This transcript has been edited for clarity.
Konstantinos Siontis, MD: Greetings. I'm Kostas Siontis, an electrophysiology fellow at Mayo Clinic. During today's roundtable we will be discussing the CABANA trial.[1,2] I'm joined by Dr Doug Packer, Dr Tom Munger, and Dr Peter Noseworthy. Welcome, everyone.
Dr Munger, let me start with you. What was the CABANA trial and why was it done?
CABANA Overview
Thomas Munger, MD: CABANA was conceived by Doug more than a decade ago. The trial looked at mortality, stroke events, symptoms, and other endpoints in patients with atrial fibrillation (AF) and at least one risk factor for stroke who were randomized to ablation procedures or antiarrhythmic therapy.
Douglas Packer, MD: We wanted to study patients who had not been treated to a large extent. We wanted it to be an opportunity to really find out if there is a difference between those therapies.
Munger: The average age of the patients in the trial ended up being in the 60s.
Packer: Yes, the median age was 68 years in both groups.
Strengths and Limitations
Siontis: Dr Packer, what are the strengths and limitations of the CABANA trial?
Packer: CABANA is a great trial from the standpoint that it had 2200 patients, so it's probably the largest ablation trial that has ever been done. It enrolled well, albeit a little slowly, with more than 1000 patients in each arm. Some were randomized to drug therapy, some to overall ablative therapy. Ninety percent finished with a median follow-up of 48 months. I think a strength of CABANA is that it clearly demonstrates that ablation is substantially better than drug therapy for preventing the recurrence of AF. That is the strongest point. The second point is that it appears to be fairly safe. When we look at total mortality and hospitalization, patients who were ablated did better than those who were not.
The headlines about CABANA are about the primary endpoint. The primary endpoint was a composite of total mortality, disabling stroke, sudden death, or serious bleeding—things that have to do with AF treatment. In the primary endpoint, we did not see the difference that we thought we would. We did not see that ablation was going to be substantially better than drug therapy; they were fairly equivalent.
The most important secondary endpoint was the primary secondary endpoint of total mortality. That was done with the intention-to-treat approach, which is an important clinical trial statistical analysis tool. In a nutshell, if you use intention-to-treat, CABANA shows that mortality rates were about the same.
Take-Home Messages
Siontis: Dr Munger, considering all of the above, what does the CABANA trial mean for the practicing clinician, electrophysiologist, and general cardiologist?
Munger: The initial take-home points I got from CABANA were from some of the secondary endpoints that Doug mentioned in the intention-to-treat analysis. It confirmed that ablation reduces symptoms significantly, better than antiarrhythmic therapy. There were reduced hospitalizations in the ablation group compared with the drug arm. This is important for all clinicians because we are under the gun in trying to reduce hospitalizations and cost of medicine. The mortality signal was negative in the intention-to-treat analysis, but there are data looking at some of the patients who crossed over—how they did long-term and whether there was an effect on mortality.
New Questions
Siontis: Dr Packer, questions can come up after the first results of any clinical trial are presented. Tell us a little bit more about specific analyses, outcomes, and issues that came up and how you put this all together as the clinical trial was being presented.
Packer: With any clinical trial there can always be questions. Even before the trial came out, one of the questions was, what would quality of life look like? Would quality of life tell us anything? In point of fact, Dan Mark's work[3] found that quality of life was substantially better in those patients who were ablated, just like the issue of freedom from recurrence of AF. That is important.
This is a strategy trial, and it looks at an interventional approach. If it were a drug trial, this would have been easy because you randomize to one or the other, and most of the time, patients stay in their arm of randomization. That makes life substantially easier. In CABANA, 301 patients started out on drug therapy and crossed over because the drugs did not work, and 102 patients in the ablation arm did not get ablated. Immediately you have two crossover issues. Some patients checked out of the trial early. This creates a problem with intention-to-treat. That is the one area where intention-to-treat can actually be biased and can push towards the null. That is not intended to be a tremendous criticism of intention-to-treat; it is the way it should be. If you go to the text books or to different manuscripts, you will see that even intention-to-treat has some problems.
We looked at per-protocol or as-treated analyses. Per-protocol patients were randomized and stayed in their treatment arms. If they crossed over, they were taken out of the analysis. That means you are going to have fewer subjects, but it does not mean that you are going to lose the benefit of randomization. I think that is what some bloggers had trouble with early on in the trial. It's an explanatory analysis—not exploratory—and it gives you a fairly good idea of whether there really was a mortality benefit or not. The relative risk reductions for the primary endpoint and the secondary endpoint were on the order of 25%-45%.
