Approaches to multiplicity in publicly funded pragmatic randomised controlled trials: a survey of clinical trials units and a rapid review of published trials.

BACKGROUND: Opinions and practices vary around the issue of performing multiple statistical tests in randomised controlled trials (RCTs). We carried out a study to collate information about opinions and practices using a methodological rapid review and a survey, specifically of publicly funded pragmatic RCTs that are not seeking marketing authorisation. The aim was to identify the circumstances under which researchers would make a statistical adjustment for multiplicity. METHODS: A review was performed extracting information from articles reporting primary analyses of pragmatic RCTs in one of seven high quality medical journals, in January to June (inclusive) 2018. A survey (Survey Monkey) eliciting opinions and practices around multiplicity was distributed to the 47 registered clinical trials units (CTUs) in the UK. RESULTS: One hundred and thirty-eight RCTs were included in the review, and survey responses were received from 27/47 (57%) CTUs. Both the review and survey indicated that adjusting for multiplicity was considered most important for multiple treatment comparisons; adjustment was performed for 11/23 (48%) published trials, and 24/27 (89%) CTU statisticians reported they would consider adjustment. Opinions and practices varied around adjustment for multiplicity arising from multiple primary outcomes and interim analyses. Adjustment was considered less important for multiplicity due to multiple secondary outcomes (adjustment performed for 17/136 [13%] published trials and 3/27 [11%] CTU statisticians would consider adjustment) and subgroup analyses (8/85 [9%] published trials adjusted and 6/27 CTU [22%] statisticians would consider adjustment). CONCLUSIONS: There is variation in opinions about adjustment for multiplicity among both statisticians reporting RCTs and applied statisticians working in CTUs. Further guidance is needed on the circumstances in which adjustment should be considered in relation to primary trial hypotheses, and if there are any situations in which adjustment would be recommended in the context of secondary analyses.

Analytical challenges in estimating the effect of exposures that are bounded by follow-up time: experiences from the Blood Stream Infection-Focus on Outcomes study.

OBJECTIVE: To illustrate the challenges of estimating the effect of an exposure that is bounded by duration of follow-up on all-cause 28-day mortality, whilst simultaneously addressing missing data and time-varying covariates. STUDY DESIGN AND METHODS: BSI-FOO is a multicentre cohort study with the primary aim of quantifying the effect of modifiable risk factors, including time to initiation of therapy, on all-cause 28-day mortality in patients with bloodstream infection. The primary analysis involved two Cox proportional hazard models, first one for non-modifiable risk factors and second one for modifiable risk factors, with a risk score calculated from the first model included as a covariate in the second model. Modifiable risk factors considered in this study were recorded daily for a maximum of 28 days after infection. Follow-up was split at daily intervals from day 0 to 28 with values of daily collected data updated at each interval (i.e., one row per patient per day). ANALYTICAL CHALLENGES: Estimating the effect of time to initiation of treatment on survival is analytically challenging since only those who survive to time t can wait until time t to start treatment, introducing immortal time bias. Time-varying covariates representing cumulative counts were used for variables bounded by survival time e.g. the cumulative count of days before first receipt of treatment. Multiple imputation using chained equations was used to impute missing data, using conditional imputation to avoid imputing non-applicable data e.g. ward data after discharge. CONCLUSION: Using time-varying covariates represented by cumulative counts within a one row per day per patient framework can reduce the risk of bias in effect estimates. The approach followed uses established methodology and is easily implemented in standard statistical packages.

Modifiable healthcare factors affecting 28-day survival in bloodstream infection: a prospective cohort study.

