Subgroup Analysis of Trials Is Rarely Easy (SATIRE): a study protocol for a systematic review to characterize the analysis, reporting, and claim of subgroup effects in randomized trials

<p>Abstract</p> <p>Background</p> <p>Subgroup analyses in randomized trials examine whether effects of interventions differ between subgroups of study populations according to characteristics of patients or interventions. However, findings from subgroup analyses may be misleading, potentially resulting in suboptimal clinical and health decision making. Few studies have investigated the reporting and conduct of subgroup analyses and a number of important questions remain unanswered. The objectives of this study are: 1) to describe the reporting of subgroup analyses and claims of subgroup effects in randomized controlled trials, 2) to assess study characteristics associated with reporting of subgroup analyses and with claims of subgroup effects, and 3) to examine the analysis, and interpretation of subgroup effects for each study's primary outcome.</p> <p>Methods</p> <p>We will conduct a systematic review of 464 randomized controlled human trials published in 2007 in the 118 Core Clinical Journals defined by the National Library of Medicine. We will randomly select journal articles, stratified in a 1:1 ratio by higher impact versus lower impact journals. According to 2007 ISI total citations, we consider the <it>New England Journal of Medicine, JAMA, Lancet, Annals of Internal Medicine</it>, and <it>BMJ </it>as higher impact journals. Teams of two reviewers will independently screen full texts of reports for eligibility, and abstract data, using standardized, pilot-tested extraction forms. We will conduct univariable and multivariable logistic regression analyses to examine the association of pre-specified study characteristics with reporting of subgroup analyses and with claims of subgroup effects for the primary and any other outcomes.</p> <p>Discussion</p> <p>A clear understanding of subgroup analyses, as currently conducted and reported in published randomized controlled trials, will reveal both strengths and weaknesses of this practice. Our findings will contribute to a set of recommendations to optimize the conduct and reporting of subgroup analyses, and claim and interpretation of subgroup effects in randomized trials.</p

Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial

IntroductionPerioperative Ischaemic Evaluation-2 (POISE-2) is an international 2×2 factorial randomised controlled trial of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients who undergo non-cardiac surgery. Perioperative aspirin (and possibly clonidine) may reduce the risk of postoperative acute kidney injury (AKI).Methods and analysisAfter receipt of grant funding, serial postoperative serum creatinine measurements began to be recorded in consecutive patients enrolled at substudy participating centres. With respect to the study schedule, the last of over 6500 substudy patients from 82 centres in 21 countries were randomised in December 2013. The authors will use logistic regression to estimate the adjusted OR of AKI following surgery (compared with the preoperative serum creatinine value, a postoperative increase ≥26.5 μmol/L in the 2 days following surgery or an increase of ≥50% in the 7 days following surgery) comparing each intervention to placebo, and will report the adjusted relative risk reduction. Alternate definitions of AKI will also be considered, as will the outcome of AKI in subgroups defined by the presence of preoperative chronic kidney disease and preoperative chronic aspirin use. At the time of randomisation, a subpopulation agreed to a single measurement of serum creatinine between 3 and 12 months after surgery, and the authors will examine intervention effects on this outcome.Ethics and disseminationThe authors were competitively awarded a grant from the Canadian Institutes of Health Research for this POISE-2 AKI substudy. Ethics approval was obtained for additional kidney data collection in consecutive patients enrolled at participating centres, which first began for patients enrolled after January 2011. In patients who provided consent, the remaining longer term serum creatinine data will be collected throughout 2014. The results of this study will be reported no later than 2015.Clinical Trial Registration NumberNCT01082874

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018

National practice variation in pneumonectomy perioperative care among Canadian thoracic surgeons.

