Warren P. Newton, MD, MPH

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: Acute cough and bronchitis are common primary care diagnoses often treated withβ₂-agonists (eg, albuterol). This systematic review sought to assess whether β₂-agonists constitute effective treatment for these conditions.

POPULATION STUDIED: A total of 492 patients older than 2 years was gathered from randomized controlled trials measuring the efficacy of β₂-agonists versus placebo or erythromycin for treatment of “acute cough,” “acute bronchitis,” or “acute transient cough” without clear etiology (pneumonia, pertussis, or sinusitis). The maximum mean duration of cough acceptable for inclusion was 30 days. Although no information was provided about specific diagnostic criteria, numbers of adult smokers and wheezers, or specifics of clinical presentation (fever, tachypnea), the population studied seems similar to that of a typical family practice.

STUDY DESIGN AND VALIDITY: The authors searched multiple databases, including MEDLINE and EMBASE, The Cochrane Library, reference lists of retrieved articles, review articles, textbooks, and information from manufacturers. Two investigators examined the search results, forwarding those that met inclusion criteria to the remaining 3 investigators, who graded the studies using the Jadad methodology scale, on the basis of randomization, blinding, and withdrawals. Disagreement regarding study quality was common (κ= 0.27) and was resolved by discussion. Included studies were then divided into 3 groups for analysis: 2 pediatric trials comparing β₂-agonists with placebo; 4 adult trials comparing β₂-agonists with placebo; and 1 adult trial comparing β₂-agonists with erythromycin. Summary statistics were generated using Review Manager 4.1.

OUTCOMES MEASURED: Outcomes measured included cough severity, duration, and productivity; lost work days; night cough; and adverse effects. Only one trial measured compliance. Cost and patient satisfaction were not addressed.

RESULTS: The overall quality of the included studies was fair. The pediatric studies revealed no benefit from albuterol. In the adult placebo trials, 1 demonstrated no benefit and 3 demonstrated slight improvement in cough severity. In the erythromycin study, those in the albuterol group had less cough or productive cough after 7 days, but the groups did not differ in night cough, time to improvement, or missed work days. When all the adult studies were combined, there was no difference in cough after 7 days, in productive cough, or in night cough. Studies that had enrolled more wheezing patients were more likely to show benefits than those that had not.

ABSTRACT

BACKGROUND: Acute cough and bronchitis are common primary care diagnoses often treated withβ₂-agonists (eg, albuterol). This systematic review sought to assess whether β₂-agonists constitute effective treatment for these conditions.

POPULATION STUDIED: A total of 492 patients older than 2 years was gathered from randomized controlled trials measuring the efficacy of β₂-agonists versus placebo or erythromycin for treatment of “acute cough,” “acute bronchitis,” or “acute transient cough” without clear etiology (pneumonia, pertussis, or sinusitis). The maximum mean duration of cough acceptable for inclusion was 30 days. Although no information was provided about specific diagnostic criteria, numbers of adult smokers and wheezers, or specifics of clinical presentation (fever, tachypnea), the population studied seems similar to that of a typical family practice.

STUDY DESIGN AND VALIDITY: The authors searched multiple databases, including MEDLINE and EMBASE, The Cochrane Library, reference lists of retrieved articles, review articles, textbooks, and information from manufacturers. Two investigators examined the search results, forwarding those that met inclusion criteria to the remaining 3 investigators, who graded the studies using the Jadad methodology scale, on the basis of randomization, blinding, and withdrawals. Disagreement regarding study quality was common (κ= 0.27) and was resolved by discussion. Included studies were then divided into 3 groups for analysis: 2 pediatric trials comparing β₂-agonists with placebo; 4 adult trials comparing β₂-agonists with placebo; and 1 adult trial comparing β₂-agonists with erythromycin. Summary statistics were generated using Review Manager 4.1.

OUTCOMES MEASURED: Outcomes measured included cough severity, duration, and productivity; lost work days; night cough; and adverse effects. Only one trial measured compliance. Cost and patient satisfaction were not addressed.

RESULTS: The overall quality of the included studies was fair. The pediatric studies revealed no benefit from albuterol. In the adult placebo trials, 1 demonstrated no benefit and 3 demonstrated slight improvement in cough severity. In the erythromycin study, those in the albuterol group had less cough or productive cough after 7 days, but the groups did not differ in night cough, time to improvement, or missed work days. When all the adult studies were combined, there was no difference in cough after 7 days, in productive cough, or in night cough. Studies that had enrolled more wheezing patients were more likely to show benefits than those that had not.

ABSTRACT

BACKGROUND: Acute cough and bronchitis are common primary care diagnoses often treated withβ₂-agonists (eg, albuterol). This systematic review sought to assess whether β₂-agonists constitute effective treatment for these conditions.

