William J. Kerns, MD

Evidence summary

Diastolic heart failure, defined as classic evidence of congestive heart failure with “preserved” or “normal” left ventricular ejection fraction (LVEF),¹ is often encountered in medical practice. Unfortunately, studies that address diastolic heart failure don’t use a uniform ejection fraction to define preserved systolic function. Treatments for diastolic failure have included diuretics, ACEIs, ARBs, beta-blockers, calcium channel blockers, digoxin, and statins.

ACEIs decrease mortality
One small prospective study in France enrolled 358 subjects who were admitted for a first episode of heart failure but had ejection fractions ≥50%. Patients were separated into 2 groups based on whether or not they were prescribed an ACEI—lisinopril (32.3%), ramipril (25.6%), perindopril (23.8%), or enalapril (5.5%)—at discharge. The authors attempted to adjust for selection bias by developing a propensity score and comparing matched controls.

Patients who had been prescribed ACEIs had a 10% reduction in 5-year mortality (number needed to treat [NNT]=10).²

ARBs produce mixed outcomes
Evidence regarding outcomes with ARBs is not clear cut. Candesartan was studied in the CHARM-Preserved Trial, which enrolled 3023 patients from 618 centers in 26 countries with New York Heart Association functional class II to class IV congestive heart failure of at least 4 weeks’ duration and LVEF >40%.³ The treatment group showed a significant decrease in hospital admission for congestive heart failure (NNT=30, covariate adjusted), but no improvement in mortality.

Losartan improved exercise duration and quality of life compared with placebo or hydrochlorothiazide in 2 small RCTs totaling 60 patients.^4,5

In the I-PRESERVE Trial, irbesartan didn’t improve primary or secondary outcomes, including death from any cause or hospitalization for a cardiovascular cause (P=.35), death or hospitalization from heart failure, or quality of life (P=.44).⁶ However, concomitant use of other medications could have been a factor because 39%, 28%, and 73% of patients in the irbesartan group and 40%, 29%, and 73% in the placebo group were taking an ACEI, spironolactone, or a beta-blocker, respectively.

Propranolol reduces mortality, but data on other beta-blockers are lacking
One prospective randomized trial of heart failure patients with LVEF ≥40% already treated with an ACEI and a diuretic, found that propranolol reduced total mortality by 35% after 1 year of therapy (absolute risk reduction=20%; NNT=5).⁷ Studies of other beta-blockers haven’t reported patient-oriented outcomes as an end point.

Diuretics alone outperform diuretics plus other meds
A study that randomized 150 elderly patients with symptomatic heart failure and LVEF >45% to diuretics alone (80% were given furosemide), diuretics plus irbesartan, or diuretics plus ramipril found that diuretics alone improved the quality of life score by 46% after 52 weeks and also improved symptoms of heart failure.⁸ No significant symptomatic or other benefit was noted with the addition of irbesartan or ramipril.

Statins are linked to lower mortality
A prospective cohort study followed 137 patients with heart failure and ejection fraction >50% for a mean of 21 months.⁹ After adjustment for differences in baseline clinical variables between groups, therapy with various statins (68% of patients were on atorvastatin) was associated with lower mortality (NNT=5).

Little evidence exists to support the use of calcium channel blockers, digoxin, or other vasodilators in diastolic heart failure.

Recommendations

The TABLE summarizes recommendations of the American College of Cardiology Foundation and the American Heart Association.¹

TABLE
Treating the patient with heart failure and normal LVEF: Recommendations from the ACCF and AHA

Evidence summary

Diastolic heart failure, defined as classic evidence of congestive heart failure with “preserved” or “normal” left ventricular ejection fraction (LVEF),¹ is often encountered in medical practice. Unfortunately, studies that address diastolic heart failure don’t use a uniform ejection fraction to define preserved systolic function. Treatments for diastolic failure have included diuretics, ACEIs, ARBs, beta-blockers, calcium channel blockers, digoxin, and statins.

ACEIs decrease mortality
One small prospective study in France enrolled 358 subjects who were admitted for a first episode of heart failure but had ejection fractions ≥50%. Patients were separated into 2 groups based on whether or not they were prescribed an ACEI—lisinopril (32.3%), ramipril (25.6%), perindopril (23.8%), or enalapril (5.5%)—at discharge. The authors attempted to adjust for selection bias by developing a propensity score and comparing matched controls.

Patients who had been prescribed ACEIs had a 10% reduction in 5-year mortality (number needed to treat [NNT]=10).²

ARBs produce mixed outcomes
Evidence regarding outcomes with ARBs is not clear cut. Candesartan was studied in the CHARM-Preserved Trial, which enrolled 3023 patients from 618 centers in 26 countries with New York Heart Association functional class II to class IV congestive heart failure of at least 4 weeks’ duration and LVEF >40%.³ The treatment group showed a significant decrease in hospital admission for congestive heart failure (NNT=30, covariate adjusted), but no improvement in mortality.

Losartan improved exercise duration and quality of life compared with placebo or hydrochlorothiazide in 2 small RCTs totaling 60 patients.^4,5

In the I-PRESERVE Trial, irbesartan didn’t improve primary or secondary outcomes, including death from any cause or hospitalization for a cardiovascular cause (P=.35), death or hospitalization from heart failure, or quality of life (P=.44).⁶ However, concomitant use of other medications could have been a factor because 39%, 28%, and 73% of patients in the irbesartan group and 40%, 29%, and 73% in the placebo group were taking an ACEI, spironolactone, or a beta-blocker, respectively.

Propranolol reduces mortality, but data on other beta-blockers are lacking
One prospective randomized trial of heart failure patients with LVEF ≥40% already treated with an ACEI and a diuretic, found that propranolol reduced total mortality by 35% after 1 year of therapy (absolute risk reduction=20%; NNT=5).⁷ Studies of other beta-blockers haven’t reported patient-oriented outcomes as an end point.

Diuretics alone outperform diuretics plus other meds
A study that randomized 150 elderly patients with symptomatic heart failure and LVEF >45% to diuretics alone (80% were given furosemide), diuretics plus irbesartan, or diuretics plus ramipril found that diuretics alone improved the quality of life score by 46% after 52 weeks and also improved symptoms of heart failure.⁸ No significant symptomatic or other benefit was noted with the addition of irbesartan or ramipril.

Statins are linked to lower mortality
A prospective cohort study followed 137 patients with heart failure and ejection fraction >50% for a mean of 21 months.⁹ After adjustment for differences in baseline clinical variables between groups, therapy with various statins (68% of patients were on atorvastatin) was associated with lower mortality (NNT=5).

Little evidence exists to support the use of calcium channel blockers, digoxin, or other vasodilators in diastolic heart failure.

Recommendations

The TABLE summarizes recommendations of the American College of Cardiology Foundation and the American Heart Association.¹

TABLE
Treating the patient with heart failure and normal LVEF: Recommendations from the ACCF and AHA

Evidence summary

Diastolic heart failure, defined as classic evidence of congestive heart failure with “preserved” or “normal” left ventricular ejection fraction (LVEF),¹ is often encountered in medical practice. Unfortunately, studies that address diastolic heart failure don’t use a uniform ejection fraction to define preserved systolic function. Treatments for diastolic failure have included diuretics, ACEIs, ARBs, beta-blockers, calcium channel blockers, digoxin, and statins.

