Evidence Table 9

Placebo controlled trials of beta blockers for heart failure

Mean EF
NYHA Class
Eligibility criteriaExclusion criteriaInterventions (drug, regimen, duration)Allowed other medications/interventionsMethod of outcome assessment and timing of assessmentAge
Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedOutcomesMethod of adverse effects assessment?Adverse effects reportedWithdrawals due to adverse events (%, adverse n/enrolled n)Comments

The Cardiac Insufficiency Bisoprolol Study (CIBIS I)

70 centers in 9European countries

Fair quality

NYHA Class
III: 95%
IV: 5%
Age 18–75, CHF, dyspnea or fatigue corresponding to NYHA III or IV, ambulatory, clinically stable past 3 weeks and no heart failure past 6 weeks. Mandatory background medication diuretic and vasodilator therapy. Ejection fraction <40%.

Etiology of heart failure: (1) idiopathic dilated cardiomyopathy with no known cause, (2) ischemia with documented history, (3) hypertension with history of therapy, (4) valvular heart disease repaired >6 months and nonischemic dilated cardiomyopathy with significant mitral valve insufficiency.
CHF due to hypertrophic or restrictive cardiomyopathy with predominant left ventricular diastolic dysfunction; or secondary to mitral or aortic valve disease surgically repaired <6 months, or not repaired.

MI <3 months. Awaiting bypass surgery or transplantation. Disabling permanent dyspnea at rest, insulin-dependent diabetes, asthma, renal insufficiency, hypothyroidism or hyperthyroidism, short life expectancy due to severe illness or malignancy.

Resting heart rate <65 bpm; systolic blood pressure <100 or >160 mm Hg. No digitalis or amiodarone treatment <6 weeks before or 2 months after inclusion. Beta-adrenergic agonist or antagonist drugs and phosphodiesterase inhibitors prohibited.
Bisoprolol (bis) 5 mg vs. placebo (pla) for 1+ years

Initial dose 1.25 mg/day titrated over 1 month. Clinician choice for dose levels at 1.25 mg (17%), 2.5 mg (30%) , 3.75 mg (2%) or 5 mg (51%) per day.
Diuretic: 100%
ACEIs: 90%
Calcium antagonists: 6%
Other: 40%
Digitalis: 57%
Amiodarone: 20%
Other: 6%
Anticoagulant: 39%
Antiplatelet: 26%
Primary: Total mortality.

Secondary: Bisoprolol tolerability (premature withdrawals, NYHA functional status, number of nonlethal critical events.

Followup every 3 months, mean duration 1.9 years.
Mean age 59.6

82.5% Male

Race NR
CHF etiology:
IDC: 36%
Ischemia: 55%
Hypertension: 5%
Valvular disease: 4%

History of acute episodes of
heart failure: 56%
History of MI: 47%

Mean LVEF: 25.4%
Total screened & eligible: NR
Enrolled: 641

bis (n= 320)
pla (n= 321)
Total withdrawn: 157/641 (24.5%)
Bis 75/320 (23.4%)
Pla 82/321 (25.5%)

1 patient lost to follow-up.

Primary (All Deaths):
Bis: 53/320 (16.6%)
Pla: 67/321 (20.9%) (NS)
Sudden death:
Bis: 15/320 (4.7%)
Pla: 17/321 (5.3%) (NS)

NYHA class improvement:
Bis: 68/320 (21%)
Pla: 48/321 (15%) (P<0.03)
NYHA class deterioration:
Bis: 41/320 (13%)
Pla: 35/321 (11%) (NS) Heart failure:
Bis: 11/320 (3.4%)
Pla: 22/321 (6.9%) (NS)

Subgroup deaths, no MI history:
Bis: 18/151 (12%)
Pla: 42/187 (22.5%) (P=0.01)
NRNR, except
Bis: 2 sinus bradycardia, 2 atrioventricular blockade

Non CV events:
Bis: 44/320 (13.7%)
Pla: 54/321 (16.8%)

The Cardiac Insufficiency Bisoprolol Study (CIBIS II)

Good quality

NYHA Class
III: 83%
IV: 17%
Age 18–80, CHF diagnosis >3 months previous, dyspnea on exertion, orthopnea or paroxysmal nocturnal dyspnoea, and fatigue, corresponding to NYHA III or IV; ambulatory, clinically stable past 6 weeks or 3 months for acute MI. CV therapy unchanged past 2 weeks. Mandatory medication diuretic and ACE inhibitor or other vasodilator if ACEI intolerant. Ejection fraction <35%.Uncontrolled hypertension, MI or unstoppable angina pectoris in past 3 months, revascularization in past 6 months, previous or scheduled heart transplant, atrioventricular block > first degree without pacemaker, resting heart rate < 60 bpm, systolic blood pressure <100, renal failure, reversible obstructive lung disease or planned therapy with beta-adrenoreceptor blockers. No treatment with beta blockers (also eye drops), calcium antagonists, inotropic agents except digitalis, and antiarrhythmic drugs except amiodarone during trial.Bisoprolol (bis) 10 mg. vs. placebo (pla) for 1+ years

Initial dose 1.25 mg/day titrated weekly for 3 weeks to 5 mg (13%), then 4-week intervals to 7.5 mg (11%) and 10 mg/day (43%).

No run-in period.
Diuretic: 99% Vasodilator:
-ACE inhibitors: 96%
-Calcium antagonists: 2%
- Nitrates: 58%
Digoxin: 52%
-Amiodarone: 15%
Anticoagulant: 31%
Antiplatelet: 41%
Primary: Total mortality.

Secondary: All-cause hospital admission, all CV deaths, combined endpoint, permanent treatment withdrawals.

Followup every 3 months, mean duration 1.3 years.

Study stopped early with significant results.
Mean age 61

80.5% Male

Race NR
CHF etiology:
- Primary dilated
cardiomyopathy: 12%
- Ischemia: 50%
- Other heart failure: 39%
Total screened & eligible: NR
Enrolled: 2647
Bisoprolol (n= 1327)
Placebo (n= 1320)
Total: 69/2647 (2.6%)
Bis: 41/1327 (3.1%)
Pla: 28/2647 (2.1%)

6 patients lost to follow-up.

