Network meta-analysis of the efficacy and safety of monoclonal antibodies and traditional conventional dichotomous agents for chronic obstructive pulmonary disease.

Introduction: Monoclonal antibodies (mAbs) against cytokines and chemokines or their receptors promise to be a potential therapeutic option to address chronic obstructive pulmonary disease (COPD). We aim to provide a comprehensive literature review of the improvement in FEV1 and safety when comparing mAbs with conventional dichotomous agents. Methods: We systematically searched 3 electronic databases (PubMed, EMBASE, and CENTRAL) up to August 1, 2023 to collect eligible randomized controlled trials (RCTs). A frequentist network meta-analysis using a random-effects model was deployed to calculate mean differences (MD) for FEV1, relative risk (RR) of treatment-emergent adverse events (TEAEs), and estimate the surface under cumulative rankings (SUCRA). A higher SUCRA indicates a better outcome. Results: This study included 23 RCTs involving a total of 20,853 patients. Overall, except for Dupilumab, mAbs did not significantly improve FEV1 compared to traditional conventional dichotomous agents. Among all the interventions included, Aclidinium bromide/Formoterol (AB/FF) (SUCRA 97.7%) ranked highest, followed by Umeclidinium/vilanterol (UMEC/VI) (SUCRA 93.5%), and Glycopyrrolate Formoterol Fumarate (GFF) (SUCRA 84.7%). Dupilumab (SUCRA 66.9%) ranked the fourth among all interventions but ranked the first among all the mAbs. Importantly, all mAbs demonstrated a good safety profile compared with placebo. Conclusion: Considering the improvement in FEV1 and its safety, the development of mAbs for COPD still holds significant clinical potential. Systematic review registration: PROSPERO, CRD42023452714.

The efficacy and safety of prophylactic antibiotics for post-acute stroke infection: A systematic review and meta-analysis.

AIMS: Infections are common complications after stroke and associated with unfavourable outcomes. We aimed to evaluate the efficacy and safety of prophylactic antibiotics for post-acute stroke infection. METHODS: We searched PubMed, Embase, the Cochrane Library, SinoMed, China National Knowledge Infrastructure, WanFang Data, China Science and Technology Journal Database, and clinical trial register platforms from inception to 15 February 2022. We included randomized clinical trials that evaluated the efficacy and safety of prophylactic antibiotics. Primary outcomes were mortality rate and incidence of pneumonia. The pooled risk ratio (RR) and mean differences with 95% confidence interval (CI) were calculated using the random or fixed-effect model depending on heterogeneity. The quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: Twelve studies (4809 participants) were included. There was no significant difference in the mortality rate (12 trials, n = 4740, RR 1.03 [95% Cl: 0.91-1.16], high-quality evidence), incidence of pneumonia (7 trials, n = 4352, RR 0.94 [95% CI: 0.79-1.11], high-quality evidence) and the incidence of adverse events between the prophylactic antibiotics and control groups. Prophylactic antibiotics significantly reduced the incidence of infections (8 trials, n = 4517, RR 0.72 [95% CI: 0.58-0.89], moderate-quality evidence) and urinary tract infections (7 trials, n = 4352, RR 0.39 [95% CI: 0.3-0.49], moderate-quality evidence). None of the subgroup analyses showed a significant difference in mortality or the incidence of pneumonia. CONCLUSION: For acute stroke patients, prophylactic antibiotics were significantly associated with fewer incidences of any infections and urinary tract infections without significant differences in mortality rate and pneumonia.

Efficacy and safety of sertraline for the treatment of premature ejaculation: Systematic review and meta-analysis.

BACKGROUD: Evidence on the efficacy and safety of sertraline in patients with premature ejaculation (PE) was inconsistent. The objective of this article is to evaluate the efficacy and safety of sertraline for the treatment of PE. METHODS: We searched Medline (OVID), Embase, the Cochrane Library, and 2 Chinese databases for randomized controlled trials (RCTs) and randomized crossover trials (RTs) that evaluated the efficacy and safety of sertraline in patients with PE. A meta-analysis was performed to calculate their pooled estimates with 95% confidence interval. RESULTS: Of the 645 records obtained, we included 12 RCTs and 2 RTs (n = 977). Meta-analysis showed that sertraline prolonged intravaginal ejaculation latency time (IELT) in PE patients ((standard mean difference (SMD) = 2.14, 95% CI 1.20 to 3.08). Subgroup analyses indicated a prolonged IELT for different treatment courses: 4 weeks (SMD = 2.66, 1.06 to 4.26), 6 weeks (SMD = 0.95, 0.31 to 1.58), and 8 weeks (SMD = 1.81, 0.78 to 2.85). The sexual satisfaction rates of patients (SMD = 2.20, 1.57 to 2.84) and spouses (SMD = 2.27, 1.44 to 3.09) were also improved. We observed a significant increased risk of gastrointestinal upset (risk ratio = 2.71, 1.39 to 5.28) in the sertraline group. CONCLUSION: Sertraline can prolong IELT of PE patients, improve sexual satisfaction rates of patients and spouses, but increase risk of gastrointestinal upset.

