Role of Ablation Type and Risk Factors in Paroxysmal AF: PROGRESSIVE-AF Interview

John M. Mandrola, MD; Jason G. Andrade MD


November 14, 2022

This transcript has been edited for clarity.

John M. Mandrola, MD: Hi, everyone. This is John Mandrola from | Medscape Cardiology. I'm here in Chicago at the American Heart Association meeting, and I'm pleased to be with my colleague, Dr Jason Andrade, from the University of British Columbia, who presented a late-breaking clinical trial today called PROGRESSIVE-AF that was also published in The New England Journal of Medicine.

That's not why I'm intimidated by Jason. I'm intimidated because he has an amazing power output on a bike, and I know this because I follow him on Zwift.

Jason, welcome.

Jason G. Andrade, MD: Thank you, John. It's always a pleasure to see you.

Mandrola: Tell us about the trial you presented today and how it ended up.

Andrade: For the trial we presented today, we took 303 patients with treatment-naive atrial fibrillation and randomized them to first treatment with antiarrhythmic drugs or first treatment with ablation. The key result that we saw was a 75% lower progression of persistent atrial fibrillation after ablation relative to drugs.

Mandrola: This trial was sort of a continuation of the EARLY-AF trial. Tell us about how that separated out.

Andrade: EARLY-AF is your standard endpoint that we had in each of the six first-line trials. You're looking at 30 seconds of atrial fibrillation on a loop recorder. You could argue about how meaningful that endpoint is.

EARLY-AF really was in line with HRS-recommended follow-up duration and endpoints, and it ended at a year; PROGRESSIVE-AF was that second phase. Instead of looking at binary recurrence, now we're looking at whether we're actually modifying the disease. That's our 3-year follow-up study.

Why Is AF Progression Important?

Mandrola: I'm going to ask you about the patients, but first tell me why progression of atrial fibrillation or progression to persistent atrial fibrillation is so important.

Andrade: There is the idea that atrial fibrillation is a progressive disease. It starts with an isolated electrical problem. Every episode of atrial fibrillation leads to more electrical and structural changes. Eventually, with time, that will induce abnormalities in the heart that cause the atrial fibrillation episodes to last longer. We know that when you get to persistent atrial fibrillation that the rates of stroke are higher, the mortality is higher, and new-onset heart failure is higher.

If we're walking this back to a treatment-naive population, if I have a therapy that I can provide — whatever that is — that can halt that progression, maybe we're going to see that long-term benefit, especially when we apply it to 40-year-olds instead of 70-year-olds.

Mandrola: That's a lead-in to the patients. This patient population was a young, fairly healthy population, yet you still could show reduction of progression of atrial fibrillation.

Andrade: That's exactly what we were targeting. Most of the ablation studies are done in 60- to 70-year-olds who have many comorbidities. Those comorbidities lead to structural changes to begin with. For our study, we really want to get at the crux of the issue. If it's an electrical problem that is potentially fixable with an ablation, are we going to realize that benefit long term in terms of halting the progression?

Mandrola: It's pretty well known that ablation is better than drugs. One of the things that I liked about your trial is that you really pushed on the drug arm to make sure that patients received adequate drug therapy and had to have failed drug therapy before they crossed over.

Andrade: Anticipating what the criticism is going to be, you always want to know that your control arm — or whatever your comparator is — is as well treated as it can be. If I did this study and the antiarrhythmic drug arm was undertreated, then the results are not important anymore because you kind of handicapped the trial.

We did have aggressive titration protocols. All those are available in the supplement so you can use them in your own practice. Our goal was 90 days to get those patients as stable as you can get them and suppress all their atrial fibrillation on a loop recorder. Only after that 90 days did we start counting outcomes.

Mandrola: Tell us the role of the loop recorder and why that is so important.

Andrade: In this trial, the reason we had the loop recorder is its truth. If you're not monitoring atrial fibrillation all the time, you run the risk of introducing error where you're just not seeing the episodes, and you may make a false conclusion based on what you're seeing. Having a loop recorder, we're monitoring every minute of every day for all of those patients, out to 3 years now in this most recent study. We can definitively say, looking at burden and the timing of the episodes, that there is truly a difference.