POPULATION STUDIED: A total of 492 patients older than 2 years was gathered from randomized controlled trials measuring the efficacy of β₂-agonists versus placebo or erythromycin for treatment of “acute cough,” “acute bronchitis,” or “acute transient cough” without clear etiology (pneumonia, pertussis, or sinusitis). The maximum mean duration of cough acceptable for inclusion was 30 days. Although no information was provided about specific diagnostic criteria, numbers of adult smokers and wheezers, or specifics of clinical presentation (fever, tachypnea), the population studied seems similar to that of a typical family practice.

STUDY DESIGN AND VALIDITY: The authors searched multiple databases, including MEDLINE and EMBASE, The Cochrane Library, reference lists of retrieved articles, review articles, textbooks, and information from manufacturers. Two investigators examined the search results, forwarding those that met inclusion criteria to the remaining 3 investigators, who graded the studies using the Jadad methodology scale, on the basis of randomization, blinding, and withdrawals. Disagreement regarding study quality was common (κ= 0.27) and was resolved by discussion. Included studies were then divided into 3 groups for analysis: 2 pediatric trials comparing β₂-agonists with placebo; 4 adult trials comparing β₂-agonists with placebo; and 1 adult trial comparing β₂-agonists with erythromycin. Summary statistics were generated using Review Manager 4.1.

OUTCOMES MEASURED: Outcomes measured included cough severity, duration, and productivity; lost work days; night cough; and adverse effects. Only one trial measured compliance. Cost and patient satisfaction were not addressed.

RESULTS: The overall quality of the included studies was fair. The pediatric studies revealed no benefit from albuterol. In the adult placebo trials, 1 demonstrated no benefit and 3 demonstrated slight improvement in cough severity. In the erythromycin study, those in the albuterol group had less cough or productive cough after 7 days, but the groups did not differ in night cough, time to improvement, or missed work days. When all the adult studies were combined, there was no difference in cough after 7 days, in productive cough, or in night cough. Studies that had enrolled more wheezing patients were more likely to show benefits than those that had not.

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.

BACKGROUND: There is concern about the effect of antihistamines in children on alertness and school performance. This study assessed the impact of first- and second-generation antihistamines on school performance.

POPULATION STUDIED: The investigators enrolled 63 children aged 8 to 10 years with antihistamine-treated allergic rhinitis but no current symptoms. Subjects underwent skin testing to prove they were allergic to allergens not currently in season. They had no known learning disabilities or illnesses that might have an impact on the study. In general, the subjects seem similar to patients family physicians see, although no information about the study group composition by weight, sex, ethnicity, specific allergy history, or other medical history was given.

STUDY DESIGN AND VALIDITY: This was a double-blind placebo-controlled study. Participants were randomized to 1 of 3 treatment groups: diphenhdramine (Benadryl, dye-free) 25 mg twice daily, loratadine (Claritin) 10 mg in the morning with placebo in the evening, or placebo twice daily. To simulate an everyday classroom experience, an existing laboratory school was used on 3 consecutive weekends. The medications were administered on study days 1, 2, and 8 at 7:45 AM and 1:45 PM. The subjects were given 1-hour lectures and 1-hour reading assignments on plant biology. After 90 to 120 minutes, they completed computerized testing to assess retention and reaction times. Covariate analysis was performed, with adjustments for sex, age, baseline reading ability, and weight, along with correction for multiple comparisons. The methodology of this study was strong. The major strengths were the randomized design, the use of patients with known allergies, and the realistic laboratory school setting with appropriate and innovative “blinded” testing. The major weaknesses of the study were the relatively small sample size, and—despite the commendable efforts of the investigators—the inherent artificiality of a weekend school that takes place only over a few weekends. Other minor limitations include the short duration of the study and the lack of assessment of baseline medical history. Interpretation was hampered by the lack of information regarding the results of randomization.

OUTCOME MEASURED: Outcomes measured by computer assessment were: (1) retention of material presented orally (average number of errors in 25 questions about teacher presentations); (2) retention of materials presented in a written format (average number of errors in 25 questions from the readings); (3) reaction time for answers (average for all correct computer test questions); and (4) child self report of somnolence.

RESULTS: At the end of the trial, there were no significant differences noted in the verbal instruction score, reading test score, reaction time, or somnolence scale among students in the 3 treatment groups. Female subjects tended to rate somnolence slightly higher than male subjects did; heavier subjects rated somnolence lower.

BACKGROUND: There is concern about the effect of antihistamines in children on alertness and school performance. This study assessed the impact of first- and second-generation antihistamines on school performance.

POPULATION STUDIED: The investigators enrolled 63 children aged 8 to 10 years with antihistamine-treated allergic rhinitis but no current symptoms. Subjects underwent skin testing to prove they were allergic to allergens not currently in season. They had no known learning disabilities or illnesses that might have an impact on the study. In general, the subjects seem similar to patients family physicians see, although no information about the study group composition by weight, sex, ethnicity, specific allergy history, or other medical history was given.

