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Blood pressure lowering efficacy of nonselective beta-blockers for primary hypertension

  1. Gavin WK Wong*,
  2. James M Wright

Editorial Group: Cochrane Hypertension Group

Published Online: 28 FEB 2014

Assessed as up-to-date: 11 OCT 2013

DOI: 10.1002/14651858.CD007452.pub2


How to Cite

Wong GWK, Wright JM. Blood pressure lowering efficacy of nonselective beta-blockers for primary hypertension. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD007452. DOI: 10.1002/14651858.CD007452.pub2.

Author Information

  1. University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver, BC, Canada

*Gavin WK Wong, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. gavin.wong@ti.ubc.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2014

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Characteristics of included studies [ordered by study ID]
Chalmers 1976

MethodsSingle-center, randomized, double-blind, placebo-controlled, cross-over study. 8-week run-in period followed by 4 × 8-week treatment phases


Participants23 participants

Age range: 30-60 years, 20/23 participants completed the study

Inclusion criteria: DBP 95-120 mmHg

Exclusion criteria: pre-existing condition: obstructive airway diseases, diabetes


InterventionsTimolol 10 mg 3 times daily, hydrochlorothiazide 50 mg once daily, hydrochlorothiazide 50 mg plus timolol 10 mg, placebo


OutcomesSupine, standing, casual SBP, DBP, mean BP

Resting HR

Plasma renin activity

WDAE


NotesNo WDAE


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo pill was used. Participants took the same number of pills every time. Physicians were also blinded but unblinded by effect on pulse rate

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskReported how many participants dropped out

Selective reporting (reporting bias)Low riskSBP, DBP, HR were primary outcomes.

WDAE were reported

Dargie 1986

MethodsRandomized, double-blind, cross-over study. Each period of treatment lasted for 4 weeks


Participants14 participants (9 women, 5 men)

Mean age (range): 51.6 years (30-65)

Inclusion criteria: DBP 95-110 mmHg on single-drug therapy


InterventionsVerapamil 120 mg 3 times daily, p

ropranolol 80 mg 3 times daily, v

erapamil 120 mg plus propranolol 80 mg 3 times daily,

placebo


OutcomesSupine and standing SBP, DBP


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo Information

Blinding (performance bias and detection bias)
All outcomes
High riskNo information other than stated the study was double blind

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo report of follow-up procedure or number of drop-outs

Selective reporting (reporting bias)High riskHR and WDAE not reported

De Plean 1981

MethodsRandomized, double-blind, cross-over study. Each treatment period lasted for 4 weeks. BP was measured about 6 hours after drug intake. Mean of 2 or 3 readings is used for BP data


Participants16 participants entered the study. 10/16 participants completed the study. 1 person WDAE

Age range: 30-56 years

Baseline: mean SBP 163.9 mmHg, mean DBP 117.1 mmHg, mean HR 88.8 beats per minute, mean body weight 83.2 kg


InterventionsPenbutolol 80 mg once daily, hydrochlorothiazide 100 mg once daily, placebo


OutcomesSupine and standing SBP, DBP, HR

Biochemical data

Total withdrawal and WDAE


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The order of the active treatments was selected according to a predetermined random code"

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High risk"Both active drugs and placebo were available in capsules of identical size, shape and color", but pulse would unblind BP measurements

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskReported SBP, DBP and HR

Selective reporting (reporting bias)Low riskSBP and DBP were primary outcomes

HR and WDAE were reported

Dupont 1984

MethodsRandomized, double-blind, placebo-controlled, cross-over study. Each treatment period lasted 4 weeks


Participants10 participants

Mean age (range): 54.4 years (45-62)

Inclusion criteria: ambulatory DBP 95-115 mmHg


InterventionsNadolol 80 mg once daily, placebo


OutcomesMean ABP, HR, CO, GFR, renal blood flow, renal vascular resistance


NotesSBP and DBP data were not reported. Only HR data were relevant to this review


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
High riskSBP and DBP data were not reported

Selective reporting (reporting bias)High riskSBP and DBP data were not reported

Fasano 1991

MethodsRandomized, double-blind, placebo-controlled, parallel study. 4-week washout followed by 4-week treatment period


Participants20 participants (12 male)

Mean age (range:) 39 years (18-57)

Inclusion criteria: primary hypertension

Exclusion criteria:

secondary hypertension; cardiovascular diseases; chronic diseases; metabolic diseases; history of severe side effects with beta-blockers; pregnancy, lactation or use of oral contraceptive


