Circulation January 18, 2022 Issue

Please join author Mohamed Abdel-Wahab and Associate
Editor Stefan James as they discuss the article "Comparison of a
Pure Plug-Based Versus a Primary Suture-Based Vascular Closure
Device Strategy for Transfemoral Transcatheter Aortic Valve
Replacement: The CHOICE-CLOSURE Randomized Clinical
Trial."


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 Center 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, a very interesting topic, looking
at closure devices at the sites of access for patients that are
undergoing TAVR procedures. But before we get to that, how about
if 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 would love to and I would like to describe not just one, but
two articles from recent SGLT2 inhibitor trials. So, the first
paper is an analysis of the DAPA-HF trial. Now we know that
circulating high sensitivity, cardiac troponin T predominantly
reflects myocardial injury. And higher levels are associated with
a higher risk of worsening heart failure and death in patients
with heart failure with reduced ejection fraction or HFrEF. But
what about the prognostic significance of changes in high
sensitivity troponin T over time and the effects of Dapagliflozin
and on clinical outcomes in relation to baseline levels, as well
as the effect of dapagliflozin on the high sensitivity troponin T
levels? Well, this is what this study answers. It's a biomarker
substudy of the DAPA-HF trial from Dr. Berg of the TIMI study
group at Brigham women's hospital and colleagues.


Dr. Greg Hundley:


Wow. Carolyn, very interesting. So remind us about the DAPA heart
failure trial. What was it about?


Dr. Carolyn Lam:


Ah, well, DAPA-HF was a randomized double blind placebo control
trial of dapagliflozin in patients with symptomatic HFrEF defined
by injection fraction 40% or less wherein dapagliflozin
significantly reduced the primary endpoint of cardiovascular
death or worsening heart failure events. And in today's biomarker
substudy increases in high sensitivity, cardiac troponin T over a
one year interval of time were highly predictive of subsequent
risk of worsening heart failure and cardiovascular death. The
effect of dapagliflozin on the primary endpoint was consistent
irrespective of baseline troponin T concentration with no
evidence of attenuated treatment benefit in those with very high
troponin T concentrations.


Dr. Greg Hundley:


Very interesting Carolyn. Now you've got another study. Is this
one on EMPA?


Dr. Carolyn Lam:


You are right. Thank you. The next paper is and analysis of the
Emperor-Preserved trial. As a reminder, Emperor-preserved study
the SGLT2 inhibitor empagliflozin in patients with HFpEF this
time, which is a left ventricular ejection fraction above 40, and
showed a significant reduction in the risk of cardiovascular
death or heart failure hospitalization. The current paper
evaluated the efficacy of empagliflozin on health related quality
of life in patients with HFpEF and whether the clinical benefit
observed with empagliflozin varied according to baseline health
status.


Dr. Greg Hundley:


Very nice, super review Carolyn. So what were the results of this
study?


Dr. Carolyn Lam:


In Emperor-Preserved, baseline health status and quality of life
did not influence the magnitude of effect of empagliflozin on the
risk of cardiovascular death or hospitalization for heart
failure. Empagliflozin improved health status and quality of life
as assessed by the Kansas city cardiomyopathy questionnaire
across all domains and at all measured time points. Thus an
effect that appeared early and was sustained for at least one
year.


Dr. Greg Hundley:


Very nice. So two really informative papers on SGLT2 inhibitors.
Well Carolyn, I'm going to turn the conversation to the world of
preclinical science and talk about Titin. So Carolyn, titin
truncation variants are the most common inheritable risk factor
for dilated cardiomyopathy and their pathogenicity has been
associated with structural localization. The A-band variants with
overlapping myosin heavy chain binding domains appear more
pathogenic than the I-band variants and the mechanisms for this
are not well understood. So these investigators led by Dr. Hinson
at the Jackson Laboratory for genomic medicine, performed a study
demonstrating why A-Band variants are highly pathogenic for
dilated cardiomyopathy and how they could reveal new insights
into dilated cardiomyopathy pathogenesis. Titin functions and
therapeutic targets were assessed.


Dr. Carolyn Lam:


Wow, interesting. So what did they enroll in? How did they do
this? what did they find?


Dr. Greg Hundley:


Great Carolyn, so human Cardiomyocytes and cardiac micro tissue
functional assays revealed that highly pathogenic A-Band Titin
truncation mutations generate four shortened titin poisoned
peptides and diminish full length, titin protein levels. While
less pathogenic I-band titin mutations only diminish titin
protein levels. And so Carolyn, the authors developed a one and
done, genome editing therapeutic approach using CRISPR technology
to repair the reading frame of Titin truncation mutations in
cardiomyocytes. And therefore these genome editing therapeutics
could correct the underlying genetic lesion responsible for
dilated cardiomyopathy due to these Titin mutations.


