Circulation January 28, 2020 Issue

Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly
podcast summary and backstage pass to the journal and its
editors. I'm Dr Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg Hundley: I'm Dr Greg Hundley, also Associate Editor, the
Director of the Pauley Heart Center at VCU Health in Richmond,
Virginia.


Dr Carolyn Lam: Say, Greg, you know the feature paper this week
talks about the perennially hot topic now and that is
transcatheter aortic valve replacement or TAVR or TAVI. It's
actually data from the France TAVI Registry comparing balloon
expandable versus self-expanding transcatheter aortic valve
replacement.


I'm sure you want to hear more about it, but first I'm going to
tell you about another paper in the same issue, this time also
comparing a balloon expandable versus a self-expanding
transcatheter aortic valve implantation, but data from a
nationwide analysis and from corresponding author Dr Fauchier
from Centre Hospitalier Universitaire Trousseau. He and his
colleagues basically did a head to head comparison of the two
competing transcatheter aortic valve replacement technologies
that have been published but have not really been followed for
long-term clinical outcomes. This was comparing balloon
expandable versus self-expanding technology.


They collected information from more than 31,000 consecutive
patients treated with Tavern in France between 2014 and 2018 and
based this on the French administrative hospital discharge
database. They did propensity score matching, which was used for
the analysis of outcomes according to the Sapien 3 balloon
expandable versus the Evolut R self-expanding TAVR technology and
studied this as nationwide level in France.


Dr Greg Hundley: Wow. Carolyn, 31,000 patients. That's a really
large study. What did they find?


Dr Carolyn Lam: They basically found that balloon expandable TAVR
was associated with lower mortality rehospitalization heart
failure and pacemaker implantation compared with the
self-expanding TAVR. Now, that's of course a pretty big finding
and this is discussed along with the feature paper that we're
going to hear about in an editorial by Drs. Abdel-Wahab and
Thiele from Heart Center Leipzig.


I want to tell you about another paper before I let you tell you
about yours, okay?


Dr Greg Hundley: Sounds great, Carolyn.


Dr Carolyn Lam: Greg, what is your clinical impression of Impella
use in the United States among patients undergoing PCI? Do you
think it's increasing or decreasing over time? As a reminder,
Impella was approved for mechanical circulatory support in 2008,
so from then, what do you think?


Dr Greg Hundley: You know, Carolyn, I really think it's
increasing, especially used more frequently rather than an
intra-aortic balloon pump. How about you? What's going on in your
area of the world?


Dr Carolyn Lam: My impression too, but you know, you're lucky
because we now have data looking at the trends in Impella use,
but in the United States, and this comes from the corresponding
author, Dr Amit Amin from Washington University School of
Medicine and colleagues who describe clinical outcomes and costs
across U.S. hospitals in PCI patients treated with mechanical
circulatory support, which is either the Impella or the
intra-aortic balloon pump.


They found that among more than 48,300 real world patients
undergoing PCI with mechanical circulatory support at 432
hospitals between 2004 and 2016 in the Premier Healthcare
Database, Impella use was indeed found to be rapidly increasing
with marked variability across hospitals and not only its use,
but also in its associated adverse outcomes. When analyzed by
time periods or at the level of the hospitals or at the level of
the patients, Impella use was associated with higher rates of
adverse events and higher hospital costs.


Dr Greg Hundley: You know, I wasn't thinking about the higher
rate of adverse events. You wonder sometimes, are we using a
technology in a sicker group of patients? Did this study shine
any light on that?


Dr Carolyn Lam: Those are great, great thoughts. The authors
concluded that the variability in Impella use, the variability in
its associated outcomes, and the association of Impella use with
higher adverse events and costs really, really underscore the
need for better defining of the appropriate use of mechanical
circulatory devices and that was what you indicated as well,
Greg, and what we need there is adequately powered randomized
clinical trials and prospective real world evidence, which we
don't quite have yet. Until then, perhaps a more measured
approach is needed in clinical practice that balances risks
versus benefits in complex patients undergoing PCI who require
mechanical circulatory support.


Dr Greg Hundley: That's going to be really needed, I think in
this era, especially with the results from this study. Well,
Carolyn, I'm going to switch over to the world of basic science
and the first study I'm going to talk about is from Dr Richard
Lee from Harvard University and it's a very interesting study.
Just as some background, current differentiation protocols to
produce cardiomyocytes from human induced pluripotent stem cells
are capable of generating highly pure cardiomyocyte populations,
but these cardiomyocytes remain immature and they really more
closely resemble the fetal state.


As a result, they have a lower maximum contractile force, slower
upstroke velocity, and immature mitochondrial function compared
to adult cardiomyocytes. Also, they're prone to ventricular
arrhythmias. During development, cardiomyocytes undergo a shift
from a proliferative state in the fetus to a more mature but
quiescent state after birth. The mechanistic target of Rapamycin
mTOR signaling pathway plays a key role in nutrient sensing and
growth, and Dr Lee and colleagues hypothesized that transient
inhibition of the mTOR signaling pathway could lead
cardiomyocytes to a quiescent state and enhance cardiomyocyte
maturation.


Dr Carolyn Lam: Wow Greg, I really love the way you explained
that. That's so interesting. What did they find?


Dr Greg Hundley: Among human induced pluripotent stem cell lines,
transient treatment with Torin 1, an inhibitor of the mTOR
pathway, shifted cells to a quiescent state and enhanced their
cardiomyocyte maturity. Also, the investigative team suggests
that further testing will be necessary to evaluate whether
delivery of Torin 1 treated cardiomyocytes could reduce the risk
of ventricular arrhythmias in newly differentiated myocytes
derived from pluripotent stem cells. Really an important advance
in this whole area of developing mature cardiomyocytes from our
own pluripotent stem cells.


Well, Carolyn, my second basic science paper comes from Dr Calum
MacRae from Brigham And Women's Hospital, also at the Harvard
Medical School. Carolyn, this study used both highly purified
human pluripotent stem cell derived cardiomyocytes displaying
physiological and molecular characteristics of atrial cells with
human MYL4 mutations in a zebrafish MYL4 knockout model, which
exhibited molecular, cellular, and physiologic abnormalities that
parallel those in humans bearing the cognate mutations associated
with definitive genetic causes of atrial fibrillation.


Dr Carolyn Lam: Oh, that's really interesting. Is this new
genetic predispositions that they discovered?


Dr Greg Hundley: I think the answer's yes. They found there was
evidence of increased retinoic acid signaling in both human
pluripotent stem cell derived cardiomyocytes and zebrafish mutant
models, as well as abnormal expression and localization of
cytoskeletal proteins and loss of intracellular NAD and NADH, and
thereby established a mechanistic link between the
transcriptional, metabolic, and electrical pathways previously
implicated in the atrial fibrillation substrate of MYL4. In the
future, these data could lead to novel therapies for some
patients with atrial fibrillation.


Dr Carolyn Lam: Wow. That really is fascinating, Greg. Well, let
me round up by telling you about some of the other things in the
issue. There is a research letter by Dr Parish on the effects of
Omega-3 fatty acid supplements on arrhythmias and here, these
authors reported more comprehensively on atrial fibrillation and
other arrhythmias using additional data extracted from linked
electronic health records in the ASCEND trial, remember, which
was 1 gram of Omega-3 fatty acid supplementation daily in people
with diabetes but without known atherosclerotic cardiovascular
disease.


Dr Greg Hundley: Oh wow. That's fantastic, Carolyn. I've got a
couple other really interesting articles in the issue. First
there's an In Depth review from Dr Yvan Devaux from Luxembourg
Institute of Health, and he discusses regulatory RNAs in heart
failure. In a perspective piece, Dr Alejandro Lucia from
Universidad European de Madrid discusses the role of aerobic and
resistance training as a therapy in addition to prescribed
medications in patients with resistant hypertension. Really
interesting.


Then finally, Dr Ify Mordi from University of Dundee examines
metformin use and clinical outcomes among patients with diabetes,
with or without heart failure, kidney dysfunction observations
from the SAVOR-TIMI 53 trial in which Dr Bergmark and colleagues
found that metformin use was associated with a reduction in
all-cause mortality and cardiovascular death, but not due to
myocardial infarction or stroke, particularly in patients without
a prior history of heart failure.


What could the mechanism be, if not related to presumed
atherosclerosis? Dr Mordi and colleagues proposed possibilities,
and Dr Brian Bergmark from the TIMI study group and the
cardiovascular division of Brigham and Women's hospital at
Harvard Medical School and colleagues, they write a very nice
response. It's really interesting listening to how could
metformin reduce events but not related to atherosclerosis? How
about onto our feature article?


Dr Carolyn Lam: You bet.


Dr Amit Khera: This is Amit Khera, digital strategies editor for
Circulation from UT Southwestern Medical Center joined by my
colleague, Dr Dharam Kumbhani who's also an associated editor at
Circulation and we're pleased to have Dr Eric Van Belle,
Professor Van Belle, from Lille University Hospital to discuss
the featured article today, "Transcatheter Aortic Valve
Replacement Propensity Match Comparison From the France TAVI
Registry." Welcome to you both.


Dr Van Belle, I'm going to start with you and we always like to
hear a little bit. Perhaps you can tell us some of the
background, what led up to this investigation, what led to your
group pursuing this manuscript?


Dr Eric Van Belle: Nowadays, the TAVI procedure, the TAVR
procedure, is becoming very prominent kind of way of treating
patients without stenosis, and basically we have two different
type of devices that are available to treat the patients. Once
series is based on the balloon expandable concept and the other
one on the self-expandable concept. These two type of devices are
considered to be used primarily in every kind of patient.
Theoretically, we can use any of these two devices, any kind of
patient, if we follow the recommendation of the manufacturer and
I'll just say that that'd been done.


These two devices are being validated against surgery, so
basically, we could potentially use any kind of them. In today,
there is no direct and there was no direct comparison between the
two different kinds of concept, although they are very different.
Again, the device is different. The way we implant the device is
different. The major question that we had behind was to say,
okay, what is the outcome? If it's a mean patient get one of the
devices or can we expect or should we expect a different outcome?
That was the main question behind it.


Dr Amit Khera: Okay, so essentially there's two valves, they're
both being used fairly regularly and without any kind of direct
comparisons. Tell us a little bit about the study design and what
you found in this project.


Dr Eric Van Belle: For methodology, we used what is called a
French study registry, basically nationwide registry with almost
all patients treated in France included, and we used it as a
database of patients between 2013 and 2015 with an overall group
of 12,000 patients treated with either of these two kinds of
devices. This is one of the aspect of this registry. The other
very important aspect of this registry, and that's the mortality
data survival that was obtained in all the patients in 2008
through 2016, so we have a set of 12,000 patients. It was a cool
kind of device with complete mortality data by April 2016 so
basically, this is the main methodological aspect. On top of
this, we did the best to do some matching on the older clinical
variables and all the matching valuables that we had to create
pairs of patients that could be matched to one to one. We had, at
the end, a group of almost 4,000 patients.


Dr Amit Khera: Okay and tell us a little bit about some of your
main findings of this study.


Dr Eric Van Belle: The two main findings were those differences
between the two groups of patients, that is a patient treated
with self-expandable devices at a higher risk of valvular
regurgitation. This was mainly a confirmation because this
finding was already reported previously in previous studies
trying to compare the two devices, but what was more striking was
the difference in mortality. It was a difference mostly in
hospital mortality but also in mortality after two years. That
was significant with an absolute difference in mortality around
3% by two years.


Dr Amit Khera: Well, obviously important, as you mentioned that
paravalvular leak had been seen before and this now a long-term
mortality difference. Certainly an important finding and one of
the main findings of your study. One of the concerns about
comparative effectiveness research, essentially you're using
observational data such as this is that there still could be
residual confounding. There still may be patient characteristics
or decisions made by interventionalists that aren't fully
accounted for. How did you all really try to account for some of
these components, this residual confounding to try to get the
best answer that you could?


Dr Eric Van Belle: That's going to be a major comment, and
everything you can do, every best way to try to control for this,
there is no better answer than to do a randomized study, and
probably we'll discuss on this. Let's see, indeed, we try to do
our best to minimize as much as we could, all these potential
confounders, so we did it in a different way, indeed.


The first way to do it was to adjust all the potential
differences among group but what was very also interesting to
remind is that, when you look at the 25 clinical and imaging
variables and creating the aortic annulus diameter that was
incorporated in the matching, that actually 21 of the 25
variables were already there. We were balanced between the two
groups, existing that indeed most of the case, the operators, we
are not so much directing or at least if there was selecting it
was not captured but all of these valuables because again, out of
25, the correction needed to do the matching was only affecting 4
variables, mainly. Those variables were already pretty
well-matched between the two populations.


The other way we did it was to look at what is called
falsification endpoint, that it is endpoints that are supposed to
be unrelated to the devices to verify that indeed, we have not
selected a population that will have issues that are not related
to the device itself. We look at, let's say, mortality by
infection, mortality by cancer, to verify that, indeed, this kind
of event where it did well balanced between the two groups
suggesting that the mortality effects that we observed was not
related to this kind of unbalance related to something else that
was not captured by analysis.


Dr Amit Khera: Yeah, I think that was quite an important
observation you mentioned. The first that these two groups are
generally well-balanced to begin with, even before with all the
matching parameters and then certainly the falsification endpoint
helped to add validity to the findings.


Dharam, I'm going to turn it over to you. Maybe you can show this
from an associate editor's perspective. What are some of the
observations you found interesting about this study and what are
some of the considerations we had in some of the discussions
about it?


Dr Dharam Kumbhani: I'll just remind our listeners that this was
also a late breaker at AHA last year in 2019, so this is really a
very important finding. As Eric briefly pointed out, there
haven't really been head to head comparisons between, the two
dominant valves in the market even though TAVR has pretty much
become the dominant strategy for treatment of aortic stenosis.


At the end of the day, it's an observational analysis. We have to
take the findings with that in mind. At a minimum, it's first a
lot of debate and discussion about the need to have randomized
trials and our belief that, perhaps, TAVR is a class effect may
not always be true. I think that hypothesis would certainly need
to be tested and that's what this paper really sparks as far as
discussion going forward.


Dr Amit Khera: Maybe I'll ask both of you. One of the challenges
of any type of observational research is time period. First there
was a hint towards even maybe a greater effect in the more recent
time period than the distant time period. Also, there's always
commonly changes in technology, especially interventional field
where a study comes out and it's already obsolete because there's
some new technology. There are some newer generations of valves
that have come out. Do you think that it would affect these
findings in any way? Maybe we'll start with you, Eric.


Dr Eric Van Belle: That's always an issue. Again, because it's a
very rapidly evolving field and if you want to have strong data,
you need to have really long-term follow-up. You need to have
mortality data. There is some kind of contradiction between both
that the field is evolving very quickly but then to have solid
data, you need to have some time.


What we could say, indeed, as a study period was 2013 and 2015,
but the device that we are using at that time were already really
well matured and also the devices that were used at that time was
usually the ones that were used for the comparison with the
surgical techniques. Again, these devices are not so much
obsolete since they were accepted and used again, when you need
this one device study to compare with surgery.


Of course these devices have still had some evolution and change,
and it is for the good of the patient, but again, as mentioned
there, I'm seeing what is very, very important is that this
finding is, in my view, intriguing enough to say, okay, even if
it's difficult to conduct this kind of randomized study, it has
to be done now because we need to really know. Let's say 80% of
the patients could indeed be treated with any of the two device
in this large margin of patients. Do we have to choose one or the
other one to start with? This has already been well answered in a
larger randomized trial.


Dr Amit Khera: Dharam, maybe I'll ask you, do you think this
large randomized trial, are you optimistic that that would
happen? Certainly it sounds like it's something that would be
very helpful for the field. What are your thoughts on whether
that's actually going to occur?


Dr Dharam Kumbhani: I know that there are some head to head
trials ongoing. I don't know if they will have the sample size to
really drill down, as far as hard endpoints, mortality, for
example. I think the field clearly needs it. The question is,
who's going to sponsor a trial like that? There's probably not
much incentive for industry to sponsor something like that.
Really it would fall down to whether there's a way for government
agencies to partner with industry or other ways to run this. I do
agree with Eric that that's really very important and hopefully
we'll see that in the field going forward.


I did want to comment on the next iteration of devices as far as
what we may see now. The mortality signal, I know we've talked
about it. It's an observation study. It's hard to know if there's
confounding, and even with all the sophisticated statistical
analyses that the team did, there's always a possibility that
somehow there was sicker patients that received self-expanding
valves.


The signal for paravalvular regurgitation is not just in this
study. We've observed it in many other studies and for other
self-expanding platforms as well. Both the SCOPE trial and the
St. Jude trial last year, both came around the same time. They
were self-expanding platforms and both of them showed a higher
paravalvular regurgitation rate compared to the balloon
expandable rate. That may be a real thing, and I don't know if
that is an inherent design flaw in the self-expanding platform or
if there are ways that that could be mitigated going forward.
Again, I think the trials, for it to be meaningful, it would be
obviously important to collect and have short term and imaging
markers. Really, what the field needs is long-term evaluation of
these two strategies.


Dr Amit Khera: I want to take both Dharam Kumbhani and Dr Eric
Van Belle l from Lille University Hospital. Thank you both for
joining today.


Dr Greg Hundley: This program is copyright, the American Heart
Association 2020.