Primary - Total mortality:
Bis: 156/1327 (12%)
Pla: 228/1320 (17%) (P<0.0001)
- Sudden death:
Bis: 48/1327 (3.6%)
Pla: 83//1320 (6.3%) (P=0.0011)

Subgroup analysis of mortality:
- Ischemic etiology
Bis: 75/662 (11.3%)
Pla: 121/654 (18.5%) (P<0.001)

- All CV deaths
Bis: 119/1327 (9.0%)
Pla: 161/1320 (12.2%) (P=0.0049)
- All-cause hospital admission
Bis: 440/1327 (33.2%)
Pla: 513/1320 (38.9%) (P=0.0006)

Subgroup analysis of hospital admission:
- for worsening heart failure
Bis: 159/1327 (12.0%)
Pla: 232/1320 (17.6%) (P=0.0001)
- for stroke
Bis: 31/1327 (2.3%)
Pla: 16/1320 (1.2%) (P=0.04)
- for ventricular tachycardia and fibrillation
Bis: 6/1327 (0.5%)
Pla: 20/1320 (1.5%) (P=0.006)
- for hypotension:
Bis: 3/1327 (0.2%)
Pla: 11/1320 (0.8%) (P=0.03)
- for bradycardia:
Bis: 14/1327 (1.1%)
Pla: 2/1320 (0.2%) (P<0.004)

Multicenter Oral
Carvedilol Heart
Failure Assessment (MOCHA)

Fair quality

NYHA class
II: 46%
II: 52%
IV: 2%
Age 18–85, ejection fraction ≤ 35%, symptomatic ischemic or dilated cardiomyopathy heart failure, symptoms present ≥ 3 months, walk test 150–450 m, stability (no change in NYHA class and absence of hospitalization) ≥ past 1 month, any digoxin use started ≥ 2 months prior and stable dose ≥ past 1 month, resting heart rate ≥ 68 bpm.Uncorrected valvular disease, hypertrophic or postpartum cardiomyopathy, uncontrolled symptomatic or sustained ventricular tachycardia, acute MI within 3 months, planned or likely revascularization or transplantation within 6 months after screening. Also, sick sinus syndrome, 2nd- or 3rd-degree heart block not treated with pacemaker, symptomatic peripheral vascular disease limiting exercise testing, sitting systolic blood pressure <85 mm Hg or >160 mm Hg, CV accident within last 3 months, cor pulmonale, obstructive pulmonary disease requiring oral bronchodilator or steroid therapy, and other selected disorders and sensitivities.

Excluded drugs: alcohol intake >100 g/day, use of investigational drug within 30 days, CCBs, amiodarone within 3 months, and others.
Carvedilol (car) 12.5 mg, 25 mg, 50 mg daily
Placebo (pla) x 6 months

3-week screening phase.
2-week run-in with open-label car. to establish tolerability prior to randomization.
2-week titration phase.
ACE inhibitors: 94%
Digitalis: 92%
Loop-activity diuretics: 95%
Thiazide diuretics: 18%
Vasodilators: 35%
Improvement in submaximal exercise, using 6-minute walk test and 9-minute self-powered treadmill test.

Changes in quality of life, NYHA class, EF, need for hospitalization due to heart failure and other CV causes, and signs and symptoms of heart failure.
Mean age 59.5

76% Male

78% White
Ischemic cause: 52%Screened: NR
Eligible for run-in: 376
Enrolled: 345

car. 50 mg (n=89)
car. 25 mg (n=89)
car.12.5 mg (n=83)
placebo (n=84)
Total: 52/345 (15%)

Lost to QOL assessment: 38/345 (11%)

Lost to hospitalization assessment: 23/345 (6.7%)

Lost to exercise result: NR

No effect on exercise duration.

No effect on NYHA class.

Crude mortality at 6 months:
car 25 bid: 1/89 (1.1%)(P≤0.001)
car 12.5 bid: 6/89 (6.7%) (P=0.07)
car 6.25 bid: 5/83 (6.0%) (P≤0.05)
Pla: 13/84 (15.5%)
(P values vs. placebo)

Sudden death
Car (all)=6/261(2.3%); pla=6/84(7.1%)

CV Hospitalizations Total:
car 25 bid: 9/82 (11.0%)
car 12.5 bid: 11/82 (13.4%)
car 6.25 bid: 9/80 (11.3%)
Pla: 17/78 (21.8%)
(no linear trend)
(all car. vs. pl, P=0.03)

QOL mean score change:
car 25 bid: −5.5
car 12.5 bid: −7.3
car 6.25 bid: −7.9
Pla: −7.3 (NS)
All car: 83/261 (31.8%)
car 25 bid: 34/89 (38.2%)
car 12.5 bid: 29/89 (32.6%)
car 6.25 bid: 20/83 (24.1%)
pla: 19/84 (22.6%)
(linear trend, P=0.01)
(all car vs. pla, P=0.11)
Cardiac failure:
All car: 56/261 (21.4%)
car 25 bid: 22/89 (24.7%)
car 12.5 bid: 23/89 (25.8%)
car 6.25 bid: 11/83 (13.3%)
pla: 19/84 (22.6%)
(linear trend, P=0.34)
(all car vs. pla, P=0.82)
Edema or weight gain:
All car: 30/261 (11.5%)
car 25 bid: 9/89 (10.1%)
car 12.5 bid: 10/89 (11.2%)
car 6.25 bid: 11/83 (13.3%)
pla: 5/84 (6.0%)
(linear trend, P=0.60)
(all car vs. pla, P=0.14)
All car: 21/261 (8.0%)
car 25 bid: 10/89 (11.2%)
car 12.5 bid: 10/89 (11.2%)
car 6.25 bid: 1/83 (1.2%)
pla: 1/84 (1.2%)
(linear trend, P=0.001)
(all car vs. pla, P=0.03)
All car: 17/261 (6.5%)
car 25 bid: 6/89 (6.7%)
car 12.5 bid: 6/89 (6.7%)
car 6.25 bid: 5/83 (6.0%)
Pla: 4/84 (4.8%)
(linear trend, P=0.60)
(all car vs. pla, P=0.56)
Withdrawals due to any adverse events:
car(all)=18%; pla=11%


Fair quality

NYHA class
II: 40%
III: 56%
IV: 4%
Chronic heart failure (dyspnea or fatigue ≥3 months), LVEF ≤35% despite ≥2 months treatment with diuretics and ACEI.Uncorrected primary valvular disease, active myocarditis or obstructive or restrictive cardiomyopathy; MI, stroke, unstable angina or CABG within 3 months; symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or implantable defibrillator; sick sinus syndrome or advanced heart block (without pacemaker); any condition other than heart failure that could limit exercise; systolic blood pressure >160 or <85 mm Hg or diastolic blood pressure >100 mm Hg; heart rate <68 bpm; significant hepatic, renal or endocrine disease; drug or alcohol abuse; or any condition that could limit survival.

