Discontinuation vs. continuation of renin–angiotensin system inhibition before non-cardiac surgery: the SPACE trial

Abstract

Background and Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin–angioAims tensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin–angiotensin system inhibitors were withheld for different durations (2–3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45–1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16–1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies. Structured Graphical Abstract Key Question Does discontinuing renin-angiotensin II system inhibitors (RAS inhibitors) before elective non-cardiac surgery reduce myocardial injury? Key Finding In a randomized controlled trial enrolling 260 patients preoperative BP was higher when RAS inhibitors were stopped. A total of 48% patients sustained myocardial injury after stopping RAS inhibitors, compared with 41% patients who continued therapy. Hypertensive adverse events were more frequent when RAS inhibitors were stopped, without affecting hypotension rates. Take Home Message Discontinuing RAS inhibitors before non-cardiac surgery does not reduce myocardial injury, and may increase the risk of clinically significant acute hypertension. Pre-op Surgery Post-op STOP Primary 24h 48h Adverse outcome events 48% 9% 12% ACE-I and/or Randomize ARB Low High Troponin 41% 8% 5% 24h 48h Pre-op Surgery Post-op CONTINUE In a randomized controlled trial enrolling 260 patients, did stopping renin–angiotensin system (RAS) inhibitors [angiotensin-converting-enzyme inhibitors (ACE-I)/angiotensin II receptor blockers (ARB)] before elective non-cardiac surgery reduce myocardial injury, taking into account the pharmacokinetic profile of individual RAS inhibitors? Pre-operative blood pressure was higher when RAS inhibitors were stopped. Forty-eight per cent of patients sustained myocardial injury after stopping RAS inhibitors, compared with 41% of patients who continued therapy. Hypertensive adverse events were more frequent when RAS inhibitors were stopped, without affecting hypotension rates. Discontinuing RAS inhibitors before non-cardiac surgery does not appear to reduce myocardial injury, and could increase the risk of clinically significant acute hypertension.