Prophylaxis for Patients at Risk to Eliminate Post-operative Atrial Fibrillation (PREP-AF)

After surgery on the lungs or esophagus, 12-46% of patients experience an irregular heart rhythm called atrial fibrillation. Although usually transient, post-operative atrial fibrillation is associated with longer stay in hospital, greater complications, and increased risk of death. Several medications have been shown to be effective at reducing the risk of atrial fibrillation after their surgery with the greatest effectiveness and safety demonstrated with amiodarone. Nevertheless, amiodarone has potential side effects, and so it is only recommended in patients with increased risk of developing atrial fibrillation. A tool has been developed and validated to identify high-risk patients but no clinical trial has looked at the effectiveness of administering amiodarone in this high-risk group. This study aims to assess the feasibility and safety of conducting a clinical trial where patients are randomized to receive amiodarone or placebo. This is critical before considering a full-scale trial to assess the effectiveness of amiodarone in reducing atrial fibrillation after surgery on the lungs or esophagus.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Amiodarone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andrew JE Seely, MD, PhD; Phone Number: 74052 613-737-8899; Email: aseely@ohri.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • The Ottawa Hospital
      • Principal Investigator: Andrew JE Seely, MD, PhD, FRCSC
      • Contact: Andrew JE Seely, MD, PhD, FRCSC; Phone Number: 74052 613-737-8899; Email: aseely@ohri.ca
      • Principal Investigator: Heather Smith, MD
      • Principal Investigator: Salmaan Kanji, Pharm. D
      • Sub-Investigator: Diem TT Tran, MD, MSc, FRCPC
      • Sub-Investigator: Calum Redpath, MD
      • Sub-Investigator: Kednapa Thavorn, Pharm PhD
      • Sub-Investigator: Tori Lenet, MD
      • Sub-Investigator: Greg Sigler, MD
      • Sub-Investigator: Sebastien Gilbert, MD, FRCSC
      • Sub-Investigator: Donna Maziak, MDCM, MSc, FRCSC
      • Sub-Investigator: Patrick Villeneuve, MD, FRCSC, PhD
      • Sub-Investigator: Sudhir Sundaresan, MD, FRCSC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 18 years or greater
• Undergoing major non-cardiac pulmonary or esophageal surgery (including esophagectomy, pulmonary wedge resection, lobar resection, pneumonectomy, or gastrectomy)
• POAF prediction score greater than or equal to 4

Exclusion Criteria:

• Aged less than 18 years
• History of atrial arrhythmia (paroxysmal or persistent), or Wolf-Parkinson-White syndrome (WPW), or 2nd or 3rd degree heart block without a pacemaker
• Current antiarrythmic therapy (including amiodarone, propafenone, sotalol, flecainide, and dronedarone)
• Previous severe adverse reaction or contraindication to amiodarone (including pre-existing interstitial lung disease, or history of hepatotoxicity from amiodarone)
• QTc interval longer than 450ms
• Serum alanine transaminase or aspartate transaminase over 3 times the upper limit of normal, or Child-Pugh class C
• Allergy to amiodarone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Arm; Patients randomized to amiodarone treatment	Drug: Amiodarone; Patients will undergo one of the two regimens of amiodarone, based on their ability to tolerate po (per os) intake in the post-operative period: • All patient will receive 1050mg of amiodarone in 100mL of 5% dextrose administered intravenously initiated at the time of anesthesia induction at a rate of 0.73mg/min or 43.75mg/h and continued over 24 hours followed by: If able to tolerate po intake: 400mg po BID for post-operative days 1 to 5 or until the day of discharge (whichever occurs first).; If unable to tolerate po intake: daily infusion of 1050mg in 100mL of 5% dextrose for postoperative days 1 to 5 or until the day of discharge (whichever occurs first).
Placebo Comparator: Control Arm; Patients randomized to placebo treatment	Drug: Placebo; Patients will undergo one of the two schedules or intravenous infusion, based on their ability to tolerate po intake in the post-operative period: All patients will receive 100mL of 5% dextrose administered intravenously initiated at the time of anesthesia induction at a rate of 0.73mg/min or 43.75mg/h and continued over 24 hours followed by:o If able to tolerate po intake: 400mg po BID for post-operative days 1 to 5 or until the day of discharge (whichever occurs first).; Esophagectomy patient will receive 100mL of 5% dextrose at the time of anesthesia induction at a rate of what would be 0.73mg/min or 43.75mg/h if it contained 1050mg of amiodarone, followed by daily infusion of 100mL of 5% dextrose for 4 days or until the day of discharge (whichever occurs first).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Capability for enrolment	Capacity for enrolment will be assessed, in order to determine recruitment potential and an optimal sample size estimated for a full-scale RCT, by measuring the following outcomes: proportion of patients risk stratified and screened, proportion of eligible individuals consenting to involvement in the study, proportion of recruited individuals who are enrolled in the study.	Upon study completion, 1 year following study initiation
Proportion of patients randomized who receive the intervention	Feasibility of the randomization process will be evaluated including the proportion of patients randomized who receive the intervention	Upon study completion, 1 year following study initiation
Knowledge of which patients received intervention and placebo	Feasibility of blinding of participant, care provider, investigator, and outcomes assessor to the intervention allocation of participants will be evaluated by administering a survey to assess their knowledge of which patients received the intervention and placebo	Upon study completion, 1 year following study initiation
Intervention delivery	Intervention delivery will be assessed by determining if protocol adherence rates exceed >90% and recording observational data on the quality of intervention delivery using a data collection sheet	Upon study completion, 1 year following study initiation
Protocol compliance	Monitoring of protocol compliance will be measured by the frequency, rate, and rationale of events when study activities diverge from the REB-approved protocol	Upon study completion, 1 year following study initiation
Adherence to safety protocol	Monitoring of safety will be assessed by determining the rate and efficiency of reporting adverse events if they occur and monitoring adherence rates to safety and monitoring protocols	Upon study completion, 1 year following study initiation
Proportion of patients for which data could be abstracted	Feasibility of data extraction analysis will be evaluated by the proportion of patients for which the required data could be abstracted: medication use, incidence of post-operative atrial fibrillation, post-operative outcomes, etc.	Upon study completion, 1 year following study initiation
Resources	Resources required to conduct a future multi-centre PREP-AF trial will be assessed by evaluating the administrative capacity of the POAF research team, including the required number of hours of research assistant time, as well as the feasibility of the designated study budget	Upon study completion, 1 year following study initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative atrial fibrillation	Incidence of postoperative atrial fibrillation, as defined by atrial fibrillation proved by electrocardiogram with an irregular narrow complex tachycardia without p waves	Within 30 days post-surgery
Severity of postoperative atrial fibrillation	Severity of postoperative atrial fibrillation, as classified by the Clavien-Dindo classification schema, defined for thoracic surgery using the published Ottawa Thoracic Morbidity and Mortality system	Within 30 days post-surgery
Hospital length of stay	Hospital length of stay, as defined as the number of days inclusive between the day of surgery, and the day of discharge	Within 30 days post-surgery
Other postoperative complications	Other postoperative complications using the taxonomy of the Ottawa Thoracic Morbidity and Mortality definitions. All complications are recorded with incidence, date, and severity. Of note, post-operative mortality is a grade V complication and is recorded along with its cause as well	Within 30 days post-surgery

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Investigators: Principal Investigator: Andrew JE Seely, MD, PhD, The Ottawa Hospital

Publications and helpful links

General Publications

• Smith HA, Kanji S, Tran DTT, Redpath C, Ferguson D, Lenet T, Sigler G, Gilbert S, Maziak D, Villeneuve P, Sundaresan S, Seely AJE. Prophylaxis for patients at Risk to Eliminate Post-operative Atrial Fibrillation (PREP-AF trial): a protocol for a feasibility randomized controlled study. Trials. 2021 Jun 7;22(1):384. doi: 10.1186/s13063-021-05318-1.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2022
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: May 6, 2020
• First Submitted That Met QC Criteria: May 13, 2020
• First Posted (Actual): May 19, 2020

Study Record Updates

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

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: 20190583-01H

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
• product manufactured in and exported from the U.S.: No