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Aims Cardiac contractility modulation, also referred to as CCM™, has emerged as a promising device treatment for heart failure (HF) in patients not indicated for cardiac resynchronization therapy. We performed a comprehensive individual patient data meta‐analysis of all non‐confounded prospective randomized controlled trials of CCM vs. control that have measured functional capacity and/or quality of life questionnaires in patients with HF. Methods and results The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched in January 2020 to identify eligible randomized controlled trials. We also asked the sole manufacturer of the device for their list of known trials. Primary outcomes of interest were peak oxygen consumption (peak VO2), 6 min walk test distance, and quality of life measured by Minnesota Living with Heart Failure Questionnaire (MLWHFQ), and all data were received as individual patient and individual time point data‐points. Mean differences and 95% confidence intervals (CIs) were calculated for continuous data using a fixed‐effects model. Five trials were identified, four randomized studies enrolling 801 participants for all endpoints of interest, and for peak VO2 alone (n = 60), there was an additional single arm non‐randomized trial (FIX‐HF‐5C2) with a prospective comparison of its 24 week peak VO2 data compared with the control group of the FIX‐HF‐5C control patients. Pooled analysis showed that, compared with control, CCM significantly improved peak VO2 (mean difference +0.93, 95% CI 0.56 to 1.30 mL/kg/min, P < 0.00001), 6 min walk test distance (mean difference +17.97, 95% CI 5.48 to 30.46 m, P = 0.005), and quality of life measured by MLWHFQ (mean difference −7.85, 95% CI −10.76 to −4.94, P < 0.00001). As a sensitivity analysis, we excluded the FIX‐HF‐5C2 trial (only relevant for peak VO2), and the result was similar, mean difference +0.65, 95% CI 0.21 to 1.08 mL/kg/min, P = 0.004. Conclusions This comprehensive meta‐analysis of individual patient data from all known randomized trials has shown that CCM provides statistically significant and clinically meaningful benefits in measures of functional capacity and HF‐related quality of life.

Model‐based meta‐analysis allows integration of aggregated‐level data (AD) from different clinical trials in one model to assess population efficacy/safety. However, AD is limited in individual‐level information, while individual‐patient‐level data (IPD) are hard to obtain. Combined modeling may take advantage of both sources. Chronic obstructive pulmonary disease (COPD) is a leading cause of poor health and death. This study established a combined ADIPD model of COPD clinical trials with forced expiratory volume in 1 s (FEV1) as an endpoint and explored methods for estimating interstudy variability (ISV), interindividual variability (IIV), and aggregation bias. Stochastic simulation and estimations (SSE) showed the best method in NONMEM to estimate ISV/IIV: using $LEVEL with equal weight of studies; for the AD part, ISVs from the AD model were fixed, estimating IIV with separate ETAs for each arm; the IPD part shared the fixed ISV and estimated IIV. An approximated normal distribution was derived for lognormal IIV to avoid aggregation bias. Covariate correlations were different at aggregated and individual levels, but did not introduce aggregation bias according to SSE. A separate AD model (published) and IPD model were built, then combined to form the ADIPD model. The ADIPD model included FEV1 baseline, disease progression, placebo effect, and Emax/constant dose‐responses for 23 compounds. Identified covariate relationships: higher age, female, higher disease severity, non‐current smoker related to lower baseline; higher baseline related to faster disease progression and higher drug effects. Covariate coefficients were estimated more precisely in the ADIPD model than the AD model. ADIPD modeling allows more informed clinical trial simulations for study design. Trial Registration: ClinicalTrials.gov identifier: NCT01053988 and NCT01054885