InterventionsTertatolol 5 mg once daily, placebo


OutcomesSupine and standing SBP, DBP, HR, cardiac workload


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskNo description of placebo pills

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
High risk2 participants dropped out without any information on follow-up

Selective reporting (reporting bias)High riskSBP, DBP and HR were primary outcomes

WDAE was not reported

Ferrara 1987

MethodsRandomized, double-blind, cross-over study. Washout period for 2 weeks followed by 3-week test period for each treatment


Participants7 participants (3 women, 4 men)

Age range: 26-62 years

Inclusion criteria: primary hypertension


InterventionsPropranolol 80 twice daily, placebo


OutcomesSupine SBP, DBP, HR,

oral glucose tolerance test, insulin sensitivity


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskNo description of placebo pills

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskWDAE was not reported

Galloway 1976

MethodsRandomized, double-blind, placebo-controlled, cross-over study. Eligible participants were seen in hypertension clinic 2 weeks after discharge from hospital. Each treatment period lasted for 4 weeks


Participants24 participants (6 men)

Mean age (range): 46 years (19-65)

Mean body weight: 62.6 kg

Inclusion criteria: DBP > 90 mmHg but < 105 mmHg


InterventionsPropranolol 20 mg 3 times daily, propranolol 40 mg 3 times daily, propranolol 80 mg 3 times daily, placebo


OutcomesSupine, standing, postexercise SBP, DBP, HR


NotesDrop-outs and WDAE not reported. However, author stated that no dose-related adverse event was recorded


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The order of administration was determine by a random code"

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskEach pill was identical in appearance

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskData analysis was based on data from all 24 participants. There was no report of drop-outs

Selective reporting (reporting bias)Low riskSBP, DBP and HR were primary outcomes. No drop-outs

Kelemen 1990

MethodsRandomized, double-blind, placebo-controlled, parallel study. After screening, participant entered a 4-week single-blind placebo washout period. During which all antihypertensive drugs were replaced by placebo. After washout, patients were tested for baseline readings. Eligible participants were then randomized to a double-blind treatment group for 11 weeks


ParticipantsInclusion criteria: DBP > 90 mmHg but < 105 mmHg

Exclusion criteria: history of coronary, valvular, renal, cerebral vascular, hepatic or neurological diseases; history of alcohol or drug abuse; any contraindication for propranolol and diltiazem and exercise


InterventionsParticipants first started on propranolol 160 mg, diltiazem 240 mg or placebo in the first week. Then they were force titrated to propranolol 240 mg or diltiazem 360 mg per day or equal amount of placebo pills. After titration, all participants entered a 10-week exercise training program


OutcomesEchocardiogram; resting supine and exercise SBP, DBP, HR; plasma lipid and lipoprotein


NotesOnly exercise HR was reported. Resting HR was not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo pills were in the same number of active treatments, but pulse rate effect would unblind BP measurement

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low risk1 participant withdrew from propranolol group

Selective reporting (reporting bias)High riskHR was not reported

Lepantalo 1985

MethodsAfter 4-week washout period, participants were randomly allocation to 3x 4-week treatment period. Participants would cross-over to another treatment at the end of each treatment period without washout


Participants34 participants (17 male)

Mean age (range): 54.1 years (52-68)

Inclusion criteria: mild primary hypertension

Exclusion criteria: diabetes, peripheral arteries disease


InterventionsPropranolol 80 mg twice daily, metoprolol 100 mg twice daily, placebo


OutcomesBP, ankle:arm systolic BP ratio, calf blood flow, peripheral resistance


NotesHR was not reported. There were no drop-outs. Same as Lepantalo 1983


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High risk"All pills were of the same appearance" but pulse rate would unblind BP measurement

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskNo drop-outs

Selective reporting (reporting bias)High riskHR was not reported

Malacco 1985

MethodsAfter 3-week washout period, participants were randomized to 3x 4-week treatment periods. Each treatment period was separated by a 7-day washout period. BP was measured at the end of each period


Participants12 participants (6 male)

Aged: < 60 years

Inclusion criteria: SBP ≥ 150 mmHg, DBP ≥ 100 mmHg

Exclusion criteria: congestive heart failure, lung disease, ischemic heart disease, chronic alcoholism, diabetes, renal insufficiency, bradycardia


InterventionsPropranolol 80 mg twice daily, indenolol 60 mg twice daily, placebo


OutcomesMBP, HR, CO


NotesOnly HR data were used in analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo was given at same frequency as active treatments, but pulse rate would unblind BP measurement

