Joan Nashelsky, MLS

Evidence summary

No studies of inhaled beta-agonists have been conducted with patients who have an explicit diagnosis of acute cough due to URI. While some clinicians feel a distinction between URI and acute bronchitis should be made, there is significant overlap between these diagnoses in clinical practice, as well as in the available studies.

A systematic review looking at beta-agonists for acute bronchitis included the clinical diagnoses of both acute bronchitis and acute cough because a standard definition of bronchitis is lacking.¹ Only two trials in this review examined inhaled beta-agonists. When results from these trials were combined for the outcome of productive cough at 7 days, inhaled beta-agonists showed no benefit. However, the authors note that details of the individual trials may help to clarify the effect of inhaled beta-agonists.

One trial, a randomized controlled trial of adult patients with acute bronchitis in 2 community-based family practices, compared 23 patients receiving albuterolin a multidose inhaler (MDI) with 23 patients receiving placebo inhaler.² Patients were also randomized to receive erythromycin or placebo tablets. Patients with pneumonia or a history of asthma or chronic obstructive pulmonary disease (COPD) were excluded. At 7 days, 61% of patients in the albuterol group reported cough compared with 91% in the control group (P=.02, NNT=3). No statistically significant difference was seen in productive cough or night cough. Smokers responded to inhaled albuterol similarly to nonsmokers. Erythromycin had no effect on cough and side effects were similar among all groups.

The other trial was a randomized controlled trial of 80 adults with cough due to acute respiratory infection; it compared fenoterol aerosol 4 times daily with placebo.³ Inhaled fenoterol is not available in the US but is similar to albuterol. This study showed no difference in cough at 7 days (relative risk [RR]=0.83; 95% confidence interval [CI], 0.52–1.30). In a subgroup analysis, however, smokers and those wheezing on initial exam had lower overall symptom scores when treated with fenoterol.

Recommendations from others

We were unable to find any guidelines on the use of albuterol via MDI for cough from bronchitis or URIs.

Evidence summary

No studies of inhaled beta-agonists have been conducted with patients who have an explicit diagnosis of acute cough due to URI. While some clinicians feel a distinction between URI and acute bronchitis should be made, there is significant overlap between these diagnoses in clinical practice, as well as in the available studies.

A systematic review looking at beta-agonists for acute bronchitis included the clinical diagnoses of both acute bronchitis and acute cough because a standard definition of bronchitis is lacking.¹ Only two trials in this review examined inhaled beta-agonists. When results from these trials were combined for the outcome of productive cough at 7 days, inhaled beta-agonists showed no benefit. However, the authors note that details of the individual trials may help to clarify the effect of inhaled beta-agonists.

One trial, a randomized controlled trial of adult patients with acute bronchitis in 2 community-based family practices, compared 23 patients receiving albuterolin a multidose inhaler (MDI) with 23 patients receiving placebo inhaler.² Patients were also randomized to receive erythromycin or placebo tablets. Patients with pneumonia or a history of asthma or chronic obstructive pulmonary disease (COPD) were excluded. At 7 days, 61% of patients in the albuterol group reported cough compared with 91% in the control group (P=.02, NNT=3). No statistically significant difference was seen in productive cough or night cough. Smokers responded to inhaled albuterol similarly to nonsmokers. Erythromycin had no effect on cough and side effects were similar among all groups.

The other trial was a randomized controlled trial of 80 adults with cough due to acute respiratory infection; it compared fenoterol aerosol 4 times daily with placebo.³ Inhaled fenoterol is not available in the US but is similar to albuterol. This study showed no difference in cough at 7 days (relative risk [RR]=0.83; 95% confidence interval [CI], 0.52–1.30). In a subgroup analysis, however, smokers and those wheezing on initial exam had lower overall symptom scores when treated with fenoterol.

Recommendations from others

We were unable to find any guidelines on the use of albuterol via MDI for cough from bronchitis or URIs.

Evidence summary

No studies of inhaled beta-agonists have been conducted with patients who have an explicit diagnosis of acute cough due to URI. While some clinicians feel a distinction between URI and acute bronchitis should be made, there is significant overlap between these diagnoses in clinical practice, as well as in the available studies.

A systematic review looking at beta-agonists for acute bronchitis included the clinical diagnoses of both acute bronchitis and acute cough because a standard definition of bronchitis is lacking.¹ Only two trials in this review examined inhaled beta-agonists. When results from these trials were combined for the outcome of productive cough at 7 days, inhaled beta-agonists showed no benefit. However, the authors note that details of the individual trials may help to clarify the effect of inhaled beta-agonists.

One trial, a randomized controlled trial of adult patients with acute bronchitis in 2 community-based family practices, compared 23 patients receiving albuterolin a multidose inhaler (MDI) with 23 patients receiving placebo inhaler.² Patients were also randomized to receive erythromycin or placebo tablets. Patients with pneumonia or a history of asthma or chronic obstructive pulmonary disease (COPD) were excluded. At 7 days, 61% of patients in the albuterol group reported cough compared with 91% in the control group (P=.02, NNT=3). No statistically significant difference was seen in productive cough or night cough. Smokers responded to inhaled albuterol similarly to nonsmokers. Erythromycin had no effect on cough and side effects were similar among all groups.

The other trial was a randomized controlled trial of 80 adults with cough due to acute respiratory infection; it compared fenoterol aerosol 4 times daily with placebo.³ Inhaled fenoterol is not available in the US but is similar to albuterol. This study showed no difference in cough at 7 days (relative risk [RR]=0.83; 95% confidence interval [CI], 0.52–1.30). In a subgroup analysis, however, smokers and those wheezing on initial exam had lower overall symptom scores when treated with fenoterol.

Recommendations from others

We were unable to find any guidelines on the use of albuterol via MDI for cough from bronchitis or URIs.

Evidence summary

The concept of a continuous graded relationship between DBP and cardiovascular risk is supported by a meta-analysis of 14 randomized clinical trials showing that lowering DBP by 6 mm Hg reduced the risk of coronary heart disease by 14% (95% confidence interval [CI], 4%–22%; P<.01; NNT=200).¹ Throughout the range of DBP in study subjects, 70–115 mm Hg, a lower DBP was associated with a lower risk of coronary heart disease.

However, there is concern that lowering DBP too much may actually increase cardiovascular risk. A 10-year observational study showed that in patients with a history of ischemic heart disease, the incidence of fatal MI was lowest when DBP was between 85 to 90 mm Hg and increased with DBP <85 mm Hg, thus demonstrating a J-shaped curve.²

Farnett et al³ derived a summary curve from 13 studies that stratified cardiovascular outcomes by level of achieved blood pressure; the nadir of the curve for ischemic heart disease events occurred at 86 to 89 mm Hg DBP. The risk was independent of type of drug therapy, and more pronounced in study subjects with known cardiovascular disease.

A meta-analysis of 7 randomized controlled trials involving 40,233 hypertensive patients used statistical modeling to determine the shape of the “mortality curve” over a range of DBP categories, defined in 10-mm Hg increments from 65 to 106. The subjects received mainly beta-blockers or thiazide diuretics; controls received placebo or no treatment.⁴ Both groups demonstrated increased risk for cardiovascular and all-cause death at the lowest DBP levels. Among treated patients, overall death rate was lowest with a DBP in the range of 76 to 85 mm Hg; among controls the nadir was 86 to 95 mm Hg.

The Hypertension Optimal Treatment (HOT) trial⁵ was specifically designed to determine the optimal target blood pressure for hypertensive patients: 18,790 men and women with DBP 100 to 115 mm Hg were randomly assigned to target DBP groups of <90, <85, or <80 mm Hg. All were treated with felodipine and other agents in a stepped-care protocol; average follow-up was 3.8 years. The lowest incidence of cardiovascular events occurred at a mean DBP of 82.6 mm Hg and fewest cardiovascular deaths at 86.5 mm Hg. Further reductions in DBP neither lowered nor increased cardiovascular risk.

A French cohort study⁶ followed over 4700 hyper-tensive men for an average of 14 years. These men had their hypertension treated in usual fashion by their own physicians. In this group, SBP was much more accurate than DBP in classifying severity of hypertension and in predicting cardiovascular risk.

Recommendations from others

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)⁷ and the World Health Organization–International Society of Hyper-tension Guidelines⁸ state that the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold. Target blood pressure goals are <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg for individuals with diabetes or kidney disease. The National High Blood Pressure Education Program stressed that SBP, not DBP, should become the major criterion for diagnosis and treatment of hypertension.⁹

Evidence summary

The concept of a continuous graded relationship between DBP and cardiovascular risk is supported by a meta-analysis of 14 randomized clinical trials showing that lowering DBP by 6 mm Hg reduced the risk of coronary heart disease by 14% (95% confidence interval [CI], 4%–22%; P<.01; NNT=200).¹ Throughout the range of DBP in study subjects, 70–115 mm Hg, a lower DBP was associated with a lower risk of coronary heart disease.

