Leilani St. Anna, MLIS, AHIP

EVIDENCE SUMMARY

A meta-analysis of 13 randomized, placebo or standard of care-controlled statin trials (113,148 patients, 81% without diabetes at enrollment, mean ages 55-76 years) found that statin therapy increased the incidence of diabetes by 9% over 4 years (odds ratio [OR]=1.09; 95% confidence interval [CI], 1.02-1.17), or one additional case per 255 patients.¹ The increased risk was similar for lipophilic (pravastatin, rosuvastatin) and hydrophilic (atorvastatin, simvastatin, lovastatin) statins, although the analysis wasn’t adjusted for doses used.

In a meta-regression analysis, baseline body mass index or percentage change in low-density lipoprotein cholesterol didn’t appear to confer additional risk. The risk of diabetes with statins was generally higher in studies with older patients (data given graphically).

Higher statin doses mean higher risk

A meta-analysis of 5 placebo and standard-of-care randomized controlled trials (39,612 patients, 83% without diabetes at enrollment, mean age 58-64 years) found that the risk of diabetes was higher with higher-dose statins.² Therapy with atorvastatin 80 mg or simvastatin 40 to 80 mg was defined as intensive. Treatment with simvastatin 20 to 40 mg, atorvastatin 10 mg, or pravastatin 40 mg was defined as moderate.

At a mean follow-up of 4.9 years, intensive statin therapy was associated with a higher risk of developing diabetes than moderate therapy (OR=1.12; 95% CI, 1.04-1.22) with 2 additional cases of diabetes per 1000 patient-years in the intensive therapy group. The authors noted significant heterogeneity between trials with regard to major cardiovascular events.

Similar results were found in a subsequent population-based cohort study of 471,250 nondiabetic patients older than 66 years who were newly prescribed a statin.³ The study authors used the incidence of new diabetes in patients taking pravastatin as the baseline, since it had been associated with reduced rates of diabetes in a large cardiovascular prevention trial.⁴ Without adjusting for dose, patients were at significantly higher risk of diabetes if prescribed atorvastatin (hazard ratio [HR]=1.22; 95% CI, 1.15-1.29), rosuvastatin (HR=1.18; 95% CI, 1.10-1.26), or simvastatin (HR=1.10; 95% CI, 1.04-1.17) compared with pravastatin. The risk with fluvastatin and lovastatin was similar to pravastatin.

A subanalysis that compared moderate- and high-dose statin therapy with low-dose therapy (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <80 mg, or any dose of fluvastatin, lovastatin, or pravastatin) found a 22% increased risk of diabetes (HR=1.22; 95% CI, 1.19-1.26) for moderate-dose therapy (atorvastatin 20-79 mg, rosuvastatin 10-39 mg, or simvastatin >80 mg) and a 30% increased risk (HR=1.3; 95% CI, 1.2-1.4) for high-dose therapy (atorvastatin ≥80 mg or rosuvastatin ≥40 mg).

A cohort trial also shows increased diabetes risk

A smaller subsequent cohort trial based on data from Taiwan National Health Insurance records compared 8412 nondiabetic adult patients (mean age 63 years) taking statins with 33,648 age- and risk-matched controls not taking statins over a mean duration of 7.2 years.⁵ Statin use was associated with a 15% higher risk of developing diabetes (HR=1.15; 95% CI, 1.08-1.22).

RECOMMENDATIONS

The 2013 American College of Cardiology/American Heart Association guidelines for lipid-lowering therapy recommend that patients taking statins be screened for diabetes according to current screening recommendations.⁶ The guidelines advise encouraging patients who develop diabetes while on statin therapy to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of cardiovascular events.

EVIDENCE SUMMARY

A meta-analysis of 13 randomized, placebo or standard of care-controlled statin trials (113,148 patients, 81% without diabetes at enrollment, mean ages 55-76 years) found that statin therapy increased the incidence of diabetes by 9% over 4 years (odds ratio [OR]=1.09; 95% confidence interval [CI], 1.02-1.17), or one additional case per 255 patients.¹ The increased risk was similar for lipophilic (pravastatin, rosuvastatin) and hydrophilic (atorvastatin, simvastatin, lovastatin) statins, although the analysis wasn’t adjusted for doses used.

In a meta-regression analysis, baseline body mass index or percentage change in low-density lipoprotein cholesterol didn’t appear to confer additional risk. The risk of diabetes with statins was generally higher in studies with older patients (data given graphically).

Higher statin doses mean higher risk

A meta-analysis of 5 placebo and standard-of-care randomized controlled trials (39,612 patients, 83% without diabetes at enrollment, mean age 58-64 years) found that the risk of diabetes was higher with higher-dose statins.² Therapy with atorvastatin 80 mg or simvastatin 40 to 80 mg was defined as intensive. Treatment with simvastatin 20 to 40 mg, atorvastatin 10 mg, or pravastatin 40 mg was defined as moderate.

At a mean follow-up of 4.9 years, intensive statin therapy was associated with a higher risk of developing diabetes than moderate therapy (OR=1.12; 95% CI, 1.04-1.22) with 2 additional cases of diabetes per 1000 patient-years in the intensive therapy group. The authors noted significant heterogeneity between trials with regard to major cardiovascular events.

Similar results were found in a subsequent population-based cohort study of 471,250 nondiabetic patients older than 66 years who were newly prescribed a statin.³ The study authors used the incidence of new diabetes in patients taking pravastatin as the baseline, since it had been associated with reduced rates of diabetes in a large cardiovascular prevention trial.⁴ Without adjusting for dose, patients were at significantly higher risk of diabetes if prescribed atorvastatin (hazard ratio [HR]=1.22; 95% CI, 1.15-1.29), rosuvastatin (HR=1.18; 95% CI, 1.10-1.26), or simvastatin (HR=1.10; 95% CI, 1.04-1.17) compared with pravastatin. The risk with fluvastatin and lovastatin was similar to pravastatin.

A subanalysis that compared moderate- and high-dose statin therapy with low-dose therapy (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <80 mg, or any dose of fluvastatin, lovastatin, or pravastatin) found a 22% increased risk of diabetes (HR=1.22; 95% CI, 1.19-1.26) for moderate-dose therapy (atorvastatin 20-79 mg, rosuvastatin 10-39 mg, or simvastatin >80 mg) and a 30% increased risk (HR=1.3; 95% CI, 1.2-1.4) for high-dose therapy (atorvastatin ≥80 mg or rosuvastatin ≥40 mg).

A cohort trial also shows increased diabetes risk

A smaller subsequent cohort trial based on data from Taiwan National Health Insurance records compared 8412 nondiabetic adult patients (mean age 63 years) taking statins with 33,648 age- and risk-matched controls not taking statins over a mean duration of 7.2 years.⁵ Statin use was associated with a 15% higher risk of developing diabetes (HR=1.15; 95% CI, 1.08-1.22).

RECOMMENDATIONS

The 2013 American College of Cardiology/American Heart Association guidelines for lipid-lowering therapy recommend that patients taking statins be screened for diabetes according to current screening recommendations.⁶ The guidelines advise encouraging patients who develop diabetes while on statin therapy to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of cardiovascular events.

