Jun 20, 2022
This week, please join author Roderick Tung, editorialist William Stevenson, and Associate Editor Sami Viskin as they discuss the article "First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE-SCD Randomized Trial" and the editorial "Can Early Ablation of Ventricular Tachycardia Improve Survival?"
Dr. Greg Hundley:
Welcome listeners to this June 21st, 2022 issue of Circulation on the Run. And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Listeners, what a very interesting forum that we're going to have in this session today with Dr. Rod Tung, bringing us an article from first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy with concurrent defibrillator implantation. Some results from the Pause sudden cardiac death randomized clinical trial.
This article is really interesting because it is collecting data from multiple centers from multiple countries in Asia. But before we get to that article, why don't we grab a cup of coffee and go through some of the other articles in the issue? Well, the first is entitled cardiovascular magnetic resonance for rejection surveillance after cardiac transplantation. And it comes to us from Dr. Jim Pouliopoulos from the Victor Chang Cardiac Research Institute. In this study, CMR based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between cardiovascular magnetic resonance and endomyocardially based measures of cardiac rejection and determine the CMR cutoff values between various cardiac rejection grades.
Then after that, a prospective randomized noninferiority pilot study was undertaken in adult orthotopic heart transplant recipients who were randomized at four weeks post orthotopic heart transplant to either CMR or endomyocardially based rejection surveillance. And clinical endpoints were also assessed at 52 weeks. And so listeners, what did this investigative team find? Well, despite similarities in immunosuppression requirements, kidney function and mortality between the groups, the rates of hospitalization and the rates of infection were lower in the CMR group.
On 15 occasions, patients that were randomized to the CMR arm underwent endomyocardial biopsy for clarification or logistic reasons, representing a 94% reduction in the requirement for endomyocardially based surveillance. And so listeners, a noninvasive CMR based surveillance strategy for evidence of rejection in the first year after orthotopic heart transplantation is feasible. And interesting, listeners, these results really suggest the possibility for further studies to confirm whether CMR and perhaps in combination with other modalities could be used to survey orthotopic heart transplant patients for acute rejection without necessarily having to undergo endomycardial biopsy. There's an excellent editorial by Dr. Jim Fang from the University of Utah who also reviewed this paper.
Well, listeners, let's next turn to the world of preclinical science. And this paper comes to us from professor Simon Sedej from Medical University of Graz. It involves the insulin and insulin growth factor one or IGF-1 pathway. And that is known as a key regulator of cellular metabolism and aging. Now, although its inhibition promotes longevity across species, the effect of attenuated IGF-1 signaling on cardiac imaging really remains controversial. So what did the authors find? Well, they found that cardiomyocyte IGF-1R over expression in mice resulted in physiological hypertrophy and superior cardiac function in early life, but led to accelerated cardiac aging, heart failure and reduced lifespan in late life. Mechanistically, increased cardiomyocyte IGF-1R signaling accentuated cardiac dysfunction by reducing autophagy and mitochondrial oxidative capacity at old age, and therefore clinically pharmacologic inhibition of cardiac IGF-1R signaling in late life could suppress the age related deterioration of cardiac performance and perhaps increase lifespan. And therefore age should be considered as a major outcome determinant in future clinical trials, testing IGF-1R P13K inhibitors for cardiac benefits.
Well listeners, what is our next study? And this study is somewhat related to our feature discussion, which we'll get to in a few minutes. It's from Dr. Paolo Della Bella from San Rafael Hospital, and it is a two phase prospective multicenter randomized clinical trial that was performed to evaluate the benefit of ablation after first implantable cardiovert defibrillator, or ICD shock. And patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock. And that was phase A of the study. Then afterwards, they were re-consented and patients were randomly assigned in a one-to-one fashion in the second phase or phase B to immediate ablation. That's within two months from shock delivery or continuation of standard therapy.
And the primary endpoint of the study was a composite of death from any cause or hospitalization for worsening heart failure. And amiodarone intake was not allowed except for documented atrial tac-arrhythmias. So listeners, what were the results from this trial? Well, ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined endpoint of death or worsening heart failure for hospitalization, lower mortality and fewer ICD shocks. And these findings therefore provide support for considering ventricular tachycardia ablation after the first ICD shock.
