AF Ablation vs Drugs: Insights From CABANA Investigators

An Interview With Douglas Packer, MD, and Kerry Lee, PhD

Interviewer: John M. Mandrola, MD; Interviewees: Douglas L. Packer, MD; Kerry L. Lee, PhD


May 18, 2018

The following is an edited transcript of a Facebook Live interview conducted May 10, 2018, at the Heart Rhythm Scientific Sessions in Boston.

John M. Mandrola, MD: First of all, congratulations on accomplishing this. Completing the CABANA trial[1] is a great achievement.

Douglas L. Packer, MD

Douglas L. Packer, MD: It took some work to even design it. We still have a lot of analysis to do to peel out the issues of quality of life, health economics, and those sorts of things. It's not done yet.

Mandrola: Catheter ablation of atrial fibrillation (AF) versus best antiarrhythmic drug therapy: This is the question that CABANA asked, correct?

Packer: We wanted to know whether ablative therapy was better than the best drug therapy. We wanted to look at the primary endpoint of total mortality, disabling stroke, other bleeding, and cardiac arrest. We had a variety of secondary endpoints. One was mortality and another was the combination of total mortality and cardiovascular hospitalization. There's a variety of other endpoints, and then we get down to number eight, and that's recurrent AF. After that, we get to quality of life, healthcare economics, event rates, and those sorts of things.

You can say that this is a neutral study. I think that's missing the point. I think that there's a lot more to the study than that.

Mandrola: When CABANA started back in 2009 (I can remember this), it was started as a mortality trial—hard outcomes. But that changed.

Packer: We changed that in February 2013. It was recommended by the Data and Safety Monitoring Board (DSMB) because enrollment rates were slower and the event rates were lower [than expected]. We wanted to bring the trial home, so the recommendation was to flip the primary and secondary endpoints. You've seen that in a number of different trials; it's not new to CABANA. It's something that has happened at other institutions with a variety of different trials.

Mandrola: The investigators were blinded to the treatment at that time. Is that important?

Kerry L. Lee, PhD

Packer: That's incredibly important. If you're going to change anything in the trial, then the people who are making the decisions to change it better not know anything about the trial. No treatment-specific data were known to anybody involved in making those decisions. Kerry, would you like to comment on that?

Kerry L. Lee, PhD: I would just echo that and underscore the importance of that. This was a decision made by the leadership of the trial without any knowledge of the treatment-specific outcomes. They did have information about the overall aggregated mortality rate but no treatment-specific outcome data.

Neutral Primary Outcome ITT Analysis

Mandrola: The big news from today's presentation is that there was no statistical difference in the composite primary endpoint.

Packer: I think that if you look at the trial and if you look at that composite primary endpoint, there was no difference between ablation versus drug therapy. In that case, it's a neutral trial; everything hovered around the null, even though in the subgroup analyses there were some signals about some groups of patients that behaved differently. From the standpoint of an intention-to-treat (ITT) analysis, you can say that this is a neutral study. I think that's missing the point. I think that there's a lot more to the study than that.

Even in the ITT analysis, if you look at total mortality and cardiovascular hospitalization, there was a significant difference. There was a significant difference in recurrence of AF. There are still two endpoints that were quite different.

Then there is the question of what to do when you have the level of crossover [that we saw in the trial]. How do you analyze those patients? How do you make sense out of that, to make a decision about whether that affects the trial?

If they [trial participants] all stay in place, I would go with ITT every day of the week and twice on Sundays.

Mandrola: This gets to the question I want to ask: The original analysis is ITT; everybody stays in their treatment arm. You made a comment in the presentation that if you don't get ablation, you cannot benefit from it. That's where the per-protocol and as-treated analyses come in.

Packer: I'm not sure that I would say that ITT was the only intended analysis. We also had on-treatment analysis prespecified. We also had per-protocol prespecified to deal with the potential of crossovers, to deal with the issue of patients who didn't get ablated or patients who didn't go through with drug therapy.

High Crossover Rate

Mandrola: Crossovers go both ways.

Packer: That's absolutely right. In the ablation arm, 102 patients didn't get ablated. The main reason for that is that patients changed their minds, or a physician changed their mind for them. Or if you go to China or Korea, there are other conditions that are important there. [Editor's note: In Packer's HRS presentation, he said of these countries that often "if you don't go into the hospital with a bag of money, you will not get ablated."] On the other hand, 301 patients in the drug therapy arm switched over to ablation and they actually did better than their counterparts who didn't.

Mandrola: That's my next question. Weren't there significant differences with the patients who did get ablation?

Packer: There were significant differences in outcomes, not significant differences in demographics, history, or anything like that. If you are asking whether there's something different about the 102 patients who didn't get ablated, the good news is that the demographics and other considerations, such as the histories, were all the same but the outcomes were different. That's why I got into the on-treatment analysis; if you don't get the treatment, it's hard to know whether the treatment is going to do anything.

Kerry, would you like to comment on that?

Lee: [A high crossover rate] has the effect of potentially diminishing the benefit of the therapy when the treatment arms are compared according to ITT. As Doug has emphasized, the ITT comparisons are certainly important and we pay attention to those, but the study is more complex than a simple ITT comparison. In order to properly interpret the potential impact and benefits of ablation therapy, one has to do additional analyses, which is what we've done, but they were all prespecified.

Packer: I think one of the issues here is that ITT can be good news or bad news depending on what the patients are doing. If they all stay in place, I would go with ITT every day of the week and twice on Sundays. But it's not the only analysis, and other analyses have to be invoked. It's a bit misleading to say that it's the only way that trials can be assessed.