EVIDENCE SUMMARY

A meta-analysis of 13 randomized, placebo or standard of care-controlled statin trials (113,148 patients, 81% without diabetes at enrollment, mean ages 55-76 years) found that statin therapy increased the incidence of diabetes by 9% over 4 years (odds ratio [OR]=1.09; 95% confidence interval [CI], 1.02-1.17), or one additional case per 255 patients.¹ The increased risk was similar for lipophilic (pravastatin, rosuvastatin) and hydrophilic (atorvastatin, simvastatin, lovastatin) statins, although the analysis wasn’t adjusted for doses used.

In a meta-regression analysis, baseline body mass index or percentage change in low-density lipoprotein cholesterol didn’t appear to confer additional risk. The risk of diabetes with statins was generally higher in studies with older patients (data given graphically).

Higher statin doses mean higher risk

A meta-analysis of 5 placebo and standard-of-care randomized controlled trials (39,612 patients, 83% without diabetes at enrollment, mean age 58-64 years) found that the risk of diabetes was higher with higher-dose statins.² Therapy with atorvastatin 80 mg or simvastatin 40 to 80 mg was defined as intensive. Treatment with simvastatin 20 to 40 mg, atorvastatin 10 mg, or pravastatin 40 mg was defined as moderate.

At a mean follow-up of 4.9 years, intensive statin therapy was associated with a higher risk of developing diabetes than moderate therapy (OR=1.12; 95% CI, 1.04-1.22) with 2 additional cases of diabetes per 1000 patient-years in the intensive therapy group. The authors noted significant heterogeneity between trials with regard to major cardiovascular events.

Similar results were found in a subsequent population-based cohort study of 471,250 nondiabetic patients older than 66 years who were newly prescribed a statin.³ The study authors used the incidence of new diabetes in patients taking pravastatin as the baseline, since it had been associated with reduced rates of diabetes in a large cardiovascular prevention trial.⁴ Without adjusting for dose, patients were at significantly higher risk of diabetes if prescribed atorvastatin (hazard ratio [HR]=1.22; 95% CI, 1.15-1.29), rosuvastatin (HR=1.18; 95% CI, 1.10-1.26), or simvastatin (HR=1.10; 95% CI, 1.04-1.17) compared with pravastatin. The risk with fluvastatin and lovastatin was similar to pravastatin.

A subanalysis that compared moderate- and high-dose statin therapy with low-dose therapy (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <80 mg, or any dose of fluvastatin, lovastatin, or pravastatin) found a 22% increased risk of diabetes (HR=1.22; 95% CI, 1.19-1.26) for moderate-dose therapy (atorvastatin 20-79 mg, rosuvastatin 10-39 mg, or simvastatin >80 mg) and a 30% increased risk (HR=1.3; 95% CI, 1.2-1.4) for high-dose therapy (atorvastatin ≥80 mg or rosuvastatin ≥40 mg).

A cohort trial also shows increased diabetes risk

A smaller subsequent cohort trial based on data from Taiwan National Health Insurance records compared 8412 nondiabetic adult patients (mean age 63 years) taking statins with 33,648 age- and risk-matched controls not taking statins over a mean duration of 7.2 years.⁵ Statin use was associated with a 15% higher risk of developing diabetes (HR=1.15; 95% CI, 1.08-1.22).

RECOMMENDATIONS

The 2013 American College of Cardiology/American Heart Association guidelines for lipid-lowering therapy recommend that patients taking statins be screened for diabetes according to current screening recommendations.⁶ The guidelines advise encouraging patients who develop diabetes while on statin therapy to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of cardiovascular events.

EVIDENCE SUMMARY

Two RCTs found short-term (0-14 days) improvement in breastfeeding after frenotomy. One, which evaluated the effect of frenotomy on infants with significant ankyloglossia and breastfeeding difficulties, found short-term improvement in maternal nipple pain. Investigators randomized 58 infants (mean age 6 days) with ankyloglossia (rated 8 out of 10 on a standardized severity scale) to receive either frenotomy or no intervention.¹ They used the 50-point Short Form McGill Pain Questionnaire to measure maternal nipple pain at baseline, immediately after, and at 2, 4, 8, and 52 weeks.

Mothers in the intervention group reported a 10% greater reduction in nipple pain after frenotomy compared with the control group (11 points vs 6 points; P=.001). The improvement persisted at 2 weeks (graphic representation in study, P value not supplied) but not at 4 weeks or beyond.

An earlier, unblinded RCT randomized 40 infants (mean age 14 days) with ankyloglossia and breastfeeding problems to frenotomy or lactation support.² It found maternal subjective ratings of “improvement” (not quantified) by telephone interview at 24 hours (85% vs 3%; P<.01). Investigators performed frenotomy on all 19 of the unimproved control infants at 48 hours.

Frenotomy doesn’t improve breastfeeding overall

Two newer RCTs evaluating frenotomy and LATCH (Latch, Audible swallowing, nipple Type, Comfort, and Hold) scores, which include a component measuring maternal comfort, found no breastfeeding improvements. (LATCH is a validated 10-point score with moderate predictive value for identifying mothers at risk for early weaning because of sore nipples.³)

A double-blind RCT that assessed frenotomy in 57 infants (mean age 32 days) with ankyloglossia and breastfeeding problems (severity of both unspecified) found no improvement in breastfeeding overall or nipple pain.⁴ Investigators randomized infants to frenotomy or sham frenotomy and used independent observers to measure outcomes with the LATCH score and the Infant Breastfeeding Assessment Tool (IBFAT), a standardized method of assessing overall feeding.

They observed no significant differences in LATCH or IBFAT scores between groups. More mothers in the frenotomy group reported improved breastfeeding, but most were able to determine whether their baby had undergone frenotomy.

A single-blinded, RCT of early frenotomy in 107 younger infants with breastfeeding difficulties and mild to moderate ankyloglossia also found no improvement in LATCH scores.⁵ Researchers randomized infants younger than 2 weeks (blinded to researchers and unblinded to mothers) to either immediate frenotomy or standard care. They measured LATCH scores at baseline and after 5 days (by intention to treat).

Investigators found no difference in LATCH scores at 5 days postfrenotomy (pretreatment score 6.4 ± 2.3, posttreatment 6.8 ± 2.0; not significant).

RECOMMENDATIONS

There is no evidence of improved latching after frenotomy, and evidence concerning improvements in maternal comfort is conflicting. A 2011 position statement from the Community Paediatrics Committee of the Canadian Paediatric Society notes that ankyloglossia is a relatively uncommon congenital anomaly, and associations between ankyloglossia and breastfeeding problems in infants have been inconsistent.⁶ For these reasons, the Committee doesn’t recommend frenotomy.

However, if the clinician deems surgical intervention necessary based on a clear association between significant tongue-tie and major breastfeeding problems, then frenotomy should be performed by a clinician experienced in the procedure and with appropriate analgesia. The Committee states that although ankyloglossia release appears to be a minor procedure, it may cause complications such as bleeding, infection, or injury to the Wharton’s duct.

The Academy of Breastfeeding Medicine, a worldwide organization of physicians dedicated to the promotion, protection, and support of breastfeeding and human lactation, is currently revising its guidelines on neonatal ankyloglossia.⁷

EVIDENCE SUMMARY

Two RCTs found short-term (0-14 days) improvement in breastfeeding after frenotomy. One, which evaluated the effect of frenotomy on infants with significant ankyloglossia and breastfeeding difficulties, found short-term improvement in maternal nipple pain. Investigators randomized 58 infants (mean age 6 days) with ankyloglossia (rated 8 out of 10 on a standardized severity scale) to receive either frenotomy or no intervention.¹ They used the 50-point Short Form McGill Pain Questionnaire to measure maternal nipple pain at baseline, immediately after, and at 2, 4, 8, and 52 weeks.

