Preoperative activation of the renin-angiotensin system and myocardial injury in noncardiac surgery: exploratory mechanistic analysis of the SPACE randomised controlled trial

Ana Gutierrez Del Arroyo; Tom E F Abbott; Akshaykumar Patel; Salma Begum; Priyanthi Dias; David Brealey; Rupert M Pearse; Vikas Kapil; Gareth L Ackland; SPACE trial investigators

doi:10.1016/j.bja.2024.10.040

Preoperative activation of the renin-angiotensin system and myocardial injury in noncardiac surgery: exploratory mechanistic analysis of the SPACE randomised controlled trial

Br J Anaesth. 2024 Dec 20:S0007-0912(24)00703-7. doi: 10.1016/j.bja.2024.10.040. Online ahead of print.

Authors

Ana Gutierrez Del Arroyo¹, Tom E F Abbott¹, Akshaykumar Patel¹, Salma Begum¹, Priyanthi Dias¹, David Brealey², Rupert M Pearse¹, Vikas Kapil³, Gareth L Ackland⁴; SPACE trial investigators

Affiliations

¹ Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK.
² Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK; UCL Hospitals NHS Foundation Trust, London, UK; NIHR University College London Hospitals Biomedical Research Centre, London, UK.
³ Clinical Pharmacology & Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK.
⁴ Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK. Electronic address: [email protected].

PMID: 39709293
DOI: 10.1016/j.bja.2024.10.040

Abstract

Background: Hypertension therapy in older adults is often suboptimal, in part because of inadequate suppression of the renin-angiotensin-aldosterone system (RAAS). We hypothesised that distinct endotypes of RAAS activation before noncardiac surgery are associated with increased risk of myocardial injury.

Methods: This was a prespecified exploratory analysis of a multicentre randomised controlled trial (ISRCTN17251494) which randomised patients ≥60 yr old undergoing elective noncardiac surgery to either continue or stop RAAS inhibitors (determined by pharmacokinetic profiles). Unsupervised hierarchical cluster analysis identified distinct groups of patients with similar RAAS activation from samples obtained before induction of anaesthesia, quantified by enzyme-linked immunoassays for plasma renin, aldosterone, angiotensin-converting enzyme 2, and dipeptidyl peptidase-3. The primary outcome, masked to investigators and participants, was myocardial injury (plasma high-sensitivity troponin-T).

Results: We identified three clusters, with similar proportions of RAAS inhibitors randomised to stop or continue. Cluster 1 (n=52; mean age [standard deviation], 75 yr [8 yr]; 54% female) and cluster 3 (n=25; 75 yr [6 yr]; 44% female) had higher rates of myocardial injury (23/52 [44%] and 13/25 [52%], respectively), compared with cluster 2 with 51/164 (31.1%; n=153; 70 yr [6] yr; 46% female; odds ratio: 1.95, 95% confidence interval (CI) 1.12-3.39, P=0.018). Cluster 2 was characterised by lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration (mean difference 698 pg ml^-1, 95% CI 576-820 pg ml^-1) and higher renin concentration (mean difference 350 pg ml^-1, 95% CI 123-577 pg ml^-1), compared with clusters 1 and 3 which had higher rates of myocardial injury.

Conclusions: This mechanistic exploratory analysis suggests that effective preoperative RAAS inhibition is associated with lower risk of myocardial injury after noncardiac surgery, independent of stopping or continuing RAAS inhibitors before surgery.

Clinical trial registration: ISRCTN17251494.

Keywords: major cardiac events; myocardial injury; noncardiac surgery; perioperative care; renin–angiotensin system inhibitors.