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Cureus Jul 2022The renin-angiotensin-aldosterone system (RAAS) plays a vital role in cardiovascular homeostasis by regulating blood pressure, salt, and water balance. The kidneys... (Review)
Review
Effects of Renin-Angiotensin-Aldosterone System Inhibition on Left Ventricular Hypertrophy, Diastolic Function, and Functional Status in Patients With Hypertrophic Cardiomyopathy: A Systematic Review.
The renin-angiotensin-aldosterone system (RAAS) plays a vital role in cardiovascular homeostasis by regulating blood pressure, salt, and water balance. The kidneys produce renin which converts angiotensinogen to angiotensin-1 (AT-I) and angiotensin-converting enzyme (ACE) to angiotensin-II (AT-II). AT-II binds to receptors in the adrenal cortex to release aldosterone. AT-II and aldosterone promote water and salt retention, vascular tone, and myocardial contractility. These physiological changes raise blood pressure and circulation. Reduced renal perfusion pressure sensed by baroreceptors and the sympathetic nervous system's β-adrenergic receptors trigger renin release and RAAS activation. RAAS restores hemodynamic stability in pathological states associated with low perfusion. This adaptive response is important for restoring perfusion and hemodynamic stability, but prolonged RAAS activation has deleterious effects on the cardiovascular system. Long-term mineralocorticoid exposure has been linked to left ventricular hypertrophy (LVH) and remodeling. AT-II activates fibroblasts and cardiac myocytes to promote cardiac remodeling. Blocking RAAS can eliminate the long-term negative effects of RAAS activation. Direct renin inhibitors, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists are RAAS blockers. RAAS blockade improves mortality and hospitalization in systolic heart failure and acute myocardial infarction. RAAS blockade has not demonstrated the same benefits in other cardiac populations, such as those with preserved ejection fraction. Hypertrophic cardiomyopathy (HCM) causes LVH and asymmetric septal hypertrophy. When the outflow tract gradient exceeds 30 mmHg and is associated with septal hypertrophy, it is known as obstructive HCM. Dyspnea on exertion, syncope, and exertional angina are symptoms of HCM. RAAS activation worsens LVH by increasing blood pressure and by directly affecting cardiac myocytes with AT-II and aldosterone. RAAS blockade reverses myocardial fibrosis and slows HCM progression in animal models. We performed a meta-analysis of randomized clinical trials to further investigate the potential benefit of RAAS blockade in HCM patients. Although our findings included significant results for some of the RAAS blockade agents, these findings were not consistent throughout all the studies. Mavacamten, one of the newest treatments, has shown promising outcomes.
PubMed: 35949750
DOI: 10.7759/cureus.26642 -
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 -
Frontiers in Genetics 2022Some studies have been carried out to investigate the association between Trp64Arg polymorphism in beta-3 adrenergic receptor gene () and susceptibility to overactive...
Some studies have been carried out to investigate the association between Trp64Arg polymorphism in beta-3 adrenergic receptor gene () and susceptibility to overactive bladder (OAB), but the results remain inconsistent. We carried out a meta-analysis to acquire a more accurate estimation. All eligible studies were searched in PubMed, Web of Science, Embase, and Cochrane Library. Pooled odds ratios, with 95% confidence intervals, were assessed for the association using fixed and random effects models. The overall results of this meta-analysis demonstrated that there might be an association between Trp64Arg polymorphism and susceptibility to OAB in allele model, dominant model, and heterozygote comparison with a relative risk of 2.00 (95% CI 1.36-2.93), 2.13 (95% CI 1.20-3.76), and 2.07 (95% CI: 1.13-3.79), respectively. However, in the recessive model and homozygote comparison, no significant association between Trp64Arg polymorphism and susceptibility to OAB was observed, with a relative risk of 2.47 (95% CI 0.63-9.73) and 3.12 (95% CI: 0.79-12.35), respectively. Based on trail sequential analysis, the results turned out to be true positive in the allele model, false positive in the dominant model and heterozygote comparison, and negative in the recessive model and homozygote comparison, respectively. Our analysis indicated that Trp64Arg polymorphisms in might increase the risk of OAB twice in the allele model, but further well-designed studies with large sample sizes are required to confirm the present findings in other modes and comparisons.
