Evidence Table 14

Randomized controlled trials of beta blockers for arrhythmia

Author
Year
Country
Study design SettingEligibility 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Other population characteristics (diagnosis, etc)Number screened/ eligible/ enrolledNumber withdrawn/ lost to fu/ analyzedOutcomesMethod of adverse effects assessment?Adverse effects reportedWithdrawals due to adverse events (%, adverse n/enrolled n)
Head-to-head trials
Katritsis
2003

Fair quality
RCT multicenterPatients subjected to cardioversion of persistent AF (> 7 days)Terminal illness, age > 80 years, left ventricular ejection fraction <30, concomitant treatment with class I or III antiarrhythmic drugs, amiodarone use within 3 months before randomization, previous treatment with bisoprolol or carvedilol, and contraindications to beta blockade, such as conduction disturbances, asthma, or severe chronic obstructive pulmonary artery diseaseBisoprolol 10 mg daily (or 5 mg daily if LVEF < 40%)
carvedilol 50 mg daily (or 25 mg daily if LVEF M 40%) x 12 months
No restrictions, with exception of class I or III antiarrhythmic drugsClinic visits at months 1, 3, 6 and 12Mean
age=65.5
82% male
Ethnicity NR
Heart rate=71.3 beats per minute
Left atrial diameter=4.4 cm
Systemic blood pressure > 140/90 mm Hg=60%
Coronary artery disease=18.9%
Lone atrial fibrillation=11.1%
Other conditions (valve disease, hyperthyroidism, dilated cardiomyopathy)=21.1%
Diabetes mellitus=14.4%
NR/102/908 (8.9%) withdrew/3 (3.3%) lost to fu/82 analyzed for efficacyBisoprolol (n=43) vs Carvedilol (n=39)

Relapse into AF= 23 (53.4%) vs 17 (43.6%); P=NS
Median time to relapse (days) 20 vs 14; P=NS
NRNRWithdrew due to side effects: 3 (6.4%) vs 2 (4.7%); P=NS
Placebo- controlled trials
Metoprolol vs placebo
Kuhlkamp
2000
Germany
RCT multicenterPatients at 71 centers with persistent atrial fibrillation of 3 days to 1 year. Must be converted to sinus rhythm. Sufficient anticoagulation for 1+ months strongly recommended to providers.Use of Class 1 or 3 antiarrhythmic drug, beta- blockers or calcium channel blockers; chronic treatment with amiodarone within 6 months; contraindications to beta-adrenergic blocking agents; untreated thyroid dysfunction; paroxysmal atrial fibrillation or history of it; cardiac surgery in the previous two monthsn = 403 metoprolol (met): start 100 mg/day vs. identical placebo (pla) x 6 months

Maintain 100 mg/day:
met = 122/197 (62%)
pla = 131/197 (67%)
To 200 mg/day:
met = 33/197 (17%)
pla = 50/197 (25%)
To 50 mg/day:
met = 36/197 (18%)
pla = 12/197 (6%)
Digoxin/digitoxin, ACE inhibitor, diuretics, nitrates, calcium-channel blockers of dihydropyridine typePrimary endpoint: relapse into atrial fibrillation or flutter.

Mean followup time:
met = 93 days
pla = 73 days
Mean age
60.5
70% male
Race: NR
Previous cardioversion:
met = 18/197 (9%) pla = 22/197 (11%)
Hypertension:
met = 96/197 (49%) pla = 91/197 (46%)
Coronary artery disease:
met = 52/197 (26%) pla = 48/197 (24%)
Heart failure:
met = 51/197 (26%) pla = 49/197 (25%)
Stroke/TIA:
met = 15/197 (8%) pla = 12/197 (12%)
Diabetes mellitus:
met = 23/197 (12%) pla = 17/197 (9%)
NYHA 1:
met = 125/197 (64%) pla = 137/197 (70%)
NYHA2:
met = 64/197 (33%) pla = 54/197 (27%)
NYHA3:
met = 8/197 (4%) pla = 6/197 (3%)
Screened = NR
Eligible = NR
Enrolled = 403
Lost for efficacy data (no followup ECG) = 9/403 (2%)
Lost for safety data = 4/403 (1%)