Mothers in the intervention group reported a 10% greater reduction in nipple pain after frenotomy compared with the control group (11 points vs 6 points; P=.001). The improvement persisted at 2 weeks (graphic representation in study, P value not supplied) but not at 4 weeks or beyond.

An earlier, unblinded RCT randomized 40 infants (mean age 14 days) with ankyloglossia and breastfeeding problems to frenotomy or lactation support.² It found maternal subjective ratings of “improvement” (not quantified) by telephone interview at 24 hours (85% vs 3%; P<.01). Investigators performed frenotomy on all 19 of the unimproved control infants at 48 hours.

Frenotomy doesn’t improve breastfeeding overall

Two newer RCTs evaluating frenotomy and LATCH (Latch, Audible swallowing, nipple Type, Comfort, and Hold) scores, which include a component measuring maternal comfort, found no breastfeeding improvements. (LATCH is a validated 10-point score with moderate predictive value for identifying mothers at risk for early weaning because of sore nipples.³)

A double-blind RCT that assessed frenotomy in 57 infants (mean age 32 days) with ankyloglossia and breastfeeding problems (severity of both unspecified) found no improvement in breastfeeding overall or nipple pain.⁴ Investigators randomized infants to frenotomy or sham frenotomy and used independent observers to measure outcomes with the LATCH score and the Infant Breastfeeding Assessment Tool (IBFAT), a standardized method of assessing overall feeding.

They observed no significant differences in LATCH or IBFAT scores between groups. More mothers in the frenotomy group reported improved breastfeeding, but most were able to determine whether their baby had undergone frenotomy.

A single-blinded, RCT of early frenotomy in 107 younger infants with breastfeeding difficulties and mild to moderate ankyloglossia also found no improvement in LATCH scores.⁵ Researchers randomized infants younger than 2 weeks (blinded to researchers and unblinded to mothers) to either immediate frenotomy or standard care. They measured LATCH scores at baseline and after 5 days (by intention to treat).

Investigators found no difference in LATCH scores at 5 days postfrenotomy (pretreatment score 6.4 ± 2.3, posttreatment 6.8 ± 2.0; not significant).

RECOMMENDATIONS

There is no evidence of improved latching after frenotomy, and evidence concerning improvements in maternal comfort is conflicting. A 2011 position statement from the Community Paediatrics Committee of the Canadian Paediatric Society notes that ankyloglossia is a relatively uncommon congenital anomaly, and associations between ankyloglossia and breastfeeding problems in infants have been inconsistent.⁶ For these reasons, the Committee doesn’t recommend frenotomy.

However, if the clinician deems surgical intervention necessary based on a clear association between significant tongue-tie and major breastfeeding problems, then frenotomy should be performed by a clinician experienced in the procedure and with appropriate analgesia. The Committee states that although ankyloglossia release appears to be a minor procedure, it may cause complications such as bleeding, infection, or injury to the Wharton’s duct.

The Academy of Breastfeeding Medicine, a worldwide organization of physicians dedicated to the promotion, protection, and support of breastfeeding and human lactation, is currently revising its guidelines on neonatal ankyloglossia.⁷

EVIDENCE SUMMARY

Two RCTs found short-term (0-14 days) improvement in breastfeeding after frenotomy. One, which evaluated the effect of frenotomy on infants with significant ankyloglossia and breastfeeding difficulties, found short-term improvement in maternal nipple pain. Investigators randomized 58 infants (mean age 6 days) with ankyloglossia (rated 8 out of 10 on a standardized severity scale) to receive either frenotomy or no intervention.¹ They used the 50-point Short Form McGill Pain Questionnaire to measure maternal nipple pain at baseline, immediately after, and at 2, 4, 8, and 52 weeks.

Mothers in the intervention group reported a 10% greater reduction in nipple pain after frenotomy compared with the control group (11 points vs 6 points; P=.001). The improvement persisted at 2 weeks (graphic representation in study, P value not supplied) but not at 4 weeks or beyond.

An earlier, unblinded RCT randomized 40 infants (mean age 14 days) with ankyloglossia and breastfeeding problems to frenotomy or lactation support.² It found maternal subjective ratings of “improvement” (not quantified) by telephone interview at 24 hours (85% vs 3%; P<.01). Investigators performed frenotomy on all 19 of the unimproved control infants at 48 hours.

Frenotomy doesn’t improve breastfeeding overall

Two newer RCTs evaluating frenotomy and LATCH (Latch, Audible swallowing, nipple Type, Comfort, and Hold) scores, which include a component measuring maternal comfort, found no breastfeeding improvements. (LATCH is a validated 10-point score with moderate predictive value for identifying mothers at risk for early weaning because of sore nipples.³)

A double-blind RCT that assessed frenotomy in 57 infants (mean age 32 days) with ankyloglossia and breastfeeding problems (severity of both unspecified) found no improvement in breastfeeding overall or nipple pain.⁴ Investigators randomized infants to frenotomy or sham frenotomy and used independent observers to measure outcomes with the LATCH score and the Infant Breastfeeding Assessment Tool (IBFAT), a standardized method of assessing overall feeding.

They observed no significant differences in LATCH or IBFAT scores between groups. More mothers in the frenotomy group reported improved breastfeeding, but most were able to determine whether their baby had undergone frenotomy.

A single-blinded, RCT of early frenotomy in 107 younger infants with breastfeeding difficulties and mild to moderate ankyloglossia also found no improvement in LATCH scores.⁵ Researchers randomized infants younger than 2 weeks (blinded to researchers and unblinded to mothers) to either immediate frenotomy or standard care. They measured LATCH scores at baseline and after 5 days (by intention to treat).

Investigators found no difference in LATCH scores at 5 days postfrenotomy (pretreatment score 6.4 ± 2.3, posttreatment 6.8 ± 2.0; not significant).

RECOMMENDATIONS

There is no evidence of improved latching after frenotomy, and evidence concerning improvements in maternal comfort is conflicting. A 2011 position statement from the Community Paediatrics Committee of the Canadian Paediatric Society notes that ankyloglossia is a relatively uncommon congenital anomaly, and associations between ankyloglossia and breastfeeding problems in infants have been inconsistent.⁶ For these reasons, the Committee doesn’t recommend frenotomy.

However, if the clinician deems surgical intervention necessary based on a clear association between significant tongue-tie and major breastfeeding problems, then frenotomy should be performed by a clinician experienced in the procedure and with appropriate analgesia. The Committee states that although ankyloglossia release appears to be a minor procedure, it may cause complications such as bleeding, infection, or injury to the Wharton’s duct.

The Academy of Breastfeeding Medicine, a worldwide organization of physicians dedicated to the promotion, protection, and support of breastfeeding and human lactation, is currently revising its guidelines on neonatal ankyloglossia.⁷

EVIDENCE SUMMARY

A Cochrane meta-analysis designed to determine the efficacy of ICS in patients with stable COPD found 55 randomized, controlled trials (RCTs) with a total of 16,154 participants that compared ICS with placebo for 2 weeks to 3 years duration.¹ COPD varied from moderate to severe in most studies.

