Evidence Table 3

Author
Year
Country
Study Design
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Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedOutcomesMethod of adverse effects assessment?Adverse Effects ReportedWithdrawals due to adverse events (%, adverse n/enrolled n)Comments
Head-to-head trials
Chieffo
1986
Italy
Patients with comorbid essential hypertension (WHO Classes I–II) and stable angina pectorisSevere bradycardia (< 50 beats per minute); congestive heart failure; myocardial infarction less than three months before the start of the trial; asthma and renal insufficiencyLabetalol 200 mg + chlorthalidone
20 mg (lab+chl) daily (n=5)
Atenolol 100 mg + chlorthalidone
25 mg (ate+chl) (n=5) x 8 weeks
sl ntgPatient daily recordMean age=56.8
100% male
Race nr
NRNR/NR/10NR/NR/10 analyzedEffect on angina(# patients with reduced frequency on both ‘daily incidence of angina attacks’ and ‘dosage of sublingual nitroglycerin’): lab+chl=4/5(80%); ate+chl=3/5(60%)NRNRNRComorbid HTN
Fair quality
RCT
Dorow
1990

Fair quality
RCT Crossover
Outpatients aged between 41 and 67 years, suffering from angina pectoris due to coronary artery disease and concomitant reversible, chronic obstructive bronchitis; three angina attacks per week over the last three months (with or without therapy)Unstable angina or angina at rest; myocardial infarction within the last 6 months; heart failure with or without digitalis treatment; arterial hypertension with supine diastolic blood pressure values under a thiazide diuretic of >/= 105 mm Hg; cardiac arrhythmias requiring treatment; bronchial asthma; restrictive airway disease; pulmonary hypertension; diseases that could impair the implementations of bicycle ergometryAtenolol (ate) 50 mg daily
Bisoprolol (bis) 5 mg daily x 6 months
Diuretics
Short-acting and other nitrates
Bronchodilators
Inhaled corticoids
Antibiotics
Mucolytics
Expectorants
Method of measurement of ‘Frequency of angina pectoris attacks’ nrMean age: 55
% Male: 82.5
Race nr
% Smokers: 17.6
% Coronary artery disease: 100
% angina pectoris pretreatment: 80
% MI in case history: 20
% pathological exercise ECG: 100
NR/NR/400 withdrawn/1 lost/40 analyzedAngina attacks/week(% decrease in mean): ate=(−82.8%); bis=(−64.3%)NRNRNR
Frishman
1979
United States

Fair quality RCT
Patients with angina pectoris due to ischemic coronary artery disease as documented by coronary angiography or previous MI; positive treadmill exercise test showing at least a 1 mm ECG ST segment depression of the ischemic type in association with typical angina pectoris pain; at least 5 attacks of angina pectoris/2 weeks for three months with no evidence for an accelerated courseCo-existent valvular heart disease, congestive heart failure, hypertension, bronchial asthma requiring continued treatment with bronchodilators, severe bradycardia, intermittent claudication, and either myocardial infarction or a coronary artery bypass within 3 monthsPindolol (pin) 10–40 mg daily (n=23)
Propranolol (pro) 40–240 mg daily (n=18) x 8 weeks
NitroglycerinPatient daily record
Treadmill (protocol nr)
Mean age: 55
85.4% male
Race nr
Diagnosis of coronary artery disease
Coronary angiography: 80.5%
NR/NR/40NR/NR/40 analyzedAngina attacks/2 weeks(% reduction):pin=(− 41.8%); pro=(−47.0%)
Exercise tolerance(% increase in mets): pin=(+21.2%); pro=(+18.5%)
NROverall incidence: pin=4/23(17.4%); pro=17/18(94.4%)

Pindolol
Nasal stuffiness=1/23(4.3%)
Nocturia=1/23(4.3%)
Impotence=1/23(4.3%)
Palpitations=1/23(4.3%)

Propranolol
Rash=1/18(5.5%)
Blurred vision=2/18(11.1%)
Fatigue=8/18(44.4%)
Dyspnea on exertion=1/18(5.5%)
Mild hypotension=5/18(27.8%)
NR
van der Does
1999
Europe

