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The Cochrane Database of Systematic... May 2018Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments.
OBJECTIVES
To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults.
SEARCH METHODS
This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction.
MAIN RESULTS
The search identified 23 RCTs (2806 participants).Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).There were either no adverse events or they were not reported (very low quality evidence).Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants).There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence).There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst).
AUTHORS' CONCLUSIONS
We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed.
Topics: Adult; Antidepressive Agents; Antidepressive Agents, Tricyclic; Fluoxetine; Humans; Mianserin; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sleep Initiation and Maintenance Disorders; Trazodone
PubMed: 29761479
DOI: 10.1002/14651858.CD010753.pub2 -
The Cochrane Database of Systematic... May 2021Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.
OBJECTIVES
To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.
SELECTION CRITERIA
Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).
DATA COLLECTION AND ANALYSIS
Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.
MAIN RESULTS
Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.
AUTHORS' CONCLUSIONS
Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.
Topics: Adolescent; Antidepressive Agents; Bias; Child; Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Fluoxetine; Humans; Male; Mirtazapine; Network Meta-Analysis; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Suicidal Ideation; Venlafaxine Hydrochloride; Vilazodone Hydrochloride; Vortioxetine
PubMed: 34029378
DOI: 10.1002/14651858.CD013674.pub2 -
The Cochrane Database of Systematic... Apr 2018This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is the first update of a review published in 2009. Sustained moderate to severe elevations in resting blood pressure leads to a critically important clinical question: What class of drug to use first-line? This review attempted to answer that question.
OBJECTIVES
To quantify the mortality and morbidity effects from different first-line antihypertensive drug classes: thiazides (low-dose and high-dose), beta-blockers, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers (ARB), and alpha-blockers, compared to placebo or no treatment.Secondary objectives: when different antihypertensive drug classes are used as the first-line drug, to quantify the blood pressure lowering effect and the rate of withdrawal due to adverse drug effects, compared to placebo or no treatment.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work.
SELECTION CRITERIA
Randomized trials (RCT) of at least one year duration, comparing one of six major drug classes with a placebo or no treatment, in adult patients with blood pressure over 140/90 mmHg at baseline. The majority (over 70%) of the patients in the treatment group were taking the drug class of interest after one year. We included trials with both hypertensive and normotensive patients in this review if the majority (over 70%) of patients had elevated blood pressure, or the trial separately reported outcome data on patients with elevated blood pressure.
DATA COLLECTION AND ANALYSIS
The outcomes assessed were mortality, stroke, coronary heart disease (CHD), total cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. We used a fixed-effect model to to combine dichotomous outcomes across trials and calculate risk ratio (RR) with 95% confidence interval (CI). We presented blood pressure data as mean difference (MD) with 99% CI.
MAIN RESULTS
The 2017 updated search failed to identify any new trials. The original review identified 24 trials with 28 active treatment arms, including 58,040 patients. We found no RCTs for ARBs or alpha-blockers. These results are mostly applicable to adult patients with moderate to severe primary hypertension. The mean age of participants was 56 years, and mean duration of follow-up was three to five years.High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84).Low- to moderate-quality evidence showed that first-line high-dose thiazides reduced stroke (1.9% with control versus 0.9% with treatment; RR 0.47, 95% CI 0.37 to 0.61) and total CVS (5.1% with control versus 3.7% with treatment; RR 0.72, 95% CI 0.63 to 0.82), but did not reduce mortality (3.1% with control versus 2.8% with treatment; RR 0.90, 95% CI 0.76 to 1.05), or coronary heart disease (2.7% with control versus 2.7% with treatment; RR 1.01, 95% CI 0.85 to 1.20).Low- to moderate-quality evidence showed that first-line beta-blockers did not reduce mortality (6.2% with control versus 6.0% with treatment; RR 0.96, 95% CI 0.86 to 1.07) or coronary heart disease (4.4% with control versus 3.9% with treatment; RR 0.90, 95% CI 0.78 to 1.03), but reduced stroke (3.4% with control versus 2.8% with treatment; RR 0.83, 95% CI 0.72 to 0.97) and total CVS (7.6% with control versus 6.8% with treatment; RR 0.89, 95% CI 0.81 to 0.98).Low- to moderate-quality evidence showed that first-line ACE inhibitors reduced mortality (13.6% with control versus 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95), stroke (6.0% with control versus 3.9% with treatment; RR 0.65, 95% CI 0.52 to 0.82), coronary heart disease (13.5% with control versus 11.0% with treatment; RR 0.81, 95% CI 0.70 to 0.94), and total CVS (20.1% with control versus 15.3% with treatment; RR 0.76, 95% CI 0.67 to 0.85).Low-quality evidence showed that first-line calcium channel blockers reduced stroke (3.4% with control versus 1.9% with treatment; RR 0.58, 95% CI 0.41 to 0.84) and total CVS (8.0% with control versus 5.7% with treatment; RR 0.71, 95% CI 0.57 to 0.87), but not coronary heart disease (3.1% with control versus 2.4% with treatment; RR 0.77, 95% CI 0.55 to 1.09), or mortality (6.0% with control versus 5.1% with treatment; RR 0.86, 95% CI 0.68 to 1.09).There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24), and beta-blockers (3.1% with control versus 14.4% with treatment; RR 4.59, 95% CI 4.11 to 5.13). No data for these outcomes were available for first-line ACE inhibitors or calcium channel blockers. The blood pressure data were not used to assess the effect of the different classes of drugs as the data were heterogeneous, and the number of drugs used in the trials differed.
