Do outcomes reported in randomised controlled trials of joint replacement surgery fulfil the OMERACT 2.0 Filter? A review of the 2008 and 2013 literature.

Background It is not known, whether outcome reporting in trials of total joint arthroplasty in the recent years is adequate or not. Our objective was to assess whether outcomes reported in total joint replacement (TJR) trials fulfil the Outcome Measures in Rheumatology (OMERACT) Filter 2.0. Methods We systematically reviewed all TJR trials in adults, published in English in 2008 or 2013. Searches were conducted in the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. Two authors independently applied the inclusion criteria for the studies, and any disagreement was resolved with a third review author. All outcome measures were abstracted using a pre-piloted standardised data extraction form and assessed for whether they mapped to one of the three OMERACT Filter 2.0 core areas: pathophysiological, life impact, and death. Results From 1635 trials identified, we included 70 trials (30 in 2008 and 40 in 2013) meeting the eligibility criteria. Twenty-two (31%) trials reported the three essential OMERACT core areas. Among the 27 hip replacement surgery trials and 39 knee replacement surgery trials included, 11 hip (41%) and nine knee (23%) trials reported all three essential OMERACT core areas. The most common outcome domains/measures were pain (20/27, 74%) and function (23/27, 85%) in hip trials and pain (26/39, 67%) and function (27/39, 69%) in knee trials. Results were similar for shoulder and hand joint replacement trials. Conclusions We identified significant gaps in the measurement of OMERACT core outcome areas in TJR trials, despite the majority reporting outcome domains of pain and function. An international consensus of key stakeholders is needed to develop a core domain set for reporting of TJR trials

Effect of vitamin D supplementation on blood pressure:a systematic review and meta-analysis incorporating individual patient data

D-PRESSURE Collaboration: et al.[Importance]: Low levels of vitamin D are associated with elevated blood pressure (BP) and future cardiovascular events. Whether vitamin D supplementation reduces BP and which patient characteristics predict a response remain unclear.[Objective]: To systematically review whether supplementation with vitamin D or its analogues reduce BP.[Data Sources]: We searched MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.com augmented by a hand search of references from the included articles and previous reviews. Google was searched for gray literature (ie, material not published in recognized scientific journals). No language restrictions were applied. The search period spanned January 1, 1966, through March 31, 2014.[Study Selection]: We included randomized placebo-controlled clinical trials that used vitamin D supplementation for a minimum of 4 weeks for any indication and reported BP data. Studies were included if they used active or inactive forms of vitamin D or vitamin D analogues. Cointerventions were permitted if identical in all treatment arms.[Data Extraction and Synthesis]: We extracted data on baseline demographics, 25-hydroxyvitamin D levels, systolic and diastolic BP (SBP and DBP), and change in BP from baseline to the final follow-up. Individual patient data on age, sex, medication use, diabetes mellitus, baseline and follow-up BP, and 25-hydroxyvitamin D levels were requested from the authors of the included studies. For trial-level data, between-group differences in BP change were combined in a random-effects model. For individual patient data, between-group differences in BP at the final follow up, adjusted for baseline BP, were calculated before combining in a random-effects model.[Main Outcomes and Measures]: Difference in SBP and DBP measured in an office setting.[Results]: We included 46 trials (4541 participants) in the trial-level meta-analysis. Individual patient data were obtained for 27 trials (3092 participants). At the trial level, no effect of vitamin D supplementation was seen on SBP (effect size, 0.0 [95% CI, −0.8 to 0.8] mm Hg; P = .97; I2 = 21%) or DBP (effect size, −0.1 [95% CI, −0.6 to 0.5] mm Hg; P = .84; I2 = 20%). Similar results were found analyzing individual patient data for SBP (effect size, −0.5 [95% CI, −1.3 to 0.4] mm Hg; P = .27; I2 = 0%) and DBP (effect size, 0.2 [95% CI, −0.3 to 0.7] mm Hg; P = .38; I2 = 0%). Subgroup analysis did not reveal any baseline factor predictive of a better response to therapy.[Conclusions and Relevance]: Vitamin D supplementation is ineffective as an agent for lowering BP and thus should not be used as an antihypertensive agent.Peer reviewe

Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer

Objective: To date, no standard regimen for salvage chemotherapy after gemcitabine (Gem) failure has been defined for patients with advanced pancreatic cancer (PC). Oral capecitabine (Cap) has shown promising activity in first-line chemotherapy trials in PC patients. Methods: Within a prospective single-center study, Cap was offered to patients who had already received at least 1 previous treatment regimen containing full-dose Gem (as a single agent, as part of a combination chemotherapy regimen or sequentially within a chemoradiotherapy protocol). Cap was administered orally at a dose of 1,250 mg/m(2) twice daily for 14 days followed by 7 days of rest. Study endpoints were objective tumor response rate by imaging criteria (according to RECIST), carbohydrate antigen 19-9 (CA19-9) tumor marker response, time to progression, overall survival and toxicity. Results: A median of 3 treatment cycles (range 1-36) was given to 39 patients. After a median follow-up of 6.6 months, 27 patients were evaluable for response: no complete or partial responses were observed, but 15 patients (39%) had stable disease. A CA19-9 reduction of >20% after 2 cycles of Cap was documented in 6 patients (15%). Median time to progression was 2.3 months (range 0.5-45.1) and median overall survival (since start of Cap treatment) was 7.6 months (range 0.7-45.1). Predominant grade 2 and 3 toxicities (per patient analysis) were hand-foot syndrome 28% (13% grade 3); anemia 23%; leg edema 15%; diarrhea 13%; nausea/vomiting 10%, and leukocytopenia 10%. Conclusion: Single-agent Cap is a safe treatment option for Gem-pretreated patients with advanced PC. Further evaluation of Cap in controlled clinical trials of Gem-pretreated patients with advanced PC is recommended. Copyright (C) 2008 S. Karger AG, Basel

The effect of statins on average survival in randomised trials, an analysis of end point postponement

OBJECTIVE: To estimate the average postponement of death in statin trials. SETTING: A systematic literature review of all statin trials that presented all-cause survival curves for treated and untreated. INTERVENTION: Statin treatment compared to placebo. PRIMARY OUTCOME MEASURES: The average postponement of death as represented by the area between the survival curves. RESULTS: 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively. CONCLUSIONS: Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered

Instrumental variable meta-analysis of randomised trials of epidural analgesia in labour to adjust for non-compliance

Objective: Intention-to-treat analysis of randomised controlled trials may cause bias towards the null where non-compliance with the allocated intervention occurs. Instrumental variable analysis allows estimation of the causal effect adjusted for non-compliance. The aim of this study is to compare intention-to-treat and instrumental variable meta-analysis of the association between epidural analgesia in labour and caesarean section. Study design and Setting: The study was restricted to 27 trials in a recent Cochrane Systematic Review. For trials with data on compliance, the association between epidural analgesia in labour and caesarean section was calculated using intention-to-treat analysis and instrumental variable analysis. Fixed-effects meta-analysis was used to calculate pooled risk ratios. Results: In 18 trials with data on compliance, 23% of women allocated to epidural analgesia did not comply and 27% of women allocated to the control received epidural analgesia. Data on outcomes in non-compliant groups were available for 10 trials. The pooled risk ratio for caesarean section following epidural analgesia in labour was 1.37 (95% CI 1.00-1.89, p=0.049) using instrumental variable analysis compared to 1.19 (95% CI 0.93-1.51, p=0.16) using intention-to-treat analysis. Conclusion: Intention-to-treat meta-analysis underestimates the effect of receiving epidural analgesia in labour on caesarean section compared to instrumental variable meta-analysis.NHMR

The Differential Effect of Anxiety and ADHD Symptoms on Inhibitory Control and Sustained Attention for Threat Stimuli: A Go/No-Go Eye-Movement Study

Objective: This study examined the synergistic effects of ADHD and anxiety symptoms on attention and inhibitory control depending on the emotional content of the stimuli. Method: Fifty-four typically developing individuals (27 children/adolescents and 27 adults) completed an eye-movement based emotional Go/No-Go task, using centrally presented (happy, angry) faces and neutral/symbolic stimuli. Sustained attention was measured through saccade latencies and saccadic omission errors (Go trials), and inhibitory control through saccadic commission errors (No-Go trials). ADHD and anxiety were assessed dimensionally. Results: Elevated ADHD symptoms were associated with more commission errors and slower saccade latencies for angry (vs. happy) faces. In contrast, angry faces were linked to faster saccade onsets when anxiety symptoms were high, and this effect prevailed when both anxiety and ADHD symptoms were high. Conclusion: Social threat impacted performance in individuals with sub-clinical anxiety and ADHD differently. The effects of anxiety on threat processing prevailed when both symptoms were high

Effectiveness of adult community-based physical activity interventions with objective physical activity measurements and long-term follow-up: a systematic review and meta-analysis.

