Should antioxidants be added to simvastatin and niacin for patients with coronary disease?

ABSTRACT

BACKGROUND: Antioxidant vitamins are commonly used in patients with coronary disease, but benefits have not been demonstrated. This randomized controlled trial studied whether addition of antioxidants to a simvastatin–niacin regimen improved outcomes.

POPULATION STUDIED: The investigators enrolled 160 patients with known coronary disease from the Seattle area and Canada. Subjects were included if they had clinical coronary disease (previous myocardial infarction [MI], coronary interventions, or confirmed angina); 3 or more coronary arteries with more than 30% stenosis or 1 stenosis more than 50%; high-density lipoprotein (HDL) cholesterol levels less than 35 mg/dL in men or 40 mg/dL in women; low-density lipoprotein (LDL) cholesterol levels less than 145 mg/dL; and triglyceride levels less than 400 mg/dL.

STUDY DESIGN AND VALIDITY: This was a double-blinded, placebo-controlled trial. Patients were randomly assigned to 1 of 4 regimens: simvastatin–niacin, antioxidant vitamins, simvastatin–niacin plus antioxidants, or placebo. Patients receiving simvastatin had their dose titrated to a goal LDL level of 40 to 90 mg/dL (mean final dose 13 mg/day). In patients receiving niacin, the dose was titrated over 1 month to at least 1000 mg twice per day (mean final dose 2.4 grams/day). Niacin 50 mg twice per day was used as the placebo to produce a flushing effect and thus keep patients blinded. Antioxidants were given twice daily, with total dosage of 800 IU vitamin E, 1000 mg vitamin C, 25 mg natural beta carotene, and 100 μg selenium. Coronary angiography was performed at baseline and finish; comparison of films was blinded. Patients were followed over 3 years. Analysis was by intent to treat with control for confounding with Cox proportional hazards.

OUTCOMES MEASURED: The primary clinical endpoint was the occurrence of a cardiovascular event: revascularization, nonfatal MI, or death from coronary causes. The angiographic primary endpoint was the change in stenosis of the most severe lesion in the 9 proximal coronary segments. Cost, quality of life, and patient satisfaction were not addressed.

RESULTS: The groups were similar at baseline, with the exception that diabetics were more prevalent in the group receiving simvastatin–niacin plus antioxidants and less prevalent in the simvastatin–niacin alone group (P = .04). Patients receiving simvastatin–niacin had significantly fewer cardiovascular events than those given placebo (21% vs 2.6%, P = .003, number needed to treat = 4.7). Addition of antioxidants actually blunted this effect: when antioxidant therapy was added to lipid lowering, the rate of clinical events increased to that observed with placebo. There was also no difference between patients receiving antioxidants alone and those receiving placebo. These clinical results were mirrored by the angiographic data: patients receiving simvastatin and niacin experienced a reduction in average coronary stenosis (P < .001), whereas all other groups showed an increase in stenosis (P < .005).

ABSTRACT

BACKGROUND: Antioxidant vitamins are commonly used in patients with coronary disease, but benefits have not been demonstrated. This randomized controlled trial studied whether addition of antioxidants to a simvastatin–niacin regimen improved outcomes.

POPULATION STUDIED: The investigators enrolled 160 patients with known coronary disease from the Seattle area and Canada. Subjects were included if they had clinical coronary disease (previous myocardial infarction [MI], coronary interventions, or confirmed angina); 3 or more coronary arteries with more than 30% stenosis or 1 stenosis more than 50%; high-density lipoprotein (HDL) cholesterol levels less than 35 mg/dL in men or 40 mg/dL in women; low-density lipoprotein (LDL) cholesterol levels less than 145 mg/dL; and triglyceride levels less than 400 mg/dL.

STUDY DESIGN AND VALIDITY: This was a double-blinded, placebo-controlled trial. Patients were randomly assigned to 1 of 4 regimens: simvastatin–niacin, antioxidant vitamins, simvastatin–niacin plus antioxidants, or placebo. Patients receiving simvastatin had their dose titrated to a goal LDL level of 40 to 90 mg/dL (mean final dose 13 mg/day). In patients receiving niacin, the dose was titrated over 1 month to at least 1000 mg twice per day (mean final dose 2.4 grams/day). Niacin 50 mg twice per day was used as the placebo to produce a flushing effect and thus keep patients blinded. Antioxidants were given twice daily, with total dosage of 800 IU vitamin E, 1000 mg vitamin C, 25 mg natural beta carotene, and 100 μg selenium. Coronary angiography was performed at baseline and finish; comparison of films was blinded. Patients were followed over 3 years. Analysis was by intent to treat with control for confounding with Cox proportional hazards.