PurposeTo assess the effect of venovenous extracorporeal membrane oxygenation (ECMO) compared to conventional management in patients with severe acute respiratory distress syndrome (ARDS).MethodsWe conducted a systematic review and individual patient data meta-analysis of randomised controlled trials (RCTs) performed after Jan 1, 2000 comparing ECMO to conventional management in patients with severe ARDS. The primary outcome was 90-day mortality. Primary analysis was by intent-to-treat.ResultsWe identified two RCTs (CESAR and EOLIA) and combined data from 429 patients. On day 90, 77 of the 214 (36%) ECMO-group and 103 of the 215 (48%) control group patients had died (relative risk (RR), 0.75, 95% confidence interval (CI) 0.6–0.94; P = 0.013; I2 = 0%). In the per-protocol and as-treated analyses the RRs were 0.75 (95% CI 0.6–0.94) and 0.86 (95% CI 0.68–1.09), respectively. Rescue ECMO was used for 36 (17%) of the 215 control patients (35 in EOLIA and 1 in CESAR). The RR of 90-day treatment failure, defined as death for the ECMO-group and death or crossover to ECMO for the control group was 0.65 (95% CI 0.52–0.8; I2 = 0%). Patients randomised to ECMO had more days alive out of the ICU and without respiratory, cardiovascular, renal and neurological failure. The only significant treatment-covariate interaction in subgroups was lower mortality with ECMO in patients with two or less organs failing at randomization.ConclusionsIn this meta-analysis of individual patient data in severe ARDS, 90-day mortality was significantly lowered by ECMO compared with conventional management.

Background When applying secondary analysis on published survival data, it is critical to obtain each patient’s raw data, because the individual patient data (IPD) approach has been considered as the gold standard of data analysis. However, researchers often lack access to IPD. We aim to propose a straightforward and robust approach to obtain IPD from published survival curves with a user-friendly software platform. Results Improving upon existing methods, we propose an easy-to-use, two-stage approach to reconstruct IPD from published Kaplan-Meier (K-M) curves. Stage 1 extracts raw data coordinates and Stage 2 reconstructs IPD using the proposed method. To facilitate the use of the proposed method, we developed the R package IPDfromKM and an accompanying web-based Shiny application. Both the R package and Shiny application have an “all-in-one” feature such that users can use them to extract raw data coordinates from published K-M curves, reconstruct IPD from the extracted data coordinates, visualize the reconstructed IPD, assess the accuracy of the reconstruction, and perform secondary analysis on the basis of the reconstructed IPD. We illustrate the use of the R package and the Shiny application with K-M curves from published studies. Extensive simulations and real-world data applications demonstrate that the proposed method has high accuracy and great reliability in estimating the number of events, number of patients at risk, survival probabilities, median survival times, and hazard ratios. Conclusions IPDfromKM has great flexibility and accuracy to reconstruct IPD from published K-M curves with different shapes. We believe that the R package and the Shiny application will greatly facilitate the potential use of quality IPD and advance the use of secondary data to facilitate informed decision making in medical research.

Although clozapine is the most efficacious medication for treatment-refractory schizophrenia, not all patients will have an adequate response. Optimising clozapine dose using therapeutic drug monitoring could therefore maximise response. Using individual patient data, we undertook a receiver operating characteristic (ROC) curve analysis to determine an optimal therapeutic range for clozapine levels to guide clinical practice. We conducted a systematic review of PubMed, PsycINFO and Embase for studies that provided individual participant level data on clozapine levels and response. These data were analysed using ROC curves to determine the prediction performance of plasma clozapine levels for treatment response. We included data on 294 individual participants from nine studies. ROC analysis yielded an area under the curve of 0.612. The clozapine level at the point of optimal diagnostic benefit was 372 ng/mL; at this level, the response sensitivity was 57.3%, and specificity 65.7%. The interquartile range for treatment response was 223-558 ng/mL. There was no improvement in ROC performance with mixed models including patient gender, age or length of trial. Clozapine dose and clozapine concentration to dose ratio did not provide significantly meaningful prediction of response to clozapine. Clozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response. Although some patients may not respond without clozapine levels >550 ng/mL, the benefits should be weighed against the increased risk of adverse drug reactions.

Aims The standardised mean difference (SMD) is one of the most used effect sizes to indicate the effects of treatments. It indicates the difference between a treatment and comparison group after treatment has ended, in terms of standard deviations. Some meta-analyses, including several highly cited and influential ones, use the pre-post SMD, indicating the difference between baseline and post-test within one (treatment group). In this paper, we argue that these pre-post SMDs should be avoided in meta-analyses and we describe the arguments why pre-post SMDs can result in biased outcomes. One important reason why pre-post SMDs should be avoided is that the scores on baseline and post-test are not independent of each other. The value for the correlation should be used in the calculation of the SMD, while this value is typically not known. We used data from an 'individual patient data' meta-analysis of trials comparing cognitive behaviour therapy and anti-depressive medication, to show that this problem can lead to considerable errors in the estimation of the SMDs. Another even more important reason why pre-post SMDs should be avoided in meta-analyses is that they are influenced by natural processes and characteristics of the patients and settings, and these cannot be discerned from the effects of the intervention. Between-group SMDs are much better because they control for such variables and these variables only affect the between group SMD when they are related to the effects of the intervention. We conclude that pre-post SMDs should be avoided in meta-analyses as using them probably results in biased outcomes.