STUDY DESIGN AND VALIDITY: This was a double-blind placebo-controlled study. Participants were randomized to 1 of 3 treatment groups: diphenhdramine (Benadryl, dye-free) 25 mg twice daily, loratadine (Claritin) 10 mg in the morning with placebo in the evening, or placebo twice daily. To simulate an everyday classroom experience, an existing laboratory school was used on 3 consecutive weekends. The medications were administered on study days 1, 2, and 8 at 7:45 AM and 1:45 PM. The subjects were given 1-hour lectures and 1-hour reading assignments on plant biology. After 90 to 120 minutes, they completed computerized testing to assess retention and reaction times. Covariate analysis was performed, with adjustments for sex, age, baseline reading ability, and weight, along with correction for multiple comparisons. The methodology of this study was strong. The major strengths were the randomized design, the use of patients with known allergies, and the realistic laboratory school setting with appropriate and innovative “blinded” testing. The major weaknesses of the study were the relatively small sample size, and—despite the commendable efforts of the investigators—the inherent artificiality of a weekend school that takes place only over a few weekends. Other minor limitations include the short duration of the study and the lack of assessment of baseline medical history. Interpretation was hampered by the lack of information regarding the results of randomization.

OUTCOME MEASURED: Outcomes measured by computer assessment were: (1) retention of material presented orally (average number of errors in 25 questions about teacher presentations); (2) retention of materials presented in a written format (average number of errors in 25 questions from the readings); (3) reaction time for answers (average for all correct computer test questions); and (4) child self report of somnolence.

RESULTS: At the end of the trial, there were no significant differences noted in the verbal instruction score, reading test score, reaction time, or somnolence scale among students in the 3 treatment groups. Female subjects tended to rate somnolence slightly higher than male subjects did; heavier subjects rated somnolence lower.

BACKGROUND: There is concern about the effect of antihistamines in children on alertness and school performance. This study assessed the impact of first- and second-generation antihistamines on school performance.

POPULATION STUDIED: The investigators enrolled 63 children aged 8 to 10 years with antihistamine-treated allergic rhinitis but no current symptoms. Subjects underwent skin testing to prove they were allergic to allergens not currently in season. They had no known learning disabilities or illnesses that might have an impact on the study. In general, the subjects seem similar to patients family physicians see, although no information about the study group composition by weight, sex, ethnicity, specific allergy history, or other medical history was given.

STUDY DESIGN AND VALIDITY: This was a double-blind placebo-controlled study. Participants were randomized to 1 of 3 treatment groups: diphenhdramine (Benadryl, dye-free) 25 mg twice daily, loratadine (Claritin) 10 mg in the morning with placebo in the evening, or placebo twice daily. To simulate an everyday classroom experience, an existing laboratory school was used on 3 consecutive weekends. The medications were administered on study days 1, 2, and 8 at 7:45 AM and 1:45 PM. The subjects were given 1-hour lectures and 1-hour reading assignments on plant biology. After 90 to 120 minutes, they completed computerized testing to assess retention and reaction times. Covariate analysis was performed, with adjustments for sex, age, baseline reading ability, and weight, along with correction for multiple comparisons. The methodology of this study was strong. The major strengths were the randomized design, the use of patients with known allergies, and the realistic laboratory school setting with appropriate and innovative “blinded” testing. The major weaknesses of the study were the relatively small sample size, and—despite the commendable efforts of the investigators—the inherent artificiality of a weekend school that takes place only over a few weekends. Other minor limitations include the short duration of the study and the lack of assessment of baseline medical history. Interpretation was hampered by the lack of information regarding the results of randomization.

OUTCOME MEASURED: Outcomes measured by computer assessment were: (1) retention of material presented orally (average number of errors in 25 questions about teacher presentations); (2) retention of materials presented in a written format (average number of errors in 25 questions from the readings); (3) reaction time for answers (average for all correct computer test questions); and (4) child self report of somnolence.

RESULTS: At the end of the trial, there were no significant differences noted in the verbal instruction score, reading test score, reaction time, or somnolence scale among students in the 3 treatment groups. Female subjects tended to rate somnolence slightly higher than male subjects did; heavier subjects rated somnolence lower.

BACKGROUND: Some clinicians recommend cesarean delivery for all babies with breech presentation, while others encourage a trial of vaginal delivery for selected women. This randomized trial compared planned cesarean delivery (PCD) with planned vaginal delivery (PVD) for term breech babies.

