Management of Angiotensin Inhibitors During the Perioperative Period (AIPOP)

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers During the Perioperative Period: to Withdraw or to Continue? A Multicenter Randomized Controlled Trial

This is a multicenter randomized clinical trial to determine the effect of continuation versus withdrawal of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in the perioperative period on postoperative complications.

Study Overview

• Status: Terminated
• Conditions: Surgery; Perioperative Complication; Angiotensin Hypertension
• Intervention / Treatment: Drug: Perioperative withdrawal of angiotensin converting enzyme inhibitors and angiotenin receptor blockers; Diagnostic test: Blood draw; Behavioral: Diary to register drug adherence; Behavioral: Quality of life questionnaire; Behavioral: WHODAS questionnaire

Detailed Description

Rationale:

Angiotensin inhibitors including angiotensin convertying enzyme inhibitors (ACEI), and angiontensin receptors blockers (ARB) are frequently used to treat patients with chronic hypertension. These drugs reduce morbidity and mortality on the long term. However, when patients who use ACEI or ARB undergo surgery, hypotension may occur in the perioperative period, which may can lead to organ hypoperfusion and damage. On the other hand, when ACEI and ARB are temporarily discontinued in the perioperative period, hypertension may occur which also may lead to complications. Therefore, before surgery the anesthesiologist advises the patient to continue or to temporarily withdraw this drug. Importantly, it is currently unclear which strategy is best, and international guidelines are disconcordant on this point. Policy varies between hospitals and even between anesthesiologists: in some hospitals, patients are advised to temporarily withdraw the ACEI/ARB, whilst in other hospitals patients are advised to continue this drug. The latest research on this topic suggests that perioperative continuation of ACEI/ARB may lead to more complications, but definitive evidence is lacking. Therefore it is important to perform a randomized trial to compare the two options: perioperative continuation versus withdrawal of ACEI/ARB.

Objective:

The objective of this trial is to determine the effect of continuation versus withdrawal of ACEI and ARB in the perioperative period on postoperative complications, expressed as acute kidney injury (AKI), myocardial injury, and quality of life (QoL).

Study design:

This is a multicenter randomized clinical trial.

Study population:

Patients who use ACEI/ARB chronically for treatment of hypertension and who are scheduled for an elective intermediate to high risk non-cardiac surgical procedure with an expected postoperative length of hospital stay of at least 2 days, are eligible for inclusion. Patients who use a combination pill of ACEI/ARB with a diuretic are eligible as well. Patients who use a combination pill ACEIwith another drug will be excluded, as well as patients who use other drugs acting on the renin aldosterone angiotensin system.

Intervention:

The intervention is the withdrawal of ACEI/ARB in the perioperative period, i.e. 24 hours before surgery until 24-48 hours after surgery. The ACEI/ARB medication is resumed on the second or third day after surgery, as soon as the clinical condition allows based on judgement by the attending physician.

This intervention will be compared to perioperative continuation of ACEI/ARB.

Main study parameters/endpoints:

The primary outcome for this study is postoperative acute kidney injury, defined according to the Kidney Disease Improving Global Outcomes (KDIGO) guideline.

Secondary outcomes include postoperative myocardial injury, intraoperative and postoperative hypotension and hypertension, length of stay in the hospital or nursing home, kidney function loss and end-stage renal disease within three months after surgery, major cardiovascular complications (myocardial infarction, coronary revascularization, heart failure, arrhythmia, stroke) within three months after surgery, all-cause mortality within three months after surgery and a quality of life (QoL) assessment.

• Study Type: Interventional
• Enrollment (Actual): 342
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lynn Miggelbrink, MD; Phone Number: +31887571396; Email: l.a.miggelbrink@umcutrecht.nl

Study Locations

• Canada
  • Ontorio
    • Toronto, Ontorio, Canada
      • University Health Network Toronto
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC location AMC
  • Amsterdam, Netherlands
    • Amsterdam UMC location VU
  • Breda, Netherlands
    • Amphia Hospital
  • Nieuwegein, Netherlands
    • Antonius hospital
  • Rotterdam, Netherlands
    • Erasmus MC
  • Utrecht, Netherlands
    • UMC Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Chronic ACEI or ARB use for the treatment of hypertension. Patients who use a com-bination pill with a diuretic are eligible as well;
• Scheduled for elective intermediate to high risk noncardiac surgery, defined according to the European Society of Cardiology / European Society of Anesthesiology guidelines on noncardiac surgery;
• Expected postoperative length of stay of at least two days.

