Jun 6, 2022
This week, please join author Ratika Parkash and Editorialist Sean D. Pokorney as they discuss the article "Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients with Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial" and the editorial "The Evidence Builds for Catheter Ablation for Atrial Fibrillation and Heart Failure."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Centre and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature discussion, oh, so exciting. We enter the month of June, and it pertains to heart failure and atrial fibrillation. And we are going to learn a little bit more from the RAFT-AF trial, involving randomizing patients to ablation and rhythm control, as opposed to just settling for rate control for patients with AFib. But before we do that, how about we grab a cup of coffee and start with some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
I absolutely would. And I will start by asking everyone a question. Could a single high-sensitivity cardiac troponin T level, below the limit of detection of six nanograms per liter, exclude an acute myocardial infarction? Well, you are going to find out because, remember that data for excluding AMI with a single high-sensitivity cardiac troponin level relies largely on the limit of detection, which is really a threshold of five nanograms per liter, which cannot be reported in the United States, per the FDA, because there, only the lowest reportable concentration is allowed, which is the limit of quantitation of six nanograms per liter.
Dr. Carolyn Lam:
So, today's authors Dr. Sandoval from Mayo Clinic and colleagues, very cleverly sought to determine whether a single high-sensitivity cardiac troponin T level below the limit of quantitation of six nanograms per liter could indeed identify patients at low risk for AMI.
Dr. Greg Hundley:
Very interesting, Carolyn. So we have the limit of quantitation and then the limit of detection. This is really intriguing. And of course, cardiac troponin T, as cardiologists, we receive a lot of requests for consults on this. So, what did this study find, Carolyn?
Dr. Carolyn Lam:
A total of over 85,000 patients were first evaluated in the CV data marked biomarker cohort, amongst which 29% had a baseline high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter. Among 11,962 patients with this baseline high-sensitivity cardiac troponin below six nanogram per liter and serial measurements, only 1.2% developed acute myocardial injury, resulting in a negative predictive value of 98.8% and a sensitivity of 99.6%.
Dr. Carolyn Lam:
In an adjudicated cohort, among those with a non-ischemic electrocardiogram, only 0.2% had myocardial infarction or death at 30 days. So in summary, Greg, this is the largest study evaluating a single high-sensitivity cardiac troponin T level below this limit of quantitation of six nanograms per liter to identify patients at low risk for AMI.
Dr. Carolyn Lam:
And indeed, the present study demonstrates that a single high-sensitivity cardiac troponin level below six nanogram per litter is a safe and rapid method to identify a substantial number of patients at very low risk for acute myocardial injury and infarction.
Dr. Greg Hundley:
Oh wow, Carolyn, really informative study. Well, Carolyn, my next study comes from the world of preclinical science. And Carolyn, vascular smooth muscle cell phenotypic switching contributes to cardiovascular diseases. And epigenetic regulation is emerging as a key regulatory mechanism with the methylcytosine dioxygenase Tet2, acting as a master regulator of the smooth muscle cell phenotype.
Dr. Greg Hundley:
The histone acetyltransferases, HATs p300, and CBP are highly homologous and often considered to be interchangeable. And their roles in smooth muscle cell phenotypic regulation are not known. So Carolyn, these authors led by Dr. Kathleen Martin from Yale University School of Medicine assessed the roles of p300 and CBP in human vascular smooth muscle cells with knockdown in inducible, smooth muscle specific knockout mice, and in samples of human intimal hyperplasia.
Dr. Carolyn Lam:
Cool, Greg. So what did they find?
Dr. Greg Hundley:
Right, Carolyn. So, they found that p300 and CBP serve non-redundant and opposing function in vascular smooth muscle cell phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with Tet2 or HDACs. And Carolyn, targeting specific histone acetyltransferases therefore may hold therapeutic promise for future cardiovascular disease interventions.
Dr. Carolyn Lam:
Oh, that's great, Greg. Well, to round it all up, there are some other papers in today's issue. There's a Research Letter from Professor Zhang, entitled “Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time-Window of Cardiomyocyte Proliferation and Myocardial Regeneration.” There's also a Research Letter from Dr. Vaduganathan, entitled “Estimating the Benefits of Combination Medical Therapy in Heart Failure with Mildly Reduced and Preserved Ejection Fraction.” Ah, that's such a cool issue. Now, let's go on to our feature discussion. Shall we, Greg?
Dr. Greg Hundley:
You bet, and learn a little bit more about rhythm versus rate control in patients with heart failure and atrial fibrillation.