Analyzed = 394/403 (98%) and 399/403 (99%)
Death:
met = 3/200 (2%) pla = 0

Premature discontinuation due to relapse to
atrial fibrillation/flutter:
met = 96/197 (49%)
pla = 118/197 (60%)

Total relapse to atrial fibrillation:
met = 87/197 (44%)
pla = 118/197 (60%)
NRDizziness/vertigo:
met = 20/200 (10%)
pla = 6/199 (3%)
Bradycardia:
met = 14/200 (7%)
pla = 0
Cardiac failure:
met = 3/200 (2%)
pla = 0
Hypotension:
met = 2/200 (1%)
pla = 1/199 (1%)
Total: 26/394 (7%)
Serious adverse events:
met = 4/197 (2%)
pla = 2/197(1%)
Nonserious adverse events:
met = 16/197 (8%)
pla = 4/197(2%)
Khand
2003
UK

Fair quality
RCT multicenterPatients with persistent atrial fibrillation (> 1 month) and heart failure (appropriate symptoms of heart failure for more than two months and echocardiographic evidence of cardiac dysfunction [LVEF < 40% or preserved LV systolic function, together with LV hypertrophy, suggesting diastolic dysfunction in the absence of an alternative potential cause of symptoms]) who were receiving digoxin and diureticsHeart rate at rest < 60 beats/min, systolic blood pressure < 90 mm Hg, sick sinus synddrome or complete heart block, current treatment with a beta- blocker or HR-lowering calcium channel antagonist or > 200 mg amiodarone, recent major cardiovascular event or procedures, asthma or reversible obstructive airways disease, serum creatinine > 250 μmol/l or significant hepatic disease, uncorrected significant valvular heart disease, or any life-threatening noncardiac diseasePhase I
Open digoxin +placebo
Open digoxin+carvedilol 50 mg daily (or 100 mg daily for patients > 85 kg) x 4 months

Phase II
Digoxin
Carvedilol 50 mg daily (or 100 mg daily for patients > 85 kg) x 6 months
ACE inhibitors
Warfarin
1) LVEF
2) Ventricular rate control by 24-hour ambulatory ECG
3) Symptoms rated using patient self-administered, quantitative questionnaire designed to measure perception of the frequency and severity of symptoms (chest pain/discomfort, fatigue, and shortness of breath at rest, during walking at normal pace, and while climbing stairs and palpitations) and their functional capacity on 4- point scale (0=absent to 3=severe symptoms); responses were summed to produce a symptom score rangingn from 0 (no symptoms to 33 (worst symptoms)
4) Exercise tolerance by 6- minute corridor walk distance
Mean
age=68.5
61.7% male
Ethnicity NR
IHD etiology=40.4%
Mean duration of AF=131.5 weeks
Mean previous cardioversion attempts=0.5
Mean resting heart rate of ECG=85.5 beats/minute
Mean LVEF=24.1%
Mean LVEDD=53.7 mm
Mean LA size=48.4 mm
NYHA class
I=4.2%
II=57.4%
III=31.9%
IV=6.4%
Digoxin dose=0.245 mg
Digoxin plasma concentration=1.54 mmol/l
ACE inhibitors=70.2%
Anticoagulated=80.8%
NR/NR/47Phase I
6 (12.8%)/0/NR

Phase II
NR/NR/NR
Phase 1 (Combination vs Digoxin)
LVEF: 30.6% vs 26%; P=0.048
Symptom score: 7 vs 8; P=0.039
6-min WD (ms): 394 vs 414; P=NS
Mean 24-hour ventricular rate reduction: 65.2 vs 74.9 ; P≤0.0001

Phase II (carvedilol vs digoxin)
LVEF: 21.6% vs 27.2%; P=NS
Symptom score: 6 vs 8; P=NS
6-min WD (ms): 374 vs 403; P=NS
Mean 24-hour ventricular rate reduction: 88.8 vs. 75.7; P=NS
NRDeaths
Phase I: 4.2% vs 4.3%;
P=NS
Phase II: 5% vs 4.8%;
P=NS
Withdrawals due to adverse events
Phase I: 3 (12.5%) vs 1 (4.3%); P=NS
Phase II: 3 (15%) vs 1 (4.8%); P=NS

Withdrawals due to worsening heart failure
Phase I: 0 vs 0
Phase II: 3 (15%) vs 1 (4.8%); P=NS

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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