At Issue: CABANA sparks debate over appropriateness of ablation in AF

BOSTON — The results of the CABANA trial presented at the Heart Rhythm Society Annual Scientific Sessions ignited vigorous debate over whether catheter ablation is a better option than conventional drug therapy in patients with atrial fibrillation.

At a median follow-up of 4 years, for the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest, the difference between patients assigned ablation and those assigned drug therapy was not significant in the intention-to-treat analysis, but favored ablation in both the on-treatment analysis and the per-protocol analysis.

In the intention-to-treat analysis, the catheter ablation group had lower risk for death, disabling stroke, serious bleeding or cardiac arrest for all-cause mortality or CV hospitalization and less AF recurrence, but similar risk for all-cause mortality, disabling stroke, serious bleeding and cardiac arrest compared with the drug therapy group.

In the on-treatment analysis, all-cause mortality and death or CV hospitalization favored the ablation group, and in the per-protocol analysis, the treatment effect of catheter ablation for the primary outcome was even greater in those younger than 65 years.

The findings prompted discussion over whether the intention-to-treat analysis should hold sway and CABANA should be considered a negative trial, whether the on-treatment and per-protocol analyses should hold sway and CABANA should be considered a positive trial, or whether judgment should be withheld until the findings are published and more is learned about who benefited the most from ablation.

Here are insights from various experts interviewed by Cardiology Today during and after the meeting.

 

Until now, we have not had a randomized study evaluating ablation as a first approach that was large enough to look at stroke and mortality. When the data are published, I would love to see more about how the results differed by age. As people get older, they have more comorbidities and more reasons they could die aside from their arrhythmia, whereas younger people afflicted with these diseases may have arrhythmia as their only disease, which would be the entire source of the problem. There will be so much we will be able to learn from these data.

This may change my decision-making process as to who gets ablation. We can now tell patients that those who underwent the procedure did better. I will also tell them that if you include everybody, the results did not show as much of a difference. But physicians and patients will likely make the assumption that if you get the treatment, you might do better. Of course, I will not start strong-arming people to get ablation, because I did not see the stroke and mortality benefit in the entire population.

Christine M. Albert, MD, MPH

Director, Center for Arrhythmia Prevention
Brigham and Women’s Hospital
Professor of Medicine, Harvard Medical School

 Albert reports no relevant financial disclosures.

CABANA was the 800-lb gorilla at HRS. A ton of data were presented, but until the actual manuscript is published and we can pore over the data, it is going to be hard to say anything definitive.

The first controversy is whether we need to go by the intention-to-treat analysis or the on-treatment analysis. My personal belief is that a little bit of both is the right answer. The trial was less ablation vs. medication than it was a trial of ablation vs. an attempt at medication before moving on to ablation if necessary. In that setting, it is fair to say that as long as its framed as a trial of medication before ablation, given that almost one-third of the medication group eventually received ablation, the message is that it is reasonable to wait and try medicines before moving to ablation rather than going directly to ablation.

The headline coverage in the mainstream media has been a little disappointing, as several articles essentially said that ablation does not work. That’s very clearly not the takeaway if you look at the data. Even within the intention-to-treat analysis, there were endpoints that reached statistical significance, including the composite endpoint of CV hospitalization plus mortality.

 

Chirag R. Barbhaiya, MD

Cardiology Today Next Gen Innovator
Assistant Professor of Medicine, NYU Langone Health

 Barbhaiya reports he has received speaker fees/honoraria from Abbott, Medtronic and Zoll.

 

My take on CABANA is overall positive. We learned that patients who actually receive catheter ablation do far better than patients who don’t. The overall results were negative, almost certainly because of a very high rate of crossover from the medication arm to the ablation arm. But the on-treatment analysis demonstrated a mortality benefit with ablation.

I look forward to the formal publication and substudies to come. It appears that younger patients tended to derive more benefit from catheter ablation. The ultimate way to demonstrate benefit would be a sham-controlled AF ablation trial, where some patients receive a true AF ablation and others are put under general anesthesia and nothing is done. That would unequivocally demonstrate the value of AF ablation and silence the naysayers.

 

David S. Frankel, MD

Cardiology Today Next Gen Innovator
Assistant Professor of Medicine
Director, Cardiac Electrophysiology Fellowship Program
Hospital of the University of Pennsylvania

 Frankel reports no relevant financial disclosures.

