether simvastatin will reduce morbidity and mortality in a large cohort of patients at substantial risk of death.
Design. Randomized, double-blind, 2 x 2 factorial, placebo-controlled, multicenter.
Patients. 20,536 patients, 40-80 years old, with a history of coronary artery disease, peripheral vascular disease, stroke, diabetes, or hypertension and low-to-average total or low-density lipoprotein cholesterol (LDL-C) (>= 3.5 mmol/L [135 mg/dL]). Patients in whom statin therapy was considered indicated by their physicians were not included. Patients with chronic liver disease; creatinine >200 µmol/L; severe renal disease; inflammatory muscle disease; creatine kinase >750 IU/L; cyclosporine, fibrates, or niacin therapy; women with childbearing potential; severe heart failure; severe chronic lung disease; or other life-threatening disease were excluded.
Follow-up. 5 years.
Regimen. After a run-in period of placebo treatment for 4 weeks and 4-6 weeks of fixed dose of simvastatin 40 mg/d, patients were randomized to either simvastatin (40 mg/d) (n=10,269) or placebo (n=10,267) and to vitamins (vitamin E 600 mg, vitamin C 250 mg, and ß-carotene 20 mg) or placebo.
Additional Therapy. A nonstudy statin treatment was encouraged if the patient's physician thought it was indicated.
Results. Of the 63,603 patients screened, 32,145 patients were enrolled for the run-in phase, and 20,536 patients were further randomized. In the simvastatin allocated group, 85% of the patients were taking study or nonstudy statins at the end of the follow-up, whereas 32% of the patients allocated to placebo were receiving nonstudy statins. At the end of the 5th year, the mean ± standard error of the difference between the simvastatin and placebo groups was -1.2 ± 0.02 mmol/L for total cholesterol; -1.0 ± 0.02 mmol/L for LDL-C; 0.03 ± 0.01 mmol/L for HDL-C; and -0.3 ± 0.03 mmol/L for triglycerides. The absolute difference in LDL-C between the simvastatin and placebo groups was -0.9, -1.0, and -1.0 mmol/L for patients with baseline LDL-C <3.0, 3.0-3.5, and >=3.5 mmol/L, group and 14.7% in the placebo group (rate ratio 0.87; 95% CI=0.81-0.94; p=0.0003), vascular mortality was 7.6% and 9.1%, respectively (rate ratio 0.83; 95% CI=0.75-0.91; p <0.0001), and nonvascular mortality 5.3% and 5.6%, respectively (rate ratio 0.95; 95% CI=0.85-1.07; p=0.4). Coronary mortality was 5.7% in the simvastatin group and 6.9% in the placebo group (p=0.0005). Stroke occurred in 4.3% of the patients in the simvastatin group vs 5.7% in the placebo (rate ratio 0.75; 95% CI=0.66-0.85; p <0.0001). Major coronary events occurred in 8.7% in the simvastatin group and 11.8% in the placebo group (rate ratio 0.73; 95% CI=0.67-0.79; p <0.0001). Major vascular events occurred in 19.8% of the patients in the simvastatin group and in 25.2% in the placebo group (rate ratio 0.76; 95% CI=0.72-0.81; p <0.0001). A total of 5.0% vs 7.1% of the patients in the simvastatin and placebo groups, respectively, underwent coronary revascularization (p <0.0001), and 4.4% vs 5.2% underwent noncoronary revascularization (p=0.006). The benefit of simvastatin was irrespective of age, gender, and baseline total cholesterol or LDL-C levels. The benefit of simvastatin was apparent even among the 6793 patients with baseline LDL-C <3.0 mmol/L (major vascular events occurred in 17.6% and 22.2% of the patients in the simvastatin and placebo group, respectively; p <0.0001). There were no signifi- cant side effects. A significant elevation (>4 x upper limit of normal [ULN]) in alanine aminotransferase was detected in 0.42% of the patients in the simvastatin group vs 0.31% in the placebo group. Creatine kinase elevation 4-10 x ULN was detected in 0.19% and 0.13% of the patients, respectively, and >10 x ULN in 0.11% and 0.06% of the patients, respectively. Rhabdomyolysis was detected in 0.05% of the patients in the simvastatin group and 0.03% in the placebo group.
Conclusions. Simvastatin 40 mg/d was safe and effective in reducing the incidence of death, myocardial infarction, stroke, and revascularization in a wide range of high-risk patients, regardless of total or LDL cholesterol levels at baseline, age, or gender.
Title. MRC/BHF Heart Protection Study of antioxidant vitamin supplement in 20,536 high-risk individuals: a randomised placebo-controlled trial.
Authors. Heart Protection Study Collaborative Group.
Reference. Lancet 2002;360:23-33.
Disease. Atherosclerosis.
Purpose. To assess the effects of antioxidant vitamins on vascular and nonvascular morbidity and mortality in a large cohort of patients at high risk.