BACKGROUND: Bloodstream infection is common in the UK and has significant mortality depending on the pathogen involved, site of infection and other patient factors. Healthcare staffing and ward activity may also impact on outcomes in a range of conditions, however there is little specific National Health Service (NHS) data on the impact for patients with bloodstream infection. Bloodstream Infections - Focus on Outcomes is a multicentre cohort study with the primary aim of identifying modifiable risk factors for 28-day mortality in patients with bloodstream infection due to one of six key pathogens. METHODS: Adults under the care of five NHS Trusts in England and Wales between November 2010 and May 2012 were included. Multivariable Cox regression was used to quantify the association between modifiable risk factors, including staffing levels and timing of appropriate therapy, and 28-day mortality, after adjusting for non-modifiable risk factors such as patient demographics and long-term comorbidities. RESULTS: A total of 1676 patients were included in the analysis population. Overall, 348/1676 (20.8%) died within 28 days. Modifiable factors associated with 28-day mortality were ward speciality, ward activity (admissions and discharges), movement within ward speciality, movement from critical care, and time to receipt of appropriate antimicrobial therapy in the first 7 days. For each additional admission or discharge per 10 beds, the hazard increased by 4% (95% CI 1 to 6%) in medical wards and 11% (95% CI 4 to 19%) in critical care. Patients who had moved wards within speciality or who had moved out of a critical care ward had a reduction in hazard of mortality. In the first 7 days, hazard of death increased with increasing time to receipt of appropriate antimicrobial therapy. CONCLUSION: This study underlines the importance of appropriate antimicrobials within the first 7 days, and the potential for ward activity and ward movements to impact on survival in bloodstream infection.

Liberal or restrictive transfusion after cardiac surgery.

BACKGROUND: Whether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain. METHODS: We conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.5 g per deciliter) or a liberal transfusion threshold (hemoglobin level <9 g per deciliter). The primary outcome was a serious infection (sepsis or wound infection) or an ischemic event (permanent stroke [confirmation on brain imaging and deficit in motor, sensory, or coordination functions], myocardial infarction, infarction of the gut, or acute kidney injury) within 3 months after randomization. Health care costs, excluding the index surgery, were estimated from the day of surgery to 3 months after surgery. RESULTS: A total of 2007 patients underwent randomization; 4 participants withdrew, leaving 1000 in the restrictive-threshold group and 1003 in the liberal-threshold group. Transfusion rates after randomization were 53.4% and 92.2% in the two groups, respectively. The primary outcome occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P=0.30); there was no indication of heterogeneity according to subgroup. There were more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% CI, 1.00 to 2.67; P=0.045). Serious postoperative complications, excluding primary-outcome events, occurred in 35.7% of participants in the restrictive-threshold group and 34.2% of participants in the liberal-threshold group. Total costs did not differ significantly between the groups. CONCLUSIONS: A restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or health care costs. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN70923932.).

Implementation of NICE guidance on urinary tract infections in children in primary and secondary care.

AIM: To audit compliance with the 2007 National Institute of Clinical Excellence guidelines on the management of urinary tract infection in children under the age of 16 years across primary and secondary care services in England. METHODS: A retrospective multisite audit of 10 general practice, 3 paediatric, 2 paediatric emergency and 2 emergency general units. Four distinct geographical areas were represented. Data were collected between 1 January 2010 and 31 December 2010. Six criteria were audited, which focused on the following: improving the rate of diagnosis, management of the very young child with UTI and selection of children for imaging. RESULTS: A total of 1149 children were audited (682 from primary care and 467 from secondary care). Overall compliance was as follows: criterion 1: 28%; criterion 2: 68%; criterion 3: 89%; criterion 4: 43%; criterion 5 (comprising 12 subcriteria): 13% and for criterion 6: 45%. CONCLUSION: The results indicate significant shortcomings in the implementation of NICE guidance on childhood UTI in England. The guidance is complex and this makes its implementation challenging. It was difficult to identify children presenting with nonspecific fever from clinical data systems. Adequate IT systems throughout the NHS are a key step to improving implementation of this and other NICE guidance.

Point of care platelet activity measurement in primary PCI [PINPOINT-PPCI]: a protocol paper.