ACEIs decrease mortality
One small prospective study in France enrolled 358 subjects who were admitted for a first episode of heart failure but had ejection fractions ≥50%. Patients were separated into 2 groups based on whether or not they were prescribed an ACEI—lisinopril (32.3%), ramipril (25.6%), perindopril (23.8%), or enalapril (5.5%)—at discharge. The authors attempted to adjust for selection bias by developing a propensity score and comparing matched controls.

Patients who had been prescribed ACEIs had a 10% reduction in 5-year mortality (number needed to treat [NNT]=10).²

ARBs produce mixed outcomes
Evidence regarding outcomes with ARBs is not clear cut. Candesartan was studied in the CHARM-Preserved Trial, which enrolled 3023 patients from 618 centers in 26 countries with New York Heart Association functional class II to class IV congestive heart failure of at least 4 weeks’ duration and LVEF >40%.³ The treatment group showed a significant decrease in hospital admission for congestive heart failure (NNT=30, covariate adjusted), but no improvement in mortality.

Losartan improved exercise duration and quality of life compared with placebo or hydrochlorothiazide in 2 small RCTs totaling 60 patients.^4,5

In the I-PRESERVE Trial, irbesartan didn’t improve primary or secondary outcomes, including death from any cause or hospitalization for a cardiovascular cause (P=.35), death or hospitalization from heart failure, or quality of life (P=.44).⁶ However, concomitant use of other medications could have been a factor because 39%, 28%, and 73% of patients in the irbesartan group and 40%, 29%, and 73% in the placebo group were taking an ACEI, spironolactone, or a beta-blocker, respectively.

Propranolol reduces mortality, but data on other beta-blockers are lacking
One prospective randomized trial of heart failure patients with LVEF ≥40% already treated with an ACEI and a diuretic, found that propranolol reduced total mortality by 35% after 1 year of therapy (absolute risk reduction=20%; NNT=5).⁷ Studies of other beta-blockers haven’t reported patient-oriented outcomes as an end point.

Diuretics alone outperform diuretics plus other meds
A study that randomized 150 elderly patients with symptomatic heart failure and LVEF >45% to diuretics alone (80% were given furosemide), diuretics plus irbesartan, or diuretics plus ramipril found that diuretics alone improved the quality of life score by 46% after 52 weeks and also improved symptoms of heart failure.⁸ No significant symptomatic or other benefit was noted with the addition of irbesartan or ramipril.

Statins are linked to lower mortality
A prospective cohort study followed 137 patients with heart failure and ejection fraction >50% for a mean of 21 months.⁹ After adjustment for differences in baseline clinical variables between groups, therapy with various statins (68% of patients were on atorvastatin) was associated with lower mortality (NNT=5).

Little evidence exists to support the use of calcium channel blockers, digoxin, or other vasodilators in diastolic heart failure.

Recommendations

The TABLE summarizes recommendations of the American College of Cardiology Foundation and the American Heart Association.¹

TABLE
Treating the patient with heart failure and normal LVEF: Recommendations from the ACCF and AHA

Evidence summary

The many definitions used to describe case management present a challenge in summarizing its effect.^1,2 A Cochrane review of case management by a “diabetes specialist nurse/nurse case manager” included 6 trials and 1382 patients with either type 1 or type 2 diabetes. It revealed a short-term benefit (lower HbA1c) in only 1 trial at 6 months and no difference in HbA1c or improvement in quality of life in any trial at 12 months.³

However, a review of 66 RCTs of case management for type 2 diabetes found a mean reduction in HbA1c of 0.52% (95% confidence interval [CI], 0.31-0.73) after adjusting for study size (smaller studies tended to report larger changes) and whether or not patients were “poorly controlled” at baseline (studies with higher HbA1c levels at baseline also reported larger effects).¹ The most striking HbA1c reduction occurred when case managers could make medication adjustments without physician approval (change in HbA1c=0.80%; 95% CI, 0.51-1.10). Moreover, using a multidisciplinary team reduced HbA1c by 0.37% more than interventions without such a team (95% CI, 0.16-0.58).

The authors of an earlier review of 15 case management studies for type 2 diabetes concluded that case management alone was beneficial, resulting in an HbA1c improvement of 0.40% (interquartile range=0.46-0.65).⁴ However, they further noted that studies that showed case management to be effective also involved disease management or included additional interventions such as education, reminders, or other supports.

But studies don’t always show robust outcomes

Outcomes in other studies often aren’t as robust. In the year-long Informatics for Diabetes Education and Telemedicine (IDEATel) project,⁵ for example, nurse case managers supervised by diabetologists and working with primary care physicians were able to direct care based on pre-established algorithms. Those in the intervention group with a baseline HbA1c >7 had an HbA1c reduction of 0.32% and small but statistically significant reductions in blood pressure (3.4 mm Hg systolic and 1.9 mm Hg diastolic) and low-density lipoprotein (9.5 mg/dL).

Intensive control produces positive results, a few harms

The Diabetes Control and Complications Trial (DCCT)⁶ showed that, in patients with type 1 diabetes, “intensive” diabetic control managed by a large team of health care providers for an average of 6.5 years reduced the development of retinopathy (number needed to treat [NNT]=6; 95% CI, 5-7), progression of retinopathy (NNT=5; 95% CI, 4-7), and development or progression of clinical neuropathy (NNT=13; 95% CI, 11-18).⁷ Intensive therapy also caused harms, including episodes of hypoglycemia (number needed to harm [NNH]=3), and “hypoglycemia requiring assistance” (NNH=36).

In the follow-up to DCCT—the Epidemiology of Diabetes Interventions and Complications study (EDIC)—93% of the patients in the original cohort were followed for an average of 17 years.⁸ The risk of developing any predetermined cardiovascular event was 42% less in the intervention group (NNT=14; 95% CI, 9-65), and the combined risk of death, nonfatal myocardial infarction, or stroke was 57% lower (NNT=10; 95% CI, 7-49). Harms, such as hypoglycemia, were not reported.

Recommendations

According to the American Diabetes Association, patients with diabetes should receive medical care from a physician-coordinated team, which may include nurse practitioners, physician’s assistants, nurses, dieticians, pharmacists, and mental health professionals.⁹

The Centers for Disease Control and Prevention strongly recommends that patients with diabetes be assigned “a case manager to plan, coordinate, and integrate care,” because case management improves glycemic control and physician monitoring.¹⁰

The American Association of Clinical Endocrinologists states: “Managing diabetes mellitus requires a team approach to patient care. However, because diabetes is primarily a self-managed disease, education in self-management skills is essential in implementing interventions.”¹¹

Evidence summary

The many definitions used to describe case management present a challenge in summarizing its effect.^1,2 A Cochrane review of case management by a “diabetes specialist nurse/nurse case manager” included 6 trials and 1382 patients with either type 1 or type 2 diabetes. It revealed a short-term benefit (lower HbA1c) in only 1 trial at 6 months and no difference in HbA1c or improvement in quality of life in any trial at 12 months.³

However, a review of 66 RCTs of case management for type 2 diabetes found a mean reduction in HbA1c of 0.52% (95% confidence interval [CI], 0.31-0.73) after adjusting for study size (smaller studies tended to report larger changes) and whether or not patients were “poorly controlled” at baseline (studies with higher HbA1c levels at baseline also reported larger effects).¹ The most striking HbA1c reduction occurred when case managers could make medication adjustments without physician approval (change in HbA1c=0.80%; 95% CI, 0.51-1.10). Moreover, using a multidisciplinary team reduced HbA1c by 0.37% more than interventions without such a team (95% CI, 0.16-0.58).