Design. Randomized, double-blind, 2 x 2 factorial, placebo-controlled, multicenter.
Patients. 20,536 patients, 40-80 years old, with a history of coronary artery disease, peripheral vascular disease, stroke, diabetes, or hypertension and low-to-average total or low-density lipoprotein cholesterol (LDL-C) (>= 3.5 mmol/L [135 mg/dL]). Patients in whom statin therapy was considered indicated by their physicians were not included. Patients with chronic liver disease; creatinine >200 µmol/L; severe renal disease; inflammatory muscle disease; creatine kinase >750 IU/L; cyclosporine, fibrates, or niacin therapy; women with childbearing potential; severe heart failure; severe chronic lung disease; or other life-threatening disease were excluded.
Follow-up. 5 years.
Regimen. After 2-month run-in period of active vitamins, patients were randomized to vitamins (vitamin E 600 mg, vitamin C 250 mg, and ß-carotene 20 mg) (n=10,269) or placebo (n=10,267) and to either simvastatin (40 mg/d) or placebo.
Results. 83% of the patients in each group were compliant with the study medication. All-cause mortality was 14.1% in the vitamin group and 13.5% in the placebo group (rate ratio 1.04; 95% CI=0.97-1.12; p=0.3). Coronary mortality was 6.5% and 6.1%, respectively, and vascular mortality was 8.6% in the vitamin group and 8.2% in the placebo group (rate ratio 1.05; 95% CI=0.95-1.15; p=0.3). Nonvascular mortality was 5.5% and 5.3%, respectively (rate ratio 1.04; 95% CI=0.92-1.17; p=0.5). Major coronary events occurred in 10.4% of the patients in the vitamin group vs 10.2% in the placebo group (p=0.7). Stroke occurred in 5.0% of the patients in each group (p=0.8). Vitamins did not reduce the rate of coronary (6.1% vs 6.0%) or noncoronary (4.6% vs 5.0%) revascularization. Major vascular events occurred in 22.5% of the patients in each group (p >0.9). Subgroup analysis did not identify treatment benefit in any of the different prior disease categories. Vitamins had no effect on incidence of cancer or on hospitalization for any other nonvascular cause.
Conclusions. Among high-risk patients, 5-year treatment with antioxidant vitamins did not reduce morbidity and mortality.
Title. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial.
Authors. Heart Protection Study Collaborative Group.
Reference. Lancet 2002;360:7-22.
Disease. Atherosclerosis.
Purpose. To evaluate whether simvastatin will reduce morbidity and mortality in a large cohort of patients at substantial risk of death.
Design. Randomized, double-blind, 2 x 2 factorial, placebo-controlled, multicenter.
Patients. 20,536 patients, 40-80 years old, with a history of coronary artery disease, peripheral vascular disease, stroke, diabetes, or hypertension and low-to-average total or low-density lipoprotein cholesterol (LDL-C) (>= 3.5 mmol/L [135 mg/dL]). Patients in whom statin therapy was considered indicated by their physicians were not included. Patients with chronic liver disease; creatinine >200 µmol/L; severe renal disease; inflammatory muscle disease; creatine kinase >750 IU/L; cyclosporine, fibrates, or niacin therapy; women with childbearing potential; severe heart failure; severe chronic lung disease; or other life-threatening disease were excluded.
Follow-up. 5 years.
Regimen. After a run-in period of placebo treatment for 4 weeks and 4-6 weeks of fixed dose of simvastatin 40 mg/d, patients were randomized to either simvastatin (40 mg/d) (n=10,269) or placebo (n=10,267) and to vitamins (vitamin E 600 mg, vitamin C 250 mg, and ß-carotene 20 mg) or placebo.
Additional Therapy. A nonstudy statin treatment was encouraged if the patient's physician thought it was indicated.
