Eligible Randomized Clinical Trials Research Articles

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer

Recent studies have investigated the combination of immune checkpoint inhibitors (ICIs) with (neo)adjuvant chemotherapy in early-stage breast cancer. However, there is an ongoing debate about the optimal approach for integrating this strategy. To evaluate the association of neoadjuvant ICIs with pathologic complete response (pCR) across molecular phenotypes, to quantify the survival benefits of ICIs beyond pCR status, and to estimate the incidence of specific adverse events. The PubMed database was searched on December 10, 2023, to identify all potential eligible studies. Randomized clinical trials (RCTs) that assessed (neo)adjuvant ICI plus chemotherapy in early breast cancer. Data from the eligible RCTs were extracted by 2 reviewers. An extracted individual patient data meta-analysis and a trial-level random-effect meta-analysis were performed. Outcomes were pCR, event-free survival (EFS) in patients with and without pCR, and adverse events. Hazard ratios were estimated using stratified Cox proportional hazards regression models. Nine RCTs involving 5114 patients met the inclusion criteria (2097 triple-negative breast cancer [TNBC], 1924 hormone receptor-positive [HR+]/ERBB2-negative [ERBB2-], and 1115 ERBB2+ tumors). In TNBC, the addition of ICIs was associated with an improved pCR rate regardless of programmed cell death ligand 1 (PD-L1) status (absolute improvement, >10%). In HR+/ ERBB2- tumors, the administration of ICIs was associated with improved pCR only in the PD-L1-positive (PD-L1+) population (absolute improvement, +12.2%), whereas no benefit was observed in ERBB2+ tumors. In patients with TNBC achieving a pCR, the addition of ICIs was associated with improved EFS (hazard ratio, 0.65; 95% CI, 0.42-1.00), resulting in a 5-year EFS of 92.0% with ICIs compared with 88.0% without them. In patients with residual disease, ICIs also showed better EFS (hazard ratio, 0.77; 95% CI, 0.61-0.98), resulting in a 5-year EFS of 63.3% with ICIs and 56.1% without them. Adjuvant ICI did not show numerical improvement in patients with either pCR or residual disease (all hazard ratios >1). During the neoadjuvant treatment, the incidence of grade 3 or greater immune-related adverse events with ICI was 10.3%. These findings suggest that neoadjuvant ICI therapy improves efficacy outcomes in early-stage TNBC and PD-L1+ HR+/ERBB2- tumors with an acceptable safety profile; however, no benefit was observed with adjuvant ICI. Given the financial and toxicity costs associated with ICIs, future research should prioritize identifying patients most likely to benefit from the addition of ICIs to neoadjuvant chemotherapy.

Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock

There is uncertainty about whether prolonged infusions of β-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. To determine whether prolonged β-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of β-lactam antibiotics in critically ill adults with sepsis or septic shock. Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of β-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. PROSPERO Identifier: CRD42023399434.

Comparative efficacy and safety of JAK/TYK2 inhibitors and other oral drugs for moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis.

Background Janus kinase (JAK)/tyrosine kinase 2 (TYK2) inhibitors are novel treatments for moderate-to-severe plaque psoriasis. Objective To perform a network meta-analysis to compare the efficacy and safety of TYK2 inhibitors with other oral drugs in moderate-to-severe psoriasis. Methods Eligible randomised clinical trials (RCTs) were identified from public databases (published before November 2, 2023). Random-effect frequentist network meta-analysis was performed with ranking based on the surface under the cumulative ranking curve (SUCRA) of Physician's Global Assessment of "clear" or "almost clear" (PGA 0/1), 75% reduction from baseline in Psoriasis Area and Severity Index (PASI-75). Results Twenty RCTs containing 7,564 patients with moderate-to-severe psoriasis were included. Deucravacitinib at all dose levels (except for 3 mg every other day) and tofacitinib (10 mg BID) ranked best in achieving PGA 0/1 and PASI-75 at 12- 16 weeks. Tofacitinib (10 mg BID) was considered the most unsafe. Analysis of Ranking according to efficacy and safety showed deucravacitinib (3 mg QD and 3 mg BID) was the best treatment. Analysis of Ranking according to efficacy and safety showed deucravacitinib (3 mg QD and 3 mg BID) was the best treatment. Limitations Insufficiency of eligible data and no long-term follow-up data. Conclusion Deucravacitinib showed superior efficacy and safety for treating moderate-to-severe psoriasis over other included drugs.

Comparing the protective effects of local and remote ischemic preconditioning against ischemia-reperfusion injury in hepatectomy: a systematic review and network meta-analysis.

