Clinical Inquiries

Evidence summary

SSRIs were more effective than imipramine or alprazolam in a meta-analysis,¹ but equivalent to these drugs in an effect-size analysis.² The absolute difference in efficacy is difficult to determine; few studies directly compare SSRIs with other drugs. In 2 randomized head-to-head trials,^3,4 remission rates (eliminating symptoms) were 50%-65% for paroxetine, 37%-53% for clomipramine, and 32%-34% for placebo after 9-12 weeks of therapy; differences between the 2 active drugs were not significant. Clomipramine is serotoninergic and was more effective than other tricyclics in an RCT.⁵ Adding a BDZ to an SSRI for the first 3 weeks can rapidly stabilize symptoms⁶ (Table).

Two meta-analyses concluded that CBT is as effective as antidepressants or BDZs during acute treatment⁷ and during long-term follow-up (31-121 weeks).⁸ CBT and imipramine each reduce symptoms in 45%-48% of patients; combining them reduces symptoms in 60%.⁹ Imipramine is more effective initially; CBT is more durable⁹ but effects may be therapist-dependent. When used in conjunction with medication, graded exposure to panicinducing situations reduces agoraphobia⁷ but does not improve relapse rates.⁸ Behavioral therapy with exposure homework has good long-term results.¹⁰

An adequate trial of medication requires 6-8 weeks.¹¹ Before treating, evaluate patients for comorbid mood, anxiety, personality, substance use, or medical disorders, which affect 40%-50% of patients with panic disorder, and may influence the choice of treatment.¹² Current practice is to slowly taper and discontinue medication after 12-18 months of maintenance treatment¹² if there are no significant residual symptoms, no increased psychosocial stressors, and no history of severe or recurrent relapse.

TABLE
Drugs used to treat panic disorder

Recommendations from others

The American Psychiatric Association Guideline states that CBT and pharmacotherapy are equivalently effective, and that SSRIs, TCAs, BDZs, and MAOIs are equivalently effective.¹² The International Consensus Group on Depression and Anxiety concludes that SSRIs, TCAs, and BDZs are effective. SSRIs and BDZs are tolerated better than TCAs, and BDZs act faster (1 week vs. 4-8 weeks).¹¹

Read a Clinical Commentary by William A. Hensel, MD, at www.fpin.org.

Evidence summary

SSRIs were more effective than imipramine or alprazolam in a meta-analysis,¹ but equivalent to these drugs in an effect-size analysis.² The absolute difference in efficacy is difficult to determine; few studies directly compare SSRIs with other drugs. In 2 randomized head-to-head trials,^3,4 remission rates (eliminating symptoms) were 50%-65% for paroxetine, 37%-53% for clomipramine, and 32%-34% for placebo after 9-12 weeks of therapy; differences between the 2 active drugs were not significant. Clomipramine is serotoninergic and was more effective than other tricyclics in an RCT.⁵ Adding a BDZ to an SSRI for the first 3 weeks can rapidly stabilize symptoms⁶ (Table).

Two meta-analyses concluded that CBT is as effective as antidepressants or BDZs during acute treatment⁷ and during long-term follow-up (31-121 weeks).⁸ CBT and imipramine each reduce symptoms in 45%-48% of patients; combining them reduces symptoms in 60%.⁹ Imipramine is more effective initially; CBT is more durable⁹ but effects may be therapist-dependent. When used in conjunction with medication, graded exposure to panicinducing situations reduces agoraphobia⁷ but does not improve relapse rates.⁸ Behavioral therapy with exposure homework has good long-term results.¹⁰

An adequate trial of medication requires 6-8 weeks.¹¹ Before treating, evaluate patients for comorbid mood, anxiety, personality, substance use, or medical disorders, which affect 40%-50% of patients with panic disorder, and may influence the choice of treatment.¹² Current practice is to slowly taper and discontinue medication after 12-18 months of maintenance treatment¹² if there are no significant residual symptoms, no increased psychosocial stressors, and no history of severe or recurrent relapse.

TABLE
Drugs used to treat panic disorder

Recommendations from others

The American Psychiatric Association Guideline states that CBT and pharmacotherapy are equivalently effective, and that SSRIs, TCAs, BDZs, and MAOIs are equivalently effective.¹² The International Consensus Group on Depression and Anxiety concludes that SSRIs, TCAs, and BDZs are effective. SSRIs and BDZs are tolerated better than TCAs, and BDZs act faster (1 week vs. 4-8 weeks).¹¹

Read a Clinical Commentary by William A. Hensel, MD, at www.fpin.org.

Evidence summary

SSRIs were more effective than imipramine or alprazolam in a meta-analysis,¹ but equivalent to these drugs in an effect-size analysis.² The absolute difference in efficacy is difficult to determine; few studies directly compare SSRIs with other drugs. In 2 randomized head-to-head trials,^3,4 remission rates (eliminating symptoms) were 50%-65% for paroxetine, 37%-53% for clomipramine, and 32%-34% for placebo after 9-12 weeks of therapy; differences between the 2 active drugs were not significant. Clomipramine is serotoninergic and was more effective than other tricyclics in an RCT.⁵ Adding a BDZ to an SSRI for the first 3 weeks can rapidly stabilize symptoms⁶ (Table).

Two meta-analyses concluded that CBT is as effective as antidepressants or BDZs during acute treatment⁷ and during long-term follow-up (31-121 weeks).⁸ CBT and imipramine each reduce symptoms in 45%-48% of patients; combining them reduces symptoms in 60%.⁹ Imipramine is more effective initially; CBT is more durable⁹ but effects may be therapist-dependent. When used in conjunction with medication, graded exposure to panicinducing situations reduces agoraphobia⁷ but does not improve relapse rates.⁸ Behavioral therapy with exposure homework has good long-term results.¹⁰

An adequate trial of medication requires 6-8 weeks.¹¹ Before treating, evaluate patients for comorbid mood, anxiety, personality, substance use, or medical disorders, which affect 40%-50% of patients with panic disorder, and may influence the choice of treatment.¹² Current practice is to slowly taper and discontinue medication after 12-18 months of maintenance treatment¹² if there are no significant residual symptoms, no increased psychosocial stressors, and no history of severe or recurrent relapse.

TABLE
Drugs used to treat panic disorder

Recommendations from others

The American Psychiatric Association Guideline states that CBT and pharmacotherapy are equivalently effective, and that SSRIs, TCAs, BDZs, and MAOIs are equivalently effective.¹² The International Consensus Group on Depression and Anxiety concludes that SSRIs, TCAs, and BDZs are effective. SSRIs and BDZs are tolerated better than TCAs, and BDZs act faster (1 week vs. 4-8 weeks).¹¹

Read a Clinical Commentary by William A. Hensel, MD, at www.fpin.org.

