ACE Inhibitors and ARBs Before Surgery

The optimal preoperative management of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) remains debated. This meta-analysis of randomized controlled trials (RCTs) assessed withholding vs. continuing ACEIs/ARBs on intraoperative hypotension and postoperative outcomes. PubMed, Web of Science, and China Biology Medicine were comprehensively searched to identify RCTs comparing preoperative withholding ACEIs/ARBs with a continuing therapy in adult patients. Two authors independently extracted and pooled data using a random-effects model. The primary outcome was the incidence of intraoperative hypotension. Secondary outcomes included duration of intraoperative hypotension, vasopressor use, postoperative hypotension and hypertension, major adverse cardiovascular events, acute kidney injury, duration of mechanical ventilation, length of stay in ICU and hospital, and 30-d mortality. Evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Fourteen RCTs with 4063 patients were included. Withholding ACEIs/ARBs before noncardiac surgery was associated with a reduced incidence of intraoperative hypotension (36.4% vs. 48.4%; risk ratio = 0.73, 95% confidence interval = 0.60-0.88, p = 0.001, I2 = 63%; a very low certainty of evidence); it was associated with a shorter duration of intraoperative hypotension (mean difference = -5.41 min), reduced vasopressor use (37.5% vs. 51.2%), and increased postoperative hypertension (27.8% vs. 20.2%), without affecting other outcomes (low or very low certainty of evidence). While withholding ACEIs/ARBs may reduce intraoperative hypotension, the very low certainty of evidence underscores the need for future research to confirm clinical implications. PROSPERO (CRD42021253965).

Before surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines. To evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery. Randomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France. Patients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115). The primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery. Of the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes. Among patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy. ClinicalTrials.gov Identifier: NCT03374449.

The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown. In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes. Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24&#x2009;h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery. Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24&#x2009;h before surgery.

The renin-angiotensin-aldosterone system is mainly involved in the regulation of arterial blood pressure and fluid balance. One of the main stimuli for the secretion of renin present in the renal juxtamedullary cells, but also in some other tissues, is provided by the sympathetic nervous system via the action of norepinephrine on beta 1-adrenoceptors. There is good evidence in animal experiments that angiotensin II (Ang II) facilitates sympathetic neurotransmission by several mechanisms, all of which seem to involve distinct, but perhaps heterogeneous, Ang II receptors. Acting within the central nervous system, angiotensin augments sympathetic nerve outflow directly, but probably also by inhibiting the reflex decrease in sympathetic nerve activity following an increase in arterial pressure. Ang II also stimulates adrenomedullary and ganglionic transmission as well as enhances the release of sympathetic transmitter by a presynaptic action. In addition, there is some evidence that angiotensin can inhibit norepinephrine reuptake and augment its biosynthesis and responses mediated via both extrasynaptic alpha 2- and intrasynaptic alpha 1-adrenoceptors. Angiotensin-converting enzyme inhibitors, particularly when the endogenous renin-angiotensin activity is high, attenuate sympathetic neurotransmission. Despite a clear demonstration that the renin-angiotensin system augments the activity of the sympathetic nervous system in animals, evidence for such a role in humans is tenuous. This is probably mainly due to the difficulty in quantitatively monitoring and assessing the autonomic function in humans. It is possible that in congestive heart failure, where the renin-angiotensin system can be highly activated, sympathetic facilitation by angiotensin as well as its attenuation by converting enzyme inhibitors may be important.

A large number of patients undergoing noncardiac surgeries are on long-term use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). The current guidelines regarding the continuation or discontinuation of renin-angiotensin-aldosterone system inhibitors (RAAS) inhibitors before noncardiac surgery are conflicting. This meta-analysis aims to evaluate whether continuing or withholding RAAS inhibitors before noncardiac surgery influences perioperative mortality and complications. A thorough literature search was performed across PubMed/MEDLINE, Embase, and the Cochrane Library from their inception up to August 30, 2024 to identify eligible randomized controlled trials (RCTs) and cohort studies. Clinical outcomes were evaluated using a random-effects model to pool odds ratios (ORs) with 95&#xa0;% confidence intervals (CIs). The analysis included 16 studies with a total of 59,105 patients on RAAS inhibitors before noncardiac surgery. Withholding RAAS inhibitors was associated with a significantly lower incidence of intraoperative hypotension (OR&#xa0;=&#xa0;0.49; 95&#xa0;% CI&#xa0;=&#xa0;0.29 to 0.83) and acute kidney injury (AKI) (OR&#xa0;=&#xa0;0.88; 95&#xa0;% CI&#xa0;=&#xa0;0.82 to 0.95) than continuing the therapy. However, there was no statistically significant difference in reducing mortality (OR&#xa0;=&#xa0;1.10; 95&#xa0;% CI&#xa0;=&#xa0;0.86 to 1.40), major adverse cardiovascular events (MACE) (OR&#xa0;=&#xa0;1.27; 95&#xa0;% CI&#xa0;=&#xa0;0.75 to 2.16), myocardial infarction (OR&#xa0;=&#xa0;0.83; 95&#xa0;% CI&#xa0;=&#xa0;0.27 to 2.59) or stroke events (OR&#xa0;=&#xa0;0.70; 95&#xa0;% CI&#xa0;=&#xa0;0.36 to 1.36) between the two groups. Withholding RAAS inhibitors before noncardiac surgery reduces intraoperative hypotension and AKI with nonsignificant effects on mortality and MACE.

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. In a preplanned analysis of a phase 2a trial in six UK centres, patients &#x2265;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 &#x2265;15 ng L-1 or a &#x2265;5 ng L-1 increase, when preoperative high-sensitivity troponin-T &#x2265;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. 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]). 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.