Local ischemic preconditioning (LIPC) has been proven to be a protective strategy against hepatic ischemia-reperfusion injury (HIRI) during hepatectomy. Growing evidence suggests remote ischemic preconditioning (RIPC) has the potential to reduce liver injury in hepatectomy. Few studies have directly compared the protective effects of these two mechanical preconditioning strategies. Therefore, we performed a network meta-analysis to compare the efficacy of LIPC and RIPC for hepatic injury during liver resection. We searched Cochrane, PubMed, Embase, and China National Knowledge Infrastructure (CNKI) from the database inception to January 2023. We included studies directly comparing the effectiveness of LIPC and RIPC and those comparing LIPC or RIPC with no-preconditioning in liver resection. Postoperative liver function and surgical events were analyzed. Data were expressed as standardized mean differences (SMDs) or odds ratios (ORs) and analyzed using network meta-analysis with random effects model. Following the screening of 268 citations, we identified 26 eligible randomized clinical trials (RCTs) involving 1,476 participants (LIPC arm: 789, RIPC arm: 859, no-preconditioning arm: 1,072). LIPC and RIPC were superior to no-preconditioning in reducing postoperative serum transaminase levels [aspartate aminotransferase (AST): SMD RIPC versus no-preconditioning: -2.05, 95% confidence interval (CI): -3.39, -0.71; SMD LIPC versus no-preconditioning: -1.10, 95% CI: -2.07, -0.12; alanine aminotransferase (ALT): SMD RIPC versus no-preconditioning: -2.24, 95% CI: -4.15, -0.32; SMD LIPC versus no-preconditioning: -1.32, 95% CI: -2.63, -0.01]. No significant difference was observed between RIPC and LIPC in postoperative liver function and surgical outcomes (AST: SMD RIPC versus LIPC: -0.95, 95% CI: -2.52, 0.62; ALT: SMD RIPC versus LIPC: -0.91, 95% CI: -3.11, 1.28). In addition, the subgroup analysis revealed the potential benefits of RIPC in improving liver function, especially in patients who diagnosed with cirrhosis or underwent major resection. RIPC and LIPC could serve as effective strategies in relieving HIRI during hepatectomy. No significant differences were observed between LIPC and RIPC, however, RIPC may be an easily applicable strategy to relieve liver injury in hepatectomy.

Side effects and cognitive benefits of buspirone: A systematic review and meta-analysis

Buspirone, a 5-hydroxytryptamine 1A (5-HT1A) receptor agonist, has been investigated for its use in various diseases. However, knowledge about its side effects and potential cognitive benefits in different conditions is limited. Cognitive impairment is also a prevalent symptom in many diseases, yet effective treatments are still lacking. Therefore, to explore the potential side effects of buspirone and the possible cognitive benefits of buspirone, we conducted a comprehensive search of several databases, including PubMed, Embase, Web of Science, Cochrane Review, Cochrane Trial, and ClinicalTrials.gov, to identify eligible randomized clinical trials. Our primary outcome measures included both side effects (adverse events) and cognitive benefits. For continuous variables, we utilized effect size with a 95% confidence interval (CI), whereas for dichotomous variables, we used odds ratios (OR) with a 95% CI. In total, 16 studies were included in this analysis, with 13 studies reporting on buspirone's side effects and 4 studies focusing on cognitive tasks. In terms of side effects, buspirone exhibited a higher rate of dizziness (OR = 4.66, 95% CI: 2.07–10.47), constipation (OR = 4.11, 95% CI: 1.34–12.55), and gastric distress (OR = 1.97, 95% CI: 1.03–3.78) than the placebo group. Regarding cognitive functions, buspirone showed significant benefits (g = 0.20, 95% CI: 0.06–0.34) while the placebo did not. Subgroup analysis indicated superior performance in visual learning and memory (g = 0.49, 95% CI: 0.21–0.78), logical reasoning (g = 0.42, 95% CI: 0.14–0.71), and attention (g = 0.37, 95% CI: 0.13–0.61) when compared to placebo. Our findings indicated that participants in the buspirone group experienced side effects of dizziness, constipation, and gastric distress in different diseases. Despite these adverse events, however, buspirone demonstrated significant cognitive benefits, particularly in the domains of visual learning and memory, logical reasoning, and attention.

Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications

Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomized clinical trials (RCTs) limits the generation of appropriate evidence to guide cardiovascular risk management (CVRM). To evaluate the underrepresentation of patients with CKD in cardiovascular RCTs, and to highlight evidence gaps in CVRM medications in this population. A systematic search was conducted in ClinicalTrials.gov from February 2000 through October 2021 for RCTs with full-text publications. If no full-text publications were found in ClinicalTrials.gov, MEDLINE, Embase, and Google Scholar were also searched. Eligible RCTs were those evaluating the effectiveness of antiplatelets, anticoagulants, blood pressure-lowering drugs, glucose-lowering drugs, or cholesterol-lowering drugs in adults with cardiovascular disease or cardiovascular risk factors. Trials with a sample size of fewer than 100 patients were excluded. In total, 1194 RCTs involving 2 207 677 participants (mean [SD] age, 63 [6] years; 1 343 970 males [64%]) were included. Since 2000, the percentage of cardiovascular RCTs excluding patients with CKD has increased from 66% to 79% (74% overall [884 RCTs]). In 864 RCTs (72%), more patients were excluded than anticipated on safety grounds (63% [306] of trials required no dose adjustment, and 79% [561] required dose adjustment). In total, 158 RCTs (13%) reported results for patients with CKD separately (eg, in subgroup analyses). Significant evidence gaps exist in most CVRM interventions for patients with CKD, particularly for those with CKD stages 4 to 5. Twenty-three RCTs (2%) reported results for patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2, 15 RCTs (1%) reported for patients receiving dialysis, and 1 RCT (0.1%) reported for recipients of kidney transplant. Results of this systematic review suggest that representation of patients with CKD in cardiovascular RCTs has not improved in the past 2 decades and that these RCTs excluded more patients with CKD than expected on safety grounds. Lack of reporting or underreporting of results for this patient population is associated with evidence gaps in the effectiveness of most CVRM medications in patients with all stages of CKD, particularly CKD stages 4 to 5.

Both clinical trial register and electronic bibliographic database searches were needed to identify randomized clinical trials for systematic reviews: an evaluation study

ObjectivesTo determine whether clinical trial register (CTR) searches can accurately identify a greater number of completed randomized clinical trials (RCTs) than electronic bibliographic database (EBD) searches for systematic reviews of interventions, and to quantify the number of eligible ongoing trials. Study Design and SettingWe performed an evaluation study and based our search for RCTs on the eligibility criteria of a systematic review that focused on the underrepresentation of people with chronic kidney disease in cardiovascular RCTs. We conducted a combined search of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform through the Cochrane Central Register of Controlled Trials to identify eligible RCTs registered up to June 1, 2023. We searched Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE for publications of eligible RCTs published up to June 5, 2023. Finally, we compared the search results to determine the extent to which the two sources identified the same RCTs. ResultsWe included 92 completed RCTs. Of these, 81 had results available. Sixty-six completed RCTs with available results were identified by both sources (81% agreement [95% CI: 71–88]). We identified seven completed RCTs with results exclusively by CTR search (9% [95% CI: 4–17]) and eight exclusively by EBD search (10% [95% CI: 5–18]). Eleven RCTs were completed but lacked results (four identified by both sources (36% [95% CI: 15–65]), one exclusively by EBD search (9% [95% CI: 1–38]), and six exclusively by CTR search (55% [95% CI: 28–79])). Also, we identified 42 eligible ongoing RCTs: 16 by both sources (38% [95% CI: 25–53]) and 26 exclusively by CTR search (62% [95% CI: 47–75]). Lastly, we identified four RCTs of unknown status by both sources. ConclusionCTR searches identify a greater number of completed RCTs than EBD searches. Both searches missed some included RCTs. Based on our case study, researchers (eg, information specialists, systematic reviewers) aiming to identify all available RCTs should continue to search both sources. Once the barriers to performing CTR searches alone are targeted, CTR searches may be a suitable alternative.

Evaluating the efficacy and acceptability of vagus nerve stimulation for fibromyalgia: a PRISMA-compliant protocol for a systematic review and meta-analysis.

Fibromyalgia has imposed substantial burdens on patients' health and well-being, yet effective therapeutic options for this condition remain limited. Recently, vagus nerve stimulation (VNS) has emerged as a promising therapy for fibromyalgia. Nonetheless, despite the increasing number of randomized clinical trials (RCTs), current evidence remains inconclusive. Therefore, this protocol of a systematic review and meta-analysis aims to synthesize the existing evidence to clarify the efficacy and acceptability of VNS for treating fibromyalgia. A comprehensive search for eligible RCTs will be conducted across nine bibliographic databases, namely PubMed, Cochrane Library, Embase, AMED, PsycINFO, PEDro, Chinese BioMedical Literature Database, Chinese National Knowledge Infrastructure, and Wangfang database. Data obtained from the included studies will be synthesized quantitively using RevMan 5.4.1 for meta-analyses. The methodological soundness of included RCTs will be assessed via the Cochrane's updated risk of bias tool (version 2.0). Additionally, sensitivity analyses, publication bias assessment, and subgroup analyses will be conducted as appropriate. Finally, we will utilize the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to evaluate the certainty for the body of evidence. The findings of our study are anticipated to ascertain the efficacy and acceptability of VNS as a promising treatment option for fibromyalgia. This will not only fill current research gap but also identify potential areas for future research. The findings will provide essential guidance for evidence-based treatment decisions for fibromyalgia, benefiting both patients and clinicians.

