Meta-Analysis of Randomized Controlled Trials of Pharmacologic Agents in Non-alcoholic Steatohepatitis

BackgroundCurrently, there is no standardized treatment regimen for non-alcoholic steatohepatitis.AimWe performed a meta-analysis of high quality randomized controlled trials that evaluated treatment response to metformin, thiazolidinediones (TZDs), and vitamin E in adult patients with non-alcoholic steatohepatitis. Outcome measures were improvement in liver histology, biochemical, and anthropometric measures.Material and methodsNine trials met inclusion criteria (3 with TZD, 3 with Metformin, 2 with Vitamin E and 1 with both TZD and Vitamin E.).ResultsWith metformin, weighted liver histologic scores for steatosis, ballooning, and fibrosis did not demonstrate significant improvement and lobular inflammation worsened significantly (weighted mean increase 0.21, 95% CI 0.11 to 0.31, P < 0.0001). The liver histology score including steatosis (OR 3.51, 95% CI 2.14 to 5.78) and lobular inflammation (OR 2.65, 95% CI 1.69 to 4.15) improved with TZDs. Hepatic fibrosis (OR 1.58, 95% CI 0.98 to 2.54) and ballooning scores (OR 1.84, 95% CI 0.94 to 3.58) did not demonstrate significant improvement. With Vitamin E, weighted liver histologic scores for steatosis (weighted mean decrease -0.60, 95% CI -0.85 to -0.35, P < 0.0001), lobular inflammation (weighted mean decrease -0.40, 95% CI -0.61 to -0.20, P = 0.0001) and ballooning (weighted mean decrease -0.30, 95% CI -0.54 to -0.07, P = 0.01) demonstrated significant improvement compared to placebo. Fibrosis did not significantly change.ConclusionIn patients with NASH, TZDs and Vitamin E improve liver histologic scores but metformin does not. Insulin resistance also improves with both TZDs and metformin. Fibrosis does not improve with any of the agents.     

Multivessel Versus Culprit-Only Revascularization in STEMI and Multivessel Coronary Artery Disease: Meta-Analysis of Randomized Trials

ObjectivesThe goal of this systematic review and meta-analysis was to provide a comprehensive evaluation of contemporary randomized trials addressing the efficacy and safety of multivessel versus culprit vessel–only percutaneous coronary intervention (PCI) among patients presenting with ST-segment elevation myocardial infarction and multivessel coronary artery disease.BackgroundMultivessel coronary artery disease is present in about one-half of patients with ST-segment elevation myocardial infarction. Randomized controlled trials comparing multivessel and culprit vessel–only PCI produced conflicting results regarding the benefits of a multivessel PCI strategy.MethodsA comprehensive search for published randomized controlled trials comparing multivessel PCI with culprit vessel–only PCI was conducted on ClinicalTrials.gov, PubMed, Web of Science, EBSCO Services, the Cochrane Central Register of Controlled Trials, Google Scholar, and scientific conference sessions from inception to September 15, 2019. A meta-analysis was performed using a random-effects model to calculate the risk ratio (RR) and 95% confidence interval (CI). Primary efficacy outcomes were all-cause mortality and reinfarction.ResultsTen randomized controlled trials were included, representing 7,030 patients: 3,426 underwent multivessel PCI and 3,604 received culprit vessel–only PCI. Compared with culprit vessel–only PCI, multivessel PCI was associated with no significant difference in all-cause mortality (RR: 0.85; 95% CI: 0.68 to 1.05) and lower risk for reinfarction (RR: 0.69; 95% CI: 0.50 to 0.95), cardiovascular mortality (RR: 0.71; 95% CI: 0.50 to 1.00), and repeat revascularization (RR: 0.34; 95% CI: 0.25 to 0.44). Major bleeding (RR: 0.92; 95% CI: 0.50 to 1.67), stroke (RR: 1.15; 95% CI: 0.65 to 2.01), and contrast-induced nephropathy (RR: 1.25; 95% CI: 0.80 to 1.95) were not significantly different between the 2 groups.ConclusionsMultivessel PCI was associated with a lower risk for reinfarction, without any difference in all-cause mortality, compared with culprit vessel–only PCI in patients with ST-segment elevation myocardial infarction.     

