Time Stamps

  • 02:05 Pearl 1 – Rhythm control
  • 11:23 Pearl 2 – Electrical cardioversion
  • 17:53 Pearl 3 – Class III antiarrhythmics and side effects
  • 26:31 Pearl 4 – Class Ic antiarrhythmics and side effects
  • 31:55 Pearl 5 – Catheter ablation


Show Notes

Pearl 1: What are the benefits of early rhythm control versus rate control alone?

  1. Rhythm control demonstrates mortality and quality of life benefit over rate control.
    1. EAST-AFNET 4: Published in 2020, the trial showed that early rhythm-control therapy is associated with lower risk of adverse CV outcomes vs usual care
    2. AFFIRM Subgroup analysis: Effective way of maintaining sinus rhythm may improve survival.
      1. Sinus rhythm, but not antiarrhythmic drug use, was associated with decreased mortality.
      2. Reason why we may have not seen a difference in the primary endpoint:
        1. In the initial AFFIRM trial, warfarin was mandated in the rate control group but could be discontinued in the rhythm control group after 4 weeks in sinus rhythm.
      3. Findings suggest an effective mechanism of maintaining SR may improve survival.
  2. Why is sinus superior?
    1. Structural dysfunction
      1. Atrial fibrillation can cause and/or exacerbate pre-existing heart failure (HF).
      2. Complex relationship between atrial fibrillation and heart failure is not completely understood.
      3. Increased risk of heart failure in AF – AF occurs in more than half of individuals with HF, and HF occurs in more than one third of individuals with AF
        1. Some proposed mechanisms of how afib precipitates heart failure:
          1. Tachycardia-mediated cardiomyopathy
          2. Atrial remodeling
          3. Loss of cardiac output from atrial kick
          4. Antecedent to valvular heart disease, including MR
  3. Symptoms 
    1. Can be subtle – people may not recognize symptoms until they convert.
    2. Heart rhythm society guidelines recommend electrical cardioversion to tease out whether individuals are having symptoms or not.


Pearl 2: When is electrical cardioversion used and what information can it tell us?

  1. Therapeutic use
    1. Can help acutely unstable or highly symptomatic patients.
    2. Use in patients too sick to wait for ablation or to be loaded on a drug.
  2. Diagnostic use
    1. Electrical cardioversion is NOT intended to keep patients out of afib long-term.
    2. Provides information about relief of symptoms when in sinus.
    3. Can reveal if patients are “early return to AF” (ERAF), which suggests they more likely have “early” persistent AF or more advanced persistent AF.
      1. Provides data for future rhythm management strategies.
  3. Patient considerations
    1. Need to be anticoagulable! 
      1. Anticoagulant for 4 weeks prior to electrical cardioversion and approximately 4 weeks after.
      2. Alternatively, can do TEE prior to cardioversion if unable to anticoagulant beforehand.
    2. Optimize comorbidities to allow  the greatest chance of success!


Pearl 3: Class III Antiarrhythmics and Side Effects

  1. Amiodarone 
    1. Oral amiodarone is a more gradual load, generally takes longer to convert than certain other class III and  1c antiarrhythmics.
      1. Good medication to start outpatient – less risk of conversion pauses that could make patients pass out. 
      2. Better at maintaining sinus rhythm than sotalol or class 1c antiarrhythmics
        1. Additional study comparing amiodarone with sotalol
      3. Remember side effects: Pulmonary, thyroid, and hepatotoxicity (PFTs, TFTs, LFTs)
        1. Also photosensitivity, corneal and retinal deposits.
      4. Consider alternative agents in patients who will need to be on it long term.
      5. IV amio, on the other hand, has better bioavailability and does not take as long as oral amiodarone!
  2. Dofetilide and sotalol 
    1. Relative to oral amio, tend to decrease time to conversion.
      1. Watch out for those conversion pauses!
    2. QTc prolongation is a major side effect. Can require inpatient load over 3 days with serial EKGs.
      1. If a patient misses > 2 doses, may need to admit to be reloaded.
    3. Renally cleared
      1. May not be the best agent in patients with CKD or dynamic renal function.
    4. After the initial load, monitor outpatient EKGs, GFR, K, and Mg q3-6 months or more often if indicated.
    5. Numerous drug-drug interactions
    6. Sotalol is also contraindicated in patients with reduced left ventricular ejection fraction
      1. Based on results from the SWORD trial that demonstrated increased mortality when sotalol was used in HFrEF.


Pearl 4: Class Ic Antiarrhythmics and Side Effects

  1. Flecainide and propafenone (Class 1c antiarrhythmics)
    1. Compared to amiodarone, it accelerates time to conversion.
      1. Can be used for “pill in pocket” approach
        1. But patients must be able to feel when they go into afib! 
        2. Otherwise if they take the pill after being in afib > 48 hours, risk having a stroke from an atrial thrombus.
    2. Avoid in structural heart disease
      1. CAST trial demonstrated increased mortality (sudden death and lethal ventricular arrhythmias) in patients using flecainide or encainide with ischemic heart disease. 
      2. Avoid in structural heart disease = systolic dysfunction and/or CAD.
        1. Gray area on whether need to avoid in nonobstructive CAD.
    3. Obtain stress EKG after fully loaded to eval for QRS widening and pro-arrhythmic effect
    4. Can induce atrial flutter that conducts 1:1. 
      1. Need to administer with a beta blocker or other AV-nodal blocking agent.
    5. Flecainide specifically can also cause vertigo, double vision, blurriness and GI symptoms.


Pearl 5:  When should catheter ablation be considered in patients with atrial fibrillation?