It's fair to talk about that, and it's fair to point out that many of the early blogs did not have the data so they did not have anything to go by. Much of the information was wrong and it was not peer reviewed. At the end of the day, CABANA does say that there is a substantial benefit to patients treated with ablative therapy.
Real-World Outcomes of AF Ablation
Siontis: Dr Noseworthy, you recently led a large-scale analysis based on observational data and administrative claims database analysis, looking at the real-world outcomes of AF ablation and medications. What did this study tell us in addition to CABANA, and how does that tie into the findings of the CABANA trial?
Peter Noseworthy, MD: CABANA was one of the most hotly anticipated trials certainly in our career and in electrophysiology. A couple years ago, Dr Packer and I were talking at one of the CABANA meetings and I said, "What's it going to show? What's your hunch?" He said, "I don't know, but whatever it shows, it's going to raise as many questions as it does answers." And that was clear. If the trial hit it out of the park with a mortality benefit, people were going to ask whether the results were generalizable to everyday practice and to community practice outside of these expert centers. If there was an equivocal result, we were going to need more numbers. If there were interesting subgroups that could not be resolved with 1000 ablation patients, we would have to look.
We went to a large administrative national dataset with 180,000 patients with AF and it allowed us to answer a lot of those questions. We saw that about three quarters of patients in practice look like CABANA patients, so whatever you believe about CABANA, it's likely to be applicable to the patients we encounter in everyday practice. The remarkable thing was that the hazard ratio in our analysis was very similar to the per-protocol analysis. Patients selected for ablation in everyday practice look like those who underwent ablation in the trial and relative to medical therapy have very similar outcomes.
Last, we see that trial eligibility had a lot to do with the likelihood of a benefit of ablation, so patients who were lower-risk, who had no CHA2DS2VASc score risk factors, who were less than 65 years actually had very low event rates. Clinicians often ask, "If there is a hint of a mortality or stroke benefit with ablation, should we be ablating earlier? Should we try to ablate those people at 45 or 50 years old when they present, even if they are minimally symptomatic?" I take from our data that those patients have very low event rates, and we should focus on the things that we know benefit those patients—anticoagulation if indicated, risk-factor modifications, diet, exercise, etc—and then ablate for symptoms in those patients. It's a nice example of the complementary nature of observational data and randomized trial data; presenting these together rounds out a full picture of the data.
Siontis: That is extremely interesting, and we will definitely look forward to seeing those results fully published.
Safety Outcomes
Siontis: Dr Munger, does CABANA tell us anything about the safety of ablation and medications?
Munger: The ablation dataset in CABANA showed a really great safety profile for ablation. Of course, there have been data from registries and studies looking at populations and large datasets. The safety profile of ablation was actually quite remarkable. With the post–myocardial infarction trials from the '80s and '90s and the MUST (Multicenter Unsustained Tachycardia Trial Investigators) dataset from the early 2000s,[4] we clearly saw that antiarrhythmics have their own downsides, depending on the substrate of the patient.
Packer: We were a little bit surprised about the safety profile. Patients on drug therapy looked like they had been on amiodarone but they were not. With ablation, the only place where there really was an issue was perforation, and even those event rates were low. You may suppose that they were healthier patients, but they were not. They were 68 or older and their median CHA2DS2VASc score was 3, so they were not cherry-picked.
Final Thoughts
Siontis: Dr Packer, what are your final thoughts and overall high-level take-home points from the CABANA trial?
Packer: Using an intention-to-treat analysis with CABANA—which is the way you should start—we did not see that much more benefit with ablation than we did with drug therapy in the primary endpoint and in total mortality. They were about equivalent. In those regards, it suggests that the trial was indeterminate. It's important to keep in mind that it had a bit slower enrollment, and there were fewer events than what we had anticipated. But there was a substantial difference in that patients who were ablated had better freedom from recurrent AF and less mortality in composite with hospitalization. If you look at the per-protocol component of this, there was a clear difference with ablation versus patients who were treated with antiarrhythmic drugs. Again, that is where there is some conflict. More information will be coming out in manuscripts, and that will be incredibly helpful as we try to decide how to treat patients over the next decade.
Siontis: Great discussion. Thank you all for these very important insights, and thank you all for joining us on theheart.org on Medscape Cardiology.
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© 2019 Mayo Clinic
Cite this: Konstantinos Siontis, Douglas L. Packer, Thomas Munger, et. al. CABANA Post-publication Takeaways for Catheter Ablation of AF - Medscape - Mar 15, 2019.
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