Patients receiving CCBs, alpha- or beta-adrenergic agonist or antagonists or specific antiarrhythmic drugs.
Carvedilol (car) 50 mg daily vs. placebo (pla) for 6 months

Begin 6.25 mg bid titrated over 2–6 weeks (50 mg bid for weight ≥85 kg) − 87% reached target, avg 28 mg/day.
Digitalis: 90%
Loop-active diuretic: 99%
ACEI: 97%
Direct-acting vasodilator: 29%
Exercise tolerance on 6-minute corridor walk and 9-minute treadmill.

Secondary: global assessment, NYHA class, LVEF, quality of life
Mean age 60.3

73% Male

Race NR
Cause of heart failure
- CAD : 52%
- Nonischemic dilated cardiomyopathy: 48%
Screened: NR
Eligible for run-in: 301
Enrolled: 278

car (n= 133)
pla (n= 145)
49/278 (18%) withdrawn

Lost to follow-up for NYHA class and global assessment: 9%

Lost to follow-up for AE report: 10/278 (4%)

Analyzed: 278
6-minute exercise test increase: car: 17 m
pla: 6 m (NS)
No difference in 9-minute treadmill test.

NYHA class III/IV improvement:
car: 28/130 (21.5%)
pla: 9/130 (6.9%) (P=0.014)
NYHA class deterioration:
car: 3% vs. pla: 15% (P=0.001)

No difference in QOL scores.

LVEF change:
car: +8%
pla: +3% (P<0.001)

Deaths (ITT):
car: 6/133 (4.5%)
pla: 11/145 (7.6%) (NS)

CV hospitalization (ITT):
car: 22/133 (16.5%)
pla: 37/145 (25.5%) (NS)
car: 31/129 (24.0%)
pla: 16/139 (11.5%) (P<0.01)

Heart failure:
car: 15/129 (11.6%)
pla: 31/139 (22.3%) (P<0.025)

Weight gain: NR

car: 7/129 (5.4%)
pla: 1/139 (0.7%) (P<0.025)

car: 8/129 (6.2%)
pla: 3/139 (2.2%) (NS)
Withdrawals due to any adverse event: car=7(5.3%); pla=11(8.3%)

U.S. Carvedilol Heart Failure Study Group (Mild)

Fair quality

NYHA class
II: 85%
III: 15%
Age 18–85 with chronic symptomatic heart failure (dyspnea or fatigue) ≥3 months), LVEF ≤35% despite ≥2 months treatment with diuretics and ACEI.Uncorrected primary valvular disease, nondilated or hypertrophic cardiomyopathy; MI, stroke, unstable angina or CABG within 3 months; symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or implantable defibrillator within 3 months; likelihood of revascularization or transplantation within 12 months; sick sinus syndrome or advanced heart block (without pacemaker); any condition other than heart failure that could limit exercise; systolic blood pressure >160 or <85 mm Hg or diastolic blood pressure >100 mm Hg; clinically significant hepatic or renal disease, or any condition that could limit survival.

Patients receiving amiodarone within 3 months before screening.
Carvedilol (car) 50 mg daily vs.
placebo (pla)
for 12 months (mean 7 months)

Begin 12.5 mg bid titrated (50 mg bid for weight ≥85 kg) − 85% achieved max dose.

Terminated early with significant results.
Background therapy held constant if possible, adjusted for AEPrimary: progression of heart failure.

LVEF, NYHA class, heart failure score, global assessments, quality of life, 9-minute self-powered treadmill test, and heart size
Mean age 55

85% Male

Race NR
Cause of heart failure:
Ischemic: 42%
Nonischemic: 58%
Screened: NR
Eligible for run-in: 389
Enrolled: 366

car (n=232)
pla (n=134)
Withdrawals=8.5%; Lost to fu NR; Analyzed=366Primary:
Clinical progression of heart failure:
car: 25/232 (10.8%)
pla: 28/134 (20.9%) (P=0.008)

All deaths:
car: 2/232 (0.9%)
pla: 5/134 (3.7%) (P=0.048)

CV deaths:
car: 0
pla: 4/134 (3.0%) (P<0.01)

Hospitalization for heart failure:
car: 9/232 (3.9%)
pla: 8/134 (6.0%) (NS)

NYHA class improved:
car: 12% vs. pla: 9%
NYHA class worsened:
car: 4% vs. pla: 15%
(overall change favors car, P=0.003)

QOL score mean change:
car: −4.9 vs. pla: −2.4 (NS)

No difference in exercise test.
car: 81/232 (34.9%)
pla: 27/134 (20.1%) (P<0.01)

cardiac failure:
car: 26/232 (11.2%)
pla: 22/134 (16.4%) (NS)

weight increase:
car: 29/232 (12.5%)
pla: 10/134 (7.5%) (NS)
car: 30/232 (12.9%)
pla: 1/134 (0.7%) (P<0.001)

car: 21/232 (9.1%)
pla: 4/134 (3.0%) (P<0.05)

U.S. Carvedilol Heart Failure Study Group

Poor quality

NYHA class
II: 1%
III: 86%
IV: 14%
Age 22–85; symptoms of heart failure (dyspnea or fatigue) ≥3 months); LVEF ≤35% despite ≥2 months treatment with diuretics and ACEI; able to walk less than 150 m on 6-minute corridor walk test assigned to severe protocol (relaxed to <350 m due to slow enrollment).Uncorrected primary valvular disease, nondilated or hypertrophic cardiomyopathy; MI, stroke, unstable angina or CABG within 3 months; symptomatic or sustained ventricular tachycardia not controlled by antiarrhythmic drugs or implantable defibrillator within 3 months; likelihood heart transplantation within 6 months; sick sinus syndrome or advanced heart block without pacemaker; any condition other than heart failure that could limit exercise; systolic blood pressure >160 or <85 mm Hg or diastolic blood pressure >100 mm Hg; clinically significant hepatic or renal disease, or any condition that could limit survival.Carvedilol (car) 50 mg daily
Placebo (pla) x 6 months, mean 3 months.
Diuretic: 98%
ACEI: 93%
Digoxin: 90%
quality of life

mortality, CV hospitalizations, global assessments, NYHA class, LVEF, 6-minute walk exercise test
Mean age 60