POPULATION STUDIED: A total of 2088 women from 121 centers in 26 different countries were enrolled. Each woman had an uncomplicated complete or frank breech at more than 37 weeks’ gestation. Most of the women were aged younger than 30 years; approximately 50% were primiparous. Ultrasound sizing was performed on 40%, and external cephalic version was attempted in 20%. Fifty percent of the countries had a low perinatal mortality rate. Thus, the clinical setting is probably similar to that of family physicians in the United States.

STUDY DESIGN AND VALIDITY: This was a well-designed study. Participating subjects were randomly assigned (masked allocation) to either PCD (n=1043) or to PVD by an accoucheur experienced in breech delivery (n=1045). The accoucheur’s experience was confirmed by the department head, and approximately 60% had more than 10 years’ vaginal breech delivery experience. For those women assigned to vaginal delivery, a standardized labor protocol was used and was comparable with practice in the United States. The method of delivery was by assisted or spontaneous breech delivery with control of the after-coming head either by use of a forceps or the Mauriceau-Smellie-Veit maneuver. Cesarean deliveries were scheduled for women with gestation greater than 38 weeks. The follow-up rate was 99.8%. Analysis was by intention to treat, with lethal congenital anomalies excluded. Multiple logistic regression was used to assess for interaction; the Fisher exact test and the Wilcoxon rank-sum test were used to test outcomes, with a one-sided P value used for neonatal outcomes and a two-sided P value for maternal outcomes.

OUTCOMES MEASURED: The main outcome was perinatal or neonatal mortality and serious neonatal morbidity, including birth injury, seizures, and an APGAR score less than 4 at 5 minutes. A secondary outcome was maternal mortality or serious maternal morbidity in the first 6 weeks; cesarean delivery itself was not included as maternal morbidity.

RESULTS: At enrollment the groups were similar. Because of early results showing an important difference in outcomes, the trial was stopped early. In the PCD group, 10% delivered vaginally compared with 57% of the PVD group. Perinatal and neonatal mortality was lower in the PCD group than in the PVD group (0.3% vs 1.3%; relative risk [RR]=0.23; 95% confidence interval [CI], 0.07-0.81; number needed to treat [NNT]=100) as was serious neonatal morbidity (1.4% vs 3.8%; RR=0.36; 95% CI, 0.19-0.65; NNT=42). The benefit of PCD was greater in countries with low mortality rates (combined mortality and morbidity, 0.4% vs 5.7%; P <.005; NNT=19). There was no difference in maternal mortality or morbidity.

BACKGROUND: Some clinicians recommend cesarean delivery for all babies with breech presentation, while others encourage a trial of vaginal delivery for selected women. This randomized trial compared planned cesarean delivery (PCD) with planned vaginal delivery (PVD) for term breech babies.

POPULATION STUDIED: A total of 2088 women from 121 centers in 26 different countries were enrolled. Each woman had an uncomplicated complete or frank breech at more than 37 weeks’ gestation. Most of the women were aged younger than 30 years; approximately 50% were primiparous. Ultrasound sizing was performed on 40%, and external cephalic version was attempted in 20%. Fifty percent of the countries had a low perinatal mortality rate. Thus, the clinical setting is probably similar to that of family physicians in the United States.

STUDY DESIGN AND VALIDITY: This was a well-designed study. Participating subjects were randomly assigned (masked allocation) to either PCD (n=1043) or to PVD by an accoucheur experienced in breech delivery (n=1045). The accoucheur’s experience was confirmed by the department head, and approximately 60% had more than 10 years’ vaginal breech delivery experience. For those women assigned to vaginal delivery, a standardized labor protocol was used and was comparable with practice in the United States. The method of delivery was by assisted or spontaneous breech delivery with control of the after-coming head either by use of a forceps or the Mauriceau-Smellie-Veit maneuver. Cesarean deliveries were scheduled for women with gestation greater than 38 weeks. The follow-up rate was 99.8%. Analysis was by intention to treat, with lethal congenital anomalies excluded. Multiple logistic regression was used to assess for interaction; the Fisher exact test and the Wilcoxon rank-sum test were used to test outcomes, with a one-sided P value used for neonatal outcomes and a two-sided P value for maternal outcomes.

OUTCOMES MEASURED: The main outcome was perinatal or neonatal mortality and serious neonatal morbidity, including birth injury, seizures, and an APGAR score less than 4 at 5 minutes. A secondary outcome was maternal mortality or serious maternal morbidity in the first 6 weeks; cesarean delivery itself was not included as maternal morbidity.

RESULTS: At enrollment the groups were similar. Because of early results showing an important difference in outcomes, the trial was stopped early. In the PCD group, 10% delivered vaginally compared with 57% of the PVD group. Perinatal and neonatal mortality was lower in the PCD group than in the PVD group (0.3% vs 1.3%; relative risk [RR]=0.23; 95% confidence interval [CI], 0.07-0.81; number needed to treat [NNT]=100) as was serious neonatal morbidity (1.4% vs 3.8%; RR=0.36; 95% CI, 0.19-0.65; NNT=42). The benefit of PCD was greater in countries with low mortality rates (combined mortality and morbidity, 0.4% vs 5.7%; P <.005; NNT=19). There was no difference in maternal mortality or morbidity.

