Sarah Safranek, MLIS

Evidence summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival² (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure³ (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II⁴ (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial⁵ (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial¹ demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis.⁶

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest⁷ included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing.⁸

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease.⁹ A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations.¹⁰ A trend toward improved survival was noted but did not reach statistical significance.

TABLE
Selected trials of beta-blockers for systolic dysfunction

Recommendations from others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Chronic heart failure
Complementary actions of diuretics, ACE inhibitors, and beta blockers
Evidence shows that the combination of diuretics, ACE inhibitors, and 1 of 3 beta-blockers—carvedilol, metoprolol, bisoprolol—is more effective than just diuretics plus ACE inhibitors. The clinical effect of their combined actions is reduced workload on the failing heart.

Evidence summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival² (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure³ (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II⁴ (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial⁵ (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial¹ demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis.⁶

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest⁷ included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing.⁸

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease.⁹ A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations.¹⁰ A trend toward improved survival was noted but did not reach statistical significance.

TABLE
Selected trials of beta-blockers for systolic dysfunction

Recommendations from others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Chronic heart failure
Complementary actions of diuretics, ACE inhibitors, and beta blockers
Evidence shows that the combination of diuretics, ACE inhibitors, and 1 of 3 beta-blockers—carvedilol, metoprolol, bisoprolol—is more effective than just diuretics plus ACE inhibitors. The clinical effect of their combined actions is reduced workload on the failing heart.

Evidence summary

The Table shows the 5 largest trials of beta-blockers in systolic dysfunction, including patients with both ischemic and nonischemic heart disease. In all trials, the majority of subjects were taking diuretics and either an ACE inhibitor or angiotensin receptor blocker.

The Carvedilol Prospective Randomized Cumulative Survival² (COPERNICUS) trial, Metoprolol CR/XL Randomized Intervention Trial in Heart Failure³ (MERIT-HF), and Cardiac Insufficiency Bisoprolol Study II⁴ (CIBIS-II) all showed similar reductions in mortality in moderately ill patients with heart failure.

In contrast, the Beta-Blocker Evaluation of Survival Trial⁵ (BEST) demonstrated no effect with bucindolol. This suggests there may be differences in effectiveness among beta-blockers in reducing mortality in heart failure, and that it would be unwise to assume that protection is a class effect. We found no meta-analysis that pooled data on individual drugs for comparison purposes.

The US Carvedilol trial¹ demonstrated a larger reduction in mortality than that seen in other beta-blocker trials. However, it had several methodologic problems: it was a composite of 4 smaller studies that used exercise tolerance as the primary endpoint; median duration of data collection on subjects was only 6 months; it included many minimally symptomatic patients; the actual number of deaths was small (producing a wide confidence interval); and subjects who did not survive the run-in phase were excluded from analysis.⁶

Three randomized controlled trials have compared carvedilol and metoprolol head-to-head. The largest⁷ included 150 subjects with ejection fractions below 35% who were randomized to 1 of the 2 drugs and followed for more than 3 years. Symptom scores and quality of life assessments were similar in the 2 groups. A trend toward lower mortality in the carvedilol group did not reach statistical significance. Peak oxygen uptake during exercise was greater in the metoprolol group. The carvedilol group had a statistically greater improvement in ejection fraction (+10.9 ± 11.0 vs +7.2 ± 7.7 at rest). The Carvedilol or Metoprolol European Trial (COMET), a larger head-to-head trial of carvedilol and metoprolol (N=3029), is ongoing.⁸

No large studies of older beta-blockers adequately assess mortality in heart failure. One study of propranolol (N=158) showed a 27% reduction in mortality in mild heart failure in the setting of ischemic heart disease.⁹ A study of atenolol versus placebo in subjects with ejection fraction ≤25% from various causes (N=100) was halted early when atenolol produced a 50% reduction in worsening heart failure and a 71% reduction in cardiac hospitalizations.¹⁰ A trend toward improved survival was noted but did not reach statistical significance.

TABLE
Selected trials of beta-blockers for systolic dysfunction

Recommendations from others

We found no guidelines that specifically endorsed one beta-blocker over another for heart failure.

Chronic heart failure
Complementary actions of diuretics, ACE inhibitors, and beta blockers
Evidence shows that the combination of diuretics, ACE inhibitors, and 1 of 3 beta-blockers—carvedilol, metoprolol, bisoprolol—is more effective than just diuretics plus ACE inhibitors. The clinical effect of their combined actions is reduced workload on the failing heart.

Evidence summary

Metlay and colleagues¹ found only 4 high-quality, prospective cohort trials evaluating the sensitivity and specificity of the clinical history and physical examination in pneumonia. In each of the 4 studies, the reference standard for the diagnosis of pneumonia was a new infiltrate on chest radiograph. Subjects were community-dwelling adults with acute cough who were seen in ambulatory settings, and who had an average pneumonia prevalence of 7% (range, 3%–38%).¹ Although no study specifically addressed the interobserver reliability of the history and physical examination findings in pneumonia, other studies of chest findings typically found variable reproducibility. In a study by Spiteri and associates,² 24 physicians examined 24 patients with a variety of respiratory conditions: only 4 had pneumonia on chest x-ray. The most reliable findings (dullness to percussion and wheezing) had only fair agreement among examiners (kappa approximately 0.5).