The authors of an earlier review of 15 case management studies for type 2 diabetes concluded that case management alone was beneficial, resulting in an HbA1c improvement of 0.40% (interquartile range=0.46-0.65).⁴ However, they further noted that studies that showed case management to be effective also involved disease management or included additional interventions such as education, reminders, or other supports.

But studies don’t always show robust outcomes

Outcomes in other studies often aren’t as robust. In the year-long Informatics for Diabetes Education and Telemedicine (IDEATel) project,⁵ for example, nurse case managers supervised by diabetologists and working with primary care physicians were able to direct care based on pre-established algorithms. Those in the intervention group with a baseline HbA1c >7 had an HbA1c reduction of 0.32% and small but statistically significant reductions in blood pressure (3.4 mm Hg systolic and 1.9 mm Hg diastolic) and low-density lipoprotein (9.5 mg/dL).

Intensive control produces positive results, a few harms

The Diabetes Control and Complications Trial (DCCT)⁶ showed that, in patients with type 1 diabetes, “intensive” diabetic control managed by a large team of health care providers for an average of 6.5 years reduced the development of retinopathy (number needed to treat [NNT]=6; 95% CI, 5-7), progression of retinopathy (NNT=5; 95% CI, 4-7), and development or progression of clinical neuropathy (NNT=13; 95% CI, 11-18).⁷ Intensive therapy also caused harms, including episodes of hypoglycemia (number needed to harm [NNH]=3), and “hypoglycemia requiring assistance” (NNH=36).

In the follow-up to DCCT—the Epidemiology of Diabetes Interventions and Complications study (EDIC)—93% of the patients in the original cohort were followed for an average of 17 years.⁸ The risk of developing any predetermined cardiovascular event was 42% less in the intervention group (NNT=14; 95% CI, 9-65), and the combined risk of death, nonfatal myocardial infarction, or stroke was 57% lower (NNT=10; 95% CI, 7-49). Harms, such as hypoglycemia, were not reported.

Recommendations

According to the American Diabetes Association, patients with diabetes should receive medical care from a physician-coordinated team, which may include nurse practitioners, physician’s assistants, nurses, dieticians, pharmacists, and mental health professionals.⁹

The Centers for Disease Control and Prevention strongly recommends that patients with diabetes be assigned “a case manager to plan, coordinate, and integrate care,” because case management improves glycemic control and physician monitoring.¹⁰

The American Association of Clinical Endocrinologists states: “Managing diabetes mellitus requires a team approach to patient care. However, because diabetes is primarily a self-managed disease, education in self-management skills is essential in implementing interventions.”¹¹

Evidence summary

The many definitions used to describe case management present a challenge in summarizing its effect.^1,2 A Cochrane review of case management by a “diabetes specialist nurse/nurse case manager” included 6 trials and 1382 patients with either type 1 or type 2 diabetes. It revealed a short-term benefit (lower HbA1c) in only 1 trial at 6 months and no difference in HbA1c or improvement in quality of life in any trial at 12 months.³

However, a review of 66 RCTs of case management for type 2 diabetes found a mean reduction in HbA1c of 0.52% (95% confidence interval [CI], 0.31-0.73) after adjusting for study size (smaller studies tended to report larger changes) and whether or not patients were “poorly controlled” at baseline (studies with higher HbA1c levels at baseline also reported larger effects).¹ The most striking HbA1c reduction occurred when case managers could make medication adjustments without physician approval (change in HbA1c=0.80%; 95% CI, 0.51-1.10). Moreover, using a multidisciplinary team reduced HbA1c by 0.37% more than interventions without such a team (95% CI, 0.16-0.58).

The authors of an earlier review of 15 case management studies for type 2 diabetes concluded that case management alone was beneficial, resulting in an HbA1c improvement of 0.40% (interquartile range=0.46-0.65).⁴ However, they further noted that studies that showed case management to be effective also involved disease management or included additional interventions such as education, reminders, or other supports.

But studies don’t always show robust outcomes

Outcomes in other studies often aren’t as robust. In the year-long Informatics for Diabetes Education and Telemedicine (IDEATel) project,⁵ for example, nurse case managers supervised by diabetologists and working with primary care physicians were able to direct care based on pre-established algorithms. Those in the intervention group with a baseline HbA1c >7 had an HbA1c reduction of 0.32% and small but statistically significant reductions in blood pressure (3.4 mm Hg systolic and 1.9 mm Hg diastolic) and low-density lipoprotein (9.5 mg/dL).

Intensive control produces positive results, a few harms

The Diabetes Control and Complications Trial (DCCT)⁶ showed that, in patients with type 1 diabetes, “intensive” diabetic control managed by a large team of health care providers for an average of 6.5 years reduced the development of retinopathy (number needed to treat [NNT]=6; 95% CI, 5-7), progression of retinopathy (NNT=5; 95% CI, 4-7), and development or progression of clinical neuropathy (NNT=13; 95% CI, 11-18).⁷ Intensive therapy also caused harms, including episodes of hypoglycemia (number needed to harm [NNH]=3), and “hypoglycemia requiring assistance” (NNH=36).

In the follow-up to DCCT—the Epidemiology of Diabetes Interventions and Complications study (EDIC)—93% of the patients in the original cohort were followed for an average of 17 years.⁸ The risk of developing any predetermined cardiovascular event was 42% less in the intervention group (NNT=14; 95% CI, 9-65), and the combined risk of death, nonfatal myocardial infarction, or stroke was 57% lower (NNT=10; 95% CI, 7-49). Harms, such as hypoglycemia, were not reported.

Recommendations

According to the American Diabetes Association, patients with diabetes should receive medical care from a physician-coordinated team, which may include nurse practitioners, physician’s assistants, nurses, dieticians, pharmacists, and mental health professionals.⁹

The Centers for Disease Control and Prevention strongly recommends that patients with diabetes be assigned “a case manager to plan, coordinate, and integrate care,” because case management improves glycemic control and physician monitoring.¹⁰

The American Association of Clinical Endocrinologists states: “Managing diabetes mellitus requires a team approach to patient care. However, because diabetes is primarily a self-managed disease, education in self-management skills is essential in implementing interventions.”¹¹

Evidence summary

Amitriptyline and other tricyclic and tetracyclic antidepressants moderately improve pain control for patients with chronic back pain.^1,2 The pain reduction was independent of the presence of depression, although patients who were depressed had a significant improvement in mood. The outcome on chronic pain of antidepressants with serotonin and norepinephrine reuptake inhibitory activity is still being evaluated. It appears that those with only SSRI activity are not effective improving chronic pain.²

Tricyclics are effective for diabetic neuropathy (number needed to treat [NNT]=3.5 for 50% reduction of pain),³ and they are effective for reducing pain but not for global symptoms in irritable bowel syndrome.⁴ Amitriptyline reduces the pain of diabetic peripheral neuropathy in a dose related manner up to 150 mg/d, although much lower doses are often effective and cause fewer anticholinergic side-effects.

