In conversation with Boston Scientific's global medical chief, Ken Stein, taking the pulse of pulsed field ablation

Conor Hale: I would ask you how things are going with Farapulse’s commercial rollout, but I did catch the company’s earnings call last week and it does seem to be pretty popular.

Kenneth Stein: It’s going well. I don't know if [CEO] Mike [Mahoney] said it on the call, but he’s said it previously, that this has to be one of the most successful novel product launches in his career, and he's got a pretty long career.

CH: You're an electrophysiologist yourself, and you’ve had experience with treating arrhythmias. What are your thoughts about the promise of pulsed field ablation as a whole?

KS: I mean, it's a cliché, but this is one of the things that really is game changing, and it's game changing in a number of different respects. 

First of all, atrial fibrillation is an incredibly common rhythm disturbance—it's the most common, sustained rhythm disturbance that exists. It increases with advancing age. Previous estimates were that as many as 1 in 4 Americans over the age of 40 have experienced atrial fibrillation at some point in their lives. 

And actually the most recent data says that may even be an underestimate. 

The problem with atrial fibrillation is that a drug therapy, to try to restore people back to a normal rhythm, is almost uniformly unsuccessful and can cause significant side effects.

And that's why over the past nearly two decades, people have been trying to refine techniques to do ablation and eliminate the tissue that's causing the atrial fibrillation.

Up until pulsed field ablation, there were two alternatives: One was to burn away the tissue that you want to destroy with radiofrequency energy, or to freeze it away using cryoablation.

And while both of those techniques for many patients were clearly better than drug therapy, they still have limitations. 

One of the limitations was a concern around safety. The problem is, these kinds of thermal energy sources are not specific to heart tissue, so there's a risk of damaging adjacent structures to the heart, which can be very serious—such as the esophagus, the pulmonary veins and the phrenic nerve that enables you to keep breathing.

The second problem with these technologies is that they are require a huge degree of skill to deploy. They are not straightforward procedures, and they also tend to be lengthy, which limits the ability to expand doing ablation for the huge number of patients who need it. 

What's unique about pulsed field ablation—and particularly what's unique about Farapulse and the Farapulse waveform—is that it's relatively myocardially selective. You can ablate heart tissue with very low risks of damaging adjacent structures. So that enabled us to create a system that enables people to safely ablate atrial fibrillation, to do it much more efficiently than with thermal energy sources. 

And I think what we're going to see, as more data comes out—because you don't have the safety concern, and because it's such a straightforward procedure, and we know we see at least the same efficacy—I believe we'll be able to prove more efficacy for some types of atrial fibrillation, compared to thermal ablation.

The first of that efficacy data was in a sub-analysis of our pivotal trial for Farapulse called ADVENT, and the sub-analysis was presented at the Heart Rhythm Society meeting earlier this year. 

Often in clinical trials, what we've looked at to define effectiveness was complete freedom from any recurrent episodes of atrial fibrillation. So if you had even a 30-second asymptomatic recurrence, that was called a “failure.”

People have come to recognize that's not a really clinically meaningful indication of success versus failure. And they started looking more towards atrial fibrillation burden, which measures how much atrial fibrillation you are having over time.

And as long as that burden is less than 0.1%, then that's associated with a very good outcome over time. So the sub-study of ADVENT—and it was not the primary analysis, so you have to take it with a grain of salt—but the sub-study of ADVENT showed actual superiority for Farapulse compared to thermal ablation in terms of getting to that burden of less than 0.1%.

CH: In talking about more data coming in the future, what about long term impacts on rates of stroke?

KS: That’s a really fascinating subject. Right now, the predominant reason to ablate atrial fibrillation is to control the symptoms. It is still unclear whether successful AF ablation adequately mitigates the risk of stroke after the procedure, so that people can avoid other therapies, such as blood thinner medications or therapies like the Watchman [left atrial appendage closure implant].

And that's why professional society guidelines today still do say that even if you had an AF ablation, if you're at high risk of stroke from afib, ablation in and of itself is not a reason to be able to discontinue anticoagulation.

There will be some data from an independent trial called OCEAN that's going to look at that, and we expect to see that data probably a year from now, in the fall. The suspicion is it's going to be nuanced—that depending on just how high your risk is will determine whether ablation in and of itself is sufficient to mitigate the risk.

