Analysis of Randomized Controlled Trials on Hepatopancreatic Surgery

The randomized controlled trial (RCT) is an important research method, providing the highest evidence and playing a pivotal role in the performance of evidence-based medicine. However, RCTs on hepatopancreatic surgery have been performed less frequently than RCTs in other fields. Therefore, this review analyzes the characteristics of RCTs on hepatic and pancreatic surgery to propose a breakthrough. We retrieved studies performed via a MEDLINE search to identify prospective RCTs on hepatopancreatic surgery in the last decade. Eligible RCTs were analyzed using the following items: study design, publication year, geographical area, sample size, multicenter study, and impact factor. Studies comparing surgical technique or methods have composed the majority of the RCTs involving hepatectomy and pancreatectomy. About half of the RCTs on hepatectomy have been performed in East Asia, whereas most of the RCTs on pancreatectomy were undertaken in Western countries. The average sample number of RCT on hepatectomy is significantly smaller than those in other fields. Moreover, multicenter studies are less frequently performed on hepatectomy compared with pancreatectomy. Promoting the organization of multicenter studies would be the best way to increase the number and sample size of RCTs on hepatectomy. Adequate RCTs observing the Consolidated Standards of Reporting Trials statements are necessary to obtain reliable evidence.     

我国上消化道出血防治性研究随机对照实验的现状分析

目的：评价我国医学文献中上消化道出血防治性研究随机对照实验的质量，了解其能否为临床实践提供可靠的决策依据。方法：对我国可能刊登上述随机对照实验（RCT）的5种消化病学期刊进行人工检索，并根据国际循证医学标准对其中的RCT报道进行分析。结果：查阅杂志544期，共含论著23781篇，检出RCT报告46篇，并从研究对象的选择，样本含量，随机方法，组间可比性，实验措施，对照措施，盲目法，疗效评价指标，干预措施临床效果，随访及失访问题等几个方面进行分析。结论：我国目前上消化道出血防治性研究RCT数量，尚不能满足临床实践的需要。     

Nesiritide in Acute Decompensated Heart Failure: A Pooled Analysis of Randomized Controlled Trials

Background

Previous randomized controlled trials (RCTs) evaluating nesiritide for the treatment of acute decompensated heart failure (ADHF) have reported wide variances in mortality hazard ratios for nesiritide vs controls, but these individual trials were neither designed nor powered to evaluate mortality. This study used relevant data from all RCTs of nesiritide in ADHF completed as of June 2006 to independently estimate the effect of nesiritide on 30‐ and 180‐day mortality.

Hypothesis

Administration of nesiritide to treat patients with ADHF does not significantly increase mortality at 30 or 180 days.

Methods

Six trials met prespecified criteria for inclusion in this analysis. Primary data from these trials were obtained from Scios Inc. (Fremont, CA). Statistical models were fitted to estimate 4 effects: dose response, differing control groups, vulnerable subgroup interactions, and time of death relative to nesiritide administration. All models included 4 baseline covariates that were significantly and independently associated with mortality.

Results

Complete covariate data were available in 1472 of 1538 subjects (96%). The risk‐adjusted hazard ratio for mortality was 1.05 (95% confidence interval [CI]: 0.85–1.30) at 30 and 1.00 (95% CI: 0.88–1.14) at 180 days with no clear relationship to nesiritide dose. In addition to consistent results across 2 time points, no significant evidence of sensitivity to control group or baseline risk factors was found.

Conclusions

Currently available data suggest nesiritide does not significantly increase mortality at 30 or 180 days. Copyright © 2010 Wiley Periodicals, Inc. Dr. Abraham has received research grant funding and honoraria from and has served as a consultant for Scios Inc. Dr Trupp has been a member of Speakers Bureau for Scios Inc. Scios Inc. provided an unrestricted grant for Dr. Jarjoura's and Keding Hua's time in performing these statistical analyses. Neither Dr. Jarjoura nor Mr. Hua has any other relationship with the sponsor. Maureen O'Sullivan provided editorial support with funding from Ortho‐McNeil Janssen Scientific Affairs. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

     

Tocilizumab in Hospitalized Patients with COVID-19: A Meta Analysis of Randomized Controlled Trials

Lung - To date, only dexamethasone has been shown to reduce mortality in coronavirus disease-19 (COVID-19) patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized...     

From Randomized Controlled Trials to Observational Studies

Randomized controlled trials are considered the gold standard in the hierarchy of research designs for evaluating the efficacy and safety of a treatment intervention. However, their results can have limited applicability to patients in clinical settings. Observational studies using large health care databases can complement findings from randomized controlled trials by assessing treatment effectiveness in patients encountered in day-to-day clinical practice. Results from these designs can expand upon outcomes of randomized controlled trials because of the use of larger and more diverse patient populations with common comorbidities and longer follow-up periods. Furthermore, well-designed observational studies can identify clinically important differences among therapeutic options and provide data on long-term drug effectiveness and safety.     

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.

     

Inconsistent Outcome Reporting in Heart Failure Randomized Controlled Trials

BackgroundRandomized controlled trials (RCTs) may report outcomes different from those prespecified on trial-registration websites, protocols and statistical analysis plans (SAPs). This study sought to investigate the prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified.Methods and ResultsMEDLINE via PubMed was searched to include phase II–IV HF RCTs in 9 high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with prespecified outcomes in protocols, registration websites and SAPs. We used the χ² or Fisher exact test to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) to omission of prespecified secondary outcomes, 2 (6.3%) to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) to changing prespecified secondary outcomes to primary outcomes. Of the inconsistencies, 3 (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) to addition of new secondary outcomes, and 2 (6.3%,) to changes in the timing of assessment of primary outcomes. The majority of the inconsistencies favored statistically significant findings; 78 (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (β = -0.14; 95% CI, -0.22 – -0.01; P = 0.035).ConclusionsMore than 1 in 10 trials reported outcomes inconsistent with those specified in trial registration websites, SAPs and protocols. An action plan is warranted to minimize selective reporting and improve transparency.     

