Protocol for balanced versus saline trialists: living systematic review and individual patient data meta-analysis of randomised controlled trials (BEST-Living study)

Balanced crystalloids versus saline for critically ill patients (BEST-Living): a systematic review and individual patient data meta-analysis

A systematic review of analytical methods used to study subgroups in (individual patient data) meta-analyses

CARI Guideline: Evidence-Based Recommendations for Balanced Electrolyte Solutions to Improve Kidney Transplant Outcomes.

BackgroundThe cardiovascular safety of testosterone treatment in low testosterone is widely acknowledged to be unclear. Testosterone increases haematocrit, thereby potentially increasing venous thromboembolism risk. The FDA lists cardiovascular risk and stroke as adverse effects of testosterone. Systematic reviews and meta-analyses of published data have limited ability to confirm source data quality and categorisation. Some published meta-analyses have included participants with distinct risk profiles (e.g. cancer, HIV), with serum testosterone atypical for hypogonadism (>12nmol/L), short durations of testosterone treatment, and studies without placebo treatment. Furthermore, subtypes of cardiovascular or cerebrovascular events (e.g. stable angina) during testosterone treatment are seldom published, so have not been analysed previously.ObjectiveEvaluate frequencies of all-cause mortality, and all cardiovascular or cerebrovascular event subtypes, and analyse efficacy of testosterone monotherapy compared to placebo for men with low testosterone, using individual patient data (IPD) and aggregate data meta-analyses.MethodsMEDLINE, EMBASE, Science Citation Index, CENTRAL and clinical trial registries (PROSPERO CRD42018111005) were searched for placebo-controlled RCTs including men with serum testosterone <12nmol/L. One-stage meta-analyses were performed for studies providing IPD and two-stage meta-analyses were performed to integrate IPD and aggregated data. Primary outcomes were all-cause mortality and cardiovascular and/or cerebrovascular events at 12 months or nearest time point.ResultsIPD were obtained from 17 of 35 eligible RCTs (3431/5601 participants) in men with low testosterone. Most participants had functional hypogonadism. Risks of cardiovascular and/or cerebrovascular events were similar between the testosterone and placebo arms (testosterone 120/1601, 7.5%; placebo, 110/1519, 7.2% OR 1.07, 95% CI 0.81-1.42 p=0.62). Frequencies of all cardiovascular or cerebrovascular event subtypes were also similar between testosterone and placebo arms, but testosterone increased risks of oedema and erythrocytosis. No subgroups at higher cardiovascular and/or cerebrovascular event risk were identified. Fewer deaths were recorded in the testosterone arm, but this difference was non-significant (testosterone, 6/1621, 0.4%; placebo, 12/1537, 0.8% OR 0.46, 95% CI 0.17-1.24 p=0.13). Testosterone significantly reduced serum total cholesterol, high-density lipoprotein (HDL), and triglycerides versus placebo. No significant differences in serum low-density lipoprotein (LDL), blood pressure, glycaemic parameters, diabetes incidence or prostate outcomes were observed between groups. Testosterone had positive, albeit varied, effects on quality of life and sexual function.ConclusionsThis is the most comprehensive study to date interrogating the safety of testosterone treatment in men with low testosterone. We were unable to find evidence from our IPD meta-analyses that testosterone increases risks of mortality or cardiovascular and/or cerebrovascular events in the short- to medium-term in men with low testosterone, most of whom have various forms of functional hypogonadism. These data provide some reassurance to men with low testosterone and their clinicians about the safety of testosterone in the short-to-medium term although more long-term data are required.Acknowledgement: NIHR TestES Consortium.Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.