Now this study and the feature which will be coming up in a few minutes is nicely reviewed in an editorial from Bill Stevenson at Vanderbilt University. Well listeners, what other articles are in this issue? Well, from the mail bag, we have a research letter from Professor Solomon entitled Health Status Trajectories Before and after hospitalization for Heart Failure. Also, there is a second research letter from Professor Eikelboom entitled Rivaroxaban 2.5 Milligrams Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients with Chronic Atherosclerosis. And then next there's an ECG challenge from Professor Rosenfeld entitled Around and Around, a Wide Complex Tachycardia.
Well listeners, what a great series of articles. And now we're going to get on and visit with Rod Tung, Sami Biskin and Bill Stevenson to evaluate first line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy, concurrent with defibrillator implantation.
Well, listeners, welcome to this June 21st feature discussion. And we're very fortunate today to have with us Dr. Roderick Tung from the University of Arizona in Phoenix. We also have our own associate editor, Dr. Sami Viskin from Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee. Welcome gentlemen. Well, Roderick, we're going to start with you. Rod, can you describe for us some of the background information that went into the construct of your study and what was the hypothesis that you wanted to address?
Dr. Roderick Tung:
Well, thank you, Greg, Pause is really the culmination of a lot of personal academic and cultural exchanges between many Asian centers and particularly in China. In terms of exchanges, where we would go across overseas, do a lot of different VT cases. And this all started in about 2013. And at that point in time, I was struck by a lot of differences that we were seeing, particularly whenever they wanted us to do a case, it tended to be a nonischemic etiology patient, and they always wanted to see some sort of epicardial procedure. And these are the ones that are enriched for epicardial substrates. As many listeners know, the ischemics tend to have more endocardially based scars. And that's why epicardial BT ablation is typically reserved for those that either have failed endocardial or those ARVC patients or non-ischemic cardiomyopathy.
So that was the first thing, is there's a paucity of ischemic cardiomyopathy in Asia, which is still inexplicable. The second thing that was really interesting in my observations going to Asia was that the defibrillator penetration and adoption is not widespread like it is in America. And in a very Amero-centric view, we always think that, oh, well, everything else is a departure from a standard of care. Well, when you look at 1.4 billion people, that's a really significant population at risk for sudden death that's not being treated the same way that we typically see it in a lot of Western cultures. So I felt like it was a perfect fertile grounds for clinical exploration. And that's really where Pause was born, is to be able to look at the impact of catheter ablation and ICD therapies on the risk of sudden death. And that's really how the trial began.
Dr. Greg Hundley:
And what was the hypothesis, Rod, that you wanted to address?
Dr. Roderick Tung:
Well, when we started designing Pause in 2014, 2015, there had only been two prior trials that were published and that was Smashed VT in New England Journal. And then there was VTAC by Karlheinz Cook in Lancet. So really the hypothesis was to be able to assess whether preemptive or first line catheter ablation at the time of defibrillator implantation, which is not what we do in the US, we usually wait till there's therapies, if that decreases the composite endpoint of recurrent VT cardiovascular hospitalization mortality.
Dr. Greg Hundley:
Very nice. And so describe for us, Rod, your study population, and then the design that you use to address the hypothesis.
Dr. Roderick Tung:
So this was a randomized controlled trial, multicenter across 11 centers in China, Korea, Japan, Taiwan. These were really well respected and regarded academic centers. I do want to give a shout out to many of them, Kyoko Sojima, who trained with Bill Stevenson, wrote so many seminal papers in VT. In Japan, Akid Nogogami who really was charged with and responsible for opacity some of the mechanisms of particular VT, then there's Yao Yin in Beijing who's done great work in atrial fibrillation, cardiac neuroablation. Ming Long Chen, Chan Yang Jeng. So some really great names, and it was done over 11 centers, one to one randomization between control, which was just ICD, and the active arm was ICD with catheter ablation within 90 days of the ICD implantation.
Dr. Greg Hundley:
And how many patients, and then what were your study results?