CH: I mention stroke because I know the company is seeing a lot of clinicians pair up Watchman with a Farapulse procedure.

KS: Yes, in a concomitant procedure. The beauty of doing it all in one procedure is that a lot of the aspects of the procedures are the same. They both require transeptal access, they both require manipulation of catheters within the left atrium—so if a patient is going to have both done, it's clearly beneficial in safety terms to have them both done at the same time. 

It had been hampered a little bit by a lack of reimbursement for concomitant procedures in the U.S., but CMS just approved a new [diagnosis-related group] that covers it. 

The next thing to come is that we have a trial called OPTION that's going to be reported out at the American Heart Association meeting in November. OPTION is not a trial of concomitant procedures per se, but OPTION’s the first time we've done a trial where we're putting Watchmen up head-to-head against NOAC and DOAC drugs, the novel oral anticoagulants. And in OPTION we are studying them specifically in people who've had an AF ablation.

So taking patients who are good candidates for long-term anticoagulation and randomizing them either to the anticoagulant or to the Watchman implant—some of those procedures in that trial were done concomitantly, and some of them were done as staged procedures. 

The trial isn't really designed to say if they all should be done concomitantly, but it’s designed to ask, do you get equivalent protection from stroke with Watchman compared with the NOACs in this patient setting? And it’s also is going to hopefully show whether or not that's associated with a reduction in the bleeding complications that you see in people who are on anticoagulants.

CH: Interesting. Just to take it back to Farapulse for a minute, can you tell me more about your role in the initial investment in the company and its eventual acquisition? What first attracted you to their platform?

KS: Yes, we were among the earliest venture investors in the company. We actually invested before it was even called Farapulse—back when it was called IOWA Approach. It came from a very smart guy at the University of Iowa named Steven Mickelsen. 

There were two related things that attracted us, in terms of promise. One was the relatively myocardial selective nature of the Farapulse waveform. 

That has been the Achilles’ heel of ablation up to now: You take an arrhythmia that is very common, and if you do have life-threatening side effects—even if they're relatively rare—when you put them out over the millions of people with afib, that's a lot of people who may end up being harmed by the procedure. 

So the number one thing is the promise of greater safety. I'd then add to that the promise of being more straightforward and more efficient, and therefore more scalable as you look at tackling the overall problem of afib.

CH: Boston Scientific has bought a lot of companies in the past few years. Where does Farapulse rank among them in terms of return on investment, or at least the speed of that return?

KS: I don't know that I can answer that specifically, but I'd say again that I think it is one of the most successful new product launches in cardiovascular medicine in the last decade, that I can think of. 

I think it’s important that people realize none of this is a fast or easy process. The timeline to get us to here today with Farapulse is a decade of painstaking research and development. It had to go through a lot of iterations of the approach to do the ablation, of the catheter design, the waveform. There was a lot of preclinical testing, a lot of early feasibility human testing, and then a lot of clinical trials. 

One thing we're really proud of is that we’ve got over 125,000 patients who've been treated commercially with the system already—and I’ll remind everyone we only got our U.S. approval in February this year—but we've also got published data on almost 20,000 of those patients.

It's that long process of making sure that Farapulse—and eventually us, because we acquired them—got the design and the system optimized. And then there was a commitment to collecting clinical trial data to prove out the performance of the system. That’s the secret sauce. 

CH: Like you said, it's been less than a year since any of these devices were approved in the U.S.—but the pace of innovation you're describing seems to have accelerated greatly since then. 

We're already seeing “second-generation” or “next generation” systems. Boston Scientific received Farapulse Nav approval earlier this month. You’re also developing Farapoint and Faraflex catheters for different use cases.

Where do you see this pace of innovation headed?

KS: You have to keep innovating, you have to keep iterating products. We talked about Watchman, and we had the only approved device of its type in the U.S. for a long time, it’s been a market leader. We could have stayed with our first approved Watchman device, but we didn't. We chose to iterate and we went from Watchman to Watchman FLX and now we have Watchman FLX Pro. And we've got further iterations in development. 

Patients deserve to see continued innovation. You never get to perfect, but you continually want to strive towards perfect. 

And the same thing applies to Farapulse. The approach we’re taking with Farapulse is to provide a full toolbox.

We want to design the catheters so that they are exquisitely tuned to the types of ablation that someone wants to do. The beauty of Farapulse and what makes it a straightforward procedure is that it is exquisitely well designed for doing pulmonary vein isolation. We're testing it for posterior wall ablation as well, and the flower-basket design is designed to be able to do that. But you don’t always need to do that. 

