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Evidence Table 11

Head-to-head trials of beta blockers for heart failure

Author
Year
Country
Study
Design
Setting
Eligibility criteriaExclusion criteriaInterventions (drug, regimen, duration)Allowed other medications/interventionsMethod of outcome assessment and timing of assessmentAge
Gender
Ethnicity
Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledAuthor
Year
Country
Number withdrawn/lost to fu/analyzedOutcomesMethod of adverse effects assessment?Adverse effects reportedWithdrawals due to adverse events (%,adverse n/enrolled n)
Sanderson
1999
China
RCTPatients with typical symptoms of heart failure and reduced LV ejection fraction (<0.45)Valvular heart disease as the etiology of LV dysfunction, active myocarditis, unstable angina, a documented history of sustained ventricular tachycardia or symptomatic nonsustained ventricular tachycardia or second- or third degree atrioventricular block; chronic obstructive lung diseases, asthma, long-term alcohol or drug abuse or chronic renal failure (serum creatine >200 μmol/liter), hepatic hematological, neurological or collagen vascular diseaseMetoprolol (met) 100 mg
daily (n=26)
Carvedilol (car) 50 mg
daily (n=25) x 12 weeks
Frusemide
ACE inhibitor
Angiotensin II
receptor antagonist
Minnesota Heart Failure Symptom
Questionnaire
NYHA Functional Class assessment
6-min corridor walk test at weeks 4, 8 and 12
Mean age: met=60.4;
car=58.7
%male: met=88.5;
car=68.0
100% Chinese
Mean NYHA class: met=2.7;
car=2.6
Mean symptom questionnaire
score: met=13.1; car=17.2
Mean ETT (6-min walk, feet):
met=1164; car=1122
Etiology
IDC%: met=38.5; car=52
ICM%: met=19.2; car=24
HTHD%: met=42.3; car=24
NR/NR/51Sanderson
1999
China
met=3;
car=5/nr/nr
Symptom questionnaire score mean: met=4.8; car=8.1
NYHA functional class mean: met=2.1; car=2.2
ETT(6-min walk, feet) mean: met=1263; car=1194
NRNR
Kukin
1999
RCT
Open
Patients with chronic heart failure secondary to ischemic heart disease, valvular myopathy, or idiopathic cardiomyopathy; symptomatic (NYHA class II, III, or IV) and had documented systolic dysfunction, with a radionuclide gated blood pool scan ejection fraction </= 35%; taking stable outpatient doses of digoxin and ACEIs or angiotensin II receptor antagonists for >/= 6 weeks and a stable dose of diuretics for >/= 2 weeksObstructive valvular disease, acute myocardial infarction within 6 weeks, or active anginaMetoprolol (met) (n=30) or Carvedilol (car) (n=37) at a target dose of 50 mg daily for patients weighing < 85 kg and 100 mg daily for patients weighing > 85 kg x 6 monthsDigoxin
ACEIs
Angiotensin II
receptor antagonists
Diuretics
Minnesota Living with Heart Failure questionnaire (Minn LwHFQ)
6-minute corridor walk tests Maximal exercise bicycle tests at 4 and 6 months
Mean age: met=55;
car=60
%male: met=66.7;
car=70.3
Race NR
Etiology
Ischemic%: met=33.3; car=48.6
Idiopathic%: met=60; car=43.2
Valvular%: met=6.7; car=8.1
NYHA II%: met=23.3; car=16.2
NYHA III%: met=70; car=72.9
NYHA IV%: met=6.7; car=10.8
Minn LwHFQ mean: met=52;
car=52
6-min walk test mean (ft):
met=1228; car=1133
NR/NR/67Kukin
1999
14 withdrawn/0
lost/53
analyzed
NYHA class (#pts at baseline/month 6)
I: met=0/1; car=0/0
II: met=5/11; car=5/9;
III: met=17/11; car=22/21
IV: met=1/0; car=3/0
Minn LwHFQ at 6 months (mean change in points): met=(−15); car=(−15)
6-minute walk (mean change in ft. at 6 months): met=(+81); car=(+63)
NRNRNR
Metra
2000
RCTPatients with chronic heart failure caused by an ischemic or nonischemic cardiomyopathy; NYHA class II, III, or IV symptoms for >/= 6 months; LV ejection fraction </= 0.35 by radionuclide ventriculography, and a peak VO2 </= 25 mL/kg- 1/min-1 by cardiopulmonary exercise testing; concomitant treatment with furosemide and an ACEI (or angiotensin-receptor blocker if the ACEI was not tolerated) and had constant doses of background medicaiton as an outpatient for 1 week before the studyPatients with unstable angina, an acute myoardial infarction, or a coronary revascularization procedure within 3 months; history of alcohol abuse; primary valve disease; congenital heart disease; systolic blood pressure <90 mm Hg; concomitant disease that might adversely influence prognosis or impair exercise capacity; contraindications to b- blocker therapy; concomitant treatment with other β-blockers, α-antagonists, calcium antagonists or antiarrhythmic agents (except amiodarone)Weight <75 kg/Weight >/= 75 kg
Metoprolol tartrate (met):
100/200 mg daily (n=75)
Carvedilol (car): 50/100 mg daily (n=75) x 44 months
Frusemide
ACE inhibitor
Angiotensin II receptor antagonist
LVEF
Bicycle exercise testing
6-minute walk test
Minnesota Living with Heart
Failure Questionnaire (Minn LwHFQ)
NYHA functional classification administered every 3 months
Death and urgent transplantation
Age= met=58; car=55
Gender(%male):
met=90.7; car=90.7
Race NR
Etiology
IDC(%): met=46(61.3); car=47(62.7)
CAD(%): met=29(38.7); car=28(37.3)
NYHA class n(%)
II: met=23(30.7); car=23(30.7)
III: met=44(58.7); car=46(61.3)
IV: met=8(10.7); car=6(8)
NR/NR/150Metra
2000
28 withdrawn/0
lost/122
analyzed
NYHA class (#pts at baseline/month 12)
I: met=0/14, car=0/17
II: met=22/32, car=18/32
III: met=36/15, car=40/11
IV: met=3/1, car=3/1.
6-minute walk (mean change in ft at 12 mos): met = 416 to 479m =+63m or 206ft (vs +81) and car= 447 to 497m =+50m or 164ft (vs +63)
Minn LwHFQ mean score, baseline/12 months(change): met=39/32(−7); car=32/24(−8)
Bicycle exercise testing duration; sec, mean at baseline/12 mo (change):
met=593/649(+56); car=531/576(+45)
Death/urgent transplantation: met=21; car=17
NRMost common AE's
met
worsening heart failure=13(17.3%)
dizziness=1(1.3%)
hypotension=2(2.7%)
symptomatic bradycardia=2(2.7%)