BackgroundThe number of individual patient data meta-analyses published is very low especially in surgical domains. Our aim was to assess the feasibility of individual patient data (IPD) meta-analyses in orthopaedic surgery by determining whether trialists agree to send IPD for eligible trials.MethodsWe performed a literature search to identify relevant research questions in orthopaedic surgery. For each question, we developed a protocol synopsis for an IPD meta-analysis and identified all related randomized controlled trials (RCTs) with results published since 2000. Corresponding authors of these RCTs were sent personalized emails that presented a project for an IPD meta-analysis corresponding to one of the research questions, with a link to the protocol synopsis, and asking for IPD from their RCT. We guaranteed patient confidentiality and secure data storage, and offered co-authorship and coverage of costs related to extraction.ResultsWe identified 38 research questions and 273 RCTs related to these questions. We could contact 217 of the 273 corresponding authors (79 %; 56 had unavailable or non-functional email addresses) and received 68/273 responses (25 %): 21 authors refused to share IPD, 10 stated that our request was under consideration and 37 agreed to send IPD. Four corresponding authors required authorship and three others asked for financial support to send the IPD. Overall, we could obtain IPD for 5,110 of 33,602 eligible patients (15 %). Among the 38 research questions, only one IPD meta-analysis could be potentially initiated because we could receive IPD for more than 50 % of participants.ConclusionThe present study illustrates the difficulties in initiating IPD meta-analyses in orthopaedic surgery. Significant efforts must be made to improve data sharing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0376-6) contains supplementary material, which is available to authorized users.

Publication biases and collection limitations are the main disadvantages of a traditional meta-analysis based on aggregate patient data (APD) from published articles. Individual patient data (IPD) meta-analysis, as the gold standard of systematic review, is a possible alternative in this context. However, the publications relative to IPD meta-analyses are still rare compared with the traditional ones, especially in the research oriented to Chinese medicine (CM). In this article, the strengths and detailed functioning of IPD meta-analysis are described. Furthermore, the need for IPD meta-analysis to assess the treatments based on CM was also discussed. Compared with the traditional APD meta-analysis, the IPD meta-analysis might give a more accurate and unbiased assessment and is worth to be recommended to CM researchers.

Individual patient data (IPD) meta-analyses have been proposed as a major improvement in meta-analytic methods to study subgroup effects. Subgroup effects of conventional and IPD meta-analyses using identical data have not been compared. Our objective is to compare such subgroup effects using the data of six trials (n = 1,643) on the effectiveness of antibiotics in children with acute otitis media (AOM). Effects (relative risks, risk differences [RD], and their confidence intervals [CI]) of antibiotics in subgroups of children with AOM resulting from (i) conventional meta-analysis using summary statistics derived from published data (CMA), (ii) two-stage approach to IPD meta-analysis using summary statistics derived from IPD (IPDMA-2), and (iii) one-stage approach to IPD meta-analysis where IPD is pooled into a single data set (IPDMA-1) were compared. In the conventional meta-analysis, only two of the six studies were included, because only these reported on relevant subgroup effects. The conventional meta-analysis showed larger (age < 2 years) or smaller (age > or = 2 years) subgroup effects and wider CIs than both IPD meta-analyses (age < 2 years: RDCMA -21 percent, RDIPDMA-1 -16 percent, RDIPDMA-2 -15 percent; age > or =2 years: RDCMA -5 percent, RDIPDMA-1 -11 percent, RDIPDMA-2 -11 percent). The most important reason for these discrepant results is that the two studies included in the conventional meta-analysis reported outcomes that were different both from each other and from the IPD meta-analyses. This empirical example shows that conventional meta-analyses do not allow proper subgroup analyses, whereas IPD meta-analyses produce more accurate subgroup effects. We also found no differences between the one- and two-stage meta-analytic approaches.

Objective:To compare the effectiveness of perennial and co-seasonal high-dose sublingual immunotherapy (SLIT) treatments as well as ultra-rush and classical titrations in a real-world setting for pollen allergens.Methods:An individual patient data (IPD) meta-analysis was performed of three open, prospective observational studies on high-dose SLIT using IR-standardised allergen extracts in patients with allergic rhinitis with and without asthma.Results:In total, 1052 patients aged 24.9 years (mean) were treated with SLIT and included in this IPD meta-analysis. Individual studies and total data pool analyses revealed consistent improvements in rhinoconjunctivitis symptom scores. Stratified analyses revealed consistent improvements in symptomatic score and medication score regardless of the type of sensitisation and type of treatment. Ultra-rush titration resulted in considerably more pronounced improvement in symptom scores than classical titration, possibly due to better compliance of patients receiving that supervised titration. Adverse events occurred in 24% of patients during titration and in 18% of patients during maintenance treatment. The vast majority of events (89% and 87%) were mild-to-moderate, predominantly local symptoms in the oral cavity. There were no differences detected between the study titration or treatment schedules. No serious adverse reactions were reported. Nearly all patients (88%) decided to continue SLIT after completion of the studies.Conclusion:High-dose SLIT with seasonal allergens given as co-seasonal or perennial treatment appears to be effective and well-tolerated in daily medical practice. Improved compliance under ultra-rush titration and seasonal SLIT treatment may further enhance effectiveness. Randomised controlled trials are requested for the further evaluation of these findings.

