Impact of Renin-Angiotensin System Inhibitors Continuation on Outcome After Major Surgery

NCT03374449 | Completed DMC

• 1 other identifier: P160933J
• Study Type: interventional
• Target: 2,222
• Locations: 1 country
• Sites: 1

Brief Summary

More than 200 million major surgical procedures are performed annually worldwide. Many of these patients have comorbidities including hypertension and/or heart failure. Chronic treatment of hypertension and/or heart failure very often includes a Renin-Angiotensin System (RAS) inhibitor (Angiotensin-Converting Enzyme Inhibitors (ACE-Is) or Angiotensin Receptor Blockers (ARBs). To stop or not to stop these medications before major surgery remain unknown. Data on management of RAS inhibitors before major surgery and anesthesia remain lacking and matter of debate. It is much likely that the strategy regarding management of RAS inhibitors in the peri-operative setting have important impact on peri-operative complications. The lack of evidence leads to conflicting guidelines with respect to RAS inhibitors management before major surgery. While French guidelines are to stop RAS inhibitors patients with hypertension to avoid profound anesthestic-drugs-induced hypotension, international guidelines differ. The American heart association task force states that continuation of RAS inhibitors perioperatively is reasonable (class IIa recommendation,level of evidence: B). The purpose of this study is to determine the prognostic impact of withholding vs continuing ARBs before major non cardiac surgery.

Conditions

Renin Angiotensin System; Surgery

Keywords

Major surgery; Postoperative morbidity and mortality; Renin angiotensin system inhibitors

Outcome Measures

Primary Outcomes (1)

• composite outcome composed of all-cause mortality and major postoperative complications within 28 days after surgery.

  Complications will be validated by an adjudication committee, blinded to the treatment arm. Death; Acute Myocardial infarction; Arterial or venous thrombosis; Stroke; Acute pulmonary oedema; Post-operative cardiogenic shock; Acute severe hypertension crisis; Cardiac arrhythmia requiring therapeutic intervention; Postoperative episodes of sepsis; Postoperative respiratory complication; Need for unplanned intensive care unit admission or readmission; Acute kidney injury: KDIGO criteria Baseline serum creatinine is obtained from the pre-operative blood sample; Surgical complications: need for reoperation for any reason and radiologic interventions for abscess drainage; Severe Hyperkalemia: serum potassium level \>5.5 mmol/L and requiring therapeutic intervention (insulin/glucose infusion and/or sodium bicarbonate infusion and/or intravenous B2 agonists and/or intravenous calcium gluconate and/or renal replacement therapy and/or ventricular tachycardia or ventricular fibrillation).

  after surgery until day 28

Secondary Outcomes (5)

• Episodes of hypotension

  during anesthesia and surgery

• Acute kidney injury

  after surgery until day 28

• Maximum SOFA score

  from postoperative day 1 to day 7

• Duration of hospital stay

  after surgery until day 28

• Hospital free-days

  censored at 28 days following surgery

Study Arms (2)

continuation of the RAS-inhibitors

EXPERIMENTAL

in the continuation of the RAS-inhibitors arm the treatment will be continued until the morning the day of surgery.

Procedure: continuation of the RAS-inhibitors

discontinuation of the RAS-inhibitors

ACTIVE COMPARATOR

In this arm : discontinuation of the RAS-inhibitors 48 hours before surgery Patients won't receive the drug on the morning of the day of the surgery.

Procedure: discontinuation of the RAS-inhibitors

Interventions

continuation of the RAS-inhibitors PROCEDURE

drug intake

continuation of the RAS-inhibitors

discontinuation of the RAS-inhibitors PROCEDURE

no drug intake

discontinuation of the RAS-inhibitors

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients requiring major non-cardiac surgery (surgery with an expected duration of more than 2 hours from the surgical incision and a post-operative hospital stay of least 3 days) (according to the study RELIEF, DOI : 10.1056/NEJMoa1801601))
• Age≥18 years
• Patients chronically treated (\>3 months before surgery) with RAS inhibitors
• Signed informed consent

You may not qualify if:

• Emergency surgery (surgical treatment needed within 24 hours)
• Hyperkalemia (\> 5.5mmol/L) known at the time of the anesthetic consultation
• Patients for which death is deemed imminent and inevitable or patients with an underlying disease process with a life expectancy of less than 1 month
• Patient with severe renal insufficiency, known at the time of the anesthestic consultation (as defined by estimated glomerular filtration rate (creatinine clearance \<15 ml/min/1.73m2 or requiring renal replacement therapy)
• Patient with preoperative shock (defined by the need for vasoactive drugs before surgery)
• Inability to obtain informed consent either from the patient.
• Lack of Social Insurance

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hospital Lariboisiere

Paris, 75010, France

Location

Related Publications (9)

• Legrand M, Payen D. Case scenario: Hemodynamic management of postoperative acute kidney injury. Anesthesiology. 2013 Jun;118(6):1446-54. doi: 10.1097/ALN.0b013e3182923e8a. No abstract available.