58% Male

71% White
21% Black
8% Other
Cause of heart failure:
Ischemic: 45%
Nonischemic: 55%
Screened: NR
Eligible for run-in: 131
Enrolled: 105

car (n= 70)
pla (n= 35)
Reported withdrawn: 12/105 (11%)
(4 deaths, 2 transplants. 5 AE)

Reports 1 lost to follow-up.
Final sample sizes often NR.
Lost to LVEF test: 50/105 (52%).
Lost to follow-up in 2 months:
35/105 (33%)
Lost to follow-up in 6 months:
92/105 (88%)
[carry-forward analysis]

QOL score improvement: car=11.6; pla=8.8

No difference in NYHA class.
No difference in CV hospitalization.
No difference in deaths.

6-minute exercise test increase:
car: 19.0 m
pla: 28.4 m (NS)
NR[sample size NR - unreliable]

car: 24.3%
pla: 31.4%

worsening heart failure:
car: 10.0%
pla: 22.9%

weight gain:
car: 10.0%
pla: 5.7%
Withdrawals due to:
Bradycardia/heart block: car=3(1.4%); pla=0
Dizziness/hypotension: car=3(1.4%); pla=0
Worsening heart failure: car=5(2.4%); pla=2(0.9%)
1995, 1997

Australia/New Zealand Heart Failure Research Collaborative Group Study

Good quality

NYHA class
II: 30%
III: 54%
IV: 16%
Chronic stable heart failure due to ischemic heart disease; LVEF <45%; NYHA functional class II or III or previous NYHA class II–IVCurrent NYHA class IV; heart rate below 50 beats per minute; sick sinus syndrome; second or third degree heart block; systolic BP <90 mm Hg or >160/100 mm Hg; treadmill exercise duration <2 minutes or >18 minutes; coronary event or procedure within previous 4 weeks; primary myocardial or valvular disease; current treatment with beta- blocker, beta-agonist or verapamil; insulin-dependent DM; obstructive airways disease; hepatic disease; any other life-threatening non- cardiac disease.Carvedilol (car) 50 mg daily
Placebo (pla) x 12 months

Begin 6.25 mg bid titrated over2–5 weeks. At 6 months, avg. 46 mg daily.
ACEI: 85%
Diuretic: 76%
Digoxin: 79%
Change in LVEF and treadmill exercise duration (Naughton protocol 2-min. stages)

Change in LV dimension, 6-minute walk distance, symptoms of heart failure, frequency of death, hospital admission, and worsening heart failure

Clinical assessment at 5 weeks and 3 months, then every 3 months.
Mean age 67

80% male

Race NR
Previous MI: 88.6%
Previous hospital admission for CHF: 42%
Previous highest NYHA class:
II: 26.5%
III: 30%
IV: 43%
Current NYHA class:
I: 30%
II: 54%
III: 16%
Current treatment for heart failure:
ACEI: 85.5%
Diuretic: 75.6%
Digoxin: 38%
Screened: NR
Eligible for run-in: 442
Enrolled: 415

car (n= 207)
pla (n= 208)
Total withdrawn at 6 months:
43/415 (10%)/lost to fu

No significant improvement in treadmill duration

No significant improvement in 6-min. walk distance

NYHA class (12 months)
improved: car 26%; pla 28%
no change: car=58%; pla=58%
worse: car 16%; pla 13%

Total mortality:
car: 20/208 (9.6%)
pla: 26/207 (12.6%) (NS)

Sudden death:
car: 10/208 (4.8%)
pla: 11/207 (5.3%) (NS)

All hospital admissions:
car: 99/208 (47.6%)
pla: 120/207 (58.0%) (NS)

All CV hospitalizations:
car: 70/208 (33.7%)
pla: 83/207 (40.1%)
NRnrWithdrawals due to:
car: 3/207 (1.4%)
pla: 0 (NS)

Worsening heart failure:
car: 5/207 (2.4%)
pla: 2/208 (0.9%) (NS)

Bradycardia/Heart block:
car: 3/207 (1.4%)
pla: 0 (NS)
Cleland, 2003

Carvedilol Hibernating Reversible Ischaemia Trial: Marker of Success (CHRISTMAS)

Fair quality

NYHA Class
I: 11.1%
II: 60.3%
III: 28.5%
Stable chronic heart failure (defined as freedom from an acute cardiovascular event for 3 months; freedom from all-cause admission for 1 month; stable treatment for heart failure for at least 2 weeks) with objective evidence of left ventricular systolic dysfunction (ECG wall motion index cutoff of 1.3 or less; corresponding to an LVEF of <40%) due to coronary artery disease (defined as history of myocardial infarction, coronary revascularisation, or coronary artery disease on arteriography); NYHA Class I–IIIPatients younger than 40 years and women of child-bearing age; resting heart rate less than 60 beats per minute; sitting systolic blood pressure less than 85 mm Hg; unstable angina; arrhythmias; uncontrolled hypertension; obstructive pulmonary disease; poorly controlled diabetes; or clinically relevant renal or hepatic disease; those receiving non-dihydropiridine calcium-channel blockers; beta blockers, or antiarrhythmic agents other than amiodaroneCarvedilol (car) 6.25–50 mg daily
Placebo (pla) x 4 months maintenance
Angiotensin-converting enzyme inhibitors treatment compulsoryPrimary: Change in LVEF in hibernators versus non- hibernators Secondary: (1) LVEF change in carvedilol versus placebo, irrespective of hibernation status; (2)relation between volume of hibernating myocardium and change in LVEF; (3) change in contractile dysfunction in hibernators versus non- hibernators; (4) change in number of segments with reversible exercise-induced myocardial perfusion defects on carvedilol versus placebo; (5) composite of death or worsening of heart failure in carvedilol vs placeboAge: 62.5
% male: 90
% white: 91.1
Current smokers: 16.7%
Diabetes: 22.3%
Previous MI: 90.2%
Previous CABG: 45.2%
NYHA Class
I: 11.1%
II: 60.3%
III: 28.5%
LVEF (mean): 29.5%
489 screened/440 eligible/387 enrolled82(21.2%) withdrawn/lost to fu NR/305 analyzedExercise time (seconds): car=405; pla=427 (NS)
Death: car=8/188(4.3%); pla=6/188=3.2%(NS)
Composite of all-cause mortality and worsening heart failure: car=44/187(23.5%); pla=37/188(19.7%) (NS)
nrOverall adverse events: frequent in both groups (rates NR)

