Woodward Burgert, III, MD

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).

ABSTRACT

BACKGROUND: For women at high risk of preterm delivery, it is the standard of care to administer an initial course of corticosteroids to promote lung maturity. Uncertainty remains, however, about the value of continuing treatments on a regular (weekly) schedule. This randomized controlled trial compared the efficacy of single versus weekly corticosteroids in reducing neonatal morbidity in women at high risk of preterm delivery.

POPULATION STUDIED: A total of 502 women between 24 weeks’ and 32 weeks and 6 days’ gestation at high risk for preterm delivery were recruited from 13 US academic centers. High risk was defined as preterm labor, preterm rupture of membranes, maternal medical illness, or suspected intrauterine growth restriction. Women were excluded if they needed immediate delivery, had active tuberculosis or human immunodeficiency virus infection, or if their fetuses had mature lungs or severe anomalies. Approximately equal proportions of subjects were white, Hispanic, and African American, and 67% were receiving government assistance. Also, 33% were nulliparous; 54% had preterm labor; and 14.5% had multiple gestations.

STUDY DESIGN AND VALIDITY: This was a randomized placebo-controlled double-blinded trial. Women at high risk for preterm delivery who received an initial course of corticosteroids and had not delivered in 1 week were randomized to receive either betamethasone 12 mg twice in 24 hours every week until 34 weeks or similarly administered placebo. Analysis was by intention to treat, using chi-square tests and t tests with assessment of study site as a potential confounder. The study was halted after 502 of a planned 1000 patients were recruited, due to emerging evidence that weekly corticosteroids might produce long-term neurologic sequelae. The methodology of this study was strong. The major weakness was lack of statistical power.

OUTCOMES MEASURED: The primary outcome was composite neonatal morbidity (including severe RDS, BPD and IVH, periventricular leukomalacia, sepsis, NEC, or death). Secondary outcomes included each individual outcome, maternal side effects, and clinical course. Utilization, cost, and patient satisfaction were not addressed.

RESULTS: The groups were similar at baseline and follow up was 97%. There was no significant difference in composite morbidity between the weekly course group and the single-course group. Exploratory analysis showed that weekly corticosteroids decreased severe RDS (15.3% vs 24.1%; P=.01), but there also a trend toward an increased risk of severe IVH in the weekly course group (7.6% vs 2.0%; P=.06). The weekly course group had shorter time to delivery (5.0 vs 5.8 weeks; P=.02) and a trend towards more chorioamnionitis (24.1% vs 17.8%; P=.09). There was no significant difference between the 2 treatment regimens in endometritis, wound infections, hemorrhage, or length of stay.

ABSTRACT

BACKGROUND: For women at high risk of preterm delivery, it is the standard of care to administer an initial course of corticosteroids to promote lung maturity. Uncertainty remains, however, about the value of continuing treatments on a regular (weekly) schedule. This randomized controlled trial compared the efficacy of single versus weekly corticosteroids in reducing neonatal morbidity in women at high risk of preterm delivery.

POPULATION STUDIED: A total of 502 women between 24 weeks’ and 32 weeks and 6 days’ gestation at high risk for preterm delivery were recruited from 13 US academic centers. High risk was defined as preterm labor, preterm rupture of membranes, maternal medical illness, or suspected intrauterine growth restriction. Women were excluded if they needed immediate delivery, had active tuberculosis or human immunodeficiency virus infection, or if their fetuses had mature lungs or severe anomalies. Approximately equal proportions of subjects were white, Hispanic, and African American, and 67% were receiving government assistance. Also, 33% were nulliparous; 54% had preterm labor; and 14.5% had multiple gestations.

