Evidence Table 1

Randomized controlled trials of beta blockers for hypertension

Author
Year
Country
Study designEligibility 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Other population characteristics (diagnosis, etc)Number screened/ eligible/ enrolledNumber withdrawn/ lost to fu/ analyzedOutcomesMethod of adverse effects assessment?Adverse effects reportedWithdrawals due to adverse events (%, adverse n/enrolled n)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 controlled trials
Walle
1994

Fair
Head-to- head Crossover Double blindPatients of either sex, more than 21 years of age, with mild to moderate hypertension (diastolic blood pressure in the range of 95 to 110 mmHg) were eligible for the study. The study subjects were either to have received no previous antihypertensive treatment or to have been previously treatedCardiiovascular diseases, such as angina pectoris, secondary hypertension, grade II or III AV block, heart failure, or a history of myocardial infarction (within 12 months); cerebrovascular ischemia: asthma/ chronic bronchitis; insulin-dependent diabetes; and malignancy or chronic disease requiring treatmentRun-in: 4-wk, SB, placebo

Treatment periods:
Metoprolol CR 100 mg vs. Atenolol 100 mg x 6 weeks
Washout: NR
NoPsychologic General Well-Being (PGWB) index

Minor Symptom Evaluation (MSE) profile
Mean age: 58 y/o, 43.3% male.

Ethinicity: NR
mean weight: 76kg
mean height: 171cm
mean duration of hypertention: 9 yrs mean BP: 102/178
NR/NR/602/0/58Metoprolol CR vs. atenolol

PGWB Index (total mean scores): 102.7 vs. 102.0; P=NS
MSE profile - morning (mean values); all P=NS
Contentment: 33.1 vs. 32.4
Vitality: 35.2 vs. 35.4
Sleep: 31.8 vs. 30.0
MSE profile - morning (single items rated using VAS)
Sexual interest: favored atenolol (P<0.05) (data NR)
Muscular tension, numbness, self-consciousness, sociability, appetite, sweating, physical competance, dreams:
P=NS, data NR
Clinical observation, active questionningOverall AEs: no differences (data NR)

Serious AEs: 0 vs. 2 (bradycardia and syncope; both leading to withdrawal)
meto vs. ate = 0 vs. 2 (3.3%)
Sundar
1991
Head-to- head CrossoverPatients, who were between the age 35 and 60 years, either never received antihypertensive treatment or had discontinued the drugs for at least 2 weeks prior to entry into trialPatients with accociated conditions like moderate to severtr congestive infarction within 6 months, accelerated hypertension and those with severe gastrointestinal, renal or hepatie dysfunction were excludedWash-out period: 2 weeks between the interventions

atenolol (ate): 100mg per day propranolol (pro): 80mg per day

duration of treatment: 4 weeks
NRQuality of life questionnaire (5-point scale)
-the sense of well being and satisfaction with life
-the physical state
-the enotional state
-intellectual functions
-ability to perform in social roles
-sexual life
Age, Ethnicity: NR
Gender: 100% male
NRNR/NR/4418/0/26ate vs. pro:

-the sense of well being and satisfaction with life
-the physical state
-the enotional state
-intellectual functions
-ability to perform in social roles
-sexual life
*all NS
Reported by patientsate vs. pro (%)
headache: 0 vs. 0
weakness: 10.5 vs. 10.7
warmth: 2.6 vs. 0
oedema: 0 vs. 0
dyspnoea: 5.3 vs. 0
constipation: 0 vs. 0
NR
Steiner
1990
Head-to- head ParallelThe patients were required to have been diagnosed with mild-to-moderate essential hypertension for at least 1 yea, be at least 21 years of age, emloyed or retired, eucated at high-school level or equivalent, and married or libing with an significant other.Patients could not have major concomitant medical or mental problems or significant changes in living conditions (e.g., recent death of spouse), or require concomitant therapy that could confound the study resultsplacebo run-in for 3–5 weeks titration for 1–4 weeks (lowering of DBP by at least 10 mmHg or to 90mmHg or less) maintenance for 4 weeks

Propranolol 80–240mg per day (mean=133.4mg per day)

Atenolol 50–100mg per day (mean=56.4mg per day)
NoFour-point scale in the Symptom Check
List-90-R (SCL) (by patients)
Psychological General Well-Being (PGWB) Index (by patients and spouses or significant others)
Insomnia Symptom Questionnaire
Sexual Function Questionnaire for male patients (modified)
Life satisfaction Index
Age, Ethnicity: NR
Gender: 100% male
NR489/360/344 (179 for pro and ate)27/1/151

pro: 73
ate: 78
Propranolol vs. Atenolol PGWB Index (patients)
-Global, anxiety, depressed mood, positive well-being, general health vitality: NS
-Self-control: −0.17 vs. 0.32, P<0.05

PGWB Index (significant other)
-Global, anxiety, depressed mood, self-control, general health vitality: NS
-Positive well-being: −0.65 vs. 0.33, P<0.05

Symptom Checklist
-Global: −0.02 vs. −3.46, P<0.05
-Anxiety: -0.35 vs. −1.49, P<0.05
-Obsession: 0.03 vs. −1.34, P<0.05
-Hostility: 0.38 vs. −0.65, P<0.05

Life Satisfaction Index
-Global: −1.13 vs. 1.19, P<0.05
-Social satisfaction: −0.24 vs. 0.71, P<0.05
-Life satisfaction, work satisfaction: NS

Sleep function, Sexual function: all NS
Reported by patientspro(%) vs. ate(%), all NS
Bradycardia: 4(4.5) vs. 9(10)
Gastrointestinal distress: 9(10.1) vs. 7(7.8)
Dry mouth: 5(5.6) vs. 4(4.4)
Anxiety: 7(7.9) vs. 2(2.2)
Sleep disturbance: 4(4.5) vs. 6(6.7)
Libido decreased/impotence: 8(9): 5(5.6)
Weakness/fatigue: 15(16.9) vs. 8(8.9)
Headache: 12(13.5) vs. 9(10)
Total: 57(64) vs. 50(55.6)
pro: 5(6.85)
ate: 0(0)
Dahlof 1988Head-to-head
Crossover
Patients with either sex with mild to moderate primary hypertension, either newly diagnosed or previously treated with monoterapy1. The patient had not followed the instructions to fill in and return the questionnaire on 3 occasions during the run-in period
2. The diastolic blood pressure <90mmHg or >105mmHg
3. Previous treatment with metoprolol or atenolol
4. AV-block 2 or 3
5. Non-compensated congestive heart failure
6. Insulin-treated diabetes
7. Bradycardia (heart rate <50 beats/min)
8. Bronchial asthma
9. Any serious concomitant illness or drug abuse which can interfere with the treatment
10. Unwillingness to participate in the study
placebo run-in: 2 weeks

atenolol (ate) 50 mg od
metoprolol CR (meto) 100 mg od

Duration: 6 weeks
NRMSE-profile
Jern's quality of life questionnaires
Beta-blocker questionnaires (subjective symptoms reported)

Timing: before, during and after the intervention
mean age: 54.4 +8.8, 51(66%) male

Ethnicity: NR
Duration of hypertension: 3.5+5 years
WHO I: 75
WHO II: 2
Supine BP: SBP 159+14.9, DBP 97.8+4.8
Heart rate: 74+10.4
NR/NR/773/0/74meto vs. ate

MSE-profile, contentment, hedonic tone, vitality, activity, sleep, relaxation: NS

Subjective symptoms-leg fatigue, constipation, diarrhoea, bradycardia, cold hands and feet, heavy breathing: NS
Palpitation: meto> ate, P<0.05

Preference (n): 31 vs. 23, NS
Beta-blocker questionnaires (subjective symptoms reported)Subjective symptoms-leg fatigue, constipation, diarrhoea, bradycardia, cold hands and feet, heavy breathing: NS
Palpitation: meto> ate, P<0.05
2(2.6%)
Blumenthal 1988Head-to-head
exposure design unclear
Participants were eligible for the study if they had resting diastolic blood pressures that were within 90 to 110 mmHg on four separate occassions, using a random zero device, during a 2-week screening interval before testing. Subjects did not take any antihypertensive medication for at least 6 weeks before the screening and were free of any significant disease other than hypertension.NRWeek 1 (b.i.d):
Atenolol (ate): 50mg+placebo
Propranolol (pro): 40mg+40mg
Placebo (pla): placebo+placebo

Week 2 (b.I.d): If BP was not reduced by 10mmHg and remained below 90mmHg, increase dosage to: ate 100mg; pro 80mg.

Duration: 2 weeks
NRPsychmetric testing:
-The profile of mood states (POMS)
-SCL-90
-A side effects measure

Timing: before and after drug administration
mean age=42.5, 100%
male (22 whites and 4 blacks)
15 (62%) had not taken any antihypertensive medication at any time before participation in the study. 0 (0%) took any sedative medication 23 (80%) had at least some college education 25 (98%) were employed on a full-time basis.NR/ NR/ 260/0/26POMS (before vs. after):
ate: tension- 11.87 vs. 6.12, P<0.002
depression- NS
anger- 7.12 vs. 2.00, P<0.03
pro: all NS; pla: all NS

SCL-90 (before vs. after):
ate: anxiety- NS
hostility- 55.00 vs. 48.37, P<0.04
phobic anxiety- NS; depression- NS
pro: all NS; pla: all NS
Questionnaire.
Reported by patients
sleep items: NS
sexual functioning: NS
energy: 4 (ate) and 4 (pro) reported being more tired in the morning, while 6 (pla) reported less fatigue.
0
Buhler 1986Head-to-head
rossover
Double blind
Patients with a diastolic blood pressure (DBP) of 100–120 mmHg (Korotkoff V) om the seated positionPatients were on other antihypertensive drugs, had contraindications for beta-blocker therapy, severe disease, or who were known for their poor compliance. Patients with impaired renal function, i.e., serum creatinine>150 umol/l, were also excluded.Wash-out period: 2 weeks

Bisoprolol (bis) 10mg or Atenolol (ate) 50 mg for 2 weeks. Then, if DBP> 95mmHg, increase to: bis 20mg or ate 100mg.

Total duraion: 8 weeks

Wash-out period: 2 weeks. Then crossover.
NRself-assessment questionnaire86 (82.7%) male
male: mean age=53.8
female: mean age=50.8

Ethinicity: NR
10 were not available for the crossover comparison because of: intercurrent disease (n=1), BP response deemed unsatisfactory by the investigator (n=3), and unwanted effects (n=6).138/134/11612/0/104Baseline:bis/ baseline:ate (all NS)
headache- 20:7/ 19:9
tiredness- 17:20/ 17:13
Nervousness- 17:10/ 10:8
Sleep problems- 18:11/ 15:10
Cold extremities- 14:13/ 16:12
Sweating- 12:9/ 11:11
Tingling sensations- 12:6/ 9:5
Feeling of weakness- 11:6/ 5:7
Dizziness- 11:3/ 8:7
Joint pain- 9:9/ 6:8
Depressed mood- 12:11/ 9:5
Sex problems- 5:7/ 6:4
self-assessment questionnaireBaseline:bis / baseline:ate (number), all NS
headache- 20:7/ 19:9
tiredness- 17:20/ 17:13
Nervousness- 17:10/ 10:8
Sleep problems- 18:11/ 15:10
Cold extremities- 14:13/ 16:12
Sweating- 12:9/ 11:11
Tingling sensations- 12:6/ 9:5
Feeling of weakness- 11:6/ 5:7
Dizziness- 11:3/ 8:7
Joint pain- 9:9/ 6:8
Depressed mood- 12:11/ 9:5
Sex problems- 5:7/ 6:4
bis (1): dizziness
ate (5): diarrhea, skin rash, asthmatic
bronchitis, vertigo, headache
Placebo-controlled trials
Oberman, 1990
Wassertheil-Smoller, 1991
Wassertheil-Smoller, 1992
United States