For chronic back pain, a Cochrane review including 1964 patients found strong evidence for pain reduction and modest evidence for functional improvement from intensive (>100 hours) multidisciplinary biopsychosocial rehabilitation. Less intense and less comprehensive psychophysical programs did not reduce pain or improve function.⁵ It was unclear if the intensive programs were generalizable. Another review found that cognitive and progressive relaxation therapy had a moderate effect on short-term pain control vs waiting-list controls for chronic back pain. However, only a third of the studies were of “high quality,” and the total number of patients in the relaxation analysis was 39.⁶

A systematic review of 25 studies (1672 patients) found significant effect sizes for cognitive therapies in reducing pain and other symptoms in chronic musculoskeletal pain, including rheumatoid arthritis, fibromyalgia, back, and other pain syndromes.⁷ However, many of the trials were small or taken from “samples of convenience” from rehabilitation and pain clinics, and most lacked documentation of randomization. For rheumatoid arthritis alone, a systematic review of 19 studies found cognitive therapies had a small but statistically significant effect on pain, functional disability, depression, coping, and self-efficacy for 1298 patients at initial follow-up. However, only “tender points” and coping remained improved at subsequent follow-ups averaging 8.5 months.⁸

In adults with cancer pain, a recent meta-analysis of 1723 patients showed modest but significant effects on pain from psycho-educational interventions in 25 studies.⁹ Although just 3 of the studies lasted 52 weeks or longer, effects were found from good-quality studies for “relaxation-promoting,” educational, and supportive counseling plus content therapies.

A significant confounder in many of these studies may be that some treatments seem more effective in secondary care than in primary care settings, as based on a systemic review of interventions for somatic symptoms in primary care.¹⁰

Recommendations from others

The NIH states that antidepressants are effective adjuvants in pain management, and that cognitive-behavioral treatments may be beneficial.¹¹ The American Society of Anesthesiology states that “the literature supports the use of antidepressants for reducing chronic pain without notable adverse effects.”¹² The Arthritis Foundation lists amitriptyline, duloxetine, fluoxetine, and paroxetine as treatment options for pain and for helping sleep in fibromyalgia.¹³

Evidence summary

Amitriptyline and other tricyclic and tetracyclic antidepressants moderately improve pain control for patients with chronic back pain.^1,2 The pain reduction was independent of the presence of depression, although patients who were depressed had a significant improvement in mood. The outcome on chronic pain of antidepressants with serotonin and norepinephrine reuptake inhibitory activity is still being evaluated. It appears that those with only SSRI activity are not effective improving chronic pain.²

Tricyclics are effective for diabetic neuropathy (number needed to treat [NNT]=3.5 for 50% reduction of pain),³ and they are effective for reducing pain but not for global symptoms in irritable bowel syndrome.⁴ Amitriptyline reduces the pain of diabetic peripheral neuropathy in a dose related manner up to 150 mg/d, although much lower doses are often effective and cause fewer anticholinergic side-effects.

For chronic back pain, a Cochrane review including 1964 patients found strong evidence for pain reduction and modest evidence for functional improvement from intensive (>100 hours) multidisciplinary biopsychosocial rehabilitation. Less intense and less comprehensive psychophysical programs did not reduce pain or improve function.⁵ It was unclear if the intensive programs were generalizable. Another review found that cognitive and progressive relaxation therapy had a moderate effect on short-term pain control vs waiting-list controls for chronic back pain. However, only a third of the studies were of “high quality,” and the total number of patients in the relaxation analysis was 39.⁶

A systematic review of 25 studies (1672 patients) found significant effect sizes for cognitive therapies in reducing pain and other symptoms in chronic musculoskeletal pain, including rheumatoid arthritis, fibromyalgia, back, and other pain syndromes.⁷ However, many of the trials were small or taken from “samples of convenience” from rehabilitation and pain clinics, and most lacked documentation of randomization. For rheumatoid arthritis alone, a systematic review of 19 studies found cognitive therapies had a small but statistically significant effect on pain, functional disability, depression, coping, and self-efficacy for 1298 patients at initial follow-up. However, only “tender points” and coping remained improved at subsequent follow-ups averaging 8.5 months.⁸

In adults with cancer pain, a recent meta-analysis of 1723 patients showed modest but significant effects on pain from psycho-educational interventions in 25 studies.⁹ Although just 3 of the studies lasted 52 weeks or longer, effects were found from good-quality studies for “relaxation-promoting,” educational, and supportive counseling plus content therapies.

A significant confounder in many of these studies may be that some treatments seem more effective in secondary care than in primary care settings, as based on a systemic review of interventions for somatic symptoms in primary care.¹⁰

Recommendations from others

The NIH states that antidepressants are effective adjuvants in pain management, and that cognitive-behavioral treatments may be beneficial.¹¹ The American Society of Anesthesiology states that “the literature supports the use of antidepressants for reducing chronic pain without notable adverse effects.”¹² The Arthritis Foundation lists amitriptyline, duloxetine, fluoxetine, and paroxetine as treatment options for pain and for helping sleep in fibromyalgia.¹³

Evidence summary

Amitriptyline and other tricyclic and tetracyclic antidepressants moderately improve pain control for patients with chronic back pain.^1,2 The pain reduction was independent of the presence of depression, although patients who were depressed had a significant improvement in mood. The outcome on chronic pain of antidepressants with serotonin and norepinephrine reuptake inhibitory activity is still being evaluated. It appears that those with only SSRI activity are not effective improving chronic pain.²

Tricyclics are effective for diabetic neuropathy (number needed to treat [NNT]=3.5 for 50% reduction of pain),³ and they are effective for reducing pain but not for global symptoms in irritable bowel syndrome.⁴ Amitriptyline reduces the pain of diabetic peripheral neuropathy in a dose related manner up to 150 mg/d, although much lower doses are often effective and cause fewer anticholinergic side-effects.

For chronic back pain, a Cochrane review including 1964 patients found strong evidence for pain reduction and modest evidence for functional improvement from intensive (>100 hours) multidisciplinary biopsychosocial rehabilitation. Less intense and less comprehensive psychophysical programs did not reduce pain or improve function.⁵ It was unclear if the intensive programs were generalizable. Another review found that cognitive and progressive relaxation therapy had a moderate effect on short-term pain control vs waiting-list controls for chronic back pain. However, only a third of the studies were of “high quality,” and the total number of patients in the relaxation analysis was 39.⁶

A systematic review of 25 studies (1672 patients) found significant effect sizes for cognitive therapies in reducing pain and other symptoms in chronic musculoskeletal pain, including rheumatoid arthritis, fibromyalgia, back, and other pain syndromes.⁷ However, many of the trials were small or taken from “samples of convenience” from rehabilitation and pain clinics, and most lacked documentation of randomization. For rheumatoid arthritis alone, a systematic review of 19 studies found cognitive therapies had a small but statistically significant effect on pain, functional disability, depression, coping, and self-efficacy for 1298 patients at initial follow-up. However, only “tender points” and coping remained improved at subsequent follow-ups averaging 8.5 months.⁸

In adults with cancer pain, a recent meta-analysis of 1723 patients showed modest but significant effects on pain from psycho-educational interventions in 25 studies.⁹ Although just 3 of the studies lasted 52 weeks or longer, effects were found from good-quality studies for “relaxation-promoting,” educational, and supportive counseling plus content therapies.