Dr. Carolyn Lam:
Our feature discussion today is about the long-awaited results of the RAFT-AF trial, and that is the randomized ablation-based rhythm control versus rate control trial in patients with heart failure and atrial fibrillation. Thank you so much, Dr. Ratika Parkash for joining us today as the first and corresponding author from Queen Elizabeth II Health Sciences Center in Canada, as well as Dr. Sean Pokorney, the editorialist from Duke University.
Dr. Carolyn Lam:
I am so, so excited to be discussing this paper. I really meant it. You know, as a heart failure cardiologist, we've been waiting for these results and trying to understand everything in context. So maybe, Ratika, could you please start off by telling us about the RAFT-AF trial and what you found?
Dr. Ratika Parkash:
Thank you, Carolyn. I'm happy to be able to talk about this study on behalf of the RAFT-AF investigators and my co-PI, Dr. Anthony Tang. So the trial... First of all, the rationale for the study, I think many of us, as heart failure or heart rhythm specialists, understand that in the past, we've done many trials looking at rate versus rhythm control, the AFFIRM trial being the largest, and then of course, specifically in heart failure patients, the AF-CHF trial, both of which were negative in reducing cardiovascular events and mortality in patients with or without heart failure, in terms of a rate to rhythm control.
Dr. Ratika Parkash:
One of the issues with those trials is that the form of rhythm control was antiarrhythmic drugs. So we have learned that catheter ablation is superior to antiarrhythmic drugs in maintaining sinus rhythm. And based on that premise, we decided to go forward with the RAFT-AF study.
Dr. Carolyn Lam:
That's great, Ratika, so thanks. And what were the results?
Dr. Ratika Parkash:
The main finding, so the primary outcome of the study was mortality and heart failure events. Heart failure events was defined as a heart failure hospitalization or any escalation of heart failure therapy that was done in the outpatient settings, including the use of intravenous Lasix in an emergency department setting.
Dr. Ratika Parkash:
So the main findings were that ablation-based rhythm control was not statistically significant in reducing mortality and heart failure events over rate control in patients with atrial fibrillation and heart failure. The study included patients both with preserved ejection fraction, as well as reduced eject fraction. And we did stratify based on ejection fraction at the entry point into the trial. The hazard ratio was 0.71 and the 95% confidence interval just crossed unity, ranging from 0.49 to 1.03 with a P value of 0.066.
Dr. Carolyn Lam:
Oh, ouch. So, thank you. And again, truly, congratulations on a very, very important trial. Sean, I said it before, I'll say it again, really, really loved your editorial. Could you put these findings in the context of... Maybe, start with even the most recent guidelines, the 2022 ACC/AHA/HFSA heart failure guidelines, which I believe gives catheter ablation a class 2A recommendation. Maybe, start from there, and how does this fall in place?
Dr. Sean Pokorney:
Yeah, no, absolutely. I think, first of all, it's a really important trial and it's great to have this additional data. I do think, as you said, that it's important to understand the context. We now have several recent guidelines that have commented on the role of catheter ablation in patients with heart failure.
Dr. Sean Pokorney:
You mentioned the most recent heart failure guidelines. We also have additional AFib guidelines and we have the 2019 AHA/ACC/HRS guidelines for atrial fibrillation that give catheter ablation a 2B recommendation in patients who have heart failure, to potentially lower mortality and reduce hospitalization. And it has a 2A indication in the 2020 ESC guidelines. And we're currently undergoing some revisions of the guidelines for atrial fibrillation, and there'll be new guidelines around atrial fibrillation coming out from AHA/ACC/HRS in the coming years. And so that will also be helpful, I think, to incorporate some of this additional data.
Sean Pokorney:
When you really look at the guidelines and see what's driving the guidelines, there are several trials now that are really driving the guidelines. And so I think, looking back on the data, we have the AATAC trial, which was a trial of 203 patients that looked at ablation versus amiodarone. And we have the CASTLE-AF trial, which had 363 patients in it and was looking at atrial fibrillation in patients with heart failure with reduced ejection fraction and defibrillators.
Dr. Sean Pokorney:
And when you put that data into context, the AATAC trial did find lower rates of death and hospitalization as a secondary outcome, and CASTLE-AF did identify a reduction in heart failure hospitalizations and death. At the three year follow-up, there was a statistically significant reduction, although the event number was lower than the previously sort of calculated target sample size.
Dr. Sean Pokorney:
And so in aggregate, these trials do show a modest evidence of benefit for clinical outcomes in this population. And that's where adding more data is really critical.
Dr. Carolyn Lam:
That's so true. And actually, Ratika, is there any plan for some meta-analysis or sort of adding the data? And if you could, also speak to, the trial was interrupted at some point, so how that may have impacted things as well.