Trial of Antihypertensive Interventions and Management (TAIM)

Fair quality
Placebo-controlled21–65 years old; between 110 and 160% ideal weight (Metropolitan Life Insurance Height-Weight Tables); diastolic BP at baseline of 90–100 mm HgHistory of myocardial infarction, stroke, or asthma, or a serum creatinine level of 177 mmol/d or greater, insulin-dependent diabetes, allergy to thiazides or beta-blockers, pregnancy, or likelihood of difficulty in complying with the interventionsAtenolol (ate) 50 mg
Chlorthalidone (chl) 25 mg
Placebo (pla)
Dietary interventions
1) Usual Diet
2) Low sodium (goal of 52 mmol/d for participants weighing 50 kg or less to 100 mmol/d for those weighing 92 kg) + high potassium (goal: 62 mmol/d to 115 mmol/d) 3) Weight loss group (goal: 4.5 kg or 10% of baseline weight, whichever was greater)
Life Satisfaction Scale
Physical Complaints Inventory
Symptoms Checklist
Per protocol analysis (n=697)
Mean age=49
56% male
68% white
Previous dug treatment = 66.2%
Smokers = 14%
Alcohol use (at least once a week) = 39.7%
10, 148 screened/878 eligible/878 randomized181(20.6%) withdrawn/0 lost to fu/697 analyzedPer protocol analysis (pla n=232; ate n=238)
(*negative score indicates improvement)
*Total physical problems: pla=(−0.15); ate=(−0.14)
*Overall psychological functioning: pla=(−0.14); ate=(−0.14)
Overall life satisfaction: pla=(−0.04); ate=0.02
*Sexual physical problems: pla=(−0.12); ate=(−0.09)
*Depression: pla=(−0.15); ate=(−0.14)
*Anxiety: pla=(−0.14); ate=(−0.15)
*Sleep disturbances: (−0.29); ate=(−0.26)
*Fatigue: (−0.20); ate=(−0.15)
Satisfaction with physical health: pla=0.21; ate=0.19
Sexual satisfaction: pla=(−0.14); ate=0.04
NRNRNR
Perez-Stable, 2000