Evidence summary

Aortic stenosis is a narrowing of the aortic valve. Degree of severity is judged by valve area: mild (1.5–2.0 cm²), moderate (1.0–1.5 cm²), severe (< 1.0 cm²). Alternatively, stenosis may be classified by transvalvular gradient or jet velocity, the latter being the easier quantity to measure by echocardiogram. Prevalence of aortic stenosis increases with age; one series of 1243 elderly women (mean age of 82) found mild stenosis in 10%, moderate stenosis in 6%, and severe stenosis in 2%.¹ Natural history studies show that once classic symptoms develop, average survival decreases to 5 years with the onset of angina, 3 years after cardiac syncope, and 2 years after heart failure.² The incidence of sudden death increases from < 1% annually among asymptomatic patients to 15% to 20% among symptomatic patients.^3,4

Aortic stenosis is suggested by such findings as a harsh systolic murmur at the right upper sternal border, pulsus parvus et tardus, and a sustained point of maximal impulse. Exercise stress testing may provide additional information. In one prospective study of 123 patients, those who had a greater increase in valve area, cardiac output, and blood pressure and a smaller decrease in stroke volume on stress echocardiogram were more likely to remain asymptomatic for the entire length of their time in the study, an average of 2.5 years.⁵

Asymptomatic patients with aortic stenosis who undergo coronary artery bypass grafting (CABG) often have their aortic valve replaced at the same time; the timing of aortic valve replacement in patients not requiring CABG is controversial. One prospective study found the severity of stenosis at baseline to be the strongest prognostic predictor. Patients with a jet velocity of < 3.0 m/s were unlikely to develop symptoms within 5 years; those with a jet velocity of 4.0 m/s had a > 50% likelihood of developing symptoms or dying within 2 years.⁵ Another study followed 128 patients for 4 years and found that moderate to severe valvular calcification and an increase in jet velocity of 0.3 m/s/year were the best prognostic predictors.⁶ Almost 80% of those with both calcification and a rapid change in jet velocity underwent surgery or died within 2 years⁶ (Table).

TABLE
Indications for possible valve replacement with asymptomatic aortic stenosis

Recommendations from others

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines recommends echocardiograms every 5 years for mild stenosis, every 2 years for moderate stenosis, and annually for severe stenosis.⁴ There is no guideline for exercise testing. Aortic valve replacement is recommended for symptomatic patients and patients with severe stenosis undergoing CABG or other valvular or aortic surgery.

Clinical Commentary by Ken Grauer, MD; and search strategy, at www.fpin.org.

Evidence summary

Aortic stenosis is a narrowing of the aortic valve. Degree of severity is judged by valve area: mild (1.5–2.0 cm²), moderate (1.0–1.5 cm²), severe (< 1.0 cm²). Alternatively, stenosis may be classified by transvalvular gradient or jet velocity, the latter being the easier quantity to measure by echocardiogram. Prevalence of aortic stenosis increases with age; one series of 1243 elderly women (mean age of 82) found mild stenosis in 10%, moderate stenosis in 6%, and severe stenosis in 2%.¹ Natural history studies show that once classic symptoms develop, average survival decreases to 5 years with the onset of angina, 3 years after cardiac syncope, and 2 years after heart failure.² The incidence of sudden death increases from < 1% annually among asymptomatic patients to 15% to 20% among symptomatic patients.^3,4

Aortic stenosis is suggested by such findings as a harsh systolic murmur at the right upper sternal border, pulsus parvus et tardus, and a sustained point of maximal impulse. Exercise stress testing may provide additional information. In one prospective study of 123 patients, those who had a greater increase in valve area, cardiac output, and blood pressure and a smaller decrease in stroke volume on stress echocardiogram were more likely to remain asymptomatic for the entire length of their time in the study, an average of 2.5 years.⁵

Asymptomatic patients with aortic stenosis who undergo coronary artery bypass grafting (CABG) often have their aortic valve replaced at the same time; the timing of aortic valve replacement in patients not requiring CABG is controversial. One prospective study found the severity of stenosis at baseline to be the strongest prognostic predictor. Patients with a jet velocity of < 3.0 m/s were unlikely to develop symptoms within 5 years; those with a jet velocity of 4.0 m/s had a > 50% likelihood of developing symptoms or dying within 2 years.⁵ Another study followed 128 patients for 4 years and found that moderate to severe valvular calcification and an increase in jet velocity of 0.3 m/s/year were the best prognostic predictors.⁶ Almost 80% of those with both calcification and a rapid change in jet velocity underwent surgery or died within 2 years⁶ (Table).

TABLE
Indications for possible valve replacement with asymptomatic aortic stenosis

Recommendations from others

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines recommends echocardiograms every 5 years for mild stenosis, every 2 years for moderate stenosis, and annually for severe stenosis.⁴ There is no guideline for exercise testing. Aortic valve replacement is recommended for symptomatic patients and patients with severe stenosis undergoing CABG or other valvular or aortic surgery.

Clinical Commentary by Ken Grauer, MD; and search strategy, at www.fpin.org.

Evidence summary

Aortic stenosis is a narrowing of the aortic valve. Degree of severity is judged by valve area: mild (1.5–2.0 cm²), moderate (1.0–1.5 cm²), severe (< 1.0 cm²). Alternatively, stenosis may be classified by transvalvular gradient or jet velocity, the latter being the easier quantity to measure by echocardiogram. Prevalence of aortic stenosis increases with age; one series of 1243 elderly women (mean age of 82) found mild stenosis in 10%, moderate stenosis in 6%, and severe stenosis in 2%.¹ Natural history studies show that once classic symptoms develop, average survival decreases to 5 years with the onset of angina, 3 years after cardiac syncope, and 2 years after heart failure.² The incidence of sudden death increases from < 1% annually among asymptomatic patients to 15% to 20% among symptomatic patients.^3,4

Aortic stenosis is suggested by such findings as a harsh systolic murmur at the right upper sternal border, pulsus parvus et tardus, and a sustained point of maximal impulse. Exercise stress testing may provide additional information. In one prospective study of 123 patients, those who had a greater increase in valve area, cardiac output, and blood pressure and a smaller decrease in stroke volume on stress echocardiogram were more likely to remain asymptomatic for the entire length of their time in the study, an average of 2.5 years.⁵

Asymptomatic patients with aortic stenosis who undergo coronary artery bypass grafting (CABG) often have their aortic valve replaced at the same time; the timing of aortic valve replacement in patients not requiring CABG is controversial. One prospective study found the severity of stenosis at baseline to be the strongest prognostic predictor. Patients with a jet velocity of < 3.0 m/s were unlikely to develop symptoms within 5 years; those with a jet velocity of 4.0 m/s had a > 50% likelihood of developing symptoms or dying within 2 years.⁵ Another study followed 128 patients for 4 years and found that moderate to severe valvular calcification and an increase in jet velocity of 0.3 m/s/year were the best prognostic predictors.⁶ Almost 80% of those with both calcification and a rapid change in jet velocity underwent surgery or died within 2 years⁶ (Table).