car
dizziness=11(14.7%)
worsening heart failure=6(8.0%)
symptomatic bradycardia=3(4.0%)
hypotension=2(2.7%)
Raynaud's phenomenon=1(1.3%)
met=3; car=2
Metra
2002
USA, Italy
RCTPatients with chronic HF caused by an ischemic or nonischemic cardiomyopathy who had NYHA function II–IV symptoms, a LVEF </=35% by radionuclide ventriculography, and ongoing treatment with furosemide and an ACEIPatients with an acute ischemic event or a coronary revascularization procedure within 3 months; a history of alcohol abuse; primary valve disease or congenital heart disease; frequent ventricular premature beats and/or runs of ventricular tachycardia; contraindications to beta- blocker therapy; concomitant treatment with other beta-blockers, α-antagonists, calcium antagonists or antiarrhythmic agents (except amiodarone)Weight <75 kg/Weight >/= 75 kg
Metoprolol tartrate (met):
100/200 mg daily (n=17)
Carvedilol (car): 50/100 mg daily (n=17) x 9–12 months
Furosemide
ACE inhibitor
NYHA functional classification x 9–12 monthsMean age: met=60; car=56
Gender(%male):
met=17.6; car=23.5
Race NR
Etiology
IDC n(%): met=11(64.7); car=11(64.7)
CAD n(%): met=6(35.3); car=6(35.3)

NYHA functional class
II n(%): met=5(29.4); car=3(17.6)
III n(%): met=12(70.6); car=13(76.5)
IV n(%): met=0; car=1(5.9)
NR/NR/34Metra
2000
USA, Italy
29 analyzedPer protocol analysis met n=14; car n=15
NYHA class, n at end of study(%)
I: met=3(21.4); car=4(26.7)
II: met=10(71.4); car=7(46.7)
III: met=1(7.1); car=3(20.0)
IV: met=0; car=1(6.7)
NRNRNR
Poole-Wilson
2003/Cleland
2006/Torp-Pedersen
2005/Torp-Pedersen 2007
Europe

Carvedilol Or Metoprolol European Trial (COMET)
RCTMen or women with symptomatic chronic heart failure (HYHA class II–IV); at least one cardiovascular admission during the previous 2 years; on stable heart failure treatment with ACE inhibitors for at least 4 weeks unless contraindicated; on treatment with diuretics (≥40 mg of frusemide or equivalent) for at least 2 weeks; LVEF </= 35% measured within the previous 3 months by echocardiography or radionuclide ventriculographyRecent change in treatment within 2 weeks before randomization; requirement for intravenous inotropic therapy; current treatment with non-dihydropyridine calcium channel blockers (diltiazem, verapamil); amiodarone (>200 mg per day); class-I antiarrhythmic drugs; unstable angina; myocardial infarction; coronary revascularisation or stroke within the previous 2 months; uncontrolled hypertension (SBP >170 mm Hg or DBP >105 mm Hg); hemodynamically significant valvular disease; symptomatic and sustained ventricular arrhythmias within the past 2 months note adequately treatment with antiarrhythmic drugs or implantation of an automatic defibrillator; pregnancy; women with childbrearing potential on inadequate contraception; known drug or alcohol misuse; poor compliance; any other serious systemic disease; contraindication to beta blockersCarvedilol (car) 50 mg
Metoprolol (met) 100 mg x
58 months (mean)
ACE inhibitor
Diuretic
Digitalis
Angiotensin II inhibitor
Other vasodilator
Follow-up visits at 4-month intervalsMean age: 62
79.8% male
98.9% White
NYHA class:
II: 48.4%
III: 47.8%
IV: 3.8%

Duration congestive heart failure: 42.4 months

Cause
Ischemic heart disease: 52.5%
Hypertension: 17.7%
Dilated cardiomyopathy: 43.9%
Previous valve surgery: 2.5%

Left ventricular ejection fraction (mean): 26%
NR/NR/3029
(car n=1511; met n=1518)
Poole-Wilson
2003
Europe

Carvedilol Or Metoprolol European Trial (COMET)
964(31.8%)
withdrawn(car= 481;
met=483)/5(0.03%) lost to fu/3029 analyzed
All deaths
car=512(34%)
met=600(40%)
Hazard ratio(95% CI): 0.83(0.74–0.93)
NNT: 18
p=0.002
Cardiovascular deaths
car=438(29%)
met=534(35%)
Hazard ratio(95% CI): 0.80(0.70–0.90)
NNT=17
p=0.0004
Non-cardiovascular deaths: car=74(5%); met=66(4%) (NS)
All deaths and all-cause admission: car=1116(74%); met=1160(76%) (NS)
Sudden Death: car=218 (14.4%), met=261 (17.2%); HR 0.81, 95% CI 0.68–0.97, P=0.02
Circulatory failure: car=168 (11.1%), met=197 (13%); HR 0.83, 95% CI 0.67–1.02, P=0.07
Death from stroke: car=13 (0.9%), met= 38 (2.5%); HR 0.33, 95% CI 0.18–0.62, P=0.0006
Fatal or nonfatal MI: car=57 (3.8%), met=79 (5.2%); HR 0.70, 95% CI 0.50–0.99, P=0.04
Other outcomes:
Well-being/morbidity/mortality (combined endpoint: death, days in hospital, well- being/symptoms and need for increased diuretic use) - total days of life lost over 4 yrs: car 939,534/2,206,060 (42.6%) vs met 1,000,147/2,216,280 (45.2%)
Outcomes from Remme et al (2007)
cardovascular events:
car=584(38.6%); met=667 (43.9%); HR 0.85, 95% CI 0.76–0.95, P=.003
Unstable angina:
car=56 (3.7%); met=77 (5%); HR .71, 95% CI 0.501–0.998 P=.049
All reports of adverse events were included irrespective of whether the investigators thought they had been caused by the treatment; adverse events that were fatal or life-threatening, required or extended admission, or resulted in persistent or significant disability or incapacity were labelled seriousOverall adverse event incidence:
car=1420(94%);
met=1457(96%)
Bradycardia: car= 144
(10%), met= 135 (9%)
Hypotension: car= 215 (14%), met= 160 (11%)
Incidence of new onset diabetes-related adverse events: car=10.6%
(122/1151), met=13%
(149/1147) (HR 0.78, 95%
CI 0.61 – 0.99, P = 0.039)
New onset diabetes: car= 119, met=145 (HR 0.78; 95% CI 0.61–0.997; P = 0.048)
NR
Galatius
2004
Denmark