To develop maternal, fetal, and neonatal composite outcomes relevant to the evaluation of diet and lifestyle interventions in pregnancy by individual patient data (IPD) meta-analysis. Delphi survey. The International Weight Management in Pregnancy (i-WIP) collaborative network. Sample Twenty-six researchers from the i-WIP collaborative network from 11 countries. A two-generational Delphi survey involving members of the i-WIP collaborative network (26 members in 11 countries) was undertaken to prioritise the individual outcomes for their importance in clinical care. The final components of the composite outcomes were identified using pre-specified criteria. Composite outcomes considered to be important for the evaluation of the effect of diet and lifestyle in pregnancy. Of the 36 maternal outcomes, nine were prioritised and the following were included in the final composite: pre-eclampsia or pregnancy-induced hypertension, gestational diabetes mellitus (GDM), elective or emergency caesarean section, and preterm delivery. Of the 27 fetal and neonatal outcomes, nine were further evaluated, with the final composite consisting of intrauterine death, small for gestational age, large for gestational age, and admission to a neonatal intensive care unit (NICU). Our work has identified the components of maternal, fetal, and neonatal composite outcomes required for the assessment of diet and lifestyle interventions in pregnancy by IPD meta-analysis.

IntroductionPregnant women are more vulnerable to malaria leading to adverse impact on both mothers and fetuses. However, knowledge on the efficacy and safety of antimalarials in pregnancy is limited by...

BackgroundThe purpose of the optic nerve sheath diameter (ONSD) research group project is to establish an individual patient-level database from high quality studies of ONSD ultrasonography for the detection of raised intracranial pressure (ICP), and to perform a systematic review and an individual patient data meta-analysis (IPDMA), which will provide a cutoff value to help physicians making decisions and encourage further research. Previous meta-analyses were able to assess the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP but failed to determine a precise cutoff value. Thus, the ONSD research group was founded to synthesize data from several recent studies on the subject and to provide evidence on the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP.MethodsThis IPDMA will be conducted in different phases. First, we will systematically search for eligible studies. To be eligible, studies must have compared ONSD ultrasonography to invasive intracranial devices, the current reference standard for diagnosing raised ICP. Subsequently, we will assess the quality of studies included based on the QUADAS-2 tool, and then collect and validate individual patient data. The objectives of the primary analyses will be to assess the diagnostic accuracy of ONSD ultrasonography and to determine a precise cutoff value for detecting raised ICP. Secondly, we will construct a logistic regression model to assess whether patient and study characteristics influence diagnostic accuracy.DiscussionWe believe that this IPD MA will provide the most reliable basis for the assessment of diagnostic accuracy of ONSD ultrasonography for detecting raised ICP and to provide a cutoff value. We also hope that the creation of the ONSD research group will encourage further study.Trial registrationPROSPERO registration number: CRD42012003072