TABLE
Indications for possible valve replacement with asymptomatic aortic stenosis

Recommendations from others

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines recommends echocardiograms every 5 years for mild stenosis, every 2 years for moderate stenosis, and annually for severe stenosis.⁴ There is no guideline for exercise testing. Aortic valve replacement is recommended for symptomatic patients and patients with severe stenosis undergoing CABG or other valvular or aortic surgery.

Clinical Commentary by Ken Grauer, MD; and search strategy, at www.fpin.org.

Evidence summary

Infants experience normal physiologic variation in stool frequency and consistency, moderated in part by diet.¹ Childhood functional defecation disorders represent a continuum from infant dyschezia, to functional constipation, to functional fecal retention^2,3 (Table 1). Most infants have dyschezia or functional constipation. Infant dyschezia, a self-limited condition related to immature muscle coordination, requires only parental reassurance.

We found no placebo-controlled trials of osmotic laxatives in infants. One uncontrolled trial of 220 functionally constipated, bottle-fed infants younger than 6 months showed normalization of stools in 90% of infants within 2 weeks of treatment with 2% or 4% lactulose.⁴ No other evidence has been published about the benefits or harms of sorbitol-containing juices, fiber, osmotic laxatives, formula switching, rectal stimulation with rectal thermometers, or glycerin suppositories.

We found no trials of mineral oil or sodium phosphate enemas in constipated infants. Mineral oil has been associated with lipoid aspiration pneumonia in infants less than 1 year of age.^5,6 Sodium phosphate enemas in children under 2 years of age have been associated with electrolyte disturbances, dehydration, and cardiac arrest.⁷

TABLE 1
Rome II childhood functional defecation disorders²

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends glycerin suppositories for rectal disimpaction for acutely constipated infants; sorbitol-containing juices, such as prune, pear, and apple, for decreasing constipation; barley malt extract, corn syrup, lactulose, or sorbitol (osmotic laxatives) as stool softeners; and avoidance of enemas, mineral oil, and stimulant laxatives due to potential adverse effects⁸ (Table 2).

TABLE 2
Recommended interventions for infant constipation⁸

Clinical Commentaries by Brian T. Easton, MD, and Susan E. Graves, MD, at http://www.fpin.org.

Evidence summary

Infants experience normal physiologic variation in stool frequency and consistency, moderated in part by diet.¹ Childhood functional defecation disorders represent a continuum from infant dyschezia, to functional constipation, to functional fecal retention^2,3 (Table 1). Most infants have dyschezia or functional constipation. Infant dyschezia, a self-limited condition related to immature muscle coordination, requires only parental reassurance.

We found no placebo-controlled trials of osmotic laxatives in infants. One uncontrolled trial of 220 functionally constipated, bottle-fed infants younger than 6 months showed normalization of stools in 90% of infants within 2 weeks of treatment with 2% or 4% lactulose.⁴ No other evidence has been published about the benefits or harms of sorbitol-containing juices, fiber, osmotic laxatives, formula switching, rectal stimulation with rectal thermometers, or glycerin suppositories.

We found no trials of mineral oil or sodium phosphate enemas in constipated infants. Mineral oil has been associated with lipoid aspiration pneumonia in infants less than 1 year of age.^5,6 Sodium phosphate enemas in children under 2 years of age have been associated with electrolyte disturbances, dehydration, and cardiac arrest.⁷

TABLE 1
Rome II childhood functional defecation disorders²

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends glycerin suppositories for rectal disimpaction for acutely constipated infants; sorbitol-containing juices, such as prune, pear, and apple, for decreasing constipation; barley malt extract, corn syrup, lactulose, or sorbitol (osmotic laxatives) as stool softeners; and avoidance of enemas, mineral oil, and stimulant laxatives due to potential adverse effects⁸ (Table 2).

TABLE 2
Recommended interventions for infant constipation⁸

Clinical Commentaries by Brian T. Easton, MD, and Susan E. Graves, MD, at http://www.fpin.org.

Evidence summary

Infants experience normal physiologic variation in stool frequency and consistency, moderated in part by diet.¹ Childhood functional defecation disorders represent a continuum from infant dyschezia, to functional constipation, to functional fecal retention^2,3 (Table 1). Most infants have dyschezia or functional constipation. Infant dyschezia, a self-limited condition related to immature muscle coordination, requires only parental reassurance.

We found no placebo-controlled trials of osmotic laxatives in infants. One uncontrolled trial of 220 functionally constipated, bottle-fed infants younger than 6 months showed normalization of stools in 90% of infants within 2 weeks of treatment with 2% or 4% lactulose.⁴ No other evidence has been published about the benefits or harms of sorbitol-containing juices, fiber, osmotic laxatives, formula switching, rectal stimulation with rectal thermometers, or glycerin suppositories.

We found no trials of mineral oil or sodium phosphate enemas in constipated infants. Mineral oil has been associated with lipoid aspiration pneumonia in infants less than 1 year of age.^5,6 Sodium phosphate enemas in children under 2 years of age have been associated with electrolyte disturbances, dehydration, and cardiac arrest.⁷

TABLE 1
Rome II childhood functional defecation disorders²

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends glycerin suppositories for rectal disimpaction for acutely constipated infants; sorbitol-containing juices, such as prune, pear, and apple, for decreasing constipation; barley malt extract, corn syrup, lactulose, or sorbitol (osmotic laxatives) as stool softeners; and avoidance of enemas, mineral oil, and stimulant laxatives due to potential adverse effects⁸ (Table 2).

TABLE 2
Recommended interventions for infant constipation⁸

Clinical Commentaries by Brian T. Easton, MD, and Susan E. Graves, MD, at http://www.fpin.org.

Evidence summary

SSRI-related sexual dysfunction may be dose dependent and diminish with time, but these aspects have not been evaluated prospectively. Data suggest that bupropion, nefazodone, and mirtazapine have little to no effect on sexual functioning.¹ Changing from SSRIs to one of these agents may alleviate SSRI-induced sexual dysfunction. In a randomized double-blind study, patients experiencing sexual dysfunction on sertraline improved when switched to nefazodone 400 mg daily.² Additional open-label nonrandomized studies of all 3 agents suggest improved sexual functioning in 60% to 85% of patients with little to no loss of antidepressant efficacy.^1,3,6 The potential for placebo effects makes interpreting these open-label trials more difficult.

Three augmentation therapies have been tested in double-blind placebo-controlled trials. In the first, buspirone augmentation resulted in a statistical improvement in sexual functioning at weeks 2 and 3 of therapy, but not at weeks 1 and 4 (mean dose 48.5 mg per day).⁷ In the second, adding buspirone 20 to 30 mg per day, amantadine 50 to 100 mg per day, or placebo resulted in equal improvement in women’s sexual function.⁸ Finally, in a third trial, adding bupropion or placebo showed equal improvement in sexual function.⁹ Multiple other agents have been tested in open-label nonrandomized studies, case series, and case reports. Most showed a beneficial effect, but results must be interpreted with caution. One open-label nonrandomized study of weekend “drug holidays” showed no benefit for fluoxetine and inconsistent results for paroxetine and sertraline.¹⁰

Recommendations from others

Tertiary literature sources recommend the strategies described above.¹¹

Clinical Commentary by Michael Fisher, MD, additional references, search strategy, and detailed evidence table at http://www.fpin.org.

Evidence summary

SSRI-related sexual dysfunction may be dose dependent and diminish with time, but these aspects have not been evaluated prospectively. Data suggest that bupropion, nefazodone, and mirtazapine have little to no effect on sexual functioning.¹ Changing from SSRIs to one of these agents may alleviate SSRI-induced sexual dysfunction. In a randomized double-blind study, patients experiencing sexual dysfunction on sertraline improved when switched to nefazodone 400 mg daily.² Additional open-label nonrandomized studies of all 3 agents suggest improved sexual functioning in 60% to 85% of patients with little to no loss of antidepressant efficacy.^1,3,6 The potential for placebo effects makes interpreting these open-label trials more difficult.

Three augmentation therapies have been tested in double-blind placebo-controlled trials. In the first, buspirone augmentation resulted in a statistical improvement in sexual functioning at weeks 2 and 3 of therapy, but not at weeks 1 and 4 (mean dose 48.5 mg per day).⁷ In the second, adding buspirone 20 to 30 mg per day, amantadine 50 to 100 mg per day, or placebo resulted in equal improvement in women’s sexual function.⁸ Finally, in a third trial, adding bupropion or placebo showed equal improvement in sexual function.⁹ Multiple other agents have been tested in open-label nonrandomized studies, case series, and case reports. Most showed a beneficial effect, but results must be interpreted with caution. One open-label nonrandomized study of weekend “drug holidays” showed no benefit for fluoxetine and inconsistent results for paroxetine and sertraline.¹⁰

Recommendations from others

Tertiary literature sources recommend the strategies described above.¹¹

Clinical Commentary by Michael Fisher, MD, additional references, search strategy, and detailed evidence table at http://www.fpin.org.

Evidence summary

SSRI-related sexual dysfunction may be dose dependent and diminish with time, but these aspects have not been evaluated prospectively. Data suggest that bupropion, nefazodone, and mirtazapine have little to no effect on sexual functioning.¹ Changing from SSRIs to one of these agents may alleviate SSRI-induced sexual dysfunction. In a randomized double-blind study, patients experiencing sexual dysfunction on sertraline improved when switched to nefazodone 400 mg daily.² Additional open-label nonrandomized studies of all 3 agents suggest improved sexual functioning in 60% to 85% of patients with little to no loss of antidepressant efficacy.^1,3,6 The potential for placebo effects makes interpreting these open-label trials more difficult.

Three augmentation therapies have been tested in double-blind placebo-controlled trials. In the first, buspirone augmentation resulted in a statistical improvement in sexual functioning at weeks 2 and 3 of therapy, but not at weeks 1 and 4 (mean dose 48.5 mg per day).⁷ In the second, adding buspirone 20 to 30 mg per day, amantadine 50 to 100 mg per day, or placebo resulted in equal improvement in women’s sexual function.⁸ Finally, in a third trial, adding bupropion or placebo showed equal improvement in sexual function.⁹ Multiple other agents have been tested in open-label nonrandomized studies, case series, and case reports. Most showed a beneficial effect, but results must be interpreted with caution. One open-label nonrandomized study of weekend “drug holidays” showed no benefit for fluoxetine and inconsistent results for paroxetine and sertraline.¹⁰

Recommendations from others

Tertiary literature sources recommend the strategies described above.¹¹

Clinical Commentary by Michael Fisher, MD, additional references, search strategy, and detailed evidence table at http://www.fpin.org.

Evidence summary

Two randomized controlledtrials and 1 cohort study demonstrated a decrease in all-cause mortality in individuals aged 65 and older with known CHD by treating elevated cholesterol levels with either pravastatin or simvastatin.^1-3 The overall decrease in absolute risk of death was similar (range, 4.1%–6.2%; numbers needed to treat [NNT] = 17–25). The LIPID trial demonstrated a reduction in CHD-related death (relative risk [RR] = 0.76; 95% CI, 0.62–0.93; NNT = 37) and myocardial infarctions (RR = 0.74; 95% CI, 0.60–0.91; NNT = 36) in elderly patients taking pravastatin 40 mg once daily for 6 years compared with placebo.³

Unfortunately, no comparable evidence is available to guide practitioners in their care of older patients without known CHD. A 1993 report on results of the Framingham study showed the association between all-cause mortality and cholesterol level only in individuals younger than 50 years.⁴ Two other cohort studies showed an association between elevated cholesterol levels and increased CHD mortality.^5,6 It is unclear whether all-cause or CHD mortality is the better outcome to measure.

The best available evidence addressing the benefit of lowering lipid levels in persons with elevated cholesterol but without CHD is from the West of Scotland Coronary Prevention study, which included patients aged 45 to 64 years.⁷ This study showed a 0.5% reduction in CHD mortality (NNT = 200) and a 0.9% reduction in all-cause mortality (NNT = 111). Neither reduction reached statistical significance.

Several reports have demonstrated that statins safely and effectively lower cholesterol levels in patients aged 65 and older.^1-3,8,9 Moreover, statins do not decrease health-related quality of life.¹⁰ Approximately 1% to 4% of those who take statins experience side effects, including abnormal liver function, arthralgias, myalgias, rash, sinusitis, and diarrhea.

Recommendations from others

The National Cholesterol Education Program published its updated guidelines in 2001, lending support for statin treatment of elevated low-density lipoprotein cholesterol levels in selected men aged 65 or older and women aged 75 or older without CHD.¹¹ The target low-density lipoprotein level varied from 100 to 160 mg/dL depending on presence of other cardiac risk factors. The recommendation emphasized lifestyle changes, noninvasive testing for subclinical atherosclerosis, and consideration of treatment for individuals with extensive subclinical disease or multiple risk factors, rather than focusing merely on chronological age.

Clinical Commentary by Nicholas Solomos, MD, at http://www.fpin.org.

Evidence summary

Two randomized controlledtrials and 1 cohort study demonstrated a decrease in all-cause mortality in individuals aged 65 and older with known CHD by treating elevated cholesterol levels with either pravastatin or simvastatin.^1-3 The overall decrease in absolute risk of death was similar (range, 4.1%–6.2%; numbers needed to treat [NNT] = 17–25). The LIPID trial demonstrated a reduction in CHD-related death (relative risk [RR] = 0.76; 95% CI, 0.62–0.93; NNT = 37) and myocardial infarctions (RR = 0.74; 95% CI, 0.60–0.91; NNT = 36) in elderly patients taking pravastatin 40 mg once daily for 6 years compared with placebo.³

Unfortunately, no comparable evidence is available to guide practitioners in their care of older patients without known CHD. A 1993 report on results of the Framingham study showed the association between all-cause mortality and cholesterol level only in individuals younger than 50 years.⁴ Two other cohort studies showed an association between elevated cholesterol levels and increased CHD mortality.^5,6 It is unclear whether all-cause or CHD mortality is the better outcome to measure.

