Highlights
– In the RAFF4 randomized clinical trial (n=350), vernakalant converted a greater proportion of patients to sinus rhythm within 30 minutes than procainamide (62.4% vs 48.3%; adjusted absolute difference 15.0%).
– Vernakalant achieved conversion faster (mean 21.8 vs 44.7 minutes) and reduced the need for attempted electrical cardioversion (33.7% vs 44.2%).
– Adverse events were similar and generally mild in both groups; subgroup benefit was greatest in patients younger than 70 years.
Background: clinical context and unmet need
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in emergency departments (EDs). Many patients present with recent-onset symptomatic AF and seek rapid symptom relief and definitive rhythm control. For suitable patients, urgent pharmacological cardioversion in the ED can restore sinus rhythm, relieve symptoms, shorten length of stay, and permit discharge without inpatient admission. However, the ideal intravenous agent balances rapid and reliable conversion with a favorable safety profile and ease of use in busy ED settings.
Procainamide (a class IA antiarrhythmic) is a long-standing option for ED cardioversion of recent-onset AF and is recommended in many protocols. Vernakalant is an atrial‑selective antiarrhythmic developed for rapid cardioversion of recent-onset AF; it targets atrial‑specific currents and atrial sodium channels, aiming to minimize ventricular proarrhythmia. Comparative, head‑to‑head evidence in contemporary ED populations has been limited until RAFF4.
Study design: RAFF4 randomized clinical trial
RAFF4 was a multicentre, randomized, open‑label trial conducted at 12 tertiary care emergency departments in Canada. The trial enrolled adult patients with acute (recent-onset) atrial fibrillation for whom acute rhythm control was considered safe and appropriate by treating clinicians. Patients were randomized 1:1 to receive an intravenous infusion of vernakalant or intravenous procainamide. If pharmacological conversion did not occur promptly, electrical cardioversion was offered per local practice.
The prespecified primary endpoint was conversion to sinus rhythm within 30 minutes of completion of the drug infusion. Key secondary endpoints included time to conversion and the proportion of patients who required attempted electrical cardioversion. Safety outcomes included adverse events, hemodynamic instability, and disposition (discharge versus hospital admission).
Trial registration: ClinicalTrials.gov NCT04485195. Full trial methods and statistical plans are reported in the primary publication (Stiell et al., BMJ 2025).
Key findings and detailed results
RAFF4 randomized 350 eligible patients: 178 to vernakalant and 172 to procainamide. Baseline clinical characteristics were similar between groups.
Primary outcome
Conversion to sinus rhythm within 30 minutes of infusion completion occurred in 62.4% of patients treated with vernakalant versus 48.3% treated with procainamide. The adjusted absolute difference was 15.0% (95% CI 4.6% to 25.0%, P=0.005). The adjusted odds ratio for conversion with vernakalant was 1.87 (95% CI 1.2 to 2.9, P=0.006).
Time to conversion
Conversion was substantially faster with vernakalant: mean time to conversion was 21.8 minutes versus 44.7 minutes with procainamide (mean difference –22.9 minutes; 95% CI –29.9 to –16.0; P < 0.001). Faster conversion has practical implications for ED throughput and patient comfort.
Need for electrical cardioversion
Fewer patients randomized to vernakalant underwent attempted electrical cardioversion (33.7% vs 44.2%). The odds ratio for needing electrical cardioversion was 0.62 (95% CI 0.39 to 0.96, P=0.033), indicating a clinically meaningful reduction in escalation to electricity-based therapy.
Safety and disposition
Adverse events were similar in frequency between groups and were generally mild and transient. Reported adverse events included procedural sensations (e.g., dysgeusia), transient hypotension, and infusion‑related symptoms. Most patients in both arms were discharged home from the ED. There were no new safety signals reported in RAFF4; detailed event tables and adjudication are available in the BMJ paper.
Subgroup findings
A notable subgroup result was that vernakalant’s benefit was most pronounced in patients younger than 70 years: conversion rates were 73.3% versus 47.2% (adjusted OR 3.1; 95% CI 1.7 to 5.5, P=0.001), with a significant interaction (P=0.005). This interaction suggests age may modify treatment effect, though subgroup analyses are hypothesis‑generating and should be interpreted cautiously.