 

 

Overall, we are excited for this pivotal trial to have come to its conclusion and are eager to accept the results. As presented, there was not an all-cause mortality advantage to ablation over medical therapy with antiarrhythmic or rate-control drugs in the population that was studied.

We have never had a trial of this type with average 4-year follow-up. Complications and efficacy were captured well.

We learned that there is not a mortality disadvantage to doing ablation, so it is good to know we are not hurting a group of patients. It takes trials this big and long to capture rare events. And sometimes when a trial comes up neutral like this, it provides equipoise. There is more than one valid option. There are some signals as to who may benefit most from ablation, which we will learn more about when the data are published.

Of note, there was a more than 30% reduction in the primary endpoint (mortality, disabling stroke, serious bleeding, cardiac arrest) in favor of ablation in the analysis of patients who actually received an ablation (on treatment analysis). That was important. 

As expected, people who had ablation were more likely to be in sinus rhythm and this confirmed over a very long follow-up that our procedures have efficacy.

For this trial, symptoms were not a prerequisite for getting into the study, so perhaps for older and truly asymptomatic patients, we don’t have to be as aggressive with ablation. There were some signals in subgroup analysis that patients over 75 may not benefit as much. Patients under 65 and those with congestive HF seemed to derive the most from ablation.

Clinically, this was an extremely important trial. It will change clinical practice. I feel in my practice that my AF patients who are younger, with HF and especially those with symptoms should be offered ablation and perhaps earlier. Older patients and especially those without a lot of symptoms may be managed more conservatively without denying them a mortality benefit.

John Holshouser, MD

Adult Cardiac Electrophysiologist
Sanger Heart & Vascular Center
Atrium Health

 Holshouser reports he was a site principal investigator for the CABANA trial.

The CABANA trial was important and in many ways supports what investigators have seen in other trials such as CASTLE-AF, which is that AF ablation particularly benefits those with HF.

In the intention-to-treat analysis, there was no significant difference between the groups in the primary endpoint or all-cause mortality, but there was a significant difference in favor of ablation for death or CV hospitalization as well as for AF recurrence. However, there was substantial crossover, which clearly had an impact on the overall results. When the results were analyzed based on the treatments people actually received, the significant differences bore out favoring ablation both for primary and secondary endpoints. On subgroup analysis, those who were younger or had HF seemed to benefit more from ablation.

CABANA is our first step in the right direction to determine who should get ablation. We need randomized, double-blind trials investigating the difference in hard outcomes between ablation and antiarrhythmic drug therapy. I look forward to seeing the published results where the data can be scrutinized in detail.

David S. Park, MD

Cardiology Today Next Gen Innovator
Assistant Professor of Medicine, NYU Langone Health

 Park reports no relevant financial disclosures.

 

These were long-awaited and very exciting results. There was a lot of crossover, and many patients (approximately 9%) assigned to ablation did not receive it. In addition, approximately 27% of patients randomly assigned to drug therapy crossed over to ablation. The primary outcome (composite of all-cause mortality, disabling stroke, serious bleeding or cardiac arrest) demonstrated no difference between drugs and ablation in an intention-to-treat analysis. You can’t benefit from ablation if you don’t receive an ablation. When the investigators looked at an analysis of patients who actually received ablation and compared them to patients who received drugs, the primary combined endpoint of death, stroke, cardiac arrest or serious bleeding was better in the ablation group. It’s hard to know how to interpret what has been publicized so far, without more details from the final manuscript. We also need more information about the drug group. Were they mostly on amiodarone? Were heart rates controlled?

There was also a suggestion that some subgroups, such as younger patients or those with HF, may derive greater benefit from ablation. We need to learn more about the benefit of ablation in younger patients. Was it because they are younger, or is it because older patients have longer-standing disease and may have more left atrial enlargement and more scarring that might make them worse candidates for ablation?

We need more data before we decide to change current practice. When further analyses are performed, we may find that certain subgroups of patients may benefit more than others. Some of it is likely to confirm things we already knew. For example, if you’re older and have had AF for a long time, you may have a lot of fibrosis or scarring with a large atrium and may be less likely to benefit from ablation. We need to see more details prior to changing current practice.