However, there is concern that lowering DBP too much may actually increase cardiovascular risk. A 10-year observational study showed that in patients with a history of ischemic heart disease, the incidence of fatal MI was lowest when DBP was between 85 to 90 mm Hg and increased with DBP <85 mm Hg, thus demonstrating a J-shaped curve.²

Farnett et al³ derived a summary curve from 13 studies that stratified cardiovascular outcomes by level of achieved blood pressure; the nadir of the curve for ischemic heart disease events occurred at 86 to 89 mm Hg DBP. The risk was independent of type of drug therapy, and more pronounced in study subjects with known cardiovascular disease.

A meta-analysis of 7 randomized controlled trials involving 40,233 hypertensive patients used statistical modeling to determine the shape of the “mortality curve” over a range of DBP categories, defined in 10-mm Hg increments from 65 to 106. The subjects received mainly beta-blockers or thiazide diuretics; controls received placebo or no treatment.⁴ Both groups demonstrated increased risk for cardiovascular and all-cause death at the lowest DBP levels. Among treated patients, overall death rate was lowest with a DBP in the range of 76 to 85 mm Hg; among controls the nadir was 86 to 95 mm Hg.

The Hypertension Optimal Treatment (HOT) trial⁵ was specifically designed to determine the optimal target blood pressure for hypertensive patients: 18,790 men and women with DBP 100 to 115 mm Hg were randomly assigned to target DBP groups of <90, <85, or <80 mm Hg. All were treated with felodipine and other agents in a stepped-care protocol; average follow-up was 3.8 years. The lowest incidence of cardiovascular events occurred at a mean DBP of 82.6 mm Hg and fewest cardiovascular deaths at 86.5 mm Hg. Further reductions in DBP neither lowered nor increased cardiovascular risk.

A French cohort study⁶ followed over 4700 hyper-tensive men for an average of 14 years. These men had their hypertension treated in usual fashion by their own physicians. In this group, SBP was much more accurate than DBP in classifying severity of hypertension and in predicting cardiovascular risk.

Recommendations from others

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)⁷ and the World Health Organization–International Society of Hyper-tension Guidelines⁸ state that the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold. Target blood pressure goals are <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg for individuals with diabetes or kidney disease. The National High Blood Pressure Education Program stressed that SBP, not DBP, should become the major criterion for diagnosis and treatment of hypertension.⁹

Evidence summary

The concept of a continuous graded relationship between DBP and cardiovascular risk is supported by a meta-analysis of 14 randomized clinical trials showing that lowering DBP by 6 mm Hg reduced the risk of coronary heart disease by 14% (95% confidence interval [CI], 4%–22%; P<.01; NNT=200).¹ Throughout the range of DBP in study subjects, 70–115 mm Hg, a lower DBP was associated with a lower risk of coronary heart disease.

However, there is concern that lowering DBP too much may actually increase cardiovascular risk. A 10-year observational study showed that in patients with a history of ischemic heart disease, the incidence of fatal MI was lowest when DBP was between 85 to 90 mm Hg and increased with DBP <85 mm Hg, thus demonstrating a J-shaped curve.²

Farnett et al³ derived a summary curve from 13 studies that stratified cardiovascular outcomes by level of achieved blood pressure; the nadir of the curve for ischemic heart disease events occurred at 86 to 89 mm Hg DBP. The risk was independent of type of drug therapy, and more pronounced in study subjects with known cardiovascular disease.

A meta-analysis of 7 randomized controlled trials involving 40,233 hypertensive patients used statistical modeling to determine the shape of the “mortality curve” over a range of DBP categories, defined in 10-mm Hg increments from 65 to 106. The subjects received mainly beta-blockers or thiazide diuretics; controls received placebo or no treatment.⁴ Both groups demonstrated increased risk for cardiovascular and all-cause death at the lowest DBP levels. Among treated patients, overall death rate was lowest with a DBP in the range of 76 to 85 mm Hg; among controls the nadir was 86 to 95 mm Hg.

The Hypertension Optimal Treatment (HOT) trial⁵ was specifically designed to determine the optimal target blood pressure for hypertensive patients: 18,790 men and women with DBP 100 to 115 mm Hg were randomly assigned to target DBP groups of <90, <85, or <80 mm Hg. All were treated with felodipine and other agents in a stepped-care protocol; average follow-up was 3.8 years. The lowest incidence of cardiovascular events occurred at a mean DBP of 82.6 mm Hg and fewest cardiovascular deaths at 86.5 mm Hg. Further reductions in DBP neither lowered nor increased cardiovascular risk.

A French cohort study⁶ followed over 4700 hyper-tensive men for an average of 14 years. These men had their hypertension treated in usual fashion by their own physicians. In this group, SBP was much more accurate than DBP in classifying severity of hypertension and in predicting cardiovascular risk.

Recommendations from others

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)⁷ and the World Health Organization–International Society of Hyper-tension Guidelines⁸ state that the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold. Target blood pressure goals are <140/90 mm Hg in uncomplicated hypertension and <130/80 mm Hg for individuals with diabetes or kidney disease. The National High Blood Pressure Education Program stressed that SBP, not DBP, should become the major criterion for diagnosis and treatment of hypertension.⁹

Evidence summary

ACE inhibitors have been used most commonly for the treatment of congestive heart failure and hypertension and to slow the progression of proteinuria. Their primary mechanism of action is the suppression of angiotensin II by blocking its formation via renin and angiotensin I, thereby reducing the main deleterious effects of angiotensin II, which are mediated through vaso-constriction. Other pathways of angiotensin II formation exist and may escape inhibition of the converting enzyme.¹ ARBs block the action of angiotensin II at the AT1 receptor and may, in theory, provide additive benefit.

The data describing the use of the combination of an ACE inhibitor and an ARB in heart failure are from the Valsartan Heart Failure Trial (ValHeFT),² the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Trial (CHARM),³ and in the Valsartan in Acute Myocardial Infarction Trial (VALIANT).⁴

In ValHeFT, 5010 patients with systolic dysfunction were randomized to the ARB valsartan or placebo in addition to background therapy, which included an ACE inhibitor in 93% of subjects. The primary endpoints were mortality and combined mortality and morbidity. An increase in mortality was found among patients on the triple therapy combination of valsartan, an ACE inhibitor, and a beta-blocker (relative risk [RR]=1.4; 95% confidence interval [CI], 1.1–1.9). Among those not on beta-blockers, adding valsartan to baseline therapy of an ACE inhibitor resulted in a modest improvement in the combined endpoint (RR=0.8; 95% CI, 0.7–0.9), but no change in mortality alone was found.²

In CHARM, candesartan was added to baseline therapy among patients with heart failure. Baseline therapy included diuretics (90%), beta blockers (55%), spironolactone (17%), and other cardiovascular medications as necessary. In this study, those in the treatment arm had a decrease in the combined endpoint of cardiovascular death plus congestive heart failure admission (RR=0.85; 95% CI, 0.75–0.96), but no difference was seen in overall mortality. Of note, no adverse interaction was demonstrated for those on the triple combination of ACE inhibitors, ARBs, and beta-blockers.³

Similarly, VALIANT demonstrated the safety but the lack of incremental efficacy in adding valsartan to ACE inhibitors for patients with left ventricular dysfunction after a myocardial infarction.⁴

Limited evidence is available from randomized controlled trials on the safety or efficacy of combination therapy exclusively for hyperten-sive patients. The available published trials were short-term and assessed blood pressure rather than more clinically significant endpoints such as risk of cardiovascular events and mortality. One trial of 177 patients found no significant difference in 24-hour ambulatory mean diastolic blood pressure with combination therapy vs ACE inhibitor or ARB monotherapy, but did show a decrease in clinic diastolic blood pressure.⁵ Another small trial of 20 patients demonstrated improved ambulatory blood pressure control with combination therapy vs ACE inhibitor monotherapy.⁶

Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.⁷ The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.⁸

Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).

Recommendations from others

We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.

Evidence summary

ACE inhibitors have been used most commonly for the treatment of congestive heart failure and hypertension and to slow the progression of proteinuria. Their primary mechanism of action is the suppression of angiotensin II by blocking its formation via renin and angiotensin I, thereby reducing the main deleterious effects of angiotensin II, which are mediated through vaso-constriction. Other pathways of angiotensin II formation exist and may escape inhibition of the converting enzyme.¹ ARBs block the action of angiotensin II at the AT1 receptor and may, in theory, provide additive benefit.