BACKGROUND: Some clinicians recommend cesarean delivery for all babies with breech presentation, while others encourage a trial of vaginal delivery for selected women. This randomized trial compared planned cesarean delivery (PCD) with planned vaginal delivery (PVD) for term breech babies.

POPULATION STUDIED: A total of 2088 women from 121 centers in 26 different countries were enrolled. Each woman had an uncomplicated complete or frank breech at more than 37 weeks’ gestation. Most of the women were aged younger than 30 years; approximately 50% were primiparous. Ultrasound sizing was performed on 40%, and external cephalic version was attempted in 20%. Fifty percent of the countries had a low perinatal mortality rate. Thus, the clinical setting is probably similar to that of family physicians in the United States.

STUDY DESIGN AND VALIDITY: This was a well-designed study. Participating subjects were randomly assigned (masked allocation) to either PCD (n=1043) or to PVD by an accoucheur experienced in breech delivery (n=1045). The accoucheur’s experience was confirmed by the department head, and approximately 60% had more than 10 years’ vaginal breech delivery experience. For those women assigned to vaginal delivery, a standardized labor protocol was used and was comparable with practice in the United States. The method of delivery was by assisted or spontaneous breech delivery with control of the after-coming head either by use of a forceps or the Mauriceau-Smellie-Veit maneuver. Cesarean deliveries were scheduled for women with gestation greater than 38 weeks. The follow-up rate was 99.8%. Analysis was by intention to treat, with lethal congenital anomalies excluded. Multiple logistic regression was used to assess for interaction; the Fisher exact test and the Wilcoxon rank-sum test were used to test outcomes, with a one-sided P value used for neonatal outcomes and a two-sided P value for maternal outcomes.

OUTCOMES MEASURED: The main outcome was perinatal or neonatal mortality and serious neonatal morbidity, including birth injury, seizures, and an APGAR score less than 4 at 5 minutes. A secondary outcome was maternal mortality or serious maternal morbidity in the first 6 weeks; cesarean delivery itself was not included as maternal morbidity.

RESULTS: At enrollment the groups were similar. Because of early results showing an important difference in outcomes, the trial was stopped early. In the PCD group, 10% delivered vaginally compared with 57% of the PVD group. Perinatal and neonatal mortality was lower in the PCD group than in the PVD group (0.3% vs 1.3%; relative risk [RR]=0.23; 95% confidence interval [CI], 0.07-0.81; number needed to treat [NNT]=100) as was serious neonatal morbidity (1.4% vs 3.8%; RR=0.36; 95% CI, 0.19-0.65; NNT=42). The benefit of PCD was greater in countries with low mortality rates (combined mortality and morbidity, 0.4% vs 5.7%; P <.005; NNT=19). There was no difference in maternal mortality or morbidity.

BACKGROUND: In some settings, “diastolic dysfunction” has become a diagnosis of exclusion used to define any patient with symptoms suggestive of CHF but with normal left ventricular (LV) systolic function on echocardiography. This descriptive case series identifies potential diagnoses other than diastolic dysfunction in such patients.

POPULATION STUDIED: The investigators identified 159 consecutive patients with suspected heart failure referred for an outpatient echocardiogram in Scotland. No information was given regarding the previous work-up of these patients or criteria for referral. Fifty (31%) were found to have LV systolic dysfunction, atrial fibrillation, or valvular heart disease and were excluded from further study. Of the remaining 109, most were elderly; 73% were women; and all are presumed to be white. It is likely that the patients are similar to many seen by family physicians in the United States, but clinicians should be cautious about extending the findings to younger persons, men, and people of color.

STUDY DESIGN AND VALIDITY: This study was a case series of patients with preserved LV systolic function but suspected CHF. They obtained a full standardized clinical history for every patient and objective measures including body mass index (BMI), pulmonary function testing, electrocardiograms, and transthoracic echocardiography. The study was purely descriptive in design and provides only prevalence rates of specific abnormalities. The methodology of this study was limited. Although the case series establishes many potential explanations for patients’ symptoms of dyspnea, lower extremity edema, and other findings suggestive of CHF, it cannot establish which diagnosis is causing the symptoms without follow-up, comparison groups, or trials of treatment. This study also has other minor weaknesses: (1) lack of reporting of reasons for initial referral, or possible selection bias; (2) lack of attention to inter-rater reliability and quality of the echocardiography; and (3) lack of attention to confounding factors such as the variability of other cardiac evaluation and of the use of medications and other health interventions that might alter symptoms.