Mechanistic plausibility
Vernakalant’s pharmacology helps explain the trial findings. It preferentially inhibits atrial‑specific potassium currents (including IKur) and frequency‑dependent atrial sodium channels, prolonging atrial refractoriness and slowing conduction primarily in atrial tissue. This atrial selectivity reduces the likelihood of ventricular proarrhythmia and enables rapid termination of re‑entrant atrial circuits. Procainamide, a sodium channel blocker with class IA properties, also terminates AF but may act less selectively and—based on RAFF4—appears slower and less likely to achieve rapid conversion in the ED setting studied.
Expert commentary and interpretation
RAFF4 provides high‑quality, randomized head‑to‑head evidence comparing two intravenous antiarrhythmics commonly considered for recent‑onset AF in ED practice. The open‑label design is a limitation but was pragmatic and reflects real‑world ED management. Conversion within a tight 30‑minute window and time‑to‑conversion are clinically meaningful endpoints for emergency physicians focused on symptom relief, disposition planning, and resource utilization.
Important considerations for clinicians interpreting RAFF4:
- Population and setting: RAFF4 was conducted at tertiary EDs in Canada in patients selected as candidates for acute rhythm control. Results may not generalize to patients with structural heart disease, hemodynamic instability, or centers with different practice patterns.
- Open‑label care: Knowledge of treatment allocation could influence decisions about proceeding to electrical cardioversion; however, the objective primary endpoint (sinus rhythm on ECG within 30 minutes) is robust to such bias.
- Age interaction: The marked benefit in patients <70 years is intriguing but requires validation. It could reflect differences in atrial remodeling, comorbidities, or pharmacokinetics across age groups.
- Resource and regulatory context: Vernakalant availability and local regulatory approvals vary by country; cost, familiarity, and drug availability will shape implementation.
Clinical implications
For ED clinicians managing recent‑onset AF in appropriately selected patients, vernakalant offers faster and more frequent pharmacological conversion to sinus rhythm than procainamide, reducing the need for electrical cardioversion. Advantages include shorter time in the ED for conversion, potential reductions in procedural sedation use, and more rapid discharge for many patients. Adoption should consider local formularies, clinician experience, and patient selection criteria.
Limitations and research gaps
RAFF4’s open‑label design and conduct at tertiary EDs may limit generalizability to community settings. Longer‑term outcomes (recurrent AF, hospital readmissions, and cost‑effectiveness) were not the primary focus and require further study. The age interaction warrants replication and mechanistic exploration. Comparative effectiveness versus other agents used for ED cardioversion (for example, ibutilide or amiodarone in select settings) remains to be defined in randomized designs.
Conclusion
In the randomized RAFF4 trial, intravenous vernakalant was superior to procainamide for rapid pharmacologic cardioversion of recent‑onset atrial fibrillation in the emergency department: higher conversion rates within 30 minutes, markedly faster times to sinus rhythm, and fewer patients requiring electrical cardioversion. Safety profiles were similar and generally benign in the short term. Vernakalant is a valuable option for ED rhythm control in appropriately selected patients, though availability, local practice, and patient characteristics should guide therapy selection.
Funding and trial registration
Trial registration: ClinicalTrials.gov NCT04485195. Funding and declarations of interest are reported in the primary BMJ publication (Stiell et al., 2025); readers should consult the full article for sponsor details and investigator disclosures.
References
1. Stiell IG, Taljaard M, Eagles D, et al. 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; PMCID: PMC12603894.
2. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio‑Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373-498. doi:10.1093/eurheartj/ehaa612.
3. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 Guideline for the Management of Patients With Atrial Fibrillation. Circulation. 2019;140(2):e125-e151. (Focused update content relevant to ED management and cardioversion strategies.)
Visual prompt for article thumbnail
A high‑contrast clinical scene in an emergency department: a middle‑aged patient on a stretcher with cardiac monitor tracings transitioning from irregular atrial fibrillation to organized sinus rhythm; a clinician adjusts an infusion pump labeled ‘IV antiarrhythmic’ while another staff member stands by with a defibrillator; cool clinical lighting, clear medical devices, slightly cinematic composition.