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskNo drop-outs

Selective reporting (reporting bias)High riskSBP and DBP were not reported

McCorvey 1993

MethodsRandomized, double-blind, placebo-controlled, cross-over study. Eligible participants discontinued all previous antihypertensive treatment and were then randomized to treatment or placebo immediately. All participants were forced titrated to maximum dose 3 days after randomization. The dosage remained the same for the next 4 weeks. All cross-over procedures were the same as stated above


Participants17 participants

Inclusion criteria: primary hypertension with documented elevated BP for the previous 12 months

Exclusion criteria: history of stroke, MI, angina, hepatic dysfunction, serum creatinine > 1.5 mg/dL, history of bronchospasm, AV block greater than first degree, congestive heart failure, gout, alcohol and drug abuse, participants who were unable to comply with protocol


InterventionsPropranolol 120 mg once daily, hydrochlorothiazide 25 mg once daily, enalapril 10 mg once daily, placebo for first 3 days. Then dose was double for the reminder of the treatment period


OutcomesBP, HR, QoL


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High risk"All drugs were dispensed in similar appearing gelatin capsules, but pulse rate would unblind BP measurement

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskWDAE not reported

McInnes 1985

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 4 weeks of washout period, participants were randomized to 4 × 4-week treatment periods. BP was measured at the end of each period


Participants14 participants

Inclusion criteria: DBP 95-110 mmHg with single-drug therapy


InterventionsVerapamil 120 mg 3 times daily, propranolol 80 mg 3 times daily, verapamil 120 mg plus propranolol 80 mg 3 times daily, placebo


OutcomesSBP, DBP, HR, PR interval, end systolic dimension, end diastolic dimension, fractional shortening


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The order of treatment is systematically varied to minimize any effect of sequence"

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskWDAE was not reported

Nicaise 1981

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 1 month of placebo washout, participants were randomized to treatment for 2 months and then crossed-over to the other treatment for another 2 months


Participants30 participants (8 males)

Mean age (range): 79 years (69-93)

Inclusion criteria: SBP ≥ 160 mmHg, DBP ≥ 95 mmHg, or both


Interventions(-)moprolol 75 mg twice daily, placebo


OutcomesMAP, HR, drop-outs, WDAE


Notes7 people dropped out, 5 WDAE (3 in placebo, 2 in moprolol)

SD not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskParticipants who dropped out were not included

Selective reporting (reporting bias)High riskSBP, DBP and SD were not reported

Oh 1985

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 2 weeks of washout, participants were randomized to treatment or placebo for 4 weeks


Participants15 Chinese participants

Mean age (range): 39.3 years (23-57)

Inclusion criteria: BP > 144/94 but < 200/115 mmHg


InterventionsPropranolol 160 mg once daily, propranolol 320 mg once daily, placebo


OutcomesResting, exercise and after exercise SBP, DBP, HR, adverse effects


NotesThere were 4 groups (A, B, C, D); however, only group A data were reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskDouble dummy, but decreased pulse rate would unblind BP measurement

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskWDAE not reported

Pearson 1979

MethodsRandomized, double-blind, placebo-controlled, cross-over study. Without washout period, participants were randomized to treatment upon entry. Each treatment period lasted for 6 weeks


Participants16 participants (8 males)

Mean age: 54 years

Inclusion criteria: DBP ≥ 100 mmHg with single-drug therapy

Exclusion criteria: angina, MI, heart failure, stroke, COPD, gout, women of child-bearing potential or using oral contraceptive pills


InterventionsPropranolol 80 mg twice daily, tienilic acid 250 mg every morning, propranolol 80 mg plus tienilic acid 250 mg, placebo


OutcomesSBP, DBP, HR, adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High risk"The tablets in each treatment period were identical in number and appearance", but pulse rate would unblind BP measurement

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskSEM were extracted from figures. WDAE not reported

Petrie 1976

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 14-day washout period, participants were randomized to a sequence of 4 week treatments


Participants24 participants (13 males)

Inclusion criteria: DBP > 105 mmHg but < 125 mmHg

Exclusion criteria: recent MI, evidence of heart failure, heart block, gross ischemia, grade III or IV retinopathy, diabetes, gout, impaired liver function, or creatinine clearance < 60mL/minute or if they were on any other drug treatment


InterventionsMethyldopa 250 mg 3 times daily, practolol 200 mg 3 times daily, propranolol 80 mg 3 times daily, methyldopa 250 mg plus propranolol 80 mg both 3 times daily, methyldopa 250 mg plus practolol 200 mg both 3 times daily, placebo


