Background: Hypertension therapy in older adults is often suboptimal, in part due to 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 pre-specified analysis of a multicentre randomised controlled trial (ISRCTN17251494) which randomised patients ≥60 years undergoing elective non-cardiac 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 anesthesia, quantified by enzyme-linked immunoassays for plasma renin, aldosterone, angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-3 (DPP3). 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/continue. Cluster 1 (n=52; mean age (SD), 75±8 years; 54% female) and cluster 3 (n=25; 75±6 years; 44% female) had higher rates of myocardial injury (23/52 (44%) and 13/25 (52%), respectively), compared with 51/164 (31.1%) in cluster 2 (n=153; 70±6 years; 46% female; odds ratio:1.95, 95% CI:1.12-3.39, p=0.018). Cluster 2 was characterized by lower NT-proBNP (mean difference, 698pg.ml-1, 95% CI, 576-820) and higher renin (mean difference:350pg.ml-1, 95% CI:123-577), compared with clusters 1 and 3 with the higher rate of myocardial injury. Conclusion: Effective preoperative RAAS inhibition is associated with lower risk of myocardial injury before non-cardiac surgery, independent of stopping/continuing RAAS inhibitors before surgery.

The authors have declared no competing interest.

ISRCTN17251494). From 07/31/2017 to 10/01/2021, the Stopping Perioperative ACE-inhibitors/ARBs (SPACE) phase 2a trial (EudraCT:2016-004141-90)

https://www.qmul.ac.uk/ccpmg/sops--saps/statistical-analysis-plans-saps

G.L.A. was supported by the National Institute for Academic Anaesthesia (British Oxygen Company research chair grant); NIHR Advanced Fellowship [NIHR300097], and a British Heart Foundation Programme grants (RG/14/4/30736; RG/19/5/34463). T.E.F.A. and R.M.P. were supported by NIHR.

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