BACKGROUND: Optimal treatment of acute ST-elevation myocardial infarction (STEMI) involves rapid diagnosis, and transfer to a cardiac centre capable of percutaneous coronary intervention (PCI) for immediate mechanical revascularisation. Successful treatment requires rapid return of perfusion to the myocardium achieved by thromboaspiration, passivation of the culprit lesion with stent scaffolding and systemic inhibition of thrombosis and platelet activation. A delicate balance exists between thrombosis and bleeding and consequently anti-thrombotic and antiplatelet treatment regimens continue to evolve. The desire to achieve reperfusion as soon as possible, in the setting of high platelet reactivity, requires potent and fast-acting anti-thrombotic/anti-platelet therapies. The associated bleeding risk may be minimised by use of short-acting anti-thrombotic intravenous agents. However, effective oral platelet inhibition is required to prevent recurrent thrombosis. The interaction between baseline platelet reactivity, timing of revascularisation and effective inhibition of thrombosis is yet to be formally investigated. METHODS/DESIGN: We present a protocol for a prospective observational study in patients presenting with acute STEMI treated with primary PCI (PPCI) and receiving bolus/infusion bivalirudin and prasugrel therapy. The objective of this study is to describe variation in platelet reactivity, as measured by the multiplate platelet function analyser, at presentation, the end of the PPCI procedure and 1, 2, & 24 hours post-procedure. We intend to assess the prevalence of high residual platelet reactivity within 24 hours of PPCI in acute STEMI patients receiving prasugrel and bivalirudin. Additionally, we will investigate the association between high platelet reactivity before and after PPCI and the door-to-procedure completion time.This is a single centre study with a target sample size of 108 participants. DISCUSSION: The baseline platelet reactivity on presentation with a STEMI may impact on the effect of acute anti-thrombotic and anti-platelet therapy and expose patients to a heightened risk of bleeding or ongoing thrombosis. This study will define the baseline variation in platelet reactivity in a population of patients experiencing acute STEMI and assess the pharmacodynamic response to combined treatment with bivalirudin and prasugrel. The data obtained from this trial will be hypothesis generating for future trials testing alternative pharmacotherapies in the acute phase of treatment for STEMI. TRIAL REGISTRATION: This study has approval from Wiltshire research ethics committee (10/H0106/87) and is registered with current controlled trials (http://www.controlled-trials.com/ISRCTN82257414).

A multi-centre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and healthcare resource use following cardiac surgery: study protocol.

Thresholds for red blood cell transfusion following cardiac surgery vary by hospital and surgeon. The TITRe2 multi-centre randomised controlled trial aims to randomise 2000 patients from 17 United Kingdom centres, and tests the hypothesis that a restrictive transfusion threshold will reduce postoperative morbidity and health service costs compared to a liberal threshold. Patients consent to take part in the study pre-operatively but are only randomised if their haemoglobin falls below 9 g/dL during their post-operative hospital stay. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first three months after randomisation. Many challenges have been encountered in the set-up and running of the study.

Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness-a protocol for a randomised controlled trial (ASTUTE trial).

INTRODUCTION: Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care. METHODS AND ANALYSIS: The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted. ETHICS AND DISSEMINATION: The trial received Research Ethics Committee (REC) approval from South Central - Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available. TRIAL REGISTRATION: ISRCTN31474800. Registered 14 April 2020.

The clinical and cost-effectiveness of elective primary total knee replacement with PAtellar Resurfacing compared to selective patellar resurfacing: a pragmatic multicentre randomized controlled Trial (PART).

Aims: During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon's decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods: The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion: The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing.

Characteristics of children with cerebral palsy in the ORACLE children study.