PubMed: 35903356
DOI: 10.3389/fgene.2022.930084 -
ESC Heart Failure Oct 2022Due to concerns regarding neurohormonal activation and fluid retention, adrenergic alpha-1 receptor antagonists (A1Bs) are generally avoided in the setting of heart... (Meta-Analysis)
Meta-Analysis
Due to concerns regarding neurohormonal activation and fluid retention, adrenergic alpha-1 receptor antagonists (A1Bs) are generally avoided in the setting of heart disease, namely, symptomatic heart failure (HF) with reduced ejection fraction (HFrEF). However, this contraindication is mainly supported by ancient studies, having recently been challenged by newer ones. We aim to perform a comprehensive meta-analysis aimed at ascertaining the extent to which A1Bs might influence cardiovascular (CV) outcomes. We systematically searched PubMed, Cochrane Central Register of Controlled Trials and Web of Science for both prospective and retrospective studies, published until 1 December 2020, addressing the impact of A1Bs on both clinical outcomes-namely, acute heart failure (AHF), acute coronary syndrome (ACS), CV and all-cause mortality-and on CV surrogate measures, specifically left ventricular ejection fraction (LVEF) and exercise tolerance, by means of exercise duration. Both randomized controlled trials (RCTs) and studies including only HF patients were further investigated separately. Study-specific odds ratios (ORs) and mean differences (MDs) were pooled using traditional meta-analytic techniques, under a random-effects model. A record was registered in PROSPERO database, with the code number CRD42020181804. Fifteen RCTs, three non-randomized prospective and two retrospective studies, encompassing 32 851, 19 287, and 71 600 patients, respectively, were deemed eligible; 62 256 patients were allocated to A1B, on the basis of multiple clinical indications: chronic HF itself [14 studies, with 72 558 patients, including seven studies with 850 HFrEF or HF with mildly reduced ejection fraction (HFmrEF) patients], arterial hypertension (four studies, with 44 184 patients) and low urinary tract symptoms (two studies, with 6996 patients). There were 25 998 AHF events, 1325 ACS episodes, 955 CV deaths and 33 567 all-cause deaths. When considering only RCTs, A1Bs were, indeed, found to increase AHF risk (OR 1.78, [1.46, 2.16] 95% CI, P < 0.00001, i 2%), although displaying no significant effect on neither ACS nor CV or all-cause mortality rates (OR 1.02, [0.91, 1.15] 95% CI, i 0%; OR 0.95, [0.47, 1.91] 95% CI, i 17%; OR 1.1, [0.84, 1.43] 95% CI, i 17%, respectively). Besides, when only HF patients were evaluated, A1Bs revealed themselves neutral towards not only ACS, CV, and all-cause mortality events (OR 0.49, [0.1, 2.47] 95% CI, i 0%; OR 0.7, [0.21, 2.31] 95% CI, i 21%; OR 1.09, [0.53, 2.23] 95% CI, i 17%, respectively), but also AHF (OR 1.13, [0.66, 1.92] 95% CI, i 0%). As for HFrEF and HFmrEF, A1Bs were found to exert a similarly inconsequential effect on AHF rates (OR 1.01, [0.5-2.05] 95% CI, i 6%). Likewise, LVEF was not significantly influenced by A1Bs (MD 1.66, [-2.18, 5.50] 95% CI, i 58%). Most strikingly, exercise tolerance was higher in those under this drug class (MD 139.16, [65.52, 212.8] 95% CI, P < 0.001, i 26%). A1Bs do not seem to exert a negative influence on the prognosis of HF-and even of HFrEF-patients, thus contradicting currently held views. These drugs' impact on other major CV outcomes also appear trivial and they may even increment exercise tolerance.
Topics: Humans; Adrenergic alpha-Antagonists; Heart Failure; Hospitalization; Randomized Controlled Trials as Topic; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 35894772
DOI: 10.1002/ehf2.14012 -
Advances in Therapy Nov 2022Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual maintenance therapies for... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD.
METHODS
A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented.
RESULTS
The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 μg, glycopyrronium 50 μg, glycopyrronium 18 μg, tiotropium 18 μg and salmeterol 50 μg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation.
CONCLUSION
UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.
Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Dyspnea; Forced Expiratory Volume; Glycopyrrolate; Humans; Muscarinic Antagonists; Network Meta-Analysis; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome
PubMed: 35857184
DOI: 10.1007/s12325-022-02234-x -
Archivio Italiano Di Urologia,... Jun 2022Alpha-adrenoreceptor antagonists or alpha-blockers are used in the treatment of hypertension, in the therapy of benign prostatic hyperplasia and in medical expulsive... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alpha-adrenoreceptor antagonists or alpha-blockers are used in the treatment of hypertension, in the therapy of benign prostatic hyperplasia and in medical expulsive treatment of ureteral stones. These agents may affect the sexual function, with differences between drugs within the same class, depending on their selectivity for receptor subtypes. The aim of this review was to analyze the effects of alpha-blockers on sexual function.