Efficacy and safety of saxagliptin in patients with type 2 diabetes: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the comparative efficacy and safety of saxagliptin for type 2 diabetes (T2D). METHODS: A systematic search of PubMed, Embase, the Cochrane Library, Web of Science, ClinicalTrials.gov and two Chinese databases for randomized controlled trials (RCTs) comparing saxagliptin with placebo or active comparators was performed up to July 2017. A complementary search was done to cover literature until March 2018. For continuous data, estimates were pooled using inverse variance methodology to calculate weighted mean differences (WMDs). Dichotomous data were presented as Mantel-Haenzel risk ratios (RRs). RESULTS: Thirty-nine references of 30 RCTs involving 29,938 patients were analyzed. Compared with placebo, saxagliptin significantly reduced glycated hemoglobin (HbA1c, WMD -0.52%, 95% CI -0.60 to -0.44) and fasting plasma glucose (WMD -13.78 mg/dL, 95% CI -15.31 to -12.25), and increased the proportion of patients achieving HbA1c <7% (RR 1.64, 95% CI 1.53 to 1.75). When combined with submaximal-dose metformin, saxagliptin significantly increased the proportion of patients achieving HbA1c <7% compared with acarbose (RR 2.38, 95% CI 1.17 to 4.83) and uptitrated metformin (RR 1.30, 95% CI 1.04 to 1.63). Saxagliptin was similar to other DPP-4 inhibitors but inferior to liraglutide and dapagliflozin on glycemic control. Saxagliptin significantly decreased the incidences of overall adverse events compared with acarbose (RR 0.71, 95% CI 0.57 to 0.89) and liraglutide (RR 0.41, 95% CI 0.24 to 0.71) when added to metformin. Weight gain and hypoglycemia with saxagliptin was slightly but significantly higher than placebo and lower than sulfonylureas. Saxagliptin did not increase the risk of arthralgia, heart failure, pancreatitis and other adverse events. CONCLUSIONS: Generally, saxagliptin has similar efficacy compared with most oral antidiabetic drugs and may be more effective than acarbose, while having a better safety profile than both acarbose and sulfonylureas.

Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis.

BACKGROUND AND OBJECTIVE: The association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients. METHODS: Studies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1. RESULTS: Seven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation. CONCLUSION: Based on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).

The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain: a systematic review and meta-analysis.

BACKGROUND: Individual response to opioid analgesics varies among patients. OBJECTIVE: This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain. STUDY DESIGN: A systematic review and meta-analysis of associations between genetic single-nucleotide polymorphisms (SNPs) and opioids used for acute postoperative pain. SETTING: This meta-analysis examined all studies involving an association between genetic polymorphisms and the analgesic efficacy or clinical outcome of opioid analgesics for postoperative pain. METHODS: A literature search was performed up to January 31, 2014, using the PubMed, EMBase, ISI Web of Science, and Cochrane Library databases. RESULTS: Fifty-nine studies were included in this systematic review, and 23 studies (a total of 5,902 patients) were included in the final meta-analysis. The results showed that human µ-opioid receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = -0.17, 95% CI = [-0.25, -0.10], P < 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative period. Moreover, CYP3A4*1G carriers consumed less opioids than homozygous CYP3A4*1/*1 patients during the first 24 hours postoperative period (MD = 45.12, 95% CI = [36.17, 54.06], P < 0.00001). No significant differences were found in CYP3A5*3, ABCB1 C3435T, and G2477T/A genetic polymorphisms. LIMITATIONS: Some potential non-genetic factors can modify the effects of gene SNP on pain and opioid consumption during the postoperative period, such as age, gender, mood, anxiety, and drug-drug interactions. But further analyses could not be performed in the present meta-analysis due to limited information. CONCLUSION: The results indicate that among the genetic SNPs we studied which include those affecting analgesic drug metabolism, transport of analgesic agents across the blood-brain barrier, and their activity at target receptors and ion channels and in the modulation of neurotransmitter pathways, the A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians to properly manage the analgesic use of opioids individually for better pain management.