In pooled data, ICS for 2 or more years didn’t consistently improve lung function, the primary outcome (TABLE). However, the largest RCT (N=2617) of 3 years duration showed a small decrease in decline of FEV₁ (55 mL compared with 42 mL, P value not provided). Regarding the secondary outcomes of mortality and exacerbations, ICS for a year or longer didn’t reduce mortality but decreased exacerbations by 19%.

Clinically significant adverse effects of ICS use included pneumonia, oropharyngeal candidiasis, and bruising; for ICS treatment longer than one year, the numbers needed to harm (NNH) compared with placebo were 30, 27, and 32, respectively. Bone fractures weren’t more common among ICS users. Investigators observed a statistical, but not clinical, QOL benefit as measured by the St. George’s Respiratory Questionnaire (SGRQ) in 5 RCTs with a total of 2507 patients (mean difference, ‒1.22 units/year; 95% confidence interval, ‒1.83 to ‒.60). The minimum clinically important difference on the 76-item questionnaire was 4 units.²

A Cochrane meta-analysis of 14 double-blind RCTs comprising a total of 11,794 participants with severe COPD compared LABA plus ICS with LABA alone over 8 weeks to 3 years.³ Primary outcomes were exacerbations, mortality, hospitalizations, and pneumonia. Secondary outcomes included oropharyngeal candidiasis and health-related QOL.

The LABA-plus-ICS group had lower rates of exacerbations than the LABA group, but the data were of low quality because of significant heterogeneity among studies and high rates of attrition. No significant difference in mortality or hospitalizations was found between the groups. The risk of pneumonia in the LABA-plus-ICS group was higher than in the LABA-alone group, with a NNH of 48.

Candidiasis occurred more often in patients on combination fluticasone and salmeterol than salmeterol alone, with a NNH of 22. QOL scores (measured by the SGRQ) in patients on combination therapy were statistically better, but clinically insignificant.

Discontinuing ICS doesn’t increase exacerbations

A meta-analysis of 3 RCTs that enrolled a total of 877 patients with COPD compared the number of exacerbations in patients who continued fluticasone 500 mcg inhaled twice daily and patients who were withdrawn from the medication. All patients had been treated with ICS for at least 3 months, and had been on fluticasone for at least 2 weeks. Subjects had a baseline FEV1 between 25% and 80% predicted. No significant increase in exacerbations occurred after discontinuing ICS.⁴

RECOMMENDATIONS

The American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society, in a joint guideline, recommend against using ICS as monotherapy for patients with stable COPD. They acknowledge that these drugs are superior to placebo in reducing exacerbations, but note that concerns about their side-effect profile (thrush, potential for bone loss, and moderate to severe easy bruisability) make them less desirable than LABAs or long-acting inhaled anticholinergics.⁵

The Global Initiative for Chronic Obstructive Lung Disease likewise discourages long-term use of ICS because of the risk of pneumonia and fractures.⁶ Both groups note that patients with severe COPD may benefit from a combination of ICS and a long-acting medication (usually a LABA).

EVIDENCE SUMMARY

A Cochrane meta-analysis designed to determine the efficacy of ICS in patients with stable COPD found 55 randomized, controlled trials (RCTs) with a total of 16,154 participants that compared ICS with placebo for 2 weeks to 3 years duration.¹ COPD varied from moderate to severe in most studies.

In pooled data, ICS for 2 or more years didn’t consistently improve lung function, the primary outcome (TABLE). However, the largest RCT (N=2617) of 3 years duration showed a small decrease in decline of FEV₁ (55 mL compared with 42 mL, P value not provided). Regarding the secondary outcomes of mortality and exacerbations, ICS for a year or longer didn’t reduce mortality but decreased exacerbations by 19%.

Clinically significant adverse effects of ICS use included pneumonia, oropharyngeal candidiasis, and bruising; for ICS treatment longer than one year, the numbers needed to harm (NNH) compared with placebo were 30, 27, and 32, respectively. Bone fractures weren’t more common among ICS users. Investigators observed a statistical, but not clinical, QOL benefit as measured by the St. George’s Respiratory Questionnaire (SGRQ) in 5 RCTs with a total of 2507 patients (mean difference, ‒1.22 units/year; 95% confidence interval, ‒1.83 to ‒.60). The minimum clinically important difference on the 76-item questionnaire was 4 units.²

A Cochrane meta-analysis of 14 double-blind RCTs comprising a total of 11,794 participants with severe COPD compared LABA plus ICS with LABA alone over 8 weeks to 3 years.³ Primary outcomes were exacerbations, mortality, hospitalizations, and pneumonia. Secondary outcomes included oropharyngeal candidiasis and health-related QOL.

The LABA-plus-ICS group had lower rates of exacerbations than the LABA group, but the data were of low quality because of significant heterogeneity among studies and high rates of attrition. No significant difference in mortality or hospitalizations was found between the groups. The risk of pneumonia in the LABA-plus-ICS group was higher than in the LABA-alone group, with a NNH of 48.

Candidiasis occurred more often in patients on combination fluticasone and salmeterol than salmeterol alone, with a NNH of 22. QOL scores (measured by the SGRQ) in patients on combination therapy were statistically better, but clinically insignificant.

Discontinuing ICS doesn’t increase exacerbations

A meta-analysis of 3 RCTs that enrolled a total of 877 patients with COPD compared the number of exacerbations in patients who continued fluticasone 500 mcg inhaled twice daily and patients who were withdrawn from the medication. All patients had been treated with ICS for at least 3 months, and had been on fluticasone for at least 2 weeks. Subjects had a baseline FEV1 between 25% and 80% predicted. No significant increase in exacerbations occurred after discontinuing ICS.⁴

RECOMMENDATIONS

The American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society, in a joint guideline, recommend against using ICS as monotherapy for patients with stable COPD. They acknowledge that these drugs are superior to placebo in reducing exacerbations, but note that concerns about their side-effect profile (thrush, potential for bone loss, and moderate to severe easy bruisability) make them less desirable than LABAs or long-acting inhaled anticholinergics.⁵

The Global Initiative for Chronic Obstructive Lung Disease likewise discourages long-term use of ICS because of the risk of pneumonia and fractures.⁶ Both groups note that patients with severe COPD may benefit from a combination of ICS and a long-acting medication (usually a LABA).

EVIDENCE SUMMARY

A Cochrane meta-analysis designed to determine the efficacy of ICS in patients with stable COPD found 55 randomized, controlled trials (RCTs) with a total of 16,154 participants that compared ICS with placebo for 2 weeks to 3 years duration.¹ COPD varied from moderate to severe in most studies.

In pooled data, ICS for 2 or more years didn’t consistently improve lung function, the primary outcome (TABLE). However, the largest RCT (N=2617) of 3 years duration showed a small decrease in decline of FEV₁ (55 mL compared with 42 mL, P value not provided). Regarding the secondary outcomes of mortality and exacerbations, ICS for a year or longer didn’t reduce mortality but decreased exacerbations by 19%.