MATERIALS AND METHODS
We conducted a systematic review and meta-analysis by searching PubMed, EMBASE and other databases for randomized controlled trials (RCTs) reporting sexual adverse effects in patients treated with alpha-blockers. Odds ratios for sexual dysfunction were calculated using random effects Mantel-Haenszel statistics.
RESULTS
Out of 608 records retrieved, 75 eligible RCTs were included in the meta-analysis. Compared with placebo, alphablockers were associated with increased odds of ejaculatory disorders both in patients with lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH) (OR: 7.53, 95% CI: 3.77-15.02, Z = 5.73, p < 0.00001, I2 = 55%) and in patients with ureteral stones (OR: 2.88, 95% CI: 1.50-5.44, Z = 3.19, p < 0.001, I2 = 31%). Uroselective alpha-blockers showed higher odds of ejaculatory disorders. Conversely, nonselective alpha-blockers were not associated with higher odds of ejaculatory dysfunction. Silodosin was associated with increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18-5.68, 15 series, 1512 participants, Z = 5.15, p < 0.00001, I2 = 0%). Naftopidil and alfuzosin showed lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers.No statistically significant differences in the odds of erectile dysfunction were observed when alpha-blockers were compared to placebo.
Topics: Adrenergic alpha-Antagonists; Humans; Lower Urinary Tract Symptoms; Male; Prostatic Hyperplasia; Randomized Controlled Trials as Topic
PubMed: 35775356
DOI: 10.4081/aiua.2022.2.252 -
Neuropsychopharmacology : Official... Nov 2022Alcohol use disorder (AUD) is a significant public health concern, contributing to a myriad of social, psychological, and physiological issues. Despite substantial...
Alcohol use disorder (AUD) is a significant public health concern, contributing to a myriad of social, psychological, and physiological issues. Despite substantial efforts within the alcohol research field, promising preclinical findings have failed to translate to clinical use, highlighting the necessity to develop safe and effective pharmacological probes with the ability to be used in preclinical and clinical research. Yohimbine, an α2 adrenergic receptor antagonist, is a well-validated pharmacological tool that has been widely employed in alcohol studies to evaluate noradrenergic activation. This scoping systematic review examines published literature in rodent and human studies involving the use of yohimbine relevant to alcohol research. We conducted a systematic literature review of MEDLINE, Embase, Web of Science Core Collection, CINAHL, PsycInfo, and Cochrane Central Register of Controlled Trials to identify: (1) Experimental Characteristics and Methodology, (2) Sex Differences, (3) Neurochemical Systems and Brain Regions, and (4) Discussion of Applications for Medication Development. Sixty-seven (62 preclinical and 5 clinical) studies were identified meeting the stated criteria, comprising extensive evidence supporting the use of yohimbine as a safe, titratable pharmacological agent for translational alcohol research. Support for the use of yohimbine as a fully translational tool, however, is hindered by limited available findings from human laboratory studies, as well as a dearth of studies examining sex differences in yohimbine's mechanistic actions. Additional consideration should be given to further translational modeling, ideally allowing for parallel preclinical and clinical assessment of yohimbine, methodological assessment of neurochemical systems and brain regions.
Topics: Adrenergic alpha-2 Receptor Antagonists; Alcohol Drinking; Animals; Ethanol; Female; Humans; Male; Rodentia; Yohimbine
PubMed: 35760866
DOI: 10.1038/s41386-022-01363-9 -
Clinical and Experimental Medicine Jul 2023Preclinical data have revealed that beta-adrenergic stimulation can affect the growth and progression of different types of malignancies. Beta-adrenergic receptor... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Preclinical data have revealed that beta-adrenergic stimulation can affect the growth and progression of different types of malignancies. Beta-adrenergic receptor blockers have been associated with improved survival in patients with many types of cancer. We performed a meta-analysis to investigate the association between beta-blocker use and hepatocellular carcinoma (HCC) prognosis.
METHODS
In this meta-analysis, a full search was conducted using PubMed, the Cochrane library and Embase to identify all relevant studies published up to May 2021. Available hazard ratios (HRs) were extracted for overall survival (OS), cancer-specific survival (CSS) and pooled using a random-effects meta-analysis.
