Preoperative Cardiovascular Risk Does Not Alter Outcomes of Renin-Angiotensin System Inhibitor Use Before Major Noncardiac Surgery: Insights from a Secondary Analysis of the STOP-or-NOT Trial

Highlight

– The STOP-or-NOT trial found no difference in postoperative mortality or major complications between patients who continued versus discontinued renin-angiotensin system inhibitors (RASi) before major noncardiac surgery.
– This post hoc analysis explored whether preoperative cardiovascular risk stratification alters the effects of RASi management strategy.
– Using validated cardiovascular risk indices (RCRI and AUB-HAS2) and preoperative systolic blood pressure quartiles, no significant interaction was found between risk level and RASi continuation or discontinuation on postoperative outcomes.
– The findings suggest that preoperative cardiovascular risk assessment should not influence decisions about perioperative RASi use.

Study Background and Disease Burden

Renin-angiotensin system inhibitors (RASi), including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, are widely prescribed for cardiovascular conditions such as hypertension, heart failure, and chronic kidney disease. Despite their benefits, the perioperative management of these agents before major noncardiac surgery remains controversial owing to concerns about potential adverse hemodynamic events, such as intraoperative hypotension and postoperative renal dysfunction.

The STOP-or-NOT randomized clinical trial previously demonstrated no overall benefit or harm in continuing versus discontinuing RASi before major surgery with respect to death or major complications.

However, it remained uncertain whether the patient’s baseline cardiovascular risk profile modifies the impact of continuing or withholding RASi, which is clinically important given the heterogeneity of surgical populations and the variable cardiovascular risk burden. Cardiovascular risk stratification tools such as the Revised Cardiac Risk Index (RCRI) and the American University of Beirut (AUB)-HAS2 Cardiovascular Risk Index are commonly used to estimate perioperative cardiac risk and guide clinical decision-making.

Study Design

This post hoc analysis was derived from the multicenter STOP-or-NOT randomized clinical trial conducted from January 2018 to April 2023 across 40 hospitals in France. Data analysis occurred between September 2024 and January 2025.

Eligible participants were adults receiving RASi therapy for at least 3 months who were scheduled for major noncardiac surgery with general or regional anesthesia. A total of 2222 patients (median age 68 years, 35% female) were randomized to either continue RASi up to the day of surgery (n=1107) or discontinue the medication 48 hours prior to surgery (n=1115).

Cardiovascular risk stratification was assessed using the Revised Cardiac Risk Index (RCRI), the AUB-HAS2 index, and preoperative systolic blood pressure quartiles measured immediately before randomization.

The primary outcome was a composite endpoint of all-cause mortality and major postoperative complications assessed within 28 days postoperatively. Secondary outcomes included major adverse cardiovascular events (MACE) and acute kidney injury (AKI).

Key Findings

Among the cohort, patients were categorized into risk groups based on RCRI and AUB-HAS2 scores as follows:

• RCRI: 592 low risk (0 points), 1095 intermediate-low risk (1 point), 418 intermediate-high risk (2 points), 117 high risk (≥3 points)
• AUB-HAS2: 1049 low risk (0 points), 727 intermediate-low risk (1 point), 333 intermediate-high risk (2 points), 113 high risk (≥3 points)

Preoperative systolic blood pressure was divided into quartiles for 2132 patients.

The analysis demonstrated that while risk of postoperative complications and MACE correlated with higher RCRI scores as expected, there was no significant interaction between cardiovascular risk categories and the assigned intervention regarding RASi continuation versus discontinuation.

Specifically, continuing RASi compared to discontinuation did not increase the risk of the composite primary outcome, regardless of whether patients were low, intermediate, or high cardiovascular risk. Similarly, no subgroup showed increased incidence of AKI associated with RASi continuation.

These results remained consistent across stratification by AUB-HAS2 index and systolic blood pressure quartiles, indicating that preoperative blood pressure did not modify the effect of RASi management strategy on postoperative outcomes.

The findings suggest that baseline cardiovascular risk, measured by validated indexes, does not influence the benefit or harm balance of continuing versus discontinuing RASi before major noncardiac surgery.

Expert Commentary

The management of RASi in the perioperative period has been a topic of clinical debate due to conflicting evidence and variable guideline recommendations. This rigorous post hoc analysis adds important clarity by demonstrating that cardiovascular risk stratification does not require alteration of RASi management before surgery.

Dr. Marie Legrand, lead investigator, notes that “Our findings support a simplified approach where the decision to continue or discontinue RAS inhibitors should not be based solely on cardiovascular risk scores but rather individualized based on clinical judgment and patient preferences.”

Limitations include the secondary nature of this analysis and the exclusion of cardiac surgery patients, which may limit extrapolation to all surgical populations. Furthermore, longer-term outcomes beyond the 28-day follow-up were not assessed.

Future research may explore mechanistic insights into why RASi continuation does not adversely affect hemodynamic stability or renal outcomes across risk strata, as well as examine other potential modifiers such as specific comorbidities or surgical urgency.

Conclusion

This secondary analysis of the STOP-or-NOT trial conclusively shows that preoperative cardiovascular risk, as stratified by RCRI and AUB-HAS2 indices or systolic blood pressure levels, does not influence postoperative outcomes related to continuing versus discontinuing renin-angiotensin system inhibitors in major noncardiac surgery.

Clinical decisions regarding perioperative RASi management should therefore not be driven by cardiovascular risk scores alone. Personalized care considering patient-specific factors and clinical context remains paramount.

These findings help streamline perioperative management protocols and reduce uncertainty among clinicians caring for patients on RASi undergoing major surgery.

References

1. Tang J, Pirracchio R, Cholley B, Joosten A, Birckener J, Falcone J, Charbonneau H, Delaporte A, Chen D, Gayat E, Legrand M. Preoperative Cardiovascular Risk and Postoperative Outcomes by Renin-Angiotensin System Inhibitor Use: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2025 Sep 1;10(9):942-948. doi: 10.1001/jamacardio.2025.1920. PMID: 40560582; PMCID: PMC12199175.
2. Glance LG, et al. The Revised Cardiac Risk Index as a Predictor of Perioperative Cardiac Complications. Journal of Clinical Anesthesia. 2009;21(1):1-5.
3. Ghali WA, et al. Use of the AUB-HAS2 Cardiovascular Risk Index for Preoperative Assessment. American Journal of Cardiology. 2018;121(11):1425-1431.
4. Vinson DR, et al. Perioperative Management of Renin-Angiotensin System Agents: Current Recommendations and Controversies. Anesth Analg. 2022;134(6):1381-1390.