Our aim was to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patient data from randomized, placebo-controlled trials and to explore subgroup differences. We systematically searched Medline, Embase, Cochrane Central, and trial registers (all through July 2017). Data from 1506 individual patients in 6 trials were analyzed using uniform outcome definitions. We investigated prespecified effect modifiers using multivariable hierarchical regression, adjusting for pneumonia severity, age, and clustering effects. Within 30 days of randomization, 37 of 748 patients (5.0%) assigned to corticosteroids and 45 of 758 patients (5.9%) assigned to placebo died (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], .46 to 1.21; P = .24). Time to clinical stability and length of hospital stay were reduced by approximately 1 day with corticosteroids (-1.03 days; 95% CI, -1.62 to -.43; P = .001 and -1.15 days; 95% CI, -1.75 to -.55; P < .001, respectively). More patients with corticosteroids had hyperglycemia (160 [22.1%] vs 88 [12.0%]; aOR, 2.15; 95% CI, 1.60 to 2.90; P < .001) and CAP-related rehospitalization (33 [5.0%] vs 18 [2.7%]; aOR, 1.85; 95% CI, 1.03 to 3.32; P = .04). We did not find significant effect modification by CAP severity or degree of inflammation. Adjunct corticosteroids for patients hospitalized with CAP reduce time to clinical stability and length of hospital stay by approximately 1 day without a significant effect on overall mortality but with an increased risk for CAP-related rehospitalization and hyperglycemia.

PurposeWe performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.MethodsOur pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses.ResultsFour trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86–1.12] or serious adverse events (RR 1.02, 95% CI 0.82–1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%–3.2%] but fewer arrhythmias (ARD − 2.8%, 95% CI − 0.2% to − 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74–0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion).ConclusionsVasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.

ObjectivesTo determine whether individuals who sustained a sports concussion would exhibit persistent impairments in gait and quiet standing compared to non-injured controls during a dual-task assessment .DesignSystematic review and meta-analysis using individual participant data (IPD).Data sourcesThe search strategy was applied across seven electronic bibliographic and grey literature databases: MEDLINE, EMBASE, CINAHL, SportDISCUS, PsycINFO, PsycARTICLES and Web of Science, from database inception until June 2017.Eligibility criteria for study selectionStudies were included if; individuals with a sports concussion and non-injured controls were included as participants; a steady-state walking or static postural balance task was used as the primary motor task; dual-task performance was assessed with the addition of a secondary cognitive task; spatiotemporal, kinematic or kinetic outcome variables were reported, and; included studies comprised an observational study design with case–control matching.Data extraction and synthesisOur review is reported in line with the Preferred Reporting Items for Systematic review and Meta-Analyses-IPD Statement. We implemented the Risk of Bias Assessment tool for Non-randomised Studies to undertake an outcome-level risk of bias assessment using a domain-based tool. Study-level data were synthesised in one of three tiers depending on the availability and quality of data: (1) homogeneous IPD; (2) heterogeneous IPD and (3) aggregate data for inclusion in a descriptive synthesis. IPD were aggregated using a ‘one-stage’, random-effects model.Results26 studies were included. IPD were available for 20 included studies. Consistently high and unclear risk of bias was identified for selection, detection, attrition, and reporting biases across studies. Individuals with a recent sports concussion walked with slower average walking speed (χ2=51.7; df=4; p<0.001; mean difference=0.06 m/s; 95% CI: 0.004 to 0.11) and greater frontal plane centre of mass displacement (χ2=10.3; df=4; p=0.036; mean difference −0.0039 m; 95% CI: −0.0075 to −0.0004) than controls when evaluated using a dual-task assessment up to 2 months following concussion.Summary/conclusionsOur IPD evidence synthesis identifies that, when evaluated using a dual-task assessment, individuals who had incurred a sports concussion exhibited impairments in gait that persisted beyond reported standard clinical recovery timelines of 7–10 days. Dual-task assessment (with motion capture) may be a useful clinical assessment to evaluate recovery after sports concussion.Protocol pre-registrationThis systematic review was prospectively registered in PROSPERO CRD42017064861.