Effect of Remote Ischaemic preConditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA study): A multicentre double-blind randomised controlled clinical trial

(a) Research Design: Multi-centre double-blind randomised controlled clinical trial. (b) Study Population: High-risk patients (additive Euro-SCORE of 6 or more) undergoing CABG±valve surgery. (c) Planned Interventions: Remote ischaemic preconditioning (RIC) comprising three 5 min cycles of inflation (to 200mmHg) and deflation of a cuff placed on the upper arm. Control will comprise placing an un-inflated cuff on the upper arm for 30 minutes. (d) Proposed outcome measures: Primary outcome: Major adverse cardiac and cerebral events at one year (MACCE- death, myocardial infarction, revascularisation, stroke). Secondary outcomes: Peri-operative myocardial and renal injury; Length of ITU/hospital stay and inotrope score; 6 minute walk test; Quality of life analysis and cost-effectiveness analysis. There will be an echo substudy assessing left ventricular ejection fraction. (e) Assessment and follow up: Outcome measures will be assessed from the patient GP and medical notes, questionnaires (at 3, 6, 9 months) and 6 week and one year outpatient appointments. Safety will be assessed using a Standard Operating Procedure. (f) Proposed sample size: In the SYNTAX study, the MACCE rate was 12.4% at 12 months in CABG patients at lower risk than those proposed for this trial (mean EuroSCORE 3.8)(Serruys et al NEJM 2009;360:961). In a study of high-risk patients with left main stem coronary lesions the MACCE rate at 12 months was 25% (Lee et al JACC 2006;47:864). For our high-risk patients we have estimated a MACCE rate of 20%. Therefore, to detect a 27% relative risk reduction in this primary endpoint (from 20.0% to 14.6%), with a power of 80% and a significance level of 5%, a sample size of 770 patients will be required for each trial arm (1540 in total). A trial of this size would detect an observed relative reduction of 20% (i.e. a risk ratio of 0.8) as statistically significant based on an event rate in the control arm of 20%. To allow for dropouts (4-5% in SYNTAX study) we plan to recruit 1610 patients in total based on 4.5% dropout rate. (g) Statistical analysis: Survival analyses will be carried out for the primary MACCE clinical endpoint at one year. MACCE as well as individual components (e.g. mortality); hazard ratios and confidence intervals, together with p-values will be calculated using Cox’s proportional hazards modelling. All analyses will be carried out on an intention-to-treat basis. (h) Project timetables including recruitment rate: Total duration of study: 48 months. (1) 0-6 months- Study preparation; (2) 6-30 months- Patient recruitment; (3) 18-42 months- One year follow-up; (4) 42-48 months- Data analysis, reporting and dissemination of results. To recruit 1610 high-risk CABG±valve patients over 24 months, each of the 9 recruiting centres will need to recruit on average 2 patients per week (180 patients in total), which is about 25% of the eligible 7-10 patients per week.