OBJECTIVE: To identify randomised controlled trials (RCTs) of physical activity (PA) interventions with objective PA outcomes in adults and to evaluate whether intervention effects were sustained beyond 12 months. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Seven databases (Medline, Embase, PsycINFO, Web of Science, Cochrane library, CINAHL (Cumulative Index of Nursing and Allied Health Literature) and ASSIA (Applied Social Sciences Index and Abstracts)) were searched from January 2000 until December 2019. ELIGIBILITY CRITERIA: RCTs reporting objective PA outcomes beyond 12 months with community-based participants aged ≥18 years were included; those where controls received active interventions, including advice to increase PA levels, were excluded. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers completed extraction of aggregate data and assessed risk of bias. Meta-analyses used random-effects models at different follow-up points. Primary outcomes were daily steps and weekly minutes of moderate-to-vigorous PA (MVPA). RESULTS: Of 33 282 records identified, nine studies (at generally low risk of bias) were included, five in meta-analyses with 12 months to 4 year follow-up. We observed 12 month increases for intervention vs control participants in steps/day (mean difference (MD)=554 (95% CIs: 384 to 724) p<0.0001, I2=0%; 2446 participants; four studies) and weekly MVPA minutes (MD=35 (95% CI: 27 to 43) p<0.0001, I2=0%; 2647 participants; four studies). Effects were sustained up to 4 years for steps/day (MD=494 (95% CI: 251 to 738) p<0.0001, I2=0%; 1944 participants; four studies) and weekly MVPA minutes (MD=25 (95% CI: 13 to 37) p<0.0001, I2=0%; 1458 participants; three studies). CONCLUSIONS: There are few PA interventions with objective follow-up beyond 12 months, more studies are needed. However, this review provided evidence of PA intervention effects beyond 12 months and sustained up to 4 years for both steps/day and MVPA. These findings have important implications for potential long-term health benefits. PROSPERO REGISTRATION NUMBER: CRD42017075753

Neuroendovascular clinical trials disruptions due to COVID-19. Potential future challenges and opportunities

Objective: To assess the impact of COVID-19 on neurovascular research and deal with the challenges imposed by the pandemic. Methods: A survey-based study focused on randomized controlled trials (RCTs) and single-arm studies for acute ischemic stroke and cerebral aneurysms was developed by a group of senior neurointerventionalists and sent to sites identified through the clinical trials website (https:// clinicaltrials. gov/), study sponsors, and physician investigators. Results: The survey was sent to 101 institutions, with 65 responding (64%). Stroke RCTs were being conducted at 40 (62%) sites, aneurysm RCTs at 22 (34%) sites, stroke single-arm studies at 37 (57%) sites, and aneurysm single-arm studies at 43 (66%) sites. Following COVID-19, enrollment was suspended at 51 (78%) sites—completely at 21 (32%) and partially at 30 (46%) sites. Missed trial-related clinics and imaging follow-ups and protocol deviations were reported by 27 (42%), 24 (37%), and 27 (42%) sites, respectively. Negative reimbursements were reported at 17 (26%) sites. The majority of sites, 49 (75%), had put new trials on hold. Of the coordinators, 41 (63%) worked from home and 20 (31%) reported a personal financial impact. Remote consent was possible for some studies at 34 (52%) sites and for all studies at 5 (8%) sites. At sites with suspended trials (n=51), endovascular treatment without enrollment occurred at 31 (61%) sites for stroke and 23 (45%) sites for aneurysms. A total of 277 patients with acute ischemic stroke and 184 with cerebral aneurysms were treated without consideration for trial enrollment. Conclusion: Widespread disruption of neuroendovascular trials occurred because of COVID-19. As sites resume clinical research, steps to mitigate similar challenges in the future should be considered

Peer Reviewed Evaluation of Registered End-Points of Randomised Trials (the PRE-REPORT study): a stepped wedge, cluster-randomised trial.

OBJECTIVE: To test whether providing relevant clinical trial registry information to peer reviewers evaluating trial manuscripts decreases discrepancies between registered and published trial outcomes. DESIGN: Stepped wedge, cluster-randomised trial, with clusters comprised of eligible manuscripts submitted to each participating journal between 1 November 2018 and 31 October 2019. SETTING: Thirteen medical journals. PARTICIPANTS: Manuscripts were eligible for inclusion if they were submitted to a participating journal during the study period, presented results from the primary analysis of a clinical trial, and were peer reviewed. INTERVENTIONS: During the control phase, there were no changes to pre-existing peer review practices. After journals crossed over into the intervention phase, peer reviewers received a data sheet describing whether trials were registered, the initial registration and enrolment dates, and the registered primary outcome(s) when enrolment began. MAIN OUTCOME MEASURE: The presence of a clearly defined, prospectively registered primary outcome consistent with the primary outcome in the published trial manuscript, as determined by two independent outcome assessors. RESULTS: We included 419 manuscripts (243 control and 176 intervention). Participating journals published 43% of control-phase manuscripts and 39% of intervention-phase manuscripts (model-estimated percentage difference between intervention and control trials = -10%, 95% CI -25% to 4%). Among the 173 accepted trials, published primary outcomes were consistent with clearly defined, prospectively registered primary outcomes in 40 of 105 (38%) control-phase trials and 27 of 68 (40%) intervention-phase trials. A linear mixed model did not show evidence of a statistically significant primary outcome effect from the intervention (estimated difference between intervention and control=-6% (90% CI -27% to 15%); one-sided p value=0.68). CONCLUSIONS: These results do not support use of the tested intervention as implemented here to increase agreement between prospectively registered and published trial outcomes. Other approaches are needed to improve the quality of outcome reporting of clinical trials. TRIAL REGISTRATION NUMBER: ISRCTN41225307