Dr. Ratika Parkash:
Those are important questions. So, first of all, there is a planned longer term follow-up for the study, to look at whether or not following these patients out beyond our meeting follow-up of 37 months, it will actually produce a different result than what we observed in the current findings.
Dr. Ratika Parkash:
I think a meta-analysis is obviously going to show benefit for ablation-based rhythm control, based on the data that Sean had just described. One of the things that we'd need to keep in mind is that this trial, the RAFT-AF study really enrolled patients who were suitable for either ablation-based rhythm control or rate control. So it wasn't a study that looked at rhythm control only.
Dr. Ratika Parkash:
So, the CASTLE-AF trial had essentially two rhythm control arms. The medical therapy arm was, was amiodarone in that trial, versus catheter ablation. So patients could get rhythm control in both. And so, the types of patients that would've gotten into CASTLE-AF were different than the patients in our trial, even when you look at the reduced ejection fraction patients.
Dr. Ratika Parkash:
Having said that, our curves, when you look at the reduced ejection fraction group in our study does mirror what was observed in CASTLE-AF. So, even if a patient is not deteriorating initially with rate control, it appears that over time they begin to deteriorate. And that's what all of these trials have shown, is that patients do better with ablation-based rhythm control, the best form of sinus rhythm maintenance that we have.
Dr. Ratika Parkash:
And it takes time for them to deteriorate and it takes time to accrue those events. And this is evident in all trials of atrial fibrillation. You either need a very large sample size, like 15,000 patients, to look at heart failure in a short period of time, or you follow them longer, so that you can accrue those events.
Dr. Ratika Parkash:
In terms of the stopping of the trial, certainly, had we reached the sample size of 600, which was the intended sample size after recalculation during the study from 1000 down to 600, I believe we would have reached a positive outcome. But again, we hope that our longer term follow-up might shed some light on that. The interruption of the study was based on the DSMC decision and certainly could have affected the power of the study.
Dr. Ratika Parkash:
We have to remember that the other possibilities are that ablation-based rhythm control is not superior to rate control. And as someone who is pro-ablation, it's difficult to say that, but we see hints of benefit and we have to recognize that.
Dr. Ratika Parkash:
The other issue is that the secondary endpoints in our trial were all significant, as overall, it doesn't matter which group you looked at, NT-proBNP, six-minute walk test, quality of life, both for heart failure and atrial fibrillation, as well as ejection fraction, were all improved. And for many of the studies that have been done previously, those were the primary endpoints of those studies.
Dr. Ratika Parkash:
The idea of whether ablation-based rhythm control reduces heart failure per se, is from our study, purely from our study, we can't be a hundred percent certain. There's definitely a hint of clinical benefit there. From all the secondary endpoints, which are the current guidelines, is what they indicate ablation should be done for, is to improve quality of life. Our study was certainly supportive of that.
Dr. Carolyn Lam:
You know, Sean, I especially appreciated your discussion of these issues, the early stopping of the trial, the secondary endpoints. Could you know, share some of those thoughts?
Dr. Sean Pokorney:
I think it's really an important topic. I think that, again, as Ratika said, part of why this trial is so important is that many of the previous trials that have been published and many of the data sets have really looked at rhythm control versus rhythm control in this population, even including the analysis from CABANA, which included almost 780 patients from CABANA that had heart failure. And in that population, they did show a reduction in the composite primary endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. And again, CABANA was, as well, a study of rhythm control with ablation versus medical therapy, most patients getting rhythm control in that medical therapy arm.
Dr. Sean Pokorney:
And so this data really is additive. I think that one of the challenges is always, how do we make sure to get the most information out of a clinical trial once we commit patients to that scientific process? And I think here, at least in retrospect, it's obviously unfortunate that the trial was stopped early. I think that more data would certainly be helpful.
Dr. Sean Pokorney:
I appreciate the fact that longer term data may help solve that gap and close that gap a little bit. I think that, I guess, it'd be interesting to hear from Ratika a little bit more about the process that was involved with interaction with the DSMC and stopping the trial.
Dr. Ratika Parkash:
Yeah. Thanks, Sean. That also is a very good question. The DSMC really evaluated the data, evaluated the progress of the trial, back in 2017. It had been six years since we'd started the study. The data they had, in fact, did not show any benefit to ablation-based rhythm control over rate control at the time. So the follow-up period at the time was around two years.
Dr. Ratika Parkash:
And again, if you look at our Kaplan-Meier curves, you can understand why they would have made that decision at the time, based on 363 patients for the data that was available to them. They had a futility index that they looked at. it was calculated. The cutoff for stopping of the study was 0.8, and it was 0.81. So, there was a 19% chance that the study was going to show any benefit. And based on that, plus the progress of the trial, they made a decision to stop the study.