  1. Guidelines recommend ablation may be considered a first-line option in select patients, particularly for:
    1. Young patients with symptomatic paroxysmal afib 
      1. In symptomatic paroxysmal afib, EARLY-AF and STOP-AF trials have found that ablation was more effective in preventing atrial fibrillation recurrence versus drug therapy 
        1. Earlier referral (i.e. within 6 months of diagnosis) in symptomatic paroxysmal afib has demonstrated less hospital utilization in the following 2 years 
    2. Patients with HFrEF who are on GDMT.
      1. Improved cardiovascular mortality with ablation compared to drug therapy  in patients with HFrEF, as demonstrated in  CABANA trial subgroup analysis, AATAC, CASTLE-AF 
  2. In patients with normal structural function and persistent AF, requires risks/benefits discussion.
    1. Can present an opportunity to get off of medications.
    2. The role of ablation is being studied in other populations, including those with HFpEF
  3. What to do with antiarrhythmic drugs after ablation
    1. Continue antiarrhythmics  few months after ablation while cardiomyocytes heal.
  4. Success rates vary. 
    1. Some studies report >60% conversation rates for paroxysmal afib and <30% in persistent afib, however results largely vary on a case-by-case basis.
  5. Ablation can also increase the efficacy of formerly unsuccessful antiarrhythmics
  6. Risk of complications
    1. Complications to consider: stroke, atrial-esophageal fistula, tamponade, death, pulmonary vein stenosis, to name a few.
  7. Who may not be best suited for ablation
    1. Advanced comorbidities that poses significant risk to general anesthesia.
    2. Patients who cannot be anticoagulated
    3. Asymptomatic paroxysmal atrial fibrillation


Dr. Rachita Navara: And now the latest guidelines, in direct response to EAST AFNET-4 will be recommending that every new atrial fibrillation patient is started on rhythm control even within one year of their diagnosis. So this is a bit of a paradigm shift in our field, but really enthusiastic about getting patients rhythm control.

Dr. Shreya Trivedi: That’s Dr. Rachita Navara, she was an electrophysiologist trained at Washington University before she became founder of SafeBeat Rx, with a mission to improve rhythm disorders using machine learning. I’m Dr. Shreya Trivedi. Welcome to the Core IM 5-Pearls Podcast, bringing you high-yield evidence-based pearls. 

Dr. Hanna Knauss: And I’m Dr. Hanna Knauss, an internal medicine resident at Beth Israel. As Dr. Navara alluded to, the focus of this episode will be the pandoras box in rhythm in atrial fibrillation.  

Dr. Shreya Trivedi: Yes! Let’s dive into the pearls we’ll be covering today. Test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Hanna Knauss: Pearl 1 – Rhythm control.

Dr. Shreya Trivedi: What are the benefits of early rhythm control over rate control alone?

Dr. Hanna Knauss: Pearl 2 – Electrical cardioversion.

Dr. Shreya Trivedi: When is electrical cardioversion used and what information does it tell us?

Dr. Hanna Knauss: Pearl 3 – Class III Antiarrhythmics and side effects.

Dr. Shreya Trivedi: What side effects should we need to monitor for when it comes to medications like amiodarone, dofetilide, and sotalol?

Dr. Hanna Knauss: Pearl 4 – Class 1c Antiarrhythmics and side effects.

Dr. Shreya Trivedi: What side effects should we watch out for when it comes to medications like propafenone and flecainide?

Dr. Hanna Knauss: Pearl 5 – Catheter ablation.

Dr. Shreya Trivedi: When should catheter ablation be considered in patients with atrial fibrillation?

Pearl 1 – Rhythm Control

Dr. Shreya Trivedi: Ok Hanna, I don’t know about you but was pretty surprised to hear at the top of the episode that now rhythm control is the first line for new afib within a year of diagnosis!

Dr. Hanna Knauss: I know! Especially since we’ve all probably heard the AFFIRM trial dropped at some point in our training. I know this isn’t Journal Club, but AFFIRM is the 2002 landmark trial that set the paradigm that rate control was better than rhythm control.

Dr. Rachita Navara: Interestingly, if you look at AFFIRM and some of these larger trials that led us to believe rate and rhythm control are equivalent when specifically doing a subanalysis, looking at patients who were receiving rhythm control and receiving drug medication, there is actually a mortality benefit that can be seen in those patients as well. So while it didn’t make the headline as far as the trial outcome, it’s important to realize that all along intuitively, right, patients who are in sinus compared to in an abnormal rhythm most of the time, fare better in terms of major adverse cardiac events.

Dr. Hanna Knauss: So now the reason that rhythm control did not make the headline in the AFFIRM trial was there were a bunch of issues with the way the trial was set up. So for example, a significant number of patients on antiarrhythmic agents didn’t actually achieve sinus rhythm. And anticoagulation could be discontinued in the rhythm control group after 4 weeks in sinus rhythm but was mandated in the rate control group.

Dr. Shreya Trivedi: So it sounds like it was definitely worthwhile to re-explore rhythm control. And to think about just that, we sat down with Dr. Eric Prystowsky, an electrophysiologist at Ascension St. Vincent in Indianapolis, and consulting professor of medicine at Duke.

Dr. Eric Prystowsky: Now, fast forward to several studies that have analyzed early sinus rhythm. Okay? There’s the AFib E study. There’s been several studies that have looked at this and everyone’s been consistent that attacking things early to maintain sinus, regardless of the method you do, is a good long-term goal for the patient. They do better. They look at multiple endpoints, death and stroke and heart failure, and certainly quality of life indices in almost every study.

Dr. Hanna Knauss: The study  he is referring to EAST-AFNET 4. This study randomized patients with recently diagnosed afib with a median of 36 days from diagnosis to either rhythm control or usual care which typically involved rate control. The rhythm control group had a lower risk of death from cardiovascular events, stroke, heart failure hospitalization, and acute coronary syndrome. 

Dr. Shreya Trivedi: So it sounds like in EAST-AFNET 4, rhythm control as early as just over 1 month from a new afib diagnosis can lower the risk of mortality from cardiovascular events, which is a big deal! Hanna, this is all great but I cant help but ask – why is sinus superior? 