Poor Quality
RCTPatients who fulfilled all standard indications for BB treatment in patients with systolic CHFPatients who had contraindications for BB treatment; and those who had been admitted, had attended an emergency room, or who had been treated in the heart failure clinic for acute decompensation within 2 weeks prior to randomization. Patients were excluded from data analysis if they died before two months of follow-up.Bisopolol started at 1.25 mg daily and titrated up (if tolerated) to 10mg/day
Carvedilol started at 3.125 mg bid and titrated up (if tolerated) to 25 mg bid
Diruetics = 90.1%
ACE Inhibitors or
ARB = 90.0%
Digoxin = 21.8%
Spironolactone = 21.8%
BB tolerance (no BB treatment at discharge or study end)

Timing: 2 month of follow-up and at discharge from the clinic
Mean Age=70.15
75.6% male
Ethnicity NR
NYHA class III–IV=19.9%
Months of CHF=25.2
Ischemic heart disease=52.9%
Heart rate, mean bpm=76.3
SBP, mmHg =139.0
NR/90/87Galatius
2004
Denmark

Poor Quality
0/3/87BB tolerance (no BB treatment at discharge or study end):
car=19(40%), bis=16(39%); NS

40%(n=35) of the patients didn’t tolerate BB treatment. The reasons are dizziness(41%), bradycardia/arrythmia(16%), worsening of claudication/Raybaud’s phenomenon(16%), depression/sleep disturbances(9%), asthma(9%), nausea(3%), other(6%)
NR in methods40%(n=35) of the patients didn’t tolerate BB treatment. The reasons are dizziness(41%), bradycardia/arrythmia(16 %), worsening of claudication/Raybaud’s phenomenon(16%), depression/sleep disturbances(9%), asthma(9%), nausea(3%), other(6%)0
Lombardo
2006
RCTCaucasion patients aged ≥ 35 years w/CHF, LV ejection fraction ≤ 40%, NYHA class II–III, stable clinical condition during prior 4 weeks.SBP <90mm Hg; DBP <60mm Hg; HR <50 bpm; cerebral vascular accidents w/in previous 6 months; heart or vascular surgery or MI w/in previous 3 months; serious valvular conditions that required surgery; atrioventricular conduction abnormalites; milignancies; serious liver, kidney, connective tissue, respiratory, or hematologic disease; history of allergy; intolerance to ACE inhibitors; unstable angina, DM; digitalis intolerance; BMI >30; excercise tolerance limited by other disorders; pregnancy.Carvedilol (car) started at 3.125 twice daily and titrated (if tolerated) to 25 mg twice daily.
Nebivolol (neb) started at 1.25 mg daily and titrated (if tolerated) to 5mg daily if SEP ramined > 110mm Hg and HR remained at >60 bpm.
X 6 months
NRNYHA functional class advers events
Timing: periodically

6-minute walk test
Timing: baseline and at 6 months
Car vs. Neb.
Mean Age: 66; 68
Male: 54%; 62%
Ethnicity: 100%
Caucasion
Car vs. Neb.
NYHA function class 2.48; 2.31
BMI: 26; 28
SBP (mm Hg) 138; 141
DBP (mm Hg) 83; 85
HR (bpm) 83; 81
DM 8; 11
NR/70/70Lombardo
2006
Italy
2/0/70NYHA functional Class:
Car (baseline/6 mo) 2.5/2.2 (−0.3)(P=.05)
Neb (baseline/6 mo)
2.3/2.2 (−0.1) (NS)
6 minute walk test (m):
Car (baseline/6 mo)
227/259
Neb (baseline/6 mo)
249/279 (NS)
NRMost common AE’s
Car. vs. Neb.
Any:
7 (20%); 9 (26%)
Hypotension: 1 (3%); 1 (3%)
asthenia/fatigue/dizziness:
6 (17%); 8 (23%)
bradycardia/ECG pauses
>2.5 sec: 3 (9%); 1 (3%)
increase of furosemide dosage: 4 (11%); 3 (8.6%)
worsening of dyspnea: 4
(11%); 3 (8.6%)
hospitalization for HF: 4
(11%); 2 (6%)
death: 1 (3%); 1 (3%)
no statistically sig.
differences.
2.8% (2/70)
car 1/35; neb 1/35

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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