AIMS: We have identified an excess of children with cerebral palsy (CP) born to women who received antibiotic treatment for spontaneous preterm labour (SPL). This nested study investigated the profile of impairment among children with CP in the ORACLE Children Study (OCS), and contrasted outcomes with those in 4Child, a population CP registry. METHOD: The study group comprised 167 children aged from 7 to 10 years (100 males, 67 females) with CP from the OCS, who were subdivided into a preterm rupture of membranes (PROM) group (87 children) and an SPL group (80 children). The OCS sought follow-up information regarding the health and behaviour of surviving children at 7 years of age in the UK using a parent-report postal questionnaire. Families provided further information to define wider aspects of function and were offered a physiotherapy assessment. RESULTS: The prevalence of CP was higher among children in the OCS than among those in 4Child (standardized morbidity ratios: SPL group, 3.12 [95% confidence interval {CI} 2.47-3.87); PROM group: 1.56 (CI 1.24-1.92)]. The proportion of children with CP born after 32 weeks of gestation was higher in in the SPL group (73%) than in the PROM group (30%); the prevalence of CP was higher in the SPL group than in the PROM group or 4Child. Children with CP in the OCS tended to have similar distributions of neuroimpairment as children in 4Child, but motor impairment and associated vision and hearing problems were found to be less severe. INTERPRETATION: The pattern of CP in both the PROM and the SPL groups was similar, but functional outcomes were milder, compared with children with CP in the general population. However, in these groups the risk of CP was increased independently of gestational age. This is consistent with findings that ongoing inflammatory damage can cause CP.

Thoracic epidural anesthesia improves early outcomes in patients undergoing off-pump coronary artery bypass surgery: a prospective, randomized, controlled trial.

BACKGROUND: The aim of this two-center, open, randomized, controlled trial was to evaluate the impact of thoracic epidural anesthesia on early clinical outcomes in patients undergoing off-pump coronary artery bypass surgery. METHODS: Two hundred and twenty-six patients were randomized to either general anesthesia plus epidural (GAE) (n = 109) or general anesthesia only (GA) (n = 117). The primary outcome was length of postoperative hospital stay. Secondary outcomes were: arrhythmia, inotropic support, intubation time, perioperative myocardial infarction, neurologic events, intensive care stay, pain scores, and analgesia requirement. RESULTS: Baseline characteristics were similar in the two groups. One patient died in the GAE group. Median postoperative stay was significantly reduced in the GAE, compared with the GA, group (5 days, interquartile range [5-6] vs. 6 days, interquartile range [5-7], hazard ratio = 1.39, 95% CI [1.06-1.82]; P = 0.017). The incidence of arrhythmias and the median intubation time were both significantly lower in the GAE, compared with the GA, group (odds ratio = 0.41, 95% CI [0.22-0.78], P = 0.006 and hazard ratio = 1.73, 95% CI [1.31-2.27], P < 0.001, respectively). Patients in the GAE group were more likely to need vasoconstrictors intraoperatively than in the GA group (odds ratio = 2.50, 95% CI [1.22-5.12]; P = 0.012). The GAE, compared with GA, group reported significantly lower levels of impairment for all pain domains and reduced morphine usage (odds ratio = 0.07, 95% CI [0.03-0.17]; P < 0.001). CONCLUSION: In patients undergoing off-pump coronary artery bypass surgery, the addition of thoracic epidural to general anesthesia significantly reduces the incidence of postoperative arrhythmias and improves pain control and overall quality of recovery, allowing earlier extubation and hospital discharge.

Cost-effectiveness of rapid laboratory-based mass-spectrometry diagnosis of bloodstream infection: evidence from the RAPIDO randomised controlled trial.

