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The Journal of Head Trauma...To systematically review the available literature on the pharmacological management of agitation and/or aggression in patients with traumatic brain injury (TBI),...
OBJECTIVE
To systematically review the available literature on the pharmacological management of agitation and/or aggression in patients with traumatic brain injury (TBI), synthesize the available data, and provide guidelines.
DESIGN
Systematic review of systematic reviews.
MAIN MEASURES
A literature review of the following websites was performed looking for systematic reviews on the treatment of agitation and/or aggression among patients with TBI: PubMed, CINAHL, DynaMed, Health Business Elite, and EBSCO (Psychology and behavioral sciences collection). Two researchers independently assessed articles for meeting inclusion/exclusion criteria. Data were extracted on year of publication, reviewed databases, dates of coverage, search limitations, pharmacological agents of interest, and a list of all controlled studies included. The included controlled studies were then examined to determine potential reasons for any difference in recommendations.
RESULTS
The literature review led to 187 citations and 67 unique publications after removing the duplicates. Following review of the title/abstracts and full texts, a total of 11 systematic reviews were included. The systematic reviews evaluated the evidence for safety and efficacy of the following medications: amantadine, amphetamines, methylphenidate, antiepileptics, atypical and typical antipsychotics, benzodiazepines, β-blockers, and sertraline.
CONCLUSIONS
On the basis of the results of this literature review, the authors recommend avoiding benzodiazepines and haloperidol for treating agitation and/or aggression in the context of TBI. Atypical antipsychotics (olanzapine in particular) can be considered as practical alternatives for the as-needed management of agitation and/or aggression in lieu of benzodiazepines and haloperidol. Amantadine, β-blockers (propranolol and pindolol), antiepileptics, and methylphenidate can be considered for scheduled treatment of agitation and/or aggression in patients with TBI.
Topics: Aggression; Antipsychotic Agents; Brain Injuries, Traumatic; Humans; Psychomotor Agitation; Systematic Reviews as Topic
PubMed: 33656478
DOI: 10.1097/HTR.0000000000000656 -
The Cochrane Database of Systematic... Sep 2020Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Beta-blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta-blockers varies across the day. This review focuses on the subclass of beta-blockers with partial agonist activity (BBPAA).
OBJECTIVES
To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24-hour period in adults with essential hypertension.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.
SELECTION CRITERIA
We sought to include all randomised and non-randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow-up of three weeks.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end-point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24-hour ambulatory BP monitoring (ABPM) device.
MAIN RESULTS
Fourteen non-randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta-analysis. Beta-blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes. We analysed and presented data by each hour post-dose. Very low-certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24-hour period, the magnitude of SBP lowering at each hour ranged from -3.68 mmHg to -17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from -2.27 mmHg to -9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from -0.29 beats/min to -10.29 beats/min (4 studies, 71 participants). When comparing between three 8-hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low-certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion.
AUTHORS' CONCLUSIONS
There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP-lowering efficacy of BBPAA over a 24-hour period, in adults with essential hypertension. Very low-certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.
Topics: Acebutolol; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Bias; Blood Pressure; Circadian Rhythm; Controlled Clinical Trials as Topic; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Pindolol; Time Factors
PubMed: 32888198
DOI: 10.1002/14651858.CD010054.pub2 -
The Cochrane Database of Systematic... Sep 2019Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and...
BACKGROUND
Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in an unselected population remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update, and assesses the evidence in non-cardiac surgery only.
OBJECTIVES
To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing non-cardiac surgery.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles.
SELECTION CRITERIA
We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing non-cardiac surgery. If studies included surgery with different types of anaesthesia, we included them if 70% participants, or at least 100 participants, received general anaesthesia. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.
MAIN RESULTS
We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period.The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence).We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants.
AUTHORS' CONCLUSIONS
The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.