STUDY DESIGN AND VALIDITY: This was a randomized placebo-controlled double-blinded trial. Women at high risk for preterm delivery who received an initial course of corticosteroids and had not delivered in 1 week were randomized to receive either betamethasone 12 mg twice in 24 hours every week until 34 weeks or similarly administered placebo. Analysis was by intention to treat, using chi-square tests and t tests with assessment of study site as a potential confounder. The study was halted after 502 of a planned 1000 patients were recruited, due to emerging evidence that weekly corticosteroids might produce long-term neurologic sequelae. The methodology of this study was strong. The major weakness was lack of statistical power.

OUTCOMES MEASURED: The primary outcome was composite neonatal morbidity (including severe RDS, BPD and IVH, periventricular leukomalacia, sepsis, NEC, or death). Secondary outcomes included each individual outcome, maternal side effects, and clinical course. Utilization, cost, and patient satisfaction were not addressed.

RESULTS: The groups were similar at baseline and follow up was 97%. There was no significant difference in composite morbidity between the weekly course group and the single-course group. Exploratory analysis showed that weekly corticosteroids decreased severe RDS (15.3% vs 24.1%; P=.01), but there also a trend toward an increased risk of severe IVH in the weekly course group (7.6% vs 2.0%; P=.06). The weekly course group had shorter time to delivery (5.0 vs 5.8 weeks; P=.02) and a trend towards more chorioamnionitis (24.1% vs 17.8%; P=.09). There was no significant difference between the 2 treatment regimens in endometritis, wound infections, hemorrhage, or length of stay.

ABSTRACT

BACKGROUND: For women at high risk of preterm delivery, it is the standard of care to administer an initial course of corticosteroids to promote lung maturity. Uncertainty remains, however, about the value of continuing treatments on a regular (weekly) schedule. This randomized controlled trial compared the efficacy of single versus weekly corticosteroids in reducing neonatal morbidity in women at high risk of preterm delivery.

POPULATION STUDIED: A total of 502 women between 24 weeks’ and 32 weeks and 6 days’ gestation at high risk for preterm delivery were recruited from 13 US academic centers. High risk was defined as preterm labor, preterm rupture of membranes, maternal medical illness, or suspected intrauterine growth restriction. Women were excluded if they needed immediate delivery, had active tuberculosis or human immunodeficiency virus infection, or if their fetuses had mature lungs or severe anomalies. Approximately equal proportions of subjects were white, Hispanic, and African American, and 67% were receiving government assistance. Also, 33% were nulliparous; 54% had preterm labor; and 14.5% had multiple gestations.

STUDY DESIGN AND VALIDITY: This was a randomized placebo-controlled double-blinded trial. Women at high risk for preterm delivery who received an initial course of corticosteroids and had not delivered in 1 week were randomized to receive either betamethasone 12 mg twice in 24 hours every week until 34 weeks or similarly administered placebo. Analysis was by intention to treat, using chi-square tests and t tests with assessment of study site as a potential confounder. The study was halted after 502 of a planned 1000 patients were recruited, due to emerging evidence that weekly corticosteroids might produce long-term neurologic sequelae. The methodology of this study was strong. The major weakness was lack of statistical power.

OUTCOMES MEASURED: The primary outcome was composite neonatal morbidity (including severe RDS, BPD and IVH, periventricular leukomalacia, sepsis, NEC, or death). Secondary outcomes included each individual outcome, maternal side effects, and clinical course. Utilization, cost, and patient satisfaction were not addressed.

RESULTS: The groups were similar at baseline and follow up was 97%. There was no significant difference in composite morbidity between the weekly course group and the single-course group. Exploratory analysis showed that weekly corticosteroids decreased severe RDS (15.3% vs 24.1%; P=.01), but there also a trend toward an increased risk of severe IVH in the weekly course group (7.6% vs 2.0%; P=.06). The weekly course group had shorter time to delivery (5.0 vs 5.8 weeks; P=.02) and a trend towards more chorioamnionitis (24.1% vs 17.8%; P=.09). There was no significant difference between the 2 treatment regimens in endometritis, wound infections, hemorrhage, or length of stay.