Fair quality RCT
Male or female (postmenopausal or using reliable contraceptive methods) treated or untreated patients (</=80 years) with chronic angina pectoris, stable for at least preceding 2 months (symptomatic upon exertion and responsive to ntg and/or rest); documented coronary heart disease either by previous angiography (>70% narrowing of a major coronary vessel) or MI (electrocardiogram or cardiac enzymes), or a previous positive exercise test with occurrence of angina and ST- segment depression; capable of performing upright bicycle ergometric exercise tests; not to be at risk while temporarily receiving placeboContraindications to study drugs/exercise testing; other forms of angina pectoris (vasospastic, unstable); MI/cardiac surgery within 3 months; main stem stenosis; ventricular aneurysm; marked left ventricular hypertrophy; hypertrophic subaortic stenosis; hemodynamically relevant vascular defects; decompensated cardiac failure; orthostasis; phlebothrombosis; disorders of impulse formation/conduction (resting heart rate <45 beats/min, bundle brach block, pacemaker); obstructive airways disease; insulin-dependent DM; relevant hepatic impairment; gross obesity; alcohol/drug abuse; epilepsy; concomitant drugs interfering with study objectives (e.g., other antianginal agents); other clinical study participation within 30 daysCarvedilol (car) 100 mg daily (n=247)
Metoprolol (met) 200 mg daily (n=120) x 3 months
NitratesErect bicycle ergometric exerciseMean age: car=62; met=61
%male: car=72; met=71
Race nr
%smokers: car=14; met=19
%systemic hypertension: car=38; met=33
%diabetes mellitus: car=15; met=13
%dyslipidemia: car=32; met=31
%anterior MI: car=9; met=11
%posterior MI: car=18; met=17
%positive angiography: car=23; met=22
%1-vessel disease: car=13; met=10
%2-vessel disease: car=5; met=8
%3-vessel disease: car=5; met=3
nr/393 enrolled/368 randomized36 withdrawn/lost nr/344 analyzed for efficacyPer protocol analysis: car=231; met=113
Mean change in total exercise time(s): car=(+60); met=(+60)
Mean change in time to angina(s): car=(+77); met=(+76)
Volunteered by subjects or observed by investigator were recorded regardless of their nature and regardless of whether a causal relation to study medication was assumedcar n=248; met n=120
Any adverse event: car=25%; met=30%

Most common AE's, n(%)
Dizziness: car=12(4.8), met=6(5.0)
Bronchitis: car=9(3.6); met=3(2.5)
Asthenia: car=8(3.2); met=3(2.5)
Headache: car=8(3.2); met=4(3.3)
Back pain: car=6(2.4); met=2(1.7)
AE withdrawals: car=18; met=6
Narahara
1990
United States

Fair quality
Patients of either sex who were > 30 years of age; history of stable angina pectoris of > 3 months' duration; reproducible exercise-induced angina in conjunction with ≥ 1 mm of horizontal or downsloping ST-segment depression measured 0.08 second after the J pointContraindications to beta blockade including sinus bradycardia (<50 beats/min), greater than first-degree atrioventricular block, congestive heart failure, asthma, peripheral vascular disease or insulin-dependent diabetes; women of child-bearing potential and patients with unstable angina pectoris or a myocardial infarction within the preceding 3 monthsBetaxolol 20 mg once daily
Betaxolol 40 mg once daily
Propranolol 40 mg 4 times daily
Propranolol 80 mg 4 times daily x
10 weeks
Sublingual nitroglycerinPatient diary used to measure (1) angina frequency; and (2) nitroglycerin consumption