OUTCOMES MEASURED: The primary clinical endpoint was the occurrence of a cardiovascular event: revascularization, nonfatal MI, or death from coronary causes. The angiographic primary endpoint was the change in stenosis of the most severe lesion in the 9 proximal coronary segments. Cost, quality of life, and patient satisfaction were not addressed.

RESULTS: The groups were similar at baseline, with the exception that diabetics were more prevalent in the group receiving simvastatin–niacin plus antioxidants and less prevalent in the simvastatin–niacin alone group (P = .04). Patients receiving simvastatin–niacin had significantly fewer cardiovascular events than those given placebo (21% vs 2.6%, P = .003, number needed to treat = 4.7). Addition of antioxidants actually blunted this effect: when antioxidant therapy was added to lipid lowering, the rate of clinical events increased to that observed with placebo. There was also no difference between patients receiving antioxidants alone and those receiving placebo. These clinical results were mirrored by the angiographic data: patients receiving simvastatin and niacin experienced a reduction in average coronary stenosis (P < .001), whereas all other groups showed an increase in stenosis (P < .005).

ABSTRACT

BACKGROUND: Antioxidant vitamins are commonly used in patients with coronary disease, but benefits have not been demonstrated. This randomized controlled trial studied whether addition of antioxidants to a simvastatin–niacin regimen improved outcomes.

POPULATION STUDIED: The investigators enrolled 160 patients with known coronary disease from the Seattle area and Canada. Subjects were included if they had clinical coronary disease (previous myocardial infarction [MI], coronary interventions, or confirmed angina); 3 or more coronary arteries with more than 30% stenosis or 1 stenosis more than 50%; high-density lipoprotein (HDL) cholesterol levels less than 35 mg/dL in men or 40 mg/dL in women; low-density lipoprotein (LDL) cholesterol levels less than 145 mg/dL; and triglyceride levels less than 400 mg/dL.

STUDY DESIGN AND VALIDITY: This was a double-blinded, placebo-controlled trial. Patients were randomly assigned to 1 of 4 regimens: simvastatin–niacin, antioxidant vitamins, simvastatin–niacin plus antioxidants, or placebo. Patients receiving simvastatin had their dose titrated to a goal LDL level of 40 to 90 mg/dL (mean final dose 13 mg/day). In patients receiving niacin, the dose was titrated over 1 month to at least 1000 mg twice per day (mean final dose 2.4 grams/day). Niacin 50 mg twice per day was used as the placebo to produce a flushing effect and thus keep patients blinded. Antioxidants were given twice daily, with total dosage of 800 IU vitamin E, 1000 mg vitamin C, 25 mg natural beta carotene, and 100 μg selenium. Coronary angiography was performed at baseline and finish; comparison of films was blinded. Patients were followed over 3 years. Analysis was by intent to treat with control for confounding with Cox proportional hazards.

OUTCOMES MEASURED: The primary clinical endpoint was the occurrence of a cardiovascular event: revascularization, nonfatal MI, or death from coronary causes. The angiographic primary endpoint was the change in stenosis of the most severe lesion in the 9 proximal coronary segments. Cost, quality of life, and patient satisfaction were not addressed.

RESULTS: The groups were similar at baseline, with the exception that diabetics were more prevalent in the group receiving simvastatin–niacin plus antioxidants and less prevalent in the simvastatin–niacin alone group (P = .04). Patients receiving simvastatin–niacin had significantly fewer cardiovascular events than those given placebo (21% vs 2.6%, P = .003, number needed to treat = 4.7). Addition of antioxidants actually blunted this effect: when antioxidant therapy was added to lipid lowering, the rate of clinical events increased to that observed with placebo. There was also no difference between patients receiving antioxidants alone and those receiving placebo. These clinical results were mirrored by the angiographic data: patients receiving simvastatin and niacin experienced a reduction in average coronary stenosis (P < .001), whereas all other groups showed an increase in stenosis (P < .005).