RESULTS
Four studies involving 7252 patients with HCC met the inclusion criteria and were included in the systemic review. Three studies that reported OS data of 5148 patients were included in the meta-analysis. The random-effects model showed that beta-blocker use was associated with significantly improved OS in HCC (HR = 0.69, 95% CI = 0.54-0.88, P = 0.0031), without significant heterogeneity (I = 41%; Q = 6.42, P = 0.18).
CONCLUSION
This meta-analysis suggested that beta-blocker use can be associated with prolonged OS of patients with HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Proportional Hazards Models; Receptors, Adrenergic, beta
PubMed: 35737170
DOI: 10.1007/s10238-022-00842-z -
ESC Heart Failure Aug 2022Recent studies have suggested potential sex differences in treatment response to pharmacological therapies in heart failure (HF). We performed a systematic review and... (Meta-Analysis)
Meta-Analysis
AIMS
Recent studies have suggested potential sex differences in treatment response to pharmacological therapies in heart failure (HF). We performed a systematic review and meta-analysis of studies comparing treatment effects between men and women with HF and reduced ejection fraction (HFrEF) using established guideline-directed medical therapy and other emerging pharmacological treatments.
METHODS AND RESULTS
Systematic search was performed on PubMed, Embase, and Cochrane Library for randomized controlled trials published in 1990-2021. Outcomes were all-cause mortality and combined outcome of all-cause mortality and/or hospitalization for HF. Of 618 articles identified, 25 articles and 100 213 patients (mean age 62 ± 1.7 years, women 23.1%, mean left ventricular ejection fraction 26.6 ± 1.3%) were included in the systematic review and meta-analysis. For the outcome of all-cause mortality, there was no evidence of treatment heterogeneity by sex for renin-angiotensin system inhibitors (RASi) [hazard ratio (HR) 0.86 (95% confidence interval 0.75-0.99) in men; HR 0.97 (0.77-1.23) in women; P = 0.288], or for beta-blockers (BB) [HR 0.71 (0.59-0.86) in men; HR 0.87 (0.73-1.03) in women; P = 0.345]. Similarly, for the composite outcome of death or HF hospitalization, there was no evidence of treatment heterogeneity by sex for RASi [HR 0.84 (0.77-0.93) in men; HR 0.94 (0.81-1.08) in women; P = 0.210] or BB [HR 0.76 (0.64-0.90) in men; HR 0.72 (0.60-0.86) in women; P = 0.650]. Results for mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) from previously published meta-analyses were included in the review. For the combined outcome of cardiovascular death or HF hospitalization, no significant interaction for sex was observed for MRA (P = 0.78) or SGLT2i (P = 0.37). Results for emerging pharmacological treatments, such as soluble guanylate cyclase stimulators and cardiac myosin activators, were included in the review and showed consistent treatment effects between men and women.
CONCLUSIONS
Our meta-analysis showed no differences between sex in treatment effect for BB and RASi. Review on previously published trials for MRA, SGLT2i, and emerging therapies presented consistent treatment effects between men and women.
Topics: Female; Humans; Male; Middle Aged; Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Mineralocorticoid Receptor Antagonists; Sex Characteristics; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ventricular Function, Left
PubMed: 35603531
DOI: 10.1002/ehf2.13974 -
The Cochrane Database of Systematic... May 2022Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain.... (Review)
Review
BACKGROUND
Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015.
OBJECTIVES
The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain.
SEARCH METHODS
For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021.
SELECTION CRITERIA
We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model. The review primary outcomes were: participant-reported pain relief of 50% or greater; participant-reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow-up period. We assessed the certainty of evidence using GRADE and created two summary of findings tables.
MAIN RESULTS
We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double-blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double-blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias. TC compared to placebo There was no evidence of a difference in number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant-reported pain relief of 30% or greater during longest follow-up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow-up period (12 weeks) or very much improved on PGIC during the longest follow-up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow-up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow-up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence). TC compared to active comparator There was no evidence of a difference in the number of participants with participant-reported pain relief of 50% or greater during longest follow-up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported.
AUTHORS' CONCLUSIONS
This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC.
Topics: Adult; Analgesics; Chronic Pain; Clonidine; Diabetic Neuropathies; Humans; Neuralgia; Randomized Controlled Trials as Topic
PubMed: 35587172
DOI: 10.1002/14651858.CD010967.pub3