Dr. Hanna Knauss: Yes! I love this question. To understand the answer to this, we have to look at  2 major buckets of atrial fibrillation management: structural dysfunction and symptoms.

Dr. Shreya Trivedi: Okay! Lets start with structural dysfunction, which just to make sure we are on the same page structural dysfunction means a fancy cards way of saying cardiomyopathy.

Dr. Hanna Knauss: And I really liked how Dr. Shu Yang, an electrophysiology fellow here at BIDMC explained just how intertwined atrial fibrillation and cardiomyopathy can be.

Dr. Shu Yang: There are a couple phenotypes. There are the people that have atrial fibrillation, it’s a new onset, they’re relatively healthy or they don’t have a lot of other risk factors, and all of a sudden they have a terrible systolic myopathy in the setting of atrial fibrillation. Then they’re the people that they have AFib. It progresses over time and they probably remodel, and they have this, it’s more of a smoldering drop of their EF. Their EF goes from 55 to 50 to 45, and eventually it goes down or it’s over a year. So there’s sort of these phenotypes. So clearly there’s some remodeling that happens, but I think in the setting of the first person, there might be something else that’s predisposing that person developing a cardiomyopathy. So AF in that situation could be a cause, but it could simply just be a decompensating factor. And we know that because people who really rely on that atrial kick. And when you take it away and you put them in AF, they develop heart failure. So a lot of these studies, it’s hard to tell as always, like chicken or the egg, do you treat atrial fibrillation to prevent the cardiomyopathy, or do you treat it to prevent it as a trigger for decompensation of a baseline cardiomyopathy?

Dr. Hanna Knauss: Oh, wow! You know, Shreya I did not appreciate the complex interplay between afiv and heart failure before making this episode. 

Dr. Shreya Trivedi: Yeah, same! And what he was saying with the example of the atrial kick reminds me of a recent patient I had recently. His normal ejection fraction with some diastolic dysfunction. But when he went into afib from sinus, his ejection fraction dropped down 43%. He actually came in because he was taking a long walk and then syncopized and got hypotensive.

Dr. Hanna Knauss: Wait! How did you know that it was his atrial kick that caused his hypotension and syncope?

Dr. Shreya Trivedi: Yeah! It wasn’t me, it was an astute cardiologist that looked back at his old echo and saw that when this patient was in sinus, a significant portion of his LV filling was with atrial contraction, so when he went into afib adnd lost that atrial kick, he became hypotensive.

Dr. Hanna Knauss: Wow! What a great story! In addition to losing that atrial kick, afib can also remodel the heart in other ways too. So for example, it can lead to fibrosis, changes in atrial size, and even reorganizes the electrical conduction system too.

Dr. Shreya Trivedi: All structural changes that are no bueno! And while we are on the topic of structural changes, I think we should mention how ventricles can take a quite hit with some of the fast heart rates in afib. And I still can’t stop thinking about this story Dr. Prystowsky shared with us about tachymyopathies.

Dr. Eric Prystowsky: There was a young woman who ad shortness of breath over the weekend and she came to see another physician and she was in a rapid left bundle branch block tachycardia going at a rate of around 240 a minute. And she was cardioverted and now she knew exactly when it started. It was like three days or four days. She had been fine before that. He had an ejection fraction of 35%. Okay? Now no one knew her previous ejection fraction, but they had already done a cardiac cath as typically happens, and it was normal. But anyway, within a week or so now in sinus rhythm, her EF had gone up to about 55 or 60%. So that patient developed tachymyopathy within less than a week. So that was a learning point for me.

Dr. Hanna Knauss: This was a learning point for me, too. It’s actually crazy, after having this interview I saw a patient whose EF dropped from 55% down to 33% after just 1 week of having heart rates in the 130s-140s. It really cemented just how fast and serious tachymyopathies can be.

Dr. Eric Prystowsky: The key is prevention. Right? So if you see somebody in that initial office visit who is having rapid rates, you don’t have time to mess around. It’s not one of these things like, come back, I’ll do a Holter, I’ll see you in three weeks. That’s a mistake because you don’t know if that person’s at risk and it’s just not worth taking a chance.

Dr. Shreya Trivedi: Yeah, so it sounds like we gotta do everything to prevent cardiomyopathy, one, making sure they are not tachycardic and, two keeping them in that sinus rhythm. 

Dr. Hanna Knauss: Okay, so why don’t we get into the final bucket why sinus is superior – symptoms. But before we get into how sinus helps with symptoms, we have to recognize that most of the time our patients’ symptoms are often subtle, not the textbook palpitations we learn about. 

Dr. Eric Prystowsky: You realize now that he’s had all these symptoms, no, he didn’t have his heart racing out of his chest. No, he wasn’t passing out and having chest pain and shortness of breath, but fatigue, not thinking clearly, sort of fogginess and stuff, or all these subtle symptoms that if you don’t take the time to really dig, they’ll just blow right by you.

Dr. Shreya Trivedi: And what really stood out for me is that sometimes patients don’t realize they are having subtle symptoms until they’re cardioverted to sinus.

Dr. Eric Prystowsky: I’ve had patients swear to me that they were fine and I’ve cardioverted them and they come back and they say, I’ve never felt better doc. And I said, how can you never feel better when you felt fine before? I didn’t even realize I didn’t feel good. You know, I became used to that.

Dr. Shreya Trivedi: Oh man, this really motivates me to help patients get into sinus! Them not knowing how they good they could potentially feel. I mean, like, gosh, is that not what life and why many of us became clinicians. To help patients reach their full potential. I’m all about this! I can get on this bandwagon.

Dr. Hanna Knauss: Shreya, I love that! We need this positive energy.