The data describing the use of the combination of an ACE inhibitor and an ARB in heart failure are from the Valsartan Heart Failure Trial (ValHeFT),² the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Trial (CHARM),³ and in the Valsartan in Acute Myocardial Infarction Trial (VALIANT).⁴

In ValHeFT, 5010 patients with systolic dysfunction were randomized to the ARB valsartan or placebo in addition to background therapy, which included an ACE inhibitor in 93% of subjects. The primary endpoints were mortality and combined mortality and morbidity. An increase in mortality was found among patients on the triple therapy combination of valsartan, an ACE inhibitor, and a beta-blocker (relative risk [RR]=1.4; 95% confidence interval [CI], 1.1–1.9). Among those not on beta-blockers, adding valsartan to baseline therapy of an ACE inhibitor resulted in a modest improvement in the combined endpoint (RR=0.8; 95% CI, 0.7–0.9), but no change in mortality alone was found.²

In CHARM, candesartan was added to baseline therapy among patients with heart failure. Baseline therapy included diuretics (90%), beta blockers (55%), spironolactone (17%), and other cardiovascular medications as necessary. In this study, those in the treatment arm had a decrease in the combined endpoint of cardiovascular death plus congestive heart failure admission (RR=0.85; 95% CI, 0.75–0.96), but no difference was seen in overall mortality. Of note, no adverse interaction was demonstrated for those on the triple combination of ACE inhibitors, ARBs, and beta-blockers.³

Similarly, VALIANT demonstrated the safety but the lack of incremental efficacy in adding valsartan to ACE inhibitors for patients with left ventricular dysfunction after a myocardial infarction.⁴

Limited evidence is available from randomized controlled trials on the safety or efficacy of combination therapy exclusively for hyperten-sive patients. The available published trials were short-term and assessed blood pressure rather than more clinically significant endpoints such as risk of cardiovascular events and mortality. One trial of 177 patients found no significant difference in 24-hour ambulatory mean diastolic blood pressure with combination therapy vs ACE inhibitor or ARB monotherapy, but did show a decrease in clinic diastolic blood pressure.⁵ Another small trial of 20 patients demonstrated improved ambulatory blood pressure control with combination therapy vs ACE inhibitor monotherapy.⁶

Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.⁷ The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.⁸

Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).

Recommendations from others

We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.

Evidence summary

ACE inhibitors have been used most commonly for the treatment of congestive heart failure and hypertension and to slow the progression of proteinuria. Their primary mechanism of action is the suppression of angiotensin II by blocking its formation via renin and angiotensin I, thereby reducing the main deleterious effects of angiotensin II, which are mediated through vaso-constriction. Other pathways of angiotensin II formation exist and may escape inhibition of the converting enzyme.¹ ARBs block the action of angiotensin II at the AT1 receptor and may, in theory, provide additive benefit.

The data describing the use of the combination of an ACE inhibitor and an ARB in heart failure are from the Valsartan Heart Failure Trial (ValHeFT),² the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Trial (CHARM),³ and in the Valsartan in Acute Myocardial Infarction Trial (VALIANT).⁴

In ValHeFT, 5010 patients with systolic dysfunction were randomized to the ARB valsartan or placebo in addition to background therapy, which included an ACE inhibitor in 93% of subjects. The primary endpoints were mortality and combined mortality and morbidity. An increase in mortality was found among patients on the triple therapy combination of valsartan, an ACE inhibitor, and a beta-blocker (relative risk [RR]=1.4; 95% confidence interval [CI], 1.1–1.9). Among those not on beta-blockers, adding valsartan to baseline therapy of an ACE inhibitor resulted in a modest improvement in the combined endpoint (RR=0.8; 95% CI, 0.7–0.9), but no change in mortality alone was found.²

In CHARM, candesartan was added to baseline therapy among patients with heart failure. Baseline therapy included diuretics (90%), beta blockers (55%), spironolactone (17%), and other cardiovascular medications as necessary. In this study, those in the treatment arm had a decrease in the combined endpoint of cardiovascular death plus congestive heart failure admission (RR=0.85; 95% CI, 0.75–0.96), but no difference was seen in overall mortality. Of note, no adverse interaction was demonstrated for those on the triple combination of ACE inhibitors, ARBs, and beta-blockers.³

Similarly, VALIANT demonstrated the safety but the lack of incremental efficacy in adding valsartan to ACE inhibitors for patients with left ventricular dysfunction after a myocardial infarction.⁴

Limited evidence is available from randomized controlled trials on the safety or efficacy of combination therapy exclusively for hyperten-sive patients. The available published trials were short-term and assessed blood pressure rather than more clinically significant endpoints such as risk of cardiovascular events and mortality. One trial of 177 patients found no significant difference in 24-hour ambulatory mean diastolic blood pressure with combination therapy vs ACE inhibitor or ARB monotherapy, but did show a decrease in clinic diastolic blood pressure.⁵ Another small trial of 20 patients demonstrated improved ambulatory blood pressure control with combination therapy vs ACE inhibitor monotherapy.⁶

Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.⁷ The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.⁸

Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).

Recommendations from others

We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.

Evidence summary

Truly isolated hypertriglyceridemia is rare. To date, no good trials directly address the effect of reducing truly isolated hypertriglyceridemia on cardiovascular morbidity or mortality. High triglycerides are usually accompanied by other features of the “metabolic syndrome” (low HDL, high LDL, insulin resistance, diabetes, hypertension, and obesity), making it almost impossible to look at these in isolation or attribute risk to a specific component.¹

Whether high triglyceride levels pose risk in the true absence of these other metabolic factors is controversial. One meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (including 57,000 patients) showed high triglyceride levels to be predictive of cardiac events, even when adjusted for HDL and other risk factors (age, total and LDL cholesterol, smoking, body mass index, and blood pressure).² After adjusting for these other risk factors, the authors found an increased risk for all cardiac endpoints (myocardial infarction, death, etc) of 14% for men and 32% for women (Men: relative risk [RR]=1.14; 95% confidence interval [CI], 1.05–1.28; Women: RR=1.37; 95% CI, 1.13–1.66).

Another meta-analysis of 3 prospective intervention trials with 15,880 enrolled subjects found that triglyceride levels did not provide any clinically meaningful information about risk beyond that provided by other cholesterol subfractions.³

In treatment trials, the most impressive risk reductions come from the groups who fit the lipid triad of low HDL, high LDL, and high triglycerides. Low levels of HDL appear to interact with hypertriglyceridemia to increase coronary risk, and all studies showing improved outcomes have simultaneously increased HDL while lowering triglycerides.^4-6 In 3 large-scale prospective, placebo-controlled trials (the Helsinki Heart Study, a primary prevention study, and the VA-HIT and Bezafibrate Infarction Prevention trials, both secondary prevention studies), lowering triglycerides and raising HDL concurrently improved outcomes.⁵ Successful dietary and medical interventions, especially with statins and fibrates, improved overall lipid profiles—not just triglyceride levels.

Accordingly, elevated triglycerides should prompt providers to rigorously identify these other risk factors for cardiovascular morbidity and mortality, which may not be immediately obvious. In the absence of such other factors, no evidence exists to guide therapy. Expert opinion^7,8 supported by epidemiologic evidence⁹ suggests that patients with triglyceride levels of 500 to 1000 mg/dL may have an increased risk of pancreatitis. Accordingly, providers should consider therapy to lower triglycerides to less than 500 in these patients, regardless of accompanying risk factors.

Recommendations from others

The American College of Physicians, the European Society of Cardiology, and the US Preventive Services Task Force do not recommend screening for hypertriglyceridemia. Clinical guidelines of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), American Heart Association/American College of Cardiology, and the American Diabetes Association all support LDL lowering as the primary target of therapy based on the patients risk profile.¹⁰ NCEP/ATP III has identified triglyceride levels of <150 as normal, 150–199 as borderline high, 200–499 as high, and 500 as very high.7

A patient with high triglycerides should prompt a search for components of the “meta-bolic syndrome” and secondary causes, including high dietary fat, high alcohol intake, drugs (steroids, beta-blockers, high-estrogen oral contraceptives), medical conditions (hypothyroidism, nephrosis, renal failure, liver disease, Cushing disease, and lupus), and rare familial dyslipidemias.^7,10,11

Evidence summary

Truly isolated hypertriglyceridemia is rare. To date, no good trials directly address the effect of reducing truly isolated hypertriglyceridemia on cardiovascular morbidity or mortality. High triglycerides are usually accompanied by other features of the “metabolic syndrome” (low HDL, high LDL, insulin resistance, diabetes, hypertension, and obesity), making it almost impossible to look at these in isolation or attribute risk to a specific component.¹

Whether high triglyceride levels pose risk in the true absence of these other metabolic factors is controversial. One meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (including 57,000 patients) showed high triglyceride levels to be predictive of cardiac events, even when adjusted for HDL and other risk factors (age, total and LDL cholesterol, smoking, body mass index, and blood pressure).² After adjusting for these other risk factors, the authors found an increased risk for all cardiac endpoints (myocardial infarction, death, etc) of 14% for men and 32% for women (Men: relative risk [RR]=1.14; 95% confidence interval [CI], 1.05–1.28; Women: RR=1.37; 95% CI, 1.13–1.66).

