Stopping or continuing RAS-inhibitor drugs before major elective non-cardiac surgery: SPACE II trial

RESEARCH QUESTION What is the clinical and cost effectiveness of continuing or stopping RAS-inhibitors for patients undergoing major elective non-cardiac surgery? Does this differ for patients with heart failure and chronic kidney disease (CKD)? BACKGROUND Each year around 500,000 people taking RAS-inhibitors (ACE-inhibitors and Angiotensin II blockers) need major surgery. These drugs interact with anaesthetic drugs, sometimes causing very low blood pressure and myocardial injury. Many anaesthetists ask people to stop taking these drugs before their surgery, but suddenly stopping RAS-inhibitors can lead to high blood pressure during surgery which also causes myocardial injury. One in five patients who develop myocardial injury during or after surgery die within a year. We need to be certain how to manage these drugs in the perioperative period, both overall and for patients who take RAS-inhibitors for different indications (hypertension, heart failure, CKD). METHODS Multi-centre randomised superiority trial with internal pilot. Population: Patients aged =50 years taking a RAS-inhibitor and scheduled for major elective non-cardiac surgery. Patients will be excluded if they decline to participate, and where their treating clinician declines to deliver either trial intervention. Heart failure and CKD will be assessed in all patients before surgery using the NT-proBNP and creatinine blood tests. Intervention: Intervention group patients will continue their RAS-inhibitor during the perioperative period except when they need vasopressor treatment for low blood pressure. Comparator: Comparator patients will stop their RAS-inhibitor 72 hours before surgery and re-start them 72 hours after surgery. Outcomes: The primary outcome measure is Days Alive and at Home within 30 days of surgery (DAH30). Secondary outcomes are Myocardial injury within 72 hours; Acute kidney injury within 7 days; Severe high and low blood pressure events within 7 days; Non-fatal cardiac arrest within 30 days; Stroke within 30 days; All post-operative complications within 30 days; Mortality at 180 days; Health-related quality of life at 30 and 180 days; Hospital readmission within 180 days; Hospital care costs within 180 days. STATISTICAL ASPECTS: We will recruit 2214 patients (1107/group) providing 95% power to detect a Minimum Clinically Important Difference in DAH30 of 1.0 (2-sided a=0.05, SD 8.4), and 99% power to detect a reduction in myocardial injury from 50% (stop) to 40% (continue). Analyses will be performed on an intention-to-treat basis using pre-specified analysis plans. DAH30 will be compared between groups using an appropriate regression model and the treatment effect summarised as a mean difference. Pre-specified sub-group analyses will assess effects according to heart failure, chronic kidney disease (=G3a), and troponin assay type (cTnT vs cTnI). TIMELINE 48-month trial, with six months set-up, 30 months recruitment, six months completion of follow-up, and six months for data analysis. Timelines will be enabled by delivery through the PROTECT multi-centre trial platform. IMPACT SPACE-II will provide definitive evidence of clinical and cost effectiveness of continuing or stopping RAS-inhibitors, for the short and long-term health of 500,000 NHS patients taking RAS-inhibitors who undergo major surgery each year. We will work with patient researchers to ensure our findings are widely disseminated and adopted into practice and policy recommendations.