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Randomized Controlled Trial
. 2024 Apr 1;45(13):1146-1155.
doi: 10.1093/eurheartj/ehad716.

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

Gareth L Ackland  1 , Akshaykumar Patel  1 , Tom E F Abbott  1 , Salma Begum  1 , Priyanthi Dias  1 , David R Crane  1 , Sameer Somanath  2 , Alexander Middleditch  3 , Stuart Cleland  4 , Ana Gutierrez Del Arroyo  1 , David Brealey  5   6   7 , Rupert M Pearse  1 ; Stopping Perioperative ACE-inhibitors or angiotensin-II receptor blockers (SPACE) trial investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Gareth L Ackland et al. Eur Heart J. .

Abstract

Background and aims: Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin 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.

Keywords: Major cardiac events; Myocardial injury; Non-cardiac surgery; Peri-operative care; Renin–angiotensin system inhibitors.

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Figures

Structured Graphical Abstract
Structured Graphical Abstract
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.
Figure 1
Figure 1
CONSORT diagram. Details are shown regarding the screening, potential eligibility, randomized assignments, and disposition of the trial patients. Details regarding the methods that were used for screening and the determining of eligibility are provided in the Supplementary data online, Appendix. Before surgery, there were 6 patients for whom surgery was cancelled after randomization had occurred (for surgical/oncologic reasons). Two additional patients withdrew their consent after randomization but before attending for surgery. Once admitted for surgery, primary outcome data was missing for 4 patients allocated to stop their RAS inhibitor, and in 9 patients randomized to continue their RAS therapy. The primary outcome could not be met if the pre-operative sample was not collected or the day 1 and day 2 samples were not collected even though the pre-operative sample had been. The reasons for this were either that 11 patients refused to give all the required additional blood sample (but consented to continue in the trial) or samples were not obtained by research staff (n = 2).
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