Exclusion Criteria:

• Severe chronic kidney disease, defined as GFR<30 ml/min/1.73 m2;
• ACEI/ARB use for the treatment of chronic systolic heart failure, defined as left ven-tricular ejection fraction ≤40%;
• ACEI/ARB use within one year after ST-elevated myocardial infarction, according to the fourth universal definition of myocardial infarction;
• Transplant surgery;
• ACEI/ARB use in a combination pill together with a drug other than a diuretic, including calcium channel blockers, beta-blockers and neprilysin inhibitors;
• Use of drugs acting on the renin-angiotensin-aldosterone system other than ACEI/ARB, e.g. aliskiren.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Perioperative withdrawal of ACEI/ARB.	Drug: Perioperative withdrawal of angiotensin converting enzyme inhibitors and angiotenin receptor blockers; Withdrawal from 24 hours before surgery until 24-48 hours after surgery. The ACEI/ARB medication is resumed on the second or third day after surgery, as soon as the clinical condition allows based on judgement by the attending physician.; Diagnostic test: Blood draw; Blood will be drawn to measure creatinin and troponin: once before surgery, on the first and second postoperative day, and within 4-8 weeks after surgery; Behavioral: Diary to register drug adherence; To register medication adherence, patients will be asked to fill out their medication intake (of ACEI/ARB) in a diary from a week before surgery until surgery.; Behavioral: Quality of life questionnaire; Patients are asked to fill out a quality of life questionnaire (EQ-5D) before surgery and at three months after surgery; Behavioral: WHODAS questionnaire; Patients are asked to fill out a questionnaire about disabilities (WHO Disability Assessment Schedule 2.0) before surgery and at three months after surgery
Active Comparator: Control group; Perioperative continuation of ACEI/ARB.	Diagnostic test: Blood draw; Blood will be drawn to measure creatinin and troponin: once before surgery, on the first and second postoperative day, and within 4-8 weeks after surgery; Behavioral: Diary to register drug adherence; To register medication adherence, patients will be asked to fill out their medication intake (of ACEI/ARB) in a diary from a week before surgery until surgery.; Behavioral: Quality of life questionnaire; Patients are asked to fill out a quality of life questionnaire (EQ-5D) before surgery and at three months after surgery; Behavioral: WHODAS questionnaire; Patients are asked to fill out a questionnaire about disabilities (WHO Disability Assessment Schedule 2.0) before surgery and at three months after surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative acute kidney injury	Postoperative acute kidney injury, defined according to the Kidney Disease Improving Global Outcomes (KDIGO) guideline.	Within two days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative myocardial injury	Postoperative myocardial injury, defined as an increased level of serum troponin above the clinical cut-off value	Within two days after surgery
Intraoperative hypotension	Intraoperative hypotension, defined as a mean arterial pressure <65 mmHg for at least 10 minutes	From the start of anesthesia until the end of surgery
Postoperative hypotension	Postoperative hypotension, defined as a mean arterial pressure <65 mmHg	From the end of surgery up to and including the second postoperative day
Preoperative hypertension	Preoperative severe hypertension, defined as blood pressure >180/110 mmHg	Within 24 hours before start of anesthesia
Postoperative hypertension	Postoperative severe hypertension, defined as blood pressure >180/110 mmHg	From the end of surgery up to and including the second postoperative day
Length of stay	Length of stay in hospital or nursing home	Within three months after surgery
Kidney function loss	Decline in glomerular filtration rate as compared to before surgery	Within three months after surgery
End-stage renal disease	End-stage renal disease, defined as renal disease requiring dialysis or organ transplantation	Within three months after surgery
Major cardiovascular complications	Major cardiovascular complications (myocardial infarction, coronary revascularization, heart failure, arrhythmia, stroke)	Within three months after surgery
Mortality	All-cause mortality	Within three months after surgery
Quality of life	Quality of life based on the EuroQoL 5D questionnaire	At three months after surgery
Acute postoperative myocardial injury	Acute postoperative myocardial injury, defined as an absolute postoperative increase in serum troponin of more than clinical cut-off value as compared to the preoperative value	Within two days after surgery
Acute kidney function loss	Decline in glomerular filtration rate as compared to before surgery	Within two days after surgery
Disability	Disability at three months after surgery based on the World Health Organization Disability Activity Score (WHODAS): Change in WHODAS as compared to before surgery (continuous measure);; Clinically important change in WHODAS defined as an increase of 5% or more as compared to before surgery;; Disability free survival defined as WHODAS <16%;; Clinically important disability defined as WHODAS >35%.	At three months after surgery

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Judith van Waes, MD PhD, UMC Utrecht; Principal Investigator: Wilton van Klei, MD PhD, UMC Utrecht

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2020
• Primary Completion (Actual): February 6, 2023
• Study Completion (Actual): September 1, 2023

Study Registration Dates

• First Submitted: August 6, 2020
• First Submitted That Met QC Criteria: August 7, 2020
• First Posted (Actual): August 10, 2020

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Perioperative management; Noncardiac surgery; Angiotensin inhibitors
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Angiotensin-Converting Enzyme Inhibitors
• Other Study ID Numbers: AIPOP

Drug and device information, study documents

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