John M. Mandrola, MD: Hi, everyone. This is John Mandrola from theheart.org | Medscape Cardiology, and I'm at the Heart Rhythm Society meeting in Boston, where the extremely important CABANA trial was presented. I'm pleased to be joined by my friend, Dhiraj Gupta, who is an accomplished academic and clinical electrophysiologist from the UK at the Liverpool Heart and Chest Institute. Welcome, Dhiraj.
Dhiraj Gupta, MD, DM, FRCP: Thank you, John.
Mandrola: CABANA: Why is this ablation-versus-drug trial so important?
Gupta: To put it into perspective, I've been a practicing electrophysiologist for 10 years, and more than half of my practicing life has been spent waiting for the CABANA results, because ablation of atrial fibrillation (AF) is big business. There are hundreds of thousands of procedures done every year worldwide. The volumes are growing 10%, 15%, to 20% every year. It's by far the largest chunk of our practice.
While we do it to improve symptoms, and a lot of people who undergo ablation do feel better, what we haven't known until now is whether we are making any difference to hard endpoints such as stroke, serious bleeding, and mortality. CABANA was the trial to look at the hard endpoints.
Mandrola: That's a critical point. The question that CABANA was trying to answer is whether AF ablation improves outcomes in patients with atrial fibrillation. How did they go about answering this? It's a big global trial.
Gupta: It was actually planned to be even bigger than it turned out to be because of difficulties in recruitment. Essentially, it was a trial looking at a high-risk population of AF patients randomized to catheter ablation for AF or drug therapy. The primary endpoint initially was all-cause mortality, which is the ultimate hard endpoint. A couple of years ago they changed the primary endpoint to a composite of mortality, serious bleeding, stroke, and hospitalizations.
Recruitment took much longer than initially planned because, for better or for worse, AF ablation has become such an important part of our practice that a lot of electrophysiologists like myself believe in AF ablation. A lot of the patients believed in AF ablation so much that they were unwilling to be randomized.
Mandrola: I talked with the primary investigator, Dr Packer, who said that one of the reasons the primary endpoint was changed was slow enrollment. The other was low outcomes. Maybe the slow enrollment was due to the fact that we think that AF ablation is beneficial.
Gupta: Most of us electrophysiologists would not be doing ablation unless we were convinced about the benefit. Having said that, this trial needed to be done, because nowadays we are being referred patients who are less symptomatic than they used to be 5 or 10 years ago, because of the belief that we're making a difference to hard outcomes even though that had never really been studied.
There was a recent trial, CASTLE-AF, but that was only in patients with heart failure. We get referred patients who are not quite in heart failure, young patients with persistent atrial fibrillation, patients who don't want to be on antiarrhythmic drugs, patients who don't want to be on anticoagulant drugs. Whether ablation really makes a difference to them was what CABANA was looking to answer.
Mandrola: The primary endpoint was a composite of mortality, disabling stroke, major bleeding, and cardiac arrest. There was no difference with ablation versus drugs in the intention-to-treat analysis.
The Purist Approach vs On-Treatment Analysis
Gupta: Correct. If you look at the intention-to-treat results, they were all a bit underwhelming, if I'm honest, because there was no difference. Whichever way you look at the data, the Kaplan-Meier curves were identical; there was no difference with catheter ablation compared with drug therapy. The problem was if you look at intention-to-treat.
Mandrola: Let me slow you down there. The intention-to-treat analysis is where patients get counted in the arm that they were assigned [regardless of treatment received]. But there were a lot of crossovers, which led to different analyses, such as on-treatment. As Dr Packer said, you can't benefit from ablation unless you get ablation. CABANA is complicated, so tell us about the other results.
Gupta: There were about 1000 patients in both arms, but up to a third of patients who were randomized to drug therapy actually crossed over and had catheter ablation. A tenth of the patients who were in the catheter ablation arm said, "No, we're not getting the catheter ablation, thank you very much; we're going for drug therapy," so 40% of the 2000 patients in the trial didn't end up getting the treatment they were assigned to. [Editor’s Note: The 27 .5 % of the medical therapy group that eventually crossed over to ablation had received medical therapy]
Obviously, if you're looking at intention-to-treat, you're analyzing the results according to the arm they're randomized to, and not necessarily the treatment they ended up getting. Some people might say that a more accurate way to analyze the data is with an on-treatment analysis. When you compare the outcomes of people who actually ended up getting ablation with people who ended up getting drugs, there are differences in the two groups.
Mandrola: There're pretty significant differences; the ablation arm looked like it did better in the patients who got ablation.
Gupta: Correct. From that point of view, we all will agree with Dr Packer, that if you are testing ablation versus drug therapy, you ought to include patients who ended up getting the ablation. In the on-treatment analysis, there was a considerable improvement in hard endpoints with ablation compared with patients who were on drug therapy.