Efficacy of sulodexide in treating idiopathic membranous nephropathy among Chinese patients: a meta-analysis.

To evaluate the efficacy of Sulodexide in treating idiopathic membranous nephropathy (IMN) in the Chinese population. We systematically reviewed all eligible randomized clinical trials (RCTs) conducted in China that investigated the effects of Sulodexide on IMN. Three RCTs published between 2013 and 2022 were included, encompassing a total of 146 patients. The primary outcomes evaluated were changes in urine total protein (UTP), serum albumin (ALB), cholesterol (CHOL), and fibrinogen (FIB) levels. Statistically significant differences were observed in the Sulodexide treatment group compared to the control group for the following parameters: reduction in UTP and CHOL, increase in ALB, and reduction in FIB levels. Sulodexide, when combined with conventional therapy, effectively reduces UTP and CHOL levels, decreases FIB levels, and increases ALB in Chinese patients with IMN.

The role of interferential current electrical stimulation in pediatric urology: A systematic review of randomized controlled trials.

In recent years, interferential current (IFC) electrical stimulation has been studied as a novel treatment for various lower urinary tract dysfunctions in children. As the findings of multiple studies may vary, we aimed to evaluate the current view on IFC in pediatric urology problems based on the findings of randomized clinical trials (RCTs). We performed a systematic search in the Embase, Medline, and SCOPUS databases in accordance with the latest Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Eligible studies comprised studies evaluating IFC for lower urinary tract problems in children. The studies' quality was assessed using the Cochrane risk of bias (RoB) tool 2. A total of 125 articles were initially obtained, among which 40 articles were duplicates. There were six eligible RCTs with an overall low RoB. All subjects underwent 10-18 sessions of treatment. The outcomes measured consisted of the alleviation of symptoms and urodynamic parameters. The trials reported that 61-90% of patients responded positively to the treatment. Both IFC and transcutaneous electrical nerve stimulation generated improvements in the subjects. However, overall the IFC group showed better immediate and short-term improvement. IFC is a promising therapy for bladder dysfunction and enuresis in children. More comparative RCTs are required in the future to quantitatively determine the superiority of IFC to other alternatives. The safety aspects of the treatment should also be studied further before it can be used in a clinical setting as the standard and protocol for children are still unclear.

Short-term efficacy and safety of biologics and Janus kinase inhibitors for patients with atopic dermatitis: A systematic review and meta-analysis