Dr. Roderick Tung:
So we ended up with 121 patients that were randomized, 61 versus 60, 180 were eligible and screened. And what was really also different about this trial compared to others is that we involved a non-randomized registry. Those were patients that refused to be randomized, and most typically didn't want to have a defibrillator. And that's where the cultural differences of ICD acceptance are different. For two reasons. Number one, physicians actually don't truly believe a lot of the defibrillator data is relevant to non ischemics in Asia and the Asian population. So there's actually a little bit of an academic barrier of generalizing historical ICD data to Asia, which I observed with a lot of the physicians.
And number two, patients sometimes don't want that technology in there, and they have different ideas of sudden death. So these patients were actually put into a registry and followed prospectively with catheter ablation alone without background ICD therapy. And that's very unique because the amount of data that has been prospectively followed for ablation sans ICD therapy is very few. So that was 47 in the registry. And there was 121 that was one to one randomized.
Dr. Greg Hundley:
And what did you find?
Dr. Roderick Tung:
Well, we found that those that underwent concomitant ablation with their ICD implantation that presented with monomorphic VT had a lower rate of the composite triple endpoint of VT recurrence, cardiovascular hospitalization, and death. This was largely driven by a nearly 20% absolute risk reduction in VT recurrence. There was a 4% absolute risk reduction in cardiovascular hospitalization, but this is not significant. And mortality rates were low. It was seven and 8% in those arms. So one of the things that we were hoping to get to was actually looking at mortality, but I think this is challenging with background ICD therapy there. And number two, it's challenging because mortality rates are lower in non-ischemic cardiomyopathy. And that's because they don't have the concomitant comorbidities of peripheral vascular disease, coronary artery disease, older age, cetera. So we actually had a pretty low rate of mortality, which we were hoping to get to, but that wasn't able to be assessed in this because of the low rates.
Dr. Greg Hundley:
Very nice. Well, now listeners, we're going to turn to our own associate editor, Dr. Sami Biskin. And Sami, many papers come across your desk. What attracted you to this particular study?
Dr. Sami Viskin:
Well, we need to better define what is the optimal timing for VT ablation in patients with the organic heart disease. As we have seen many patients that are referred too late for ablation, where they already have an arrhythmic storm and recurrent shocks. And on the other hand, we have seen studies like the Berlin Study from Cook that fail to show any benefit on endpoints like heart failure or mortality. So the study by Tung arrived shortly after the different study by Paolo Della Bella, the PARTITA study, that was also studying patients at an earlier stage. So in the Partita study, they were studying patients at the time of the first ICD shock. And then Rod came with this study where he studied patients at the time of ICD implantation.
Now, usually authors ask to get an executive review of their article. In this occasion, we as the editors, we saw the opportunity and asked Rod to submit his paper as fast as possible and made the correction as soon as possible so we could get the two papers dealing with early VT ablation in the same issue with an invited editorial by Dr. Stevenson so we could put everything in context.
Dr. Greg Hundley:
Very nice. Well, Bill, Sami has set you up very nicely here. And as the editorialist, help us put these results from Rod into the context of what we know already today in this sphere of investigation pertaining to VT shocks, defibrillator implantation.
Dr. William Stevenson:
Yeah. So first I want to congratulate Rod on a very important study. It has been so difficult to conduct randomized trials of VT ablation and intervention, and to be able to bring this to fruition and internationally in Asia is really quite an accomplishment. We definitely need more information that guides us as to when VT ablation should be performed in people who have defibrillators and are having spontaneous episodes of VT. And we know that in patients with ischemic heart disease, with coronary artery disease, post infarct VTs, that catheter ablation can reduce the episodes of recurrent VT and reduce shocks from VT. And this is a very important quality of life issue for patients with defibrillators. But we haven't really had good data, certainly not randomized multicenter data in other patient populations. And we still are grappling with, does a reduction in VT episodes improve other outcome measures?