A significant confounder in many of these studies may be that some treatments seem more effective in secondary care than in primary care settings, as based on a systemic review of interventions for somatic symptoms in primary care.¹⁰

Recommendations from others

The NIH states that antidepressants are effective adjuvants in pain management, and that cognitive-behavioral treatments may be beneficial.¹¹ The American Society of Anesthesiology states that “the literature supports the use of antidepressants for reducing chronic pain without notable adverse effects.”¹² The Arthritis Foundation lists amitriptyline, duloxetine, fluoxetine, and paroxetine as treatment options for pain and for helping sleep in fibromyalgia.¹³

Evidence summary

Concussion, as defined by the American Association of Neurologists, is “a trauma-induced alteration in mental status that may or may not involve loss of consciousness.”¹ There are approximately 300,000 sports-related concussions sustained each season in the US, although many athletes do not recognize the symptoms of concussion or may under-report them.

While concussions usually result in no long-term sequela, persistent neurocognitive deficits and psychiatric illnesses, including depression, may result. Case reports exist of fatal brain swelling in athletes who suffer a second head injury while still recovering from a first one, although more recently the existence of a “second impact syndrome” has been disputed.²

A large prospective cohort study of 2900 US college football players found that players with 1 previous concussion had a 40% increased risk of future concussion, and those with 3 previous concussions had a three-fold increase in risk.³ High school students with concussions are 3 to 4 days slower in recovering memory function than college students,^4-6 and women with concussions are 1.7 times more likely to have cognitive impairment than men.⁷

Concussions are often accompanied by symptoms and cognitive problems that can be overlooked if not carefully and systematically assessed. A prospective study of high-school athletes demonstrated that neuropsychological dysfunction takes a week or longer to resolve in “ding” concussions (defined as no loss of consciousness and overt symptoms resolved within 15 minutes).⁸ A prospective cohort study of boxers at the US Military Academy found that it takes 3 to 7 days for recovery of neurocognitive function.⁹ Another cohort study of US college football players found that while postural stability commonly returns in just a day or 2, cognitive recovery often takes 3 to 5 days, and symptoms last over 7 days post-injury for 1 of 8 concussed athletes.¹⁰

Sport concussion assessments should include testing for cognition, postural stability, and self-reported symptoms. Results can then be compared with each individual’s preseason baseline. Examples of screening instruments include SCAT (the Sideline Concussion Assessment Tool),¹¹ SAC (the Standardized Assessment of Concussion), BESS (the Balance Error Scoring System), as well as ImPACT or other neurocognitive tests, to evaluate and document memory, brain processing speed, reaction time, and postconcussive symptoms.^10-12 SCAT, SAC, and BESS can be used on the sidelines, and each can be employed for baseline and follow up testing.

Results from these tests should be interpreted in light of all other aspects of the injury (physical exam, age, sex, history of previous concussion, etc) to guide the decision on returning to play.^11,12 After neurological and balance symptoms have resolved, noncontact exercise may be allowed. When neuropsychological testing has returned to preseason baseline, full contact may be permitted.

Athletes, their families, trainers, and coaches should be educated about concussions so that they are better equipped to both identify and report symptoms. Care for injured athletes should also include education about the long-term effects of multiple concussions.¹²

Recommendations from others

The 2nd International Conference on Concussion in Sport, Prague 2004¹¹ (emphasis added) recommended the following stages of recovery from a concussion:

1. No activity, complete rest. Once asymptomatic, proceed to level 2
2. Light aerobic exercise such as walking or stationary cycling, no resistance training
3. Sport-specific exercise (eg, skating in hockey, running in soccer), progressive addition of resistance training at steps 3 or 4
4. Noncontact training drills
5. Full contact training after medical clearance
6. Game play.

The National Athletic Training Association recommendations are:¹²

• Increase in education of staff working directly with athletes
• Increase in documentation about events surrounding and subsequent to the concussion
• Initial baseline testing for high-risk sports
• No single test should be use exclusively for return to play, as concussions can present in different ways
• Evaluations by athletic trainers or team physician after concussion Q 5 minutes
• Athletes symptomatic at rest and after exertion for 20 minutes (sprinting, push-ups) should be disqualified for that event
• Pediatric patients should have more strict/prolonged recovery periods.
• Wake athletes from sleep at home only if there has been loss of consciousness, prolonged amnesia, or significant symptoms

Evidence summary

Concussion, as defined by the American Association of Neurologists, is “a trauma-induced alteration in mental status that may or may not involve loss of consciousness.”¹ There are approximately 300,000 sports-related concussions sustained each season in the US, although many athletes do not recognize the symptoms of concussion or may under-report them.

While concussions usually result in no long-term sequela, persistent neurocognitive deficits and psychiatric illnesses, including depression, may result. Case reports exist of fatal brain swelling in athletes who suffer a second head injury while still recovering from a first one, although more recently the existence of a “second impact syndrome” has been disputed.²

A large prospective cohort study of 2900 US college football players found that players with 1 previous concussion had a 40% increased risk of future concussion, and those with 3 previous concussions had a three-fold increase in risk.³ High school students with concussions are 3 to 4 days slower in recovering memory function than college students,^4-6 and women with concussions are 1.7 times more likely to have cognitive impairment than men.⁷

Concussions are often accompanied by symptoms and cognitive problems that can be overlooked if not carefully and systematically assessed. A prospective study of high-school athletes demonstrated that neuropsychological dysfunction takes a week or longer to resolve in “ding” concussions (defined as no loss of consciousness and overt symptoms resolved within 15 minutes).⁸ A prospective cohort study of boxers at the US Military Academy found that it takes 3 to 7 days for recovery of neurocognitive function.⁹ Another cohort study of US college football players found that while postural stability commonly returns in just a day or 2, cognitive recovery often takes 3 to 5 days, and symptoms last over 7 days post-injury for 1 of 8 concussed athletes.¹⁰

Sport concussion assessments should include testing for cognition, postural stability, and self-reported symptoms. Results can then be compared with each individual’s preseason baseline. Examples of screening instruments include SCAT (the Sideline Concussion Assessment Tool),¹¹ SAC (the Standardized Assessment of Concussion), BESS (the Balance Error Scoring System), as well as ImPACT or other neurocognitive tests, to evaluate and document memory, brain processing speed, reaction time, and postconcussive symptoms.^10-12 SCAT, SAC, and BESS can be used on the sidelines, and each can be employed for baseline and follow up testing.

Results from these tests should be interpreted in light of all other aspects of the injury (physical exam, age, sex, history of previous concussion, etc) to guide the decision on returning to play.^11,12 After neurological and balance symptoms have resolved, noncontact exercise may be allowed. When neuropsychological testing has returned to preseason baseline, full contact may be permitted.