OutcomesSBP, DBP, HR, QoL


NotesSD were imputed using the mean of other studies that provided SD


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Low riskPackage were pre-packed

Blinding (performance bias and detection bias)
All outcomes
High riskParticipants took the same number of pills

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskNo drop-outs

Selective reporting (reporting bias)High riskSD were not reported

Petrie 1980

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 4-week run-in period, participants were randomized to a sequence of 4 week treatments. There were no washout periods between treatments


Participants23 participants (12 males)

Mean age (years): 40.9 years (21-59)

Inclusion criteria: DBP > 90 mmHg


InterventionsAtenolol 100 mg once daily, sustained-release oxprenolol 160 mg once daily, long-acting propranolol 160 mg once daily, placebo


Outcomes5-minute supine and 2-minute standing SBP, DBP, HR. Measurement were made 20-22 hours after dose


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskMatching placebo was used as the same frequency

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskSafety data not reported

Ravid 1985

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 2-week placebo run-in period, participants were randomly allocated to series of 5 × 4-week treatments


Participants134 participants (66 males)

Mean age: men 52 years, women 54 years

Inclusion criteria: DBP > 95 mmHg but < 120 mmHg,

normal renal function, absent of liver diseases and gross obesity


InterventionsSlow-release propranolol 160 mg once daily, slow-release oxprenolol 160 mg once daily, atenolol 100 mg once daily, metoprolol 200 mg once daily, placebo


OutcomesSBP, DBP, HR, adverse effects


NotesStudy reported male and female data separately. The data had larger than average SEM, which cause the SD to be large


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Low risk"Treatment was unknown to patients and physicians"

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo was taken as the same frequency as active treatment

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskParticipants who dropped out were not included in the analysis

Selective reporting (reporting bias)Low riskAll outcomes reported

Richardson 1968

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 1-week run-in period, participants were randomized to sequence of 5 week treatment periods


Participants19 participants (5 males)

Inclusion criteria: moderate-to-severe hypertension


InterventionsPropranolol 40 mg 3 times daily, chlorthalidone 50 mg twice daily, propranolol 40 mg 3 times daily plus chlorthalidone 50 mg twice daily, placebo


OutcomesSBP, DBP, HR, WDAE, side effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskDummy for both drugs were given

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskOnly participants who completed the study were included in analysis

Selective reporting (reporting bias)Low riskAll outcomes were reported

Rosen 1994

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 1-month single-blind run-in period, participants were randomized to series of 1 month treatments. Treatment periods were separated by 2-week washout period


Participants13 participants (100% male)

Inclusion criteria: males with prior history of hypertension and sexual dysfunction were recruited. Participants had 2 consecutive sitting DBP 90-100 mmHg

Exclusion criteria: people with diabetes, congestive heart failure, renal disease, alcoholism, or other medical or psychiatric disorders


Interventionsα-methyldopa 500 mg twice daily, propranolol 80 mg twice daily, atenolol 100 mg once daily, dyazide 50/25 mg twice daily, placebo


OutcomesSBP, DBP, sleep study, sexual function, hormone study


NotesHR data were not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskData from participant who withdrawn were analyzed separately

Selective reporting (reporting bias)High riskHR were not reported

Schoenberger 1989

MethodsRandomized, double-blind, placebo-controlled, parallel study. After 4 weeks of single-blind run-in period, participants were randomized to 6-week treatment period, followed by 2-week tapering off period


Participants302 participants (160 men)

Inclusion criteria: adults with mild-to-moderate hypertension, defined as supine DBP 95-115 mmHg

Exclusion criteria: pregnancy, child-bearing potential, significant hepatic or renal disorders, COPD, asthma, thyroid disorder, bradycardia, psychosis, use of drugs that interfere with beta-blockers 2 weeks before study, metabolic acidosis, unstable diabetes, continued need for concomitant antihypertensive medications or diuretics, heart failure, AV block, conditions that affect compliance, concomitant administration of investigational drugs


InterventionsPenbutolol 10 mg once daily, 20 mg once daily, 40 mg once daily, placebo


OutcomesSupine and standing SBP, DBP, HR 24 hours after last dose, WDAE, adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebos were used at same frequency as active drugs

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskParticipants who dropped out were not included in analysis

Selective reporting (reporting bias)Low riskAll outcomes reported

Shukla 1979

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After 2-week run-in period, eligible participants were randomized to series of 4 week treatments


