Meta-analysis Of Randomized Clinical Trials Research Articles

Network meta-analysis can inform the ethical evaluation of trials that randomise away from standard of care: The case of symptomatic carotid stenosis.

Little guidance exists on the conduct of randomised clinical trials (RCT) that seek to randomise patients away from standard of care. We sought to test the technique of network meta-analysis (NMA) to ascertain best available evidence for the purposes of informing the ethical evaluation of RCTs under these circumstances. We used the example of RCTs for patients withsymptomatic, moderate to severe carotid stenosis that seek to compare surgical intervention plus medical therapy (standard of care) versus medical therapy (less than standard of care). Network meta-analysis of RCTs of adults with symptomatic carotid artery stenosis of 50%-99% who were treated with carotid endarterectomy (CEA), carotid artery stenting (CAS), or medical therapy (MT). The primary outcome was any stroke or death until end of follow-up, and secondary outcome was 30-day risk of ipsilateral stroke/death. We analysed eight studies, with 7187 subjects with symptomatic moderate/severe stenosis (50%-99%). CEA was more efficacious than MT (HR = 0.82, 95% credible intervals [95% CrI] = 0.73-0.92) and CAS (HR 0.73, 95% CrI = 0.62-0.85) for the prevention of any stroke/death. At 30 days, the odds of experiencing an ipsilateral stroke/death were significantly lower in the CEA group compared to both MT (OR = 0.58, 95% CrI = 0.47-0.72) and CAS (OR = 0.68, 95% CrI = 0.55-0.83). Our results support the feasibility of using NMA to assess best available evidence to inform the ethical evaluation of RCTs seeking to randomise patients away from standard of care. Our results suggest that a strong argument is required to ethically justify the conduct of RCTs that seek to randomise patients away from standard of care in the setting of symptomatic moderate to severe carotid stenosis.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2  = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

The effects of blueberry and cranberry supplementation on blood pressure in patients with cardiovascular diseases: A systematic review and meta-analysis of randomized clinical trials.

Blueberries and cranberries are berry fruits with the highest number of randomized clinical trials (RCTs) focusing on blood pressure (BP). This systematic review and meta-analysis of RCTs analyzed the effects of blueberry and cranberry supplementation alone and in concert with systolic BP (SBP) and diastolic BP (DBP) in patients with cardiometabolic diseases. The searches were performed until August 2023 in the following databases: PubMed, Scopus, Web of Science, Cochrane, and Embase. Studies that examined the effects of blueberry or cranberry intake/supplementation were included. The risk of bias was evaluated using the Rob 2 scale. A meta-analysis was performed to estimate the effects of blueberry and cranberry supplementation on BP levels in patients with cardiometabolic diseases. A total of 17 articles were included, from which two found significant results from blueberry and/or cranberry supplementation in reducing BP. Pooled results revealed statistically non-significant reductions of -0.81 mm Hg for SBP (95% confidence interval [CI]: -2.26, 0.63; I2  = 0%) and -0.15 mm Hg for DBP (95% CI: -1.36, 1.05; I2  = 27%). Blueberry and/or cranberry supplementation had neutral effects on SBP and DBP in patients with cardiometabolic diseases, regardless of duration or age. Further high-quality studies are needed to firmly establish clinical efficacy.

Endoscopic Third Ventriculostomy versus Ventriculoperitoneal Shunt in Patients with Obstructive Hydrocephalus: An Updated Systematic Review and Meta-Analysis.

Endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) are surgical methods for treating obstructive hydrocephalus. However, there is still disagreement regarding the most effective technique, in terms of both operative success and postoperative complications. Therefore, we performed a systematic review and meta-analysis to compare the efficacy and safety of these two methods in patients with obstructive hydrocephalus. We performed a systematic search of the PubMed, Scopus, and Cochrane Library databases. Randomized clinical trials (RCTs) comparing ETV and VPS in pediatric or adult patients with obstructive hydrocephalus were included. The outcomes included were operative success, postoperative cerebrospinal fluid leak, postoperative infection, postoperative or intraoperative bleeding, blockage rate, and mortality. The risk ratio (RR) was calculated with a 95% confidence interval (CI). Heterogeneity was evaluated with I 2 statistics. We used a fixed-effects model for outcomes with I 2  < 25% and DerSimonian and Laird random-effects model for other conditions. The Cochrane collaboration tool for assessing the risk of bias in randomized trials was used for risk-of-bias assessment. R, version 4.2.1, was used for statistical analyses. Of the 2,353 identified studies, 5 RCTs were included, involving 310 patients with obstructive hydrocephalus, of which 163 underwent ETV. There was a significant difference in favor of ETV for postoperative infection (risk ratio [RR]: 0.11; 95% confidence interval [CI]: 0.04-0.33; p  < 0.0001; I 2  = 0%) and blockage rate (RR: 0.15; 95% CI: 0.03-0.75; p  = 0.02; I 2  = 53%). Meanwhile, there was no significant difference between groups for the postoperative or intraoperative bleeding (RR: 0.44; 95% CI: 0.17-1.15; p  = 0.09; I 2  = 0%), postoperative cerebrospinal fluid leak (RR: 0.65; 95% CI: 0.22-1.92; p  = 0.44; I 2  = 18%), operative success (RR: 1.18; 95% CI: 0.77-1.82; p  = 0.44; I 2  = 84%), and mortality (RR: 0.19; 95% CI: 0.03-1.09; p  = 0.06; I 2  = 0%). Three RCTs had some concerns about the risk of bias and one RCT had a high risk of bias due to the process of randomization and selection of reported results. Thus, this meta-analysis of RCTs evaluating ETV compared with VPS demonstrated that although there is no superiority of ETV in terms of operative success, the incidence of complications was significantly higher in patients who underwent VPS. Our results suggest that the use of ETV provides greater benefits for the treatment of obstructive hydrocephalus. However, more RCTs are needed to corroborate the superiority of ETV.

SA15 Clinical Outcomes of Pharmacological Therapies for Heart Failure in Black Vs. White Populations: A Meta-Analysis of Randomized Controlled Trials of Heart Failure Treatment

Black patients have a disproportionately high prevalence of heart failure (HF) and HF-related cardiovascular (CV) death compared to other racial groups. However, the Black population has been vastly under-represented in most randomized clinical trials (RCT) of HF medications. It remains unclear whether HF medications are comparably effective in the Black population vs. the White population. We conducted a meta-analysis of RCT to evaluate the effect of different pharmacological therapies for HF on the Black vs. White population.

Efficacy of adjuvant metronidazole therapy on peri-implantitis: a systematic review and meta-analysis of randomized clinical studies.

Peri-implant diseases are pathological conditions that affect the survival of dental implants. Etiological studies are limited, accepting a prevalence of 20% at the implant level and 24% at the patient level. The benefits of adjuvant metronidazole are controversial. A systematic review and meta-analysis of RCTs according to PRISMA and PICOS was performed with an electronic search over the last 10 years in MEDLINE (PubMed), WOS, Embase, and Cochrane Library. The risk of bias was measured using the Cochrane Risk of Bias tool and the methodological quality using the Jadad scale. Meta-analysis was performed with RevMan version 5.4.1, based on mean difference and standard deviation, with 95% confidence intervals; the random-effects model was selected, and the threshold for statistical significance was defined as p < 0.05.A total of 38 studies were collected and five were selected. Finally, one of the studies was eliminated because of unanalyzable results. All studies reached a high methodological quality. A total of 289 patients were studied with follow-up periods from 2 weeks to 1 year. Statistical significance was only found, with respect to the use of adjunctive metronidazole, in the pooled analysis of the studies (p = 0.02) and in the analysis of the radiographic values reported on peri-implant marginal bone levels, in the studies with a 3-month follow-up (p = 0.03). Discrepancies in the use of systemic metronidazole require long-term randomized clinical trials (RCTs) to determine the role of antibiotics in the treatment of peri-implantitis.

Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trials

Targeting short-term improvements in multicomponent risk scores for mortality in patients with pulmonary arterial hypertension (PAH) could result in improved long-term outcomes. We aimed to determine whether PAH risk scores were adequate surrogates for clinical worsening or mortality outcomes in PAH randomised clinical trials (RCTs). We performed an individual participant data meta-analysis of RCTs selected from PAH trials provided by the US Food and Drug Administration (FDA). We calculated predicted risk using the COMPERA, COMPERA 2.0, non-invasive FPHR, REVEAL 2.0, and REVEAL Lite 2 risk scores. The primary outcome of interest was time to clinical worsening, a composite endpoint composed of any of the following events: all-cause death, hospitalisation for worsening PAH, lung transplantation, atrial septostomy, discontinuation of study treatment (or study withdrawal) for worsening PAH, initiation of parenteral prostacyclin analogue therapy, or decrease of at least 15% in 6-min walk distance from baseline, combined with either worsening of WHO functional class from baseline or the addition of an approved PAH treatment. The secondary outcome of interest was time to all-cause mortality. We assessed the surrogacy of these risk scores, parameterised as attainment of low-risk status by 16 weeks, for improvement in long-term clinical worsening and survival using mediation and meta-analysis frameworks. Of 28 trials received from the FDA, three RCTs (AMBITION, GRIPHON, and SERAPHIN; n=2508) had the data necessary to assess long-term surrogacy. The mean age was 49 years (SD 16), 1956 (78%) participants were women, 1704 (68%) were classified as White, and 280 (11%) were Hispanic or Latino. 1388 (55%) of 2503 participants with available data had idiopathic PAH and 776 (31%) of 2503 had PAH associated with connective tissue disease. In a mediation analysis, the proportions of treatment effects explained by attainment of low-risk status ranged only from 7% to 13%. In a meta-analysis of trial-regions, the treatment effects on low-risk status were not predictive of the treatment effects on time to clinical worsening (R2 values 0·01-0·19) nor the treatment effects on time to all-cause mortality (R2 values 0-0·2). A leave-one-out analysis suggested that the use of these risk scores as surrogates might lead to biased inferences regarding the effect of therapies on clinical outcomes in PAH RCTs. Results were similar when using absolute risk scores at 16 weeks as the potential surrogates. Multicomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. Cardiovascular Medical Research and Education Fund, US National Institutes of Health.

Del Nido Cardioplegia in Adult Cardiac Surgery: Meta-Analysis of Randomized Clinical Trials

To compare the outcomes of patients receiving del Nido solution versus any other type of cardioplegia. A systematic review and meta-analysis of randomized trials. Cardiac operating rooms. Adult patients (≥18 years old) undergoing cardiac surgery. The EMBASE, MEDLINE, and CENTRAL databases were searched systematically from their inception until August 2022 for randomized controlled trials comparing del Nido versus other cardioplegias. Ten studies were included, including 1,812 patients (871 in the del Nido group and 941 in the control group), and published after 2017. There were significant reductions in postoperative stroke and/or transient ischemic attack rate in the del Nido group: 9/467 (1.9%) v 25/540 (4.6%); odds ratio (OR), 0.43; 95% CI, 0.20-0.92 (p=0.007). Del Nido cardioplegia was also associated with significantly shorter aortic cross-clamp time (mean difference, -8.99 minutes; 95% CI, -17.24 to -0.73 [p < 0.001]), significantly reduced need for defibrillation (89/582 [15%] v 252/655 [38%]; OR, 0.33; 95% CI, 0.15-0.72 [p < 0.001]), significantly lower risk of postoperative acute kidney injury (21/235 [8.9%] v 34/301 [11%]; OR, 0.50; 95% CI, 0.26-0.97 [p=0.04]), with no effect on mortality (14/607 [2.3%] v 12/681 [1.8%]; p=0.5). According to the authors' meta-analysis of recent randomized clinical trials, del Nido is a safe cardioplegic solution, which might provide better organ protection in adult cardiac surgery without differences in mortality when compared to other cardioplegic solutions.

COMPARING THE CLINICAL AND RADIOGRAPHIC OUTCOMES OF PULPOTOMIES IN PRIMARY MOLARS USING BIOACTIVE ENDODONTIC MATERIALS AND FERRIC SULFATE - A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS.