Mandrola: Wouldn't a purist, somebody like Professor Darrel Francis and other trialists, say that maybe these crossover patients have other factors that are different, and isn't that what randomization is for? I'm asking.
Gupta: I'm not a statistician; I am a jobbing electrophysiologist, and I tend to agree with that. If you are being true to science, you ought to stick to the results and present them as intention-to-treat. Having said that, when there is so much crossover, it makes that kind of analysis very difficult to make sense of. I think in this particular trial, an exception can be made.
Heart Failure and Age Subgroups
Mandrola: I want to ask you about a couple of subgroups. Patients who had heart failure seemed to do better with ablation—again, hypothesis-generating, but that's similar to what CASTLE-AF found. What are your thoughts about that?
Gupta: We all believe that patients with AF and heart failure form a distinct subgroup. These are the patients who really need sinus rhythm. They need the atrial transport that comes with sinus rhythm. CASTLE-AF showed a significant mortality benefit in these patients when they had catheter ablation. In fact, CASTLE-AF was one trial out of many smaller trials[4,5] that had shown similar signals.
The fact that the CABANA subgroup analysis shows a similar trend is reassuring. All trials seem to be pointing in the same direction. For most electrophysiologists, what that means is that we should probably be more aggressive in trying to get a patient with AF and heart failure to sinus rhythm than somebody who doesn't have heart failure.
Mandrola: In another subgroup analysis, patients under the age of 65 years did well with ablation, but on the other hand, patients over the age of 75 years did worse. Again, we can't draw too many conclusions. To me, it makes common sense that older patients might do worse with ablation.
Gupta: Obviously we have to see the full paper when it's published, but my initial thoughts on that are twofold. First of all, the older patients have competing causes of mortality. They have comorbidities much more often than younger people do. It's difficult for one particular strategy, such as AF ablation, to make a difference to a wide composite endpoint.
The second reason is one that I'm sure you recognize as an electrophysiologist: The results of AF ablation are a lot better in young people compared with older people. If you're getting poorer results, and they've got competing causes for those primary endpoints, it's no surprise that older patients did not do as well.
Mandrola: Before we get into the clinical implications, I want to ask you about safety. One of the headlines will be that ablation was safe, because the complication rates were low. I think that's complicated too. Do you agree?
Gupta: Yes, I do. By and large, AF ablation has become a lot safer now than it was 10 years ago. There's no question about it—as long as the procedures are done in high-volume centers and in experienced hands. That seems to be the case in Europe and in the UK. Speaking to my colleagues in the US, that's perhaps not quite so much [the case] here. Don't forget that in CABANA, all of these were largely academic centers, so these were high-volume centers. And so it's no surprise that the complication rates were so low.
My concern is that if the CABANA results are extrapolated and every center starts offering AF ablation irrespective of their experience level or their volumes, those low complication rates may not be replicated.
What Does It Mean Now?
Mandrola: Exactly. We have to wait for the paper, of course, but what do you think CABANA means for AF ablation, for AF patients, and the electrophysiology community at large?
Gupta: The electrophysiology community, by and large, falls into two groups. The large group is the believers in AF ablation, and they will look only at the on-treatment results and say it proves what we've always known: that AF ablation works. There is a smaller group of people who are still not convinced, and they will take the purist point of view. They'll look at the intention-to-treat results and say that perhaps there's equipoise there.
Most important, what does it mean for patients? We have to see the full paper. But for me, younger people, people with heart failure, people who have more to gain over a longer period with sinus rhythm, should probably have a lower threshold for AF ablation, especially if they're symptomatic anyway. I'm not going to be offering asymptomatic patients AF ablation based on CABANA yet. For patients who are minimally symptomatic, this trial would support my proactive approach in offering them AF ablation.
Mandrola: Final thing: If there's minimal mortality benefit, minimal stroke benefit, and most of the benefit looks like it's in quality of life and subjective outcomes—for instance, cardiovascular hospitalization is a subjective outcome—what do you think the next step is?
Gupta: It's interesting, isn't it, that a lot of people believe that there's a very strong placebo element in the improvement seen with AF ablation. We all know that. We all have patients who come to us thanking us because we have changed their life, and then you look at the ECG and it still shows AF. The fact of the matter is that most cardiovascular interventions will have a very strong placebo element to them, and there is no surprise that that's true of AF ablation as well.
It would be really good if we could design a trial that could tease out that placebo element and then show AF ablation in a truly honest light. We all also have patients with defibrillators or pacemakers, and we can see that the AF melts away following ablation. How much of the improvement in AF ablation is because of that real decrease in AF incidence, and how much of it is placebo? Perhaps we need to design a trial for that?
Mandrola: Excellent. Dhiraj, thank you for being with us. I really appreciate your time.
Gupta: You're welcome. Thank you for having me here.
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Cite this: What Is the Role of Ablation for AF in a Post-CABANA World? - Medscape - May 21, 2018.