  PMID: 23558177 BACKGROUND

• Augoustides JG. Angiotensin blockade and general anesthesia: so little known, so far to go. J Cardiothorac Vasc Anesth. 2008 Apr;22(2):177-9. doi: 10.1053/j.jvca.2008.01.002. No abstract available.

  PMID: 18375316 BACKGROUND

• Mets B. To stop or not? Anesth Analg. 2015 Jun;120(6):1413-9. doi: 10.1213/ANE.0000000000000758. No abstract available.

  PMID: 25988640 BACKGROUND

• Mets B, Hennrikus E. Perioperative angiotensin axis blockade, to continue or discontinue, that is the question? Anesth Analg. 2014 Nov;119(5):1223-4. doi: 10.1213/ANE.0000000000000430. No abstract available.

  PMID: 25329033 BACKGROUND

• Fleisher LA, Fleischmann KE, Auerbach AD, Barnason SA, Beckman JA, Bozkurt B, Davila-Roman VG, Gerhard-Herman MD, Holly TA, Kane GC, Marine JE, Nelson MT, Spencer CC, Thompson A, Ting HH, Uretsky BF, Wijeysundera DN; American College of Cardiology; American Heart Association. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014 Dec 9;64(22):e77-137. doi: 10.1016/j.jacc.2014.07.944. Epub 2014 Aug 1. No abstract available.

  PMID: 25091544 BACKGROUND

• Pirracchio R, Cholley B, Falcone J, Charbonneau H, Delaporte A, Lemoine A, Joosten A, Gayat E, Legrand M; STOP-or-NOT trial group. Impact of continuing renin-angiotensin-aldosterone system inhibitors before surgery on intraoperative hypotensive events: a secondary analysis of the STOP-or-NOT Trial. Br J Anaesth. 2026 Jan 8:S0007-0912(25)00860-8. doi: 10.1016/j.bja.2025.11.049. Online ahead of print.

  PMID: 41513520 DERIVED

• 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 DERIVED

• Legrand M, Falcone J, Cholley B, Charbonneau H, Delaporte A, Lemoine A, Garot M, Joosten A, Meistelman C, Cheron-Leroy D, Rives JP, Pastene B, Dewitte A, Sigaut S, Danguy des Deserts M, Truc C, Boisson M, Lasocki S, Cuvillon P, Schiff U, Jaber S, Le Guen M, Caillard A, Bar S, Pereira de Souza Neto E, Colas V, Dimache F, Girardot T, Jozefowicz E, Viquesnel S, Berthier F, Vicaut E, Gayat E; Stop-or-Not Trial Group. Continuation vs Discontinuation of Renin-Angiotensin System Inhibitors Before Major Noncardiac Surgery: The Stop-or-Not Randomized Clinical Trial. JAMA. 2024 Sep 24;332(12):970-978. doi: 10.1001/jama.2024.17123.

  PMID: 39212270 DERIVED

• Legrand M, Futier E, Leone M, Deniau B, Mebazaa A, Plaud B, Coriat P, Rossignol P, Vicaut E, Gayat E; STOP-OR-NOT study investigators. Impact of renin-angiotensin system inhibitors continuation versus discontinuation on outcome after major surgery: protocol of a multicenter randomized, controlled trial (STOP-or-NOT trial). Trials. 2019 Mar 5;20(1):160. doi: 10.1186/s13063-019-3247-1.

  PMID: 30836981 DERIVED

Study Officials

• Eienne Gayat, MD, PhD

  Hospital Laribioisière, APHP

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Endpoint validated by an adjudication commitee blinded to the arm.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The aim of this study is to evaluate the impact of Renin-Angiotensin System inhibitors management (Continuation or discontinuation 48 hours before surgery) on outcome in patients undergoing scheduled major non-cardiac surgery (surgery with an expected duration of more than 2 hours from the surgical incision and a post-operative hospital stay of least 3 days)

Study Record Dates

• First Submitted: December 11, 2017
• First Posted: December 15, 2017
• Study Start: February 6, 2018
• Primary Completion: December 24, 2023
• Study Completion: December 24, 2023
• Last Updated: May 22, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)