Dr. Carolyn Lam:


Wow. Interesting. One and done genome editing. You learn
something new every day with circulation. You've got another
paper?


Dr. Greg Hundley:


Yes, Carolyn. Thank you. And so this paper comes to us from Dr.
Beiyan Zhou From the Yukon health, school of medicine and again,
from the world of preclinical science. So Carolyn, while several
interventions can effectively lower lipid levels and people at
risk for atherosclerotic cardiovascular disease, cardiovascular
event risks remain, suggesting an unmet medical need to identify
factors contributing to this cardiovascular event risk. Now
monocytes and macrophages play central roles in atherosclerosis,
but previous work has yet to provide a detailed view of
macrophage populations involved in increased atherosclerotic
cardiovascular disease risk.


Dr. Carolyn Lam:


Huh? Okay. Well, I'm super excited to hear what these
investigators did Greg.


Dr. Greg Hundley:


Right, Carolyn. Well these authors developed a novel
computational program. They call AtheroSpectrum, which identified
a specific gene expression profile associated with inflammatory
macrophage foam cells. And additionally, a subset of 30 genes
expressed in circulating monocytes jointly contributed to the
prediction of symptomatic atherosclerotic vascular disease. So
therefore Carolyn, in the future, perhaps incorporating this new
pathogenic foaming gene set with known risk factors may
significantly strengthen the power to predict atherosclerotic
cardiovascular disease risk.


Dr. Carolyn Lam:


Wow. Super interesting and well summarized. Thank you, Greg. Well
also in today's issue, there's a Perspective by Dr. Kirtane on
“The Long-Awaited Revascularization Guidelines are Out. What's In
Them?” A Research Letter by Dr. Laffin on rise in blood pressure
observed among us adults during the COVID 19 pandemic.


Dr. Greg Hundley:


Very Nice Carolyn. Well in our Cardiovascular News Segment,
there's a piece on metabolic risk factors and how they drive the
burden of Ischemic heart disease. Well, what a great issue here
and now, how about we get onto that feature discussion?


Dr. Carolyn Lam:


Very Cool. Closure devices after TAVR. Here we go.


Dr. Greg Hundley:


Well, listeners welcome today to our feature discussion and we
have with us Dr. Mohamed Abdel Wahab from Leipzig Germany. And we
are going to discuss some issues pertaining to transcatheter
aortic valve replacement, in terms of access to the arteries in
the lower extremity. Welcome Mohamed. And can you start with,
what was some of the background that led you to perform your
study and what was the hypothesis that you wanted to address?


Dr. Mohamed Abdel-Wahab:


Thank you, Greg. And thank you for having me here. So as you
mentioned, there are several cardiovascular procedures that
currently require large-bore arterial access. The most common of
these procedures is transcatheter aortic valve replacement. But
there are other procedures as well, like endovascular aortic
repair, mechanical circulatory devices. All of these require
large-bore arterial access and of course, closure afterwards. And
what we were interested in looking at was whether different types
of vascular access site closure devices or strategies behave
differently in the setting. Particularly in the setting of
transcatheter aortic valve replacement. The reason behind this is
that for many years, we only had one technique, to percutaneously
close arterial access sites after these procedures. And these
were mainly based on suture based devices or suture based
techniques. Very recently, alternative techniques based on
collagen plugs have been introduced.


Dr. Mohamed Abdel-Wahab:


And we know these types of devices or closure techniques from
usual coronary intervention procedures for smaller access sites
or for smaller sheath size. But they have been developed a step
further for these large-bore procedures. These newer devices,
particularly what we call the MANTA device, which is based on the
collagen plug has been shown in initial visibility studies and
also in registry based analysis to be very safe and effective. It
leads to a very rapid hemostasis. And data from observational
studies have suggested that it may be even superior to the suture
based techniques, largely based on what we call the ProGlide
device or the [inaudible 00:10:56]. And this is actually what we
were aiming to look at. To compare these two different strategies
based on two different devices. The suture based, the classical
suture based technique using two ProGlides compared to the newer
plug based technique using the MANTA in a population treated with
TAVR.


Dr. Greg Hundley:


Very nice. And describe for us, your study design. And then also
maybe explain a little bit more about the study population. Who
did you include in this study?


Dr. Mohamed Abdel-Wahab:


So the design was more or less, very inclusive. So we designed
the trial to more or less represent real word population. More or
less [inaudible 00:11:40] population receiving transcatheter
aortic valve replacement. So we included patients, of course
where the procedure is being thought to be indicated and feasible
by a multidisciplinary heart team. And also where the heart team
thought that the transfemoral access route, which is the main
route for the majority of patients, is obtainable and use of a
percutaneous closure device is also possible.