To compare the clinical and radiographic outcomes of pulpotomies in primary molars using bioactive endodontic materials and ferric sulfate. The search was conducted in PubMed, Ebscohost, ProQuest, and Scopus databases till June 2021. Children undergoing pulpotomy therapy in primary molars treated with ferric sulfate (FS) and bioactive endodontic materials were evaluated for clinical and radiographic success. Meta-analysis was performed on a random-effects model to assess the success at 6,12,18, and 24 months. The quality of studies was evaluated using the Cochrane risk of bias tool for randomized trials RESULTS: No significant difference was observed between Mineral trioxide aggregate (MTA) and FS at 24 months for both clinical [RR0.98 (95%CI 0.15,6.34), I2 = 0%] and radiographic [RR0.74 (95%CI: 0.23,2.43), I2 = 0%] success. At 6 months [RR1.36 (95%CI: 0.10,19.34), I2 = 33%], no difference was observed in the clinical [RR1.00 (95%CI: 0.95,1.05), I2 = 0%] and radiographic success [RR0.99 (95%CI: 0.88,1.11), I2 = 51%] between Biodentine (BD), FS and radiographic success of calcium enriched cement and FS [RR0.25 (95%CI: 0.03, 2.22), I2 = 0%]. Amongst bioactive materials, MTA and FS demonstrated equal success rates in both clinical and radiographic outcomes with follow-up periods of up to 24 months. Future, high-quality trials are required to verify the result of the current review.

[Cardiac contractility modulation in heart failure with reduced ejection fraction treatment].

Heart failure with reduced left ventricular ejection fraction (LV EF) (HFrEF) is a significant issue of health care due to increasing indexes of morbidity and mortality. The emergence of a number of drugs and implantable devices for the treatment of HFrEF has allowed improvement of patients' well-being and prognosis. However, high mortality and recurrent decompensated heart failure remain a substantial issue and stimulate the search for new methods of CHF treatment. Cardiac contractility modulation (CCM) is a method of managing patients with HFrEF. Available data from randomized clinical trials (RCT) indicate the efficacy of CCM in improvement of patients' well-being and quality of life. The question remains open: what effect does CCM have on LV reverse remodeling? Experimental data and results of observational studies suggest a possibility of reverse remodeling by CCM; however, this has not been confirmed in RCT. Also, it remains unclear how CCM influences the frequency of hospitalizations for decompensated heart failure and the death rate of patients with HFrEF. Results of both RCTs and observational studies have shown a moderate improvement of quality of life associated with CCM. Furthermore, RCTs have not found any increase in LV EF due to the therapy, nor has a meta-analysis of RCTs revealed any improvement of the prognosis associated with CCM. Further RCTs are needed to evaluate the effect of CCM on reverse remodeling, survival rate, and to determine the place of CCM in the treatment of patients with CHF.

Thiazide Diuretics and Fracture Risk: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Thiazide diuretics are commonly used antihypertensive agents. Until today, whether their use reduces fracture risk remains unclear. Our objective was to conduct a systematic review of thiazide diuretics' effects on fractures and bone mineral density (BMD) in randomized clinical trials (RCT) of adults. MEDLINE, EMBASE, CENTRAL, and the WHO's ICTRP registry were searched from inception to July 31, 2019. Two reviewers assessed studies for eligibility criteria: (i) RCTs; (ii) including adults; (iii) comparing thiazides, alone or in combination; (iv) to placebo or another medication; and (v) reporting fractures or BMD. Conference abstracts and studies comparing thiazides to antiresorptive or anabolic bone therapy were excluded. Bias was assessed using Cochrane Collaboration's Risk of Bias Tool-2. The primary outcome was fracture at any anatomical site. Secondary outcomes were osteoporotic fractures, hip fractures, and BMD at femoral neck, lumbar spine, and/or total hip. Fractures were pooled as risk ratios (RRs) using random-effect models. Prespecified subgroup analyses and post hoc sensitivity analyses were conducted. From 15,712 unique records screened, 32 trials (68,273 patients) met eligibility criteria. Thiazides were associated with decreased fractures at any site (RR=0.87, 95% confidence interval [CI] 0.77-0.98; I 2 = 0%) and osteoporotic fractures (RR=0.80; 95% CI 0.69-0.94; I 2 = 0%). Results were consistent in most subgroups and sensitivity analyses. Few studies reported hip fractures, and no association was found between thiazides and this outcome (RR=0.84; 95% CI 0.67-1.04; I 2 = 0%). Only four studies reported BMD; a meta-analysis was not conducted because BMD reporting was inconsistent. Trials were deemed at low (3 studies, weight=3%), some concerns (16 studies; 71%), or high (11 studies; 26%) risk of bias for the primary outcome. In conclusion, thiazide diuretics decreases the risk of fractures at any and at osteoporotic sites in a meta-analysis of RCTs. Additional studies are warranted in patients with high fracture risk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Does Ashwagandha supplementation have a beneficial effect on the management of anxiety and stress? A systematic review and meta-analysis of randomized controlled trials.