Does it really improve quality of life? Does it reduce hospitalizations? Does it translate to a reduction in mortality? And so Rod's study, one of the strengths of it being in Asia is that there were a lot of patients who had non-ischemic causes of heart disease. And more than a third of patients had arrhythmogenic right ventricular cardiomyopathy, and his study makes it clear that those patients really benefit substantially with a reduction in VT episodes. And that overall, VT episodes are reduced in all three of the subgroups of different diseases, the ARVC and the ischemics and the non ischemics that were included in the trial. But I think it's worth digging in a little more to the non-ischemics, because they did not seem to receive the benefit that the arrhythmogenic right ventricular cardiomyopathy and the ischemic cardiomyopathy patients received. So that the efficacy was largely driven by the benefit in the ischemics and the ARVC patients.
So one of the important considerations I think is when you're in your office with a patient who has a defibrillator and has had episodes of VT, and you're considering does this patient need a VT ablation? I think that if they've got ischemic cardiomyopathy, this data strongly supports that approach. If they've got arrhythmogenic right ventricular cardiomyopathy, again, ablation is very likely to reduce their episodes of VT/ for the non-ischemic group, which is about a third of the patient population that Rod studied, the data are less convincing in that group. And we know that's a harder group to achieve success with, with ablation. So we'll definitely want more data in that group. And I'm looking forward to some of the more detailed and sub-study sorts of analyses that I'm sure Rod is planning.
Dr. Greg Hundley:
Very nice, Bill. Well, listeners, and Bill you've teed it up nicely to really sort of circle back through each of you and ask, what is the next study to be performed in this space? So we'll start with Rod and then Sami, and then finish up with you, Bill. So Rod, what is the next study that you see needs to be performed really in follow up to yours?
Dr. Roderick Tung:
Well, we're thinking Pause too might be a nice just ARVC study alone, because again, inexplicably, there's a very high incidence of ARVC in Asia, and I was always taught that this was a disease from the Veneto region of Italy. And that might not be the case, or there's a lot of sarcoid mimicking of it as ARVC and undiagnosed. But we're thinking about a Pause too being an ARVC study, maybe without background I,CD therapy with background ICD therapy, this might provide justification for that. Because again, those in the registry did quite well, but that's because they were younger and had ARVC and normal LV function. So that might be a nice area to explore worldwide. And then lastly, just to put things in perspective for the Circ listeners, you need 8,400 patients in paradigm to show benefit mortality and heart failure hospitalization for an ARNI. Right? For IRNESTO.
We're talking about 120 patient studies when we talk about VT ablation, with these very complex ablation trials. So I think we just need larger trials. And the hard thing for us as VT ablation centers is we often will get patients that have had recurrent VT after a failed procedure. So it's hard to come by these that are very early, but I think we need 500 patient studies, a thousand patient studies. And also for the listeners, it's very hard to show mortality reduction with a background ICD therapy. And that's the problem, is that ICD is so effective as an abortive treatment that it's very hard to show reduction and mortality. You'd have to show it in terms of heart failure.
Dr. Greg Hundley:
Very nice, Rod. And Sami, what would you like to add?
Dr. Sami Viskin:
Oh, obviously the last word on the optimal timing of VT ablation is not out there. And we need more studies to really define when is the appropriate time for the VT ablation. That's what we need.
Dr. Greg Hundley:
Very good. And Bill?
Dr. William Stevenson:
Yeah, I agree with Sami. And with rod, we need larger studies to assess the benefit, to really help guide our clinical decision making that can get at quality of life issues as well as the mortality and cardiovascular hospitalization issues in even more detail. But this is a wonderful first initial step into the ischemic, non-ischemic and ARVC populations.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Rod Tung from university of Arizona, Phoenix, Dr. Sami Viskin from the Tel Aviv Medical Center in Tel Aviv, Israel, and Dr. Bill Stevenson from Vanderbilt University in Nashville, Tennessee, for bringing us this study that highlighting among patients, particularly with ARVC in an ischemic cardiomyopathy from Asia across multiple centers in different countries that early catheter ablation performed at the time of ICD implantation really reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. And these findings were really nicely driven by a reduction in the ICD therapies. Well, on behalf of Carolyn and myself, I want to wish you a great week and we will catch you next week, on the run.
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.