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

NCT04485195 | Completed Phase 4 DMC

• 1 other identifier: 20200402
• Study Type: interventional
• Target: 350
• Locations: 1 country
• Sites: 14

Brief Summary

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.

Conditions

Atrial Fibrillation

Keywords

Emergency Department; Atrial Fibrillation; Vernakalant; Procainamide

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Normal sinus rhythm

  At the time of patient disposition (approximately 3 hours after arrival)

• Patient disposition (admission or discharge)

  At the time of patient admission or discharge (approximately 3 hours after arrival)

• Length of stay in ED

  From time of arrival until time of discharge or admission (approximately 3 hours)

• Time to discharge

  From time of randomization until time of discharge or admission (approximately 3 hours)

• Time to conversion

  From time of infusion start until time of conversion to sinus rhythm (approximately 0 - 90 minutes)

Other Outcomes (5)

• Maintenance of normal sinus rhythm

  30 days post discharge

• Recurrence of acute AF

  30 days

• Death

  30 days

Study Arms (2)

Vernakalant

ACTIVE COMPARATOR

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

Procainamide

ACTIVE COMPARATOR

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

Interventions

Vernakalant DRUG

an initial infusion of 3 mg/kg infused over a 10-minute period by a pre-programmed IV pump

Also known as: BRINAVESS

Vernakalant

Procainamide DRUG

15 mg/kg in 500 mL of normal saline given over 60 minutes

Procainamide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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.

You may not qualify if:

• Appropriateness:
• unable to understand the study and integrated consent due to language barrier and/or cognitive impairment;
• have permanent (chronic) AF;
• have valvular heart disease (mitral stenosis, rheumatic or mechanical);
• 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;
• primary presentation was for another condition; examples include pneumonia, pulmonary embolism, and sepsis;
• convert spontaneously to sinus rhythm prior to randomization;
• were previously enrolled in the study; or
• have atrial flutter.
• Safety
• has heart failure Class NYHA III or NYHA IV; left ventricular ejection fraction \<30%; or has clinical or radiological evidence of acute HF;
• 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);
• has severe aortic stenosis;
• has a systolic blood pressure \< 100 mmHg;
• 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);

Sponsors & Collaborators

• Ottawa Hospital Research Institute: lead

Study Sites (14)

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, V5Z 1M9, Canada

Location

St. Paul's Hospital

Vancouver, British Columbia, Canada

Location

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, Canada

Location

Hamilton Health Sciences Centre

Hamilton, Ontario, l8L 2X2, Canada

Location

Kingston Health Sciences Centre

Kingston, Ontario, K2L 2V7, Canada

Location

Ottawa Hospital

Ottawa, Ontario, K1Y 4E9, Canada

Location

St. Michaels

Toronto, Ontario, Canada

Location

Sunnybrook Hospital

Toronto, Ontario, Canada

Location

Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval

Laval, Quebec, Canada

Location

Montreal Heart Institute

Montreal, Quebec, H1T 1C8, Canada

Location

Hopital Du Sacre-Coeur

Montreal, Quebec, Canada

Location

Hopital de L'Enfant-Jesus

Québec, Quebec, Canada

Location

Hôtel-Dieu de Lévis

Québec, Quebec, Canada

Location

Related Publications (1)

• Stiell IG, Taljaard M, Eagles D, Yadav K, Vadeboncoeur A, Hohl CM, Archambault PM, Birnie D, Brown E, Campbell SG, Chen Y, Clement CM, Cournoyer A, de Wit K, Emond M, Macle L, McRae AD, Mercier E, Morris J, Mohamad G, Nemnom MJ, Nicholls SG, Pare D, Parkash R, Sivilotti M, Thavorn K, Perry JJ. Vernakalant versus procainamide for rapid cardioversion of patients with acute atrial fibrillation (RAFF4): randomised clinical trial. BMJ. 2025 Nov 11;391:e085632. doi: 10.1136/bmj-2025-085632.

  PMID: 41218981 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation; Emergencies

Interventions

vernakalant; Procainamide

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Disease Attributes

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Ian G Stiell, MD, MSc

  Ottawa Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 14, 2020
• First Posted: July 24, 2020
• Study Start: June 17, 2021
• Primary Completion: September 15, 2024
• Study Completion: November 6, 2024
• Last Updated: April 10, 2025

Record last verified: 2025-04

Locations

CA (14)