Dr. Shreya Trivedi: Yeah, definitely! So let’s recap here on this good note. The new 2023 guidelines recommend rhythm control within 1 year of afib diagnosis to improve cardiovascular outcomes and even mortality. And if we breakdown why sinus is more superior, it really comes down to preventing cardiomyopathy and that adverse cardiac remodeling that happens the longer someone is in that atrial rhythm. 

Dr. Hanna Knauss: And I’ll that, for me, next time I have a patient in afib, I will ask about subtle symptoms, like fatigue and brain fog.

Pearl 2 – Electrical Cardioversion

Dr. Shreya Trivedi: So now we have a good case for why sinus is superior. There are now so many interventions to think throuhg. Electric cardioversion. Ablation. Chemical cardioversion with the antiarrhythmic meds, and before this episode I didn’t really have a good framework for why electrophysiology would recommended one vs another and how to explain that to patients.

Dr. Hanna Knauss: Same! Let’s dive on to one of the ways we can get patients to sinus. And we will start with electrical cardioversion. 

Dr. Shu Yang: So the cardioversion, I describe it to patients as when your computer freezes, you push down on that power button, you hold it down and it restarts the computer. It fixes the problem right there then, but it does nothing to prevent a recurrence of the problem. And it’s always worth it as a first try. That’s our first go-to whenever there’s an issue in your computer freezes. 

Dr. Shreya Trivedi: That is crazy to hear! That electric cardioversion is just a reset button and doesn’t actually prevent recurrence of afib. 

Dr. Hanna Knauss: But one thing i did learn was yes, while electrical cardioversion won’t keep someone out of afib long-term, it can be helpful in multiple ways

Dr. Shreya Trivedi: Oh, yeah how’s that, Hanna? 

Dr. Hanna Knauss: So say you have a patient acutely unstable patient who is having hemodynamic changes driven by their afib rhythm or maybe quite symptomatic. These are the patients who can’t wait for a drug load or ablation and need immediate conversion to sinus.

Dr. Shreya Trivedi: Right, so electric cardioversion makes sense in uncontrolled atrial fibrillation thats leading someone to be hypotensive or their symptomatic and having a lot of palpitations or something like that.

Dr. Hanna Knauss: Yes so that’s one therapeutic use for it, but electrical cardioversion can also be diagnostically. It can unmask symptoms like we talked about in Pearl 1, and the patients response to cardioversion actually can helps set the stage how hard this afib may be get back into sinus.

Dr. Shu Yang: And it can give you both diagnostic and therapeutic value because the diagnostic value is are they somebody that just cardioverted? They go right back into atrial fibrillation. Do they have early return of afib, that’s a category of patient who’s probably going to be more persistent, who’s probably going to need medications and ablation. But some people, you cardiovert them, they feel better. And if this is the first time they’ve ever had AFib, and they’re very symptomatic with, but they don’t have AFib for another nine months or 12 years. We tell everybody, this is a chronic condition, it’s going to come back, but the cardioversion is diagnostic and that A, it’ll tell us if you feel better in a regular rhythm. And then B, your response to that cardioversion is going to tell us what may or may not be necessary to treat you as a person?

Dr. Shreya Trivedi: So electrical cardioversion can also give us, it sounds like prognostic info – if someone gets cardioverted and flips back into afib soon after then we are thinking gosh this is going to be someone who needs ablation and even more meds one board to keep them in sinus. Which we’re going to cover in the rest of our Pearls.

Dr. Shu Yang: If you cardiovert them and they go into sinus and they’re maintaining sinus and they’re like, geez, doc, I feel a lot better. I’m going to say, look, it’s probably worth it for us to try at least a medicine, if not an ablation procedure to try and maintain sinus rhythm.

Dr. Shreya Trivedi: Yeah, so if patients do feel better in sinus, it gives us a lot of motivation to try to keep them in sinus as much as possible with all other things in our toolkit.

Dr. Hanna Knauss: Yeah! And so before cardioverting, there are a couple of things that we have to consider.

Dr. Shu Yang: They need to be anticoaguable. And even for people with CHADSVASC of zero, they need to be on unbroken anticoagulation. Three weeks before, and usually it’s about a month afterwards just because it’s just simply the mechanical electrical dissociation. Right. Even though physically you’re electrically in sinus rhythm, your atrium may not mechanically completely transform to sinus rhythm until weeks later, during which point you’re at very high risk for stroke.

Dr. Hanna Knauss: Yes, so maybe electrically things are starting from the sinus node but possibly not all the atrial cells are in sync yet!

Dr. Shreya Trivedi: Ah! It’s so interesting p waves upright in lead II is just telling us the SA node is on point but it doesn’t necessary tell us about what all the other atrial cells are doing and if they are coordinated. So if we need people to be anticoagulated for at least 3 weeks before cardioversion and 1 month after, what about the people that come in, rush into the emergency room, they’re unstable, they’re not anticoagulated, they can’t wait. What about those people? 

Dr. Hanna Knauss: Yeah! Great question! That’s when we start thinking about a trans-esophageal echocardiogram, or a TEE, immediately before the cardioversion. This would allow us to see if we can directly visualize if there’s a clot there in the left atrial appendage. 

Dr. Rachita Navara: One important factor I think with any electrical cardioversion consideration is that without intervening on the underlying arrhythmia mechanism, the cardioversion is just a bandaid. So we have to really equip patients to be in their most optimal state so that electrical cardioversion will provide longer term benefit. So what does that mean? Basically, patients should be on an anti arrhythmic drug, especially if it’s their second or third occurrence of atrial fibrillation so that they could be held in sinus rhythm once the electrical cardioversion occurs. So that’s one consideration. If a patient is in acute decompensated heart failure, then there may be room to optimize their volume status before providing electrical cardioversion.