Clinically significant adverse effects of ICS use included pneumonia, oropharyngeal candidiasis, and bruising; for ICS treatment longer than one year, the numbers needed to harm (NNH) compared with placebo were 30, 27, and 32, respectively. Bone fractures weren’t more common among ICS users. Investigators observed a statistical, but not clinical, QOL benefit as measured by the St. George’s Respiratory Questionnaire (SGRQ) in 5 RCTs with a total of 2507 patients (mean difference, ‒1.22 units/year; 95% confidence interval, ‒1.83 to ‒.60). The minimum clinically important difference on the 76-item questionnaire was 4 units.²

A Cochrane meta-analysis of 14 double-blind RCTs comprising a total of 11,794 participants with severe COPD compared LABA plus ICS with LABA alone over 8 weeks to 3 years.³ Primary outcomes were exacerbations, mortality, hospitalizations, and pneumonia. Secondary outcomes included oropharyngeal candidiasis and health-related QOL.

The LABA-plus-ICS group had lower rates of exacerbations than the LABA group, but the data were of low quality because of significant heterogeneity among studies and high rates of attrition. No significant difference in mortality or hospitalizations was found between the groups. The risk of pneumonia in the LABA-plus-ICS group was higher than in the LABA-alone group, with a NNH of 48.

Candidiasis occurred more often in patients on combination fluticasone and salmeterol than salmeterol alone, with a NNH of 22. QOL scores (measured by the SGRQ) in patients on combination therapy were statistically better, but clinically insignificant.

Discontinuing ICS doesn’t increase exacerbations

A meta-analysis of 3 RCTs that enrolled a total of 877 patients with COPD compared the number of exacerbations in patients who continued fluticasone 500 mcg inhaled twice daily and patients who were withdrawn from the medication. All patients had been treated with ICS for at least 3 months, and had been on fluticasone for at least 2 weeks. Subjects had a baseline FEV1 between 25% and 80% predicted. No significant increase in exacerbations occurred after discontinuing ICS.⁴

RECOMMENDATIONS

The American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society, in a joint guideline, recommend against using ICS as monotherapy for patients with stable COPD. They acknowledge that these drugs are superior to placebo in reducing exacerbations, but note that concerns about their side-effect profile (thrush, potential for bone loss, and moderate to severe easy bruisability) make them less desirable than LABAs or long-acting inhaled anticholinergics.⁵

The Global Initiative for Chronic Obstructive Lung Disease likewise discourages long-term use of ICS because of the risk of pneumonia and fractures.⁶ Both groups note that patients with severe COPD may benefit from a combination of ICS and a long-acting medication (usually a LABA).

EVIDENCE SUMMARY

A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.¹ Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.² Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.

The 2 groups showed no significant difference in cardiovascular events (3.2 events per 100 person-years for chlorthalidone compared with 3.4 for HCTZ; adjusted hazard ratio [aHR]=0.93; 95% CI, 0.81-1.06).

Serious hypokalemia and hyponatremia are risks

Patients taking chlorthalidone were more likely to be hospitalized for hypokalemia (0.69 per 100 person-years vs 0.27 for HCTZ; aHR=3.1; 95% CI, 2.0-4.6; number needed to harm [NNH]=238 in 1 year) or hyponatremia (0.69 per 100 person-years vs 0.49 for HCTZ; aHR=1.7; 95% CI, 1.2-2.3; NNH=434 in 1 year).² However, the all-cause hospitalization rates for the 2 drugs were the same (aHR=1.0; 95% CI, 0.93-1.07).

Chlorthalidone may reduce the risk of cardiovascular events in patients with hypertension more than HCTZ.

Lower systolic BP and serum potassium found with chlorthalidone

A smaller retrospective cohort analysis (6441 participants who received either chlorthalidone or HCTZ starting at 50 mg and stepped once to 100 mg) also assessed the difference in cardiovascular events between patients taking the 2 drugs.³ (Cardiovascular events were defined as pooled MIs, onset of angina or peripheral artery occlusive disease, or need for coronary artery bypass.) Although significant reductions in pooled events occurred in both groups over the 7-year study, these reductions were significantly lower in the chlorthalidone group than in the HCTZ group (aHR=0.79; 95% CI, 0.68-0.92).

Systolic blood pressures were statistically lower in the chlorthalidone group during Years 1 through 5 but not in Years 6 and 7 (difference 2-4 mm Hg). Serum potassium was also lower in patients taking chlorthalidone (3.8 mEq/L on chlorthalidone vs 4.0 mEq/L on HCTZ after 7 years; P<.05).

A retrospective cohort study investigated medication tolerance in veterans who had recently started either HCTZ (120,000 patients) or chlorthalidone (2200 patients) and were followed for a year.⁴ Most received doses between 12.5 and 25 mg of active drug.

One primary outcome was “nonpersistence,” defined as failure to refill the medication after double the number of days as the initial prescription. The other was “insufficient response,” defined as the need to start another antihypertensive medication. Chlorthalidone users were less likely than HCTZ users to have an insufficient response (odds ratio [OR]=0.71; 95% CI, 0.63-0.80) but more likely to exhibit nonpersistence (OR=1.6; 95% CI, 1.5-1.8).

RECOMMENDATIONS

For primary hypertension, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommends diuretic monotherapy in patients older than 55 years who are poor candidates for calcium channel blockers.⁵ If a diuretic is to be initiated or changed, NICE recommends chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) in preference to HCTZ. The guideline set forth in the eighth annual report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure makes no distinction between chlorthalidone and HCTZ; it refers only to “thiazidetype diuretics.” Thiazide-type diuretics are listed as one option (along with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) for initial monotherapy in nonblack patients.⁶

EVIDENCE SUMMARY

A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.¹ Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.² Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.

The 2 groups showed no significant difference in cardiovascular events (3.2 events per 100 person-years for chlorthalidone compared with 3.4 for HCTZ; adjusted hazard ratio [aHR]=0.93; 95% CI, 0.81-1.06).

Serious hypokalemia and hyponatremia are risks

Patients taking chlorthalidone were more likely to be hospitalized for hypokalemia (0.69 per 100 person-years vs 0.27 for HCTZ; aHR=3.1; 95% CI, 2.0-4.6; number needed to harm [NNH]=238 in 1 year) or hyponatremia (0.69 per 100 person-years vs 0.49 for HCTZ; aHR=1.7; 95% CI, 1.2-2.3; NNH=434 in 1 year).² However, the all-cause hospitalization rates for the 2 drugs were the same (aHR=1.0; 95% CI, 0.93-1.07).

Chlorthalidone may reduce the risk of cardiovascular events in patients with hypertension more than HCTZ.

Lower systolic BP and serum potassium found with chlorthalidone

A smaller retrospective cohort analysis (6441 participants who received either chlorthalidone or HCTZ starting at 50 mg and stepped once to 100 mg) also assessed the difference in cardiovascular events between patients taking the 2 drugs.³ (Cardiovascular events were defined as pooled MIs, onset of angina or peripheral artery occlusive disease, or need for coronary artery bypass.) Although significant reductions in pooled events occurred in both groups over the 7-year study, these reductions were significantly lower in the chlorthalidone group than in the HCTZ group (aHR=0.79; 95% CI, 0.68-0.92).

Systolic blood pressures were statistically lower in the chlorthalidone group during Years 1 through 5 but not in Years 6 and 7 (difference 2-4 mm Hg). Serum potassium was also lower in patients taking chlorthalidone (3.8 mEq/L on chlorthalidone vs 4.0 mEq/L on HCTZ after 7 years; P<.05).

A retrospective cohort study investigated medication tolerance in veterans who had recently started either HCTZ (120,000 patients) or chlorthalidone (2200 patients) and were followed for a year.⁴ Most received doses between 12.5 and 25 mg of active drug.