Dizziness, fatigue, syncope and bradycardia were more typical with carvedilol than with placebo (rates NR)
Packer, 2001, 2002 Krum

The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Trial

Fair quality

NYHA Class
Patients with severe chronic heart failure as a result of ischemic or nonischemic cardiomyopathyHeart failure that was caused by uncorrected primary valvular disease or a reversible form of cardiomyopathy; had received or were likely to receive a cardiac transplant; had severe primary pulmonary, renal, or hepatic disease; or had a contraindication to beta-blocker therapy; coronary revascularization, acute myocardial or cerebral ischemic event, sustained or hemodynamically destabilizing ventricular tachycardia or fibrillation within the previous two months; use of an alpha-adrenergic blocker, a calcium-channel blocker, or a class I antiarrhythmic drug within the previous four weeks or a beta-blocker within the previous two months; systolic blood pressure lower than 85 mm Hg; heart rate lower than 68 beats per minute; serum creatinine concentration higher than 2.8 mg per deciliter; serum potassium concentration lower than 3.5 mmol per liter or higher than 5.2 mmol per liter; increase of more than 0.5 mg per deciliter in the serum creatinine concentration or a change in body weight of more than 1.5 kg during the screening periodCarvedilol (car) 50 mg daily (n=1156)
Placebo (pla) (n=1133)
Usual medications for heart failurePrimary: All-cause mortality Secondary: (1) Combined risk of death/hospitalization for any reason; (2) combined risk of death or hospitalization for CV reason; (3) combined risk of death/hospitalization for HF; (4) patient global assessmentAge: pla=63.4;
%male: pla=80;
Race NR
% ischemic cause: pla=67;
% left ventricular ejection fraction: pla=19.8; car=19.9
% heart failure hospitalization within past year: pla=65; car=66
3106 screened/eligible NR/2289 randomizedwithdrawn: pla=84; car=70/0 lost/analyzed(ITT): pla=1133; car=1156n (hazard ratio; 95%CI)
All-cause mortality: pla=190; car=130 (0.65; 0.52-0.81)
Death/hospitalization for any reason: pla=507; car=425 (0.76; 0.67-0.87)
Death/hospitalization for CV reason: pla=395; car=314 (0.73; 0.84-0.63)
Death/hospitalization for HF: pla=357; pla=271
(0.69; 0.81-0.59)

No. of pts hospitalized, n(%)
Worsening HF: pla=268(23.7); car=198(17.1)
CV reason: pla=314(27.7); car=246(21.3)
For any reason: pla=432(38.1); car=372(32.2)
More than once: pla=188(16.6); car=152(13.1)
NRSerious adverse events: pla=516(45.5%); car=451(39.0%)One-year withdrawal rates: pla=18.5%; car=14.8%Study stopped early based on the finding of a significant beneficial effect of carvedilol on survival that exceeded the prespecified interim monitoring boundaries

Mortality reduction equivalent for age, gender, LVEF, cause of HF subgroups

The Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) Trial

Fair quality
NYHA class
Patient who had ischemic or nonischemic cardiomyopathy with stable symptoms (NYHA functional class II or III); LVEF ≤ 40%; age between 20 and 79 yearsValvular heart disease, hypertrophic obstructive cardiomyopathy, cardiogenic shock, systolic blood pressure < 90 mm Hg, bradycardia (<60/min), grade II or III atrioventricular block, life-threatening arrhythmia, unstable angina, resting angina, cor pulmonale, asthma, Raynaud phenomenon, and intermittent claudication; myocardial infarction or coronary artery bypass grafting had occurred within the preceding 3 monthsRun-in
Open carvedilol 2.5 mg daily x 1–2 weeks; then open carvedilol 5 mg daily x ≥ 2 weeks

Carvedilol 5 mg daily
Carvedilol 20 mg daily
Placebo x 24–48 weeks
Diuretics, digitalis, ACE inhibitors, calcium channel blockers, vasodilators, anti-arrhythmic agentsPrimary: Improvement of global assessment of CHF by attending physician (markedly improved, moderately improved, mildly improved, no change, worsened, unassessable)
Secondary: all-cause death or hospitalization for cardiovascular disease (CVD), CVD hospitalization, hospitalization for worsening CHF, changes of LVEF, and changes of NYHA class
Mean age=60
77% male
100% Japanese
Nonischemic etiology of heart failure=73%
NYHA class II/III=78%
Systolic BP (mm HG)=119
Diastolic BP (mm Hg)=72
Heart rate (beats/min)=80
Body weight=61 kg
Other medications
nr/nr/190 enrolled16 (8.4%) withdrew after run-in (prior to randomization; number withdrawn following randomization NR/lost to fu NR/analyzed=173Placebo (n=49) vs carvedilol 5 mg (n=47) vs carvedilol 20 mg (n=77); P value for carvedilol 5 mg vs placebo comparison; P value for carvedilol 20 mg vs placebo comparison

Global improvement (proportion of patients with moderate or marked improvement): 36.7% vs 44.7% vs 59.7%; P=NS; P<0.05

Death or CVD hospitalization: 24.5% vs 8.5% vs 5.2%; P=0.024; P=0.002
CVD hospitalization: 24.5% vs 4.3% vs 3.9%; P=0.003; P<0.001
Worsening CHF: 20.4% vs 2.1% vs 2.6%; P=0.004; P<0.001
Other CVD reasons for hospitalizations: 6.1% vs 2.1% vs 1.3%; P=0.229; P=0.116
Change in LVEF units (mean): 6.6 vs 8.7 vs 13.2; P=NS; P<0.05 NYHA class
Improved: 48.9% vs 80.9% vs 70.8%; P<0.001; P<0.05
No change: 40.4% vs 17.0% vs 27.8%; P<0.05; P=NS
Worsened: 10.6% vs 2.1% vs 1.4%; P=NS; P=NS
NRIncidence: 63.3% vs 51.1% vs 59.7%; P=NS; P=NSNR