Benefits of therapeutic drug monitoring of vancomycin: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The necessity of therapeutic drug monitoring (TDM) for vancomycin is controversial. The objective of the current review was to evaluate the available evidence for the necessity of TDM in patients given vancomycin to treat Gram-positive infections. METHODS: Medline, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were searched. Randomized controlled studies and observational studies that compared the clinical outcomes of TDM groups vs. non-TDM groups were included. Two reviewers independently extracted the data. The primary outcome was clinical efficacy of therapy. Secondary outcomes included vancomycin associated nephrotoxicity, duration of vancomycin therapy, length of hospital stay, and mortality. Meta-analysis was performed using the Mantel-Haenszel fixed effect method (FEM). Odds ratios (ORs) or weighted mean differences (WMD) with 95% confidence intervals (95%CIs) were calculated for categorical and continuous outcomes, respectively. RESULTS: One randomized controlled trial (RCT) and five cohort studies were included in the meta-analysis. Compared with non-TDM groups, TDM groups had significantly higher rates of clinical efficacy (OR = 2.62, 95%CI 1.34-5.11 P = 0.005) and decreased rates of nephrotoxicity (OR = 0.25, 95%CI 0.13-0.48 P<0.0001). Subgroup analyses showed that TDM group had significantly higher rates of clinical efficacy in both cohort studies subgroup (OR = 3.04, 95%CI 1.34-6.90) and in Asian population subgroup (OR = 3.04, 95%CI 1.34-6.90). TDM group had significantly decreased rates of nephrotoxicity in all subgroup. There was no significant difference in duration of vancomycin therapy (WMD = -0.40, 95%CI -2.83-2.02 P = 0.74) or length of stay (WMD = -1.01, 95%CI -7.51-5.49 P = 0.76) between TDM and non-TDM groups. Subgroup analyses showed there were no differences in duration of vancomycin therapy. Only one study reported mortality rates. CONCLUSIONS: Studies to date show that TDM significantly increases the rate of clinical efficacy and decreases the rate of nephrotoxicity in patients treated with vancomycin.

Effects of CYP2C19 loss-of-function variants on the eradication of H. pylori infection in patients treated with proton pump inhibitor-based triple therapy regimens: a meta-analysis of randomized clinical trials.

BACKGROUND: There are inconsistent conclusions about whether CYP2C19 variants could affect H. pylori eradication rate in patients treated with the proton pump inhibitor (PPI)-based therapy. We therefore performed a meta-analysis of randomized clinical trials (RCTs) to re-evaluate the impact of CYP2C19 variants on PPI-based triple therapy for the above indication. METHODS: All relevant RCTs in the PubMed, Cochrane Library, EMBASE, Web of Science and two Chinese databases (up to February 2013) were systematically searched, and a pooled analysis was performed with the odds ratio (OR) and 95% confidence interval (CI) by the STATA software. RESULTS: Sixteen RCT datasets derived from 3680 patients were included. There was no significant heterogeneity across the data available in this meta-analysis. There were significant differences in that rate between homozygous (HomEMs) and heterozygous (HetEMs) extensive metabolizers (OR 0.724; 95% CI 0.594-0.881), between HomEMs and poor metabolizers (PM) (OR 0.507; 95%CI 0.379-0.679), or between HetEMs and PMs (OR 0.688; 95%CI 0.515-0.920), regardless of the PPI being taken. Furthermore, sub-analysis of individual PPIs was carried out to explore the difference across all the PPIs used. A significantly low rate was seen in HomEMs vs. HetEMs taking either omeprazole (OR 0.329; 95%CI 0.195-0.553) or lansoprazole (OR 0.692; 95%CI 0.485-0.988), and also in HomEMs vs. PMs for omeprazole (OR 0.232; 95%CI 0.105-0.515) or lansoprazole (OR 0.441; 95%CI 0.252-0.771). However, there was no significant difference between HetEMs and PMs taking either one. No significant differences were observed for rabeprazole or esomeprazole across the CYP2C19 genotypes of interest. CONCLUSIONS: Carriage of CYP2C19 loss-of-function variants is associated with increased H. pylori eradication rate in patients taking PPI-based triple therapies when omeprazole or lansoprazole is chosen. However, there is no a class effect after use of rabeprazole or esomeprazole.

Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers.

