RAFF4 Trial: Vernakalant vs. Procainamide for Acute Atrial Fibrillation in the Emergency Department

The objective is to compare IV vernakalant to IV procainamide for the ED management of acute AF patients. If vernakalant proves to be more effective, faster, and safer than IV procainamide, this will give clinicians an important alternative for pharmacological cardioversion of acute AF. The investigators propose a pragmatic comparative effectiveness trial entailing an open label, randomized controlled trial at 12 large Canadian EDs. Study subjects will be randomized to 1 of 2 treatment arms: 1) Patients will receive an initial infusion of 3mg/kg of IV vernakalant over 10 minutes, followed by a second dose of 2mg/kg over 10 minutes, if necessary, or 2) Patients will receive a continuous infusion of 15mg/kg of IV procainamide over 60 minutes. The primary aim will be to compare conversion to normal sinus rhythm between the two drugs. The investigators will include stable patients presenting with an episode of acute AF of at least 3 hours duration, where symptoms require urgent management and where immediate cardioversion is a reasonable option. Using the integrated consent model, research assistants will obtain verbal consent from eligible patients.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Vernakalant; Drug: Procainamide

• Study Type: Interventional
• Enrollment (Estimated): 340
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ian G Stiell, MD, MSc; Phone Number: 18683 613-798-5555; Email: istiell@ohri.ca
• Study Contact Backup: Name: Erica Brown; Phone Number: 613-798-5555; Email: ericbrown@ohri.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Not yet recruiting
      • University of Alberta Hospital
      • Contact: Brian Rowe, MD; Phone Number: (780) 407-6707; Email: Brian.Rowe@ualberta.ca
      • Principal Investigator: Brian Rowe, MD
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Not yet recruiting
      • Vancouver General Hospital
      • Contact: Corinne Hohl, MD; Email: chohl@mail.ubc.ca
      • Principal Investigator: Corinne Hohl, MD
    • Vancouver, British Columbia, Canada
      • Not yet recruiting
      • St. Paul's Hospital
      • Contact: Frank Scheuermeyer, MD; Email: frank.scheuermeyer@gmail.com
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Recruiting
      • Queen Elizabeth II Health Sciences Centre
      • Contact: Samuel Campbell, MD
  • Ontario
    • Hamilton, Ontario, Canada, l8L 2X2
      • Not yet recruiting
      • Hamilton Health Sciences Centre
      • Contact: Michelle Welsford, MD; Phone Number: 905521210044832; Email: dr.m@welsford.ca
      • Contact: Natasha Clayton; Email: clayton@mcmaster.ca
    • Kingston, Ontario, Canada, K2L 2V7
      • Not yet recruiting
      • Kingston Health Sciences Centre
      • Contact: Marco Sivilotti, MD; Phone Number: 6135496666; Email: sivilott@queensu.ca
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Recruiting
      • Ottawa Hospital
      • Contact: Ian Stiell; Email: istiell@ohri.ca
      • Principal Investigator: Ian Stiell, MD
      • Contact: Erica Brown; Email: ericbrown@ohri.ca
    • Toronto, Ontario, Canada
      • Not yet recruiting
      • Sunnybrook Hospital
      • Contact: Ivy Cheng
    • Toronto, Ontario, Canada
      • Not yet recruiting
      • St. Michaels
      • Contact: Brian Steinhart, MD; Email: Brian.Steinhart@unityhealth.to
  • Quebec
    • Laval, Quebec, Canada
      • Recruiting
      • Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval
      • Contact: David Pare, MD; Email: david.pare.med@ssss.gouv.qc.ca
    • Montreal, Quebec, Canada, H1T 1C8
      • Recruiting
      • Montreal Heart Institute
      • Principal Investigator: Laurent Macle, MD
      • Contact: Alain Vadeboncoeur, MD; Email: alain.vadeboncoeur@gmail.com
      • Principal Investigator: Alain Vadeboncoeur, MD
    • Montreal, Quebec, Canada
      • Recruiting
      • Hopital du Sacre-Coeur
      • Contact: Judy Morris, MD
    • Quebec City, Quebec, Canada
      • Recruiting
      • Hôpital de L'Enfant-Jésus
      • Contact: Eric Mercier, MD
      • Contact: Marcel Emond, MD; Email: marcelemond1@me.com
    • Québec, Quebec, Canada
      • Recruiting
      • Hotel-Dieu de Levis
      • Contact: Patrick Archambault, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