Another meta-analysis of 3 prospective intervention trials with 15,880 enrolled subjects found that triglyceride levels did not provide any clinically meaningful information about risk beyond that provided by other cholesterol subfractions.³

In treatment trials, the most impressive risk reductions come from the groups who fit the lipid triad of low HDL, high LDL, and high triglycerides. Low levels of HDL appear to interact with hypertriglyceridemia to increase coronary risk, and all studies showing improved outcomes have simultaneously increased HDL while lowering triglycerides.^4-6 In 3 large-scale prospective, placebo-controlled trials (the Helsinki Heart Study, a primary prevention study, and the VA-HIT and Bezafibrate Infarction Prevention trials, both secondary prevention studies), lowering triglycerides and raising HDL concurrently improved outcomes.⁵ Successful dietary and medical interventions, especially with statins and fibrates, improved overall lipid profiles—not just triglyceride levels.

Accordingly, elevated triglycerides should prompt providers to rigorously identify these other risk factors for cardiovascular morbidity and mortality, which may not be immediately obvious. In the absence of such other factors, no evidence exists to guide therapy. Expert opinion^7,8 supported by epidemiologic evidence⁹ suggests that patients with triglyceride levels of 500 to 1000 mg/dL may have an increased risk of pancreatitis. Accordingly, providers should consider therapy to lower triglycerides to less than 500 in these patients, regardless of accompanying risk factors.

Recommendations from others

The American College of Physicians, the European Society of Cardiology, and the US Preventive Services Task Force do not recommend screening for hypertriglyceridemia. Clinical guidelines of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), American Heart Association/American College of Cardiology, and the American Diabetes Association all support LDL lowering as the primary target of therapy based on the patients risk profile.¹⁰ NCEP/ATP III has identified triglyceride levels of <150 as normal, 150–199 as borderline high, 200–499 as high, and 500 as very high.7

A patient with high triglycerides should prompt a search for components of the “meta-bolic syndrome” and secondary causes, including high dietary fat, high alcohol intake, drugs (steroids, beta-blockers, high-estrogen oral contraceptives), medical conditions (hypothyroidism, nephrosis, renal failure, liver disease, Cushing disease, and lupus), and rare familial dyslipidemias.^7,10,11

Evidence summary

Truly isolated hypertriglyceridemia is rare. To date, no good trials directly address the effect of reducing truly isolated hypertriglyceridemia on cardiovascular morbidity or mortality. High triglycerides are usually accompanied by other features of the “metabolic syndrome” (low HDL, high LDL, insulin resistance, diabetes, hypertension, and obesity), making it almost impossible to look at these in isolation or attribute risk to a specific component.¹

Whether high triglyceride levels pose risk in the true absence of these other metabolic factors is controversial. One meta-analysis of 17 population-based prospective studies of triglycerides and cardiovascular disease (including 57,000 patients) showed high triglyceride levels to be predictive of cardiac events, even when adjusted for HDL and other risk factors (age, total and LDL cholesterol, smoking, body mass index, and blood pressure).² After adjusting for these other risk factors, the authors found an increased risk for all cardiac endpoints (myocardial infarction, death, etc) of 14% for men and 32% for women (Men: relative risk [RR]=1.14; 95% confidence interval [CI], 1.05–1.28; Women: RR=1.37; 95% CI, 1.13–1.66).

Another meta-analysis of 3 prospective intervention trials with 15,880 enrolled subjects found that triglyceride levels did not provide any clinically meaningful information about risk beyond that provided by other cholesterol subfractions.³

In treatment trials, the most impressive risk reductions come from the groups who fit the lipid triad of low HDL, high LDL, and high triglycerides. Low levels of HDL appear to interact with hypertriglyceridemia to increase coronary risk, and all studies showing improved outcomes have simultaneously increased HDL while lowering triglycerides.^4-6 In 3 large-scale prospective, placebo-controlled trials (the Helsinki Heart Study, a primary prevention study, and the VA-HIT and Bezafibrate Infarction Prevention trials, both secondary prevention studies), lowering triglycerides and raising HDL concurrently improved outcomes.⁵ Successful dietary and medical interventions, especially with statins and fibrates, improved overall lipid profiles—not just triglyceride levels.

Accordingly, elevated triglycerides should prompt providers to rigorously identify these other risk factors for cardiovascular morbidity and mortality, which may not be immediately obvious. In the absence of such other factors, no evidence exists to guide therapy. Expert opinion^7,8 supported by epidemiologic evidence⁹ suggests that patients with triglyceride levels of 500 to 1000 mg/dL may have an increased risk of pancreatitis. Accordingly, providers should consider therapy to lower triglycerides to less than 500 in these patients, regardless of accompanying risk factors.

Recommendations from others

The American College of Physicians, the European Society of Cardiology, and the US Preventive Services Task Force do not recommend screening for hypertriglyceridemia. Clinical guidelines of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), American Heart Association/American College of Cardiology, and the American Diabetes Association all support LDL lowering as the primary target of therapy based on the patients risk profile.¹⁰ NCEP/ATP III has identified triglyceride levels of <150 as normal, 150–199 as borderline high, 200–499 as high, and 500 as very high.7

A patient with high triglycerides should prompt a search for components of the “meta-bolic syndrome” and secondary causes, including high dietary fat, high alcohol intake, drugs (steroids, beta-blockers, high-estrogen oral contraceptives), medical conditions (hypothyroidism, nephrosis, renal failure, liver disease, Cushing disease, and lupus), and rare familial dyslipidemias.^7,10,11

Evidence summary

Stress radionuclide imaging—specifically its diagnostic accuracy—has been the subject of numerous studies. Detrano et al¹ reported the first pooled data (56 studies); they concluded that estimates of sensitivity (85%) and specificity (85%) are biased by studies that were not blinded, included subjects with prior myocardial infarction (MI), or had a work-up (verification) bias (ie, use of the gold standard test is affected by the result on the test under question).

Another systematic review reported estimates of sensitivity ranging from 68% to 96% and specificity from 65% to 100%.² The review was accompanied by a position paper from the American College of Physicians stating that the test may be appropriate for a patient with intermediate risk of coronary artery disease.³

Four meta-analyses report diagnostic accuracy of radionuclide cardiac imaging (Table). Kwok et al⁶ analyzed data on women only and found decreased diagnostic accuracy in this population. Kim et al⁷ analyzed pharmacologic stressors used with SPECT and confirmed that accuracy is near that of exercise SPECT. Patient-centered outcomes were reported in a meta-analysis of dipyridamole-thallium imaging in the preoperative evaluation of vascular surgery patients. The summary odds ratio for any perioperative cardiac event (in patients with abnormal tests) was 3.5 (95% confidence interval [CI], 2.5–4.8); the odds ratio for MI or cardiac death was 3.9 (95% CI, 2.5–5.6), leading the authors to conclude that there is sound evidence to use radionuclide testing in intermedi.ate-risk patients during preoperative screening.⁸

TABLE
Diagnostic accuracy reported in meta-analyses of cardiac radionuclide SPECT imaging

Recommendations from others

The American Heart Association/American College Cardiology (AHA/ACC) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures and the American Society of Nuclear Cardiology updated guidelines for cardiac radionuclide imaging in 2003. In this consensus statement (a nonsystematic review of literature and expert opinion), they reported test characteristics to detect a 50% angiographic lesion as follows—exercise SPECT: sensitivity 87%, specificity 73%; vasodilator (adenosine or dipyridamole) SPECT: sensitivity 89%, specificity 75%. They noted that quantitative analysis performs as well as qualitative analysis of radionuclide images. Gated SPECT is slightly more specific and just as sensitive as nongated SPECT.

The Taskforce recommended that radionuclide perfusion scans be performed in patients with baseline electrocardiogram (ECG) abnormalities (such as left bundle branch block, hypertrophy, digitalis effect, etc), patients who cannot perform an exercise stress test, and to assess the functional effect of indeterminate lesions found on angiography. They also note that the repeat use of radionuclide testing 3 to 5 years after an event in asymptomatic high-risk patients and the initial use of radionuclide testing in patients at very high risk are both somewhat controversial, but the weight of limited evidence suggests some benefit to their use.⁹

Evidence summary

Stress radionuclide imaging—specifically its diagnostic accuracy—has been the subject of numerous studies. Detrano et al¹ reported the first pooled data (56 studies); they concluded that estimates of sensitivity (85%) and specificity (85%) are biased by studies that were not blinded, included subjects with prior myocardial infarction (MI), or had a work-up (verification) bias (ie, use of the gold standard test is affected by the result on the test under question).

