Title: Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: Propofol cardioplegia for myocardial protection randomised controlled trial (PROMPT2)
Funder: Department of Health and Social Care

Abstract: AIM: To test the hypothesis that adding propofol to the cardioplegia solution is cardioprotective for patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) and that there is a dose-response relationship with a higher dose conferring greater benefit. DESIGN: PROMPT2 is a two centre blinded parallel three-group trial comparing two doses of propofol and sham supplementation, with sequential monitoring of early safety/toxicity outcomes and a formal review of recruitment after 12 months of active recruitment. POPULATION AND SETTING: Adults undergoing first time isolated CABG surgery at a cardiac surgery centre. INTERVENTIONS: Blood cardioplegia supplemented with low dose propofol (6mcg/ml), high dose propofol (12mcg/ml) or normal saline (sham supplementation). OUTCOMES: Primary outcome: myocardial injury, assessed by serial measurements of cardiac troponin T (cTnT); secondary outcomes: serial measurements of renal function (creatinine), metabolic stress (lactate), inflammation (TNF-alpha, IL-10, IL-8, IL-6), oxidative stress (myeloperoxidase, microRNA-1 and exosomal microRNA-1) and pH in blood samples, concentration of plasma propofol in blood from the cardioplegia/bypass circuit, length of intensive care unit and hospital stay, serious adverse events and quality of life; safety/toxicity outcomes: myocardial and renal injury assessed from cTnT concentrations at 6 hours and 24 hours and creatinine concentrations at 24 hours respectively. ASSESSMENTS: Patients will be followed up from randomisation to 12 months. No additional visits to hospital are required, over and above visits made as part of routine care. SAMPLE SIZE: 240 patients, 80 per group will provide 90% power (5% significance level, 2-sided) to detect a difference of 0.25 standard deviations (SD) in cTnT between adjacent groups in an overall analysis of the 3 groups and 0.5 SD any 2 groups (corrected for multiplicity), assuming a correlation of 0.2 between outcomes measured before and after intervention and 0.7 between post-intervention outcomes measured on multiple occasions. This target difference represents a decrease in cTnT that might reduce the incidence of long term major adverse cardiac events in the year after surgery by 25%. This population attributable risk is based on results for the control group in the first PROMPT trial and evidence that a cTnT concentration >0.8 mcg/l increases the hazard of MACE by 2.13 times. RECRUITMENT: We estimate that 260 patients/per year will be eligible for PROMPT2; assuming that 75% will be invited to take part and 50% will consent (lower target rates than achieved in PROMPT) gives a projected recruitment rate of 8 participants/month. We will formally review recruitment after 12 months when we should have recruited 96 participants. STATISTICAL ANALYSIS: Trial outcomes will be analysed by intention to treat. Continuous outcomes will be analysed using mixed models for repeated measures. Models with no specified order to the groups will be compared with models which assume a linear dose response relationship. Findings will be reported as effect sizes with 95% confidence intervals. Safety/toxicity outcomes will be monitored using cumulative sum charts. TIMETABLE: Total duration 54 months: months 1-6: trial set-up and regulatory approvals; 7-36: recruitment with formal review at month 18; 37-48: complete participant follow-up; 49-54: final data cleaning, analyses and report.

Lay abstract: Almost 2.3 million people in the UK are living heart disease and >36,000 cardiac surgery operations are carried out each year. During surgery the heart is isolated from the rest of the circulation and a heart-lung machine is used to supply oxygen to the blood and pump it around the body. The heart is stopped and provided with nutrients by a (cardioplegic) solution that is injected directly into the heart arteries. This allows the surgeon to operate on the heart while it is still and not filled with blood, but looking after the heart in this way during surgery is not ideal. The heart muscle can become short of oxygen, and when the heart is restarted and blood starts to flow again the muscle can be harmed. The damage is believed to be caused mainly by the formation of highly reactive molecules known as ‘free radicals’ in the heart muscle during the time it is short of oxygen. Propofol is a general anaesthetic widely used in cardiac surgery and research suggests that propofol could protect the heart muscle against damage from free radicals. We want to investigate whether adding propofol to the cardioplegic solution in patients having isolated coronary artery bypass grafting (CABG) surgery using the heart-lung machine is beneficial and if the benefit is greater the more propofol that is used. We propose to conduct a study, known as a randomised controlled trial (RCT), in which patients undergoing CABG surgery are allocated by chance to a ‘high’ dose of propofol, a ‘low’ dose of propofol or no additional propofol. Every other aspect of care will stay the same. We will monitor all study participants to check that adding propofol to the cardioplegic solution is safe and an independent group of experts will review these data regularly. At the end of the study we will compare information about participants who received the different doses of propofol with information about participants who received no additional propofol to determine whether propofol is beneficial. We will do this by studying chemicals released by the heart and other organs in the body when they are damaged or stressed. We will measure these chemicals in blood samples taken before and after the operation. We will also collect information on post-operative complications in the first 12 months and will collect data from participants on their quality of life at 3 and 12 months. If we find that adding propofol to the cardioplegic solution reduces organ damage, patients undergoing cardiac surgery may have a faster recovery and fewer major complications in the year following surgery. This should also lead to reduced costs for the NHS. We hope to recruit a total of 240 patients to the RCT. We will recruit from the Bristol Heart Institute where we have experience in recruiting patients for a similar previous study and from the Hammersmith Hospital. The overall duration of the study will be 54 months. The team includes surgeons, anaesthetists, scientists and researchers with expertise in conducting clinical trials.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR