Circulation June 21/28, 2022 Issue

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.