Discontinuation vs. continuation of renin–angiotensin system inhibition before non-cardiac surgery: the SPACE trial
Authors: Ackland Gareth L , Patel Akshaykumar , Abbott Tom E F , Begum Salma , Dias Priyanthi , Crane David R , Somanath Sameer , Middleditch Alexander , Cleland Stuart , Gutierrez del Arroyo Ana , Brealey David , Pearse Rupert M ,   the Stopping Perioperative ACE-inhibitors or angiotensin-II receptor blockers (SPACE) trial investigators, Ackland Gareth , Martin Tim , Fernandez Maria , Seidu Fatima , Pakats Mari-Liis , Mahr Otto , MacDonald Neil , Dos Santos Filipa , Garcia Amaia Arrieta , Uddin Ruzena , Begum Salma , Pearse Rupert , Subhedar Emily , Wan Yize , Patel Akshaykumar , Shahid Tasnin , Gooneratne Mevan , Trainer Charlotte , Griffiths Bethan , Dunkley Steven , May Shaun , Walker Sophie , Fowler Alexander , Stephens Timothy , Oliveira Monica , Januszewska Marta , Niebrzegowska Edyta , Amaral Vanessa , Kassam Jamila , Young Sophie , Ahmad Shanaz , Whalley Jan , Haines Ryan , Hui Sara , Hammond Rob , Crane David , Brealey David , Bampoe Sohail , Stephens Robert , Reyes Anna , Martir Gladys , Diaz Chimverly , Cleland Stuart , Minto Gary , Wilmshurst Natasha , Affleck Debbie-Claire , Ward Tracy , Werrett Gavin , Cummins Susan , Amber Alan , Biffen Andrew , Boumphrey Stephen , Cann Elizabeth , Eglinton Charlotte , Jones Elaine , Mwadeyi Memory , Piesley Sam , Cowan Richard , Alderton Julie , Reed Fiona , Smith Joanne , Turner Amy , Madziva Lorraine , Patrick Abigail , Harris Penny , Lang Harry , Middleditch Alexander , Pickering Anthony , O'Donovan Catherine , Houlihan Rebecca , Jarvis Rosina , Shrimpton Andrew , Farmery Toni , Tucker Katy , Davis Danielle , Somanth Sameer , Duncan Louise , Melsom Helen , Clark Sarah , Kent Melanie , Wood Michelle , Laidlaw Ami , Matheson-Smith Tracy , Potts Kathryn , Kay Andrea , Hobson Stefanie , Sear John , Kapil Vikas , Archbold Andrew , Wilson Matt , Dndrejaj Drilona , Ly Dennis , Patel Akshaykumar , Richards Toby , Finney Simon , Harris Steve 
Published: November 2023

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 (&gt;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.