Nine symptoms (cough, dyspnea, sputum production, subjective fever, chills, night sweats, myalgias, sore throat, and rhinorrhea) and 3 items in the past medical history (asthma, immunosuppression, and dementia) were associated with pneumonia. For most elements of history, both the positive and negative likelihood ratios (LR+, LR−) were in the indeterminate range of 0.5 to 2.0. No single feature was sufficient to either rule in or rule out the diagnosis.¹

Regarding the physical examination, tachypnea, tachycardia, and fever had LR+s between 1.5 and 2.4 in an ambulatory setting. In one study, the absence of any vital sign abnormalities reduced the likelihood of pneumonia substantially (LR− = 0.18), but did not rule out the diagnosis completely.¹ Egophony had an LR+ of 5.3. Other physical findings (rhonchi, crackles, decreased breath sounds, dullness to percussion, and bronchial breath sounds) yielded LR+s from 1.5 to 3.5, respectively. Most individual findings were insufficient to diagnose pneumonia. For example, if the baseline prevalence of pneumonia was 5%, the presence of crackles raised the probability to 10% and their absence decreased the probability to 3%.

The sensitivity and specificity of clinical diagnosis varied with the prevalence of pneumonia. In a general practice setting, 20 of 402 patients with cough were diagnosed with pneumonia by chest x-ray.³ Physicians correctly diagnosed 7 patients clinically, and incorrectly diagnosed pneumonia in 22 additional patients.³ At a Veterans Administration hospital, a prospective cohort of 52 men with acute cough and change in sputum production underwent sequential blinded examination by 3 physicians. Rales and bronchial breath sounds were common, and chest x-ray confirmed pneumonia in 28 patients. Sensitivity of clinical diagnosis ranged from 47% to 69%, and specificity from 58% to 75%.⁴

Several researchers improved diagnostic accuracy by combining multiple elements from the history and physical examination. For example, according to Metlay and colleagues,¹ Heckerling et al calculated the probability of pneumonia if up to 5 predictors were present. However, if the prevalence of pneumonia in a primary care population is 5%, the presence of all 5 predictors raises the probability of pneumonia only to 53%.¹ The absence of 4 of the 5 findings (fever >37.8°C, heart rate >100 beats per minute, decreased breath sounds, crackles) reduces the risk of pneumonia to 1%, thus eliminating the need for radiography or antibiotics in most situations. If the patient also has asthma, the risk drops even further.

Recommendations from others

The Infectious Diseases Society of North America states that a chest x-ray is necessary for accurate diagnosis. In otherwise healthy adults with acute cough illness, antibiotic therapy is indicated only for pneumonia. A normal chest x-ray obviates the need for antibiotics.^5,6

Evidence summary

Metlay and colleagues¹ found only 4 high-quality, prospective cohort trials evaluating the sensitivity and specificity of the clinical history and physical examination in pneumonia. In each of the 4 studies, the reference standard for the diagnosis of pneumonia was a new infiltrate on chest radiograph. Subjects were community-dwelling adults with acute cough who were seen in ambulatory settings, and who had an average pneumonia prevalence of 7% (range, 3%–38%).¹ Although no study specifically addressed the interobserver reliability of the history and physical examination findings in pneumonia, other studies of chest findings typically found variable reproducibility. In a study by Spiteri and associates,² 24 physicians examined 24 patients with a variety of respiratory conditions: only 4 had pneumonia on chest x-ray. The most reliable findings (dullness to percussion and wheezing) had only fair agreement among examiners (kappa approximately 0.5).

Nine symptoms (cough, dyspnea, sputum production, subjective fever, chills, night sweats, myalgias, sore throat, and rhinorrhea) and 3 items in the past medical history (asthma, immunosuppression, and dementia) were associated with pneumonia. For most elements of history, both the positive and negative likelihood ratios (LR+, LR−) were in the indeterminate range of 0.5 to 2.0. No single feature was sufficient to either rule in or rule out the diagnosis.¹

Regarding the physical examination, tachypnea, tachycardia, and fever had LR+s between 1.5 and 2.4 in an ambulatory setting. In one study, the absence of any vital sign abnormalities reduced the likelihood of pneumonia substantially (LR− = 0.18), but did not rule out the diagnosis completely.¹ Egophony had an LR+ of 5.3. Other physical findings (rhonchi, crackles, decreased breath sounds, dullness to percussion, and bronchial breath sounds) yielded LR+s from 1.5 to 3.5, respectively. Most individual findings were insufficient to diagnose pneumonia. For example, if the baseline prevalence of pneumonia was 5%, the presence of crackles raised the probability to 10% and their absence decreased the probability to 3%.

The sensitivity and specificity of clinical diagnosis varied with the prevalence of pneumonia. In a general practice setting, 20 of 402 patients with cough were diagnosed with pneumonia by chest x-ray.³ Physicians correctly diagnosed 7 patients clinically, and incorrectly diagnosed pneumonia in 22 additional patients.³ At a Veterans Administration hospital, a prospective cohort of 52 men with acute cough and change in sputum production underwent sequential blinded examination by 3 physicians. Rales and bronchial breath sounds were common, and chest x-ray confirmed pneumonia in 28 patients. Sensitivity of clinical diagnosis ranged from 47% to 69%, and specificity from 58% to 75%.⁴

Several researchers improved diagnostic accuracy by combining multiple elements from the history and physical examination. For example, according to Metlay and colleagues,¹ Heckerling et al calculated the probability of pneumonia if up to 5 predictors were present. However, if the prevalence of pneumonia in a primary care population is 5%, the presence of all 5 predictors raises the probability of pneumonia only to 53%.¹ The absence of 4 of the 5 findings (fever >37.8°C, heart rate >100 beats per minute, decreased breath sounds, crackles) reduces the risk of pneumonia to 1%, thus eliminating the need for radiography or antibiotics in most situations. If the patient also has asthma, the risk drops even further.

Recommendations from others

The Infectious Diseases Society of North America states that a chest x-ray is necessary for accurate diagnosis. In otherwise healthy adults with acute cough illness, antibiotic therapy is indicated only for pneumonia. A normal chest x-ray obviates the need for antibiotics.^5,6

Evidence summary

Metlay and colleagues¹ found only 4 high-quality, prospective cohort trials evaluating the sensitivity and specificity of the clinical history and physical examination in pneumonia. In each of the 4 studies, the reference standard for the diagnosis of pneumonia was a new infiltrate on chest radiograph. Subjects were community-dwelling adults with acute cough who were seen in ambulatory settings, and who had an average pneumonia prevalence of 7% (range, 3%–38%).¹ Although no study specifically addressed the interobserver reliability of the history and physical examination findings in pneumonia, other studies of chest findings typically found variable reproducibility. In a study by Spiteri and associates,² 24 physicians examined 24 patients with a variety of respiratory conditions: only 4 had pneumonia on chest x-ray. The most reliable findings (dullness to percussion and wheezing) had only fair agreement among examiners (kappa approximately 0.5).

Nine symptoms (cough, dyspnea, sputum production, subjective fever, chills, night sweats, myalgias, sore throat, and rhinorrhea) and 3 items in the past medical history (asthma, immunosuppression, and dementia) were associated with pneumonia. For most elements of history, both the positive and negative likelihood ratios (LR+, LR−) were in the indeterminate range of 0.5 to 2.0. No single feature was sufficient to either rule in or rule out the diagnosis.¹

Regarding the physical examination, tachypnea, tachycardia, and fever had LR+s between 1.5 and 2.4 in an ambulatory setting. In one study, the absence of any vital sign abnormalities reduced the likelihood of pneumonia substantially (LR− = 0.18), but did not rule out the diagnosis completely.¹ Egophony had an LR+ of 5.3. Other physical findings (rhonchi, crackles, decreased breath sounds, dullness to percussion, and bronchial breath sounds) yielded LR+s from 1.5 to 3.5, respectively. Most individual findings were insufficient to diagnose pneumonia. For example, if the baseline prevalence of pneumonia was 5%, the presence of crackles raised the probability to 10% and their absence decreased the probability to 3%.

The sensitivity and specificity of clinical diagnosis varied with the prevalence of pneumonia. In a general practice setting, 20 of 402 patients with cough were diagnosed with pneumonia by chest x-ray.³ Physicians correctly diagnosed 7 patients clinically, and incorrectly diagnosed pneumonia in 22 additional patients.³ At a Veterans Administration hospital, a prospective cohort of 52 men with acute cough and change in sputum production underwent sequential blinded examination by 3 physicians. Rales and bronchial breath sounds were common, and chest x-ray confirmed pneumonia in 28 patients. Sensitivity of clinical diagnosis ranged from 47% to 69%, and specificity from 58% to 75%.⁴

Several researchers improved diagnostic accuracy by combining multiple elements from the history and physical examination. For example, according to Metlay and colleagues,¹ Heckerling et al calculated the probability of pneumonia if up to 5 predictors were present. However, if the prevalence of pneumonia in a primary care population is 5%, the presence of all 5 predictors raises the probability of pneumonia only to 53%.¹ The absence of 4 of the 5 findings (fever >37.8°C, heart rate >100 beats per minute, decreased breath sounds, crackles) reduces the risk of pneumonia to 1%, thus eliminating the need for radiography or antibiotics in most situations. If the patient also has asthma, the risk drops even further.

Recommendations from others

The Infectious Diseases Society of North America states that a chest x-ray is necessary for accurate diagnosis. In otherwise healthy adults with acute cough illness, antibiotic therapy is indicated only for pneumonia. A normal chest x-ray obviates the need for antibiotics.^5,6