One primary outcome was “nonpersistence,” defined as failure to refill the medication after double the number of days as the initial prescription. The other was “insufficient response,” defined as the need to start another antihypertensive medication. Chlorthalidone users were less likely than HCTZ users to have an insufficient response (odds ratio [OR]=0.71; 95% CI, 0.63-0.80) but more likely to exhibit nonpersistence (OR=1.6; 95% CI, 1.5-1.8).

RECOMMENDATIONS

For primary hypertension, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommends diuretic monotherapy in patients older than 55 years who are poor candidates for calcium channel blockers.⁵ If a diuretic is to be initiated or changed, NICE recommends chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) in preference to HCTZ. The guideline set forth in the eighth annual report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure makes no distinction between chlorthalidone and HCTZ; it refers only to “thiazidetype diuretics.” Thiazide-type diuretics are listed as one option (along with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) for initial monotherapy in nonblack patients.⁶

EVIDENCE SUMMARY

A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.¹ Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.² Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.

The 2 groups showed no significant difference in cardiovascular events (3.2 events per 100 person-years for chlorthalidone compared with 3.4 for HCTZ; adjusted hazard ratio [aHR]=0.93; 95% CI, 0.81-1.06).

Serious hypokalemia and hyponatremia are risks

Patients taking chlorthalidone were more likely to be hospitalized for hypokalemia (0.69 per 100 person-years vs 0.27 for HCTZ; aHR=3.1; 95% CI, 2.0-4.6; number needed to harm [NNH]=238 in 1 year) or hyponatremia (0.69 per 100 person-years vs 0.49 for HCTZ; aHR=1.7; 95% CI, 1.2-2.3; NNH=434 in 1 year).² However, the all-cause hospitalization rates for the 2 drugs were the same (aHR=1.0; 95% CI, 0.93-1.07).

Chlorthalidone may reduce the risk of cardiovascular events in patients with hypertension more than HCTZ.

Lower systolic BP and serum potassium found with chlorthalidone

A smaller retrospective cohort analysis (6441 participants who received either chlorthalidone or HCTZ starting at 50 mg and stepped once to 100 mg) also assessed the difference in cardiovascular events between patients taking the 2 drugs.³ (Cardiovascular events were defined as pooled MIs, onset of angina or peripheral artery occlusive disease, or need for coronary artery bypass.) Although significant reductions in pooled events occurred in both groups over the 7-year study, these reductions were significantly lower in the chlorthalidone group than in the HCTZ group (aHR=0.79; 95% CI, 0.68-0.92).

Systolic blood pressures were statistically lower in the chlorthalidone group during Years 1 through 5 but not in Years 6 and 7 (difference 2-4 mm Hg). Serum potassium was also lower in patients taking chlorthalidone (3.8 mEq/L on chlorthalidone vs 4.0 mEq/L on HCTZ after 7 years; P<.05).

A retrospective cohort study investigated medication tolerance in veterans who had recently started either HCTZ (120,000 patients) or chlorthalidone (2200 patients) and were followed for a year.⁴ Most received doses between 12.5 and 25 mg of active drug.

One primary outcome was “nonpersistence,” defined as failure to refill the medication after double the number of days as the initial prescription. The other was “insufficient response,” defined as the need to start another antihypertensive medication. Chlorthalidone users were less likely than HCTZ users to have an insufficient response (odds ratio [OR]=0.71; 95% CI, 0.63-0.80) but more likely to exhibit nonpersistence (OR=1.6; 95% CI, 1.5-1.8).

RECOMMENDATIONS

For primary hypertension, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommends diuretic monotherapy in patients older than 55 years who are poor candidates for calcium channel blockers.⁵ If a diuretic is to be initiated or changed, NICE recommends chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) in preference to HCTZ. The guideline set forth in the eighth annual report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure makes no distinction between chlorthalidone and HCTZ; it refers only to “thiazidetype diuretics.” Thiazide-type diuretics are listed as one option (along with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) for initial monotherapy in nonblack patients.⁶

Evidence summary

An RCT found that MVM supplementation for one academic year didn’t improve academic achievement more than placebo in 640 children, 8 to 12 years of age, from low-income urban families.¹ Scores on the Terra Nova academic achievement test of reading, math, language, science, and social sciences didn’t differ between students taking MVM supplements or placebo.

Another RCT that compared MVM supplementation with placebo among 245 children between 6 and 12 years of age found no clinically significant improvements in IQ scores overall. However, within a small subset, more children who took MVM showed a clinical increase in IQ than children who took placebo.²

Investigators randomized children to daily MVM supplementation (50% of the US recommended daily allowance) or placebo for 3 months, then measured their Wechsler IQ scores. Overall, the MVM group scored 2.5 points higher (95% confidence interval [CI], 1.85-3.15) than the placebo group (a 15-point change is clinically significant).

More children taking MVM supplements (44) than placebo (25) showed increases in nonverbal IQ scores of 15 or more points (35% compared with 21%; P<.01). The authors speculate that this result may be attributable to the fact that one in 7 schoolchildren was undernourished. A major weakness of the study was its 16% attrition rate.

Fortified milk reduced disease in young children in India

A community-based, double-blind RCT found that milk fortified with vitamins A, C, and E plus minerals reduced common illnesses over the course of a year more than unfortified milk among 633 children 1 to 3 years of age living in a peri-urban area of India.³

Children who drank fortified milk had fewer days of fever (9.1 compared with 9.7 days for placebo; P=.005), a lower incidence of diarrhea (odds ratio [OR]=0.82; 95% CI, 0.73-0.93), and a decreased rate of lower respiratory illness (OR=0.74; 95% CI, 0.57-0.97). Children 2 years and younger showed the greatest effect.

Asthma and food allergies: The data are mixed

An inception cohort study found an association between early MV use and a higher risk of asthma and food allergies.⁴ Investigators evaluated more than 8000 American women and their newborns over the first 3 years of life. The study population included more families with low socioeconomic status (50%), blacks (51%), and infants born before 37 weeks’ gestation (23%) than the general US population.

Exclusively formula-fed infants who took MV in the first 6 months were more likely to develop asthma (OR=1.27; 95% CI, 1.04-1.56) and food allergies (OR=1.6; 95% CI, 1.2-2.2) than formula-fed infants who didn’t take MV.

However, a birth cohort study of 2470 Swedish children that analyzed health data from parental questionnaires and compared serum immunoglobulin E (IgE) concentrations at 8 years of age found no association between MV use within the past 12 months and clinical allergic disease or specific IgE concentrations.⁵ Children who took MV at age 4 years or earlier had lower rates of IgE sensitization to food allergens at 8 years (OR=0.61; 95% CI, 0.39-0.97).

Recommendations

According to the American Academy of Pediatrics Committee on Nutrition,⁶ healthy children who are growing normally and consume a varied diet don’t need routine supplementation with vitamins and minerals. The Committee states that if parents wish to give their children supplements, a standard pediatric multivitamin generally poses no risk.

Evidence summary

An RCT found that MVM supplementation for one academic year didn’t improve academic achievement more than placebo in 640 children, 8 to 12 years of age, from low-income urban families.¹ Scores on the Terra Nova academic achievement test of reading, math, language, science, and social sciences didn’t differ between students taking MVM supplements or placebo.