Fair quality
Placebo-controlledPatients with mild hypertension, defined as an average diastolic blood pressure between 90 and 104 mm Hg on three readings taken during each of two screening visits 2 weeks apart; aged 18–59Concomitant use of insulin, bronchodilators, antidepressants or antihypertensive medications within 1 month of screening; coronary artery disease, vascular heart disease, renal insufficiency, cerebrovascular disease, and secondary causes of hypertensionPropranolol (pro) 80–400 mg daily (n=156)
Placebo (pla) (n=156)
NRCognitive Function Test Battery
Stimulus Evaluation/Response
Selection
Continuous Performance Task(CPT)
Digit Symbol Substitution Task(DSST)
California Veral Learning Test(CVLT)
Psychological Measures
Center for Epidemiological Studies
Depression Scale(CES-D)
Beck Depression Inventory(BDI)
Age: Pro=4; Pla=45
% male: Pro=67;
Pla=66
% White: Pro=76;
Pla=71
Current smokers: Pro=10%; Pla=11%
Current daily drinkers of alcohol:
Pro=11%; Pla=12%
Mean DBP: Pro=96; Pla=96
Mean SBP: Pro=140=Pla=141
nr/nr/312NR/NR/203Mean changes in:
Selection reaction time(ms): pro=(−3); pla=(−10)
CPT
Reaction time(ms): pro=12; pla=6
Correct responses: pro=0; pla=0
Commission errors: pro=(−1); pla=(−1)
Omission errors: pro=0.1; pla=0.1
DSST correct responses: pro=3; pla=5
CVLT
Monday total: pro=3; pla=1
Tuesday list: pro=2; pla=0
Short-delay free recall: pro=3; pla=2
Short-delay cued recall: pro=4; pla=3
Long-delay free recall: pro=5; pla=4
Long-delay cued recall: pro=5; pla=2
Recognition: pro=3; pla=3
CES-D: pro=0; pla=0
BDI: pro=(−1); pla=baseline value nr
NRNRNR
Anonymous, 1977
Greenberg, 1984
Anonymous, 1985
Miall, 1987
Anonymous, 1988a
Anonymous, 1988b
Anonymous, 1992
Lever, 1993
UK
Medical Research Council (MRC)
Fair quality
Placebo-controlled
Single blind
Mild hypertension
Men and women; aged 35–64; with mild hypertension (diastolic BP 90–109 mm Hg, together with systolic pressure below 200 mm Hg)
Secondary hypertension; already on antihypertensive treatment; cardiac failure; MI or stroke within previous 3 months, angina; intermittent claudication; diabetes; gout; asthma; other serious disease; pregnancyPropranolol (pro) up to 320 mg daily (n=4403)
Bendrofluazide (ben) 10 mg daily (n=4297)
Placebo (pla) (n=8654) with goal of maintaining DBP below 90 mm Hg x 5 years
MethydopaData for terminating events (e.g., strokes, coronary events, all cardiovascular events, and all cause mortality) were analyzed every six monthsMean age: pro=52;
ben=52; pla=52
%male: pro=51.9;
ben=52.1; pla=52.3
Race nr
(Mean values for men/women)
Body weight(kg): pro=81/70; pla=81/70
SBP(mm Hg): pro=158/165; pla=158/165
DBP(mm Hg): pro=98/98; pla=98/98
% cigarette smokers: pro=30/25;
pla=32/27
% with LV hypertrophy on ECG:
pro=0.3/0.2; pla=0.4/0.4
% with Q-wave abnormalities:
pro=1.2/1.7; pla=1.5/1.4
% with history of stroke: pro=0.7/0.7;
pla=0.7/0.7
515,000
screened/46, 350
eligible/17,35
4 enrolled
nr/nr/17,354 analyzed# events/rate per 1000 patient years
Strokes: pro=42/1.9; pla=109/2.6
Coronary events: pro=103/4.8; pla=234/5.5
All cardiovascular events: pro=146/6.7; pla=352/8.2
Non-cardiovascular deaths: pro=55/2.5; pla=114/2.7
All deaths: pro=120/5.5; pla=253/5.9
NRNR# patients/%
Impaired glucose tolerance:
pro=43/0.98%; pla=82/0.95%
Gout: pro=12/0.27%; pla=14/0.16%
Impotence: pro=50/1.14%; pla=20/0.23%
Raynaud's phenomenon: pro=75/1.70%;
pla=7/0.08%
Skin disorder: pro=21/0.48%; pla=7/0.08%
Dyspnoea: pro=110/2.5%; pla=10/0.12%
Lethargy: pro=104/2.36%; 13/0.15%
Nausea/dizziness/headache:
pro=103/2.34%; pla=49/0.57%
Overall: pro=518/11.76%; pla=202/2.33%
Head-to-head controlled trials
Brixius
2007
Head-to- headMale out-patients aged (40–55) w/newly diagnosed or existing mild (stage I; SBP 140–159 mmHg and DBP 90–99 mmHg) essential hypertension or taking antihypertensive medication. Also in a stable, monogamous heterosexual partnership for at least 6 months and to have no symptoms of sexual disfunction, even if taking beta-blockers or diuretics.Patients with history of DM, alcohol and/or drug abuse, major cardiovasuclar and non-cardiovascular diseases, or those receiving concomitant treatment related ot hypertension and/or ED.Group A: nebivolol (neb) 5 mg once daily X 12 weeks; placebo x 2 weeks, metropolol succinate 95 mg daily x 12 weeks.