Treadmill exercise testing (modified Naughton protocol) used to measure (1) exercise duration; and (2) time to angina
Mean age=61
21.4% female
92.9% white
History of prior MI = 42%
History of coronary angiography = 59%
Coronary angiography patients with NYHA functional Class II = 82%
Coronary angiography patients with NYHA functional Class III = 17%
nr/nr/11220(17.8%) withdrawn/lost to fu nr/90 analyzed for angina attacks and nitroglycerin tablet use; 82 analyzed for exercise variablesMean number of angina attacks (%reduction)
Betaxolol 20=60
Betaxolol 40=77
Propranolol 160=57
Propranolol 320=70
NS
Nitroglycerin tablets/week (% reduction)
Betaxolol 20=48
Betaxolol 40=73
Propranolol 160=59
Propranolol 320=55
NS
Exercise duration (% increase in minutes)
Betaxolol 20=14
Betaxolol 40=15
Propranolol 160=21
Propranolol 320=14
NS
NROverall side effects (considered to be due to drug therapy): B20=50%; B40=37%; P160=42%; P320=45%

# patients; sample sizes nr
Fatigue: B20=1; B40=3; P160=4; P320=3
Increased sweating: B20=0; B40-3; P160=0;
P320=0
Headache: B20=2; B40=0; P160=2; P320=0
Parasthesia: B20=0; B40=0; P160=0; P320=0
Diarrhea: B20=2; B40=0; P160=0; P320=0
Dyspepsia: B20=0; B40=2; P160=0; P320=0
Tinnitus: B20=2; B40=0; P160=0; P320=0
Angina: B20=0; B40=0; P16-=2; P320=0
Depression: B20=0; B40=2; P160=0; P320=0
Dyspnea: B20=0; B40=2; P160=0; P320=0
Abnormal vision: B20=0; B40=2; P160=0; P320=0
NR
Kardas 2007Ischemic heart disease outpatients CCS class I–II, aged 40–75, beta-blockers-niave, whose mental state enabled conscious participation in the study.Unstable angina pectoris, NYHA class III and IV heart failure, heart rate <60/min, II or III degree antrio- ventricular block, systolic blood pressure below 90 mmHg, symptomatic infection, and any conditions requiring help from others with drug administration.Betaxolol 20 mg once daily metoprolol tartrate metropolol 50 mg twice daily for 8 weeks.NitratesMEMS, Medication Event
Monitoring System used to measure patient complience.

Drug effectiveness/tollerance/health-related quality of life.
Patient diary used to measure (1) weekly number os chest pain episodes; and (2) weekly number of short-acting nitrates doses.
Mean age = 58.8
40.6% male
ethnicity NR
NRNR/NR/11213 withdrawn/0 loss to fu/96 analyzed for compliance. Analyzed 96 due to a MEMS container lost in 2 cases and failure to download compliance data from the MEMS cap in one case.Betaxolol vs. Metoprolol 8 weeks

Reduction in chest pain epidodes
.42/week vs. .46/week (NS)
Reduction in short-acting nitrate doses taken
.30/week vs. .21/week (NS)
Health Related Quality of Life-- improved
general wellbeing
73% vs. 71.7% (n=41)
sleep
31% vs. 34%
mood
42% vs. 37%
physical function
19% vs. 13%
physical function
42.9% vs. 15.2% (p<0.01)
sexual function
0.0% vs. 4.3%
Tolerance and Adverse Effects
10.7% vs. 16.1%
bradycardia 3.5% in both groups.
NR10.7% betaxolol vs. 16.1% metoprolol Bradycardia (3.5% in both groups) other adverse events NRbetaxolol vs. metoprolol
2/56 (4%) vs. 4/56 (7%)
Frishman
1989
United States

Poor quality
RCT
Patients with documented stable angina pectoris and mild to moderate hypertensionPatients with coexistent valvular heart disease, congestive heart failure, bronchial asthma, severe bradycardia (resting heart rate less than 50 beats/min), intermittent claudication, myocardial infarction within 3 months, and age above 70 years or under 18 yearsLabetalol (lab) 200–1600 mg daily Propranolol (pro) 80–640 mg daily x 4 monthsHCTZ 50 mg daily (if standing DBP > 100 mm Hg)Treadmill ergometer exercise tests (Bruce protocol)
Patient diary
Center 1
Mean age: lab=58; pro=57
Gender (%male): lab=66.7; pro=100
Race nr
Center 2
Mean age: lab=51; pro=58
Gender(%male): lab=100; pro=100%
Race nr
NRNR/NR/4112 withdrawn/1 lost to fu/34 analyzed for efficacyTotal exercise time (%D in sec)
Center 1: lab=(+7); pro=(+12)
Center 2: lab=(+23); pro=(+40)
Time to angina onset(%D in sec)
Center 1: lab=(+29); pro=(+38)
Center 2: lab=(+58); pro=(+66)
Number of patients with angina endpoint(D%)
Center 1: lab=(−67); pro=(−63)
Center 2: lab=(−38); pro=(−50)
Questioned generally about occurrence of adverse events specifically regarding occurrence of dyspnea, palpitations, sexual dysfunction, GI disturbances and dizzinessNRNRCenter 1 measured exercise parameters at or close to peak drug effect
Center 2 measured exercise parameters at or close to trough drug effect
Placebo-controlled trials
Destors
1989
Europe