BackgroundIn recent years, biologics targeting key cytokines and Janus kinase (JAK) inhibitors have demonstrated favorable efficacy and safety outcomes for atopic dermatitis (AD) therapy. To evaluate the short-term efficacy and safety of AD therapy involving biologics, JAK inhibitors, and their combination with topical corticosteroids (TCS) for patients with AD, we conducted this systematic review and meta-analysis. Using eligible randomized clinical trials (RCTs) of 12 or 16 weeks of treatment with systemic medications and 4 weeks of topical treatment for AD. MethodsPubMed, Web of Science, ScienceDirect, and the Cochrane Library were searched from inception up to October 25, 2023. English-language randomized clinical trials (RCTs) of 12 or 16 weeks of treatment with systemic medications and 4 weeks of topical treatment for AD were included. Titles, abstracts, and articles were screened in duplicate. Of 7261 citations, 37 studies were included. The data were analyzed using Review Manager 5.4 and the outcomes were measured by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), the pruritus Numerical Rating Scale (NRS), as well as instances of adverse events (AE), and serious AE (SAE), which were presented as risk ratio (RR) with a 95 % confidence interval (CI). The efficacy of the biological therapies was analyzed with the percentage of patients who have achieved EASI 75, EASI 90, IGA 0/1 and pruritus NRS4, while the safety of treatments was evaluated in terms of the number of patients who had ≥1 AE and who had at least one SAE. ResultsA total of 37 studies with 43 cohorts that examined 9 medications and placebo and involved 18172 participants were included. Compared with the placebo, all biologics and JAK inhibitors were associated with a higher response rate in efficacy outcomes, while systematic administration was presented by dupilumab 200 mg subcutaneously every 2 weeks with superior improvement in EASI 90 (RR 9.50, 95 % CI 2.31–39.03) and IGA0/1 (RR 17.00, 95 % CI 2.33–123.78), upadacitinib 30 mg once daily in EASI 75 (RR 5.14, 95 % CI 4.20–6.31) and Pruritus NRS4 (RR 5.73, 95 % CI 4.44–7.39), and external use was presented by ruxolitinib 1.5 % twice daily orally in EASI 75 (RR 4.14, 95 % CI 3.06–5.61) and Pruritus NRS4 (RR 4.08, 95 % CI 2.86–5.81), and most of doses led to a better safety profile. Most doses of baricitinib, dupilumab, tralokinumab, and upadacitinib in combination with TCS demonstrated good efficacy as compared with the control groups (placebo + TCS). However, patients receiving baricitinib at a dosage of 2 mg daily (RR 1.23, 95 % CI 1.02–1.49) and 4 mg daily (RR 1.39, 95 % CI 1.22–1.58) in combination with TCS, exhibited a higher incidence of one or more SAE as compared with those taking placebo + TCS. ConclusionOur research has revealed that ruxolitinib and dupilumab are effective and safe treatments for mild to moderate AD and moderate to severe AD, respectively. Additionally, the combination of dupilumab and TCS demonstrates greater efficacy and safety compared to baricitinib, tralokinumab, and upadacitinib with TCS as a background treatment for moderate to severe AD. We suggest that the use of topical JAK inhibitors could be a potential alternative to TCS when used in combination with systemic medications, as a novel approach to treat AD. Insufficient different data sources caused by partial interventions were only mentioned in a few articles and low event rates in safety analyses may lead to the results being biased. Further studies directly comparing existing and novel treatments are needed and will be included in forthcoming updates of this review. Our findings could form a useful foundation for developing a new generation of treatment guidelines for AD.

Abstract 17 — Overall Infection Risks of Tofacitinib in Patient with Rheumatoid Arthritis: A Meta-Analysis of Randomized Clinical Trials

Background There is an ongoing controversy surrounding whether tofacitinib increases the risk of infections in patients with rheumatoid arthritis (RA). To address this issue, we conducted a meta-analysis using data from randomized clinical trials (RCTs) to assess the overall risk of infection in these patients. Methods We conducted a comprehensive systematic search in EMBASE, MEDLINE, and CENTRAL from their inception until December 2022 to identify relevant RCTs reporting the occurrence of infections in patients with RA who were treated with the standard clinical therapeutic dosage of tofacitinib (5mg twice daily orally). The primary outcomes of the included studies in this review focused on the incidence of total infections, serious infections, non-serious infections, and opportunistic infections (including herpes zoster and tuberculosis). Additionally, we examined secondary outcomes related to the incidence of various sites of infections, including the upper respiratory tract, lower respiratory tract, gastrointestinal tract, hepatobiliary system, urinary tract, skin and soft tissue, blood, dental and oral soft tissue, genital, reproductive tract, bone and joint, and central nervous system infections. Due to the expected anticipation of clinical and methodological heterogeneity across studies, the effect estimate was pooled with a random-effects model, to obtain the RRs and 95% CIs, using Mantel-Haenszel statistical method. Results Twelve eligible RCTs, involving a total of 6,056 patients, were included in the analysis. In comparison to the control group (placebo and other active treatments), tofacitinib exhibited a significant increase in the risk of total infections (RR, 1.21; 95% CI, 1.07-1.37; I2, 28%), serious infections (RR, 1.23; 95% CI, 1.02-1.48; I2, 0%), non-serious infections (RR, 1.20; 95% CI, 1.05-1.36; I2, 29%), and opportunistic infections (RR, 1.66; 95% CI, 1.40-1.97; I2, 0%). Secondary outcomes analyses revealed a significant increase in the risk of lower respiratory infections with tofacitinib (RR, 1.27; 95% CI, 1.10–1.47; I2, 0%). Conclusion Compared with placebo and other active treatments, tofacitinib significantly increased the overall risk of infections (total infections, serious infections, non-serious infections, and opportunistic infections). These findings can help clinicians assess the risk of infections in RA patients treated with tofacitinib.