AUTHORS' CONCLUSIONS
First-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality. First-line high-dose thiazides and first-line beta-blockers were inferior to first-line low-dose thiazides.
Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Coronary Disease; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; Stroke; Thiazides
PubMed: 29667175
DOI: 10.1002/14651858.CD001841.pub3 -
Journal of Psychopharmacology (Oxford,... Feb 2016The effects of propranolol in the treatment of anxiety disorders have not been systematically evaluated previously. The aim was to conduct a systematic review and... (Comparative Study)
Comparative Study Meta-Analysis Review
The effects of propranolol in the treatment of anxiety disorders have not been systematically evaluated previously. The aim was to conduct a systematic review and meta-analysis of randomised controlled trials, addressing the efficacy of oral propranolol versus placebo or other medication as a treatment for alleviating either state or trait anxiety in patients suffering from anxiety disorders. Eight studies met the inclusion criteria. These studies concerned panic disorder with or without agoraphobia (four studies, total n = 130), specific phobia (two studies, total n = 37), social phobia (one study, n = 16), and posttraumatic stress disorder (PTSD) (one study, n = 19). Three out of four panic disorder trials qualified for pooled analyses. These meta-analyses found no statistically significant differences between the efficacy of propranolol and benzodiazepines regarding the short-term treatment of panic disorder with or without agoraphobia. Also, no evidence was found for effects of propranolol on PTSD symptom severity through inhibition of memory reconsolidation. In conclusion, the quality of evidence for the efficacy of propranolol at present is insufficient to support the routine use of propranolol in the treatment of any of the anxiety disorders.
Topics: Administration, Oral; Adrenergic beta-Antagonists; Anti-Anxiety Agents; Anxiety Disorders; Humans; Propranolol; Randomized Controlled Trials as Topic; Severity of Illness Index
PubMed: 26487439
DOI: 10.1177/0269881115612236 -
European Journal of Clinical... Nov 2022Antihypertensive drugs are among the most prescribed drugs during pregnancy. Methyldopa, labetalol, and nifedipine have been perceived safe to use during pregnancy and... (Review)
Review
PURPOSE
Antihypertensive drugs are among the most prescribed drugs during pregnancy. Methyldopa, labetalol, and nifedipine have been perceived safe to use during pregnancy and are therefore recommended in international guidelines for treatment of hypertension. In this review, we provide a complete overview of what is known on the pharmacokinetics (PK) of the antihypertensive drugs methyldopa, labetalol, and nifedipine throughout pregnancy.
METHODS
A systematic search was performed to retrieve studies on the PK of methyldopa, labetalol, and nifedipine used throughout pregnancy. The search was restricted to English and original studies. The systematic search was conducted on July 27, 2021, in Embase, Medline Ovid, Web of Science, Cochrane Library, and Google Scholar. Keywords were methyldopa, labetalol, nifedipine, pharmacokinetics, pregnancy, and placenta.
RESULTS
A total of 1459 unique references were identified of which title and abstract were screened. Based on this screening, 67 full-text papers were assessed, to retain 30 PK studies of which 2 described methyldopa, 12 labetalol, and 16 nifedipine. No fetal accumulation is found for any of the antihypertensive drugs studied.
CONCLUSION
We conclude that despite decades of prescribing methyldopa, labetalol, and nifedipine throughout pregnancy, descriptions of their PK during pregnancy are hampered by a large heterogeneity in the low number of available studies. Aiming for evidence-based and personalized dosing of antihypertensive medication in the future, further studies on the relationship of both PK and pharmacodynamics (including the optimal blood pressure targeting) during pregnancy and pregnancy-related pathology are urgently needed to prevent undertreatment, overtreatment, and side effects.