Results. Of the 63,603 patients screened, 32,145 patients were enrolled for the run-in phase, and 20,536 patients were further randomized. In the simvastatin allocated group, 85% of the patients were taking study or nonstudy statins at the end of the follow-up, whereas 32% of the patients allocated to placebo were receiving nonstudy statins. At the end of the 5th year, the mean ± standard error of the difference between the simvastatin and placebo groups was -1.2 ± 0.02 mmol/L for total cholesterol; -1.0 ± 0.02 mmol/L for LDL-C; 0.03 ± 0.01 mmol/L for HDL-C; and -0.3 ± 0.03 mmol/L for triglycerides. The absolute difference in LDL-C between the simvastatin and placebo groups was -0.9, -1.0, and -1.0 mmol/L for patients with baseline LDL-C <3.0, 3.0-3.5, and >=3.5 mmol/L, group and 14.7% in the placebo group (rate ratio 0.87; 95% CI=0.81-0.94; p=0.0003), vascular mortality was 7.6% and 9.1%, respectively (rate ratio 0.83; 95% CI=0.75-0.91; p <0.0001), and nonvascular mortality 5.3% and 5.6%, respectively (rate ratio 0.95; 95% CI=0.85-1.07; p=0.4). Coronary mortality was 5.7% in the simvastatin group and 6.9% in the placebo group (p=0.0005). Stroke occurred in 4.3% of the patients in the simvastatin group vs 5.7% in the placebo (rate ratio 0.75; 95% CI=0.66-0.85; p <0.0001). Major coronary events occurred in 8.7% in the simvastatin group and 11.8% in the placebo group (rate ratio 0.73; 95% CI=0.67-0.79; p <0.0001). Major vascular events occurred in 19.8% of the patients in the simvastatin group and in 25.2% in the placebo group (rate ratio 0.76; 95% CI=0.72-0.81; p <0.0001). A total of 5.0% vs 7.1% of the patients in the simvastatin and placebo groups, respectively, underwent coronary revascularization (p <0.0001), and 4.4% vs 5.2% underwent noncoronary revascularization (p=0.006). The benefit of simvastatin was irrespective of age, gender, and baseline total cholesterol or LDL-C levels. The benefit of simvastatin was apparent even among the 6793 patients with baseline LDL-C <3.0 mmol/L (major vascular events occurred in 17.6% and 22.2% of the patients in the simvastatin and placebo group, respectively; p <0.0001). There were no signifi- cant side effects. A significant elevation (>4 x upper limit of normal [ULN]) in alanine aminotransferase was detected in 0.42% of the patients in the simvastatin group vs 0.31% in the placebo group. Creatine kinase elevation 4-10 x ULN was detected in 0.19% and 0.13% of the patients, respectively, and >10 x ULN in 0.11% and 0.06% of the patients, respectively. Rhabdomyolysis was detected in 0.05% of the patients in the simvastatin group and 0.03% in the placebo group.
Conclusions. Simvastatin 40 mg/d was safe and effective in reducing the incidence of death, myocardial infarction, stroke, and revascularization in a wide range of high-risk patients, regardless of total or LDL cholesterol levels at baseline, age, or gender.
Title. MRC/BHF Heart Protection Study of antioxidant vitamin supplement in 20,536 high-risk individuals: a randomised placebo-controlled trial.
Authors. Heart Protection Study Collaborative Group.
Reference. Lancet 2002;360:23-33.
Disease. Atherosclerosis.
Purpose. To assess the effects of antioxidant vitamins on vascular and nonvascular morbidity and mortality in a large cohort of patients at high risk.
Design. Randomized, double-blind, 2 x 2 factorial, placebo-controlled, multicenter.
Patients. 20,536 patients, 40-80 years old, with a history of coronary artery disease, peripheral vascular disease, stroke, diabetes, or hypertension and low-to-average total or low-density lipoprotein cholesterol (LDL-C) (>= 3.5 mmol/L [135 mg/dL]). Patients in whom statin therapy was considered indicated by their physicians were not included. Patients with chronic liver disease; creatinine >200 µmol/L; severe renal disease; inflammatory muscle disease; creatine kinase >750 IU/L; cyclosporine, fibrates, or niacin therapy; women with childbearing potential; severe heart failure; severe chronic lung disease; or other life-threatening disease were excluded.
Follow-up. 5 years.
Regimen. After 2-month run-in period of active vitamins, patients were randomized to vitamins (vitamin E 600 mg, vitamin C 250 mg, and ß-carotene 20 mg) (n=10,269) or placebo (n=10,267) and to either simvastatin (40 mg/d) or placebo.
Results. 83% of the patients in each group were compliant with the study medication. All-cause mortality was 14.1% in the vitamin group and 13.5% in the placebo group (rate ratio 1.04; 95% CI=0.97-1.12; p=0.3). Coronary mortality was 6.5% and 6.1%, respectively, and vascular mortality was 8.6% in the vitamin group and 8.2% in the placebo group (rate ratio 1.05; 95% CI=0.95-1.15; p=0.3). Nonvascular mortality was 5.5% and 5.3%, respectively (rate ratio 1.04; 95% CI=0.92-1.17; p=0.5). Major coronary events occurred in 10.4% of the patients in the vitamin group vs 10.2% in the placebo group (p=0.7). Stroke occurred in 5.0% of the patients in each group (p=0.8). Vitamins did not reduce the rate of coronary (6.1% vs 6.0%) or noncoronary (4.6% vs 5.0%) revascularization. Major vascular events occurred in 22.5% of the patients in each group (p >0.9). Subgroup analysis did not identify treatment benefit in any of the different prior disease categories. Vitamins had no effect on incidence of cancer or on hospitalization for any other nonvascular cause.
Conclusions. Among high-risk patients, 5-year treatment with antioxidant vitamins did not reduce morbidity and mortality.