The effect of sodium-glucose cotransporter 2 inhibitors as an adjunct to insulin in patients with type 1 diabetes assessed by continuous glucose monitoring: A systematic review and meta-analysis

AimsPatients undergoing insulin-based therapy for type 1 diabetes often experience poor glycemic control characterized by significant fluctuations. This study was undertaken to analyze the effect of sodium-glucose cotransporter 2 inhibitors (SGLT2Is), as an adjunct to insulin, on time in range (TIR) and glycemic variability in patients with type 1 diabetes, using continuous glucose monitoring (CGM). In addition, we examined which type of SGLT2I yielded a superior effect compared to others. MethodsWe conducted a comprehensive search of PubMed, EMBASE, the Cochrane Library, Web of Science, and clinical trial registry websites, retrieving all eligible randomized clinical trials (RCTs) published up until February 2023. We analyzed the mean TIR, mean amplitude of glucose excursions (MAGE), mean daily glucose (MDG), diabetic ketoacidosis (DKA), standard deviation (SD), total insulin dose, and severe hypoglycemia to evaluate the efficacy and safety of SGLT2Is. A random-effects model was also employed. ResultsThis study encompassed 15 RCTs. The meta-analysis revealed that the use of SGLT2Is as an adjuvant therapy to insulin led to a significant increase in TIR (MD = 10.78, 95%CI = 9.33–12.23, I2 = 42 %, P < 0.00001) and a decrease in SD (MD = −0.38, 95%CI = −0.50 to −0.26, I2 = 0 %, P < 0.00001), MAGE (MD = −0.92, 95%CI = −1.17 to −0.67, I2 = 19 %, P < 0.00001), MDG(MD = −1.01, 95%CI = −1.32 to −0.70, I2 = 48 %, P < 0.00001), and total insulin dose (MD = −5.81, 95%CI = −7.81 to −3.82, I2 = 32 %, P < 0.00001). No significant increase was observed in the rate of severe hypoglycemia (RR = 1.04, 95 % CI = 0.76–1.43, P = 0.80). However, SGLT2I therapy was associated with increased DKA occurrence (RR = 2.79, 95 % CI = 1.42–5.48; P = 0.003, I2 = 16 %). In addition, the subgroup analyses based on the type of SGLT2Is revealed that dapagliflozin might exhibit greater efficacy compared to other SGLT2Is across most outcomes. ConclusionsSGLT2Is exhibited a positive effect on improving blood glucose level fluctuations. Subgroup analysis showed that dapagliflozin appeared to have more advantages. However, giving due consideration to preventing adverse effects, particularly DKA, is paramount. RegistrationProspero CRD42023408276.

Intrauterine instillation of human chorionic gonadotropin at the time of blastocyst transfer: Systematic review and meta-analysis

Intrauterine instillation (IU) of Human Chorionic Gonadotropin (hCG) before embryo transfer (ET) has been proposed to enhance implantation success rates. This is the first meta-analysis to evaluate the effect at the blastocyst-stage. A systematic literature search was performed using Medline, Embase, Cochrane Library and Google. Randomized clinical trials (RCTs) were included. The primary outcome combined live birth rate (LBR) and ongoing pregnancy rate (OPR). The secondary outcomes were clinical pregnancy rate (CPR), implantation rate (IR) and miscarriage rate (MR). 93 citations were identified, of which there were seven eligible RCTs. 2499 participants were included in the meta-analysis; 1331 were assigned to an experimental group and 1168 were assigned to the control group. The overall effect of IU hCG instillation on LBR and OPR was not significant: risk ratio (RR) 1.00 (95% CI, 0.90–1.12). Analysis of secondary outcomes found the effect of IU hCG instillation was not significant. Analysis of the data suggests that the studies conducted have too much heterogeneity to identify whether a specific cohort may have a significant benefit. The findings of this meta-analysis demonstrate that there is insufficient evidence at present to support the use of IU hCG instillation prior to blastocyst-stage ET.

Cholinesterase Inhibitors for Treatment of Psychotic Symptoms in Alzheimer Disease and Parkinson Disease

