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

Impact of Renin-Angiotensin System Inhibitors Continuation on Outcome After Major Surgery : a Multicenter, Prospective, Randomized and Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Surgery; Renin Angiotensin System
• Intervention / Treatment: Procedure: continuation of the RAS-inhibitors; Procedure: discontinuation of the RAS-inhibitors

Detailed Description

Multicenter, prospective, randomized, pragmatic, parallel-group clinical trial. The inclusion visit takes place between 4 months and no later than 3 days before the surgery visit.

• The randomization will be performed by the anesthesiologist Control group : RAS-I discontinuation Experimental group: RAS-I continuation
• A prescription for the medication strategy (stopping or pursuing the medication) will be handed to the patient during the anesthesiology consultation.

Five follow-up visits are planned

• Immediately, one hour after the surgery (Day 0)
• Then four follow-up visits are planned on day 1, 2, 7 (or hospital discharge) and 28 days+15 days (43 days maximum) after surgery will be collected data and parameters for study endpoints.

End of research visit is the 28 days+15 days (43 days maximum) follow-up visit.

• Study Type: Interventional
• Enrollment (Actual): 2222
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Hospital Lariboisière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
• Pregnancy test at inclusion visit for women of childbearing potential Women of childbearing potential must agree to use adequate contraception according to Recommendations related to contraception and pregnancy testing in clinical trials, by Clinical Trial Facilitation Group (CTFG)
• Signed informed consent

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: continuation of the RAS-inhibitors; 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; drug intake
Active Comparator: discontinuation of the RAS-inhibitors; 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; no drug intake

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Episodes of hypotension	Episodes requiring vasopressors administration	during anesthesia and surgery
Acute kidney injury	according to the KDIGO criteria	after surgery until day 28
Maximum SOFA score	patients admitted to ICU	from postoperative day 1 to day 7
Duration of hospital stay	Patients who will be outside the hospital but in other types of health care facilities at day 28 will be considered to have been discharged home	after surgery until day 28
Hospital free-days	Duration after hospital discharge	censored at 28 days following surgery

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Eienne Gayat, MD, PhD, Hospital Laribioisière, APHP

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2018
• Primary Completion (Actual): December 24, 2023
• Study Completion (Actual): December 24, 2023

Study Registration Dates

• First Submitted: December 11, 2017
• First Submitted That Met QC Criteria: December 14, 2017
• First Posted (Actual): December 15, 2017

Study Record Updates

• Last Update Posted (Actual): May 22, 2024
• Last Update Submitted That Met QC Criteria: May 21, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Major surgery; Postoperative morbidity and mortality; Renin angiotensin system inhibitors
• Other Study ID Numbers: P160933J

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No