The best available evidence addressing the benefit of lowering lipid levels in persons with elevated cholesterol but without CHD is from the West of Scotland Coronary Prevention study, which included patients aged 45 to 64 years.⁷ This study showed a 0.5% reduction in CHD mortality (NNT = 200) and a 0.9% reduction in all-cause mortality (NNT = 111). Neither reduction reached statistical significance.

Several reports have demonstrated that statins safely and effectively lower cholesterol levels in patients aged 65 and older.^1-3,8,9 Moreover, statins do not decrease health-related quality of life.¹⁰ Approximately 1% to 4% of those who take statins experience side effects, including abnormal liver function, arthralgias, myalgias, rash, sinusitis, and diarrhea.

Recommendations from others

The National Cholesterol Education Program published its updated guidelines in 2001, lending support for statin treatment of elevated low-density lipoprotein cholesterol levels in selected men aged 65 or older and women aged 75 or older without CHD.¹¹ The target low-density lipoprotein level varied from 100 to 160 mg/dL depending on presence of other cardiac risk factors. The recommendation emphasized lifestyle changes, noninvasive testing for subclinical atherosclerosis, and consideration of treatment for individuals with extensive subclinical disease or multiple risk factors, rather than focusing merely on chronological age.

Clinical Commentary by Nicholas Solomos, MD, at http://www.fpin.org.

Evidence summary

Two randomized controlledtrials and 1 cohort study demonstrated a decrease in all-cause mortality in individuals aged 65 and older with known CHD by treating elevated cholesterol levels with either pravastatin or simvastatin.^1-3 The overall decrease in absolute risk of death was similar (range, 4.1%–6.2%; numbers needed to treat [NNT] = 17–25). The LIPID trial demonstrated a reduction in CHD-related death (relative risk [RR] = 0.76; 95% CI, 0.62–0.93; NNT = 37) and myocardial infarctions (RR = 0.74; 95% CI, 0.60–0.91; NNT = 36) in elderly patients taking pravastatin 40 mg once daily for 6 years compared with placebo.³

Unfortunately, no comparable evidence is available to guide practitioners in their care of older patients without known CHD. A 1993 report on results of the Framingham study showed the association between all-cause mortality and cholesterol level only in individuals younger than 50 years.⁴ Two other cohort studies showed an association between elevated cholesterol levels and increased CHD mortality.^5,6 It is unclear whether all-cause or CHD mortality is the better outcome to measure.

The best available evidence addressing the benefit of lowering lipid levels in persons with elevated cholesterol but without CHD is from the West of Scotland Coronary Prevention study, which included patients aged 45 to 64 years.⁷ This study showed a 0.5% reduction in CHD mortality (NNT = 200) and a 0.9% reduction in all-cause mortality (NNT = 111). Neither reduction reached statistical significance.

Several reports have demonstrated that statins safely and effectively lower cholesterol levels in patients aged 65 and older.^1-3,8,9 Moreover, statins do not decrease health-related quality of life.¹⁰ Approximately 1% to 4% of those who take statins experience side effects, including abnormal liver function, arthralgias, myalgias, rash, sinusitis, and diarrhea.

Recommendations from others

The National Cholesterol Education Program published its updated guidelines in 2001, lending support for statin treatment of elevated low-density lipoprotein cholesterol levels in selected men aged 65 or older and women aged 75 or older without CHD.¹¹ The target low-density lipoprotein level varied from 100 to 160 mg/dL depending on presence of other cardiac risk factors. The recommendation emphasized lifestyle changes, noninvasive testing for subclinical atherosclerosis, and consideration of treatment for individuals with extensive subclinical disease or multiple risk factors, rather than focusing merely on chronological age.

Clinical Commentary by Nicholas Solomos, MD, at http://www.fpin.org.

Evidence summary

A meta-analysis of 16 RCTs compared the efficacy of intranasal steroids and oral antihistamines for alleviating nasal, eye, and global allergy symptoms.¹ Intranasal steroids were superior to oral antihistamines for all patient-oriented nasal symptom and global symptom ratings. Eye symptom scores and adverse events were similar in each treatment group.

Several large RCTs have addressed whether combining the 2 classes of drugs would achieve greater symptom control. Only 1 study² found combination therapy to be superior. This RCT compared beclomethasone dipropionate with loratadine or placebo daily in 154 patients.² Total symptom scores were better for the combination group mainly due to improved relief from ocular symptoms.

Fluticasone propionate aqueous nasal spray (FPANS) was evaluated alone and in combination with cetirizine in a multicenter double-blind study of 454 patients.³ The mean symptom scores for nasal and eye symptoms were not significantly different between the 2 groups. A more recent RCT had similar results when comparing FPANS with loratadine and with combined therapy.⁴ This double-blinded placebo-controlled trial, which included 600 patients, measured patient- and clinician-rated total symptom scores, individual nasal symptom scores, and overall evaluations after 7 and 14 days of therapy. Although the symptom scores for the FPANS group were significantly lower than those in the loratadine and placebo groups, no significant difference in scores was found between the FPANS and combined groups. The results were the same for the quality-of-life questionnaire scores. In an RCT of 106 patients, budesonide nasal spray’s efficacy was tested against terfenadine alone and in combination; the nasal steroid alone was more effective than the histamine.⁵ Combining the 2 drugs yielded no significant improvements.

The newer nasal steroids such as fluticasone may be more effective because of their stronger affinities to glucocorticoid receptors, but no clinical evidence confirms this hypothesis.⁶

TABLE
Intranasal steroids for treating allergic rhinitis

Recommendations from others

The Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology recommends second-generation oral antihistamines for first-line therapy, but notes that nasal steroids are the most effective medication class for controlling allergy symptoms.⁷ The task force states that combination drug therapy may be tried. A monograph from the American Academy of Family Physicians notes the lack of consensus guidelines for first-line therapy and recommends that treatment be individualized.⁸ It states that combination therapy may be tried if monotherapy fails.

Clinical Commentaries by Tsveti Markova, MD, and John W. Tipton, MD, at http://www.FPIN.org.

Evidence summary

A meta-analysis of 16 RCTs compared the efficacy of intranasal steroids and oral antihistamines for alleviating nasal, eye, and global allergy symptoms.¹ Intranasal steroids were superior to oral antihistamines for all patient-oriented nasal symptom and global symptom ratings. Eye symptom scores and adverse events were similar in each treatment group.

Several large RCTs have addressed whether combining the 2 classes of drugs would achieve greater symptom control. Only 1 study² found combination therapy to be superior. This RCT compared beclomethasone dipropionate with loratadine or placebo daily in 154 patients.² Total symptom scores were better for the combination group mainly due to improved relief from ocular symptoms.