Fair Quality
RCT
Male and female patients who were less than 70 years of age were considered for the study if they had coronary heart disease with chronic angina stabilized for at least 3 months. Women could be included if menopausal for at least 2 years or exhibiting coronary lesions at angiography. Demonstration of at least 8 attacks of angina during the last 14 days or 5 attacks of angina during the last 7 days of the 2–8 week washout periodSuffering exclusively at rest or had nocturnal attacks; angina pectoris not secondary to atherosclerosis; unstable angina pectoris; so called Prinzmetal’s angina or myocardial infarction within the past 6 months; inability to assess pain and fill in diary cards; any contraindication to either active treatment; liver or kidney conditions likely to modify drug metabolism or all reasons preventing close compliance to study protocolBepridil (bep) 100–400 mg daily
Propranolol (pro) 60–240 mg daily
Placebo (pla) x 24 weeks
sl short-acting trinitrinBicycle ergometer x wks 2, 4, 6, 8, 12, 16, 20 & 24
Patient diary cards x wks 8, 24
Mean age: pla=54.3; pro=56.1
% Male: pla=57.1; pro=73.1
Race nr
History of MI: pla=31.4%; pro=37.2%
Positive ECG for exercise: pla=77.1%; pro=76.9%
Positive ECG for attacks: pla=57.1%; pro=56.4%
Angina duration(mos): pla=69.6; pro=66.6
Mean weekly attacks: pla=10.3; pro=12.4
Mean curative ntg tablets/wk: pla=10.6; pro=12.6
Mean preventive ntg tablets/wk: pla=2.6; pro=3.0
Mean attack-free days/wk: pla=1.2; pro=1.5
Mean exercise test duration(min): pla=9.3; pro=9.7
NR/NR/19138 withdrawals/15 lost to fu/analyzed 191Angina attacks/week(% reduction)
Week 8: pla=(−49%); pro=(−65%)
Week 24: pla=(−77%); pro=(−71%)
Ntg consumption(% reduction)
Week 8: pla=(−57%); pro=(−73%)
Week 24: pla=(−79%); pro=(−74%)
Number of attack-free days
Week 8: pla=190; pro=193
Week 24: pla=270; pro=204
Total work(mean % increase):
Week 8: pla=13%; pro=48%
Week 24: pla=20%; pro=50%
Maximum workload(mean % increase):
Week 8: pla=6%; pro=27%
Week 24: pla=14%; pro=30%
Exercise duration(mean % increase):
Week 8: pla=7%; pro=22%
Week 24: pla=8%; pro=24%
NRNumber of patients with:
Hypotension: pla=1; pro=4
Bronchospasm: pla=1; pro=1
Allergic reaction: pla=0; pro=1
Raynaud phenomenon: pla=0; pro=1
Fatigue: pla=2; pro=14
Psychiatric problems: pla=1; pro=2
Gastrointestinal problems: pla=2; pro=10
Other: pla=1; pro=6
Any: pla=6; pro=23
Severe coronary events(cardiac death, MI, angina deterioration): pla=2(5.7%); pro=8(10.2%)
Development of heart failure/AV block/rhythm disturbances: pla=0; pro=5
Death due to
MI(# pts): pla=0; pro=1
CVA(# pts): pla=1; pro=1

Severe clinic events(# pts): pla=1; pro=2
Adverse reaction(# pts): pla=0; pro=1

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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