Mandrola: One of the things I want to push you on a little bit is, okay, there's this relative 75% risk reduction. I was struck by EARLY-AF, but I'm struck by this, that the actual atrial fibrillation burden in these patients is pretty low in absolute terms. What do you say to that?

Andrade: The first thought is it's hard to know what it means in absolute terms because these are the first studies that ever looked at it. If we look at EARLY-AF, if we look at CIRCA-DOSE even, the criticism on those trials is that you're looking at atrial fibrillation burdens of 1% — and what does that mean?

If you look at the patients in the ways that we normally judge them, they're highly symptomatic, they're going to the emergency room to get cardioverted, and they're having multiple episodes a month. For every subjective descriptor that they're providing, they're highly symptomatic. When you monitor this paroxysmal atrial fibrillation population, they have very low burdens of disease.

In EARLY-AF, when we published it, the main difference between the groups was 3%. What does 3% mean? It sounds like a low number, but that's 1 day less atrial fibrillation per month in a 30-day month. It's a little bit of context.

Mandrola: There is another question I wanted to ask you. How do you think that the cryoballoon ablation results that you find translate to radiofrequency (RF) ablation and other means of ablation? You might even say something about the upcoming pulsed-field ablation energy source.

Andrade: Before EARLY-AF, STOP AF First, and Cryo-FIRST, there were three RF studies that didn't show the same significant benefit with first-line ablation. Those were all point-by-point RF, and one of the reasons for initiating EARLY-AF back in the beginning was that you have a technology that is theoretically more reproducible.

In the hands of 18 centers in Canada, we can anticipate that the results are going to be very consistent. Whereas in something like CIRCA-DOSE, where the overall RF cryoballoon results were similar, we actually saw a large amount of variability in the RF group. Some RF ablators who are highly experienced will outperform cryo. The average RF ablator is going to be about as good as cryo, but then half the population are actually worse. I think that that speaks to a little bit to the generalizability question of these results.

Mandrola: In FIRE AND ICE, they were equivalent. Of course, Karl-Heinz Kuck said that these RF ablators were born to ablate and so they might not be translatable to the average ablation person.

Andrade: That's sort of the same question, right? In Canada, I think we have a lower number of centers so our expertise is a bit more concentrated. That being said, we still saw in CIRCA-DOSE a large amount of variability in the RF groups.

Mandrola: Now for the key question. One of the things that I'm concerned about is the overuse of atrial fibrillation ablation, especially in non–cost-constrained health systems like the US. How would you translate these results to regular clinical practice? How long do you wait or how much do you push on risk factor modification or drug therapy before going to early ablation?

Andrade: That's always a good question. One of the things that we outlined in the paper just before we hit our limitations piece is that this is just one piece of the puzzle. This is not the be-all and end-all. Ablation is not an absolute solution; it's part of the treatment pathway. We still have to focus on stroke prevention, and equally important is risk factor modification. You have to do them all in concert. You can't just do one.

I think that when you have a reproducible technology and you have experienced operators who can get a very reproducible result, then these results are generalizable. Turning it to other technologies that are more user dependent and where there's more variability in experience, I don't know that you're necessarily going to see the same result. I think this is where shared decision-making becomes a big piece of it. We can't forget that we have to be aggressive with risk-factor modification and the other pillars of atrial fibrillation management.

Mandrola: If you had, say, a 60-year-old person come in with risk factors in their first episode of atrial fibrillation and it was symptomatic, what would you do?

Andrade: For me, this is not a trial of first episode of atrial fibrillation; this is a trial of people who have atrial fibrillation that has gotten to the point where you now need to intervene. EARLY-AF enrolled people at a median of 1 year after diagnosis.

To me, that first episode of atrial fibrillation or the atrial fibrillation alert on your Apple Watch, that's kind of a red flag to say we need to do something to improve your chances overall. That's your signal to initiate risk-factor modification and getting everything under control so that you don't get to the point where we need to intervene on your atrial fibrillation.

This trial is really that later point of when we need to intervene.

Mandrola: Jason, thank you so much for saying that. I'm going to close because I want that to be the final word. Thank you for being here.

Andrade: Anytime.

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