Rachel L Nash

Propofol cardioplegia: A single-center, placebo-controlled, randomized controlled trial

OBJECTIVES Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is an effective treatment for coronary artery and aortic valve diseases. However, the myocardium sustains reperfusion injury after ischemic cardioplegic arrest. Our objective was to assess the benefits of supplementing cardioplegia solution with the general anesthetic propofol in patients undergoing either coronary artery bypass grafting (CABG) or aortic valve replacement (AVR). METHODS A single-center, double-blind randomized controlled trial was carried out to compare cardioplegia solution supplemented with propofol (concentration 6 μg/mL) versus intralipid (placebo). The primary outcome was cardiac troponin T release over the first 48 hours after surgery. RESULTS We recruited 101 participants (51 in the propofol group, 50 in the intralipid group); 61 underwent CABG and 40 underwent AVR. All participants were followed to 3 months. Cardiac troponin T release was on average 15% lower with propofol supplementation (geometric mean ratio, 0.85; 95% confidence interval [CI], 0.73-1.01; P = .051). There were no differences for CABG participants but propofol-supplemented participants undergoing AVR had poorer postoperative renal function (geometric mean ratio, 1.071; 95% CI, 1.019-1.125; P = .007), with a trend toward longer intensive care stay (median, 89.5 vs 47.0 hours; hazard ratio, 0.58; 95% CI, 0.31-1.09; P = .09) and fewer with perfect health (based on the EQ-5D health utility index) at 3 months (odds ratio, 0.26; 95% CI, 0.06-1.05; P = .058) compared with the intralipid group. Safety profiles were similar. There were no deaths. CONCLUSIONS Propofol supplementation in cardioplegia appears to be cardioprotective. Its influence on early clinical outcomes may differ between CABG and AVR surgery. A larger, multicenter study is needed to confirm or refute these suggestions.

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.

Modelling of longitudinal outcomes with highly skewed distributions: applications in the IVAN trial

The IVAN trial is a multi-centre factorial non-inferiority randomised controlled trial of 610 participants to compare treatments for neovascular Age-related Macular Degeneration (two drugs, Lucentis and Avastin, and two treatment regimens, treatment monthly and treatment as-needed). Many of the trial outcomes are longitudinal continuous outcomes measured at regular intervals over the two-year study period. The aim of the analyses was to obtain estimates of the drug and treatment regimen effects at two-years. For many of the outcomes, standard mixed-effects models fitted the data well. However, for some secondary outcomes, and in particular total lesion area, the distributions were highly skewed; 28% of 1536 measurements of lesion area were zero indicating a lesion was not present, which rendered standard regression modelling unsuitable. One approach taken to analyse this outcome was to dichotomise the variable into lesion present and lesion absent, and fit a logistic regression model with repeated measures. This analysis identified a statistically significant difference between the proportions of patients with no lesion present at two-years on the different treatment regimens. However the analysis did not make full use of the data available and information about the size of the lesion was not evaluated. An alternative approach that we have investigated is to use two-part modelling whereby the dichotomised data is analysed using logistic regression, and the non-zero values then analysed using mixed-effects models. We will present the results of this analysis and describe the methodological challenges faced when implementing it in the context of the IVAN trial.

Improving the efficiency of testing database functionality through statistical involvement

Background As a registered clinical trials unit we develop customised databases to collect and store study data and manage clinical trials; these databases need rigorous testing to ensure they function as intended, that data validation is implemented correctly and that study data extracts are complete and accurate. We describe how, with statistical involvement, the testing has been streamlined and the timelines reduced.

Understanding patterns of adverse events after surgery and their impact on recovery

Clinical trial reports include data on adverse events experienced by study participants. Typically the frequency of each event is reported, but patterns of events occurring in one participant are rarely described. We explore associations between complications after surgery, and their impact on time-to-discharge as a first step to deriving an objective measure of recovery from surgery.

Integrating qualitative research in a multi-centre trial - the clinical trials unit perspective

Background Recruitment into surgical trials is often hampered because of surgeon or patient preferences. Qualitative research to explore and standardise methods for communicating clinical equipoise and addressing patient concerns has been shown to be effective in maximising recruitment. Often this research runs alongside the trial without being fully integrated within it. We describe how we integrated qualitative research into the multi-centre By-Band study comparing two surgical procedures for morbid obesity.