Dr. Hanna Knauss: So it’s like asking how can I set this patient up for their best chance to stay in sinus rhythm? Is there some other stress going on in their left atrium? Like is it overloaded? Do they needs diuresis? Or do they need antiarrhythmic meds on board, which we will get into the next Pearl. 

Dr. Shreya Trivedi: Yeah! So to recap electrical cardioversion, one strong indication for electric cardioversion is if someone is hemodynamically unstable or quite symptomatic from their afib. And then, on other end, if we have someone is stable and want to cardiovert them electrically, we need to ask ourselves 1) has this patient or can this patient be anticoagulated for the at least 3 weeks or do they need a TEE before cardioversion. 2) Are they medically optimized? Particularly, how is their left atrium doing? And what else do we need to do to give their left atrium the best chance that sinus “sticks.”  And 3) depending on the patients case’s, we will likely need antiarrhythmics on board. 

Dr. Hanna Knauss: And then electrical cardioversion will tell us 1) how are their symptoms once they are in sinus and 2) based on how quickly they convert back to afib, because again this is just resetting a computer, but not fixing the underlying issue, we can then understand how hard this afib will be to keep in sinus.

Pearl 3 – Class III Antiarrhythmics and Side Effects

Dr. Shreya Trivedi: You know what I’m thinking about, Hanna? Is if we are gonna see more patients on these rhythm control meds, I think its in all of our best interest to get more comfortable these meds. When one may be indicated vs. the other and particularly what their side effects may be as we may see with more and more people on them.

Dr. Hanna Knauss: Yeah and it can feel like there are a ton of antiarrhythmic drugs. We have amiodarone, sotalol, and dofetilide, flecainide, and propafenone, among many others. 

Dr. Shreya Trivedi: Yeah! It can be a little overwhemling. Black box, on black box, on black box. All around. So why don’t we break down these meds into 2 pearls. That’ll be a little more digestable. In this pearl, why don’t we cover the common class III antiarrhythmics: amiodarone, dofetilide, and sotalol.

Dr. Hanna Knauss: Yeah, so lets start with amiodarone, one of our commonly used antiarrhythmics. And here we are talking about oral amio, not IV.

Dr. Shreya Trivedi: Yeah, amio I feel like gets a bad rap. It’s notorious on board questions and we see side effects all the time. But I was actually surprised some electrophysiology people like to reach for it because it does not work right away.

Dr. Shu Yang: I think this is a useful pearl, probably the only antiarrhythmic medication I would be comfortable starting somebody de novo who’s never, I don’t really know about when they’re already in AFib, is amio. You know if they’re, because you have no idea how they’re going to respond to an antiarrhythmic when they cardiovert, right, because frankly, a lot of people who have AFib, who who’ve been in a while, have a transient stunning of their sinus node and maybe these conversion pauses and they could pass out. And God forbid you give a pretty healthy 55 year old flecainide, he’s out driving and all of a sudden he cardioverts and he has a pause, he faints and he gets into a car accident. So amio is a little bit more of a gradual drug that doesn’t load as quickly. Right. It doesn’t have the immediate cardio effect.

Dr. Hanna Knauss: Which can also be useful if you pair amiodarone with something like the electrical cardioversion that we discussed back in Pearl 2.

Dr. Shu Yang: We’ll preload these patients with amio for a couple of weeks and bring them in for a cardioversion two, three weeks down the road when the amiodarone effects start to set in. Then you get the amio the cardio gets them out of AFib, and then the amio holds them out of AFib.

Dr. Shreya Trivedi: So it sounds like since amio is slower onset than other antiarrhythmics, it makes it safer to load outpatient. There is a lower risk of spontaneous cardioversion and that associated stunning that could make someone pass out. These are all good short-term benefit. What about long-term use of amio?

Dr. Hanna Knauss: Long-term amio, you really need to look at those side effects. I’m so used writing in my notes to check QTc and also those “FTs” – PFTs, LFTs, and TFTs.

Dr. Shu Yang: There is the risk of the pulmonary toxicity, which is reversible. There’s the risk of bad amio associated liver injury, but that’s quite rare. Most of these side effects are sort of again, these chronic smoldering side effects because it makes sense. It takes a while to build amio in your system, and the more adipose tissue you have, the longer it takes to reach a steady state. 

Dr. Shreya Trivedi: So sounds like amio is both slow to get started and also slow and takes time to build up having these smoldering side effects.

Dr. Hanna Knauss: Yes, so it’s definitely not a preferred agent for those who younger or who have liver or lung disease – in these patients, amiodarone should not be the end game. 

Dr. Rachita Navara: And anytime that you see a patient on amiodarone, the first question is to ask, well, can we take it off? Can we change it to a different drug? Can we refer to cardiology or EP to consider them for an ablation or something that can save them from being on amiodarone?

Dr. Hanna Knauss: Yep, so lots of good things to think through when you see amio. And just as quick recap from the pros of amiodarone – it can be a slower cardioverter relative to some of our other antiarrhythmics. And this allows for a safe load outpatient, which may work hand-in-hand with planned electrical cardioversion. 

Dr. Shreya Trivedi: Nice! Alright, now let’s move on to 2 other common class III antiarrhythmics: dofetilide and sotalol. I think these meds are truly a black box for most and we did our best to try to narrow down to 5 key points for internist. Right, Hanna?

Dr. Hanna Knauss: Yes! I love narrowing it down to key points.

Dr. Shreya Trivedi: Simplify, simplify, simplify.

Dr. Hanna Knauss: So let’s start off with the first point, so unlike amiodarone, both sotalol and dofetilide can have quicker times to conversion. So we need to watch out for those conversion pauses, which can cause people to pass out. 

Dr. Shreya Trivedi: Ah, no bueno. And similarly, the second thing we need to watch out for is  QTc prolongation – yes, it rears it head again, but this time requires a lot more hands on monitoring. And I will say, though, everyone’s practice is different.

