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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Renin Angiotensin System, Surgery

Intervention / Treatment
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* Procedure: continuation of the RAS-inhibitors
* Procedure: discontinuation of the RAS-inhibitors


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: continuation of the RAS-inhibitors<br>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<br>* drug intake<br>|
| Active Comparator: discontinuation of the RAS-inhibitors<br>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<br>* no drug intake<br>|

What is the study measuring?
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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; 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Major surgery, Postoperative morbidity and mortality, Renin angiotensin system inhibitors