 

Andrea M. Russo, MD, FACC, FHRS

Cardiology Today Editorial Board Member
Cooper University Hospital
Cooper Medical School of Rowan University
Camden, New Jersey

 Russo reports she was a site investigator for the CABANA trial and has spoken for and received research grants from Medtronic.

 

The results of CABANA need to be interpreted considering that this study took a while to be completed and that there has been an evolution of catheter ablation techniques and technologies in the interim. Even though trying to stay scientifically pure mandates that we work with the results of the intention-to-treat analysis, I think it is important to recognize that much of these results are impacted by the magnitude of crossovers within this study. There will be appropriate arguments from both ends making either a case for the per-protocol analysis that shows the superiority of ablation across all hard endpoints, or emphasizing the neutral results shown by the intention-to-treat analysis. The devil is in the details and the publication will help us tease through some of this controversy.

Nevertheless, I see the cup half full at this stage. Whichever way you look at it, the CABANA study highlighted that AF ablation is safe. Also, we principally do these procedures for symptom relief and improving the quality of life of our patients. On this front, I think catheter ablation still stands tall.

Notably, the study also highlighted that there are certain vulnerable populations who will benefit from catheter ablation, namely patients with congestive HF or cardiomyopathies. This certainly reinforces the signal seen in CASTLE-AF and is another important take-home message.

 

Jagmeet P. Singh, MD, DPhil, FACC, FHRS

Cardiology Today Editorial Board Member
Massachusetts General Hospital Heart Center
Harvard Medical School

 Singh reports he receives consultant fees from Abbott, Boston Scientific, Biotronik, EBR, Impulse Dynamics, LivaNova, Medtronic and Toray Inc.

 

CABANA is a great study of more than 2,200 patients with AF randomly assigned to ablation or antiarrhythmic drugs. Fortunately, it is large and multicenter, which is not typical for studies of AF ablation. The patient population was reflective of what we see in clinical practice based on age and more than half having persistent AF. This population was not cherry-picked and had the typical risk factors for AF-related stroke. The primary endpoint was supposed to be all-cause mortality, but due to lower-than-expected event rates, it was changed to a composite of death, disabling stroke, serious bleeding or cardiac arrest.

The intention-to-treat analysis did not pan out, showing no significant differences between the treatment groups in the primary endpoint. We have to respect the results as they are if a trial is designed for an intention-to-treat analysis, but the data produced a wealth of knowledge that we can gain from. We should not be blinded from looking further into the data. Among people who actually received the treatment, there were differences in mortality and AF burden, among other things. This does not change the primary outcome of the trial, but we cannot dismiss the other data that may shed light on the impact of ablation.

From a practical point of view, many of the patients we see are very symptomatic with their AF. Many try medications that do not work, and some do not even want to commit to medication for the long term. Mortality rarely comes into the discussion about why to choose one strategy over the other. I tell patients who request ablation that the intention is not to take them off anticoagulants because they remain at high risk for stroke. Anticoagulant-related decisions will be based on CHA₂DS₂-VASc score and risk factors rather than the results of the ablation. Therefore, I am not sure how much the CABANA results will affect my discussions with patients.

It may be a good thing that the trial did not completely favor one strategy over the other. Had there been a clear victor, it could have made us comfortable with the status quo and taken away the urge to learn more and improve upon current ablation and medication treatments.

Ablation technologies now have many features that were not available during the conduct of CABANA. This allows us to perform safer procedures with better control. We are now learning about how to use artificial intelligence to make the best decisions based on physiology. CABANA is an indication that we are on the right track and need to move forward. It’s a reminder that we should not just treat rhythm, we need to look at the bigger picture with each patient. Lots of data show that lifestyle modification is just as important as ablation for these patients.

Khaldoun Tarakji, MD, MPH

Cardiology Today Next Gen Innovator
Staff Physician
Section of Electrophysiology and Pacing
Robert and Suzanne Tomsich Department of Cardiovascular Medicine
Sydell and Arnold Miller Family Heart & Vascular Institute
Cleveland Clinic

 Tarakji reports no relevant financial disclosures.

 

Reference:

Packer DL, et al. LBCT01-05. Presented at: Heart Rhythm Society Annual Scientific Sessions; May 9-12, 2018; Boston.