Psychotic symptoms greatly increase the burden of disease for people with neurodegenerative disorders and their caregivers. Cholinesterase inhibitors (ChEIs) may be effective treatment for psychotic symptoms in these disorders. Previous trials only evaluated neuropsychiatric symptoms as a secondary and an overall outcome, potentially blurring the outcomes noted with ChEI use specifically for psychotic symptoms. To quantitatively assess the use of ChEIs for treatment of individual neuropsychiatric symptoms, specifically hallucinations and delusions, in patients with Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB). A systematic search was performed in PubMed (MEDLINE), Embase, and PsychInfo, without year restrictions. Additional eligible studies were retrieved from reference lists. The final search cutoff date was April 21, 2022. Studies were selected if they presented the results of placebo-controlled randomized clinical trials, including at least 1 donepezil, rivastigmine, or galantamine treatment arm in patients with AD, PD, or DLB; if they applied at least 1 neuropsychiatric measure including hallucinations and/or delusions; and if a full-text version of the study was available in the English language. Study selection was performed and checked by multiple reviewers. Original research data were requested on eligible studies. A 2-stage meta-analysis was then performed, using random-effects models. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed for extracting data and assessing the data quality and validity. Data extraction was checked by a second reviewer. Primary outcomes were hallucinations and delusions; secondary outcomes included all other individual neuropsychiatric subdomains as well as the total neuropsychiatric score. In total, 34 eligible randomized clinical trials were selected. Individual participant data on 6649 individuals (3830 [62.6%] women; mean [SD] age, 75.0 [8.2] years) were obtained from 17 trials (AD: n = 12; PD: n = 5; individual participant data were not available for DLB). An association with ChEI treatment was shown in the AD subgroup for delusions (-0.08; 95% CI, -0.14 to -0.03; P = .006) and hallucinations (-0.09; 95% CI, -0.14 to -0.04; P = .003) and in the PD subgroup for delusions (-0.14; 95% CI, -0.26 to -0.01; P = .04) and hallucinations (-0.08, 95% CI -0.13 to -0.03; P = .01). The results of this individual participant data meta-analysis suggest that ChEI treatment improves psychotic symptoms in patients with AD and PD with small effect sizes.

Carvedilol Versus Other Nonselective Beta Blockers for Variceal Bleeding Prophylaxis and Death: A Network Meta-analysis.

We aimed to perform a network meta-analysis (NWM) to examine comparative effectiveness of non-selective beta blockers (NSBBs) on prophylaxis of gastroesophageal variceal bleeding (GVB) and mortality benefit. MEDLINE (OVID) and EMBASE databases were searched for eligible randomized clinical trials (RCTs) from inception to July 3, 2021. Outcomes of interest included primary/secondary prophylaxis of GVB, failure to achieve hepatic venous pressure gradient (HVPG) decremental response, liver-related and all-cause mortality. A Bayesian NWM was performed to derive relative risk (RR) with 95% credible intervals (CrIs). The ranking probability of each NSBB was assessed by surface under cumulative ranking curve (SUCRA). Thirty-three RCTs including 3,188 cirrhosis patients with gastroesophageal varices were included. Compared with placebo, nadolol ranked first for reducing variceal bleeding [RR:0.25, (95% CrI:0.11-0.51); SUCRA:0.898], followed by carvedilol [RR:0.33, (95% CrI: 0.11-0.88); SUCRA:0.692] and propranolol [RR:0.52, (95% CrI:0.37-0.75); SUCRA:0.405]. Carvedilol was more effective than propranolol in achieving HVPG decremental response [RR:0.43, (95% CrI: 0.26-0.69)]. Carvedilol ranked first for reducing all-cause mortality [RR: 0.32, (95% CrI:0.17-0.57); SUCRA:0.963), followed by nadolol [RR:0.48, (95% CI:0.29-0.77); SUCRA:0.688], and propranolol [RR:0.77, (95% CI:0.58-1.02); SUCRA: 0.337]. Similar findings were observed for liver-related mortality. Carvedilol ranked the safest. The RR of adverse events was 4.38, (95% CrI:0.33-161.4); SUCRA:0.530, followed by propranolol [RR: 7.54, (95% CrI:1.90-47.89); SUCRA:0.360], and nadolol [RR: 18.24, (95% CrI:91.51-390.90); SUCRA:0.158]. Carvedilol is the preferred NSBB with better survival benefit and lower occurrence of adverse events among patients with gastroesophageal varices.

Oral small-molecule tyrosine kinase 2 and phosphodiesterase 4 inhibitors in plaque psoriasis: a network meta-analysis.

Orally administered small-molecule drugs including tyrosine kinase 2 (TYK2) inhibitors and phosphodiesterase 4 (PDE4) inhibitors are new candidates for systemic therapy in plaque psoriasis. However, no previous articles evaluated the benefit and risk profile of TYK2 and PDE4 inhibitors in psoriasis. The objective of this study was to compare the efficacy and safety of oral small-molecule drugs, including TYK2 and PDE4 inhibitors, in treating moderate-to-severe plaque psoriasis. PubMed, Embase, and Cochrane library were searched for eligible randomized clinical trials (RCTs). Response rates for a 75% reduction from baseline in Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment score of 0 or 1 (PGA 0/1) were used for efficacy assessment. Safety was evaluated with the incidence of adverse events (AEs). A Bayesian multiple treatment network meta-analysis (NMA) was performed. In total, 13 RCTs (five for TYK2 inhibitors and eight for PDE4 inhibitors) involving 5274 patients were included. The study found that deucravacitinib at any dose (except for 3 mg QOD), ropsacitinib (200 and 400 mg QD), and apremilast (20 and 30 mg BID) had higher PASI and PGA response rates than placebo. In addition, deucravacitinib (3 mg BID, 6 mg QD, 6 mg BID, and 12 mg QD), and ropsacitinib (400 mg QD) showed superior efficacy than apremilast (30 mg BID). In terms of safety, deucravacitinib or ropsacitinib at any dose did not lead to a higher incidence of AEs than apremilast (30 mg BID). The ranking analysis of efficacy revealed that deucravacitinib 12 mg QD and deucravacitinib 3 mg BID had the highest chance of being the most effective oral treatment, followed by deucravacitinib 6 mg BID and ropsacitinib 400 mg QD. Oral TYK2 inhibitors demonstrated satisfactory performance in treating psoriasis, surpassing apremilast at certain doses. More large-scale, long-term studies focusing on novel TYK2 inhibitors are needed. PROSPERO (ID: CRD42022384859), available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022384859, identifier CRD42022384859.

JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications

ObjectivesTo estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate.MethodsSystematic searches of databases were performed,...

Efficacy of pulmonary artery pressure monitoring in patients with chronic heart failure: a meta-analysis of three randomized controlled trials.

Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for heart failure (HF). We have conducted a meta-analysis of large randomized trials investigating this question. A systematic literature search was performed for randomized clinical trials with PA pressure monitoring devices in patients with HF. The primary outcome of interest was the total number of HF hospitalizations. Other outcomes assessed were urgent visits leading to treatment with intravenous diuretics, all-cause mortality, and composites. Treatment effects are expressed as hazard ratios, and pooled effect estimates were obtained applying random effects meta-analyses. Three eligible randomized clinical trials were identified that included 1898 outpatients in New York Heart Association functional classes II-IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. The mean follow-up was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%. Compared to patients in the control group, the hazard ratio (95% confidence interval) for total HF hospitalizations in those randomized to PA pressure monitoring was 0.70 (0.58-0.86) (P = .0005). The corresponding hazard ratio for the composite of total HF hospitalizations, urgent visits and all-cause mortality was 0.75 (0.61-0.91; P = .0037) and for all-cause mortality 0.92 (0.73-1.16). Subgroup analyses, including ejection fraction phenotype, revealed no evidence of heterogeneity in the treatment effect. The use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations.

PO-02-066 ABLATION STRATEGIES FOR PATIENTS WITH NON-PAROXYSMAL ATRIAL FIBRILLATION- NETWORK META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS

Pulmonary vein isolation (PVI) is the preferred ablation strategy for patients with paroxysmal atrial fibrillation (AF). However, for patients with non-paroxysmal AF (NPAF), there is no consensus on the most efficient ablation strategy (AS). We aimed to compare the efficacy and safety of different ablation strategies for patients with non-paroxysmal Atrial Fibrillation . We performed a comprehensive systematic search using four large databases to include randomized clinical trials (RCT) evaluating different AS in patients with NPAF. We excluded studies with <100 participants. We defined the efficacy endpoint as a recurrence of atrial tachyarrhythmia (AT) >30 seconds after catheter ablation during a minimum follow-up time of 6 months (or the longest reported). We estimated log risk ratios (log RRs) using random effects network meta-analysis (NMA). Surface under the cumulative ranking curve (SUCRA) was used to rank CA strategies (higher rank suggesting higher efficacy). Safety endpoint was defined as a occurence of one of the above: femoral vascular access complication, pericarditis, stroke/transitory ischemic attack/arterial embolism, pulmonary vein stenosis, cardiac tamponade/hemopericardium/effusion, atrioesophageal fistula, septicemia, internal bleeding, phrenic nerve palsy, and death. We included data from 32 eligible RCTs, with a total of 6950 participants, mean age 59.4±8.2 and 69.3% male, randomized to 15 different AS arms in our NMA (Figure 1a). PVI isolation with concomitant posterior wall isolation (PWI) was associated with reduced incidence of AT (log RR 0.67( 0.47; 0.96) compared to PVI alone. Otherwise, there was no significant difference in the rate of AT recurrence. The top 3 rankings based on SUCRA were hybrid ablation, PVI with ethanol ablation, followed by PVI with PWI. There was a low prevalence of safety outcome- 281 (4.1%), driven predominantly by access complications - 243 (86%).There were no differences in safety endpoint between compared strategies. Our analysis suggests PVI with PWI is linked to decreased AT recurrence compared to PVI. Hybrid ablation represents an attractive treatment option to study in patients with non-paroxysmal atrial fibrillation. Compared strategies were safe without apparent difference in incidency of safety endpoints.