OBJECTIVES AND INTERVENTION: Bloodstream infection, the presence of viable micro-organisms in the blood, is a prevalent clinical event associated with substantial mortality. Patient outcomes may be improved when the causative micro-organism is identified quickly. We assessed the cost-effectiveness of rapid microbial identification by matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry. DESIGN: Economic evaluation alongside a randomised multicentre trial (RAPIDO: RAPId Diagnosis on Outcome) assessing the impact of rapid identification by MALDI-TOF spectrometry. SETTING: Adult inpatients with bloodstream infections at seven National Health Service hospital trusts in England and Wales. PRIMARY OUTCOME: Net monetary benefit, estimated as incremental costs compared with incremental 28-day survival, of rapid identification by MALDI-TOF spectrometry compared with conventional identification. METHODS: Patients were randomised (1:1) to receive diagnosis by conventional methods of microbial identification (conventional arm) only or by MALDI-TOF spectrometry in addition to conventional identification (RAPIDO arm). RESULTS: Data from 5550 patients were included in primary analysis. Mean imputed costs in 2018/2019 prices per patient were lower by £126 in the RAPIDO arm (95% CI -£784 to £532) but the proportion of patients alive at day 28 was lower (81.4% vs 82.3%). The probability of cost-effectiveness of MALDI-TOF was <0.5 at cost-effectiveness thresholds between £20 000 and £50 000. CONCLUSIONS: Adjunctive MALDI-TOF diagnosis was unlikely to be cost-effective when measured as cost per death avoided at 28 days. However, the differences between arms in cost and effect were modest, associated with uncertainty and may not accurately reflect 'real-world' routine use of MALDI-TOF technology in this patient group. TRIAL REGISTRATION NUMBERS: ISRCTN97107018/UKCRN 11978.

Preoperative VolumE Replacement therapy in DIabetic patients undergoing coronary artery bypass grafting surgery: results from an open parallel group randomized Controlled Trial (VeRDiCT).

OBJECTIVES: To investigate the effect of preoperative volume replacement therapy (VRT) on renal function, health outcome and time to fitness for discharge in diabetic patients undergoing coronary artery bypass grafting (CABG). METHODS: In 2 parallel randomized controlled trials, diabetic patients were allocated to preoperative VRT (1 ml/kg/h of Hartmann's solution for 12 h) or usual care. Primary outcome was time to fitness for discharge. Secondary outcomes included acute kidney injury, postoperative complications, patient-reported quality of life (QoL), hospital resource use and markers of renal, cardiac and inflammatory injury. RESULTS: In total, 169 patients were randomized (84 VRT, 85 usual care; mean age 64 years; 88% male). Time to fitness for discharge was similar between groups [median 6 days; interquartile range 5.0-9.0 in both groups; hazard ratio 0.95, 95% confidence interval (CI) 0.65-1.38; P = 0.78]. Postoperative acute kidney injury was not statistically different (VRT: 27.7% vs usual care: 18.8%, odds ratio 1.72, 95% CI 0.82-3.59; P = 0.15). Estimated glomerular filtration rate (mean difference -0.92, 95% CI -4.18 to 2.25; P = 0.56), microalbumin/creatinine ratio [geometric mean ratio (GMR) 1.16, 95% CI 0.94-1.42; P = 0.16], N-acetyl-beta-d-glucosaminidase (GMR 1.08, 95% CI 0.83-1.40; P = 0.57), C-reactive protein (GMR 1.00, 95% CI 0.88-1.13; P = 0.94), troponin T (Trop-T; GMR 1.18, 95% CI 0.78-1.79; P = 0.39) and other secondary health outcomes were similar between groups. QoL improved in both groups at 3 months with no difference observed. CONCLUSIONS: The use of preoperative VRT is not superior to usual care in diabetic patients undergoing CABG. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN02159606.

Normothermic versus hypothermic cardiopulmonary bypass in low-risk paediatric heart surgery: a randomised controlled trial.