Fair quality

NYHA class avg: 2.8
Idiopathic dilated cardiomyopathy confirmed by ECGUnstabilized overt cardiac failure; alcohol abuse; secondary cardiomyopathies; firm exclusions to beta blocker treatment (asthma, advanced heart block, allergy)Metoprolol (met) 100 mg daily
Placebo (pla) x 19 months

Begin 12.5 mg bid titrated over 2 weeks to target - median dose 25 mg bid.
Digitalis: 87%
Diuretic: 80%
Vasodilators: 40%
Antiarrhythmics: 35%
Anticoagulant (warfarin): 12%
Primary: Survival

Secondary: Exercise duration (Naughton protocol)
Mean age 51

66% male

Race NR
NRScreened: NR
Eligible: 50
Enrolled: 50

met (n=25)
pla (n=25)
Dropout from treatment group:
5/25 (20%)

Overall, 2 patients lost to follow-up

met: 5/25 (20%)
pla: 6/25 (24%) (NS)

Exercise duration:
met: 9.4 min
pla: 8.2 min (NS)

Metoprolol in Dilated Cardiomyopathy (MDC) Trial

Fair quality

NYHA class
I: 3%
II: 45%
III: 49%
IV: 4%
16–75 years; symptomatic dilated cardiomyopathy; state of compensated heart failure by means of conventional treatment; systolic BP ≥90 mm Hg; heart rate ≥45 beats per minuteTreatment with beta blockers, calcium channel blockers, inotropic agents or high doses of tricyclic antidepressant drugs; significant CAD shown by angiography; clinical or histological signs of ongoing myocarditis; other life-threatening diseases; obstructive lung disease; excessive alcohol consumption; drug abuse; insulin-dependent diabetes; pheochromocytoma; thyroid diseaseMetoprolol (met) 100–150 mg daily (higher target for higher weight) vs. placebo for 18 months and 12 months

Run-in period 2–7 days. Begin 10 mg titrated over 6+ weeks to target - mean dose 108 mg/day.
Digitalis: 78%
ACEI: 79%
Nitrates: 14%
Antiarrhythmics: 16%
Frusemide: 75%
Combined - total deaths and need for transplantation.

Exercise duration (Naughton protocol in North America, bicycle exercise protocol in Europe begin 20W +10W increments); also LVEF, QOL, and NYHA change; and hospital readmissions.

At 45 days, 3, 6, 12 and 18 months.
Mean age 49

73% male

Race NR
Current smokers: 18%Screened: NR
Eligible: 417
Enrolled: 383

met (n=194)
pla (n=189)
Withdrawn from study medication at 12 months:
54/383 (14%)

Lost to LVEF measure: 44%
Lost to QOL measure: 71%
Lost to hospital followup: 6%

Total deaths or need for transplantation:
met: 25/194 (12.9%)
pla: 38/189 (20.1%) (NS)

All-cause mortality: met=23(11.8%); pla=21(11.1%)

Sudden death:
met: 18/194 (9,3%)
pla: 12/189 (6.3%) (NS)

Exercise capacity at 6 and 12 months:
met: +80s and +76s
pla: +47s and +15s
(Difference at 12 months, P=0.046)

NYHA class improvement: data NR

Quality of life: data NR

Hospitalization patients:
met: 37/184 (20.1%)
pla: 49/177 (27.7%) (NS)
Hospitalization episodes:
met: 51/184 (27.7%)
pla: 83/177 (46.9%) (P<0.05)
NRNRWithdrawals due to:
Progressive heart failure:
met: 7/194 (3.6%)
pla: 13/189 (6.9%) (NS)
All "related" adverse events: met=1(0.5%);

Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)

Fair quality

NYHA class
II: 41%
III: 55%
IV: 4%
Age 40–80; symptomatic heart failure (NYHA class II–IV) for 3 months or more and receiving optimum standard therapy; stable clinical condition during 2 week run-in phase; LVEF of <40%Acute MI or unstable angina within 28 days; indication or contraindication for treatment with beta-blockade or drugs with beta- blocking properties; heart failure secondary to systemic disease or alcohol abuse; scheduled or performed heart transplantation or cardiomyoplasty; implanted cardioversion defibrillator (expected or performed); CABG or percutaneous transluminal coronary angioplasty planned or performed in the past 4 months; atrioventricular block of the second or third degree; unstable decompensated heart failure; supine systolic BP >100 mm Hg; any serious disease that might complicate management and follow-up according to protocol; use of calcium antagonists; use of amiodarone within 6 months; poor compliance.Metoprolol (met) 200 mg/day vs. placebo for 1 year

2-week placebo run-in. Begin 12.5 mg (NYHA class III/IV) or 25 mg daily, titrated over 6 weeks to target.
Diuretics: 90%
ACEI: 89%
Angiotensin I: 7%
ACEI or Angiotensin II: 96%
Digitalis: 64%
Lipid-lowering agents: 26%
Total mortality, and combined total mortality and all-cause hospitalization (time to first event)

Worsening heart-failure mortality or hospitalization (time to first event), other CV events, NYHA class change, and QOL substudy.
Mean ages:
<60: 34%
60–69: 35%
≥70: 31%

77% male

94% White
5% Black
1% Other
Current daily smoker: 14.4%
Heart failure:
Ischemic: 65%
Nonischemic: 35%

Previous MI: 48%
Atrial fibrillation: 16.6%
Hypertension: 44%
DM: 24.6%
Screened: NR
Eligible (recruited): 4427
Enrolled: 3991

met (n=1990)
pla (n=2001)
Total withdrawn: 589/3991 (15%)

0 lost to follow-up of vital status.

All cause mortality: met=145(7.3%);
pla=217(10.8%) (P=0.0009)

Total mortality or All-cause hospitalization:
met: 641/1990 (32.2%)
pla: 767/2001 (38.3%)(P<0.001)

Sudden death: met=3.9%; pla=6.5%

Death or heart transplantation:
met: 150/1990 (7.5%)
pla: 218/2001 (10.9%) (P<0.001)

Cardiac death or nonfatal MI:
met: 139/1990 (7.0%)
pla: 225/2001 (11.2%) (P<0.001)

All hospitalization (patients):
met: 1021/1990 (51.3%)
pla: 1149/2001 (57.4%) (P=0.005)

CV hospitalization (patients):
met: 394/1990 (19.8%)
pla: 494/2001 (24.7%) (P<0.001)

NYHA class improvement favors met group (P=0.003).