Clinical trial studies revealed conflicting results on the effect of Ashwagandha extract on anxiety and stress. Therefore, we aimed to evaluate the effect of Ashwagandha supplementation on anxiety as well as stress. A systematic search was performed in PubMed/Medline, Scopus, and Google Scholar from inception until December 2021. We included randomized clinical trials (RCTs) that investigate the effect of Ashwagandha extract on anxiety and stress. The overall effect size was pooled by random-effects model and the standardized mean difference (SMD) and 95% confidence interval (CIs) for outcomes were applied. Overall, 12 eligible papers with a total sample size of 1,002 participants and age range between 25 and 48 years were included in the current systematic review and meta-analysis. We found that Ashwagandha supplementation significantly reduced anxiety (SMD: -1.55, 95% CI: -2.37, -0.74; p=.005; I2 =93.8%) and stress level (SMD: -1.75; 95% CI: -2.29, -1.22; p=.005; I2 =83.1%) compared to the placebo. Additionally, the non-linear dose-response analysis indicated a favorable effect of Ashwagandha supplementation on anxiety until 12,000 mg/d and stress at dose of 300-600 mg/d. Finally, we identified that the certainty of the evidence was low for both outcomes. The current systematic review and dose-response meta-analysis of RCTs revealed a beneficial effect in both stress and anxiety following Ashwagandha supplementation. However, further high-quality studies are needed to firmly establish the clinical efficacy of the plant.

An evidence-based evaluation of Buyang Huanwu decoction for the treatment of the sequelae of stroke: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials

BackgroundBuyang Huanwu decoction (BYHWD) is a famous traditional Chinese formula that has been widely prescribed for sequelae of stroke in China. However, the efficacy and safety of BYHWD in treating sequelae of stroke have never been systematically evaluated. PurposeTo evaluate the effectiveness and safety of BYHWD in the treatment of sequelae of stroke. Study designA Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review and meta-analysis of randomized clinical trials (RCTs). Materials and methodsA systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. Five common electronic databases were searched for relevant RCTs from their inception until May 20, 2022. The Cochrane risk-of-bias tool was used to evaluate the methodological quality and the risk of bias of the included RCTs. Review Manager 5.4 was used to analyse all the data obtained. The clinical effective rate (CER) was the primary outcome, and National Institutes of Health Stroke Scale (NIHSS) and Fugl-Meyer Assessment (FMA) scores were the secondary outcomes. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate the quality of evidence for each outcome. ResultsThirty-two clinical studies that recruited 2,527 eligible patients were included in this meta-analysis. The results of the meta-analysis suggested that compared with conventional treatment alone, the addition of BYHWD significantly improved the CER (RR = 1.24, 95% CI: 1.20-1.29, p < 0.00001), decreased the NIHSS score (MD = -5.42, 95% CI: -5.87-4.97, p < 0.00001), and increased the FMA score (MD = 17.28, 95% CI: 15.12-19.45, p < 0.00001). There were no reported adverse events in the included studies. Most results were robust, and the quality of evidence was moderate. ConclusionOur study is the first meta-analysis of RCTs evaluating the effects of BYHWD on sequelae of stroke. The addition of BYHWD to conventional treatment for sequelae of stroke significantly improved the CER and promoted neurological rehabilitation in patients, and there were no reported adverse events associated with this combination therapy. The findings of our study support the use of BYHWD as an adjunct treatment to conventional treatment in this clinical population. However, due to the limitations of the included clinical trials, high-quality clinical trials with longer follow-ups are needed to assess the long-term effectiveness and safety of BYHWD for treating the sequelae of stroke.

Restrictive versus Liberal Blood Transfusion Strategy in Patients With Acute Myocardial Infarction: A Meta-Analysis of Randomized Clinical Trials.