OBJECTIVE: To compare normothermic (35°C-36°C) versus hypothermic (28°C) cardiopulmonary bypass (CPB) in paediatric patients undergoing open heart surgery to test the hypothesis that normothermic CPB perfusion maintains the functional integrity of major organ systems leading to faster recovery. METHODS: Two single-centre, randomised controlled trials (known as Thermic-1 and Thermic-2, respectively) were carried out to compare the effectiveness and acceptability of normothermic versus hypothermic CPB in children with congenital heart disease undergoing open heart surgery. In both studies, the co-primary clinical outcomes were duration of inotropic support, intubation time and postoperative hospital stay. RESULTS: In total, 200 participants were recruited; 59 to the Thermic-1 study and 141 to the Thermic-2 study. 98 patients received normothermic CPB and 102 patients received hypothermic CPB. There were no significant differences between the treatment groups for any of the co-primary outcomes: inotrope duration HR=1.01, 95% CI (0.72 to 1.41); intubation time HR=1.14, 95% CI (0.86 to 1.51); postoperative hospital stay HR=1.06, 95% CI (0.80 to 1.40). Differences favouring normothermia were found in urea nitrogen at 2 days geometric mean ratio (GMR)=0.86 95% CI (0.77 to 0.97); serum creatinine at 3 days GMR=0.89, 95% CI (0.81 to 0.98); urinary albumin at 48 hours GMR=0.32, 95% CI (0.14 to 0.74) and neutrophil gelatinase-associated lipocalin at 4 hours GMR=0.47, 95% CI (0.22 to 1.02), but not at other postoperative time points. CONCLUSIONS: Normothermic CPB is as safe and effective as hypothermic CPB and can be routinely adopted as a perfusion strategy in low-risk infants and children undergoing open heart surgery. TRIAL REGISTRATION NUMBER: ISRCTN93129502.

The ORACLE Children Study: educational outcomes at 11†years of age following antenatal prescription of erythromycin or co-amoxiclav.

BACKGROUND: Antibiotics used for women in spontaneous preterm labour without overt infection, in contrast to those with preterm rupture of membranes, are associated with altered functional outcomes in their children. METHODS: From the National Pupil Database, we used Key Stage 2 scores, national test scores in school year 6 at 11 years of age, to explore the hypothesis that erythromycin and co-amoxiclav were associated with poorer educational outcomes within the ORACLE Children Study. RESULTS: Anonymised scores for 97% of surviving children born to mothers recruited to ORACLE and resident in England were analysed against treatment group adjusting for key available socio-demographic potential confounders. No association with crude or with adjusted scores for English, mathematics or science was observed by maternal antibiotic group in either women with preterm rupture of membranes or spontaneous preterm labour with intact membranes. While the proportion receiving special educational needs was similar in each group (range 31.6-34.4%), it was higher than the national rate of 19%. CONCLUSIONS: Despite evidence that antibiotics are associated with increased functional impairment at 7 years, educational test scores and special needs at 11 years of age show no differences between trial groups. TRIAL REGISTRATION NUMBER: ISCRT Number 52995660 (original ORACLE trial number).

A multicentre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and health-care resource use following cardiac surgery (TITRe2).

