Vernakalant: shockingly fast without the shock?

There are many different approaches to stable patients with atrial fibrillation who present to the emergency department. Personally, I have leaned towards electrical cardioversion over chemical cardioversion in patients in whom cardioversion is appropriate. In the places I work, it is usually faster and easier to get a patient sedated and electrically cardioverted than to wait for drugs to work. However, that is largely because procainamide (the best current best option) is not actually that effective, and is well known for its adverse effects. If there was a better option for chemical cardiversion, it would be reasonable to avoid the efforts required to set up an electrical cardioversion. Could vernakalant fill that role?

The paper

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

The question

Is intravenous vernakalant more effective than intravenous procainamide for the chemical cardioversion of stable atrial fibrillation? 

The methods

This is a multi-center open label superiority RCT from 12 Canadian emergency departments. 

Patients

Adult patients with an acute episode (3 hours – 7 days) of atrial fibrillation in stable condition in whom immediate cardioversion was reasonable according to current guidelines.

Cardioversion was considered safe if:

• The patient had adequate anticoagulation for more than 3 weeks
• Or, the patient had no history of stroke, TIA, or valvular heart disease and either:
  • presented with less than 12 hours of symptoms
  • or, presented with 12-48 hours of symptoms but had fewer than 2 CHAD-65 criteria
• Or, were negative for thrombus on either transesophageal echocardiogram or CT.

Patients were excluded if they had abnormal vital signs or prolonged QT.

Intervention

Vernkalant

• 3 mg/kg IV over 10 minutes
• If cardioversion did not occur within 15 minutes, a second dose of 2 mg/kg was administered

Comparison

Procainamide

• 15 mg/kg IV over 60 minutes
• The infusion was stopped if there was cardiversion prior to the maximum dose. 

Outcome

The primary outcome was cardiversion to and maintenance of sinus rhythm for at least 30 minutes from any time after randomization until 30 minutes after the completion of drug infusion. 

The results

They randomized 354 patients, and analyze data on 350. Mean age was 63, about ⅔ were male, and mean duration of symptoms was about 18 hours. 

For the primary outcome of conversion to sinus rhythm, vernakalant was superior to procainamide (62.4% vs 48.3%, adjusted ARR 15.0% 95% CI 4.6-25.0%, p=0.005). 

Fewer patients in the vernakalant group underwent attempted electrical cardioversion (34% vs 44%). 

Time to successful cardioversion was faster with vernakant (22 vs 45 minutes).

There were no differences in the rate of discharge to home (96.1% with vernakalant vs 97.7% with procainamide). Total time in the hospital was also similar and very long (8.9 vs 9.2 hours).

Adverse events were not statistically different, but the difference was big enough to be clinically important (17.4% with vernakalant vs 25.0% with procainamide). 

My thoughts

Honestly, aside from the lack of blinding, there isn’t a massive amount to discuss about this paper. The methodology is pretty good, and vernakalant looks better for most important outcomes. 

Unblinded trials always add bias. These drugs are given at different rates, and so it would have added some complexity to blind this trial, but it wouldn’t have been too hard to have 2 infusions going at the same time – one saline and one the active drug. It would have been a stronger trial if it had been blinded, but conversion to normal saline is one of the more objective outcomes you will come across, so I tend to believe these numbers.

Perhaps the biggest issue with this trial has nothing to do with the trial itself. Vernakalant was not approved in the United States due to safety concerns. The basis for these safety concerns is not entirely clear. There have been 1200 patients in vernakalant RCTs without noted safety issues. The FDA apparently wanted one extra trial, and early in that trial there was an unexpected death, and the FDA subsequently stopped the trial and voted against the drug. (Jeon 2025; Camm 2014) It has been widely approved in Europe and Canada. This trial is obviously too small to make any definitive claims about safety, but overall vernakalant looks somewhat better than the alternative, and procainamide is also well known to cause adverse events. I want to see larger studies to elucidate this issue, but I don’t see any major red flags about safety in what I am reading. 

I am not sure I understand what is happening in these emergency departments. Cardioversion took less than 45 minutes. We know most of these patients don’t need blood work or anything else. Despite that, they spent 9 hours in the emergency department. Is this just all time spent in a waiting room in dysfunctional departments, or is there something else going on here that I am missing?

Perhaps the biggest conversation point around the paper is whether cardioversion is truly an important end point. To some extent, we know it isn’t. We have a wealth of data showing that rate control and rhythm control are identical when it comes to long term outcomes. If you were going to keep these patients around the department for 9 hours anyway, maybe you are better off rate controlling them? One of the primary advantages I see to rhythm control is that when I electrically cardiovert patients, they are usually in and out of the emergency department within 2 hours.

That being said, it is clear that cardioversion is a popular option, at least in some areas of the world. If clinicians are cardioverting anyway, then rate of cardioversion and time to cardioversion become important, if somewhat artificial, outcomes. However, if you really believe conversion to sinus rhythm is an important outcome, it would probably make sense to compare it to the gold standard: electrical cardioversion. 

Personally, I don’t use chemical cardiversion. If the patient is appropriate for cardioversion and prefers it over rate control, I almost always go straight to electrical cardioversion. In a well functioning emergency department, it is way faster and I believe way more effective than chemical cardioversion. But I guess that begs the question: is electrical cardioversion faster and more effective than vernakalant? I guess we will have to wait for another RCT to see.

The final consideration is cost. Vernakalant is significantly more expensive than procainamide. However, you can’t just include the cost of the medication. Using procainamide resulted in 10% more patients requiring procedural sedation and electrical cardioversion. I would love to see a cost analysis that factored in that added step, because perhaps vernakalant is already cost effective.

Although I am not completely convinced by this trial, or the other trials I skimmed, I think this is promising. I am not even sure my hospital stocks this medication, but this trial is interesting enough that I will check. I am not sure it will sway me away from the electrical cardioversion approach, but this does look like the best available option for chemical cardioversion.

Bottom line

In this open label RCT, vernakalant was superior to procainamide for the conversion of atrial fibrillation to sinus rhythm.

Other FOAMed

Evidence based medicine is easy

The EBM bibliography

Evidence based medicine resources

EBM deep dives

References

Camm AJ. The vernakalant story: how did it come to approval in Europe and what is the delay in the U.S.A? Curr Cardiol Rev. 2014 Nov;10(4):309-14. doi: 10.2174/1573403×10666140513103709. PMID: 24821654

Jeon D, Redberg RF. Rapid cardioversion for acute atrial fibrillation. BMJ. 2025 Nov 11;391:r2264. doi: 10.1136/bmj.r2264. PMID: 41218974

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