The investigators will include stable (see below) patients presenting with an episode of acute non-valvular AF of at least 3 hours duration and no greater than 7 days, where symptoms require urgent management and where immediate cardioversion is a reasonable option because:

1. The patient has been adequately anticoagulated for a minimum of 3 weeks (warfarin and INR > 2.0 or novel oral anticoagulants [dabigatran, rivaroxaban, edoxaban, and apixaban]), or
2. The patient is not adequately anticoagulated for > 3 weeks, has no history of stroke or TIA, and does not have valvular heart disease, AND:

i) onset < 12 hours ago, or ii) if onset 12 - 48 hours ago and there are <2 of these CHADS-65 criteria (age ≥ 65, diabetes, hypertension, heart failure), or iii) negative for thrombus on transesophageal echocardiography. Of note, we will not exclude patients with prior episodes of acute AF. Patients will only be enrolled if the attending physician is confident about time of onset, based upon the patient's symptoms. Physicians are well aware of the importance of this determination and will not attempt to cardiovert patients otherwise.

Exclusion Criteria: The investigators will exclude patients who have any of the reasons listed below.

1. Appropriateness:

   1. unable to understand the study and integrated consent due to language barrier and/or cognitive impairment;
   2. have permanent (chronic) AF;
   3. have valvular heart disease (mitral stenosis, rheumatic or mechanical);
   4. increased risk of stroke because onset not clearly <48 hours and not anticoagulated (or abnormal TEE); or do not meet the inclusion criteria a or b;
   5. deemed unstable and require immediate cardioversion: i) systolic blood pressure <100 mmHg; ii) rapid ventricular preexcitation (Wolff-Parkinson-White syndrome); iii) acute coronary syndrome - chest pain and acute ischemic changes on ECG; or iv) pulmonary edema - severe dyspnea requiring immediate IV diuretic, nitrates, or BIPAP;
   6. primary presentation was for another condition; examples include pneumonia, pulmonary embolism, and sepsis;
   7. convert spontaneously to sinus rhythm prior to randomization;
   8. were previously enrolled in the study; or
   9. have atrial flutter.