Another systematic review reported estimates of sensitivity ranging from 68% to 96% and specificity from 65% to 100%.² The review was accompanied by a position paper from the American College of Physicians stating that the test may be appropriate for a patient with intermediate risk of coronary artery disease.³

Four meta-analyses report diagnostic accuracy of radionuclide cardiac imaging (Table). Kwok et al⁶ analyzed data on women only and found decreased diagnostic accuracy in this population. Kim et al⁷ analyzed pharmacologic stressors used with SPECT and confirmed that accuracy is near that of exercise SPECT. Patient-centered outcomes were reported in a meta-analysis of dipyridamole-thallium imaging in the preoperative evaluation of vascular surgery patients. The summary odds ratio for any perioperative cardiac event (in patients with abnormal tests) was 3.5 (95% confidence interval [CI], 2.5–4.8); the odds ratio for MI or cardiac death was 3.9 (95% CI, 2.5–5.6), leading the authors to conclude that there is sound evidence to use radionuclide testing in intermedi.ate-risk patients during preoperative screening.⁸

TABLE
Diagnostic accuracy reported in meta-analyses of cardiac radionuclide SPECT imaging

Recommendations from others

The American Heart Association/American College Cardiology (AHA/ACC) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures and the American Society of Nuclear Cardiology updated guidelines for cardiac radionuclide imaging in 2003. In this consensus statement (a nonsystematic review of literature and expert opinion), they reported test characteristics to detect a 50% angiographic lesion as follows—exercise SPECT: sensitivity 87%, specificity 73%; vasodilator (adenosine or dipyridamole) SPECT: sensitivity 89%, specificity 75%. They noted that quantitative analysis performs as well as qualitative analysis of radionuclide images. Gated SPECT is slightly more specific and just as sensitive as nongated SPECT.

The Taskforce recommended that radionuclide perfusion scans be performed in patients with baseline electrocardiogram (ECG) abnormalities (such as left bundle branch block, hypertrophy, digitalis effect, etc), patients who cannot perform an exercise stress test, and to assess the functional effect of indeterminate lesions found on angiography. They also note that the repeat use of radionuclide testing 3 to 5 years after an event in asymptomatic high-risk patients and the initial use of radionuclide testing in patients at very high risk are both somewhat controversial, but the weight of limited evidence suggests some benefit to their use.⁹

Evidence summary

Stress radionuclide imaging—specifically its diagnostic accuracy—has been the subject of numerous studies. Detrano et al¹ reported the first pooled data (56 studies); they concluded that estimates of sensitivity (85%) and specificity (85%) are biased by studies that were not blinded, included subjects with prior myocardial infarction (MI), or had a work-up (verification) bias (ie, use of the gold standard test is affected by the result on the test under question).

Another systematic review reported estimates of sensitivity ranging from 68% to 96% and specificity from 65% to 100%.² The review was accompanied by a position paper from the American College of Physicians stating that the test may be appropriate for a patient with intermediate risk of coronary artery disease.³

Four meta-analyses report diagnostic accuracy of radionuclide cardiac imaging (Table). Kwok et al⁶ analyzed data on women only and found decreased diagnostic accuracy in this population. Kim et al⁷ analyzed pharmacologic stressors used with SPECT and confirmed that accuracy is near that of exercise SPECT. Patient-centered outcomes were reported in a meta-analysis of dipyridamole-thallium imaging in the preoperative evaluation of vascular surgery patients. The summary odds ratio for any perioperative cardiac event (in patients with abnormal tests) was 3.5 (95% confidence interval [CI], 2.5–4.8); the odds ratio for MI or cardiac death was 3.9 (95% CI, 2.5–5.6), leading the authors to conclude that there is sound evidence to use radionuclide testing in intermedi.ate-risk patients during preoperative screening.⁸

TABLE
Diagnostic accuracy reported in meta-analyses of cardiac radionuclide SPECT imaging

Recommendations from others

The American Heart Association/American College Cardiology (AHA/ACC) Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures and the American Society of Nuclear Cardiology updated guidelines for cardiac radionuclide imaging in 2003. In this consensus statement (a nonsystematic review of literature and expert opinion), they reported test characteristics to detect a 50% angiographic lesion as follows—exercise SPECT: sensitivity 87%, specificity 73%; vasodilator (adenosine or dipyridamole) SPECT: sensitivity 89%, specificity 75%. They noted that quantitative analysis performs as well as qualitative analysis of radionuclide images. Gated SPECT is slightly more specific and just as sensitive as nongated SPECT.

The Taskforce recommended that radionuclide perfusion scans be performed in patients with baseline electrocardiogram (ECG) abnormalities (such as left bundle branch block, hypertrophy, digitalis effect, etc), patients who cannot perform an exercise stress test, and to assess the functional effect of indeterminate lesions found on angiography. They also note that the repeat use of radionuclide testing 3 to 5 years after an event in asymptomatic high-risk patients and the initial use of radionuclide testing in patients at very high risk are both somewhat controversial, but the weight of limited evidence suggests some benefit to their use.⁹

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.

Evidence summary

Three recent evidence-based guidelines^3,4,5 suggest that children and adults with acute sinusitis may benefit from treatment with antibiotics more than those with rhinitis. Clinicians must develop a strategy for accurately diagnosing sinusitis to make sound treatment decisions. In the absence of a clear diagnosis of acute sinusitis, antibiotics are very unlikely to improve symptoms and are, therefore, not indicated.

Clinical evaluation. Berg¹ studied 150 patients with clinical diagnoses of sinusitis and found that 85% of them had positive sinus puncture. In a review of the 11 studies that met evidence-based inclusion criteria, Varonen⁶ concluded that clinical evaluation has a sensitivity of roughly 0.75, whereas radiographic methodologies have sensitivities >0.80. In a prospective trial and subsequent review of the literature, Lindbaek^7,8,9 suggests that several key clinical signs and symptoms can provide a level of sensitivity that approaches that of CT or magnetic resonance imaging (MRI), while enhancing specificity:

• Purulent secretion reported as a symptom or found in the nasal cavity by the doctor
• Pain in the teeth
• Pain on bending forward (inconsistent findings between studies)
• Two phases in the illness history
• Elevated erythrocyte sedimentation rate or increased C-reactive protein
• Symptoms for at least 7 days

Lau and colleagues^5,10 reviewed 14 studies that compared various imaging studies with clinical evaluation or sinus puncture and aspiration with culture or both. A positive aspirate for bacterial pathogens was defined as the gold standard for diagnosis of sinusitis (Table).

X-ray vs sinus puncture. Depending on the criteria used to define a diagnosis of sinusitis on plain radiograph, estimates of sensitivity in these studies ranged from 0.41 to 0.90, and specificity estimates ranged from 0.61 to 0.85. Imaging studies that included “mucous membrane thickening” as a criterion for sinusitis were more sensitive but less specific than studies defining positive radiographs as “opacification of sinus.”

CT scan, MRI, ultrasound. While a CT scan is more sensitive than plain x-ray film,¹¹ and MRI is more sensitive than a CT scan,^12,13 the specificity of these studies is unclear. For example, in children and adults without symptoms of sinusitis, the prevalence of sinusitis signs on CT and MRI is 45% and 42%, respectively.^6,7,14 In light of such findings, these imaging methodologies are better reserved for patients in whom surgery is being contemplated, or for whom chronic sinusitis is a concern. In the 1980s and 1990s, ultrasound was studied enthusiastically. Variability in test performance is great.⁶ Since the cost of this procedure is similar to that of a sinus CT, ultrasound is not indicated in the diagnostic evaluation of the sinuses.

Though the sensitivity and specificity of a clinical evaluation possibly could be enhanced with the use of imaging studies, diagnostic accuracy of acute disease is not sufficiently improved to justify the cost or inconvenience of such interventions.

TABLE
Sensitivity and specificity of imaging modalities in sinusitis

Recommendations from others

In a guideline on appropriate antibiotic use in sinusitis,⁴ endorsed by the Centers for Disease Control and Prevention, American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, and the Infectious Diseases Society of America, radiography is not recommended for the diagnosis of acute sinusitis. The guideline recommends that clinicians rely on duration of illness (at least 7 days) and severity of symptoms to make an accurate diagnosis of sinusitis.