Drug-Eluting Versus Bare-Metal Stents in Older Patients: A Meta-Analysis of Randomized Controlled Trials

BackgroundDespite the high prevalence of ischemic heart disease in older patients, there is a substantial lack of evidence to guide clinical decision-making in this population. Hence, we performed a meta-analysis to determine the safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus bare-metal stents (BMS).MethodsElectronic databases were searched for randomized trials comparing DES with BMS in patients ≥70 years-old. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes included different ischemic and bleeding events. Subgroup analyses for dual-antiplatelet therapy (DAPT) duration were conducted.ResultsWe included 7 trials with a total of 5449 patients. The use of DES compared with BMS was associated with a significant reduction in MACE (odds ratio [OR]:0.76; 95% confidence interval [CI]:0.62–0.93; P = 0.007) with no increased risk of bleeding events (OR: 1.07; 95% CI: 0.89–1.27; P = 0.48). However, longer duration of DAPT (>6 months) for the DES group increased bleeding events (OR: 1.52; 95% CI: 1.05–2.20; P = 0.03). In contrast, shorter DAPT showed persistent efficacy in reducing MACE in DES-treated patients with no increased bleeding events (OR: 0.72; 95% CI: 0.60–0.87; P < 0.01 and OR: 1.01; 95% CI: 0.84–1.22; P = 0.89, respectively).ConclusionsIn older patients who had undergone PCI, DES showed superior efficacy in reducing MACE with no increased risk of bleeding compared with BMS. Persistent MACE reduction was evident with shorter DAPT durations in DES-treated patients.SummaryThis meta-analysis of randomized clinical trials demonstrated that drug-eluting stents were associated with a significant reduction in major adverse cardiovascular events with no increased risk of bleeding compared with bare-metal stents. The risk of bleeding was high with longer dual antiplatelet therapy duration for patients who underwent DES placement. However, short duration of dual antiplatelet therapy substantially reduced major adverse cardiovascular events with no increased bleeding risk.     

Single Versus Dual Antiplatelet Therapy After Transcatheter Aortic Valve Replacement: A Meta-Analysis of Randomized Clinical Trials

BackgroundGuidelines recommend dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) but guidelines predate the publication of the largest randomized trial. There have been few trials in the field to date, and with a small number of total patients; pooling their results may therefore be helpful.MethodsWe systematically identified all randomized trials comparing SAPT to DAPT after TAVR. The primary endpoint was the risk of major bleeding. Secondary endpoints included all bleeding, life-threatening bleeding, stroke, myocardial infarction, death and cardiac death.ResultsFour trials, randomizing 1086 participants, were eligible (541 randomized to SAPT and 545 randomized to DAPT). The weighted mean follow-up was 9.1 months. The risk of major bleeding was significantly increased after DAPT (relative risk (RR) 2.36, 95% confidence interval (CI) 1.27 to 4.40, P = 0.007). There was a similar increased risk for all bleeding (RR 1.65, 95% CI 1.24 to 2.19, P < 0.001), although not for life-threatening bleeding (RR 1.44, 95% CI 0.74 to 2.77, P = 0.282). There were no significant differences in the risk of stroke, myocardial infarction (MI), death or cardiac death. There was no heterogeneity observed for any endpoint (I² = 0.0%).ConclusionsDAPT after TAVR is associated with an increased risk of major bleeding and all bleeding. There is no evidence of a significant difference between DAPT or SAPT for the risks of stroke, MI, death or cardiac death. However, the total number of patients randomized is small and the duration of follow-up is short. Larger scale randomized trials with longer follow-up are required to assess for any potential differences in ischemic endpoints or mortality.     

Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials

Background and objectives

People with CKD stages 3–5 and on dialysis (5D) have dramatically increased mortality, which has been associated with hyperphosphatemia in many studies. Oral phosphate binders are commonly prescribed to lower serum phosphate. We conducted an updated meta-analysis of the noncalcium–based binder (non-CBB) sevelamer versus CBBs in CKD stages 3–5D.