BackgroundA meta-analysis of observational studies comparing differences in outcomes between restrictive blood transfusion (RBT) and liberal blood transfusion (LBT) in patients with acute myocardial infarction (AMI) reported that LBT is associated with higher all-cause mortality. Few randomized clinical trials (RCTs) have compared RBT to LBT in patients with AMI and anemia, but no meta-analysis of RCTs was performed to date.AimTo assess the clinical effect of RBT compared to LBT in patients with AMI and anemia regarding was all-cause mortality, recurrent MI, revascularization, and heart failure exacerbation.MethodsThe electronic databases Ovid MEDLINE, EMBASE, Cochrane Central, Scopus, and Google Scholar, were systematically searched to identify eligible studies published before June 19th, 2021. RCTs that assessed the effect of RBT compared to LBT were included. The primary endpoint was all-cause mortality. Secondary endpoints included recurrent MI, revascularization, and heart failure exacerbation.ResultsThree RCTs with 821 patients were included (421 received RBT, and 400 received LBT). The mean age was 75.9 ± 6.1 years, and 56% were male. Our meta-analysis showed that RBT was not associated with reduced all-cause mortality (RR = 1.61; 95% CI = 0.38–6.96, p = 0.52), recurrent MI (RR = 0.98; 95% CI = 0.48–1.96, p = 0.94), revascularization (RR = 1.18; 95% CI = 0.26–5.44, p = 0.83) and heart failure exacerbation (RR = 0.86; 95% CI = 0.23–3.22, p = 0.82) when compared to LBT.ConclusionRBT was not associated with reduced all-cause mortality, recurrence of MI, need for revascularization, or heart failure exacerbation in patients with AMI and anemia compared to LBT. A larger RCT is required to confirm the above findings.

Efficacy of ICS versus Non-ICS Combination Therapy in COPD: A Meta-Analysis of Randomised Controlled Trials

BackgroundSeveral large randomized clinical trials (RCTs) have assessed the efficacy and safety of inhaled corticosteroid (ICS) combination regimens versus non-ICS therapy in patients with chronic obstructive pulmonary disease (COPD) at increased risk of exacerbation risk with mixed results.MethodsWe performed a systematic literature review and meta-analysis of RCTs comparing the effect of ICS-containing combination therapy and non-ICS regimen in patients with COPD.ResultsA total of 54 RCTs (N = 57,333) reported treatment effects on various outcomes and were eligible for inclusion. Overall, the number of patients experiencing moderate/severe exacerbations was significantly lower for ICS-containing combination therapy versus non-ICS therapy (RR: 0.86 [95% CI: 0.80–0.93]). The annual rate of exacerbations was also significantly reduced by 22% (0.78 [0.72–0.86]) with ICS-containing versus non-ICS therapy. The annual rate of exacerbations requiring hospitalisation was reduced by 31% versus non-ICS therapy (0.69 [0.54–0.88]); similar reduction was observed for exacerbations requiring oral steroids (0.69 [0.66–0.73]). Overall, the effect on trough FEV1 was comparable between ICS-containing and non-ICS therapies (follow-up: 6–52 weeks); however, a significant improvement in lung function (trough FEV1) was observed for ICS/LABA versus LABA (MD: +0.04 L [0.03−0.05]) and ICS/LABA/LAMA versus LAMA (MD: +0.09 L [0.05−0.13]) regimens. In addition, a significant improvement in QoL was observed with ICS-containing versus non-ICS therapy (MD in SGRQ score: −0.90 [−1.50, −0.31]).ConclusionThis meta-analysis demonstrated that a wide range of patients with COPD could benefit from dual and triple ICS-containing therapy.

Evaluation of Computerized Cognitive Training and Cognitive and Daily Function in Patients Living With HIV