OUTCOMES MEASURED: Prevalence rates were reported for subjective symptoms, past medical problems, and objective measures of abnormal BMI, forced expiratory volume in 1 second (FEV1), electrocardiography, and echocardiography. The overlap of certain findings (obesity, respiratory disease, and cardiac abnormalities) were also assessed. The investigators made no attempts to measure costs, prognosis, response to therapy, functional status, quality of life, or patient satisfaction, all of which are important to assessing the value of this information in daily practice.

RESULTS: Most patients reported ankle swelling (68%) and dyspnea on exertion (92%). Fewer reported paroxysmal nocturnal dyspnea (23%) or dyspnea at rest (25%). Many had some previous medical condition (47% hypertension, 11% myocardial infarction, 28% angina, 6% coronary artery bypass graft, 23% pulmonary disease), and 81% were overweight or obese by BMI. Half of the patients had FEV1 measures less than 70% of predicted. After considering clinical history and electrocardiographic findings, 38% had evidence of coronary disease. Echocardiography detected signs of poor ventricular filling in 67% and left ventricular hypertrophy in 26% of all patients. Many patients had more than one abnormal finding. Only 7% of the patients had no abnormalities of BMI, respiratory, or coronary function.

BACKGROUND: In some settings, “diastolic dysfunction” has become a diagnosis of exclusion used to define any patient with symptoms suggestive of CHF but with normal left ventricular (LV) systolic function on echocardiography. This descriptive case series identifies potential diagnoses other than diastolic dysfunction in such patients.

POPULATION STUDIED: The investigators identified 159 consecutive patients with suspected heart failure referred for an outpatient echocardiogram in Scotland. No information was given regarding the previous work-up of these patients or criteria for referral. Fifty (31%) were found to have LV systolic dysfunction, atrial fibrillation, or valvular heart disease and were excluded from further study. Of the remaining 109, most were elderly; 73% were women; and all are presumed to be white. It is likely that the patients are similar to many seen by family physicians in the United States, but clinicians should be cautious about extending the findings to younger persons, men, and people of color.

STUDY DESIGN AND VALIDITY: This study was a case series of patients with preserved LV systolic function but suspected CHF. They obtained a full standardized clinical history for every patient and objective measures including body mass index (BMI), pulmonary function testing, electrocardiograms, and transthoracic echocardiography. The study was purely descriptive in design and provides only prevalence rates of specific abnormalities. The methodology of this study was limited. Although the case series establishes many potential explanations for patients’ symptoms of dyspnea, lower extremity edema, and other findings suggestive of CHF, it cannot establish which diagnosis is causing the symptoms without follow-up, comparison groups, or trials of treatment. This study also has other minor weaknesses: (1) lack of reporting of reasons for initial referral, or possible selection bias; (2) lack of attention to inter-rater reliability and quality of the echocardiography; and (3) lack of attention to confounding factors such as the variability of other cardiac evaluation and of the use of medications and other health interventions that might alter symptoms.

OUTCOMES MEASURED: Prevalence rates were reported for subjective symptoms, past medical problems, and objective measures of abnormal BMI, forced expiratory volume in 1 second (FEV1), electrocardiography, and echocardiography. The overlap of certain findings (obesity, respiratory disease, and cardiac abnormalities) were also assessed. The investigators made no attempts to measure costs, prognosis, response to therapy, functional status, quality of life, or patient satisfaction, all of which are important to assessing the value of this information in daily practice.

RESULTS: Most patients reported ankle swelling (68%) and dyspnea on exertion (92%). Fewer reported paroxysmal nocturnal dyspnea (23%) or dyspnea at rest (25%). Many had some previous medical condition (47% hypertension, 11% myocardial infarction, 28% angina, 6% coronary artery bypass graft, 23% pulmonary disease), and 81% were overweight or obese by BMI. Half of the patients had FEV1 measures less than 70% of predicted. After considering clinical history and electrocardiographic findings, 38% had evidence of coronary disease. Echocardiography detected signs of poor ventricular filling in 67% and left ventricular hypertrophy in 26% of all patients. Many patients had more than one abnormal finding. Only 7% of the patients had no abnormalities of BMI, respiratory, or coronary function.

BACKGROUND: In some settings, “diastolic dysfunction” has become a diagnosis of exclusion used to define any patient with symptoms suggestive of CHF but with normal left ventricular (LV) systolic function on echocardiography. This descriptive case series identifies potential diagnoses other than diastolic dysfunction in such patients.

POPULATION STUDIED: The investigators identified 159 consecutive patients with suspected heart failure referred for an outpatient echocardiogram in Scotland. No information was given regarding the previous work-up of these patients or criteria for referral. Fifty (31%) were found to have LV systolic dysfunction, atrial fibrillation, or valvular heart disease and were excluded from further study. Of the remaining 109, most were elderly; 73% were women; and all are presumed to be white. It is likely that the patients are similar to many seen by family physicians in the United States, but clinicians should be cautious about extending the findings to younger persons, men, and people of color.