Participants26 participants

Inclusion criteria: DBP 90-114 mmHg

Exclusion criteria: recent MI, heart failure, heart block, grade III/IV retinopathy, impaired hepatic or renal functions, diabetes, COPD


InterventionsPropranolol 60 mg 3 times daily, propranolol 120 mg 3 times daily, propranolol 180 mg 3 times daily, placebo


OutcomesSBP, DBP


NotesHR not reported. No drop-outs


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPills of Identical appearance were used

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Low riskNo drop-outs

Selective reporting (reporting bias)High riskHR not reported

Sica 2004

MethodsRandomized, double-blind, placebo-controlled, parallel study. After 2-3 weeks of single-blind placebo run-in, eligible participants were randomized to 1 of the treatments for 8 weeks. Participants who were randomized to propranolol 120 mg or 160 mg would start at 80 mg then force titrated to respective dose in the next 2 weeks. Participants who were randomized to propranolol 640 mg/day started at 160 mg and then up titrated to 640 mg in the next 3 weeks


ParticipantsInclusion criteria: DBP 96-114 mmHg during 2 readings while sitting

Exclusion criteria: pregnancy, lactating, renal artery stenosis, gastrointestinal diseases, kidney or liver diseases, cardiac diseases within the last 6 months, asthma, COPD, nonallergic bronchospasms, insulin-dependent diabetes, concomitant administration of drugs that affect BP


InterventionsPropranolol 80 mg once daily, propranolol 120 mg once daily, propranolol 160 mg once daily, propranolol 640 mg once daily, placebo


OutcomesSBP, DBP, HR, plasma concentration, safety


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo pills were taken at the same frequency

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)Low riskAll outcomes reported

van Herwaarden 1977

MethodsRandomized, double-blind, placebo-controlled, cross-over study. There was no run-in period. Participants were randomized to 4 consecutive treatments, each lasting 4 weeks. At the end of each treatment period, BP was measured 2 hours after the morning dose


Participants8 participants

Inclusion criteria: supine DBP after 15 minutes of rest 100-120 mmHg


InterventionsPropranolol 80 mg 3 times daily, metoprolol 100 mg 3 times daily, placebo. Each beta-blocker treatment was alternated with placebo treatment


OutcomesSBP, DBP, HR, effect of adrenaline


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)High riskRandomization might be compromised as placebo was alternated with active treatments

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo was used at the same frequency

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)High riskWDAE not reported

West 1980

MethodsRandomized, double-blind, placebo-controlled, cross-over study. After a 6-week run-in period, participants received, in random order, 5 × 6-week test phase. The BP data werethe mean of the last 4 weeks of each treatment period


Participants12 participants

Inclusion criteria: untreated DBP 95-120 mmHg


InterventionsMethyclothiazide 5 mg once daily, labetalol 300 mg twice daily, propranolol 80 mg twice daily, hydralazine 50 mg twice daily, placebo


OutcomesSBP, DBP, HR, adverse effects, WDAE


NotesSD were imputed


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information

Allocation concealment (selection bias)Unclear riskNo information

Blinding (performance bias and detection bias)
All outcomes
High riskPlacebo was given for every active treatment at respective frequency

Incomplete outcome data (attrition bias)
Primary and secondary outcomes
Unclear riskNo information

Selective reporting (reporting bias)Low riskAll outcomes reported

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ades 1988Data during treatment were not reported. Available data reported were 4-7 days after the last dose

Ades 1990Same as Ades 1988, did not provided data until after 4-7 days of last dose

Agnes 1989Did not have drugs versus placebo data

Beilin 1972Dose adjusted to side effects

Cherchi 1985Did not have parallel placebo group

Costa 1984Nonfixed dose

Davidson 1976Nonfixed dose

Kubik 1984Not randomized to placebo

Smith 1988Provided ambulatory blood pressure measurement data only

Weigmann 1998Provided ambulatory blood pressure measurement data only

 
Comparison 1. Propranolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Systolic blood pressure18Mean Difference (Fixed, 95% CI)Subtotals only

    1.1 (1x starting dose) 60, 80 mg/day
3222Mean Difference (Fixed, 95% CI)-4.67 [-8.13, -1.21]

    1.2 (2x starting dose) 120, 160 and 180 mg/day
13592Mean Difference (Fixed, 95% CI)-12.15 [-14.61, -9.69]

    1.3 (4x starting dose) 240 and 320 mg/day
699Mean Difference (Fixed, 95% CI)-21.01 [-25.43, -16.58]

    1.4 (8x starting dose) 480 and 640 mg/day
2205Mean Difference (Fixed, 95% CI)-4.31 [-9.60, 0.97]