BACKGROUND: Uncertainty about optimal red blood cell transfusion thresholds in cardiac surgery is reflected in widely varying transfusion rates between surgeons and cardiac centres. OBJECTIVE: To test the hypothesis that a restrictive compared with a liberal threshold for red blood cell transfusion after cardiac surgery reduces post-operative morbidity and health-care costs. DESIGN: Multicentre, parallel randomised controlled trial and within-trial cost-utility analysis from a UK NHS and Personal Social Services perspective. We could not blind health-care staff but tried to blind participants. Random allocations were generated by computer and minimised by centre and operation. SETTING: Seventeen specialist cardiac surgery centres in UK NHS hospitals. PARTICIPANTS: Patients aged > 16 years undergoing non-emergency cardiac surgery with post-operative haemoglobin < 9 g/dl. Exclusion criteria were: unwilling to have transfusion owing to beliefs; platelet, red blood cell or clotting disorder; ongoing or recurrent sepsis; and critical limb ischaemia. INTERVENTIONS: Participants in the liberal group were eligible for transfusion immediately after randomisation (post-operative haemoglobin < 9 g/dl); participants in the restrictive group were eligible for transfusion if their post-operative haemoglobin fell to < 7.5 g/dl during the index hospital stay. MAIN OUTCOME MEASURES: The primary outcome was a composite outcome of any serious infectious (sepsis or wound infection) or ischaemic event (permanent stroke, myocardial infarction, gut infarction or acute kidney injury) during the 3 months after randomisation. Events were verified or adjudicated by blinded personnel. Secondary outcomes included blood products transfused; infectious events; ischaemic events; quality of life (European Quality of Life-5 Dimensions); duration of intensive care or high-dependency unit stay; duration of hospital stay; significant pulmonary morbidity; all-cause mortality; resource use, costs and cost-effectiveness. RESULTS: We randomised 2007 participants between 15 July 2009 and 18 February 2013; four withdrew, leaving 1000 and 1003 in the restrictive and liberal groups, respectively. Transfusion rates after randomisation were 53.4% (534/1000) and 92.2% (925/1003). The primary outcome occurred in 35.1% (331/944) and 33.0% (317/962) of participants in the restrictive and liberal groups [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.91 to 1.34; p = 0.30], respectively. There were no subgroup effects for the primary outcome, although some sensitivity analyses substantially altered the estimated OR. There were no differences for secondary clinical outcomes except for mortality, with more deaths in the restrictive group (4.2%, 42/1000 vs. 2.6%, 26/1003; hazard ratio 1.64, 95% CI 1.00 to 2.67; p = 0.045). Serious post-operative complications excluding primary outcome events occurred in 35.7% (354/991) and 34.2% (339/991) of participants in the restrictive and liberal groups, respectively. The total cost per participant from surgery to 3 months postoperatively differed little by group, just £182 less (standard error £488) in the restrictive group, largely owing to the difference in red blood cells cost. In the base-case cost-effectiveness results, the point estimate suggested that the restrictive threshold was cost-effective; however, this result was very uncertain partly owing to the negligible difference in quality-adjusted life-years gained. CONCLUSIONS: A restrictive transfusion threshold is not superior to a liberal threshold after cardiac surgery. This finding supports restrictive transfusion due to reduced consumption and costs of red blood cells. However, secondary findings create uncertainty about recommending restrictive transfusion and prompt a new hypothesis that liberal transfusion may be superior after cardiac surgery. Reanalyses of existing trial datasets, excluding all participants who did not breach the liberal threshold, followed by a meta-analysis of the reanalysed results are the most obvious research steps to address the new hypothesis about the possible harm of red blood cell transfusion. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70923932. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 60. See the NIHR Journals Library website for further project information.

The effect of a monetary incentive on return of a postal health and development questionnaire: a randomised trial [ISRCTN53994660].

BACKGROUND: Postal questionnaires are widely used to collect data in healthcare research but a poor response rate may reduce the validity and reliability of results. There was a lack of evidence available relating to use of a monetary incentive to improve the response rate in the healthcare setting. METHODS: The MRC ORACLE Children Study is assessing the health and development of nearly 9000 seven year old children whose mothers' joined the MRC ORACLE Trial. We carried out a randomised controlled trial of inclusion of monetary incentive (five pound voucher redeemable at many high street stores) with the reminder questionnaire to parents. This trial took place between April 2002 and November 2003. When the parents were sent the reminder questionnaire about their child's health and development they were randomly assigned by concealed computer-generated allocation stratified by week of birthday to receive a five pound voucher or no incentive. The population were 722 non-responders to the initial mailing of a 12-page questionnaire. MAIN OUTCOME MEASURES: Difference in response rate between the two groups. RESULTS: Inclusion of the voucher with the reminder questionnaire resulted in a 11.7%(95% CI 4.7% to 18.6%) improvement in the response rate between the two groups. CONCLUSION: This improvement in response rate and hence the validity and reliability of results obtained appears to be justified ethically and financially.