Fluticasone propionate aqueous nasal spray (FPANS) was evaluated alone and in combination with cetirizine in a multicenter double-blind study of 454 patients.³ The mean symptom scores for nasal and eye symptoms were not significantly different between the 2 groups. A more recent RCT had similar results when comparing FPANS with loratadine and with combined therapy.⁴ This double-blinded placebo-controlled trial, which included 600 patients, measured patient- and clinician-rated total symptom scores, individual nasal symptom scores, and overall evaluations after 7 and 14 days of therapy. Although the symptom scores for the FPANS group were significantly lower than those in the loratadine and placebo groups, no significant difference in scores was found between the FPANS and combined groups. The results were the same for the quality-of-life questionnaire scores. In an RCT of 106 patients, budesonide nasal spray’s efficacy was tested against terfenadine alone and in combination; the nasal steroid alone was more effective than the histamine.⁵ Combining the 2 drugs yielded no significant improvements.

The newer nasal steroids such as fluticasone may be more effective because of their stronger affinities to glucocorticoid receptors, but no clinical evidence confirms this hypothesis.⁶

TABLE
Intranasal steroids for treating allergic rhinitis

Recommendations from others

The Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology recommends second-generation oral antihistamines for first-line therapy, but notes that nasal steroids are the most effective medication class for controlling allergy symptoms.⁷ The task force states that combination drug therapy may be tried. A monograph from the American Academy of Family Physicians notes the lack of consensus guidelines for first-line therapy and recommends that treatment be individualized.⁸ It states that combination therapy may be tried if monotherapy fails.

Clinical Commentaries by Tsveti Markova, MD, and John W. Tipton, MD, at http://www.FPIN.org.

Evidence summary

A meta-analysis of 16 RCTs compared the efficacy of intranasal steroids and oral antihistamines for alleviating nasal, eye, and global allergy symptoms.¹ Intranasal steroids were superior to oral antihistamines for all patient-oriented nasal symptom and global symptom ratings. Eye symptom scores and adverse events were similar in each treatment group.

Several large RCTs have addressed whether combining the 2 classes of drugs would achieve greater symptom control. Only 1 study² found combination therapy to be superior. This RCT compared beclomethasone dipropionate with loratadine or placebo daily in 154 patients.² Total symptom scores were better for the combination group mainly due to improved relief from ocular symptoms.

Fluticasone propionate aqueous nasal spray (FPANS) was evaluated alone and in combination with cetirizine in a multicenter double-blind study of 454 patients.³ The mean symptom scores for nasal and eye symptoms were not significantly different between the 2 groups. A more recent RCT had similar results when comparing FPANS with loratadine and with combined therapy.⁴ This double-blinded placebo-controlled trial, which included 600 patients, measured patient- and clinician-rated total symptom scores, individual nasal symptom scores, and overall evaluations after 7 and 14 days of therapy. Although the symptom scores for the FPANS group were significantly lower than those in the loratadine and placebo groups, no significant difference in scores was found between the FPANS and combined groups. The results were the same for the quality-of-life questionnaire scores. In an RCT of 106 patients, budesonide nasal spray’s efficacy was tested against terfenadine alone and in combination; the nasal steroid alone was more effective than the histamine.⁵ Combining the 2 drugs yielded no significant improvements.

The newer nasal steroids such as fluticasone may be more effective because of their stronger affinities to glucocorticoid receptors, but no clinical evidence confirms this hypothesis.⁶

TABLE
Intranasal steroids for treating allergic rhinitis

Recommendations from others

The Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology recommends second-generation oral antihistamines for first-line therapy, but notes that nasal steroids are the most effective medication class for controlling allergy symptoms.⁷ The task force states that combination drug therapy may be tried. A monograph from the American Academy of Family Physicians notes the lack of consensus guidelines for first-line therapy and recommends that treatment be individualized.⁸ It states that combination therapy may be tried if monotherapy fails.

Clinical Commentaries by Tsveti Markova, MD, and John W. Tipton, MD, at http://www.FPIN.org.

Evidence summary

Sodium restriction is a mainstay of nonpharmacologic therapy for congestive heart failure, although no evidence proves that sodium restriction alone reduces morbidity and mortality.¹ Sodium restriction reduces hypertension^2,3 and left ventricular hypertrophy,⁴ both risk factors for congestive heart failure.

Studies of multifactorial interventions correlate reduced congestive heart failure morbidity with sodium restriction or dietary counseling. These results cannot be generalized to sodium restriction independent of the other nondrug interventions. A small RCT compared a program of exercise, cognitive therapy/stress management, salt restriction, and weight reduction to treating congestive heart failure with digoxin or placebo.⁵ The nondrug interventions improved functional capacity, body weight, and mood but not ejection fraction in patients with congestive heart failure.⁵ A systematic review of 6 RCTs showed that multidisciplinary heart failure disease management programs, which emphasized dietary counseling and/or sodium intake reduction, improved functional capacity, patient satisfaction, and quality of life.⁶

A large RCT that investigated how sodium reduction affects hypertension and frequency of cardiovascular events (including congestive heart failure) in the elderly did not show a significant difference in primary prevention of cardiovascular events between the sodium-restricted group and controls.^3,7 Two prospective cohort studies linked high sodium intake to cardiovascular mortality and all-cause mortality in overweight persons independent of other cardiovascular risk factors.^8,9

Recommendations from others

Physiological principles, observational studies, common practice, and expert opinion support sodium restriction for reducing edema and the need for diuretic agents in patients with congestive heart failure.¹ No clinical trial evidence favors a 2-g over a 3- to 4-g sodium restriction. See Table for common recommendations.

TABLE
Recommended sodium restrictions

Clinical Commentary by John Tipton, MD, at http://www.fpin.org.

Evidence summary

Sodium restriction is a mainstay of nonpharmacologic therapy for congestive heart failure, although no evidence proves that sodium restriction alone reduces morbidity and mortality.¹ Sodium restriction reduces hypertension^2,3 and left ventricular hypertrophy,⁴ both risk factors for congestive heart failure.

Studies of multifactorial interventions correlate reduced congestive heart failure morbidity with sodium restriction or dietary counseling. These results cannot be generalized to sodium restriction independent of the other nondrug interventions. A small RCT compared a program of exercise, cognitive therapy/stress management, salt restriction, and weight reduction to treating congestive heart failure with digoxin or placebo.⁵ The nondrug interventions improved functional capacity, body weight, and mood but not ejection fraction in patients with congestive heart failure.⁵ A systematic review of 6 RCTs showed that multidisciplinary heart failure disease management programs, which emphasized dietary counseling and/or sodium intake reduction, improved functional capacity, patient satisfaction, and quality of life.⁶

A large RCT that investigated how sodium reduction affects hypertension and frequency of cardiovascular events (including congestive heart failure) in the elderly did not show a significant difference in primary prevention of cardiovascular events between the sodium-restricted group and controls.^3,7 Two prospective cohort studies linked high sodium intake to cardiovascular mortality and all-cause mortality in overweight persons independent of other cardiovascular risk factors.^8,9

Recommendations from others

Physiological principles, observational studies, common practice, and expert opinion support sodium restriction for reducing edema and the need for diuretic agents in patients with congestive heart failure.¹ No clinical trial evidence favors a 2-g over a 3- to 4-g sodium restriction. See Table for common recommendations.