BackgroundNetwork meta-analysis methods, which are an extension of the standard pair-wise synthesis framework, allow for the simultaneous comparison of multiple interventions and consideration of the entire body of evidence in a single statistical model. There are well-established advantages to using individual patient data to perform network meta-analysis and methods for network meta-analysis of individual patient data have already been developed for dichotomous and time-to-event data. This paper describes appropriate methods for the network meta-analysis of individual patient data on continuous outcomes.MethodsThis paper introduces and describes network meta-analysis of individual patient data models for continuous outcomes using the analysis of covariance framework. Comparisons are made between this approach and change score and final score only approaches, which are frequently used and have been proposed in the methodological literature. A motivating example on the effectiveness of acupuncture for chronic pain is used to demonstrate the methods. Individual patient data on 28 randomised controlled trials were synthesised. Consistency of endpoints across the evidence base was obtained through standardisation and mapping exercises.ResultsIndividual patient data availability avoided the use of non-baseline-adjusted models, allowing instead for analysis of covariance models to be applied and thus improving the precision of treatment effect estimates while adjusting for baseline imbalance.ConclusionsThe network meta-analysis of individual patient data using the analysis of covariance approach is advocated to be the most appropriate modelling approach for network meta-analysis of continuous outcomes, particularly in the presence of baseline imbalance. Further methods developments are required to address the challenge of analysing aggregate level data in the presence of baseline imbalance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-016-0224-1) contains supplementary material, which is available to authorized users.

IntroductionWomen and their infants are at increased risk of complications if gestational diabetes mellitus (GDM) or excessive gestational weight gain (GWG) occurs in pregnancy. Weight management interventions in pregnancy, consisting...

Background: Despite the large number of patients with early breast cancer (EBC) that have been treated with capecitabine in randomized trials no individual patient data meta-analysis has yet been conducted. So far only two literature-based meta-analyses have been published including only five neoadjuvant studies and two adjuvant trials, respectively. Whereas the first did not report an improvement in response to neoadjuvant therapy, the latter found an improvement in disease-free survival (DFS) in the capecitabine arm. Methods: In order to select trials the following criteria were used at www.clinicaltrials.gov: Use of capecitabine in EBC as adjuvant or neoadjuvant therapy; randomized; N&amp;gt;100 patients; recruitment completed and outcomes available. This yielded the following trials: GeparTrio, GeparQuattro, GAIN, ICE, ICE II, FinXX, Alliance/CALGB 49907, Roche / US Oncology 01062, NSABP-B40, ABCSG-24, CREATE-X, GEICAM 2003/10, GEICAM 2003/11_CIBOMA 2004/01. Data were available for all these trials and 15,457 patients were included in this individual patient data based meta-analysis. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS). Secondary objectives were to examine effects on distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and whether there was an interaction of occurrence of capecitabine-specific toxicity (mucositis, diarrhea, hand-foot syndrome) and treatment effect. Bi- and multivariable frailty-based Cox proportional hazards models including log-normal distributed random effects of study were used to report hazard ratios with 95% CI between the groups of patients treated with or without capecitabine for DFS, DDFS and OS. Results: Individual data from 15,457 patients was collected. Of these 7,980 received capecitabine during the course of their treatment and 7,477 patients were treated in the control arms. Median age at diagnosis was 54 years in both groups. Most patients were diagnosed with stage 2 tumors (55.9%) and the majority presented with nodal involvement (74.0%). Estrogen and progesterone receptor positivity was observed in 66.0% and 56.9%, respectively, and 15.1% of patients were diagnosed as HER2-positive. 2,816 patients (18.2%) received neoadjuvant treatment and 12,641 (81.8%) an adjuvant chemotherapy regimen. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared to treatment without capecitabine (HR 0.952; 95% CI 0.895-1.012; p-value 0.115). There was also no effect on DFS if studies were selected in which capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; p=0.455). However, capecitabine in addition to systemic treatment lead to a small but significant improvement of DFS (HR 0.888; 95% CI 0.817-0.965; p=0.005). Results concerning other endpoints will be presented at the meeting. Conclusion: Capecitabine did not alter DFS in this meta-analysis of 15,457 patients with early breast cancer from 12 prospective randomized trials, but as addition to systemic treatment DFS was improved. Subgroup analyses are needed for final interpretation and will be presented at the meeting. Citation Format: Marion van Mackelenbergh, Fenja Seither, Volker Möbus, Joyce O'Shaugnessy, Miguel Martin, Heikki Joenssuu, Michael Untch, Ulrike Nitz, Juan J Miralles, Masakazu Toi, Harry D Bear, Hymann Muss, Toralf Reimer, Valentina Nekljudova, Sibylle Loibl. Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-07.

Combining individual patient data from multiple trials require specific modelling techniques in order to provide accurate predictions