 2 Diastolic blood pressure18Mean Difference (Fixed, 95% CI)Subtotals only

    2.1 (1x starting dose) 60 and 80 mg/day
3222Mean Difference (Fixed, 95% CI)-3.28 [-5.60, -0.95]

    2.2 (2x starting dose) 120, 160 and 180 mg/day
13592Mean Difference (Fixed, 95% CI)-8.51 [-8.00, -7.03]

    2.3 (4x starting dose) 240 and 320 mg/day
699Mean Difference (Fixed, 95% CI)-13.91 [-16.74, -11.09]

    2.4 (8x starting dose) 480 and 640 mg/day
2205Mean Difference (Fixed, 95% CI)-3.03 [-6.06, 0.00]

 3 Heart rate12Mean Difference (Fixed, 95% CI)Subtotals only

    3.1 (1x starting dose) 60 and 80 mg/day
2196Mean Difference (Fixed, 95% CI)-7.30 [-9.49, -5.12]

    3.2 (2x starting dose) 120 and 160 mg/day
9497Mean Difference (Fixed, 95% CI)-11.54 [-12.95, -10.13]

    3.3 (4x starting dose) 240 and 320 mg/day
585Mean Difference (Fixed, 95% CI)-18.38 [-20.93, -15.84]

    3.4 (8x starting dose) 640 mg/day
1108Mean Difference (Fixed, 95% CI)-10.0 [-12.76, -7.24]

 4 Pulse pressure18Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 (1x starting dose) 60 and 80 mg/day
3222Mean Difference (Fixed, 95% CI)-1.45 [-4.79, 1.88]

    4.2 (2x starting dose) 120, 160 and 180 mg/day
13618Mean Difference (Fixed, 95% CI)-2.52 [-4.25, -0.79]

    4.3 (4x starting dose) 240 and 320 mg/day
699Mean Difference (Fixed, 95% CI)-2.96 [-6.50, 0.58]

    4.4 (8x starting dose) 480 and 640 mg/day
2205Mean Difference (Fixed, 95% CI)-2.29 [-8.42, 3.83]

 5 Direct comparison 2x doses3Mean Difference (Fixed, 95% CI)Subtotals only

    5.1 Systolic blood pressure
3222Mean Difference (Fixed, 95% CI)-3.01 [-5.91, -0.11]

    5.2 Diastolic blood pressure
3222Mean Difference (Fixed, 95% CI)-1.53 [-3.38, 0.32]

    5.3 Heart rate
2196Mean Difference (Fixed, 95% CI)-3.37 [-5.55, -1.20]

 
Comparison 2. Timolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Systolic blood pressure1Mean Difference (Fixed, 95% CI)Subtotals only

    1.1 30 mg/day
120Mean Difference (Fixed, 95% CI)-14.4 [-21.53, -7.27]

 2 Diastolic blood pressure1Mean Difference (Fixed, 95% CI)Subtotals only

    2.1 30 mg/day
120Mean Difference (Fixed, 95% CI)-13.50 [-18.05, -8.95]

 3 Heart rate1Mean Difference (Fixed, 95% CI)Subtotals only

    3.1 30 mg/day
120Mean Difference (Fixed, 95% CI)-16.0 [-18.88, -13.12]

 4 Pulse pressure1Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 30 mg/day
120Mean Difference (Fixed, 95% CI)-0.9 [-8.70, 6.90]

 
Comparison 3. Penbutolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Systolic blood pressure2Mean Difference (Fixed, 95% CI)Subtotals only

    1.1 (0.5x starting dose) 10 mg/day
1155Mean Difference (Fixed, 95% CI)-2.4 [-8.79, 3.99]

    1.2 (1x starting dose) 20 mg/day
1151Mean Difference (Fixed, 95% CI)-6.5 [-12.99, -0.01]

    1.3 (2x starting dose) 40 mg/day
1156Mean Difference (Fixed, 95% CI)-4.5 [-10.87, 1.87]

    1.4 (4x starting dose) 80 mg/day
110Mean Difference (Fixed, 95% CI)-18.0 [-31.33, -4.67]

 2 Diastolic blood pressure2Mean Difference (Fixed, 95% CI)Subtotals only

    2.1 (0.5x starting dose) 10 mg/day
1155Mean Difference (Fixed, 95% CI)-2.9 [-6.96, 1.16]

    2.2 (1x starting dose) 20 mg/day
1151Mean Difference (Fixed, 95% CI)-3.7 [-7.76, 0.36]