Dr. Sean Pokorney:
Yeah. I think it's really important when we look at these decisions, that there was example when we talk about this in the editorial as well with the ISIS-2 trial, where early on in the data, ISIS-2 was a trial looking at aspirin versus placebo. And basically in that trial, when you looked early on at the events that were accumulating, there was really roughly no difference between aspirin and placebo. And ultimately, that trial became positive and was a really critical trial. And if it had been stopped at that point for futility, we wouldn't have had some really critical data.
Dr. Sean Pokorney:
So, it's always a challenging decision. And obviously, the decisions are trying to be made in the best interest of the patients. Here, it just shows how important this additional follow-up data is for this trial, for RAFT in particular. And ultimately, it'll be interesting to see, as you mentioned, as we add additional long-term follow-up, how that will affect the results.
Dr. Ratika Parkash:
Absolutely. So, we hope that our additional follow-up is of benefit to clarifying our results. The unfortunate issue, I agree, was the stopping of the study, but we do trust our DSMCs. We have them for a reason and they perform an important function. So, we have to pay attention of course, to how they see things and evaluate the... at the time.
Dr. Ratika Parkash:
The other thing we should keep in context is that ablation for those, that time period, is not the same as it is today. Our safety has improved. You may have noticed that there were some adverse events in the study with ablation, and we would expect it to actually be lower, but in this day and age, but at the time, contact force wasn't available.
Dr. Ratika Parkash:
There were some tools and techniques that we now have at our disposal, improved mapping systems and so on, that allow us to do a safer and more efficacious job. But even in the context of that, our sinus rhythm maintenance was almost 80 to 90% for patients that you wouldn't normally expect to have that much sinus rhythm.
Dr. Sean Pokorney:
Yeah. I think that's a really critical point. You made a lot of really important points there, actually. Obviously, the vision of the field of electrophysiology is shifting, as you mentioned. And with data from EAST-AFNET 4, we're really shifting towards earlier rhythm control, as well as additional ablation trials attest, stop AFib or stop AF.
Dr. Sean Pokorney:
So again, there have been several studies that have shown the benefits of earlier rhythm control, EAST-AFNET 4, I think, being obviously one of the most relevant, looking at addressing atrial fibrillation of population of patients who've been diagnosed within the last year, and showing that there was a benefit to rhythm control, although the majority of rhythm control in that study was antiarrhythmic medications.
Dr. Sean Pokorney:
I think in the heart failure population, the challenge with rhythm control is that we're a lot more limited in terms of the medical therapies that are available for these patients. And I think that's where ablation really plays in a more important role, because not only have you shown that it seems to be efficacious in this patient population, with a really high rate of rhythm control, but in a lot of these patients, it's often a safer alternative than antiarrhythmic therapy.
Dr. Ratika Parkash:
Absolutely. And we've already shown that amiodarone is ineffective in this population, in AF-CHF. So, using that drug does not seem to be, in a population that could go for an ablation, the appropriate approach.
Dr. Sean Pokorney:
Yeah. And as well, I think that's important. And when you look back at data from SCD-HeFT as well, there were some concerns with safety signals of amiodarone in patients with heart failure as well, from that study, again, likely related to the side effects of the medication itself.
Dr. Sean Pokorney:
So again, it is a complex patient population in terms of decision-making and management. And I do think, again, we talked a lot about the trial being stopped earlier than we would've ideally liked. I still think that the data that you guys produced is really important and critical and additive. Again, we're consistently seeing these modest treatment effects across multiple studies. And the fact that all the studies are pointing in the same direction is very reassuring.
Dr. Ratika Parkash:
Yeah. I was just going to comment on some of the points that Sean had raised, with respect to early rhythm control and the concept of atrial substrate, and how advanced atrial substrate with a negative remodeling effect in patients with heart failure or prolonged atrial fibrillation may not necessarily be in our patient's benefits to then try to intervene, and trying to get these patients early would be useful.
Dr. Ratika Parkash:
So in RAFT-AF, patients did not have to fail an antiarrhythmic drug in order to get into the study. So that, again, critical, very much along the lines of EAST-AFNET and EARLY-AF, which was also published, demonstrating benefit for early intervention.
Dr. Carolyn Lam:
Wow. Just, thank you so much, both of you. That was such a rich discussion, really, really unpacking very, very important elements of the trial, not just the trial results, but also the implications of what happens with trial conduct and execution and so on.
Dr. Carolyn Lam:
Again, thank you so much Ratika, for publishing this very important paper in circulation, Sean, for your beautiful editorial that put it all in context, the audience for listening today. From Greg and I, you've been listening to circulation on the run. Thank you for joining us today, and don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAJournals.org.