Depending on how the trial is rolling, you may need to look at an as-treated or ITT approach, and then sometimes per-protocol is actually helpful. The reason for the per-protocol analysis in the first place is that with the as-treated approach, you get stuck with the time-dependent covariate. Sometimes there are issues that come up when you do the time-dependent covariate analysis. It doesn't mean that the analysis is wrong. You have patients who have crossed over from drug to ablation. The per-protocol analysis looks only at patients who were in the drug arm. If they crossed over, then those patients were eliminated from consideration at the time of crossover.

Conversely, the as-treated analysis looks at patients who were ablated [regardless of original treatment assignment], so it gives a more pure look at ablation and drug therapy. If every trial that was ever done was very clear-cut, and if trial participants behaved the way that they should, an ITT analysis is a great approach, but it's not the only approach.

Ablation Safety

Mandrola: There's been a lot said about safety. I wanted to ask you about this, because one of the takes is that the complication rate was low and AF ablation is safe. I think that might be complicated too.

Packer: One of the things that you and I worry about every time we go into a cath lab is whether we're going to be able to deliver a therapy and that the therapy is going to be done effectively and safely. You want to know both going into it. The way that you know that is basically according to your past experience. If you've done 300 or 400 ablations, then you have 300 or 400 ablations' worth of experience, from the standpoint of both efficacy and safety.

Any cardiologist participating in the trial had to have done at least 100 ablations. There's a certain experience that those physicians would have had that's going to weigh in on the safety. The number of adverse outcomes was low. The numbers are in line with the international ablation registries and perhaps a little bit lower. I don't think [using experienced operators] negates the findings of CABANA; it demonstrates that there's a safety factor and that that actually went reasonably well.

Another point, though, would be that not every patient undergoing ablation is going to be in that risk range. If patients have a lot of comorbidities, maybe not. If a patient's 75 or 80 years old, maybe not. On the other hand, I don't think you can just look at your left pulmonary vein stenosis rate and use that to drive considerations about what event rates are going to be. To a patient who is 75 years and going to go through an ablation, safety is everything.

Subgroup Analyses

Mandrola: Let's move to the subgroup analysis. Looking at older patients, there was an interesting finding there.

Packer: One of the things that we saw in CABANA that maybe was a little bit surprising is that there is a difference in the patients who were younger than 65 years, those between 65 and 75 years, and those who were older than 75 years. Patients who were under the age of 65 did well [with ablation]. The 95% confidence intervals were away from null. If you look at those patients who were over the age of 75, particularly if you're looking at treatment received or if you look at them in the per-protocol analysis, they did better with drug therapy. They weren't in the group that did significantly better with an ablative approach.

It's a real problem if you try to make sweeping generalizations about the entire trial from any one of these cherry-picked points.

It's something we're going to have to look at. You and I are going to have to spend some time thinking about that one because you could conclude from that that nobody over the age of 75 years should be ablated. You could conclude from that that nobody under the age of 65 years should be treated with drugs. I think it's a real problem if you try to make sweeping generalizations about the entire trial from any one of these cherry-picked points. Same thing with patients who had heart failure. Same thing with patients who had class II or III heart failure. What I think it says is that CASTLE-AF[2] was probably right.

Another thing I think that we learned from CABANA is that patients do very well with an ablative approach regardless of how we looked at it, even with ITT; then there's maybe a 40% and a 50% reduction in relative risk. You can quibble about the time to first event. One of the things that we're going to be able to do with CABANA is to see, over time—from 0 to 48 months—whether that continues.

Ultimately, we're going to look and see what happened to the patients who were in sinus rhythm the longest, regardless of therapy, versus those who were in AF the longest. If you have patients who are in AF for a very long period of time, I suspect that they're not going to do as well, but that's something that we have to prove. That may be a better thing to look at than the time to first occurrence of AF.

Lee: John, can I just go back to the question you've raised about the elderly and the observed differences in outcomes depending on the ages of the patients? I just wanted to point out that this is subject to all of the perils that people are well aware of with subgroup analysis. There's a lot more that has to be done in order to sort those issues out. Those older patients may be different in other ways besides age, which had an impact on their risk and their outcomes when treated either with drugs or ablation.

It's important that those observations be appropriately qualified as a subgroup analysis. There's much more that we need to do in terms of looking at the issue of age or heart failure; there are other factors before we draw strong conclusions about the benefit, or the lack thereof, of ablation in those patients.

The Take-Home

Mandrola: Yes; before we make assumptions about heterogeneous treatment effects, we need more information. Meanwhile, give us your three or four take-home points from CABANA right now.

Packer: This is the first pass. It's going to take some period of time to go through all of the information. What does the trial say at this time? I don't think that the trial can be painted with one brush. It's too complicated for that. I don't think you can look at it and say that the ITT part was neutral and ergo the entire trial is negative. I think that that's a mistake. I think that there are benefits from the standpoint of patient benefit and safety and the composites of total mortality and hospitalization. Dan Mark will be doing further analyses on cost and on quality of life.

I would say that CABANA is the neutral trial that wasn't neutral.

I would say that CABANA is the neutral trial that wasn't neutral. I would say that there are parts of it that are neutral, fair enough, and there are parts of it that aren't. At the end of the day, you and I make decisions with individual patients and we make decisions about what is going to be the best way to treat them. They have opinions too. They may not care about CABANA or any other trial, or they may be very much informed by what we have seen.

Mandrola: I really appreciate the time. Thank you both for being with us.

The CABANA trial was supported by the National Heart, Lung, and Blood Institute; St. Jude Medical; Biosense Webster; Medtronic; and Boston Scientific.

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