Topics: Antihypertensive Agents; Female; Humans; Hypertension; Hypertension, Pregnancy-Induced; Labetalol; Methyldopa; Nifedipine; Pregnancy; Pregnancy Complications, Cardiovascular
PubMed: 36104450
DOI: 10.1007/s00228-022-03382-3 -
Advances in Therapy Nov 2021In the absence of head-to-head trials, we performed an indirect treatment comparison of the β-adrenergic agonists vibegron and mirabegron in the treatment of overactive...
BACKGROUND
In the absence of head-to-head trials, we performed an indirect treatment comparison of the β-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB).
METHODS
PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively.
RESULTS
After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P < 0.05, each) and significantly greater improvement in volume voided versus mirabegron 25 mg (week 12), mirabegron 50 mg (weeks 12, 52), and tolterodine (week 4) (P < 0.05, each). Confidence intervals of point estimates overlapped zero for all other comparisons of vibegron and mirabegron (25 or 50 mg) or tolterodine, indicating no significant differences between treatments for these time/endpoints. Urinary tract infection, hypertension, and dry mouth were the most commonly occurring AEs for vibegron, mirabegron, and tolterodine, respectively, in the short-term trials; hypertension was the most commonly occurring AE with all three treatments in the long-term trials.
CONCLUSIONS
Vibegron was associated with significant improvement in total incontinence episodes versus mirabegron at 4 and 52 weeks and volume voided at 12 and 52 weeks. Improvement in micturitions was similar between vibegron and mirabegron or tolterodine. Incidence of AEs was generally comparable between vibegron and mirabegron.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Muscarinic Antagonists; Pyrimidinones; Pyrrolidines; Randomized Controlled Trials as Topic; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive
PubMed: 34537953
DOI: 10.1007/s12325-021-01902-8 -
The Cochrane Database of Systematic... Aug 2022Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth is the leading cause of death in newborns and children. Tocolytic drugs aim to delay preterm birth by suppressing uterine contractions to allow time for administration of corticosteroids for fetal lung maturation, magnesium sulphate for neuroprotection, and transport to a facility with appropriate neonatal care facilities. However, there is still uncertainty about their effectiveness and safety.
OBJECTIVES
To estimate relative effectiveness and safety profiles for different classes of tocolytic drugs for delaying preterm birth, and provide rankings of the available drugs.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov (21 April 2021) and reference lists of retrieved studies.
SELECTION CRITERIA
We included all randomised controlled trials assessing effectiveness or adverse effects of tocolytic drugs for delaying preterm birth. We excluded quasi- and non-randomised trials. We evaluated all studies against predefined criteria to judge their trustworthiness.
DATA COLLECTION AND ANALYSIS
At least two review authors independently assessed the trials for inclusion and risk of bias, and extracted data. We performed pairwise and network meta-analyses, to determine the relative effects and rankings of all available tocolytics. We used GRADE to rate the certainty of the network meta-analysis effect estimates for each tocolytic versus placebo or no treatment.
MAIN RESULTS
This network meta-analysis includes 122 trials (13,697 women) involving six tocolytic classes, combinations of tocolytics, and placebo or no treatment. Most trials included women with threatened preterm birth, singleton pregnancy, from 24 to 34 weeks of gestation. We judged 25 (20%) studies to be at low risk of bias. Overall, certainty in the evidence varied. Relative effects from network meta-analysis suggested that all tocolytics are probably effective in delaying preterm birth compared with placebo or no tocolytic treatment. Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio (RR) 1.12, 95% confidence interval (CI) 1.05 to 1.20; low-certainty evidence), and 7 days (RR 1.14, 95% CI 1.03 to 1.25; low-certainty evidence). COX inhibitors are possibly effective in delaying preterm birth by 48 hours (RR 1.11, 95% CI 1.01 to 1.23; low-certainty evidence). Calcium channel blockers are possibly effective in delaying preterm birth by 48 hours (RR 1.16, 95% CI 1.07 to 1.24; low-certainty evidence), probably effective in delaying preterm birth by 7 days (RR 1.15, 95% CI 1.04 to 1.27; moderate-certainty evidence), and prolong pregnancy by 5 days (0.1 more to 9.2 more; high-certainty evidence). Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12, 95% CI 1.02 to 1.23; moderate-certainty evidence). Oxytocin receptor antagonists are probably effective in delaying preterm birth by 48 hours (RR 1.13, 95% CI 1.05 to 1.22; moderate-certainty evidence), are effective in delaying preterm birth by 7 days (RR 1.18, 95% CI 1.07 to 1.30; high-certainty evidence), and possibly prolong pregnancy by 10 days (95% CI 2.3 more to 16.7 more). Nitric oxide donors are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.05 to 1.31; moderate-certainty evidence), and 7 days (RR 1.18, 95% CI 1.02 to 1.37; moderate-certainty evidence). Combinations of tocolytics are probably effective in delaying preterm birth by 48 hours (RR 1.17, 95% CI 1.07 to 1.27; moderate-certainty evidence), and 7 days (RR 1.19, 95% CI 1.05 to 1.34; moderate-certainty evidence). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days, and delay in birth (continuous outcome), followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. Betamimetics (RR 14.4, 95% CI 6.11 to 34.1; moderate-certainty evidence), calcium channel blockers (RR 2.96, 95% CI 1.23 to 7.11; moderate-certainty evidence), magnesium sulphate (RR 3.90, 95% CI 1.09 to 13.93; moderate-certainty evidence) and combinations of tocolytics (RR 6.87, 95% CI 2.08 to 22.7; low-certainty evidence) are probably more likely to result in cessation of treatment. Calcium channel blockers possibly reduce the risk of neurodevelopmental morbidity (RR 0.51, 95% CI 0.30 to 0.85; low-certainty evidence), and respiratory morbidity (RR 0.68, 95% CI 0.53 to 0.88; low-certainty evidence), and result in fewer neonates with birthweight less than 2000 g (RR 0.49, 95% CI 0.28 to 0.87; low-certainty evidence). Nitric oxide donors possibly result in neonates with higher birthweight (mean difference (MD) 425.53 g more, 95% CI 224.32 more to 626.74 more; low-certainty evidence), fewer neonates with birthweight less than 2500 g (RR 0.40, 95% CI 0.24 to 0.69; low-certainty evidence), and more advanced gestational age (MD 1.35 weeks more, 95% CI 0.37 more to 2.32 more; low-certainty evidence). Combinations of tocolytics possibly result in fewer neonates with birthweight less than 2500 g (RR 0.74, 95% CI 0.59 to 0.93; low-certainty evidence). In terms of maternal adverse effects, betamimetics probably cause dyspnoea (RR 12.09, 95% CI 4.66 to 31.39; moderate-certainty evidence), palpitations (RR 7.39, 95% CI 3.83 to 14.24; moderate-certainty evidence), vomiting (RR 1.91, 95% CI 1.25 to 2.91; moderate-certainty evidence), possibly headache (RR 1.91, 95% CI 1.07 to 3.42; low-certainty evidence) and tachycardia (RR 3.01, 95% CI 1.17 to 7.71; low-certainty evidence) compared with placebo or no treatment. COX inhibitors possibly cause vomiting (RR 2.54, 95% CI 1.18 to 5.48; low-certainty evidence). Calcium channel blockers (RR 2.59, 95% CI 1.39 to 4.83; low-certainty evidence), and nitric oxide donors probably cause headache (RR 4.20, 95% CI 2.13 to 8.25; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Compared with placebo or no tocolytic treatment, all tocolytic drug classes that we assessed (betamimetics, calcium channel blockers, magnesium sulphate, oxytocin receptor antagonists, nitric oxide donors) and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days. Tocolytic drugs were associated with a range of adverse effects (from minor to potentially severe) compared with placebo or no tocolytic treatment, although betamimetics and combination tocolytics were more likely to result in cessation of treatment. The effects of tocolytic use on neonatal outcomes such as neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection were uncertain.
Topics: Adrenergic beta-Agonists; Birth Weight; Calcium Channel Blockers; Child; Female; Headache; Humans; Infant, Newborn; Magnesium Sulfate; Network Meta-Analysis; Nitric Oxide Donors; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Receptors, Oxytocin; Tocolytic Agents; Vomiting
PubMed: 35947046
DOI: 10.1002/14651858.CD014978.pub2 -
The Cochrane Database of Systematic... Jul 2020Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive heart failure in children differs from that in adults in terms of characteristics, aetiology, and drug clearance. Therefore, paediatric needs must be specifically investigated. This is an update of a Cochrane review previously published in 2009.
OBJECTIVES
To assess the effect of beta-adrenoceptor-blockers (beta-blockers) in children with congestive heart failure.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS up to November 2015. Bibliographies of identified studies were checked. No language restrictions were applied.