Athletes, their families, trainers, and coaches should be educated about concussions so that they are better equipped to both identify and report symptoms. Care for injured athletes should also include education about the long-term effects of multiple concussions.¹²

Recommendations from others

The 2nd International Conference on Concussion in Sport, Prague 2004¹¹ (emphasis added) recommended the following stages of recovery from a concussion:

1. No activity, complete rest. Once asymptomatic, proceed to level 2
2. Light aerobic exercise such as walking or stationary cycling, no resistance training
3. Sport-specific exercise (eg, skating in hockey, running in soccer), progressive addition of resistance training at steps 3 or 4
4. Noncontact training drills
5. Full contact training after medical clearance
6. Game play.

The National Athletic Training Association recommendations are:¹²

• Increase in education of staff working directly with athletes
• Increase in documentation about events surrounding and subsequent to the concussion
• Initial baseline testing for high-risk sports
• No single test should be use exclusively for return to play, as concussions can present in different ways
• Evaluations by athletic trainers or team physician after concussion Q 5 minutes
• Athletes symptomatic at rest and after exertion for 20 minutes (sprinting, push-ups) should be disqualified for that event
• Pediatric patients should have more strict/prolonged recovery periods.
• Wake athletes from sleep at home only if there has been loss of consciousness, prolonged amnesia, or significant symptoms

Evidence summary

Concussion, as defined by the American Association of Neurologists, is “a trauma-induced alteration in mental status that may or may not involve loss of consciousness.”¹ There are approximately 300,000 sports-related concussions sustained each season in the US, although many athletes do not recognize the symptoms of concussion or may under-report them.

While concussions usually result in no long-term sequela, persistent neurocognitive deficits and psychiatric illnesses, including depression, may result. Case reports exist of fatal brain swelling in athletes who suffer a second head injury while still recovering from a first one, although more recently the existence of a “second impact syndrome” has been disputed.²

A large prospective cohort study of 2900 US college football players found that players with 1 previous concussion had a 40% increased risk of future concussion, and those with 3 previous concussions had a three-fold increase in risk.³ High school students with concussions are 3 to 4 days slower in recovering memory function than college students,^4-6 and women with concussions are 1.7 times more likely to have cognitive impairment than men.⁷

Concussions are often accompanied by symptoms and cognitive problems that can be overlooked if not carefully and systematically assessed. A prospective study of high-school athletes demonstrated that neuropsychological dysfunction takes a week or longer to resolve in “ding” concussions (defined as no loss of consciousness and overt symptoms resolved within 15 minutes).⁸ A prospective cohort study of boxers at the US Military Academy found that it takes 3 to 7 days for recovery of neurocognitive function.⁹ Another cohort study of US college football players found that while postural stability commonly returns in just a day or 2, cognitive recovery often takes 3 to 5 days, and symptoms last over 7 days post-injury for 1 of 8 concussed athletes.¹⁰

Sport concussion assessments should include testing for cognition, postural stability, and self-reported symptoms. Results can then be compared with each individual’s preseason baseline. Examples of screening instruments include SCAT (the Sideline Concussion Assessment Tool),¹¹ SAC (the Standardized Assessment of Concussion), BESS (the Balance Error Scoring System), as well as ImPACT or other neurocognitive tests, to evaluate and document memory, brain processing speed, reaction time, and postconcussive symptoms.^10-12 SCAT, SAC, and BESS can be used on the sidelines, and each can be employed for baseline and follow up testing.

Results from these tests should be interpreted in light of all other aspects of the injury (physical exam, age, sex, history of previous concussion, etc) to guide the decision on returning to play.^11,12 After neurological and balance symptoms have resolved, noncontact exercise may be allowed. When neuropsychological testing has returned to preseason baseline, full contact may be permitted.

Athletes, their families, trainers, and coaches should be educated about concussions so that they are better equipped to both identify and report symptoms. Care for injured athletes should also include education about the long-term effects of multiple concussions.¹²

Recommendations from others

The 2nd International Conference on Concussion in Sport, Prague 2004¹¹ (emphasis added) recommended the following stages of recovery from a concussion:

1. No activity, complete rest. Once asymptomatic, proceed to level 2
2. Light aerobic exercise such as walking or stationary cycling, no resistance training
3. Sport-specific exercise (eg, skating in hockey, running in soccer), progressive addition of resistance training at steps 3 or 4
4. Noncontact training drills
5. Full contact training after medical clearance
6. Game play.

The National Athletic Training Association recommendations are:¹²

• Increase in education of staff working directly with athletes
• Increase in documentation about events surrounding and subsequent to the concussion
• Initial baseline testing for high-risk sports
• No single test should be use exclusively for return to play, as concussions can present in different ways
• Evaluations by athletic trainers or team physician after concussion Q 5 minutes
• Athletes symptomatic at rest and after exertion for 20 minutes (sprinting, push-ups) should be disqualified for that event
• Pediatric patients should have more strict/prolonged recovery periods.
• Wake athletes from sleep at home only if there has been loss of consciousness, prolonged amnesia, or significant symptoms

TABLE
Inclusion and exclusion criteria for using thrombolytics for patients with acute ischemic CVA

Evidence summary

The 2003 American Heart Association guidelines recommend rtPA for acute ischemic stroke “for carefully selected patients” who also need crucial “ancillary care.”³ The evidence for these guidelines comes primarily from large double-blind placebo-controlled studies using rtPA. However, these studies—including NINDS,⁴ ECASS,⁵ and ATLANTIS⁶ —differ in their dosing regimen, timing, and other exclusion criteria, and outcome measurements.

The NINDS study, often employed as a benchmark,^3,7,8 used a slightly lower dose of rtPA than other studies and “required that no anticoagulants or antiplatelet agents be given for 24 hours after treatment and that blood pressure be maintained within prespecified values.”⁴ Patients were evaluated for inclusion according to strict criteria, similar to those shown in the Table.

Patients in research studies who were treated outside protocol guidelines, and patients treated in community hospitals, have not fared as well as the patients in NINDS. In Connecticut,⁹ a review of thrombolysis in acute ischemic stroke revealed protocol deviations in 67% of the patients treated. The number needed to harm (NNH) for death was only 4 (in other words, there was an additional patient death for every 4 patients treated with rtPA), and significant extracranial hemorrhage had an NNH of 8. In Cleveland,¹⁰ 50% of patients treated had at least 1 major protocol violation, and the NNH for symptomatic intracranial hemorrhage was 6. A quality improvement program in the Cleveland area lowered protocol violations to 19% and the NNH rose to 15.¹¹

Improved outcomes similar to NINDS have been noted where there are stroke units or teams with personnel such as neurosurgeons, strict adherence to protocols, and facilities available to give accurate and expedient interventions and imaging (eg, neuroradiologic interpretations of CTs).¹ These limits restrict the practical and safe use of rtPA to few of the millions of stroke victims.

The net positive outcome found in the Cochrane review¹ results from subtracting the significant increase in symptomatic intracranial hemorrhage (NNH=16; 95% CI, 11–25) from the larger primary decrease in disability/death (NNT=10; 95% CI, 6–22).¹ The overlapping confidence intervals of the outcomes was bothersome to the Cochrane reviewers.