STUDY DESIGN AND VALIDITY: This study was a case series of patients with preserved LV systolic function but suspected CHF. They obtained a full standardized clinical history for every patient and objective measures including body mass index (BMI), pulmonary function testing, electrocardiograms, and transthoracic echocardiography. The study was purely descriptive in design and provides only prevalence rates of specific abnormalities. The methodology of this study was limited. Although the case series establishes many potential explanations for patients’ symptoms of dyspnea, lower extremity edema, and other findings suggestive of CHF, it cannot establish which diagnosis is causing the symptoms without follow-up, comparison groups, or trials of treatment. This study also has other minor weaknesses: (1) lack of reporting of reasons for initial referral, or possible selection bias; (2) lack of attention to inter-rater reliability and quality of the echocardiography; and (3) lack of attention to confounding factors such as the variability of other cardiac evaluation and of the use of medications and other health interventions that might alter symptoms.

OUTCOMES MEASURED: Prevalence rates were reported for subjective symptoms, past medical problems, and objective measures of abnormal BMI, forced expiratory volume in 1 second (FEV1), electrocardiography, and echocardiography. The overlap of certain findings (obesity, respiratory disease, and cardiac abnormalities) were also assessed. The investigators made no attempts to measure costs, prognosis, response to therapy, functional status, quality of life, or patient satisfaction, all of which are important to assessing the value of this information in daily practice.

RESULTS: Most patients reported ankle swelling (68%) and dyspnea on exertion (92%). Fewer reported paroxysmal nocturnal dyspnea (23%) or dyspnea at rest (25%). Many had some previous medical condition (47% hypertension, 11% myocardial infarction, 28% angina, 6% coronary artery bypass graft, 23% pulmonary disease), and 81% were overweight or obese by BMI. Half of the patients had FEV1 measures less than 70% of predicted. After considering clinical history and electrocardiographic findings, 38% had evidence of coronary disease. Echocardiography detected signs of poor ventricular filling in 67% and left ventricular hypertrophy in 26% of all patients. Many patients had more than one abnormal finding. Only 7% of the patients had no abnormalities of BMI, respiratory, or coronary function.

BACKGROUND: Osteoarthritis is a major problem in primary care, but its optimal management is unclear. Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and intra-articular corticosteroids have significant toxicity and do not alter disease progression; thus, many patients have turned to glucosamine and chondroitin.

POPULATION STUDIED: The authors of this meta-analysis reviewed 15 randomized double-blind placebo-controlled trials of glucosamine and chondroitin (both together and separately) for patients with osteoarthritis of the knee or hip. Trials were included if they were longer than 4 weeks in duration and used an accepted osteoarthritis outcome measure. A total of 1710 patients were enrolled; no information was provided on age, sex, severity of osteoarthritis, or other treatments, making generalizability to a typical family practice difficult.

STUDY DESIGN AND VALIDITY: The authors’ search included MEDLINE, the Cochrane Controlled Trials Registry, rheumatology meeting abstracts, citation lists from review articles, and consultation with experts. Two trained reviewers independently examined outcomes, quality, and financial sponsorship of the articles. Disagreements were resolved by discussion. A pooled effect size was calculated by dividing the difference in mean outcomes between treatment group and control group by the standard deviation of the outcome value in the control group. The resulting effect measure combines pain outcomes with disability outcomes. Publication bias was addressed by funnel plots and regression of effects on the inverse of study variance.

OUTCOMES MEASURED: The primary outcome measured was improvement in symptoms at 4 weeks, measured by either a pain scale or a disability index. The article did not address other outcomes important for osteoarthritis, such as quality of life, cost, side effects, or radiographic progression of osteoarthritis.

RESULTS: Interrater reliability of the reviewers was excellent. The quality of the available studies was relatively poor, with only 2 employing intention-to-treat analysis. None of the studies reported independent funding from a governmental or not-for-profit organization, and there was evidence of a publication bias toward positive trials. Glucosamine showed an effect size of 0.44 (95% confidence interval [CI], 0.24-0.64), and chondroitin had an effect size of 0.96 (95% CI, 0.63-1.3). An effect size of 0 indicates equivalency with placebo, with less than 0.2 indicating a small effect, 0.2 to 0.8 a moderate effect, and greater than 0.8 a large effect. The studies were heterogenous; one trial with chondroitin seemed to be significantly different from the others. Excluding that trial weakened but did not eliminate the pooled effect of chondroitin. Shorter duration of treatment was associated with a lower effect size. Poorer-quality studies showed a larger effect than better-quality studies.