Dr. Rachita Navara: For sotalol and dofetilide, the biggest adverse effect that we watch for it is QTc prolongation. And so that’s why patients are very frequently monitored with 12 lead ECGs in a scheduled way, two hours after each dose during the initial titration period. 

Dr. Hanna Knauss: So the classic management is to monitor QTc for 3 days with serial ECGs often in the inpatient setting and then every 3-6 months outpatient.

Dr. Shreya Trivedi: And of course, that could be more frequent monitoring if someone is already on other QTc-prolonging meds and, of course, this also means checking people’s electrolytes. Making sure their magnesium level is good. All that good stuff.

Dr. Hanna Knauss: And, Shreya, I’m going to add one little caveat that’s unique to sotalol. Sotalol is actually more potent at slower heart rates. So for our patients that are more prone to bradycardia, we need to look for an increased risk for Torsades.

Dr. Shreya Trivedi: Speaking of torsades. One of our peer reviewers, Dr. Robert Knotts mentioned that dofetilide increases risk of torsades all around that some EP groups don’t even touch dofetilide if they don’t have to.

Dr. Hanna Knauss: Oh interesting! But of course, everyone’s practice is different.

Dr. Shreya Trivedi: Yeah, absolutely! The third thing to keep in mind is that both sotalol and dofetilide are renally cleared so it’s not as great for our patients withprogressive CKD. Sotalol is contraindicated in the  GFRs<40 and dofetilide is contraindicated in GFR <20.

Dr. Hanna Knauss: Yes, and forth and the most surprising learning points for me is that if a patient misses 2 or more doses of sotalol or dofetalide, they need to be reloaded in the hospital.

Dr. Shreya Trivedi: Oh man, so say somebody’s been stable on dofetilide for years, and let’s say they miss 2 doses. Maybe they ran out of their meds and couldn’t get a refill in time. Are you saying, Hanna, that they need to be readmitted, possibly, to be reloaded?

Dr. Hanna Knauss: Ah, unfortunately, Shreya, I am. 

Dr. Shreya Trivedi: Yeah, ah, I just think about all the patients that come in whose meds we hold. And all the times dofetilide or sotalol have been held before.

Dr. Rachita Navara: The half-life of these medications is within that 12 hour span. So they would need to be retitrated starting from the baseline dose all over again if the drug is held for two doses. So one consideration I would say there is, unless the patient is having an AKI or they are having aggressive nausea and vomiting and their electrolytes are imbalanced, then do continue the antiarrhythmic drug. And of course this usually involves a quick call to cardiology or EP consult to ensure the safety of continuing the drug and also reassessing the QTc at that point. But in general, I think it’s more often that I see the drug is held when it should be continued as opposed to stopped.

Dr. Shreya Trivedi: So this was a learning point for me. I think I’m definitely gonna do additional counseling with  patients that sotalol and dofetilide. You know making sure they know it can’t be skipped. And if they do miss doses, they should really let their cardiologist know as soon as possible.

Dr. Hanna Knauss: True. And one final point I will add are the numerous drug-drug interactions we should watch out for, particularly with dofetilide. 

Dr. Shu Yang: It requires a very, very in-depth look at the patient’s medication list because a lot of medications are contraindicated with dofetilide. Tons of HIV medications, a lot of antifungals, antibiotics, thiazide diuretics are contraindicated.

Dr. Shreya Trivedi: So with these antiarrhythmics, it’s worth double checking with the pharmacists or, honestly, I should probably just expect a call from pharmacy since they’re often quicker than me!

Dr. Hanna Knauss: Yeah. I think I have a personal line with pharmacy by now!

Dr. Shreya Trivedi: I know! Great colleagues.

Dr. Hanna Knauss: So to summarize, patients who are on dofetilide or sotalol, we should check an EKG, potassium, and magnesium because of the QTc-prolonging effect. Unfortunately, patients with progressive CKD may not be good candidates for sotalol and dofetilide since there are absolute GFR cutoffs. And if they’ve missed 2 or more doses, they might need inpatient monitoring while they are reloaded. 

Dr. Shreya Trivedi: Wow, starting these medications are a big deal! 

Pearl 4 – Class Ic Antiarrhythmics and Side Effects

Dr. Shreya Trivedi: Okay, lets move on to our class 1c antiarrhythmics, specifically flecainide and propafenone. And you mentioned earlier that these drugs tend to have a faster conversion to sinus.

Dr. Hanna Knauss: Yeah and the onset can be so rapid that flecainide or propafenone can be given as a “pill in the pocket” approach. So with this, for select patients who are rarely in afib and can feel when they are, they pop in flecainide or propafenone and they will convert them back to sinus, ideally within few hours after taking the medication. 

Dr. Shreya Trivedi: Interesting! That’s so convenient and may save them a trip to the hospital.

Dr. Hanna Knuass: Exactly, and can also be used long-term too, not only as a pill in the pocket approach. 

Dr. Shreya Trivedi: So it sounds like flecainide and propafenone sound great and I know, I’ve had EP friends say they try to reach for this as first-line, but the biggest limitation, especially in our complex, sick population, is that flecainide and propafenone are not that good in our patients with “structural heart disease.”

Dr. Hanna Knauss: Yeah. I heard that, too. Which got me thinking how do we actually define “structural heart disease” Is it just heart failure patients? Does does it also include patients with coronary disease? 

Dr. Shu Yang: There’s the technical definition and there’s the clinically conservative definition, and then there is the clinical cowboy definition. But I would say that for most people it’s anyone with an abnormal EF, anybody with prior coronary disease. Right. And they’re not candidates because of the CAST trial where we gave people flecainide and encainide as sort of a derivative or relative of flecainide and to suppress PVCs, and they suppressed PVCs amazingly, but then triggered probably helped organize some VF or ischemic PVCs into more sustained ventricular arrhythmias. Basically, flecainide and encainide killed people who are ischemic. So we’ve expanded that to anyone with a structural heart issue probably should not take flecainide. 