OBJECTIVES: Our objective was to assess perioperative pneumonectomy practices among Canadian thoracic surgeons as part of a quality-improvement initiative to determine practice variability and identify areas for study/improvement. METHODS: After several rounds of survey development and piloting, a 29-item survey was distributed using the Dillman method to all practicing members of the Canadian Association of Thoracic Surgeons. RESULTS: The response rate was 87% (62 of 71). Median number of pneumonectomies performed annually was 3.5 (interquartile range 2.75-5.00). Routine preoperative workup was variable, but the most consistently reported tests were diffusing capacity of the lungs for carbon monoxide (87%, n = 54) and spirometry (85%, n = 53). Reported routine use of epidurals (84%, n = 52) was more prevalent than paravertebral blocks (18%, n = 11). Many (69%, n = 43) reported intraoperative restrictionPostoperatively, 84% (n = 52) reported daily fluid restrictionstrategies, respondents appeared more focused on minimizing peak airway pressures (55%, n = 34) rather than tidal volumes (18%, n = 11). Twenty-four percent (n = 15) reported using intraoperative steroids in attempts to decrease postoperative complications. Thirty-two percent (n = 20) do not routinely insert chest tubes, whereas the most common practice (44%, n = 27) was to insert chest tubes attached to conventional drainage systems without suction. Eighty-two percent (n = 52) reported willingness to participate in multicentre studies regarding perioperative pneumonectomy practices. CONCLUSIONS: Our findings suggest significant variability in reported preoperative, intraoperative and postoperative care practices for pneumonectomy across Canada. This survey has a high response rate, representing the Canadian experience, and highlights several areas for study and quality-improvement initiatives. Many respondents report willingness to participate in multicentre initiatives

The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index

AbstractObjectivesA P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes.Study Design and SettingA review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result.ResultsThe 399 eligible trials had a median sample size of 682 patients (range: 15–112,604) and a median of 112 events (range: 8–5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0–109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up.ConclusionThe statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results

Temporal and Spatial Patterns of Inflammation and Tissue Injury in Patients with Postoperative Respiratory Failure after Lung Resection Surgery: A Nested Case–Control Study

Thoracic surgeries involving resection of lung tissue pose a risk of severe postoperative pulmonary complications, including acute respiratory distress syndrome (ARDS) and respiratory failure. Lung resections require one-lung ventilation (OLV) and, thus, are at higher risk of ventilator-induced lung injury (VILI) attributable to barotrauma and volutrauma in the one ventilated lung, as well as hypoxemia and reperfusion injury on the operated lung. Further, we also aimed to assess the differences in localized and systemic markers of tissue injury/inflammation in those who developed respiratory failure after lung surgery versus matched controls who did not develop respiratory failure. We aimed to assess the different inflammatory/injury marker patterns induced in the operated and ventilated lung and how this compared to the systemic circulating inflammatory/injury marker pattern. A case–control study nested within a prospective cohort study was performed. Patients with postoperative respiratory failure after lung surgery (n = 5) were matched with control patients (n = 6) who did not develop postoperative respiratory failure. Biospecimens (arterial plasma, bronchoalveolar lavage separately from ventilated and operated lungs) were obtained from patients undergoing lung surgery at two timepoints: (1) just prior to initiation of OLV and (2) after lung resection was completed and OLV stopped. Multiplex electrochemiluminescent immunoassays were performed for these biospecimen. We quantified 50 protein biomarkers of inflammation and tissue injury and identified significant differences between those who did and did not develop postoperative respiratory failure. The three biospecimen types also display unique biomarker patterns

Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery : the VISION study

AIMS: The aim of this study was to assess the effects of pre-operative statin therapy on cardiovascular events in the first 30-days after non-cardiac surgery. METHODS AND RESULTS: We conducted an international, prospective, cohort study of patients who were ≥45 years having in-patient non-cardiac surgery. We estimated the probability of receiving statins pre-operatively using a multivariable logistic model and conducted a propensity score analysis to correct for confounding. A total of 15 478 patients were recruited at 12 centres in eight countries from August 2007 to January 2011. The matched population consisted of 2845 patients (18.4%) treated with a statin and 4492 (29.0%) controls. The pre-operative use of statins was associated with lower risk of the primary outcome, a composite of all-cause mortality, myocardial injury after non-cardiac surgery (MINS), or stroke at 30 days [relative risk (RR), 0.83; 95% confidence interval (CI), 0.73–0.95; P = 0.007]. Statins were also associated with a significant lower risk of all-cause mortality (RR, 0.58; 95% CI, 0.40–0.83; P = 0.003), cardiovascular mortality (RR, 0.42; 95% CI, 0.23–0.76; P = 0.004), and MINS (RR, 0.86; 95% CI, 0.73–0.98; P = 0.02). There were no statistically significant differences in the risk of myocardial infarction or stroke. CONCLUSION: Among patients undergoing non-cardiac surgery, pre-operative statin therapy was independently associated with a lower risk of cardiovascular outcomes at 30 days. These results require confirmation in a large randomized trial. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov NCT0051210