Topics: Adrenergic beta-Antagonists; Anesthesia, General; Arrhythmias, Cardiac; Bradycardia; Cause of Death; Humans; Hypotension; Morbidity; Myocardial Infarction; Perioperative Care; Postoperative Complications; Quality of Life; Randomized Controlled Trials as Topic; Surgical Procedures, Operative
PubMed: 31556094
DOI: 10.1002/14651858.CD013438 -
European Child & Adolescent Psychiatry Oct 2018The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention... (Meta-Analysis)
Meta-Analysis Review
The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n = 4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Female; Humans; Male; Treatment Outcome
PubMed: 29460165
DOI: 10.1007/s00787-018-1125-0 -
European Neuropsychopharmacology : the... May 2017Treatment of unipolar depression with currently available antidepressants is still unsatisfactory. Augmentation with lithium or second generation antipsychotics is an... (Meta-Analysis)
Meta-Analysis Review
Treatment of unipolar depression with currently available antidepressants is still unsatisfactory. Augmentation with lithium or second generation antipsychotics is an established practice in non-responders to antidepressant monotherapy, but is also associated with a substantial non-response rate and with non-tolerance. Based on a systematic review of the literature, including meta-analyses, randomized controlled trials (RCTs), non-randomized comparative studies and case studies, off-label augmentation agents (administered in addition to an antidepressant, without FDA approval for treatment of MDD) were identified and evaluated regarding their efficacy using levels of evidence. The agents had to be added to an existing antidepressant regime with the aim of achieving an improved clinical response to an ongoing antidepressant treatment (augmentation) or an earlier onset of effect when starting antidepressant and augmentation agent simultaneously (acceleration). Five substances, modafinil, ketamine, pindolol, testosterone and estrogen (the latter two in hormone-deficient patients) were shown to be clinically effective in high evidence studies. For the six drugs dexamethasone, mecamylamine, riluzole, amantadine, pramipexole and yohimbine clear proof of efficacy was not possible due to low levels of evidence, small sample sizes or discordant results. For the two agents methylphenidate and memantine only studies with negative outcomes could be found. Overall, the quality of study designs was low and results were often contradictory. However, the use of pindolol, ketamine, modafinil, estrogen and testosterone might be an option for depressed patients who are not responding to antidepressant monotherapy or established augmentation strategies. Further high quality studies are necessary and warranted.
Topics: Antidepressive Agents; Depressive Disorder; Humans; Off-Label Use
PubMed: 28318897
DOI: 10.1016/j.euroneuro.2017.03.003 -
British Journal of Clinical Pharmacology Aug 2016Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in... (Comparative Study)
Comparative Study Meta-Analysis Review
AIM
Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to β1 -adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta-analysis in order to assess the comparative risk of peripheral vasoconstriction of different β-adrenoceptor blockers.
METHOD
We searched for randomized controlled trials (RCTs) including β-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of β-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the β-adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374).
RESULTS
Among 2238 records screened, 38 studies including 57 026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with β-adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not.
CONCLUSION
Our results suggest that β-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to β1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of β-adrenoceptor blockers and suggest that β-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.
Topics: Adrenergic beta-Antagonists; Dose-Response Relationship, Drug; Humans; Randomized Controlled Trials as Topic; Sympathomimetics; Vasoconstriction; Vasodilation
PubMed: 27085011
DOI: 10.1111/bcp.12980 -
Expert Opinion on Pharmacotherapy 2016The prevalence of panic disorder (PD) in the population is high and these patients have work impairment, high unemployment rates, seek medical treatment more frequently... (Review)
Review
INTRODUCTION
The prevalence of panic disorder (PD) in the population is high and these patients have work impairment, high unemployment rates, seek medical treatment more frequently and have more hospitalizations than people without panic symptoms. Despite the availability of pharmacological, psychological and combined treatments, approximately one-third of all PD patients have persistent panic attacks and other PD symptoms after treatment.
AREAS COVERED
MEDLINE/Pubmed, CENTRAL, PsycINFO and Web of Science databases were searched for clinical trials in treatment-resistant PD. Only studies published between 1980 and 2015, in English, with human subjects, considered "journal articles" and clinical trial were included. We included trials recruiting only adult subjects with treatment-resistant PD, consistent with criteria from DSM-III to DSM5. We included all prospective experimental studies. Case, case series, retrospective studies or studies with <10 PD subjects were not included.
EXPERT OPINION
Only 11 articles were included in this review. There were few quality studies, only two were randomized, controlled and double blind. Augmentation of the pharmacological treatment with cognitive-behavioral therapy demonstrated some short-term efficacy in treatment-resistant PD. There were also preliminary evidences of efficacy for monotherapy with reboxetine and olanzapine, and augmentation with pindolol, divalproex sodium, aripiprazole and olanzapine in short-term treatment.
Topics: Antidepressive Agents; Antipsychotic Agents; Cognitive Behavioral Therapy; Combined Modality Therapy; Humans; Panic Disorder; Prospective Studies; Randomized Controlled Trials as Topic; Treatment Failure
PubMed: 26635099
DOI: 10.1517/14656566.2016.1109628 -
The Journal of Clinical Psychiatry Apr 2015To comparatively analyze the efficacy, acceptability, and tolerability of various augmentation agents in adult patients with treatment-resistant depression. (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVE
To comparatively analyze the efficacy, acceptability, and tolerability of various augmentation agents in adult patients with treatment-resistant depression.
DATA SOURCES
An electronic literature search of PubMed, EMBASE, the Cochrane Library, Web of Science, EBSCO, PsycINFO, EAGLE, and NTIS for trials published up to December 2013 was conducted. Several clinical trial registry agencies and US Food and Drug Administration reports were also reviewed. No language, publication date, or publication status restrictions were imposed.