BACKGROUND: Osteoarthritis is a major problem in primary care, but its optimal management is unclear. Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and intra-articular corticosteroids have significant toxicity and do not alter disease progression; thus, many patients have turned to glucosamine and chondroitin.

POPULATION STUDIED: The authors of this meta-analysis reviewed 15 randomized double-blind placebo-controlled trials of glucosamine and chondroitin (both together and separately) for patients with osteoarthritis of the knee or hip. Trials were included if they were longer than 4 weeks in duration and used an accepted osteoarthritis outcome measure. A total of 1710 patients were enrolled; no information was provided on age, sex, severity of osteoarthritis, or other treatments, making generalizability to a typical family practice difficult.

STUDY DESIGN AND VALIDITY: The authors’ search included MEDLINE, the Cochrane Controlled Trials Registry, rheumatology meeting abstracts, citation lists from review articles, and consultation with experts. Two trained reviewers independently examined outcomes, quality, and financial sponsorship of the articles. Disagreements were resolved by discussion. A pooled effect size was calculated by dividing the difference in mean outcomes between treatment group and control group by the standard deviation of the outcome value in the control group. The resulting effect measure combines pain outcomes with disability outcomes. Publication bias was addressed by funnel plots and regression of effects on the inverse of study variance.

OUTCOMES MEASURED: The primary outcome measured was improvement in symptoms at 4 weeks, measured by either a pain scale or a disability index. The article did not address other outcomes important for osteoarthritis, such as quality of life, cost, side effects, or radiographic progression of osteoarthritis.

RESULTS: Interrater reliability of the reviewers was excellent. The quality of the available studies was relatively poor, with only 2 employing intention-to-treat analysis. None of the studies reported independent funding from a governmental or not-for-profit organization, and there was evidence of a publication bias toward positive trials. Glucosamine showed an effect size of 0.44 (95% confidence interval [CI], 0.24-0.64), and chondroitin had an effect size of 0.96 (95% CI, 0.63-1.3). An effect size of 0 indicates equivalency with placebo, with less than 0.2 indicating a small effect, 0.2 to 0.8 a moderate effect, and greater than 0.8 a large effect. The studies were heterogenous; one trial with chondroitin seemed to be significantly different from the others. Excluding that trial weakened but did not eliminate the pooled effect of chondroitin. Shorter duration of treatment was associated with a lower effect size. Poorer-quality studies showed a larger effect than better-quality studies.

BACKGROUND: Osteoarthritis is a major problem in primary care, but its optimal management is unclear. Nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and intra-articular corticosteroids have significant toxicity and do not alter disease progression; thus, many patients have turned to glucosamine and chondroitin.

POPULATION STUDIED: The authors of this meta-analysis reviewed 15 randomized double-blind placebo-controlled trials of glucosamine and chondroitin (both together and separately) for patients with osteoarthritis of the knee or hip. Trials were included if they were longer than 4 weeks in duration and used an accepted osteoarthritis outcome measure. A total of 1710 patients were enrolled; no information was provided on age, sex, severity of osteoarthritis, or other treatments, making generalizability to a typical family practice difficult.

STUDY DESIGN AND VALIDITY: The authors’ search included MEDLINE, the Cochrane Controlled Trials Registry, rheumatology meeting abstracts, citation lists from review articles, and consultation with experts. Two trained reviewers independently examined outcomes, quality, and financial sponsorship of the articles. Disagreements were resolved by discussion. A pooled effect size was calculated by dividing the difference in mean outcomes between treatment group and control group by the standard deviation of the outcome value in the control group. The resulting effect measure combines pain outcomes with disability outcomes. Publication bias was addressed by funnel plots and regression of effects on the inverse of study variance.

OUTCOMES MEASURED: The primary outcome measured was improvement in symptoms at 4 weeks, measured by either a pain scale or a disability index. The article did not address other outcomes important for osteoarthritis, such as quality of life, cost, side effects, or radiographic progression of osteoarthritis.

RESULTS: Interrater reliability of the reviewers was excellent. The quality of the available studies was relatively poor, with only 2 employing intention-to-treat analysis. None of the studies reported independent funding from a governmental or not-for-profit organization, and there was evidence of a publication bias toward positive trials. Glucosamine showed an effect size of 0.44 (95% confidence interval [CI], 0.24-0.64), and chondroitin had an effect size of 0.96 (95% CI, 0.63-1.3). An effect size of 0 indicates equivalency with placebo, with less than 0.2 indicating a small effect, 0.2 to 0.8 a moderate effect, and greater than 0.8 a large effect. The studies were heterogenous; one trial with chondroitin seemed to be significantly different from the others. Excluding that trial weakened but did not eliminate the pooled effect of chondroitin. Shorter duration of treatment was associated with a lower effect size. Poorer-quality studies showed a larger effect than better-quality studies.