High-Level Highlights
In the management of patients undergoing major noncardiac surgery, the decision to continue or discontinue renin-angiotensin system inhibitors (RASi) has long been a subject of debate. This secondary analysis of the STOP-or-NOT randomized clinical trial provides critical clarity. The key highlights include:
- Preoperative cardiovascular risk, as assessed by the Revised Cardiac Risk Index (RCRI) and the AUB-HAS2 index, does not modify the impact of RASi management on postoperative outcomes.
- The strategy of continuing RASi until the day of surgery was not associated with an increased risk of mortality or major complications compared to discontinuation, regardless of the patient’s baseline cardiovascular risk.
- These findings suggest that clinicians can individualize RASi management without the constraints of traditional cardiovascular risk stratification tools.
Background: The Perioperative RASi Dilemma
Renin-angiotensin system inhibitors (RASi), including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are cornerstones in the management of hypertension, heart failure, and chronic kidney disease. However, their use in the perioperative period presents a clinical catch-22. On one hand, continuing RASi may lead to profound intraoperative vasoplegic hypotension, which is associated with myocardial injury and acute kidney injury (AKI). On the other hand, discontinuing these agents 24 to 48 hours before surgery may trigger rebound hypertension or exacerbate underlying heart failure, potentially increasing the risk of postoperative adverse events.
The original STOP-or-NOT trial (NCT03374449) addressed this by randomizing 2,222 patients to either continue or discontinue RASi 48 hours before major noncardiac surgery. The primary results showed no significant difference in the composite outcome of all-cause mortality and major postoperative complications. However, a lingering question remained: does the patient’s baseline cardiovascular risk profile influence this outcome? For instance, would a high-risk patient benefit more from discontinuation to avoid hypotension, or would they benefit from continuation to maintain hemodynamic stability? This post hoc analysis sought to answer these questions by stratifying the trial participants using validated risk indices.
Study Design and Risk Stratification Methodology
This study was a post hoc secondary analysis of the multicenter STOP-or-NOT trial, which included 40 hospitals in France. The analysis period spanned from September 2024 to January 2025, using data collected between 2018 and 2023. The cohort consisted of 2,222 patients who had been on stable RASi therapy for at least three months and were scheduled for major noncardiac surgery.
The researchers utilized three primary methods for preoperative cardiovascular risk stratification:
1. The Revised Cardiac Risk Index (RCRI)
The RCRI is a widely used tool that assigns points based on six predictors: high-risk surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative insulin use, and preoperative serum creatinine levels. Patients were categorized into four levels: low risk (0 points), intermediate-low (1 point), intermediate-high (2 points), and high risk (3 or more points).
2. The American University of Beirut (AUB)-HAS2 Cardiovascular Risk Index
The AUB-HAS2 index is a newer model designed to improve upon the RCRI. It considers age (75 years or older), history of heart disease, symptoms of angina or dyspnea, and high-risk surgery. Similar to the RCRI, patients were stratified into four risk tiers.
3. Preoperative Systolic Blood Pressure (SBP)
Recognizing the role of baseline hemodynamics, the researchers also split 2,132 patients into four quartiles based on their systolic blood pressure measured prior to randomization.
The primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days. Secondary outcomes included major adverse cardiovascular events (MACE) and the incidence of acute kidney injury (AKI).
Key Findings: Risk Stratification vs. RASi Strategy
The demographic breakdown of the 2,222 patients showed a median age of 68 years, with 35% being female. In the randomization, 1,107 patients continued RASi, while 1,115 discontinued the medication. The distribution of risk was broad: using the RCRI, 592 were low risk, 1,095 were intermediate-low, 418 were intermediate-high, and 117 were high risk. The AUB-HAS2 index showed a similar spread, with 1,049 patients categorized as low risk and 113 as high risk.
Consistency Across Risk Profiles
The most significant finding of the study was the lack of interaction between the preoperative risk scores and the RASi management strategy. Whether a patient was categorized as low risk or high risk by the RCRI or AUB-HAS2, the risk of postoperative complications remained statistically similar between the continuation and discontinuation groups.
Outcome Rates by Risk Tier
As expected, the absolute rate of postoperative complications increased with higher RCRI and AUB-HAS2 scores. For example, patients in the highest RCRI tier had significantly higher rates of MACE and AKI compared to those in the lowest tier. However, within each of these tiers, the decision to continue or stop RASi did not change the trajectory of the outcome. Specifically, for patients with high RCRI scores (3 or more), the incidence of the primary composite outcome did not differ significantly between those who continued RASi and those who stopped.
Blood Pressure Quartiles
The analysis of preoperative SBP quartiles yielded similar results. Baseline blood pressure did not serve as a predictor for which strategy (continuation vs. discontinuation) would be more beneficial. This suggests that even in patients with higher baseline SBP, continuing RASi until the day of surgery does not necessarily provide a protective effect against postoperative complications, nor does it disproportionately increase risk.
Expert Commentary and Clinical Implications
The findings from this secondary analysis of the STOP-or-NOT trial provide a strong argument for clinical flexibility. For years, anesthesiologists and cardiologists have leaned toward a ‘one size fits all’ approach—often recommending the discontinuation of RASi to prevent intraoperative hypotension. However, recent evidence, including the primary results of STOP-or-NOT and the POISE-3 trial, has challenged the necessity of this practice.
This study adds a crucial layer by demonstrating that even our most sophisticated risk stratification tools do not identify a subgroup of patients who clearly benefit from one strategy over the other. From a mechanistic perspective, while RASi continuation may lead to more frequent episodes of intraoperative hypotension, these episodes appear to be manageable and do not translate into increased rates of myocardial infarction or renal failure, provided that standard hemodynamic monitoring and support are in place.
It is important to note the study’s limitations. As a post hoc analysis, it may not have been fully powered to detect very small differences in high-risk subgroups. Furthermore, the decision-making process for RASi management should still consider the specific indication for the drug. For instance, in patients with severe heart failure or refractory hypertension, continuation may be more clinically prudent to avoid acute decompensation, whereas in patients with a history of severe intraoperative hypotension, a brief pause may still be considered.
Conclusion
This post hoc analysis confirms that the preoperative cardiovascular risk profile of a patient—as measured by RCRI, AUB-HAS2, or baseline SBP—does not influence the safety or efficacy of continuing versus discontinuing RAS inhibitors before major noncardiac surgery. Clinicians should feel empowered to make decisions regarding RASi management based on broader clinical judgment and patient-specific factors rather than relying solely on cardiovascular risk scores. The overarching takeaway is that both strategies are safe, and the focus should remain on meticulous intraoperative hemodynamic management.
Funding and Trial Registration
The STOP-or-NOT trial was supported by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique). The trial is registered at ClinicalTrials.gov with the identifier NCT03374449.
References
- Tang J, Pirracchio R, Cholley B, et al. Preoperative Cardiovascular Risk and Postoperative Outcomes by Renin-Angiotensin System Inhibitor Use: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2025;10(9):942-948. doi:10.1001/jamacardio.2025.1920.
- Legrand M, Pirracchio R, Rosa P, et al. Discontinuation or Continuation of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Before Major Noncardiac Surgery: The STOP-or-NOT Randomized Clinical Trial. JAMA. 2024;332(2):123-131.
- Devereaux PJ, Mrkobrada M, Sessler DI, et al. Design and rationale of the PeriOperative Ischemic Evaluation-3 (POISE-3) trial. Am Heart J. 2022;244:11-21.
- Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100(10):1043-1049.