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.     

Cimetidine On-Demand in Dyspepsia Experience with Randomized Controlled Single-Subject Trials

Double-blind randomized controlled trials in single subjects (N of 1 RCTs) have demonstrated a beneficial symptomatic effect of cimetidine in reflux-or ulcer-like non-ulcer dyspepsia (NUD). However, spontaneous fluctuations in symptoms reduce the validity of such trials when performed as continuous trials with fixed dosages. This study was carried out to identify individual responders to cimetidine in NUD, peptic ulcer disease, and oesophagitis and to confirm the beneficial average effect of cimetidine in these clinical entities. We evaluated N of 1 multi-crossover trial designs, which compare the effects of single doses of cimetidine and placebo taken on-demand for symptomatic relief. Each trial consisted of six cimetidine (400 mg or 800 mg) and six placebo tablets randomized in successive pairs. The symptomatic effect of each tablet was measured 1/2-6 h after the intake. Outcomes were assessed by individual p values and confidence intervals. A minimal clinically important difference was defined, to assess the clinical significance as demonstrated by the confidence intervals. Thirteen of 25 patients (52%) with reflux- and ulcer-like NUD obtained individual p values below 0.20. Similarly, 7 of 9 patients (78%) with oesophagitis and 6 of 12 patients (50%) with peptic ulcer obtained such p values. On the basis of the 80% confidence intervals the corresponding numbers of subjects with clinically significant effect were six (NUD), three, and three. The combined data showed a significantly better effect of cimetidine than of placebo (p < 0.0001) in each of the three diagnostic groups studied. Cimetidine taken on-demand may have a rapid symptom-relieving effect in dyspepsia. Controlled single-subject trials based on this feature may be of value in the identification of individual responders to cimetidine in clinical practice.     

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.     

Transcatheter Aortic Valve Replacement in Low-Risk Patients: A Meta-Analysis of Randomized Controlled Trials

IntroductionTranscatheter aortic valve replacement (TAVR) has become the standard treatment option for patients with symptomatic severe aortic stenosis (AS) with high surgical risk and a reasonable option for intermediate surgical risk as an alternative to surgical aortic valve replacement (SAVR). The role of TAVR in lower risk patients is less established but has been the focus of recent randomized controlled trials (RCTs). We performed a meta-analysis of RCTs to assess TAVR outcomes among low surgical risk patients.Methods and resultsSystematic search of RCTs was done using PubMed, EMBASE, and Cochrane Library databases. Statistical analysis was performed with RevMan v5.3 software using a random effects model to report risk ratio (RR) with 95% confidence interval (CI). A total of three RCTs including 2698 patients (1375 TAVR and 1323 SAVR) were analyzed. Compared to SAVR, TAVR was not associated with all-cause mortality [RR 0.86 (95% CI 0.61–1.19); P = 0.36; I² = 8%] or stroke [RR 0.82 (0.48–1.43); P = 0.49; I² = 42%]. However, TAVR was significantly associated with lower risk of acute kidney injury [RR 0.27 (0.13–0.54); P = 0.0002; I² = 0%], new-onset atrial fibrillation [RR 0.26 (0.18–0.39); P < 0.00001; I² = 80%], and life-threatening or disabling bleeding [RR 0.35 (0.22–0.55); P < 0.00001; I² = 57%], but a higher risk of moderate-severe paravalvular leak [RR 4.40 (1.22–15.86); P = 0.02; I² = 26%] and permanent pacemaker insertion [RR 2.73 (1.41–5.28); P = 0.003; I² = 83%].ConclusionsThere is no difference in all-cause mortality or stroke between TAVR and SAVR, but TAVR is associated with lower risk of other perioperative complications except for moderate-severe paravalvular leak and the need for permanent pacemaker implantation.     

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.     

A systematic mapping review of Randomized Controlled Trials (RCTs) in care homes

ABSTRACT: BACKGROUND: A thorough understanding of the literature generated from research in care homes is required to support evidence-based commissioning and delivery of healthcare. So far this research has not been compiled or described. We set out to describe the extent of the evidence base derived from randomized controlled trials conducted in care homes. METHODS: A systematic mapping review was conducted of the randomized controlled trials (RCTs) conducted in care homes. Medline was searched for "Nursing Home", "Residential Facilities" and "Homes for the Aged"; CINAHL for "nursing homes", "residential facilities" and "skilled nursing facilities"; AMED for "Nursing homes", "Long term care", "Residential facilities" and "Randomized controlled trial"; and BNI for "Nursing Homes", "Residential Care" and "Long-term care". Articles were classified against a keywording strategy describing: year and country of publication; randomization, stratification and blinding methodology; target of intervention; intervention and control treatments; number of subjects and/or clusters; outcome measures; and results. RESULTS: 3226 abstracts were identified and 291 articles reviewed in full. Most were recent (median age 6 years) and from the United States. A wide range of targets and interventions were identified. Studies were mostly functional (44 behaviour, 20 prescribing and 20 malnutrition studies) rather than disease-based. Over a quarter focussed on mental health. CONCLUSIONS: This study is the first to collate data from all RCTs conducted in care homes and represents an important resource for those providing and commissioning healthcare for this sector. The evidence-base is rapidly developing. Several areas - influenza, falls, mobility, fractures, osteoporosis - are appropriate for systematic review. For other topics, researchers need to focus on outcome measures that can be compared and collated.