Dr. Hanna Knauss: And just to make sure we are on the same page, by “ischemic”, he means people with prior infarcts.

Dr. Shreya Trivedi: Okay, so it sounds like it was all from the CAST trial, that found a significant increase in lethal ventricular arrhythmias in patients on flecainide and encainide versus placebo, and now there is a black box warning for class 1c antiarrhythmics because of their proarrhythmic effect.

Dr. Hanna Knauss: And also, Shreya, it’s worth noting, class 1c antiarrhythmics are more potent at faster heart rates. So once our patient and they’re fully loaded with flecainide and propafenone, we do a stress EKG to get their heart rate up and see if the QRS widens, which may indicate pro-arrhythmic risk.

Dr. Shreya Trivedi: So once they are stable on these meds, we actually subject them to a stress test to see what their QRS morphology does on these higher heart rates. 

Dr. Hanna Knauss: Exactly! And there is another arrhythmia we should also be looking for in patients on flecainide and propafenone.

Dr. Rachita Navara: These drugs can sometimes alter the atrial repolarization enough to where the patient can actually now conduct better in atrial flutter and go one-to-one, meaning every time their atrium has an impulse, the ventricle is following is following suit.

Dr. Hanna Knauss: So flecainide and propafenone can actually promote afib or flutter conducting 1:1, which can get really fast. 

Dr. Rachita Navara: The important thing to remember there is if you see a patient on flecainide or propafenone, make sure that they also have a rate control agent on board at the same time.

Dr. Shreya Trivedi: Okay, so it sounds like I am going to look at the med rec on patients on flecainide and propafenone. Make sure they’re are on beta-blocker or calcium-channel blockers. Make sure they weren’t discontinued on admission, and held. Which also happens! Anything else before we round out flecainide and propafenone?

Dr. Hanna Knauss: Yes! One less talked about side effect of flecainide. And that’s vertigo. I was surprised to learn that vertigo affects nearly 1 out of every 5 patients on flecainide. 

Dr. Shreya Trivedi: Oh that’s a lot! A lot, enough to add to our vertigo schema! Alright. Let’s recap then these past 2 pearls, and I’m gonna try to reorganize these meds thinking about indications and contraindications to maybe cement in a little bit of a different way. So say we have a patient who does not have HF, does not have obstructive coronary disease or prior infarcts. This is somebody we may see a patient on flecainide or propafenone. Its a quick onset, it’s effective but anyone who gets started on flecainide and propafenone, it buys them two things. 1) A stress EKG to see what their QRS does at faster heart rates. And 2) it buys them a rate control agent since these meds are proarrhythmogenic.

Dr. Hanna Knauss: And then maybe your patient has some prior infarct but does NOT have chronic kidney disease, then you might see your patient on sotalol or dofetilide. These are meds that need close monitoring of QTc interval, sometimes for 3 days inpatient as well as electrolytes and kidney function. I;m gonna make sure I counsel my patients to not miss any doses of sotalol or dofetilide. 

Dr. Shreya Trivedi: Yeah! And then last but not least, we have our good old friend amiodarone. Not as fast of a cardioverter, which sounds like can be beneficial in the outpatient setting since it doesn’t carry that risk of conversion pause we see in the other meds.

Dr. Hanna Knauss: I will say that all these patients still need to be anticoagulated because there is stroke risk when they convert to sinus rhythm.

Dr. Shreya Trivedi: Ah, so no free lunch when it comes to anticoagulation!

Pearl 5 – Catheter ablation

Dr. Hanna Knauss: And that leads us to our final pearl – ablation. I’ll be honest, I didn’t have a great understanding of when to refer patients for ablation or who would be best fit for the procedure. 

Dr. Shreya Trivedi: Yeah, sometimes I think of ablation as a “last resort” option when people have fail medical management, but as we will hear from our discussants, ablation can be considered at all stages of afib.  

Dr. Eric Prystowsky: So absolutely study after study after study has shown that ablation to keep someone in sinus versus drugs wins. 

Dr. Hanna Knauss: The studies (such as the EARLY-AF and STOP-AF trials) have been so compelling that the new guidelines recommend ablation as a first line treatment in patients with paroxysmal symptomatic afib within 1 year of diagnosis.

Dr. Shreya Trivedi: Oh really? Interesting, why is it beneficial in paroxysmal afib? And what’s so special about the paroxysmal nature of it?

Dr. Shu Yang: People with paroxysm, atrial fibrillation in particular, it is more of a quality of life measure

Dr. Rachita Navara: We see more favorable ablation outcomes when a patient is closer to their time of diagnosis. And so we see, better outcomes from its first time ablation when a patient is in paroxysmal AFib, so coming in and out versus persistent. And so if you leave atrial fibrillation alone long enough, it tends to become persistent. And so that’s really one of the benefits for early intervention and early referral as well for AFib.

Dr. Shreya Trivedi: Okay, so it sounds ablation can be beneficial in symptomatic paroxysmal Afib because the the sooner you do ablation, the more effective it will be in keeping sinus and it can improve their quality of life if they are feeling going in and out of afib.

Dr. Hanna Knauss: And there is one other common group of patients that we do have a  class 1 recommendation for ablation for. And that’s in patients with afib with heart failure with reduced ejection fraction. 

Dr. Eric Prystowsky: And over time, all the studies have now shown if you have decreased heart function, that you will do better in sinus and ablation is the easiest way to keep you sinus. It’s not the only way, but sinus is better. So if somebody is in those situations, yes, I’m going to push them more towards an ablation because the data are out there suggesting they’ll benefit a lot.

Dr. Shreya Trivedi: I had no idea that in patients with a reduced ejection fraction that catheter ablation over antiarrhythmic meds alone actually had mortality benefit and less heart failure hospitalization in various trials (more here and here).