SELECTION CRITERIA
Randomised, controlled, clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted and assessed data from the included trials.
MAIN RESULTS
We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers. However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses.
AUTHORS' CONCLUSIONS
There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.
Topics: Adolescent; Adrenergic beta-Antagonists; Carbazoles; Carvedilol; Child; Child, Preschool; Heart Failure; Heart Transplantation; Humans; Infant; Infant, Newborn; Metoprolol; Propanolamines; Propranolol; Randomized Controlled Trials as Topic; Stroke Volume
PubMed: 32700759
DOI: 10.1002/14651858.CD007037.pub4 -
BJS Open Feb 2019Postoperative urinary retention (PO-UR) is an acute and painful inability to void after surgery that can lead to complications and delayed hospital discharge. Standard...
BACKGROUND
Postoperative urinary retention (PO-UR) is an acute and painful inability to void after surgery that can lead to complications and delayed hospital discharge. Standard treatment with a urinary catheter is associated with a risk of infection and can be distressing, undignified and uncomfortable. This systematic review aimed to identify effective interventions for the prevention and treatment of PO-UR that might be alternatives to urinary catheterization.
METHODS
Electronic databases were searched from inception to September 2017. Randomized trials of interventions for the prevention or treatment of PO-UR were eligible for inclusion. Studies were assessed for risk of bias using the Cochrane (2.0) tool. Two reviewers were involved at all review stages. Where possible, data were pooled using random-effects meta-analysis. The overall quality of the body of evidence was rated using the GRADE approach.
RESULTS
Some 48 studies involving 5644 participants were included. Most interventions were pharmacological strategies to prevent PO-UR. Based on GRADE, there was high-certainty evidence to support replacing morphine in a regional anaesthetic regimen, using alpha-blockers (number needed to treat to prevent one case of PO-UR (NNT) 5, 95 per cent c.i. 5 to 7), the antispasmodic drug drotaverine (NNT 9, 7 to 30) and early postoperative mobilization (NNT 5, 4 to 8) for prevention, and employing hot packs or gauze soaked in warm water for treatment (NNT 2, 2 to 4). Very few studies reported on secondary outcomes of pain, incidence of urinary tract infection or duration of hospital stay.
CONCLUSION
Promising interventions exist for PO-UR, but they need to be evaluated in randomized trials investigating comparative clinical and cost effectiveness, and acceptability to patients.
Topics: Adrenergic alpha-Antagonists; Analgesics, Opioid; Anesthesia; Early Ambulation; Humans; Hyperthermia, Induced; Morphine; Parasympatholytics; Postoperative Care; Postoperative Complications; Randomized Controlled Trials as Topic; Urinary Retention
PubMed: 30734011
DOI: 10.1002/bjs5.50114 -
European Journal of Psychotraumatology 2021: Pharmacological approaches are widely used for post-traumatic stress disorder (PTSD) despite uncertainty over efficacy. : To determine the efficacy of all... (Meta-Analysis)
Meta-Analysis
: Pharmacological approaches are widely used for post-traumatic stress disorder (PTSD) despite uncertainty over efficacy. : To determine the efficacy of all pharmacological approaches, including monotherapy, augmentation and head-to-head approaches (drug versus drug, drug versus psychotherapy), in reducing PTSD symptom severity. : A systematic review and meta-analysis of randomised controlled trials were undertaken; 115 studies were included. : Selective serotonin reuptake inhibitors (SSRIs) were found to be statistically superior to placebo in reduction of PTSD symptoms but the effect size was small (standardised mean difference -0.28, 95% CI -0.39 to -0.17). For individual monotherapy agents compared to placebo in two or more studies, we found small statistically significant evidence for the antidepressants fluoxetine, paroxetine, sertraline, venlafaxine and the antipsychotic quetiapine. For pharmacological augmentation, we found small statistically significant evidence for prazosin and risperidone. : Some medications have a small positive effect on reducing PTSD symptom severity and can be considered as potential monotherapy treatments; these include fluoxetine, paroxetine, sertraline, venlafaxine and quetiapine. Two medications, prazosin and risperidone, also have a small positive effect when used to augment pharmacological monotherapy. There was no evidence of superiority for one intervention over another in the small number of head-to-head comparison studies.
Topics: Adrenergic alpha-1 Receptor Antagonists; Antipsychotic Agents; Drug Synergism; Drug Therapy, Combination; Humans; Selective Serotonin Reuptake Inhibitors; Stress Disorders, Post-Traumatic
PubMed: 34992738
DOI: 10.1080/20008198.2020.1802920