Another RCT that compared MVM supplementation with placebo among 245 children between 6 and 12 years of age found no clinically significant improvements in IQ scores overall. However, within a small subset, more children who took MVM showed a clinical increase in IQ than children who took placebo.²

Investigators randomized children to daily MVM supplementation (50% of the US recommended daily allowance) or placebo for 3 months, then measured their Wechsler IQ scores. Overall, the MVM group scored 2.5 points higher (95% confidence interval [CI], 1.85-3.15) than the placebo group (a 15-point change is clinically significant).

More children taking MVM supplements (44) than placebo (25) showed increases in nonverbal IQ scores of 15 or more points (35% compared with 21%; P<.01). The authors speculate that this result may be attributable to the fact that one in 7 schoolchildren was undernourished. A major weakness of the study was its 16% attrition rate.

Fortified milk reduced disease in young children in India

A community-based, double-blind RCT found that milk fortified with vitamins A, C, and E plus minerals reduced common illnesses over the course of a year more than unfortified milk among 633 children 1 to 3 years of age living in a peri-urban area of India.³

Children who drank fortified milk had fewer days of fever (9.1 compared with 9.7 days for placebo; P=.005), a lower incidence of diarrhea (odds ratio [OR]=0.82; 95% CI, 0.73-0.93), and a decreased rate of lower respiratory illness (OR=0.74; 95% CI, 0.57-0.97). Children 2 years and younger showed the greatest effect.

Asthma and food allergies: The data are mixed

An inception cohort study found an association between early MV use and a higher risk of asthma and food allergies.⁴ Investigators evaluated more than 8000 American women and their newborns over the first 3 years of life. The study population included more families with low socioeconomic status (50%), blacks (51%), and infants born before 37 weeks’ gestation (23%) than the general US population.

Exclusively formula-fed infants who took MV in the first 6 months were more likely to develop asthma (OR=1.27; 95% CI, 1.04-1.56) and food allergies (OR=1.6; 95% CI, 1.2-2.2) than formula-fed infants who didn’t take MV.

However, a birth cohort study of 2470 Swedish children that analyzed health data from parental questionnaires and compared serum immunoglobulin E (IgE) concentrations at 8 years of age found no association between MV use within the past 12 months and clinical allergic disease or specific IgE concentrations.⁵ Children who took MV at age 4 years or earlier had lower rates of IgE sensitization to food allergens at 8 years (OR=0.61; 95% CI, 0.39-0.97).

Recommendations

According to the American Academy of Pediatrics Committee on Nutrition,⁶ healthy children who are growing normally and consume a varied diet don’t need routine supplementation with vitamins and minerals. The Committee states that if parents wish to give their children supplements, a standard pediatric multivitamin generally poses no risk.

Evidence summary

An RCT found that MVM supplementation for one academic year didn’t improve academic achievement more than placebo in 640 children, 8 to 12 years of age, from low-income urban families.¹ Scores on the Terra Nova academic achievement test of reading, math, language, science, and social sciences didn’t differ between students taking MVM supplements or placebo.

Another RCT that compared MVM supplementation with placebo among 245 children between 6 and 12 years of age found no clinically significant improvements in IQ scores overall. However, within a small subset, more children who took MVM showed a clinical increase in IQ than children who took placebo.²

Investigators randomized children to daily MVM supplementation (50% of the US recommended daily allowance) or placebo for 3 months, then measured their Wechsler IQ scores. Overall, the MVM group scored 2.5 points higher (95% confidence interval [CI], 1.85-3.15) than the placebo group (a 15-point change is clinically significant).

More children taking MVM supplements (44) than placebo (25) showed increases in nonverbal IQ scores of 15 or more points (35% compared with 21%; P<.01). The authors speculate that this result may be attributable to the fact that one in 7 schoolchildren was undernourished. A major weakness of the study was its 16% attrition rate.

Fortified milk reduced disease in young children in India

A community-based, double-blind RCT found that milk fortified with vitamins A, C, and E plus minerals reduced common illnesses over the course of a year more than unfortified milk among 633 children 1 to 3 years of age living in a peri-urban area of India.³

Children who drank fortified milk had fewer days of fever (9.1 compared with 9.7 days for placebo; P=.005), a lower incidence of diarrhea (odds ratio [OR]=0.82; 95% CI, 0.73-0.93), and a decreased rate of lower respiratory illness (OR=0.74; 95% CI, 0.57-0.97). Children 2 years and younger showed the greatest effect.

Asthma and food allergies: The data are mixed

An inception cohort study found an association between early MV use and a higher risk of asthma and food allergies.⁴ Investigators evaluated more than 8000 American women and their newborns over the first 3 years of life. The study population included more families with low socioeconomic status (50%), blacks (51%), and infants born before 37 weeks’ gestation (23%) than the general US population.

Exclusively formula-fed infants who took MV in the first 6 months were more likely to develop asthma (OR=1.27; 95% CI, 1.04-1.56) and food allergies (OR=1.6; 95% CI, 1.2-2.2) than formula-fed infants who didn’t take MV.

However, a birth cohort study of 2470 Swedish children that analyzed health data from parental questionnaires and compared serum immunoglobulin E (IgE) concentrations at 8 years of age found no association between MV use within the past 12 months and clinical allergic disease or specific IgE concentrations.⁵ Children who took MV at age 4 years or earlier had lower rates of IgE sensitization to food allergens at 8 years (OR=0.61; 95% CI, 0.39-0.97).

Recommendations

According to the American Academy of Pediatrics Committee on Nutrition,⁶ healthy children who are growing normally and consume a varied diet don’t need routine supplementation with vitamins and minerals. The Committee states that if parents wish to give their children supplements, a standard pediatric multivitamin generally poses no risk.

Evidence summary

A 2008 Cochrane review examined 7 RCTs comparing ICS with placebo in 1989 patients 30 to 52 years of age with mild asthma or COPD. The reviewers found no evidence of increased bone turnover, decreased bone mineral density, or increased vertebral fracture in the ICS group compared with the placebo group at 2 to 3 years’ follow-up (odds ratio [OR] for fracture=1.87; 95% confidence interval [CI], 0.5-7.0).

Steroid doses ranged from 200 to 4000 mcg beclomethasone equivalent ICS per day.¹ A 100-mcg beclomethasone equivalent ICS dose is 50 mcg fluticasone, 80 mcg budesonide, or 200 mcg triamcinolone.²

A 2008 meta-analysis of 11 RCTs that examined a number of adverse effects of ICS in adult patients with COPD found 3 studies (8131 patients) that reported no significant increase in fracture risk at 36 months in the ICS group compared with the placebo group (OR=1.09; 95% CI, 0.89-1.33). Steroid doses ranged from 1000 to 2000 mcg beclomethasone equivalent ICS per day.³

Some studies suggest an association between dose and risk
A 2008 meta-analysis that included patients with COPD or asthma, average age 43 to 81 years, showed no difference in fracture risk overall at 1 to 4 years’ follow-up (OR=1.02; 95% CI, 0.96-1.08). This analysis examined 4 RCTs, 6 case-control studies, and 3 cohort studies.⁴

A subgroup analysis of patients taking higher-dose ICS (>1500 mcg beclomethasone equivalent ICS per day) that pooled data from case-control and cohort studies suggested an increased risk of fracture (OR=1.30; 95% CI, 1.07-1.58).⁴

Investigators identified a possible dose-dependent relationship in another meta-analysis of 5 case-control studies (43,783 cases, 259,936 controls).⁵ The meta-analysis included 4 of the studies examined in the previously discussed meta-analysis.⁴

The investigators found a relative risk of 1.12 (95% CI, 1.0-1.26) for nonvertebral fracture for each 1000-mcg increase in beclomethasone equivalent ICS dose per day.⁵ Longer follow-up time wasn’t associated with greater fracture risk.

