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Evidence Table 10

Quality assessments of placebo-controlled trials of beta blockers for heart failure

Author
Year
Country
Randomization described?Allocation concealedGroups similar at baselineSimilarity to target populationNumber recruitedExclusion criteria for recruitmentEligibility criteria specifiedOutcome assessors blindedCare provider blindedPatient unaware of treatmentIntention-to-treat (ITT) analysisMaintenance of comparable groupsReporting of attrition, crossovers, adherence, and contaminationLoss to follow-up: differential/highScoreFundingControl group standard of careLength of follow-up
Anonymous
1994

The Cardiac
Insufficiency
Bisoprolol Study (CIBIS I)

Fair quality
Adequate; computer generatedNRDifferences in:
- history of MI
Bis: 169 (53%)
pla: 134 (42%) (P<0.005)
- diastolic blood pressure
Bis: 79.5 mm Hg
Pla: 77.9 mm Hg (P=0.03)
Mean Age: 59.6
Male: 82.5%
Ethnicity: NR
Screened NR
641 randomized
CHF due to hypertrophic or restrictvie 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.
YesYes, blinded independent committeeYes, allocation centrally controlled; titration blindedYesYesYesAttrition=157/641 (24.5%); others NRNoFairNRYesMean 1.9 years
Anonymous
1999

The Cardiac
Insufficiency
Bisoprolol Study (CIBIS II)
Adequate; computer generated random numbersAdequate; centralizedYesMean age: 61
Male: 80.5%
Ethnicity: NR
Screened NR
2647 randomized
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.YesYes, blinded independent committeeYesYesYesYesAttrition=69/2647 (2.6%); others NRNoGoodNRYesMean 1.3 years
MOCHA

Bristow1996

Multicenter Oral
Carvedilol Heart Failure
Assessment
NRNRYesMean age: 59.5
Male: 76%
Caucasian: 78%
Screened: NR
Eligible for run-in: 376
Enrolled: 345
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.
YesNRYesYesYesNRAttrition=52/345 (15%);
others NR
NoFairSmithKline Beecham
Pharmaceuticals
NR6 months
PRECISE
Packer1996
NRNRYesMean age: 60.3 years
Male: 73%
Ethnicity: NR
Screened: NR

Eligible for run-in: 301

Enrolled: 278
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.
YesNRYesYesUnclearNRAttrition=49/278 (18%);
others NR
NoFairSmithKline Beecham
Pharmaceuticals &
Boehringer Mannheim
Therapeutics
NR6 months
Colucci
1996

U.S. Carvedilol Heart
Failure Study Group
NRNRYesMean age: 55
Male: 85%
Ethnicity: NR
Screened: NR
Eligible for run-in: 389
Enrolled: 366
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.
YesNRYesYesYesNRAttrition=31(8.5%); others
NR
NRFairSmithKline Beecham
Pharmaceuticals &
Boehringer Mannheim
Therapeutics
NRMean 7 months
Cohn
1997

U.S. Carvedilol Heart
Failure Study Group
NRNRYesMean age: 60 years (range 22-85)
Male: 58%
Ethnicity:
- Caucasian: 71%
- Black: 21%
- Other: 8%
Screened: NR
Eligible for run-in: 131
Enrolled: 105
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.YesNRYesYesNoNRAttrition=12(11.4%); others
NR
Unclear; 87.6% of patients did not complete final QOL assessmentPoorSmithKline Beecham
Pharmaceuticals &
Boehringer Mannheim
Therapeutics
NRMean 3 months
Richards
2001
Anonymous
1995, 1997

Australia/New Zealand
Heart Failure Research
Collaborative Group
Adequate; computer generatedAdequate; centralizedYesMean age 67
80% male
Race NR
Screened: NR
Eligible for run-in: 301
Enrolled: 278
Current 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.YesYesYesYesYesNRAttrition=14.9%; others NRNRGoodSmithKline Beecham - independently initiated conducted, analyzed by ANZ
Heart Failure Research Collaborative
YesMean 19 months
Cleland 2003

Carvedilol Hibernating
Reversible Ischaemia
Trial: Marker of
Success (CHRISTMAS)
Adequate; random numbers tableAdequate; centralizedUnclear; baseline characteristics provided for only 78.8% of all randomized patientsGood
mean age=62.5
90% male
489 screened
387 randomized
Patients 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 amiodaroneYesYesYesYesNoUnclearAttrition=21.2%; others NRNRFairHoffman-La RocheYes189 days (mean)
COPERNICUS

Eichhorn 2001
Packer 2001
Packer 2002
Krum 2003
NRNRYesGood
mean age >55
higher proportion male
3106 screened
2289 randomized
Heart 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 periodYesYesYesYesYesNRattrition reported; others NRNoneFairRoche; GlaxoSmithKlineYesMean 10.4 months
Hori
2004
Japan

The Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) Trial
NRNRyes100% Japanese190 enrolled
16 (8.4%) withdrawn following run-in phase
174 randomized
Valvular 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 infarction or coronary artery bypass grafting had occurred within the preceding 3 monthsYesNRNRNRNo (1 patient that did not received any medication was excluded from ITT)NRNo
No
No
No
NRFairNRYesmean follow-up
Packer 1996
Colucci 1996
Yancy 2001
U.S. Carvedilol Heart Failure Study Group
NRNRYesGood
mean age >55 higher proportion male
Screened NR
1094 randomized
Major CV event or surgical procedure within 3 months of study entry; uncorrected, primary valvular disease; active myocarditis; sustained ventricular tachycardia or advanced heart block not controlled by antiarrhythmic intervention or a pacemaker; systolic blood pressure of more than 160 or less than 85 mm Hg or diastolic blood pressure of more than 100 mm Hg; a heart rate of less than 68 beats per minute; clinically important hepatic or renal disease; or any condition other than heart failure that could limit exercise or survival; concomitant use of calcium-channel blockers α- or β-adrenergic agonists or antagonists or class IC or III antiarrhythmic agentsYesYesYesYesYesNRAE withdrawals reported; others NRnonefairSmithKline Beecham Pharmaceuticals and Roche Laboratories

Two investigators/authors are employees and stock holders of SKB
Yes12 months
Anderson
1985
Inferior; pairsNRYesMean age 51
66% male
Race NR
Screened: NR
Eligible: 50
Enrolled: 50
Unstabilized overt cardiac failure; alcohol abuse; secondary cardiomyopathies; firm exclusions to beta blocker treatment (asthma, advanced heart block, allergy)YesNRNRNRYesNRAttrition=5/50(10%); others NRNoFairUniv. of Utah SOM and LDS Hospital, Salt Lake CityNRMean 19 months
Waagstein
1993
Computer-generated with "block size of 4," stratifiedNRYesMean age 49
73% male
Race NR
Screened: NR
Eligible: 417
Enrolled: 383
Treatment 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 diseaseYesYesNRNRYes for primary endpoint
Nor for other
NRAttrition=14.1%; others NRHigh loss for secondary endpoints except hospitalization.FairAstra Pharmaceutical divisions and Ciba-Geigy Corp., Swedish Heart & Lung Foundation & Swedish Medical Research CouncilNR12 months and
18 months (n=211/383)
MERIT-HF

Anonymous 1999
Goldstein 1999
Hjalmarson 2000
Goldstein 2001
Ghali 2002 Gottlieb 2002
Adequate; computer generatedAdequate; centralizedYesMean ages:
<60: 34% 60-69: 35% ≥70: 31%
77% male
White: 94%
Black: 5%
Other: 1%
Screened: NR
Eligible (recruited): 4427
Enrolled: 3991
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.YesYesNRNRYesNRAttrition=589/3991 (15%); others NRNoFairProject leader, coordinator, medical advisor, and acknowledgement to Astra Hassle, SwedenYes1 year (mean)
Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure Anonymous 2000

The Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study (RESOLVD)
NRNRyesMean age=61.5
82.1% male
87.1% white
Screened: NR
Eligible: 468
Enrolled: 426
NRyesyesyesyesyesNRCompliance (>80% of study medication): met CR=93%; pla=92%; others NRNRFairNRyes24 weeks
Waagstein
2003
Europe
NRNRyesMean age=56.7
80% male
Ethnicity NR
Screened: NR
Eligible: NR
Enrolled: 172
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 rateyesNRNRNRno (4 patients excluded from ITT due to never taking study medication)NRyes
no
no
no
no
no
FairMedical Research Council (Project 02529), the Swedish Heart-Lung Foundation and AstraZenecaYes6 months
Edes
2005 (ENECA)
NRpatients were allocated a patient number in ascending orderyesneb. vs. placebo
age= 71.87, 72.19
male=70.15%, 76.98%
ethnicity=99.2%, 98.4% caucasian
Screened: 354
Eligible: NR
Enrolled: 260
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.yesstated double- blind, but no details givenstated double- blind, but no details givenstated double- blind, but no details givenyesyesyes
no
no
no
no
no
FairBerlin-Chemie AG, Menarini Group, Berlin, Germanyyes12 months
Flather
2005
(SENIORS)
master randomization list carried out by phone adequateyesyesMean age:76.1
male: 63%
ethnicity: NR
Yes
Screened: NR
Eligible: NR
Enrolled: 2135
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.yesNRNRyesanalysis excluded 7 patientsyesyes
no
yes
no
no
no
FairMenarini Ricerche SpAyesmean 21
months

From: Evidence Tables

Cover of Drug Class Review: Beta Adrenergic Blockers
Drug Class Review: Beta Adrenergic Blockers: Final Report Update 4 [Internet].
Helfand M, Peterson K, Christensen V, et al.
Portland (OR): Oregon Health & Science University; 2009 Jul.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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