Subgroup: diabetic patients
Total mortality risk reduction met vs pla: 18% (95% CI 44% to −19%; P>0.2
All hospitalization risk reduction met vs pla: 37% (95% CI 53 to 15; P=0.0026)
NRWithdrawals due to:
met: 12/1990 (0.6%)
pla: 6/2001 (0.3%) (NS)

Heart failure:
met: 78/1990 (3.9%)
pla: 117/2001 (5.8%) (P<0.01)

Weight increase: NR

met: 16/1990 (0.8%)
pla: 5/2001 (0.2%) (P<0.025)

met: 12/1990 (0.6%)
pla: 5/2001 (0.2%) (NS)

Any adverse event: met=9.8%; pla=11.7%

The Randomized
Evaluation of
Strategies for Left
Dysfunction Pilot

Fair quality

I: 6.8%
II: 69.2%
III: 23.5%
IV: 0.5%
Symptomatic heart failure (Class II–IV); 6-minute walk distance of <500 m; LVEF<40%NRStage 1:
Candesartan: 4–16 mg daily
Enalapril: 20 mg daily
Candesartan 48 mg and enalapril 20 mg

Stage 2:
Addition of Metoprolol CR (met CR)
25–200 mg daily or placebo
Stage I medicationsPrimary:
1) 6-minute walk distance
2) neurohumoral parameters

1) NYHA functional class
2) Quality of life (Minnesota Living With Heart Failure questionnaire)
Mean age=61.5
82.1% male
87.1% white
Heart failure duration:
7–12 mo: 12.4%
>12 mo: 87.6%
Previous MI: 63.6%
Diabetes: 25.3%
Current: 15%
Former: 61%
Never: 23.9%
NYHA Class:
I: 6.8%
II: 69.2%
III: 23.5%
IV: 0.5%
LVEF(mean): 28.5%
nr/468/426nr/nr/4266-minute walk distance change (meters): met CR=(−1); pla=(−3)
Quality of life: met CR=pla (data NR)
NYHA functional class: met CR=pla (data NR)
All-cause deaths: met CR=8(3.7%); pla=17(8%) (NS)
Sudden death due to worsening heart failure: met CR=0.5%; pla=3(1.4%)
Hospitalizations due to heart failure: met CR=15(7%); pla=5(2.3%)
NRNROverall discontinuation due to intolerability: met
CR=11%; pla=12%
Permanent discontinuation due to:
Symptomatic hypotension: met CR=4(1.9%);
Worsening heart failure: met CR=7(3.3%);
Symptomatic bradycardia: met CR=0; pla=0

Fair quality
NYHA Class
Symptomatic patients of either sex, 18- to 80-years old, with stable
CHF (NYHA class II–III). Patients were prospectively stratified into
an ischemic heart disease (IHD) group and a dilated cardiomyopathy
(DCM) group. DCM was diagnosed based on the presence of LV
dilation and EF = 0.40 without significant coronary artery obstruction;
IHD was diagnosed based on LV dilation, EF = 0.40, and the
presences or a history of at least one significant coronary obstruction
Coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) within the previous 6 months or who were scheduled for or expected to require these treatments during the 6-month study; patients who had a major ischemic event (acute MI or unstable angina) within the previous 6 months and those with large anterior aneurysms, acute myocarditis, primary valvular heart disease, exercise-limiting angina pectoris or severe systemic disease; excessive consumption of alcohol (≥ 100 g of pure alcohol/day or ≥ 700 gram/week), resting systolic blood pressure > 190 mmHg or diastolic > 100 mmHg, systolic blood pressure <95 mmHg (unless considered occasional), heart rate < 50 beats/min, second-or third-degree atrioventricular (AV) block, sick sinus syndrome, sinoatrial block or atrial fibrillation (which makes equilibrium radionuclide angiography difficult to perform; pacemaker for third-degree AV block or a ventricular inhibited (VVI) pacemaker programmed with a fixed heart rate above the spontaneous heart rateMetoprolol 150 mg daily
Placebo x 6 months
ACE inhibitors, diuretics and digitalis in patients with overt heart failure

ACE inhibitors and digoxin could be used, as long as the dosage remained unchanged for at least 2 weeks before the study period; diuretic doses could be altered as clinically indicated
Maximal exercise capacity (bicycle tests-protocol NR)


NYHA classification
Mean age=56.7
80% male
Ethnicity NR
Weight=79.1 kg
Height=173.1 cm
Heart rate=78.1 beats/min
Systolic blood pressure=121.5 mmHg
Diastolic blood pressure=76.5 mmHg
NYHA Class
Previous MI=48.5%
Previous CABG=18.8%
Previous PTCA=9.7%
ACE inhibitor=91.5%
Mean EF=0.285
Mean duration of exercise=515.6 seconds
nr/nr/172 enrolled/169
randomized/165 started double-blind medication
3 (1.7%) withdrew prior to randomization, 31 (18.3%) withdrew following
randomization/1(0.6%) lost ot fu/165 analyzed
Metoprolol (n=71) vs placebo (n=65)

EF at 6 months (estimates from a graph)
EF at rest: 0.36 vs 0.29; P<0.001
EF at exercise: 0.37 vs 0.32; P<0.001

Maximal exercise on bicycle test: data NR; P=NS

Death during study or within 3 weeks after discontinuing study medication: 4.6% vs 3.8%; P=NS