TABLE
Recommended sodium restrictions

Clinical Commentary by John Tipton, MD, at http://www.fpin.org.

Evidence summary

Sodium restriction is a mainstay of nonpharmacologic therapy for congestive heart failure, although no evidence proves that sodium restriction alone reduces morbidity and mortality.¹ Sodium restriction reduces hypertension^2,3 and left ventricular hypertrophy,⁴ both risk factors for congestive heart failure.

Studies of multifactorial interventions correlate reduced congestive heart failure morbidity with sodium restriction or dietary counseling. These results cannot be generalized to sodium restriction independent of the other nondrug interventions. A small RCT compared a program of exercise, cognitive therapy/stress management, salt restriction, and weight reduction to treating congestive heart failure with digoxin or placebo.⁵ The nondrug interventions improved functional capacity, body weight, and mood but not ejection fraction in patients with congestive heart failure.⁵ A systematic review of 6 RCTs showed that multidisciplinary heart failure disease management programs, which emphasized dietary counseling and/or sodium intake reduction, improved functional capacity, patient satisfaction, and quality of life.⁶

A large RCT that investigated how sodium reduction affects hypertension and frequency of cardiovascular events (including congestive heart failure) in the elderly did not show a significant difference in primary prevention of cardiovascular events between the sodium-restricted group and controls.^3,7 Two prospective cohort studies linked high sodium intake to cardiovascular mortality and all-cause mortality in overweight persons independent of other cardiovascular risk factors.^8,9

Recommendations from others

Physiological principles, observational studies, common practice, and expert opinion support sodium restriction for reducing edema and the need for diuretic agents in patients with congestive heart failure.¹ No clinical trial evidence favors a 2-g over a 3- to 4-g sodium restriction. See Table for common recommendations.

TABLE
Recommended sodium restrictions

Clinical Commentary by John Tipton, MD, at http://www.fpin.org.

Evidence summary

Naltrexone (50 mg qd), nalmefene (10–80 mg qd), and acamprosate (dose based on patient weight) are all superior to placebo and other agents such as the SSRIs, disulfiram, and serotonergic agents in reducing relapse rates and the phenomena of craving and in increasing abstinence rates.^1-6 For example, naltrexone reduces relapse rates by one half to two thirds.^4,6 However, these outcomes apply only to patients who completed the study protocol; noncompleters accounted for up to more than 50% of study participants. When compared with placebo, nalmefene taken for 3 to 24 months significantly reduced relapse without affecting abstinence rates or cravings.³ When compared with placebo, disulfiram failed to significantly increase abstinence rates or decrease relapse rates or cravings.²

In European studies, acamprosate taken for 3 to 24 months significantly increased abstinence rates, but did not significantly decrease relapse or cravings as compared with placebo.³ Fifteen studies evaluating serotonergic agents, lithium, and SSRIs (including citalopram, viqualine, fluoxetine, and others) taken for 2 to 12 weeks have shown promise for increasing abstinence rates and decreasing cravings in alcoholic patients with coexisting psychiatric conditions such as depression, anxiety, and bipolar disorder.^2,7,8 Studies combining pharmacologic intervention with Alcoholics Anonymous’s 12-step program or psychological interventions showed the most significant effects on decreasing cravings and relapse rates and increasing abstinence rates.^2,3,6,9-12

TABLE
Grade of recommendation based on the evidence

Recommendations from others

According to the American Society of Addiction Medicine, patients who comply with a combination of medication, education, and counseling have favorable short-term and long-term benefits.¹ Naltraxone and acamprosate effectively reduce cravings and increase abstinence.

Clinical Commentary by William Chavey, MD, at http://www.fpin.org.

Evidence summary

Naltrexone (50 mg qd), nalmefene (10–80 mg qd), and acamprosate (dose based on patient weight) are all superior to placebo and other agents such as the SSRIs, disulfiram, and serotonergic agents in reducing relapse rates and the phenomena of craving and in increasing abstinence rates.^1-6 For example, naltrexone reduces relapse rates by one half to two thirds.^4,6 However, these outcomes apply only to patients who completed the study protocol; noncompleters accounted for up to more than 50% of study participants. When compared with placebo, nalmefene taken for 3 to 24 months significantly reduced relapse without affecting abstinence rates or cravings.³ When compared with placebo, disulfiram failed to significantly increase abstinence rates or decrease relapse rates or cravings.²

In European studies, acamprosate taken for 3 to 24 months significantly increased abstinence rates, but did not significantly decrease relapse or cravings as compared with placebo.³ Fifteen studies evaluating serotonergic agents, lithium, and SSRIs (including citalopram, viqualine, fluoxetine, and others) taken for 2 to 12 weeks have shown promise for increasing abstinence rates and decreasing cravings in alcoholic patients with coexisting psychiatric conditions such as depression, anxiety, and bipolar disorder.^2,7,8 Studies combining pharmacologic intervention with Alcoholics Anonymous’s 12-step program or psychological interventions showed the most significant effects on decreasing cravings and relapse rates and increasing abstinence rates.^2,3,6,9-12

TABLE
Grade of recommendation based on the evidence

Recommendations from others

According to the American Society of Addiction Medicine, patients who comply with a combination of medication, education, and counseling have favorable short-term and long-term benefits.¹ Naltraxone and acamprosate effectively reduce cravings and increase abstinence.

Clinical Commentary by William Chavey, MD, at http://www.fpin.org.

Evidence summary

Naltrexone (50 mg qd), nalmefene (10–80 mg qd), and acamprosate (dose based on patient weight) are all superior to placebo and other agents such as the SSRIs, disulfiram, and serotonergic agents in reducing relapse rates and the phenomena of craving and in increasing abstinence rates.^1-6 For example, naltrexone reduces relapse rates by one half to two thirds.^4,6 However, these outcomes apply only to patients who completed the study protocol; noncompleters accounted for up to more than 50% of study participants. When compared with placebo, nalmefene taken for 3 to 24 months significantly reduced relapse without affecting abstinence rates or cravings.³ When compared with placebo, disulfiram failed to significantly increase abstinence rates or decrease relapse rates or cravings.²

In European studies, acamprosate taken for 3 to 24 months significantly increased abstinence rates, but did not significantly decrease relapse or cravings as compared with placebo.³ Fifteen studies evaluating serotonergic agents, lithium, and SSRIs (including citalopram, viqualine, fluoxetine, and others) taken for 2 to 12 weeks have shown promise for increasing abstinence rates and decreasing cravings in alcoholic patients with coexisting psychiatric conditions such as depression, anxiety, and bipolar disorder.^2,7,8 Studies combining pharmacologic intervention with Alcoholics Anonymous’s 12-step program or psychological interventions showed the most significant effects on decreasing cravings and relapse rates and increasing abstinence rates.^2,3,6,9-12

TABLE
Grade of recommendation based on the evidence

Recommendations from others

According to the American Society of Addiction Medicine, patients who comply with a combination of medication, education, and counseling have favorable short-term and long-term benefits.¹ Naltraxone and acamprosate effectively reduce cravings and increase abstinence.