Group B: metropolol succinate 95 mg daily x 12 weeks, once daily placebo x 2 weeks, nebivolol (neb) 5 mg daily X 12 weeks
NRAE: NR
Timing: screening visit, baseline, every
4 weeks.
mean age: group A
48.4; group B 47.2
Male: 100%
Ethnicity: NR
BMI: group A 28.1; group B 27.2
SBP (mmHg): group A 149.4; group B
148.2
DBP (mmHg): group A 92.9; group B 93
% smokers: group A 11 (44%); group B 11 (48%)
Screened: 50
Eligible: 48
Enrolled: 48
2 (prior to randomization )/nr/48AE outcomes:
nr
nr“No critical findings regarding safety issues occurred during the study.”0 (0/48)
Yilmaz
2008
Turkey
Head-to- headMale out-patients > 18 years, who were newly diagnosed systolic or diastolic sage 1 hypertension (SBP > 140 mmHg but < 160 mmHg, or a mean seated DBP of > 90 mmHg but < 100 mmHg, prescription of first- time drug therapy, ability to describe their sleep quality.Previous use of any antihypertensive medication, hypertension beyond sage 1, cardiovascular disease, chronic obstructive pulmonary disease, symptomatic cerebrovascular disease, significant systemic disease, history of psychiatric illness (including primary insomnia, hepatic failure), serum creatinine levels of >1.4 mg/dL, DM, fasting blood glucose of >125 mg/dL, current pregnancy, hypo- or hyperthroidism, and a BMI of >25 kg/m2.. Patients using medications for other reasons: beta-blockers, diuretics, major psychotropic agents, oral steroids, daily nonsteroidal anti-inflammatory drugs, high-dose acetylsalicylic acid.Nebivolol (neb) starting dose of 2.5 mg once daily titrated to achieve target DBP of <90 mmHg and SBP of <140 mmHg.

Metoprolol succinate (extended release) starting dose of 25 mg once daily titrated to achieve target DBP of <90 mmHg and SBP of <140 mmHg.

If after 2 weeks BP was not normalized, amlodipine (5–10 mg daily) was added to treatment.

Duration: x 6 weeks.
Amlodipine was added if BP was not normalized after week 2.Primary Outcome: Quality of sleep:
Pittsburgh Sleep Quality Index (PSQI) which includes 7 component scores -- sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, use of sleep medication, daytime disfunction. Scores from each component are summed for a global PSQI score (1–21). Higher scores indicate lower quality of sleep. Score of <5 =poor sleeper. Measures at baseline and at week 6. Secondary Outcome: BP and heart rate measured at weeks 1, 2, 4, and 6.
Mean age: 40.7
Male: 20/39 (51%)
Ethnicity: NR
DBP >90 mmHg: neb 2 (9%); met 0 (0%)
SBP >140 mmHg: neb 7 (32%); met 8 (47%)
median heart rate (bpm) neb 72.5; met 71.0
Mean global PSQI score at baseline neb 5.77 (poor sleepers 12 (55%); met 5.11 (poor sleepers 5 (29%)
Screened 56
Eligible 46
Enrolled 46 (neb 24; met 22)
7/0/39Primary: Mean Global PSQI Score:
neb: decrease from 5.77 to 4.55 (indicating imporved sleep)
met: increased from 5.11 to 6.54 (indicating worsening sleep)
(mean adjusted difference: −2.31; 95% CI: −3.10, – 1.51; P<0.001)
End of treatment:
neb: 7 (32%) poor sleepers
met: 13 (76%) poor sleepers (P=0.006)

Secondary:
Target DBP and SBP were observed for all patients.
Heart rate change from baseline: neb −1.08; met 1.22 (−2.31 CI 95%, P<0.001)
Patient recorded diaryNo adverse events were reported during the couse of the study.0 (0/39)

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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