Design, setting, participants, & measurements

Randomized, controlled trials comparing sevelamer with CBBs were identified through MEDLINE and the Cochrane Central Register of Controlled Trials. Patient-level outcomes included all-cause mortality, cardiovascular events and mortality, hospitalization, and adverse effects. Intermediate outcomes included vascular calcification and bone changes. Biochemical outcomes included serum phosphate, calcium, parathyroid hormone, lipids, and hypercalcemia. We conducted and reported this review according to Cochrane guidelines.

Results

We included 25 studies to March 31, 2015 with 4770 participants (88% on hemodialysis). Patients receiving sevelamer had lower all–cause mortality (risk ratio [RR], 0.54; 95% confidence interval [95% CI], 0.32 to 0.93), no statistically significant difference in cardiovascular mortality (n=2712; RR, 0.33; 95% CI, 0.07 to 1.64), and an increase in combined gastrointestinal events of borderline statistical significance (n=384; RR, 1.42; 95% CI, 0.97 to 2.08). For biochemical outcomes, patients receiving sevelamer had lower total serum cholesterol (mean difference [MD], −20.2 mg/dl; 95% CI, −25.9 to −14.5 mg/dl), LDL-cholesterol (MD, −21.6 mg/dl; 95% CI, −27.9 to −15.4 mg/dl), and calcium (MD, −0.4 mg/dl; 95% CI, −0.6 to −0.2 mg/dl) and a reduced risk of hypercalcemia (RR, 0.30; 95% CI, 0.19 to 0.48). End of treatment intact parathyroid hormone was significantly higher for sevelamer (MD, 32.9 pg/ml; 95% CI, 0.1 to 65.7 pg/ml). Serum phosphate values showed no significant differences.

Conclusions

Patients with CKD stages 3–5D using sevelamer have lower all–cause mortality compared with those using CBBs. Because of a lack of placebo-controlled studies, questions remain regarding phosphate binder benefits for patients with CKD stages 3–5 and not on dialysis.     

Interventions for Treating Displaced Midshaft Clavicular Fractures: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Displaced midshaft clavicle fractures are frequent injuries. There are 3 treatment methods including conservative treatment, plate fixation, and intramedullary pin fixation. However, which is the best treatment remains a topic of debate.To establish the optimum treatment for displaced midshaft clavicular fractures, we did a network meta-analysis to compare 3 treatments in terms of postoperative nonunion and infection.We searched PubMed, the Cochrane Library, and Embase for relevant randomized controlled trials (RCTs) until the end of October 2014. Two investigators independently reviewed the abstract and full text of eligible studies and extracted information. We used WinBUGS 1.4 (Imperial College School of Medicine at St Mary''s, London) to perform our Bayesian network meta-analysis. We used the graphical tools in STATA12 (StataCorp, Texas) to present the results of statistical analyses of WinBUGS14. Nonunion and infection were presented as odd ratios (ORs) with 95% confidence intervals (CIs). We also presented the results using surface under the cumulative ranking curve (SUCRA). A higher SUCRA value suggests better results for respective treatment method.Thirteen RCTs were included in our network meta-analysis, with a total of 894 patients randomized to receive 1 of 3 treatments. Nonunion rates were 0.9%, 2.4%, and 11.4% for intramedullary pin fixation, plate fixation, and conservative method, respectively. Nonunion occurred more commonly in patients treated with conservative method than in patients treated with either plate fixation (OR, 0.18; 95% CI, 0.05–0.46) or intramedullary pin fixation (OR, 0.12; 95% CI, 0.01–0.50). There was no significant difference between plate and intramedullary pin fixation in nonunion (OR, 3.64; 95% CI, 0.31–17.27). Furthermore, SUCRA probabilities were 87.8%, 62.0%, and 0.2% for intramedullary pin fixation, plate fixation, and conservative method, respectively. Infection rates were 3.6% and 3.9% for intramedullary pin fixation and plate fixation, respectively. There was no significant difference between plate and intramedullary pin fixation in infection (OR, 3.64; 95% CI, 0.31–17.27). SUCRA probabilities were 46.5% and 8.5% for intramedullary pin and plate fixation, respectively.Our network meta-analysis suggested that intramedullary pin fixation is the optimum treatment method for displaced midshaft clavicle fracture because of the low probabilities of nonunion and infection.     

