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Clinical Trial
. 2024 May;132(5):857-866.
doi: 10.1016/j.bja.2024.01.010. Epub 2024 Feb 9.

Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial

Ana Gutierrez Del Arroyo  1 , Akshaykumar Patel  1 , Tom E F Abbott  1 , Salma Begum  1 , Priyanthi Dias  1 , Sameer Somanath  2 , Alexander Middleditch  3 , Stuart Cleland  4 , David Brealey  5 , Rupert M Pearse  1 , Gareth L Ackland  6 ; SPACE trial investigators
Collaborators, Affiliations
Clinical Trial

Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial

Ana Gutierrez Del Arroyo et al. Br J Anaesth. 2024 May.

Abstract

Background: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations.

Methods: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors.

Results: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]).

Conclusions: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.

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

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Conflict of interest statement

RMP, TEFA, GLA are editorial board members of the British Journal of Anaesthesia. The other authors declare that they have no conflicts of interest.

Figures

Fig 1
Fig 1
CONSORT diagram. Methods for screening and the determining of eligibility are provided in the Supplementary data. The primary outcome of significant high-sensitivity troponin-T (hsTnT) increase was not met if the preoperative sample was not collected or the day 1 or day 2 samples were also not collected. NT-proBNP, N-terminal pro-B-type natriuretic peptide; RASi, renin–angiotensin system inhibitor.
Fig 2
Fig 2
Primary outcome: myocardial injury. (a) Heat maps showing relationship between NT-proBNP concentration and presence or absence of myocardial injury in individual subjects randomised to stop or continue renin–angiotensin system (RAS) inhibitors. Multicoloured bar on left of each plot shows NT-proBNP scaled from lower limit of detection to maximal value (3100 pg ml−1). Each red bar represents high-sensitivity troponin-T (hsTnT) ≥15 ng L −1. Black bars denote VISION-defined threshold for higher risk threshold of NT-proBNP ≥100 pg ml−1. (b) Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP ≥100 pg ml−1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml−1 (odds ratio 3.50 [95% confidence interval 0.05–5.99]; P<0.0001). For subjects with preoperative NT-proBNP <100 pg ml −1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (odds ratio for stopping 2.22; 95% confidence interval 1.06–4.65; P=0.03). For preoperative NT-proBNP ≥100 pg ml−1, myocardial injury rates were similar, regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (odds ratio for stopping 0.98; 95% confidence interval 0.44–2.22). ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
Fig 3
Fig 3
Secondary outcomes: peak high-sensitivity troponin and infectious complications. (a) Peak troponin values 24–48 h after surgery, stratified by NT-proBNP in subjects randomised to stop or continue renin–angiotensin system (RAS) inhibitors. (b) Sources of infection stratified by NT-proBNP in subjects randomised to stop or continue RAS inhibitors. For subjects with preoperative NT-proBNP <100 pg ml−1, 24/75 (32%) who stopped RAS inhibitors had an infectious complication within 30 days of surgery, compared with 16/65 (24.6%) who continued RAS inhibitors (odds ratio for stopping 1.44; 95% confidence interval 0.69–3.03). For preoperative NT-proBNP ≥100 pg ml −1, 13/45 (28.9%) subjects who stopped RAS inhibitors had a postoperative infection, compared with 16/56 (28.6%) who continued RAS inhibitors (odds ratio for stopping 1.02; 95% CI 0.43–2.42). ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin-II receptor blocker; BSI, bloodstream infection; hsTNT, high-sensitivity troponin-T; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SSI, surgical site infection; UTI, urinary tract infection.
Fig 4
Fig 4
Length of hospital stay. (a) Kaplan–Meier plot showing duration of hospital stay and DAH30 for subjects randomised to continue renin–angiotensin system (RAS) inhibitors, stratified by NT-proBNP ≥100 pg ml−1 or NT-proBNP <100 pg ml −1. (b) Kaplan–Meier plot showing duration of hospital stay and DAH30 for patients randomised to stop RAS inhibitors, stratified by NT-proBNP ≥100 pg ml−1vs NT-proBNP <100 pg ml−1. P-values refer to log-rank test. NT-proBNP, N-terminal pro-B-type natriuretic peptide.
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