Dr Vivek Y Reddy:

I'm Vivek Reddy, Electrophysiologist from Mount Sinai Hospital in New York City.

What was the background behind the PFA-SHAM trial?

By way of background, we know that AF ablation is superior to medications. A number of different trials have shown this. However, the vast majority of these trials were performed without a sham control. So, patients knew what procedure that they were getting.

Now there is one exception to this, which is a trial that was presented and published about a year ago called the PVI-SHAM trial. And that trial randomised patients to either cryoballoon ablation or sham control. And what it basically showed was improvement in terms of freedom from atrial arrhythmias in the ablation group relative to sham. Now they had a bunch of secondary unpowered endpoints, including quality of life changes, et cetera, which were largely also positive.

Important trial, but it was limited by a couple of important points. Number one: the change in quality of life was a secondary endpoint. It was an unpowered secondary endpoint. And it really should be thought of as hypothesis generating based on that first trial.

Also that trial had a number of patients underwent cardioversion during the procedure. So the sham wasn't fully a sham. It was sham plus about 80% cardioversion. And the third point, it's not a limitation in the trial but, our field has moved from cryoballoon ablation and radio frequency to pulsed field ablation, or at least it's moving in that direction, let's say.

So it was also an important question as to whether or not pulsed field would perform as well against the sham procedure. And these are the different aspects that, let's say, provide the background for us doing our PFA-SHAM trial.

What was the study design and patient population?

So the way we designed the study was, on the one hand, we wanted to do a sham trial. On the other hand, we really wanted to minimise the number of patients in the trial, partly to minimise the exposure of a lot of patients to a sham procedure. So as part of the inclusion, exclusion criteria, we required patients to be highly symptomatic. And that was defined by a baseline AFEQT score of less than 50. So we brought in a very high risk population.

In terms of exclusion, we were pretty wide open. The one major exclusion that we wanted was anybody who had what was thought to be a tachycardia-induced cardiomyopathy. Because of the potential mortality benefit, it didn't seem ethical to include them in a sham trial.

Besides that, the idea was all the patients were to have implantable loop recorders, so they would receive an implantable loop recorder after signing consent, and then approximately a month later, then they would undergo the actual procedure.

The procedure started off with an EP study and the idea was if the patients had and inducible SVT then they screen out at that point. We didn't expect a lot of patients to screen out, but we expect maybe some. And then assuming that the [illegible] was negative, then they get randomised to either the pulsed field ablation, using the pentaspline Farawave catheter or to a sham.

And sham at that point is basically continuing propofol for an extra 20/30 minutes. The trial was designed again as a superiority trial, and we had two co-primary endpoints. One co-primary was freedom from atrial arrhythmia recurrence after a two-month blanking period.

And the other co-primary was improvement in quality-of-life defined by change in AFEQT score. Now as we initially started off the trial with a frequentist design, but sort of near the beginning of the trial, the SHAM-PVI trial was presented and published last year.

And when we saw that, we decided to change the design to an adaptive design. And this change occurred before we had many patients enrolled. So we changed it to an adaptive design. So after 30 patients and after every 10 patients beyond that, we would look at the data to allow for early stopping, to allow patients to cross over or whatever if they so desired. So that was the design of the study.

What were the key findings?

So, when we did the interim analysis, in order to stop the trial, both co-primaries had to reach the stopping rule. After the 30-patient interim analysis, neither reached the stopping rule. After the 40, the AF recurrence reached the stopping rule, but not the quality-of-life endpoint. After 50 patients, they both reached the stopping rule. Now by the time we did the 50 patient analysis, 60 patients had actually been enrolled. And so we followed those patients to six months, which is the primary time of follow up.

And what we saw were a couple of things. Number one, just really quickly on safety, it was very safe. So basically there were no major complications in either group, which we sort of expected. In terms of trial conduct, so all the patients reached the six-month primary follow up. So we lost no patients to follow up, which was an advantage of the trial.

There were five patients that ended up crossing over from the sham group to ablation over the course of the trial. One was a protocol violation where the patient crossed over during the blank period itself. The other four were actually allowed. So we had very specific crossover criteria. Patients had to have at least two months of consecutively low AFEQT scores and then ultimately allowed to cross over. And of course they had to have recurrences so they reached the endpoints.

Here's what we saw. We saw a couple of things. First, for the first co-primary endpoint, which is freedom from AFib recurrence, the PFA group was superior to sham with a posterior probability of superiority greater than 99.99%. So it was a highly positive trial.

The second co-primary endpoint was change in AFEQT score. Again, it was the posterior probability of superiority was greater than 99.9%, with PFA being superior to sham. The absolute magnitude of difference between the two groups was about 40 points on the AFEQT score.

And just for reference, a change of five points or improvement in five points is thought to be significant. A change in about 19 points is thought to be a moderate improvement in quality of life. So this is a highly significant difference between groups.

Now in addition to the primary endpoints, we had several power secondary endpoints. One of them was change in AF burden. And we saw significant differences: when in the PFA group, the burden went almost down to 0, versus in the sham group, there was minimal change in AF burden which is sort of what you'd expect.

We were looking at psychological stress of atrial fibrillation. It's been well described that atrial fibrillation increases depression and anxiety. And there was one trial in the past called the REMEDIAL trial that showed that ablation, they were comparing to medications, but ablation was better than medications in terms of reducing the psychological stress.

So this is assessed by a score called the HADS score: HAD score. Now that trial, the REMEDIAL trial, was a good trial but it was not a blinded trial. Ours was a blinded trial, and one of our pre-specified secondary endpoints was to look for changes in the HAD score. And indeed there was a significant improvement in the HAD score in the PFA group compared to the sham group. So basically, for both of our primary and secondary endpoints we saw significant advantages of PFA over the sham group.

What do these findings mean for the future of PFA in clinical practice?

So a couple of things, I didn't really talk about the size of the trial, and I think one of the things just from a trial conduct that we were pretty happy with is we did the study with basically 61 patients.

So one patient had a positive EP study for an SVT and ruled out, the other 60 patients, randomised 30:30 into each group. And despite a relatively modest number of patients, because our inclusion was to take highly symptomatic patients, we saw significant differences in all these.

So, I think just from a trial conduct perspective, we're very happy about that design and how it turned out. In terms of the implications, I think this combined with the sham-PVI trial that was published last year, our trial, I would argue, updated it with pulsed field ablation technology, which is obviously where our field has moved toward.

I think this puts the issue to rest about a significant placebo effect in our ablation procedures, both from an AF recurrence perspective, quality-of-life perspective, psychological distress perspective.

What further research is needed in this area?

Well, I think in our highly symptomatic patients, I don't think we need any more sham controlled trials. I think this should be done. But look, there's lots of open questions. We know, for example, that if we take the asymptomatic patients, there's very little understood about what are the changes that occur if you do ablation versus non ablation.

I'm not saying we need a sham trial necessarily, but I am saying that there's a lot more research that we need to do because we've learned, for example, each day of [illegible] told us that rhythm control is good. But rhythm control was achieved using a combination, mostly drugs, but also some ablation.

We know that ablation in general works better than drugs, but making that next leap to saying, okay, then we should be considering ablation very early, even in these asymptomatic patients, I think that's something we need to understand better. So that's probably one of several areas where we need, and of course heart failure patients, and fortunately there's several heart failure trials that are starting up. So I think that's good news.