Placebo Rates in Randomized Controlled Trials of Pouchitis Therapy

Background

Approximately half of the patients with ulcerative colitis (UC) who undergo restorative proctocolectomy develop pouchitis within 10 years of surgery. Currently, there are no approved pouchitis treatments. It is important to quantify, and ultimately minimize, placebo rates to design and conduct efficient pouchitis trials.

Aims

To quantify the placebo rate observed in pouchitis randomized controlled trials (RCTs) in meta-analysis.

Methods

Embase, MEDLINE, and the Cochrane Library were searched from inception to November 3, 2017, for placebo-controlled RCTs enrolling adult UC patients with, or at risk for developing, pouchitis. A fixed-effect binomial-normal model was used to pool placebo rates on the log-odds (logit) scale. Proportions and 95% confidence intervals were reported. Outcomes of interest included development of pouchitis, induction of remission/response, and maintenance of remission/response. The Cochrane risk of bias tool was used to evaluate study quality.

Results

Twelve trials (five prevention, five induction, and two maintenance) enrolling a total of 229 placebo patients were eligible for inclusion. The pooled placebo rates for development of pouchitis and induction of response were 47% (95% CI 39–56%) and 24% (95% CI 14–37%), respectively. An insufficient number of trials prevented additional data pooling and meta-regression analysis and no consistent definitions of outcome were identified.

Conclusions

No consistent methods for measuring pouchitis disease activity or defining response and remission were identified, highlighting the need for standardized definitions of outcomes for use in pouchitis trials. Additional high-quality trials are required to evaluate existing and novel therapies in this area.

     

Meta-Analysis of Randomized and Controlled Treatment Trials for Achalasia

Pharmacological therapy, botulinum toxin injection, pneumatic dilatation, and surgical myotomy are the primary therapeutic modalities for achalasia, for which laparoscopic myotomy is recommended as state-of-the-art therapy. However, its efficacy and safety remain unclear compared with other approaches in the treatment of achalasia. We searched electronic databases (MEDLINE, EMBASE, Cochrane Central Registry of Controlled Trials, LILACS-Latin American, Caribbean health science literature, and Science Citation Index Expanded) for randomized controlled trials to evaluate which therapeutic measures are temporary and reversible and which measures are definitive and effective by pooling data including remission rate, relapse rate, complications, and adverse effects. Seventeen studies with 761 patients met our inclusion criteria. There was better remission rate in pneumatic dilation than in botulinum toxin injection for initial intervention [relative risk (RR) 2.20, 95% confidence interval (CI) 1.51–3.20], Pneumatic dilation had lower relapse rate than did botulinum toxin injection (RR 0.12, 95% CI 0.04–0.32). Compared with pneumatic dilation, laparoscopic myotomy further increased remission rate (RR 1.48, 95% CI 1.48–1.87), and reduced clinical relapse rate (RR 0.14, 95% CI 0.04–0.58), and there was no difference in complication rate (RR 1.48, 95% CI 0.37–5.99). Based on limited randomized and controlled trials, laparoscopic myotomy is the preferred method for patients with achalasia. Future trials should investigate whether laparoscopic myotomy combined with different modalities of fundoplication is superior to isolated laparoscopic myotomy.     

Intravenous Versus Oral Iron for the Treatment of Anemia in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD). Our aim was to evaluate the comparative efficacy and harm of intravenous (IV) versus oral iron supplementation for correcting anemia in adult IBD patients.We conducted a systematic review and meta-analysis to integrate evidence from randomized controlled trials having enrolled adults with IBD, and comparing IV versus oral iron (head-to-head) for correcting iron-deficiency anemia. Medline, Embase, Scopus, and the Web of Science database were searched through July 2015. The Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform, the ClinicalTrials.gov, and international conference proceedings were also investigated. Two reviewers independently abstracted study data and outcomes, and rated each trial''s risk-of-bias. Pooled odds ratio (OR) estimates with their 95% CIs were calculated using fixed- and random-effects models.Five eligible studies, including 694 IBD patients, were identified. In meta-analysis, IV iron demonstrated a higher efficacy in achieving a hemoglobin rise of ≥2.0 g/dL as compared to oral iron (OR: 1.57, 95% CI: 1.13, 2.18). Treatment discontinuation rates, due to adverse events or intolerance, were lower in the IV iron groups (OR: 0.27, 95% CI: 0.13, 0.59). Similarly, the occurrence of gastrointestinal adverse events was consistently lower in the IV iron groups. On the contrary, serious adverse events (SAEs) were more frequently reported among patients receiving IV iron preparations (OR: 4.57, 95% CI: 1.11, 18.8); however, the majority of the reported SAEs were judged as unrelated or unlikely to be related to the study medication. We found no evidence of publication bias, or between-study heterogeneity, across all analyses. Risk of bias was high across primary studies, because patients and personnel were not blinded to the intervention.IV iron appears to be more effective and better tolerated than oral iron for the treatment of IBD-associated anemia.     