2. Safety

   1. has heart failure Class NYHA III or NYHA IV; left ventricular ejection fraction <30%; or has clinical or radiological evidence of acute HF;
   2. has presented with an acute coronary syndrome or acute decompensated heart failure, in the last 30 days; or has had a recent myocardial infarction (< 3 months);
   3. has severe aortic stenosis;
   4. has a systolic blood pressure < 100 mmHg;
   5. has a significantly prolonged QT interval at baseline e.g. uncorrected > 440 msec, congenital or acquired long QT syndrome; or a family history of Long QT syndrome; or ECG shows QTc >460ms (when heart rate >100 measured by the Fridericia formula);
   6. has severe bradycardia (heart rate < 55 bpm), sinus node dysfunction, or second or third degree atrioventricular heart block, in the absence of an in situ properly functioning pacemaker; or, has Brugada syndrome (genetic disease with increased risk of sudden cardiac death);
   7. has received an intravenous antiarrhythmic drug Class I, e.g. procainamide, or Class Ill, e.g. amiodarone or ibutilide, within the prior 4 hours; or currently takes oral class I or III antiarrhythmic drugs other than amiodarone (last dose < 5 half-lives before enrollment);
   8. has received an IV beta-blocker within the 2 hours prior
   9. has hypersensitivity to the active substance or to any of the ingredients of either drug;
   10. has advanced or end-stage liver disease; or
   11. is breast feeding or pregnant (safety not established).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vernakalant; Patients randomized to this arm will receive an initial infusion of 3 mg/kg infused over a 10-minute period by a pre-programmed IV pump.82 For patients ≤ 100 kg the infusion is prepared by adding 25 mL of BRINAVESS 20 mg/mL to 100 mL of diluent creating a total volume of 125 mL at a concentration of 4 mg/mL. For patients > 100 kg the infusion is prepared by adding 30 mL of BRINAVESS 20 mg/mL to 120 mL of diluent creating a total volume of 150 mL at a concentration of 4 mg/mL. For patients weighing ≥ 113 kg, the maximum initial dose is 339 mg (84.7 mL of 4 mg/mL solution).	Drug: Vernakalant; an initial infusion of 3 mg/kg infused over a 10-minute period by a pre-programmed IV pump; Other Names: BRINAVESS
Active Comparator: Procainamide; Patients randomized to this arm will receive a continuous infusion of IV procainamide with a dose of 15 mg/kg in 500 mL of normal saline given over 60 minutes (maximum dose 1,500 mg), by a pre-programmed pump. While the CAEP Best Practices Checklist suggests an infusion time of 30-60 minutes, we believe that a 60-minute period will avoid some adverse events.	Drug: Procainamide; 15 mg/kg in 500 mL of normal saline given over 60 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conversion to sinus rhythm for a minimum duration of 30 minutes	Conversion to and maintenance of sinus rhythm for at least 30 minutes at any time following randomization until 30 minutes past the completion of the drug infusion. Heart rhythm will be determined by an electrocardiogram (ECG).	During any time following randomization until 30 minutes past the completion of the drug infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normal sinus rhythm	Being in normal sinus rhythm at the time of ED disposition (discharge or admission). Heart rhythm will be determined by an electrocardiogram (ECG).	At the time of patient disposition (approximately 3 hours after arrival)
Patient disposition (admission or discharge)	Whether the patient was discharged home or admitted to the hospital.	At the time of patient admission or discharge (approximately 3 hours after arrival)
Length of stay in ED	Length of stay in ED in minutes, from time of arrival to time of discharge or admission	From time of arrival until time of discharge or admission (approximately 3 hours)
Time to discharge	Time to discharge in minutes, from time of randomization to time of discharge or admission	From time of randomization until time of discharge or admission (approximately 3 hours)
Time to conversion	Time to conversion to sinus rhythm in minutes, from time of start of study drug infusion	From time of infusion start until time of conversion to sinus rhythm (approximately 0 - 90 minutes)
Whether the patient required electrical cardioversion	Whether the patient required electrical cardioversion to restore normal sinus rhythm in the ED	From 30 minutes after the study drug infusion is completed.
Adverse events	will be classified as serious or other, whether occurring 0-2 hours or 2-12 hours after infusion, whether infusion had to be halted or discontinued, or treatment required	0-12 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintenance of normal sinus rhythm	Maintenance of normal sinus rhythm at 30 days after ED disposition, to be verified by hospital records, patient report, or by a smartphone application.	30 days post discharge
Recurrence of acute AF	Recurrence of acute atrial fibrillation requiring an emergency department visit	30 days
Death	within 30 days of ED disposition	30 days
Stroke	transient ischemic attack, myocardial infarction, or other thromboembolic event within 30 days of ED disposition	30 days
Return to normal activities	Return to normal daily activities measured in days	30 days

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Investigators: Principal Investigator: Ian G Stiell, MD, MSc, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2021
• Primary Completion (Estimated): September 30, 2023
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: July 21, 2020
• First Posted (Actual): July 24, 2020

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Emergency Department; Vernakalant; Procainamide
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease Attributes; Arrhythmias, Cardiac; Emergencies; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Procainamide
• Other Study ID Numbers: 20200402

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