STUDY SELECTION
Randomized controlled trials comparing 11 augmentation agents (aripiprazole, bupropion, buspirone, lamotrigine, lithium, methylphenidate, olanzapine, pindolol, quetiapine, risperidone, and thyroid hormone) with each other and with placebo for adult treatment-resistant depression were included.
DATA EXTRACTION
The proportion of patients who responded to treatment was defined as primary efficacy, and the proportion of all-cause discontinuation and side-effects discontinuation were respectively defined as acceptability and tolerability, which were assessed with odds ratios (ORs) and a Bayesian random-effects model with 95% credible intervals (CrIs).
RESULTS
A total of 48 trials consisting of 6,654 participants were eligible. In terms of the primary efficacy, quetiapine (OR = 1.92; 95% CrI, 1.39-3.13), aripiprazole (OR = 1.85; 95% CrI, 1.27-2.27), thyroid hormone (OR = 1.84; 95% CrI, 1.06-3.56), and lithium (OR = 1.56; 95% CrI, 1.05-2.55) were significantly more effective than placebo. Sensitivity analyses indicated that efficacy estimates for aripiprazole and quetiapine were more robust than those for thyroid hormone and lithium. In terms of acceptability, no significant difference was found between active agents and placebo. In terms of tolerability, compared to placebo, quetiapine (OR = 3.85; 95% CrI, 1.92-8.33), olanzapine (OR = 3.36; 95% CrI, 1.60-8.61), aripiprazole (OR = 2.51; 95% CrI, 1.11-7.69), and lithium (OR = 2.30; 95% CrI, 1.04-6.03) were significantly less well tolerated.
CONCLUSIONS
Quetiapine and aripiprazole appear to be the most robust evidence-based options for augmentation therapy in patients with treatment-resistant depression, but clinicians should interpret these findings cautiously in light of the evidence of potential treatment-related side effects.
Topics: Adult; Female; Humans; Male; Middle Aged; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Patient Acceptance of Health Care; Randomized Controlled Trials as Topic
PubMed: 25919841
DOI: 10.4088/JCP.14r09204 -
Human Psychopharmacology May 2015This systematic review and meta-analysis was conducted to assess the use of pindolol augmentation in depressed patients resistant to selective serotonin reuptake... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This systematic review and meta-analysis was conducted to assess the use of pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitor (SSRI) therapy.
METHODS
A comprehensive search of PubMed, Cochrane, Embase, Web of Science, and PsychINFO databases from 1970 through December 2013 was conducted. Only randomized controlled trials (RCTs) studied on unipolar SSRI-resistant depressed adults were included. The primary outcome was mean change scores of depressive symptom on the depression rating scales, assessed with standardized mean differences.
RESULTS
Five RCTs consisting of 154 patients met all inclusion and exclusion criteria. The overall pooled effect size in the primary and secondary efficacy analysis showed no significant effects of pindolol plus SSRI therapy (standardized mean difference = -0.43, p = 0.24; OR = 1.92, p = 0.39, respectively). In terms of acceptability, there was no statistical difference in either tolerability or safety between the two groups (OR = 0.46, p = 0.40; OR = 0.90, p = 0.94, respectively). These estimates remained robust through several sensitivity and subgroup analyses, except 7.5 mg-qd pindolol augmentation did show a significant benefit over 2.5-mg tid pindolol augmentation.
CONCLUSIONS
Pindolol augmentation may not be suitable for treatment-resistant depression patients with SSRI-resistant depression. However, once-daily high-dose pindolol (7.5 mg qd) appears to show a promising benefit in these patients.
Topics: Adult; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Humans; Pindolol; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 25689398
DOI: 10.1002/hup.2465 -
The Cochrane Database of Systematic... Nov 2014Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent and blocking beta receptors when they are active. The blood pressure (BP) lowering effect of partial agonist beta blockers has not been quantified.
OBJECTIVES
To quantify the dose-related effects of various partial agonists beta blockers on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate versus placebo in patients with primary hypertension.
SEARCH METHODS
We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register.
SELECTION CRITERIA
Randomized double-blinded placebo-controlled parallel or cross-over trials. Studies must contain a partial agonist monotherapy arm with fixed dose. Patients enrolled into the studies must have primary hypertension at baseline (defined as SBP/DBP > 140/90 mmHg). Duration of studies must be between three to 12 weeks.
DATA COLLECTION AND ANALYSIS
Two authors (GW and HB) confirmed the inclusion of studies and extracted the data independently.
MAIN RESULTS
Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67).
AUTHORS' CONCLUSIONS
There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.
Topics: Adrenergic beta-1 Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Essential Hypertension; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic
PubMed: 25427719
DOI: 10.1002/14651858.CD007450.pub2