Recommendations from others

Recommendations from the American Heart Association,² the American Academy of Neurology,⁶ and the 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy⁷ substantially agree. With minor variations, all recommend rtPA with inclusion/exclusion criteria similar to those outlined in the Table.

TABLE
Inclusion and exclusion criteria for using thrombolytics for patients with acute ischemic CVA

Evidence summary

The 2003 American Heart Association guidelines recommend rtPA for acute ischemic stroke “for carefully selected patients” who also need crucial “ancillary care.”³ The evidence for these guidelines comes primarily from large double-blind placebo-controlled studies using rtPA. However, these studies—including NINDS,⁴ ECASS,⁵ and ATLANTIS⁶ —differ in their dosing regimen, timing, and other exclusion criteria, and outcome measurements.

The NINDS study, often employed as a benchmark,^3,7,8 used a slightly lower dose of rtPA than other studies and “required that no anticoagulants or antiplatelet agents be given for 24 hours after treatment and that blood pressure be maintained within prespecified values.”⁴ Patients were evaluated for inclusion according to strict criteria, similar to those shown in the Table.

Patients in research studies who were treated outside protocol guidelines, and patients treated in community hospitals, have not fared as well as the patients in NINDS. In Connecticut,⁹ a review of thrombolysis in acute ischemic stroke revealed protocol deviations in 67% of the patients treated. The number needed to harm (NNH) for death was only 4 (in other words, there was an additional patient death for every 4 patients treated with rtPA), and significant extracranial hemorrhage had an NNH of 8. In Cleveland,¹⁰ 50% of patients treated had at least 1 major protocol violation, and the NNH for symptomatic intracranial hemorrhage was 6. A quality improvement program in the Cleveland area lowered protocol violations to 19% and the NNH rose to 15.¹¹

Improved outcomes similar to NINDS have been noted where there are stroke units or teams with personnel such as neurosurgeons, strict adherence to protocols, and facilities available to give accurate and expedient interventions and imaging (eg, neuroradiologic interpretations of CTs).¹ These limits restrict the practical and safe use of rtPA to few of the millions of stroke victims.

The net positive outcome found in the Cochrane review¹ results from subtracting the significant increase in symptomatic intracranial hemorrhage (NNH=16; 95% CI, 11–25) from the larger primary decrease in disability/death (NNT=10; 95% CI, 6–22).¹ The overlapping confidence intervals of the outcomes was bothersome to the Cochrane reviewers.

Recommendations from others

Recommendations from the American Heart Association,² the American Academy of Neurology,⁶ and the 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy⁷ substantially agree. With minor variations, all recommend rtPA with inclusion/exclusion criteria similar to those outlined in the Table.

TABLE
Inclusion and exclusion criteria for using thrombolytics for patients with acute ischemic CVA

Evidence summary

The 2003 American Heart Association guidelines recommend rtPA for acute ischemic stroke “for carefully selected patients” who also need crucial “ancillary care.”³ The evidence for these guidelines comes primarily from large double-blind placebo-controlled studies using rtPA. However, these studies—including NINDS,⁴ ECASS,⁵ and ATLANTIS⁶ —differ in their dosing regimen, timing, and other exclusion criteria, and outcome measurements.

The NINDS study, often employed as a benchmark,^3,7,8 used a slightly lower dose of rtPA than other studies and “required that no anticoagulants or antiplatelet agents be given for 24 hours after treatment and that blood pressure be maintained within prespecified values.”⁴ Patients were evaluated for inclusion according to strict criteria, similar to those shown in the Table.

Patients in research studies who were treated outside protocol guidelines, and patients treated in community hospitals, have not fared as well as the patients in NINDS. In Connecticut,⁹ a review of thrombolysis in acute ischemic stroke revealed protocol deviations in 67% of the patients treated. The number needed to harm (NNH) for death was only 4 (in other words, there was an additional patient death for every 4 patients treated with rtPA), and significant extracranial hemorrhage had an NNH of 8. In Cleveland,¹⁰ 50% of patients treated had at least 1 major protocol violation, and the NNH for symptomatic intracranial hemorrhage was 6. A quality improvement program in the Cleveland area lowered protocol violations to 19% and the NNH rose to 15.¹¹

Improved outcomes similar to NINDS have been noted where there are stroke units or teams with personnel such as neurosurgeons, strict adherence to protocols, and facilities available to give accurate and expedient interventions and imaging (eg, neuroradiologic interpretations of CTs).¹ These limits restrict the practical and safe use of rtPA to few of the millions of stroke victims.

The net positive outcome found in the Cochrane review¹ results from subtracting the significant increase in symptomatic intracranial hemorrhage (NNH=16; 95% CI, 11–25) from the larger primary decrease in disability/death (NNT=10; 95% CI, 6–22).¹ The overlapping confidence intervals of the outcomes was bothersome to the Cochrane reviewers.

Recommendations from others

Recommendations from the American Heart Association,² the American Academy of Neurology,⁶ and the 6th American College of Chest Physicians Consensus Conference on Antithrombotic Therapy⁷ substantially agree. With minor variations, all recommend rtPA with inclusion/exclusion criteria similar to those outlined in the Table.

Evidence summary

Antiarrhythmic agents have been studied in patients with heart failure because these persons have a high incidence of sudden death, presumably from ventricular arrhythmias. Although the implantable defibrillator is an alternative antiarrhythmic device that may be preferred for some patients, we restricted our review to pharmacologic antiarrhythmics.

The beta-blockers bisoprolol, carvedilol, and metoprolol^1-3 were studied in large randomized controlled trials. The relative risk reduction (RRR) for sudden death ranged from 10% to 52% in the larger trials and 30% to 39% in meta-analyses.^1-4 The absolute risk reduction (ARR) was about 2% to 3% per year for sudden death and 3% to 5% for total mortality (number needed to treat=20–33 per year).

These beta-blockers were well-tolerated, even in class IV New York Heart Association patients, and improved other endpoints. Although we cannot say whether the benefits are a class effect, they were seen with both beta-1 selective and nonselective agents.

Amiodarone was studied in 2 large randomized controlled trials enrolling patients with heart failure, in trials that included patients with or without heart failure at high risk for sudden death (usually post-myocardial infarction or with complex ventricular arrhythmias), and in meta-analyses.^5-8 The largest randomized controlled trial in heart failure showed a significant ARR of 2.9% for sudden death,⁵ but was unblinded. The largest placebo-controlled trial in heart failure failed to detect a significant decrease in sudden death.⁶

Meta-analyses, weakened by heterogeneity and the inclusion of patients without heart failure, detected a significant 21% to 25% RRR for sudden death,^7,8 and an ARR of 2% to 3% per year. The pooled data from the placebo-controlled heart failure trials showed nonsignificant trends: 1.6% per year ARR for sudden death, 0.6% per year for total mortality.

These possible benefits must be balanced against the risk of harm from amiodarone, including excess rates of pulmonary infiltrate (1.1% per year), thyroid dysfunction (6.8% per year), liver enzyme abnormalities (0.6% per year), neuropathy (0.3% per year), and bradycardia (1.6% per year), as well as a discontinuation rate of 41% compared with 27% for placebo.⁷ No evidence suggested that use of amiodarone in patients with heart failure increased mortality.