    2.3 (2x starting dose) 40 mg/day
1156Mean Difference (Fixed, 95% CI)-3.50 [-7.54, 0.54]

    2.4 (4x starting dose) 80 mg/day
110Mean Difference (Fixed, 95% CI)-11.1 [-17.90, -4.30]

 3 Heart rate2Mean Difference (Fixed, 95% CI)Subtotals only

    3.1 (0.5x starting dose) 10 mg/day
1103Mean Difference (Fixed, 95% CI)-1.2 [-9.82, 7.42]

    3.2 (1x starting dose) 20 mg/day
199Mean Difference (Fixed, 95% CI)-0.40 [-9.02, 8.22]

    3.3 (2x starting dose) 40 mg/day
1104Mean Difference (Fixed, 95% CI)-2.80 [-11.42, 5.82]

    3.4 (4x starting dose) 80 mg/day
110Mean Difference (Fixed, 95% CI)-19.7 [-27.15, -12.25]

 4 Pulse pressure2Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 (0.5x starting dose) 10 mg/day
1103Mean Difference (Fixed, 95% CI)0.5 [-7.32, 8.32]

    4.2 (1x starting dose) 20 mg/day
199Mean Difference (Fixed, 95% CI)-2.8 [-10.68, 5.08]

    4.3 (2x starting dose) 40 mg/day
1104Mean Difference (Fixed, 95% CI)-1.1 [-8.90, 6.70]

    4.4 (4x starting dose) 80 mg/day
110Mean Difference (Fixed, 95% CI)-6.9 [-18.37, 4.57]

 
Comparison 4. Tertatolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Systolic blood pressure120Mean Difference (Fixed, 95% CI)-14.0 [-26.54, -1.46]

    1.1 5 mg/day
120Mean Difference (Fixed, 95% CI)-14.0 [-26.54, -1.46]

 2 Diastolic blood pressure120Mean Difference (Fixed, 95% CI)-15.0 [-23.33, -6.67]

    2.1 5 mg/day
120Mean Difference (Fixed, 95% CI)-15.0 [-23.33, -6.67]

 3 Heart rate120Mean Difference (Fixed, 95% CI)-17.0 [-24.06, -9.94]

    3.1 5 mg/day
120Mean Difference (Fixed, 95% CI)-17.0 [-24.06, -9.94]

 4 Pulse pressure120Mean Difference (Fixed, 95% CI)1.0 [-10.07, 12.07]

    4.1 5 mg/day
120Mean Difference (Fixed, 95% CI)1.0 [-10.07, 12.07]

 
Comparison 5. Indenolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Heart rate112Mean Difference (Fixed, 95% CI)-12.0 [-15.37, -8.63]

 
Comparison 6. Nadolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Heart rate110Mean Difference (Fixed, 95% CI)-20.6 [-26.48, -14.72]

    1.1 80 mg/day
110Mean Difference (Fixed, 95% CI)-20.6 [-26.48, -14.72]

 
Comparison 7. Moprolol versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Heart rate123Mean Difference (Fixed, 95% CI)-6.0 [-13.51, 1.51]

 
Comparison 8. Pooled subclass effects (NSBB: nonselective beta-blocker)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Systolic blood pressure22Mean Difference (Fixed, 95% CI)Subtotals only