The American Academy of Allergy, Asthma and Immunology¹⁵ guideline makes the following recommendations regarding imaging:

• The use of imaging may be appropriate when there are vague symptoms, or poor response to initial management
• Standard radiographs are insensitive, but may be used for diagnosis of acute sinus disease
• CT is preferred for preoperative evaluation of the nose and paranasal sinuses
• MRI is very sensitive for diagnosis of soft tissue disease in the frontal, maxillary, and sphenoid sinuses
• Ultrasonography has limited utility but may be applicable in pregnant women and for determining the amount of retained secretions.

The Institute for Clinical Systems Improvement recommends that radiology be used only if initial treatment has failed, and notes that a primary goal of its guideline was to reduce the number of x-rays that physicians order for this diagnosis.¹⁶

The American College of Radiology’s criteria for sinusitis in the pediatric population ranked several radiographic studies based on their appropriateness for given clinical conditions. This review¹⁷ suggests that no imaging is appropriate if symptoms have persisted <10 days. For patients with symptoms lasting >10 days and with persistent fever, CT scan is recommended.

Evidence summary

Three recent evidence-based guidelines^3,4,5 suggest that children and adults with acute sinusitis may benefit from treatment with antibiotics more than those with rhinitis. Clinicians must develop a strategy for accurately diagnosing sinusitis to make sound treatment decisions. In the absence of a clear diagnosis of acute sinusitis, antibiotics are very unlikely to improve symptoms and are, therefore, not indicated.

Clinical evaluation. Berg¹ studied 150 patients with clinical diagnoses of sinusitis and found that 85% of them had positive sinus puncture. In a review of the 11 studies that met evidence-based inclusion criteria, Varonen⁶ concluded that clinical evaluation has a sensitivity of roughly 0.75, whereas radiographic methodologies have sensitivities >0.80. In a prospective trial and subsequent review of the literature, Lindbaek^7,8,9 suggests that several key clinical signs and symptoms can provide a level of sensitivity that approaches that of CT or magnetic resonance imaging (MRI), while enhancing specificity:

• Purulent secretion reported as a symptom or found in the nasal cavity by the doctor
• Pain in the teeth
• Pain on bending forward (inconsistent findings between studies)
• Two phases in the illness history
• Elevated erythrocyte sedimentation rate or increased C-reactive protein
• Symptoms for at least 7 days

Lau and colleagues^5,10 reviewed 14 studies that compared various imaging studies with clinical evaluation or sinus puncture and aspiration with culture or both. A positive aspirate for bacterial pathogens was defined as the gold standard for diagnosis of sinusitis (Table).

X-ray vs sinus puncture. Depending on the criteria used to define a diagnosis of sinusitis on plain radiograph, estimates of sensitivity in these studies ranged from 0.41 to 0.90, and specificity estimates ranged from 0.61 to 0.85. Imaging studies that included “mucous membrane thickening” as a criterion for sinusitis were more sensitive but less specific than studies defining positive radiographs as “opacification of sinus.”

CT scan, MRI, ultrasound. While a CT scan is more sensitive than plain x-ray film,¹¹ and MRI is more sensitive than a CT scan,^12,13 the specificity of these studies is unclear. For example, in children and adults without symptoms of sinusitis, the prevalence of sinusitis signs on CT and MRI is 45% and 42%, respectively.^6,7,14 In light of such findings, these imaging methodologies are better reserved for patients in whom surgery is being contemplated, or for whom chronic sinusitis is a concern. In the 1980s and 1990s, ultrasound was studied enthusiastically. Variability in test performance is great.⁶ Since the cost of this procedure is similar to that of a sinus CT, ultrasound is not indicated in the diagnostic evaluation of the sinuses.

Though the sensitivity and specificity of a clinical evaluation possibly could be enhanced with the use of imaging studies, diagnostic accuracy of acute disease is not sufficiently improved to justify the cost or inconvenience of such interventions.

TABLE
Sensitivity and specificity of imaging modalities in sinusitis

Recommendations from others

In a guideline on appropriate antibiotic use in sinusitis,⁴ endorsed by the Centers for Disease Control and Prevention, American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, and the Infectious Diseases Society of America, radiography is not recommended for the diagnosis of acute sinusitis. The guideline recommends that clinicians rely on duration of illness (at least 7 days) and severity of symptoms to make an accurate diagnosis of sinusitis.

The American Academy of Allergy, Asthma and Immunology¹⁵ guideline makes the following recommendations regarding imaging:

• The use of imaging may be appropriate when there are vague symptoms, or poor response to initial management
• Standard radiographs are insensitive, but may be used for diagnosis of acute sinus disease
• CT is preferred for preoperative evaluation of the nose and paranasal sinuses
• MRI is very sensitive for diagnosis of soft tissue disease in the frontal, maxillary, and sphenoid sinuses
• Ultrasonography has limited utility but may be applicable in pregnant women and for determining the amount of retained secretions.

The Institute for Clinical Systems Improvement recommends that radiology be used only if initial treatment has failed, and notes that a primary goal of its guideline was to reduce the number of x-rays that physicians order for this diagnosis.¹⁶

The American College of Radiology’s criteria for sinusitis in the pediatric population ranked several radiographic studies based on their appropriateness for given clinical conditions. This review¹⁷ suggests that no imaging is appropriate if symptoms have persisted <10 days. For patients with symptoms lasting >10 days and with persistent fever, CT scan is recommended.

Evidence summary

Three recent evidence-based guidelines^3,4,5 suggest that children and adults with acute sinusitis may benefit from treatment with antibiotics more than those with rhinitis. Clinicians must develop a strategy for accurately diagnosing sinusitis to make sound treatment decisions. In the absence of a clear diagnosis of acute sinusitis, antibiotics are very unlikely to improve symptoms and are, therefore, not indicated.

Clinical evaluation. Berg¹ studied 150 patients with clinical diagnoses of sinusitis and found that 85% of them had positive sinus puncture. In a review of the 11 studies that met evidence-based inclusion criteria, Varonen⁶ concluded that clinical evaluation has a sensitivity of roughly 0.75, whereas radiographic methodologies have sensitivities >0.80. In a prospective trial and subsequent review of the literature, Lindbaek^7,8,9 suggests that several key clinical signs and symptoms can provide a level of sensitivity that approaches that of CT or magnetic resonance imaging (MRI), while enhancing specificity:

• Purulent secretion reported as a symptom or found in the nasal cavity by the doctor
• Pain in the teeth
• Pain on bending forward (inconsistent findings between studies)
• Two phases in the illness history
• Elevated erythrocyte sedimentation rate or increased C-reactive protein
• Symptoms for at least 7 days

Lau and colleagues^5,10 reviewed 14 studies that compared various imaging studies with clinical evaluation or sinus puncture and aspiration with culture or both. A positive aspirate for bacterial pathogens was defined as the gold standard for diagnosis of sinusitis (Table).

X-ray vs sinus puncture. Depending on the criteria used to define a diagnosis of sinusitis on plain radiograph, estimates of sensitivity in these studies ranged from 0.41 to 0.90, and specificity estimates ranged from 0.61 to 0.85. Imaging studies that included “mucous membrane thickening” as a criterion for sinusitis were more sensitive but less specific than studies defining positive radiographs as “opacification of sinus.”

CT scan, MRI, ultrasound. While a CT scan is more sensitive than plain x-ray film,¹¹ and MRI is more sensitive than a CT scan,^12,13 the specificity of these studies is unclear. For example, in children and adults without symptoms of sinusitis, the prevalence of sinusitis signs on CT and MRI is 45% and 42%, respectively.^6,7,14 In light of such findings, these imaging methodologies are better reserved for patients in whom surgery is being contemplated, or for whom chronic sinusitis is a concern. In the 1980s and 1990s, ultrasound was studied enthusiastically. Variability in test performance is great.⁶ Since the cost of this procedure is similar to that of a sinus CT, ultrasound is not indicated in the diagnostic evaluation of the sinuses.

Though the sensitivity and specificity of a clinical evaluation possibly could be enhanced with the use of imaging studies, diagnostic accuracy of acute disease is not sufficiently improved to justify the cost or inconvenience of such interventions.

TABLE
Sensitivity and specificity of imaging modalities in sinusitis

Recommendations from others

In a guideline on appropriate antibiotic use in sinusitis,⁴ endorsed by the Centers for Disease Control and Prevention, American Academy of Family Physicians, the American College of Physicians–American Society of Internal Medicine, and the Infectious Diseases Society of America, radiography is not recommended for the diagnosis of acute sinusitis. The guideline recommends that clinicians rely on duration of illness (at least 7 days) and severity of symptoms to make an accurate diagnosis of sinusitis.

The American Academy of Allergy, Asthma and Immunology¹⁵ guideline makes the following recommendations regarding imaging:

• The use of imaging may be appropriate when there are vague symptoms, or poor response to initial management
• Standard radiographs are insensitive, but may be used for diagnosis of acute sinus disease
• CT is preferred for preoperative evaluation of the nose and paranasal sinuses
• MRI is very sensitive for diagnosis of soft tissue disease in the frontal, maxillary, and sphenoid sinuses
• Ultrasonography has limited utility but may be applicable in pregnant women and for determining the amount of retained secretions.

The Institute for Clinical Systems Improvement recommends that radiology be used only if initial treatment has failed, and notes that a primary goal of its guideline was to reduce the number of x-rays that physicians order for this diagnosis.¹⁶

The American College of Radiology’s criteria for sinusitis in the pediatric population ranked several radiographic studies based on their appropriateness for given clinical conditions. This review¹⁷ suggests that no imaging is appropriate if symptoms have persisted <10 days. For patients with symptoms lasting >10 days and with persistent fever, CT scan is recommended.

Evidence summary

A Cochrane Review of 110 trials evaluating the efficacy of nicotine replacement therapy in 35,600 smokers found higher quit rates among heavy smokers using 4-mg compared with 2-mg nicotine gum (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.69–4.22).¹ However, patients often chew too few pieces of nicotine gum daily, resulting in underdosing.³ Smokers should use the gum on a fixed schedule (at least 1 piece every 1 to 2 hours).³

The Cochrane Review finds borderline evidence of a small benefit in abstinence rates (OR, 1.21; 95% CI, 1.03–1.42) with higher-dose nicotine patches (>21 mg/24 hr or 15 mg/16 hr) for heavy or relapsed smokers.¹ Combining methods that maintain constant drug levels (transdermal patch) with those having more rapid effects (gum, spray, inhaler, lozenge) is more effective than monotherapy (OR, 1.9; 95% CI, 1.3–2.6).³ Reserve combination therapy for smokers who relapse following monotherapy.

Regarding concerns about weight gain, all nicotine replacement therapies delay but do not prevent weight gain. There is a dose-response relationship between nicotine gum and weight gain: smokers who use more gum gain less weight.³ Although abstinence rates are comparable across the 5 available forms of nicotine replacement, smokers unwilling to give up oral and behavioral rituals of smoking may perceive the inhaler as being more helpful (Table 1).⁴

Decisions about the best form of therapy can be based on patient preference, on degree of nicotine dependence (a Fagerström Test of Nicotine Dependence Scale score ≥5 [Table 2], or habitually smoking the first cigarette within 30 minutes of awakening),⁵ or nicotine replacement therapy history, which includes number and outcome of previous quit attempts, specific method used, duration, side effects, and proper usage.

Recommendations from others

The Cochrane Review states: “All of the commercially available forms of nicotine replacement therapy are effective as part of a strategy to promote smoking cessation. They increase quit rates approximately 1.5 to 2 fold regardless of setting. Use of nicotine replacement therapy should be preferentially directed to smokers who are motivated to quit, and have high levels of nicotine dependency. Choice of which form to use should reflect patient needs, tolerability and cost considerations. Patches are likely to be easier to use than gum or nasal spray in primary care settings.”¹

The US Department of Health and Human Services Clinical Practice Guideline states: “All patients attempting to quit should be encouraged to use effective pharmacotherapies for smoking cessation except in the presence of special circumstances.”³ Heavy smokers should use 4-mg nicotine gum. Combining the nicotine patch with a self-administered form of nicotine replacement therapy (gum or nicotine nasal spray) is more efficacious than a single form of therapy. Patients should be encouraged to use combined treatments if unable to quit using a single form of first-line pharmacotherapy.³

TABLE 1
Nicotine replacement therapy selection guide

TABLE 2
Fagerström test for level of nicotine dependence (abridged)

Evidence summary

A Cochrane Review of 110 trials evaluating the efficacy of nicotine replacement therapy in 35,600 smokers found higher quit rates among heavy smokers using 4-mg compared with 2-mg nicotine gum (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.69–4.22).¹ However, patients often chew too few pieces of nicotine gum daily, resulting in underdosing.³ Smokers should use the gum on a fixed schedule (at least 1 piece every 1 to 2 hours).³

The Cochrane Review finds borderline evidence of a small benefit in abstinence rates (OR, 1.21; 95% CI, 1.03–1.42) with higher-dose nicotine patches (>21 mg/24 hr or 15 mg/16 hr) for heavy or relapsed smokers.¹ Combining methods that maintain constant drug levels (transdermal patch) with those having more rapid effects (gum, spray, inhaler, lozenge) is more effective than monotherapy (OR, 1.9; 95% CI, 1.3–2.6).³ Reserve combination therapy for smokers who relapse following monotherapy.

Regarding concerns about weight gain, all nicotine replacement therapies delay but do not prevent weight gain. There is a dose-response relationship between nicotine gum and weight gain: smokers who use more gum gain less weight.³ Although abstinence rates are comparable across the 5 available forms of nicotine replacement, smokers unwilling to give up oral and behavioral rituals of smoking may perceive the inhaler as being more helpful (Table 1).⁴

Decisions about the best form of therapy can be based on patient preference, on degree of nicotine dependence (a Fagerström Test of Nicotine Dependence Scale score ≥5 [Table 2], or habitually smoking the first cigarette within 30 minutes of awakening),⁵ or nicotine replacement therapy history, which includes number and outcome of previous quit attempts, specific method used, duration, side effects, and proper usage.

Recommendations from others

The Cochrane Review states: “All of the commercially available forms of nicotine replacement therapy are effective as part of a strategy to promote smoking cessation. They increase quit rates approximately 1.5 to 2 fold regardless of setting. Use of nicotine replacement therapy should be preferentially directed to smokers who are motivated to quit, and have high levels of nicotine dependency. Choice of which form to use should reflect patient needs, tolerability and cost considerations. Patches are likely to be easier to use than gum or nasal spray in primary care settings.”¹

The US Department of Health and Human Services Clinical Practice Guideline states: “All patients attempting to quit should be encouraged to use effective pharmacotherapies for smoking cessation except in the presence of special circumstances.”³ Heavy smokers should use 4-mg nicotine gum. Combining the nicotine patch with a self-administered form of nicotine replacement therapy (gum or nicotine nasal spray) is more efficacious than a single form of therapy. Patients should be encouraged to use combined treatments if unable to quit using a single form of first-line pharmacotherapy.³

TABLE 1
Nicotine replacement therapy selection guide

TABLE 2
Fagerström test for level of nicotine dependence (abridged)

Evidence summary

A Cochrane Review of 110 trials evaluating the efficacy of nicotine replacement therapy in 35,600 smokers found higher quit rates among heavy smokers using 4-mg compared with 2-mg nicotine gum (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.69–4.22).¹ However, patients often chew too few pieces of nicotine gum daily, resulting in underdosing.³ Smokers should use the gum on a fixed schedule (at least 1 piece every 1 to 2 hours).³

The Cochrane Review finds borderline evidence of a small benefit in abstinence rates (OR, 1.21; 95% CI, 1.03–1.42) with higher-dose nicotine patches (>21 mg/24 hr or 15 mg/16 hr) for heavy or relapsed smokers.¹ Combining methods that maintain constant drug levels (transdermal patch) with those having more rapid effects (gum, spray, inhaler, lozenge) is more effective than monotherapy (OR, 1.9; 95% CI, 1.3–2.6).³ Reserve combination therapy for smokers who relapse following monotherapy.

Regarding concerns about weight gain, all nicotine replacement therapies delay but do not prevent weight gain. There is a dose-response relationship between nicotine gum and weight gain: smokers who use more gum gain less weight.³ Although abstinence rates are comparable across the 5 available forms of nicotine replacement, smokers unwilling to give up oral and behavioral rituals of smoking may perceive the inhaler as being more helpful (Table 1).⁴

Decisions about the best form of therapy can be based on patient preference, on degree of nicotine dependence (a Fagerström Test of Nicotine Dependence Scale score ≥5 [Table 2], or habitually smoking the first cigarette within 30 minutes of awakening),⁵ or nicotine replacement therapy history, which includes number and outcome of previous quit attempts, specific method used, duration, side effects, and proper usage.

Recommendations from others

The Cochrane Review states: “All of the commercially available forms of nicotine replacement therapy are effective as part of a strategy to promote smoking cessation. They increase quit rates approximately 1.5 to 2 fold regardless of setting. Use of nicotine replacement therapy should be preferentially directed to smokers who are motivated to quit, and have high levels of nicotine dependency. Choice of which form to use should reflect patient needs, tolerability and cost considerations. Patches are likely to be easier to use than gum or nasal spray in primary care settings.”¹

The US Department of Health and Human Services Clinical Practice Guideline states: “All patients attempting to quit should be encouraged to use effective pharmacotherapies for smoking cessation except in the presence of special circumstances.”³ Heavy smokers should use 4-mg nicotine gum. Combining the nicotine patch with a self-administered form of nicotine replacement therapy (gum or nicotine nasal spray) is more efficacious than a single form of therapy. Patients should be encouraged to use combined treatments if unable to quit using a single form of first-line pharmacotherapy.³

TABLE 1
Nicotine replacement therapy selection guide

TABLE 2
Fagerström test for level of nicotine dependence (abridged)

Evidence summary

Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.