In the era of antiretroviral therapy (ART), the incidence of HIV-associated neurocognitive disorder (HAND) has not yet been controlled. With the exception of ART, there is no beneficial pharmacologic treatment. However, some studies have reported that computerized cognitive training (CCT) programs may improve cognitive function among people living with HIV. To examine the association between CCT programs and 8 domains measuring cognitive function (7 domains) and daily function (1 domain) among people living with HIV. Records from the Cochrane Library, PsycINFO, PubMed, and Web of Science were searched from database inception to December 15, 2020. Supplementary searches to identify missing studies were conducted in Google Scholar using updated search terms from database inception to November 18, 2021. Studies that compared changes before and after a CCT intervention among people living with HIV were included. Search terms were a combination of words associated with HIV (eg, people living with HIV, HIV, and/or AIDS) and cognitive training (eg, cognitive intervention, nonpharmacology intervention, computer game, video game, computerized training, cognitive exercise, cognitive stimulation, and/or cognitive enhancement). Studies were included if they (1) used CCT as the primary intervention or combined CCT with other types of interventions; (2) used placebo, passive control conditions, traditional cognitive training, or single training tasks as control conditions; (3) reported changes between baseline and posttraining; (4) included participants 18 years or older; and (5) were randomized clinical trials (RCTs). Studies were excluded if they (1) were not associated with HIV, (2) were research protocols or feedback reports, (3) were case reports, or (4) did not report findings for domains of interest. Two reviewers independently extracted data. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Random-effects models were used to quantitatively synthesize the existing data. Primary outcomes were the meta-synthesized changes in each domain after CCT. Among 1245 records identified, 1043 were screened after removal of duplicates. Of those, 1019 records were excluded based on titles and abstracts, and 24 full-text articles were assessed for eligibility. After exclusions, 12 eligible RCTs were selected for inclusion in the meta-analysis. These RCTs involved 596 total participants, with 320 individuals in the CCT group (mean age, 47.5-59.7 years; 0%-94% female; 8.3-14.2 years of education) and 276 individuals in the control group (mean age, 44.2-60.0 years; 19%-90% female; 9.0-14.9 years of education). The average HIV inhibition ratio (the proportion of participants who achieved virological suppression) ranged from 30% to 100%, and the CD4+ T-cell count ranged from 471 to 833 cells/μL. The time since training ranged from 3 to 24 weeks. After receipt of CCT, function significantly improved in 6 of the 8 domains: abstraction and executive function (standardized mean difference [SMD], 0.58; 95% CI, 0.26-0.91; P < .001), attention and working memory (SMD, 0.62; 95% CI, 0.33-0.91; P < .001), memory (SMD, 0.59; 95% CI, 0.20-0.97; P = .003), motor skills (SMD, 0.50; 95% CI, 0.24-0.77; P < .001), speed of information processing (SMD, 0.65; 95% CI, 0.37-0.94; P < .001), and daily function (SMD, 0.44; 95% CI, 0.02-0.86; P = .04). Sensory and perceptual skills (SMD, 0.06; 95% CI, -0.36 to 0.48; P = .78) and verbal and language skills (SMD, 0.46; 95% CI, -0.07 to 0.99; P = .09) did not significantly improve after CCT. This meta-analysis of RCTs found that CCT programs were associated with improvements in cognitive and daily function among people living with HIV. Future studies are needed to design optimal specific training programs and use implementation science to enable the transformation of CCT from a scientific research tool to a real-world clinical intervention.

Combining Antidepressants vs Antidepressant Monotherapy for Treatment of Patients With Acute Depression

Combining antidepressants is frequently done in the treatment of acute depression, but studies have yielded conflicting results. To conduct a systematic review and meta-analysis assessing efficacy and tolerability of combination therapy. Combinations using presynaptic α2-autoreceptor antagonists or bupropion were investigated separately. MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were systematically searched from each database inception through January 2020. Randomized clinical trials (RCTs) comparing combinations of antidepressants with antidepressant monotherapy in adult patients with acute depression were included. Following guidelines from Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and recommendations from the Cochrane Handbook, 2 reviewers independently performed a literature search, study selection, data extraction, and evaluation of risk of bias. Data were pooled in random-effects analyses. Primary outcome was efficacy measured as standardized mean difference (SMD); secondary outcomes were response, remission, change from baseline in rating scale scores, number of dropouts, and number of dropouts due to adverse events. Thirty-nine RCTs including 6751 patients were eligible. Combination treatment was statistically significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Bupropion combinations were not superior to monotherapy (SMD = 0.10; 95% CI, -0.07 to 0.27). Numbers of dropouts and dropouts due to adverse events did not differ between treatments. Studies were heterogeneous, and there was indication of publication bias (Egger test result was positive; P = .007, df = 36), but results remained robust across prespecified secondary outcomes and sensitivity and subgroup analyses, including analyses restricted to studies with low risk of bias. In this meta-analysis of RCTs comparing combinations of antidepressants with antidepressant monotherapy, combining antidepressants was associated with superior treatment outcomes but not with more patients dropping out of treatment. Combinations using an antagonist of presynaptic α2-autoreceptors may be preferable and may be applied as a first-line treatment in severe cases of depression and for patients considered nonresponders.

Adjunctive Effect of Systemic Antibiotics in Regenerative/Reconstructive Periodontal Surgery-A Systematic Review with Meta-Analysis.