Class I antiarrhythmics and other class III agents have not been studied in heart failure trials, but were associated with increased mortality in studies of patients at high risk for ventricular arrhythmia,^9,10 including patients with left ventricular dysfunction. Because this increase in mortality is thought to be due to proarrhythmic properties of the drugs, further trials in heart failure patients are unlikely to occur.

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA),¹¹ European Society of Cardiology (ESC),¹² and Heart Failure Society of America (HFSA) guidelines¹³ address heart failure. ACC/AHA and ESC reports specifically mention that beta-blockers reduce sudden death. Both strongly support the use of beta-blockers in patients with heart failure.

ACC/AHA finds “conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy” of amiodarone to prevent sudden death and advises: “routine use of amiodarone to prevent sudden death is not recommended.” The ESC and HFSA also recommend against routine use of amiodarone.

All 3 guidelines, however, state that for the control of symptomatic arrhythmias in heart failure, amiodarone is the antiarrhythmic agent of choice. All 3 also recommend not using class I or other class III agents in heart failure.

Evidence summary

Antiarrhythmic agents have been studied in patients with heart failure because these persons have a high incidence of sudden death, presumably from ventricular arrhythmias. Although the implantable defibrillator is an alternative antiarrhythmic device that may be preferred for some patients, we restricted our review to pharmacologic antiarrhythmics.

The beta-blockers bisoprolol, carvedilol, and metoprolol^1-3 were studied in large randomized controlled trials. The relative risk reduction (RRR) for sudden death ranged from 10% to 52% in the larger trials and 30% to 39% in meta-analyses.^1-4 The absolute risk reduction (ARR) was about 2% to 3% per year for sudden death and 3% to 5% for total mortality (number needed to treat=20–33 per year).

These beta-blockers were well-tolerated, even in class IV New York Heart Association patients, and improved other endpoints. Although we cannot say whether the benefits are a class effect, they were seen with both beta-1 selective and nonselective agents.

Amiodarone was studied in 2 large randomized controlled trials enrolling patients with heart failure, in trials that included patients with or without heart failure at high risk for sudden death (usually post-myocardial infarction or with complex ventricular arrhythmias), and in meta-analyses.^5-8 The largest randomized controlled trial in heart failure showed a significant ARR of 2.9% for sudden death,⁵ but was unblinded. The largest placebo-controlled trial in heart failure failed to detect a significant decrease in sudden death.⁶

Meta-analyses, weakened by heterogeneity and the inclusion of patients without heart failure, detected a significant 21% to 25% RRR for sudden death,^7,8 and an ARR of 2% to 3% per year. The pooled data from the placebo-controlled heart failure trials showed nonsignificant trends: 1.6% per year ARR for sudden death, 0.6% per year for total mortality.

These possible benefits must be balanced against the risk of harm from amiodarone, including excess rates of pulmonary infiltrate (1.1% per year), thyroid dysfunction (6.8% per year), liver enzyme abnormalities (0.6% per year), neuropathy (0.3% per year), and bradycardia (1.6% per year), as well as a discontinuation rate of 41% compared with 27% for placebo.⁷ No evidence suggested that use of amiodarone in patients with heart failure increased mortality.

Class I antiarrhythmics and other class III agents have not been studied in heart failure trials, but were associated with increased mortality in studies of patients at high risk for ventricular arrhythmia,^9,10 including patients with left ventricular dysfunction. Because this increase in mortality is thought to be due to proarrhythmic properties of the drugs, further trials in heart failure patients are unlikely to occur.

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA),¹¹ European Society of Cardiology (ESC),¹² and Heart Failure Society of America (HFSA) guidelines¹³ address heart failure. ACC/AHA and ESC reports specifically mention that beta-blockers reduce sudden death. Both strongly support the use of beta-blockers in patients with heart failure.

ACC/AHA finds “conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy” of amiodarone to prevent sudden death and advises: “routine use of amiodarone to prevent sudden death is not recommended.” The ESC and HFSA also recommend against routine use of amiodarone.

All 3 guidelines, however, state that for the control of symptomatic arrhythmias in heart failure, amiodarone is the antiarrhythmic agent of choice. All 3 also recommend not using class I or other class III agents in heart failure.

Evidence summary

Antiarrhythmic agents have been studied in patients with heart failure because these persons have a high incidence of sudden death, presumably from ventricular arrhythmias. Although the implantable defibrillator is an alternative antiarrhythmic device that may be preferred for some patients, we restricted our review to pharmacologic antiarrhythmics.

The beta-blockers bisoprolol, carvedilol, and metoprolol^1-3 were studied in large randomized controlled trials. The relative risk reduction (RRR) for sudden death ranged from 10% to 52% in the larger trials and 30% to 39% in meta-analyses.^1-4 The absolute risk reduction (ARR) was about 2% to 3% per year for sudden death and 3% to 5% for total mortality (number needed to treat=20–33 per year).

These beta-blockers were well-tolerated, even in class IV New York Heart Association patients, and improved other endpoints. Although we cannot say whether the benefits are a class effect, they were seen with both beta-1 selective and nonselective agents.

Amiodarone was studied in 2 large randomized controlled trials enrolling patients with heart failure, in trials that included patients with or without heart failure at high risk for sudden death (usually post-myocardial infarction or with complex ventricular arrhythmias), and in meta-analyses.^5-8 The largest randomized controlled trial in heart failure showed a significant ARR of 2.9% for sudden death,⁵ but was unblinded. The largest placebo-controlled trial in heart failure failed to detect a significant decrease in sudden death.⁶

Meta-analyses, weakened by heterogeneity and the inclusion of patients without heart failure, detected a significant 21% to 25% RRR for sudden death,^7,8 and an ARR of 2% to 3% per year. The pooled data from the placebo-controlled heart failure trials showed nonsignificant trends: 1.6% per year ARR for sudden death, 0.6% per year for total mortality.

These possible benefits must be balanced against the risk of harm from amiodarone, including excess rates of pulmonary infiltrate (1.1% per year), thyroid dysfunction (6.8% per year), liver enzyme abnormalities (0.6% per year), neuropathy (0.3% per year), and bradycardia (1.6% per year), as well as a discontinuation rate of 41% compared with 27% for placebo.⁷ No evidence suggested that use of amiodarone in patients with heart failure increased mortality.

Class I antiarrhythmics and other class III agents have not been studied in heart failure trials, but were associated with increased mortality in studies of patients at high risk for ventricular arrhythmia,^9,10 including patients with left ventricular dysfunction. Because this increase in mortality is thought to be due to proarrhythmic properties of the drugs, further trials in heart failure patients are unlikely to occur.

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA),¹¹ European Society of Cardiology (ESC),¹² and Heart Failure Society of America (HFSA) guidelines¹³ address heart failure. ACC/AHA and ESC reports specifically mention that beta-blockers reduce sudden death. Both strongly support the use of beta-blockers in patients with heart failure.

ACC/AHA finds “conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy” of amiodarone to prevent sudden death and advises: “routine use of amiodarone to prevent sudden death is not recommended.” The ESC and HFSA also recommend against routine use of amiodarone.

All 3 guidelines, however, state that for the control of symptomatic arrhythmias in heart failure, amiodarone is the antiarrhythmic agent of choice. All 3 also recommend not using class I or other class III agents in heart failure.