Transfusion Indication Threshold Reduction (TITRe2) randomized controlled trial in cardiac surgery: statistical analysis plan.

BACKGROUND: The Transfusion Indication Threshold Reduction (TITRe2) trial is the largest randomized controlled trial to date to compare red blood cell transfusion strategies following cardiac surgery. This update presents the statistical analysis plan, detailing how the study will be analyzed and presented. The statistical analysis plan has been written following recommendations from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, prior to database lock and the final analysis of trial data. Outlined analyses are in line with the Consolidated Standards of Reporting Trials (CONSORT). METHODS AND DESIGN: The study aims to randomize 2000 patients from 17 UK centres. Patients are randomized to either a restrictive (transfuse if haemoglobin concentration <7.5 g/dl) or liberal (transfuse if haemoglobin concentration <9 g/dl) transfusion strategy. The primary outcome is a binary composite outcome of any serious infectious or ischaemic event in the first 3 months following randomization. The statistical analysis plan details how non-adherence with the intervention, withdrawals from the study, and the study population will be derived and dealt with in the analysis. The planned analyses of the trial primary and secondary outcome measures are described in detail, including approaches taken to deal with multiple testing, model assumptions not being met and missing data. Details of planned subgroup and sensitivity analyses and pre-specified ancillary analyses are given, along with potential issues that have been identified with such analyses and possible approaches to overcome such issues. TRIAL REGISTRATION: ISRCTN70923932 .

Normothermic versus hypothermic cardiopulmonary bypass in children undergoing open heart surgery (thermic-2): study protocol for a randomized controlled trial.

BACKGROUND: During open heart surgery, patients are connected to a heart-lung bypass machine that pumps blood around the body ("perfusion") while the heart is stopped. Typically the blood is cooled during this procedure ("hypothermia") and warmed to normal body temperature once the operation has been completed. The main rationale for "whole body cooling" is to protect organs such as the brain, kidneys, lungs, and heart from injury during bypass by reducing the body's metabolic rate and decreasing oxygen consumption. However, hypothermic perfusion also has disadvantages that can contribute toward an extended postoperative hospital stay. Research in adults and small randomized controlled trials in children suggest some benefits to keeping the blood at normal body temperature throughout surgery ("normothermia"). However, the two techniques have not been extensively compared in children. OBJECTIVE: The Thermic-2 study will test the hypothesis that the whole body inflammatory response to the nonphysiological bypass and its detrimental effects on different organ functions may be attenuated by maintaining the body at 35°C-37°C (normothermic) rather than 28°C (hypothermic) during pediatric complex open heart surgery. METHODS: This is a single-center, randomized controlled trial comparing the effectiveness and acceptability of normothermic versus hypothermic bypass in 141 children with congenital heart disease undergoing open heart surgery. Children having scheduled surgery to repair a heart defect not requiring deep hypothermic circulatory arrest represent the target study population. The co-primary clinical outcomes are duration of inotropic support, intubation time, and postoperative hospital stay. Secondary outcomes are in-hospital mortality and morbidity, blood loss and transfusion requirements, pre- and post-operative echocardiographic findings, routine blood gas and blood test results, renal function, cerebral function, regional oxygen saturation of blood in the cerebral cortex, assessment of genomic expression changes in cardiac tissue biopsies, and neuropsychological development. RESULTS: A total of 141 patients have been successfully randomized over 2 years and 10 months and are now being followed-up for 1 year. Results will be published in 2015. CONCLUSIONS: We believe this to be the first large pragmatic study comparing clinical outcomes during normothermic versus hypothermic bypass in complex open heart surgery in children. It is expected that this work will provide important information to improve strategies of cardiopulmonary bypass perfusion and therefore decrease the inevitable organ damage that occurs during nonphysiological body perfusion. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN93129502, http://www.isrctn.com/ISRCTN93129502 (Archived by WebCitation at http://www.webcitation.org/6Yf5VSyyG).