That's why we're looking at other arrhythmias and other use cases. No one goes out golfing with just one club. I think trying to do one thing that’s just going to work “OK” for a variety of different arrhythmias—I'd rather have the specific tool for the specific arrhythmia I want to treat.

CH: So when it comes to the rate of adoption, you've seen a lot of early adopters jump into the space. But with Boston Scientific and three other major medtechs entering the space, as well as a slate of startups that are on the way and raising money ... do you see customers wanting to wait and see before they invest in one of these systems?

KS: There's always an adoption curve, as you say, and there are always early adopters. I think we've gotten beyond the early adopters at this point. We're going to have competition, and competition is a good thing. Again, it forces us to continue iterating and continue advancing. We certainly stand behind Farapulse, in terms of its ease of use, the clinical trial results to date and the differentiated advantages that we see with the system.

We're pretty proud of the innovation we're doing within Boston Scientific. But we know we do not have a monopoly on smart engineers or ingenuity. So we always keep an eye on what other smart people are doing.

CH: I want to ask you about the AVANT GUARD trial. The company disclosed last week that it's pausing enrollment for unanticipated observations, which you said were not life threatening. For those who might not know, can you tell me about the specific patient population for this trial?

KS: Yeah, absolutely. In at least one important respect it’s a unique population. 

So currently the Farapulse system is labeled for use in treating patients with paroxysmal atrial fibrillation. We also ran a trial called ADVANTAGE AF, which is studying patients with persistent atrial fibrillation. And we have completed enrollment in that trial, and we've completed follow-up in the first phase of that trial—and we expect to submit it for the label expansion to persistent atrial fibrillation before the end of this year, with data reported out early next year. 

AVANT GUARD takes that one step further. ADVANTAGE looked at patients with persistent atrial fibrillation who've been given a trial of an anti-arrhythmic drug that failed. No one has previously done a large, randomized trial looking at any ablation modality in persistent atrial fibrillation patients as a first-line therapy. 

So what we're doing in AVANT GUARD is we’re looking at patients with their new diagnosis of persistent atrial fibrillation, who haven't even been given a drug therapy yet, and randomizing them to drug therapy versus immediately proceeding to ablation.

CH: Would you characterize that as a huge bet on the technology? 

KS: Absolutely. As I said, we disclosed that we paused the trial because we want to understand some unexplained observations that we saw in the trial. We fully intend to resume the trial in the near future and to see it out to its completion. 

I think, for a lot of folks, the frustrating thing about that is we can't go into a lot of details about what we saw in the trial because we need to preserve blinding and make sure we can get the trial done successfully. 

The other thing I can say is that we have absolute confidence in the overall performance of Farapulse—based on the clinical trials to date, published data approaching 20,000 patients and commercial experience in 125,000-plus. We are looking forward to getting that trial back on track.

CH: So what is the company doing during this pause? Do you plan on making any changes to the study or its protocol?

KS: So the absolutely transparent answer is we want to make sure we have as complete an understanding of these observations as we can, and then based on that understanding, we'll know if we need to make any changes to any aspects of the trial conduct.

CH: So AVANT GUARD was kicked off in late 2023, and the company said at the time it was looking to enroll at least 500 patients. Have you been seeing any challenges in convincing participants to undergo a device procedure first, before taking any medications?

KS: No, enrollment was going very well. And I think that maybe some of the complexity around the trial was that we were enrolling at a very, very rapid pace—which is part of why we're saying let's just slow things down for a bit. We have the freedom to take a pause like this.

CH: I think that's interesting because it sounds like it would be a very heavy lift to convince someone, or even convince their doctor to recommend an invasive procedure with anesthesia before taking oral medications. 

KS: It's very patient dependent. It’s certainly why you do it within the context of a clinical trial. If we knew which one was going to win, obviously we wouldn't do the trial. 

What gives us some of the confidence, where we say this is worth studying, is that it has been studied for paroxysmal atrial fibrillation and the data really did support moving to early ablation. 

Again, if we knew what the answer is going to be, we wouldn't be doing the trial, but based on that predicate data, and based on our confidence in the safety and efficacy of Farapulse in the populations where it has already been studied, we’ve said this is one that's worth investigating.