A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.

Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.

Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.⁴

Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.

Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.

Recommendations from others

The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”⁸

The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.⁹ The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.¹⁰

Evidence summary

Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.

A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.

Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.

Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.⁴

Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.

Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.

Recommendations from others

The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”⁸

The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.⁹ The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.¹⁰

Evidence summary

Hormone replacement therapy (HRT) is the standard treatment for vasomotor symptoms of menopause, and it is effective for this indication. With recent studies showing no benefit from long-term HRT for menopausal women and increased adverse effects with its use (especially for women at risk for coronary heart disease), there has been increased interest in nonhormonal treatments for these symptoms.

A small number of randomized clinical trials have studied treatments other than HRT for the control of vasomotor symptoms of menopause. As a group, these trials have been short-term and have involved small numbers of patients. A disproportionate number of trials have been completed in breast cancer survivors, since these patients tend to have more severe vasomotor symptoms as a result of their anti-estrogenic therapies. Whether these results can be generalized to all postmenopausal women with vasomotor symptoms cannot be determined from the evidence.

Eleven randomized trials of soy protein/isoflavone used placebo controls. Results were mixed, with 7 trials showing no effect and 4 showing a reduction in hot flushes in comparison with placebo. Studies reporting a positive effect showed approximately a 15% reduction in episodes in comparison with placebo. In one 6-month trial, there was a correlation between hot flushes and urinary isoflavone excretion regardless of treatment group, suggesting a confounding effect of dietary intake of isoflavone.

Five of six randomized controlled trials of cloni-dine have shown a reduction in frequency of hot flushes ranging from 14%–50% compared with placebo. One trial, which used oral clonidine 0.1 mg daily, also reported an improved quality of life for the treatment group. A single randomized trial has shown that gabapentin, at a dose of 900 mg/day, is effective in reducing both frequency and severity of hot flashes.⁴

Trials of specific selective serotonin reuptake inhibitors have been completed in patients with vasomotor symptoms secondary to breast cancer therapies. Individual randomized controlled trials of venlafaxine and fluoxetine have proven these agents effective, and a preliminary open-labeled trial of paroxetine has also suggested benefit.

Several reviews suggest black cohosh may be effective for short-term treatment, and it is used in Germany for this indication. The trials we found were not placebo-controlled, however, and the safety of this agent is controversial. A single English-language placebo-controlled trial did not show any benefit for black cohosh.

Recommendations from others

The American College of Obstetrics and Gynecology clinical management guideline, “The use of botanicals for management of menopausal symptoms,” gives a level C recommendation (consensus and expert opinion) that “Soy and isoflavone may be helpful in short-term (2 years) treatment of vasomotor symptoms” and “black cohosh may be helpful in the short-term (6 months) treatment of women with vasomotor symptoms.” They note that “given the possibility that these compounds may interact with estrogen, these agents should not be considered free of potential harm in women with estrogen-dependent cancers.”⁸

The North American Menopause Society notes that behavior changes, such as moderate exercise and avoidance of hot-flush triggers, may prevent some hot flushes, although there is only anecdotal evidence for this. The efficacy of paced respiration—deep, slow abdominal breathing—to lessen hot flushes has been shown in a small trial. The society states that other alternative therapies have not been shown to be efficacious, except for moderate quantities of soy products.⁹ The Medical Letter says the evidence that phytoestrogens are helpful for menopausal women comes mostly from epidemiological studies. The long-term adverse effects of phytoestrogen consumption are not known.¹⁰

Evidence summary

Patients with diabetes mellitus have a 20% to 40% lifetime risk for development of nephropathy, and microalbuminuria is the earliest easily detectable marker of renal damage.¹ Improved control of blood sugar^2,3 and blood pressure⁴ decreases but does not completely prevent development of microalbuminuria and progression to overt kidney failure. ACE inhibitors and ARBs have been shown to diminish this progression even in the absence of hypertension (the latter in type 2 diabetes only) (Table).

No prospective randomized trials of screening have been reported. There is uncertainty about what method of screening is most effective and practical in primary care settings.¹⁰ Expert opinion recommends diagnosing microalbuminuria after 2 positive test results,¹ but whether repeated tests improve diagnostic accuracy is still controversial.¹⁰

A large randomized controlled trial showing better long-term renal and vascular disease outcomes would be needed to give screening for microalbuminuria a strength of recommendation of A. Recruiting patients for such a study, and interpreting its results, would be difficult: many subjects would have other indications, such as hypertension or congestive heart failure, warranting use of potentially renoprotective medications.

TABLE
Reno- and cardioprotective efficacy of treatments for diabetic patients with microalbuminuria

Recommendations from others

The American Diabetes Association recommends annual screening for microalbuminuria—after 5 years of established type 1 disease, and at time of diagnosis for type 2 diabetes without macroalbuminuria. Initial screening can use 1 of 3 methods: measurement of the albumin-to-creatinine ratio in a random, spot collection; 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; timed (eg, 4-hour or overnight) collection. At least 2 of 3 tests measured within a 6-month period should show elevated levels before a patient is said to have microalbuminuria.¹

Evidence summary

Patients with diabetes mellitus have a 20% to 40% lifetime risk for development of nephropathy, and microalbuminuria is the earliest easily detectable marker of renal damage.¹ Improved control of blood sugar^2,3 and blood pressure⁴ decreases but does not completely prevent development of microalbuminuria and progression to overt kidney failure. ACE inhibitors and ARBs have been shown to diminish this progression even in the absence of hypertension (the latter in type 2 diabetes only) (Table).

No prospective randomized trials of screening have been reported. There is uncertainty about what method of screening is most effective and practical in primary care settings.¹⁰ Expert opinion recommends diagnosing microalbuminuria after 2 positive test results,¹ but whether repeated tests improve diagnostic accuracy is still controversial.¹⁰

A large randomized controlled trial showing better long-term renal and vascular disease outcomes would be needed to give screening for microalbuminuria a strength of recommendation of A. Recruiting patients for such a study, and interpreting its results, would be difficult: many subjects would have other indications, such as hypertension or congestive heart failure, warranting use of potentially renoprotective medications.

TABLE
Reno- and cardioprotective efficacy of treatments for diabetic patients with microalbuminuria

Recommendations from others

The American Diabetes Association recommends annual screening for microalbuminuria—after 5 years of established type 1 disease, and at time of diagnosis for type 2 diabetes without macroalbuminuria. Initial screening can use 1 of 3 methods: measurement of the albumin-to-creatinine ratio in a random, spot collection; 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; timed (eg, 4-hour or overnight) collection. At least 2 of 3 tests measured within a 6-month period should show elevated levels before a patient is said to have microalbuminuria.¹

Evidence summary

Patients with diabetes mellitus have a 20% to 40% lifetime risk for development of nephropathy, and microalbuminuria is the earliest easily detectable marker of renal damage.¹ Improved control of blood sugar^2,3 and blood pressure⁴ decreases but does not completely prevent development of microalbuminuria and progression to overt kidney failure. ACE inhibitors and ARBs have been shown to diminish this progression even in the absence of hypertension (the latter in type 2 diabetes only) (Table).

No prospective randomized trials of screening have been reported. There is uncertainty about what method of screening is most effective and practical in primary care settings.¹⁰ Expert opinion recommends diagnosing microalbuminuria after 2 positive test results,¹ but whether repeated tests improve diagnostic accuracy is still controversial.¹⁰

A large randomized controlled trial showing better long-term renal and vascular disease outcomes would be needed to give screening for microalbuminuria a strength of recommendation of A. Recruiting patients for such a study, and interpreting its results, would be difficult: many subjects would have other indications, such as hypertension or congestive heart failure, warranting use of potentially renoprotective medications.

TABLE
Reno- and cardioprotective efficacy of treatments for diabetic patients with microalbuminuria

Recommendations from others

The American Diabetes Association recommends annual screening for microalbuminuria—after 5 years of established type 1 disease, and at time of diagnosis for type 2 diabetes without macroalbuminuria. Initial screening can use 1 of 3 methods: measurement of the albumin-to-creatinine ratio in a random, spot collection; 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; timed (eg, 4-hour or overnight) collection. At least 2 of 3 tests measured within a 6-month period should show elevated levels before a patient is said to have microalbuminuria.¹