Introduction: Conflicting evidence has been published regarding the safety and efficacy of ultrasound-enhanced thrombolysis (sonothrombolysis) in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). Methods: We conducted an individual participant data meta-analysis of available randomized controlled trials (RCTs) comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in AIS patients with LVO. Results: We included 6 in total RCTs that enrolled 1077 AIS patients. A total of 138 and 134 confirmed LVO patients were randomized to treatment and control groups respectively (median age 68 years, 58% men, median baseline NIHSS score 16). Patients randomized to sonothrombolysis had increased odds of complete recanalization compared to patients receiving intravenous thrombolysis alone (40.3% vs. 22.4%; OR=2.30, 95%CI: 1.05-5.02; adjusted OR=2.33, 95%CI: 1.02-5.34). They also tended to have increased odds of any (complete or partial recanalization (66.4% vs. 53.0%; OR=1.78, 95%CI: 0.95-3.33; adjusted OR=1.85, 95%CI: 0.97-3.53). The likelihood of symptomatic intracranial hemorrhage did not differ between the two groups (7.3% vs. 3.7%, OR=2.52, 95%CI: 0.77-8.29; adjusted OR=2.55, 95%CI: 0.76-8.52). No differences in the likelihood of asymptomatic intracranial hemorrhage (adjusted OR: 1.30, 95%CI: 0.38-4.39), three-month mortality (adjusted OR: 1.23, 95%CI: 0.25-6.05), three-month favorable functional outcome (mRS-scores of 0-1; adjusted OR: 1.43, 95%CI: 0.64-3.19) and three-month functional independence (mRS-scores of 0-2; adjusted OR: 1.43, 95%CI: 0.77-2.64) were documented. Conclusion: Sonothrombolysis was associated with a two-fold increase in the odds of complete recanalization compared to intravenous thrombolysis alone in AIS patients with LVOs. Further study of the safety and efficacy of sonothrombolysis is warranted.
In view of the currently available evidence from randomized trials, we aimed to compare the collective safety and efficacy of transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) across the spectrum of risk and in important subgroups. Trials comparing TAVI vs. SAVR were identified through Medline, Embase, and Cochrane databases. The primary outcome was death from any cause at 2 years. We performed random-effects meta-analyses to combine the available evidence and to evaluate the effect in different subgroups. This systematic review and meta-analysis is registered with PROSPERO (CRD42016037273). We identified four eligible trials including 3806 participants, who were randomly assigned to undergo TAVI (n = 1898) or SAVR (n = 1908). For the primary outcome of death from any cause, TAVI when compared with SAVR was associated with a significant 13% relative risk reduction [hazard ratio (95% CI): 0.87 (0.76–0.99); P = 0.038] with homogeneity across all trials irrespective of TAVI device (Pinteraction = 0.306) and baseline risk (Pinteraction = 0.610). In subgroup analyses, TAVI showed a robust survival benefit over SAVR for patients undergoing transfemoral access [0.80 (0.69–0.93); P = 0.004], but not transthoracic access [1.17 (0.88–1.56); P = 0.293] (Pinteraction = 0.024) and in female [0.68 (0.50–0.91); P = 0.010], but not male patients [0.99 (0.77–1.28); P = 0.952] (Pinteraction = 0.050). Secondary outcomes of kidney injury, new-onset atrial fibrillation, and major bleeding favoured TAVI, while major vascular complications, incidence of permanent pacemaker implantation, and paravalvular regurgitation favoured SAVR. Compared with SAVR, TAVI is associated with a significant survival benefit throughout 2 years of follow-up. Importantly, this superiority is observed irrespective of the TAVI device across the spectrum of intermediate and high-risk patients, and is particularly pronounced among patients undergoing transfemoral TAVI and in females.
Abstract Background Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. Methods We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . Results Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8–12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = − 0.32, 95% CI [− 0.39, − 0.25], in repetitive behaviors − 0.23[− 0.32, − 0.15] and in scales measuring overall core symptoms − 0.36 [− 0.46, − 0.26]. Overall, 19%, 95% CI [16–22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. Limitations About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. Conclusions Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.
Background: Comparative effectiveness research using network meta-analysis can present a hierarchy of competing treatments, from the least to most preferable option. However, the research question associated with the hierarchy of multiple interventions is never clearly defined in published reviews. Methods and Results: We introduce the notion of a treatment hierarchy question that describes the criterion for choosing a specific treatment over one or more competing alternatives. For example, stakeholders might ask which treatment is most likely to improve mean survival by at least 2 years or which treatment is associated with the longest mean survival. The answers to these two questions are not necessarily the same. We discuss the most commonly used ranking metrics (quantities that describe or compare the estimated treatment-specific effects), how the metrics produce a treatment hierarchy and the type of treatment hierarchy question that each metric can answer. We show that the ranking metrics encompass the uncertainty in the estimation of the treatment effects in different ways, which results in different treatment hierarchies. Conclusions: Network meta-analyses that aim to rank treatments should state in the protocol the treatment hierarchy question they aim to address and employ the appropriate ranking metric to answer it.
Clinical trials are typically designed with an aim to reach sufficient power to test a hypothesis about relative effectiveness of two or more interventions. Their role in informing evidence‐based decision‐making demands, however, that they are considered in the context of the existing evidence. Consequently, their planning can be informed by characteristics of relevant systematic reviews and meta‐analyses. In the presence of multiple competing interventions the evidence base has the form of a network of trials, which provides information not only about the required sample size but also about the interventions that should be compared in a future trial. In this paper we present a methodology to evaluate the impact of new studies, their information size, the comparisons involved, and the anticipated heterogeneity on the conditional power ( CP ) of the updated network meta‐analysis. The methods presented are an extension of the idea of CP initially suggested for a pairwise meta‐analysis and we show how to estimate the required sample size using various combinations of direct and indirect evidence in future trials. We apply the methods to two previously published networks and we show that CP for a treatment comparison is dependent on the magnitude of heterogeneity and the ratio of direct to indirect information in existing and future trials for that comparison. Our methodology can help investigators calculate the required sample size under different assumptions about heterogeneity and make decisions about the number and design of future studies (set of treatments compared).
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