Dr. Hanna Knauss: So just to recap the two populations we have strong data to support early catheter ablation in is newly diagnosed paroxysmal afib, as well as those with heart failure with reduce ejection fraction. 

Dr. Shreya Trivedi: Alright. What about someone who has persistent afib or they have normal systolic function? Do we consider ablation in them?

Dr. Hanna Knauss: Ah, yeah. This were the art of medicine comes in where there is no right answer. Yes we have to keep in mind the longer someone is in afib, the harder it will be get them back to sinus.

Dr. Shreya Trivedi: Yeah afib does beget afib. And makes sense. The longer in afib they are, the larger the left atrium can be and the harder it’ll be for that ablation to be effective.

Dr. Hanna Knauss: Exactly. And all that is to say, no matter how persistently someone has been in afib for how many year, ablation is still worth a discussion with EP.

Dr. Eric Prystowsky: I think the most important thing is everybody needs a discussion, a fair discussion, not a tilted discussion. Risks and benefits. Long-term success.

Dr. Shreya Trivedi: Speaking of success, Hanna, I’m curious about an elephant in the room. And I’m curious if you read about this. How successful are ablations in getting patients to sinus? And how do we give patients the heads up? Especially cause this is a procedure and people have questions about that.

Dr. Hanna Knauss: Yeah so I was reading that some studies say the success rates can exceed 80%, particularly for people  with paroxysmal afib. But sometime, particulary in those with longer standing afib, it can be as low as less than 30%.

Dr. Rachita Navara: The worst thing that can happen right after an ablation is if patient goes right back into atrial fibrillation and thinks this procedure was a failure, and it may have been they may need another ablation procedure down the line. We certainly do redo, redo redos, redo, redo, redo ablations. 

Dr. Shreya Trivedi: And one thing Dr. Prystowsky brought up is that even if the ablation is unsuccessful there may be other benefits to ablation. 

Dr. Eric Prystowsky: So for example, you do an ablation and they go back in AFib, but not uncommonly after you’ve done an ablation. Antiarrhythmic drugs work where they didn’t before. If you go in there and you wall off the veins and you do a few other things, if you may need to do it and then they still come back in AFib, there’s not as many areas that could promote AFib anymore. And now an antiarrhythmic drug that failed previously can work really, really well.

Dr. Hanna Knauss: Okay. So ablation opens up the door for antiarrhythmics to work where they didn’t before. And even if that means you didn’t achieve the goal of getting them off medications, you were still able to get them back into sinus.

Dr. Shreya Trivedi: And as we’ve we said before, sinus is superior. I feel like that’s tattooed on some electrophysiologist’s chest. Or somewhere! Someone has a tattoo, somewhere! Sinus is superior!

Dr. Hanna Knauss: Another bonus with ablation is that its a chance for patients to get off of medications.

Dr. Shu Yang: A lot of patients, particularly the younger patient who are super bothered by their brief paroxysmal AF, they would much rather have a procedure that is very safe at this point. It’s a day procedure. They would very much rather have that than be obligated to taking even metoprolol, which is honestly patients worse. A lot of patients hate metoprolol. It is the worst thing. It makes ’em feel fatigued. They can have nightmares, they feel foggy, they don’t think clearly. They feel limited when they’re exercising. So it really is, it’s a quality of life measure that I think we, at least I under appreciated before I started joining this field.

Dr. Shreya Trivedi: Yeah and after covering the side effects of antiarrhythmics like vertigo with flecainide, I don’t blame patients for wanting to get off their meds.

Dr. Shu Yang: And what I’ve learned more and more, is patients hate medications. So if you tell them, you could potentially take fewer meds after doing this procedure, nine out of 10 people say, sign me up. But then you tell them about how this procedure could save your life. They’re like, I don’t know if I’m really interested. 

Dr. Hanna Knauss: Okay, I see why we patients would want an ablation. But are there people who we shouldn’t recommended for ablation? 

Dr. Eric Prystowsky: Let’s say they have severe COPD. There are times when you have to say to yourself, is this the right patient to take to a lab and put ’em out for two to three hours? They’re under general anesthesia. So it’s truly a case by case basis. The vast majority of patients are candidates for ablation. But if you say right upfront, there’s no way that I think this patient will benefit from sinus rhythm, then ablation would be inappropriate.

Dr. Shreya Trivedi: Okay so if patients are not safe for anesthesia, might be best not to refer them for ablation when the risks of a procedure outweighs the benefits.

Dr. Hanna Knauss: And also, Shreya, there is an increased stroke risk in the first few months after ablation. So patients need to be able to take anticoagulation.  If they aren’t anticoagulable, ablation may not be appropriate.

Dr. Shreya Trivedi: Ah, good to always bring up upfront. Okay, so before we finish up this episode, let’s wrap our head around this pearl. Ablation is a complex decision that should be had with most, if not all, patients with afib. 

Dr. Hanna Knauss: We don’t have to wait until they’ve failed medication. Ablation up front has been proven to be a more effective than medications in achieving sinus rhythm. It’s actually a class I indication for upfront use in patients who have symptomatic paroxysmal afib or those who have heart failure with reduced ejection fraction.

Dr. Shreya Trivedi: Nice! And on that note, that is a wrap for today’s episode!  Please share this with a colleague or anyone who may find this helpful. Hanna’s dad actually shared this with colleagues, co-workers!

Dr. Hanna Knauss: Yeah! He did, you just made his day, Shreya.

Dr. Shreya Trivedi: Give him a little shout out!

Dr. Hanna Knauss: And thank you to our reviewers Dr. Robert Knotts and Dr. Henry Huang. This episode was made in part from the Digital Education track at BIDMC. Thank you to all of our mentors who made this possible! 

Dr. Shreya Trivedi: Thank you to Daksh Bhatia for the audio editing. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.