Hospital/emergency room admission for cardiovascular reasons: data NR; P=NS

Improvement in NYHA class: 42% vs 33%; P=NS
NRNR11.6% vs 12.6%; P=NS
Edes 2005 (ENECA)neb. vs.
LVEF mean
25.41, 26.41
NYHA class II
52.24%, 45.24%
NYHA class III
45.52%, 47.62%
NYHA class IV
2.24%, 7.14%
Hospitalized patients or outpatients aged < 65; NYHA class II, III, IV CHF; a stable clinical course; an LVEF ≤35%; and stable basic medication for CHF with ACE inhibitors and/or ARBs, diuretics, and/or digitalis for a minimum of 2 weeks prior to inclusion.Acute corinary syndrome; a MI within the last 3 months; PTCA or coronary artery bypass surgery within the last month; obstructive or hypertrophic cardiomyopathy; hemodynamically relevant congenital or valvular heart disease; tachyarrhythmia resistant therapy (>100/min); bradycardia. Patients were also excluded if they received beta-blocker therapy in the 4 weeks prior to the beginining of the trial or known intolerance or hypersensitivity to nebibolol.nebivolol: maximum tolerated dose or maximum of 10 mg/day. Placebo: maximum tolerated does or maximum of 10 mg/day. 8 monthsintervention as add on therapy. standard medications: ACE inhibitors, diuretics and digitalisPrimary:
NYHA score, Quality of Life (Minnesota Living w/Heart Failure
Questionnaire - higher score = higher disability), hospitalization rate, survivial rate (Kaplan-Meier), safety parameters (adverse events, vital signs, and laboratory parameters) 8 months
neb. vs. placebo
age= 71.87, 72.19
male=70.15%, 76.98%
ethnicity=99.2%, 98.4% caucasian
neb. vs. placebo
height (cm) 168.73, 170.3
weight (kg) 74.56, 75.59
BMI 26.11, 26.02
previous MI 59.7%, 57.14%
atrial fibrillation 26.52%, 25.40%
diabetes 24.63%, 26.98%
NYHA class II 52.24%, 45.24%
NYHA class III 45.52%, 47.62%
NYHA class IV 2.24%, 7.14%
LVEF mean 25.41, 26.41
354/NR/26024/1/260neb. vs. plecebo

Secondary outcomes:
NYHA improvement by 1 class:
33/134 ( 24.6%), 34/126 ( 26.9%); improvement by 2 classes: 2/134 (1.4%), 3/126 (1.5%) (NS)
Quality of life:
mean score decreased 9.13 vs. 11.01 points (NS)
mean time to first hospitalization:
15.92 days, 15.77 days (NS)
survival rate: 67.47%, 62.89% (NS)
Adverse Events:
81 (60.45%) patients, 78 (61.90%) patients total mortality rate: 7/134 (5.2%), 7/126 (5.5%)
NR159/260 patients (360 total events neb.=186 vs. placebo=174)
AEs with highest freq.: worsening of CHF (14 vs. 16), ventricular tachycardia (5 vs. 7), atrial fibrillation 4 vs. 8).
most frequent drug related: (neb. vs. placebo) bradycardia (9 vs. 2)
hypotension (8 vs. 4)
dizziness (5 vs. 2)
Percentage of severe advers events:
neb 12.9; pla 15.03 (NS)
Flather 2005
neb. vs. placebo
NYHA class I
3%, 2.7%
NYHA class II
56.5%, 56.3%
NYHA class III
38.7%, 38.7%
NYHA class IV
1.8%, 2.3%
Ejection fraction:
< 35%: 64.3%, 64.8%
> 35%: 35.7%, 35.2%
Patients ≥ 70 years old, clinical history with CHF with at least one of the following: documented hospital admission within previous 12 months with discharge diagnosis of CHF, documented left ventricular EF ≤ 35% w/in previous 6 months.New drug therapy for heart failure 6 weeks prior to randomization, any change in cardiovascular drug therapy 2 weeks prior to randomization, heart failure due primarily to valvular heart disease, contraindication or previous intolerance to beta-blockers (e.g., heart rate <60 beats/min or systolic blood pressure <90 mmHg), curent use of beta-blockers, significant hepatic or renal dysfunction, cerebrovascular accidents within previous 3 months, and being on a waiting list for percutaneous coronary intervention or cardiac surgery or other major medical conditions that may have reduced survival during the period of the study.Nabivolol titrated to 10 mg once daily.
Placebo titrated to 10 mg once daily.
Duration: NR
Angiotensin converting enzyme inhibitor
neb 81.7%; pla 82.6%
Angiotensin II antagonist
neb 6.2%; pla 7.1%
Aldosterone antagonist
neb 28.8%; pla 26.4%
Primary: all cause mortality cardiovascular hospital admission (time to first event)
Secondary: all cause hospital admissions cardovascular mortality
NYHA Class assessment 6 minute walk test at 6 months follow-up at 4, 6 months and at 3 month intervals.
male: 63%
ethnicity: NR
neb. vs. placebo
NYHA class I 3%, 2.7%
NYHA class II 56.5%, 56.3%
NYHA class III 38.7%, 38.7%
NYHA class IV 1.8%, 2.3%
Ejection fraction:
< 35%: 64.3%, 64.8%
> 35%: 35.7%, 35.2%
Heart rate (beats/min)
79.2, 78.9
4.9%, 5.4%
prior MI
43.8%, 43.7%
Hypertension 61.1%, 62.3%
Atrial fibrillation:
33.8%, 35.5%
DM: 26.9%, 25.3%
nr/nr/21357/nr/2128# events nebivolol vs. placebo
Primary outcome:
all cause mortality or cardiovascular hospital admission: 332 (31.1%), 375 (35.3%) P=0.039
Cardovascular hospitalizations contributing to primary outcome:
256 (24%), 276 (26%) (NS)
Secondary outcomes:
Death (all cause) 169 (15.8%), 192 (18.1%) (NS)
NYHA Class assessment: data NR
6 minute walk test at 6 months: data NR
quality of life: data NR
NRFirst 15 advers categories by incidence overall
neb. vs. placebo
cardiac failure, aggravated
24%; 25%
15.6%; 13.4%
7.7%; 7.2%
atrial fibrillation:
7.3%; 7%
6.6%; 7.4%
11.1%; 2.6%
dyspnoea, exacerbated:
6.2%; 6.8%
6.7%; 5.8%
angina pertoris:
4.9%; 6.8%
5.2%; 5.8%
5.8%; 4.9%
oedema lower limb
5.2%; 2.3%
4.0%; 3.2%
unstable angina:
2.9%; 4.2%
3.5%; 3.6%
neb 1.6% (18/1067); pla .37% 4/1061 enrolled:

From: Beta Adrenergic Blockers: Evidence Tables

Cover of Drug Class Review: Agents for Overactive Bladder
Drug Class Review: Agents for Overactive Bladder: Final Report Update 4 [Internet].
McDonagh MS, Selover D, Santa J, et al.
Portland (OR): Oregon Health & Science University; 2009 Mar.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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