Clinical trial NCT03374449: Impact of Renin-Angiotensin System Inhibitors Continuation on Outcome After Major Surgery
Official title: Impact of Renin-Angiotensin System Inhibitors Continuation on Outcome After Major Surgery : a Multicenter, Prospective, Randomized and Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Renin Angiotensin System
Surgery
Keywords: Major surgery
Postoperative morbidity and mortality
Renin angiotensin system inhibitors
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-12-15
Enrollment: 2222
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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)
Primary purpose: OTHER

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: composite outcome composed of all-cause mortality and major postoperative complications within 28 days after surgery.
timeFrame: after surgery until day 28
Secondary outcomes:
measure: Episodes of hypotension
timeFrame: during anesthesia and surgery
measure: Acute kidney injury
timeFrame: after surgery until day 28
measure: Maximum SOFA score
timeFrame: from postoperative day 1 to day 7
measure: Duration of hospital stay
timeFrame: after surgery until day 28
measure: Hospital free-days
timeFrame: censored at 28 days following surgery
Other outcomes:
Locations:
city: Paris
country: France
facility: Hospital Lariboisiere
Study officials:
affiliation: Hospital Laribioisière, APHP
name: Eienne Gayat, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: Mets B. To stop or not? Anesth Analg. 2015 Jun;120(6):1413-9. doi: 10.1213/ANE.0000000000000758. No abstract available.
citation: 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.
citation: 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.
citation: 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.