Off-Pump Coronary Artery Bypass Surgery and Acute Kidney Injury: A Meta-Analysis of Randomized Controlled Trials

Background and objectives: Off-pump coronary artery bypass grafting (CABG) has been advocated to cause less inflammation, morbidity, and mortality than the more traditional on-pump technique. This meta-analysis compares these two surgical techniques with respect to causing acute kidney injury (AKI).Design, setting, participants, & measurements: This study searched for randomized controlled trials in MEDLINE and abstracts from the proceedings of scientific meetings through February 2010. Included were trials comparing off-pump to on-pump CABG that reported the incidence of AKI, as defined by a mixture of criteria including biochemical parameter/urine output/dialysis requirement. Mortality was evaluated among the studies that reported kidney-related outcomes. For primary and subgroup analyses, fixed-effect meta-analyses of odds ratios (OR) were performed.Results: In 22 identified trials (4819 patients), the weighted incidence of AKI in the on-pump CABG group was 4.0% (95% confidence interval [CI] 1.8%, 8.5%), dialysis requirement 2.4% (95% CI 1.6%, 3.7%), and mortality 2.6% (95% CI 1.6%, 4.0%). By meta-analysis, off-pump CABG was associated with a 40% lower odds of postoperative AKI (OR 0.60; 95% CI 0.43, 0.84; P = 0.003) and a nonsignificant 33% lower odds for dialysis requirement (OR 0.67; 95% CI 0.40, 1.12; P = 0.12). Within the selected trials, off-pump CABG was not associated with a significant decrease in mortality.Conclusions: Off-pump CABG may be associated with a lower incidence of postoperative AKI but may not affect dialysis requirement, a serious complication of cardiac surgery. However, the different definitions of AKI used in individual trials and methodological concerns preclude definitive conclusions.First introduced in the 1960s (1–3), coronary artery bypass grafting (CABG) remains the standard of care for symptomatic patients with three-vessel or left main coronary artery disease (4,5). For the past 30 years, CABG has been performed primarily with the use of an extracorporeal cardiopulmonary bypass (CPB) machine (on-pump) requiring cannulation of the heart and aorta, crossclamping of the ascending aorta, and the induction of cardioplegic arrest. However, in the 1990s, interest emerged in performing off-pump CABG (6,7) with the hope of reducing postoperative complications associated with the use of CPB, including the generalized systemic inflammatory response (8) and acute organ dysfunction such as cerebral dysfunction (9), myocardial depression (10), and prolonged mechanical ventilation (11).Acute kidney injury (AKI) is a serious complication of on-pump CABG, ranging from small postoperative increases in serum creatinine observed in 5% to 20% of patients (12,13) to severe forms requiring dialysis developing in 1% of patients (14,15). Whether defined by various serum creatinine increments or dialysis requirement, AKI has been linked to excessive in-hospital morbidity and mortality (12,14) and increased resource consumption (16,17). With an estimated 176,000 cardiac bypass procedures performed in 2007 (18), preventing AKI postoperatively is an important goal.Previously published studies comparing the effect of off-pump versus on-pump CABG on kidney end points have yielded conflicting results. Although six meta-analyses have examined this question, results were inconclusive (19,20) or the data synthesis included studies of various designs with a mixture of randomized controlled trials (RCTs) and observational studies (21–24). To shed further light on this question, we conducted a comprehensive meta-analysis restricted to all RCTs published to date, comparing the effect of off-pump versus on-pump CABG on development of AKI including dialysis requirement.