    1.1 NSBB 0.5x starting dose
1155Mean Difference (Fixed, 95% CI)-2.4 [-10.80, 6.00]

    1.2 NSBB 1x starting dose
5393Mean Difference (Fixed, 95% CI)-5.27 [-8.44, -2.11]

    1.3 NSBB 2x starting dose
15768Mean Difference (Fixed, 95% CI)-11.72 [-14.00, -9.43]

    1.4 NSBB 4x starting dose
7109Mean Difference (Fixed, 95% CI)-20.83 [-25.12, -16.54]

    1.5 NSBB 8x starting dose
2205Mean Difference (Fixed, 95% CI)-4.31 [-9.60, 0.97]

 2 Diastolic blood pressure22Mean Difference (Fixed, 95% CI)Subtotals only

    2.1 NSBB 0.5x starting dose
1155Mean Difference (Fixed, 95% CI)-2.9 [-8.23, 2.43]

    2.2 NSBB 1x starting dose
5393Mean Difference (Fixed, 95% CI)-3.59 [-5.37, -1.81]

    2.3 NSBB 2x starting dose
15768Mean Difference (Fixed, 95% CI)-8.44 [-9.83, -7.05]

    2.4 NSBB 4x starting dose
7109Mean Difference (Fixed, 95% CI)-14.17 [-16.98, -11.37]

    2.5 NSBB 8x starting dose
2205Mean Difference (Fixed, 95% CI)-3.03 [-6.06, 0.00]

 3 Heart rate17Mean Difference (Fixed, 95% CI)Subtotals only

    3.1 NSBB 0.5x starting dose
1155Mean Difference (Fixed, 95% CI)-1.2 [-12.53, 10.13]

    3.2 NSBB 1x starting dose
4367Mean Difference (Fixed, 95% CI)-8.76 [-11.99, -5.53]

    3.3 NSBB 2x starting dose
12683Mean Difference (Fixed, 95% CI)-12.56 [-14.17, -10.95]

    3.4 NSBB 4x starting dose
695Mean Difference (Fixed, 95% CI)-18.52 [-21.68, -15.36]

 4 Pulse pressure22Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 NSBB 0.5x starting dose
1155Mean Difference (Fixed, 95% CI)0.5 [-9.78, 10.78]

    4.2 NSBB 1x starting dose
5393Mean Difference (Fixed, 95% CI)-1.46 [-4.56, 1.64]

    4.3 NSBB 2x starting dose
15768Mean Difference (Fixed, 95% CI)-2.20 [-3.93, -0.47]

    4.4 NSBB 4x starting dose
7109Mean Difference (Fixed, 95% CI)-3.17 [-6.61, 0.28]

    4.5 NSBB 8x starting dose
2205Mean Difference (Fixed, 95% CI)-2.29 [-8.42, 3.83]

 5 Withdrawal due to adverse effects2729Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.38, 1.82]

    5.1 Propranolol vs. placebo
1427Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.34, 2.31]

    5.2 Penbutolol vs. placebo
1302Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.20, 2.85]

 6 Combined 1x and 2x starting dose estimates18Mean Difference (Fixed, 95% CI)Subtotals only

    6.1 Systolic blood pressure
16948Mean Difference (Fixed, 95% CI)-9.50 [-10.91, -8.09]

    6.2 Diastolic blood pressure
16948Mean Difference (Fixed, 95% CI)-6.60 [-7.43, -5.76]

    6.3 Heart rate
13864Mean Difference (Fixed, 95% CI)-11.80 [-12.90, -10.71]

    6.4 Pulse pressure
16948Mean Difference (Fixed, 95% CI)-2.02 [-3.17, -0.87]

 
Summary of findings for the main comparison. Nonselective beta-blockers compared with placebo for primary hypertension

Nonselective beta-blockers compared with placebo for primary hypertension

Patient or population: adults with primary hypertension

Intervention: nonselective beta-blockers

Comparison: placebo

OutcomesMean estimates of combining 1x and 2x starting dose (95% CI)Number of participants in the subgroups (# of studies)Quality of the evidence
(GRADE)

SBP (mmHg)-9.5 (-10.9 to -8.1)1,2,3,7948 (16)Low4,5

DBP (mmHg)-6.6 (-7.4 to -5.8)1,2,3,7948 (16)Low4,5

Heart rate (beats per minute)-11.8 (-12.9 to -10.7)1,2864 (13)Low4,5

Pulse pressure (mmHg)-2.0 (-3.2 to -0.9)1,2,3948 (16)Very low4,5,6

Withdrawal due to adverse effect0.84 (0.38 to 1.82)729 (2)Low8,9

CI: confident interval; DBP: diastolic blood pressure; HR: heart rate; SBP: systolic blood pressure.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Footnotes

  1. The recommended starting and 2x starting contained most of the data in nonselective beta-blocker analysis. Combining them provided estimates that represented the overall subclass effect.
  2. Most of the measurements were made at peak hours.
  3. Mean baseline blood pressure was 158/104 mmHg.
  4. Quality of evidence was downgraded one level due to high risk of detection bias caused by loss of blinding.
  5. Quality of evidence was downgraded one level due to high risk of publication bias and the presence of extreme outliers with exaggerated large effect.
  6. Quality of evidence was downgraded one level due to indirectness, none of the studies included reported pulse pressure. Pulse pressure was calculated by subtracting DBP from SBP.
  7. The effect estimates were likely exaggerated due to the presence of extreme outliers and other biases. If we remove the extreme outliers from the analysis, the estimate for nonselective beta-blockers was lower (-8/-5 mmHg).
  8. The quality of evidence was downgraded one level since only 2 studies reported withdrawals due to adverse effects, which leads to high risk of reporting bias.
  9. The quality of evidence was downgraded one level due to small sample size.