But the relationship isn’t clear
Although some non-RCT studies discussed here show that higher doses of steroids may lead to increased fracture risk, the strength of this association isn’t clear. The authors of the Cochrane review and the meta-analyses point out that a significant number of confounding factors can put asthma and COPD patients at increased risk for fracture. They include age, smoking status, inactivity, and severity of underlying lung disease. The fact that different authors controlled differently for these factors introduced heterogeneity into the meta-analyses described here.^1,3-5

Recommendations

Guidelines for the Diagnosis and Management of Asthma from the National Heart, Lung, and Blood Institute state that “most benefit is achieved with relatively low doses of ICS, whereas the risk of adverse effects increases with dose. … ICS use may be associated with a dose-dependent reduction in bone mineral content, although low or medium doses appear to have no major adverse effect. Elderly patients may be more at risk due to preexisting osteoporosis, changes in estrogen levels that affect calcium utilization, and a sedentary lifestyle.”⁶

Evidence summary

A 2008 Cochrane review examined 7 RCTs comparing ICS with placebo in 1989 patients 30 to 52 years of age with mild asthma or COPD. The reviewers found no evidence of increased bone turnover, decreased bone mineral density, or increased vertebral fracture in the ICS group compared with the placebo group at 2 to 3 years’ follow-up (odds ratio [OR] for fracture=1.87; 95% confidence interval [CI], 0.5-7.0).

Steroid doses ranged from 200 to 4000 mcg beclomethasone equivalent ICS per day.¹ A 100-mcg beclomethasone equivalent ICS dose is 50 mcg fluticasone, 80 mcg budesonide, or 200 mcg triamcinolone.²

A 2008 meta-analysis of 11 RCTs that examined a number of adverse effects of ICS in adult patients with COPD found 3 studies (8131 patients) that reported no significant increase in fracture risk at 36 months in the ICS group compared with the placebo group (OR=1.09; 95% CI, 0.89-1.33). Steroid doses ranged from 1000 to 2000 mcg beclomethasone equivalent ICS per day.³

Some studies suggest an association between dose and risk
A 2008 meta-analysis that included patients with COPD or asthma, average age 43 to 81 years, showed no difference in fracture risk overall at 1 to 4 years’ follow-up (OR=1.02; 95% CI, 0.96-1.08). This analysis examined 4 RCTs, 6 case-control studies, and 3 cohort studies.⁴

A subgroup analysis of patients taking higher-dose ICS (>1500 mcg beclomethasone equivalent ICS per day) that pooled data from case-control and cohort studies suggested an increased risk of fracture (OR=1.30; 95% CI, 1.07-1.58).⁴

Investigators identified a possible dose-dependent relationship in another meta-analysis of 5 case-control studies (43,783 cases, 259,936 controls).⁵ The meta-analysis included 4 of the studies examined in the previously discussed meta-analysis.⁴

The investigators found a relative risk of 1.12 (95% CI, 1.0-1.26) for nonvertebral fracture for each 1000-mcg increase in beclomethasone equivalent ICS dose per day.⁵ Longer follow-up time wasn’t associated with greater fracture risk.

But the relationship isn’t clear
Although some non-RCT studies discussed here show that higher doses of steroids may lead to increased fracture risk, the strength of this association isn’t clear. The authors of the Cochrane review and the meta-analyses point out that a significant number of confounding factors can put asthma and COPD patients at increased risk for fracture. They include age, smoking status, inactivity, and severity of underlying lung disease. The fact that different authors controlled differently for these factors introduced heterogeneity into the meta-analyses described here.^1,3-5

Recommendations

Guidelines for the Diagnosis and Management of Asthma from the National Heart, Lung, and Blood Institute state that “most benefit is achieved with relatively low doses of ICS, whereas the risk of adverse effects increases with dose. … ICS use may be associated with a dose-dependent reduction in bone mineral content, although low or medium doses appear to have no major adverse effect. Elderly patients may be more at risk due to preexisting osteoporosis, changes in estrogen levels that affect calcium utilization, and a sedentary lifestyle.”⁶

Evidence summary

A 2008 Cochrane review examined 7 RCTs comparing ICS with placebo in 1989 patients 30 to 52 years of age with mild asthma or COPD. The reviewers found no evidence of increased bone turnover, decreased bone mineral density, or increased vertebral fracture in the ICS group compared with the placebo group at 2 to 3 years’ follow-up (odds ratio [OR] for fracture=1.87; 95% confidence interval [CI], 0.5-7.0).

Steroid doses ranged from 200 to 4000 mcg beclomethasone equivalent ICS per day.¹ A 100-mcg beclomethasone equivalent ICS dose is 50 mcg fluticasone, 80 mcg budesonide, or 200 mcg triamcinolone.²

A 2008 meta-analysis of 11 RCTs that examined a number of adverse effects of ICS in adult patients with COPD found 3 studies (8131 patients) that reported no significant increase in fracture risk at 36 months in the ICS group compared with the placebo group (OR=1.09; 95% CI, 0.89-1.33). Steroid doses ranged from 1000 to 2000 mcg beclomethasone equivalent ICS per day.³

Some studies suggest an association between dose and risk
A 2008 meta-analysis that included patients with COPD or asthma, average age 43 to 81 years, showed no difference in fracture risk overall at 1 to 4 years’ follow-up (OR=1.02; 95% CI, 0.96-1.08). This analysis examined 4 RCTs, 6 case-control studies, and 3 cohort studies.⁴

A subgroup analysis of patients taking higher-dose ICS (>1500 mcg beclomethasone equivalent ICS per day) that pooled data from case-control and cohort studies suggested an increased risk of fracture (OR=1.30; 95% CI, 1.07-1.58).⁴

Investigators identified a possible dose-dependent relationship in another meta-analysis of 5 case-control studies (43,783 cases, 259,936 controls).⁵ The meta-analysis included 4 of the studies examined in the previously discussed meta-analysis.⁴

The investigators found a relative risk of 1.12 (95% CI, 1.0-1.26) for nonvertebral fracture for each 1000-mcg increase in beclomethasone equivalent ICS dose per day.⁵ Longer follow-up time wasn’t associated with greater fracture risk.

But the relationship isn’t clear
Although some non-RCT studies discussed here show that higher doses of steroids may lead to increased fracture risk, the strength of this association isn’t clear. The authors of the Cochrane review and the meta-analyses point out that a significant number of confounding factors can put asthma and COPD patients at increased risk for fracture. They include age, smoking status, inactivity, and severity of underlying lung disease. The fact that different authors controlled differently for these factors introduced heterogeneity into the meta-analyses described here.^1,3-5

Recommendations

Guidelines for the Diagnosis and Management of Asthma from the National Heart, Lung, and Blood Institute state that “most benefit is achieved with relatively low doses of ICS, whereas the risk of adverse effects increases with dose. … ICS use may be associated with a dose-dependent reduction in bone mineral content, although low or medium doses appear to have no major adverse effect. Elderly patients may be more at risk due to preexisting osteoporosis, changes in estrogen levels that affect calcium utilization, and a sedentary lifestyle.”⁶