BACKGROUND: CYP3A5 genetic polymorphisms contribute to marked interindividual differences in the metabolism of and response to tacrolimus in humans. OBJECTIVE: This study was aimed to clarify the impact of the CYP3A5*3 variant on tacrolimus dose requirements and acute rejection rates in patients with organ transplantation. METHODS: A literature search was performed up to August 2009 by using the Cochrane library, PubMed, Medline, and EMBase. RESULTS: Twenty-three studies (a total of 1779 patients) were included in this meta-analysis. Eighteen studies (1443 patients) were involved in renal transplantation and five studies (336 patients) in liver transplantation. Results of meta-analysis demonstrated that, in renal transplant patients, despite the presence of significant heterogeneity, CYP3A5 expressers required higher mean tacrolimus daily doses by 0.045 mg/kg (95% confidence interval (CI), 0.033-0.056) than nonexpressers. Furthermore, sub-analysis of the time of posttransplantation showed that CYP3A5 expressers required higher daily doses than nonexpressers by 0.010, 0.084, 0.041, 0.037, and 0.044 mg/kg at week 2, and at month 1, 3, 6, and 12, respectively. Subset analysis of the ethnicity of organ recipients indicated that mean tacrolimus daily doses were 0.056, 0.037, and 0.077 mg/kg higher in CYP3A5 expressers than non- expressers for white, Chinese, and Japanese patients, respectively. In contrast, for liver transplant patients, higher tacrolimus daily doses were required not only in CYP3A5 expressers of the organ donors than nonexpressers by 0.024 mg/kg (95% CI, 0.019-0.028), but also in CYP3A5 expresser of the organ recipients than nonexpresser by 0.012 mg/kg (95% CI, 0.005-0.018). However, a significant difference in the acute organ rejection rate was observed only at one month (odds ratio, 3.27; 95% CI, 1.57-6.81; P=0.002). CONCLUSION: Tacrolimus daily dose requirements may vary with the presence of the CYP3A5*3 variant, ethnicity of the organ recipients, and the time of posttransplantation. In addition, the acute organ rejection rate may be higher in CYP3A5 expressers than nonexpressers over the first month after transplantation.

Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis.

BACKGROUND: A common follicle-stimulating hormone (FSH) receptor (or FSHR) polymorphism Ser680Asn (rs6166) was found to be associated with altered ovarian response in women undergoing in-vitro fertilization. To further investigate such an association, a meta-analysis was conducted. METHODS: A PubMed literature search was conducted to identify all cohort studies investigating such a relationship. The following parameters-basal FSH levels, total FSH doses, oocytes retrieved, and pregnancy rates-were used to evaluate the ovarian function, its response to exogenous FSH and in-vitro fertilization and intracytoplasmic sperm injection outcome. RESULTS: A total of 1421 cases were collected from eight studies. Of them, a significantly lower basal FSH level was observed in patients harboring Asn/Asn (NN) genotype than those carrying the Ser/Ser (SS) genotype both in Asian (WMD: -2.57 mIU/ml, 95% CI: -2.96 to -2.19, P<0.0001) and Caucasian retrospective groups (WMD: -1.86 mIU/ml, 95%CI: -2.07 to -1.66, P<0.0001) with no heterogeneity. Moreover, carriers of the SS tended to require greater FSH doses than NN (WMD: -268.82IU, 95% CI: -561.28 to 23.63, P=0.07). Other parameters, such as oocytes retrieved and pregnancy rate, were not significantly different between the groups. CONCLUSION: Carriers of the SS variant have slightly higher basal FSH levels, tending to require higher doses of exogenous FSH for stimulation.

Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients: a meta-analysis.

BACKGROUND: Whether the loss-of-function allele CYP3A5*3 variant is associated with significantly impaired metabolism of cyclosporine A (CsA) in transplant patients is still controversial because of the lack of prospective, large-scale clinical studies performed among diversely ethnic populations. OBJECTIVES: This meta-analysis was designed to determine whether the CYP3A5*3 variant could affect CsA blood concentrations and the rate of acute rejection in renal transplant recipients. METHODS AND RESULTS: All relevant publications were retrieved online from 1966 to March 2010, in which 14 studies were chosen, and 1821 renal transplant patients were enrolled. The results showed that there were significant differences in the CsA dose-adjusted trough concentration (C0) between the CYP3A5*3/*3 and CYP3A5*1/*1 carriers [weighted mean difference (WMD): 10.06 mug/l per mg/kg, 95% confidence interval (CI): 3.12-17.00, P=0.004] and between the non-CYP3A5*1 allele carriers and the CYP3A5*1 allele carriers (WMD: 8.32 mug/l per mg/kg, 95% CI: 3.16-13.49, P=0.002). In addition, a subgroup analysis stratified by ethnicity indicated that a significant difference in CsA dose-adjusted C0 was observed between the non-CYP3A5*1 allele carriers and the CYP3A5*1 allele carriers in Asian patients, but not in Caucasian patients. Moreover, a significant difference in the mean daily dose was observed between the non-CYP3A5*1 allele carriers and the CYP3A5*1 allele carriers (WMD: -0.19 mg/kg, 95% CI: -0.31 to -0.07, P=0.002). However, the meta-analysis suggested that there was little or no association of the CYP3A5*3 variant with the acute rejection rate in renal transplant patients treated with CsA [odds ratio=0.94, 95% CI: 0.57-1.54, P=0.80]. CONCLUSION: We concluded that the CYP3A5*3 variant could be associated, to a certain extent, with increased CsA dose-adjusted C0 in blood and reduced mean daily doses, but that this genetic variant allele seemed to have little effect on the acute rejection rate in renal transplant patients taking CsA.