Background and Objective: Systemic antibiotics (AB) are often used in conjunction with regenerative/reconstructive periodontal surgery of intrabony defects and furcations; however, their potential benefits have not been systematically assessed. Materials and Methods: Data were retrieved from two recent systematic reviews (a total of 105 randomized clinical trials (RCTs) on clinical and radiographic outcomes in intrabony defects (ID) and molars with furcation involvement (FI) treated by surgical access with regenerative techniques. Pair-wise meta-analysis of RCTs with and without AB was performed. Meta-regressions from single-arm (subgroup) RCTs including study arms with or without adjunctive AB were also conducted. Results: No statistically significant benefits of systemic AB with regard to PPD, CAL and bone gain were detected in ID by pair-wise meta-analysis. Meta-regression revealed increased PPD reduction (−0.91 mm, 95% CI = −1.30; −0.51, p < 0.001), CAL gain (−0.92 mm, 95% CI = −1.32; −0.52, p < 0.001) and bone gain (−1.08 mm, 95% CI = −1.63; −0.53, p < 0.001) in ID but not in any of the outcomes in FI for arms treated with AB vs. study arms treated with no AB. No clear differences in adverse events were detected between AB and non-AB groups. Conclusion: There is only weak indirect evidence that AB may provide additional benefits in terms of clinical improvements in the regenerative/reconstructive periodontal surgery of intrabony defects and no evidence for a benefit in furcations. Until new data are gained and in the context of antibiotic stewardship, it may be questionable to justify the adjunctive use of systemic antibiotics.

The Use of Tocilizumab in Patients with COVID-19: A Systematic Review, Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Studies.

Background: Among the several therapeutic options assessed for the treatment of coronavirus disease 2019 (COVID-19), tocilizumab (TCZ), an antagonist of the interleukine-6 receptor, has emerged as a promising therapeutic choice, especially for the severe form of the disease. Proper synthesis of the available randomized clinical trials (RCTs) is needed to inform clinical practice. Methods: A systematic review with a meta-analysis of RCTs investigating the efficacy of TCZ in COVID-19 patients was conducted. PubMed, EMBASE, and the Cochrane COVID-19 Study Register were searched up until 30 April 2021. Results: The database search yielded 2885 records; 11 studies were considered eligible for full-text review, and nine met the inclusion criteria. Overall, 3358 patients composed the TCZ arm, and 3131 the comparator group. The main outcome was all-cause mortality at 28–30 days. Subgroup analyses according to trials’ and patients’ features were performed. A trial sequential analysis (TSA) was also carried out to minimize type I and type II errors. According to the fixed-effect model approach, TCZ was associated with a better survival odds ratio (OR) (0.84; 95% confidence interval (CI): 0.75–0.94; I2: 24% (low heterogeneity)). The result was consistent in the subgroup of severe disease (OR: 0.83; 95% CI: 0.74–0.93; I2: 53% (moderate heterogeneity)). However, the TSA illustrated that the required information size was not met unless the study that was the major source of heterogeneity was omitted. Conclusions: TCZ may represent an important weapon against severe COVID-19. Further studies are needed to consolidate this finding.

Estimating the Complier Average Causal Effect in a Meta-Analysis of Randomized Clinical Trials With Binary Outcomes Accounting for Noncompliance: A Generalized Linear Latent and Mixed Model Approach.

Noncompliance, a common problem in randomized clinical trials (RCTs), can bias estimation of the effect of treatment receipt using a standard intention-to-treat analysis. The complier average causal effect (CACE) measures the effect of an intervention in the latent subpopulation that would comply with their assigned treatment. Although several methods have been developed to estimate the CACE in analyzing a single RCT, methods for estimating the CACE in a meta-analysis of RCTs with noncompliance await further development. This article reviews the assumptions needed to estimate the CACE in a single RCT and proposes a frequentist alternative for estimating the CACE in a meta-analysis, using a generalized linear latent and mixed model with SAS software (SAS Institute, Inc.). The method accounts for between-study heterogeneity using random effects. We implement the methods and describe an illustrative example of a meta-analysis of 10 RCTs evaluating the effect of receiving epidural analgesia in labor on cesarean delivery, where noncompliance varies dramatically between studies. Simulation studies are used to evaluate the performance of the proposed method.