Atrial FibrillationPhase 4NCT04485195
RAFF4 Trial: Vernakalant vs. Procainamide for Acute Atrial Fibrillation in the Emergency Department
A Phase 4 study testing Vernakalant and Procainamide in people with Atrial Fibrillation, run by Ottawa Hospital Research Institute at 14 sites in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Atrial Fibrillation
- What is being tested?
- Vernakalant and Procainamide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 350 participants
- Where
- 14 sitesCanada
- Study dates
- 17 Jun 2021to 6 Nov 2024
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- 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.
- Appropriateness:
Show all 27Show fewer
- 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);
- 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;
- 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);
- 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);
- 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);
- has received an IV beta-blocker within the 2 hours prior
- has hypersensitivity to the active substance or to any of the ingredients of either drug;
- has advanced or end-stage liver disease; or
- is breast feeding or pregnant (safety not established).
Who cannot join
None listed.
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
Canada14 sites
University of Alberta Hospital
Edmonton, Alberta, T6G 2B7
Queen Elizabeth II Health Sciences Centre
Halifax, Nova Scotia
Hamilton Health Sciences Centre
Hamilton, Ontario, l8L 2X2
Kingston Health Sciences Centre
Kingston, Ontario, K2L 2V7
Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Laval, Quebec
Montreal Heart Institute
Montreal, Quebec, H1T 1C8
Hopital Du Sacre-Coeur
Montreal, Quebec
Ottawa Hospital
Ottawa, Ontario, K1Y 4E9
Hopital de L'Enfant-Jesus
Québec, Quebec
Hôtel-Dieu de Lévis
Québec, Quebec
St. Michaels
Toronto, Ontario
Sunnybrook Hospital
Toronto, Ontario
Vancouver General Hospital
Vancouver, British Columbia, V5Z 1M9
St. Paul's Hospital
Vancouver, British Columbia
About this study
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
- Being tested
- Vernakalant, Procainamide
- Keywords
- Emergency Department, Atrial Fibrillation, Vernakalant, Procainamide
- Medical subject headings
- Atrial Fibrillation, Emergencies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VernakalantDrug
Also called BRINAVESS
an initial infusion of 3 mg/kg infused over a 10-minute period by a pre-programmed IV pump
ProcainamideDrug
15 mg/kg in 500 mL of normal saline given over 60 minutes
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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. Receives: Drug: Procainamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: During any time following randomization until 30 minutes past the completion of the drug infusion
Secondary outcomes (7)
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).
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 0-12 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jul 2020
- Study start17 Jun 2021
- Primary completion15 Sep 2024
- Study completion6 Nov 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Atrial FibrillationStudies of the same condition, open and under way.
- More trials run by Ottawa Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 350 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ottawa Hospital Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ian G Stiell, MD, MSc, Principal investigator, Ottawa Hospital Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04485195
- Sponsor's protocol ID
- 20200402
- Status last verified
- Apr 2025
- First submitted
- 14 Jul 2020
- Last updated
- 10 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 41218981
Study at a glance
From the registry record, last updated by the sponsor on 10 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- RAFF4 Trial: Vernakalant vs. Procainamide for Acute Atrial Fibrillation in the Emergency Department
- ClinicalTrials.gov ID
- NCT04485195
- Acronym / sponsor ID
- 20200402
- Conditions
- Atrial Fibrillation
- Keywords
- Emergency Department, Atrial Fibrillation, Vernakalant, Procainamide
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 350 participants (actual)
- Lead sponsor
- Ottawa Hospital Research InstituteUniversity, hospital or other
- Study start
- 17 Jun 2021 (actual)
- Primary completion
- 15 Sep 2024 (actual)
- Study completion
- 6 Nov 2024 (actual)
- First posted
- 24 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Vernakalant | Active comparator | Drug: VernakalantPatients 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). |
| Procainamide | Active comparator | Drug: ProcainamidePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- 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:
- 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.
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VernakalantAlso: BRINAVESSan initial infusion of 3 mg/kg infused over a 10-minute period by a pre-programmed IV pump | Drug | Vernakalant |
| Procainamide15 mg/kg in 500 mL of normal saline given over 60 minutes | Drug | Procainamide |
Primary outcome
Conversion to sinus rhythm for a minimum duration of 30 minutes
Time frame: During any time following randomization until 30 minutes past the completion of the drug infusion
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).
7 secondary outcomes
Normal sinus rhythm
Time frame: At the time of patient disposition (approximately 3 hours after arrival)
Patient disposition (admission or discharge)
Time frame: At the time of patient admission or discharge (approximately 3 hours after arrival)
Length of stay in ED
Time frame: From time of arrival until time of discharge or admission (approximately 3 hours)
Time to discharge
Time frame: From time of randomization until time of discharge or admission (approximately 3 hours)
Time to conversion
Time frame: From time of infusion start until time of conversion to sinus rhythm (approximately 0 - 90 minutes)
Whether the patient required electrical cardioversion
Time frame: From 30 minutes after the study drug infusion is completed.
Adverse events
Time frame: 0-12 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Apr 2025.
- Derived from this study: PubMed 41218981Stiell 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.
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Atrial Fibrillation (AF)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ian G Stiell, MD, MSc principal investigator
Ottawa Hospital Research Institute
14 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Vernakalant and Procainamide in people with Atrial Fibrillation, run by Ottawa Hospital Research Institute at 14 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Conversion to sinus rhythm for a minimum duration of 30 minutes (time frame: During any time following randomization until 30 minutes past the completion of the drug infusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04485195, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2025.