Clinical Commentary by William Chavey, MD, at http://www.fpin.org.

Evidence summary

A randomized, double-blinded, placebo-controlled study in 1496 subjects examined side-effect rates of 3 iron salt formulations using equal dosages of elemental iron (Table).¹ Gastrointestinal (GI) side-effect rates were not significantly different. The side-effect rate in the ferrous sulfate group (23%) was significantly different from that of the placebo group (14%); thus, for every 11 patients treated with ferrous sulfate, 1 patient would have GI side effects attributable to the iron salt (number needed to harm [NNH] = 11).

Two formulations—controlled-release iron preparations and polysaccharide–iron complexes—decrease the amount of iron presented to the proximal GI tract. Three large randomized trials assessed tolerability of controlled-release iron preparations compared with ferrous sulfate.^2–4 The only double-blinded study found a lower rate of nausea and epigastric pain in the controlled-release iron formulation among 1376 blood donors receiving 200 mg/day elemental iron (3.3% vs 6.4%, P < .05, NNH = ~32).² A nonblinded randomized trial of 543 non-anemic adult patients taking 50 mg/day elemental iron also found a lower rate of stomach-related side effects in the controlled-release group (12.2% vs 27.2%, P < .001, NNH = ~7).³ However, none of the 3 studies showed a difference in the discontinuation rates between the 2 iron formulations. Comparative constipation rates among the trials were conflicting.

Two small, nonblinded, randomized trials of polysaccharide–iron complexes reported conflicting results. A study of 159 subjects found fewer subjects discontinuing the polysaccharide–iron complex taken with meals than ferrous sulfate taken on an empty stomach.⁵ A study of 60 subjects taking both preparations on an empty stomach found no difference in side-effect rates.⁶ Two small, randomized, blinded studies found no difference in rates of GI side effects between carbonyl iron and ferrous sulfate.^7,8

TABLE
Representative average wholesale prices* for various iron supplement formulations

Recommendations from others

Wintrobe’s Clinical Hematology⁹ and Williams Hematology¹⁰ recommend ferrous sulfate as the standard oral iron preparation, and assert that claims of improved tolerability of one oral iron preparation over another have not been substantiated.

Clinical Commentary by Andrea Gordon, MD, at http://www.fpin.org.

Evidence summary

A randomized, double-blinded, placebo-controlled study in 1496 subjects examined side-effect rates of 3 iron salt formulations using equal dosages of elemental iron (Table).¹ Gastrointestinal (GI) side-effect rates were not significantly different. The side-effect rate in the ferrous sulfate group (23%) was significantly different from that of the placebo group (14%); thus, for every 11 patients treated with ferrous sulfate, 1 patient would have GI side effects attributable to the iron salt (number needed to harm [NNH] = 11).

Two formulations—controlled-release iron preparations and polysaccharide–iron complexes—decrease the amount of iron presented to the proximal GI tract. Three large randomized trials assessed tolerability of controlled-release iron preparations compared with ferrous sulfate.^2–4 The only double-blinded study found a lower rate of nausea and epigastric pain in the controlled-release iron formulation among 1376 blood donors receiving 200 mg/day elemental iron (3.3% vs 6.4%, P < .05, NNH = ~32).² A nonblinded randomized trial of 543 non-anemic adult patients taking 50 mg/day elemental iron also found a lower rate of stomach-related side effects in the controlled-release group (12.2% vs 27.2%, P < .001, NNH = ~7).³ However, none of the 3 studies showed a difference in the discontinuation rates between the 2 iron formulations. Comparative constipation rates among the trials were conflicting.

Two small, nonblinded, randomized trials of polysaccharide–iron complexes reported conflicting results. A study of 159 subjects found fewer subjects discontinuing the polysaccharide–iron complex taken with meals than ferrous sulfate taken on an empty stomach.⁵ A study of 60 subjects taking both preparations on an empty stomach found no difference in side-effect rates.⁶ Two small, randomized, blinded studies found no difference in rates of GI side effects between carbonyl iron and ferrous sulfate.^7,8

TABLE
Representative average wholesale prices* for various iron supplement formulations

Recommendations from others

Wintrobe’s Clinical Hematology⁹ and Williams Hematology¹⁰ recommend ferrous sulfate as the standard oral iron preparation, and assert that claims of improved tolerability of one oral iron preparation over another have not been substantiated.

Clinical Commentary by Andrea Gordon, MD, at http://www.fpin.org.

Evidence summary

A randomized, double-blinded, placebo-controlled study in 1496 subjects examined side-effect rates of 3 iron salt formulations using equal dosages of elemental iron (Table).¹ Gastrointestinal (GI) side-effect rates were not significantly different. The side-effect rate in the ferrous sulfate group (23%) was significantly different from that of the placebo group (14%); thus, for every 11 patients treated with ferrous sulfate, 1 patient would have GI side effects attributable to the iron salt (number needed to harm [NNH] = 11).

Two formulations—controlled-release iron preparations and polysaccharide–iron complexes—decrease the amount of iron presented to the proximal GI tract. Three large randomized trials assessed tolerability of controlled-release iron preparations compared with ferrous sulfate.^2–4 The only double-blinded study found a lower rate of nausea and epigastric pain in the controlled-release iron formulation among 1376 blood donors receiving 200 mg/day elemental iron (3.3% vs 6.4%, P < .05, NNH = ~32).² A nonblinded randomized trial of 543 non-anemic adult patients taking 50 mg/day elemental iron also found a lower rate of stomach-related side effects in the controlled-release group (12.2% vs 27.2%, P < .001, NNH = ~7).³ However, none of the 3 studies showed a difference in the discontinuation rates between the 2 iron formulations. Comparative constipation rates among the trials were conflicting.

Two small, nonblinded, randomized trials of polysaccharide–iron complexes reported conflicting results. A study of 159 subjects found fewer subjects discontinuing the polysaccharide–iron complex taken with meals than ferrous sulfate taken on an empty stomach.⁵ A study of 60 subjects taking both preparations on an empty stomach found no difference in side-effect rates.⁶ Two small, randomized, blinded studies found no difference in rates of GI side effects between carbonyl iron and ferrous sulfate.^7,8

TABLE
Representative average wholesale prices* for various iron supplement formulations

Recommendations from others

Wintrobe’s Clinical Hematology⁹ and Williams Hematology¹⁰ recommend ferrous sulfate as the standard oral iron preparation, and assert that claims of improved tolerability of one oral iron preparation over another have not been substantiated.

Clinical Commentary by Andrea Gordon, MD, at http://www.fpin.org.