Dr. Mohamed Abdel-Wahab:


Of course we had some exclusions. For example, patients where the
use of a surgical access technique was necessary. They couldn't
be naturally included in the trial. Patient that already had
complications related, for example, to previous coronary
angiogram PCI at the access site, they couldn't be included. But
we were more or less, very inclusive in this trial. The trial
population reflects the patients that are currently being treated
with TAVR, so more or less an elderly population. More or less
equally split-by males and females, which is very particular,
again to the TAVR population. So this is a little bit different
than the population that receives PCI, where we usually have a
predominantly male population. This is not the case here. So
these are the broad lines. Also reflecting current practice, the
population that has been included in the trial is more or less
overall, an intermediate risk population, when you look at the
surgical scores.


Dr. Greg Hundley:


Very nice. So this was multicenter and then also patients were
randomized to each of the two therapies, I believe. And was that
a one to one randomization?


Dr. Mohamed Abdel-Wahab:


Exactly. So it was a multicenter trial. Patients were randomized
between these two techniques. We mentioned the ProGlide based and
the MANTA based in 1:1 fashion. And steering committee of course
was more or less dominated by interventional cardiologists. Of
course, in the context of this particular trial setting, the
trial was only performed in Germany and it was an investigative
initiated trial, not sponsored by the industry.


Dr. Greg Hundley:


Very nice. And can you describe for us, Mohamed, your results?


Dr. Mohamed Abdel-Wahab:


Yes. We actually hypothesized based on the observational data we
have, that we will have less vascular complications with the
MANTA based technique or the collagen based technique. At the end
of the day, what we observed is completely the opposite. So the
primary endpoint of the trial, which was what we call major and
minor vascular complications defined according to the
standardized criteria provided by the valve academic research
consortium. These events occurred significantly more common in
patients that were randomized to the MANTA based technique, as
opposed to the ProGlide based technique, which was statistically
significant.


Dr. Greg Hundley:


And did you observe those results across both the men and the
women? And also, were there any differences in the results
related to participants' age?


Dr. Mohamed Abdel-Wahab:


Yeah. So there were no interactions with various subgroups, both
the predefined ones, including age and sex, as you mentioned. But
also we looked at some post hoc subgroups, including for example,
whether this is being affected by the size of the access vessels
or by the presence and location of calcification, for example.
But there were no interactions in all subgroups we looked at,
with one exception which was chronic renal insufficiency. But all
other subgroups showed actually no significant interaction,
favoring the suture based, ProGlide based technique in all
subgroups.


Dr. Greg Hundley:


Very good. And so can you describe in terms of, for individuals
performing TAVR procedures and obtaining access, how do we use
the results of your study to inform how we might move forward
with closure of the artery in the future?


Dr. Mohamed Abdel-Wahab:


I mean, the first thing I would like to stress is the importance
of doing randomized trials in general. Because I think this is
not the first time we see opposite results when we are comparing
randomized evidence with the evidence from observation studies,
with the known limitations of observational comparative analysis.
The second thing I think is really reassuring that the suture
based technique that we know and that we have been using for many
years now is safe and appears to be even more effective than the
newly developed plug based technique. So this is one important
information I think from this trial. The third piece of
information is that the recently developed plug based technique,
although being inferior in the study, it still may have some
advantages in selected patients. And this is what we probably
need to look at in a little bit more details in the future.


Dr. Mohamed Abdel-Wahab:


For example, what we realized from the study is that it could be
a good option as a bailout device. So in some cases where the
suture based technique has failed in the study, the crossover to
the MANTA device was successful in the majority of cases. And may
lead or help avoid complex endovascular interventions and
implanting for example, stents or covered stents or even doing
surgery. So this is something that is a nice observation from the
dataset we have, but of course needs validation in larger
studies.


Dr. Greg Hundley:


Very nice. And so really you've answered, kind of one of our key
questions is, your thoughts on the next study that you see needs
to be performed really in this area of research?


Dr. Mohamed Abdel-Wahab:


Yeah, so I think there are several things. One thing is, again,
to look at potential patient subgroups that may benefit from the
plug based device from the beginning. So probably it's not
something that we should be using as a default strategy based on
the results of this trial. But there could be certain subgroups
we need maybe to dig a little bit more into the details or
subgroups, if you wish to say so. Look a little bit more
granularly at some patient groups that could benefit. But as
mentioned, I think that the bailout indication is a very
interesting one and needs to be looked at.


Dr. Mohamed Abdel-Wahab:


Not only in the TAVR setting, but also in the setting of other
procedures. Such as for example, the use of mechanical
circulatory assist device or ECMOs, where it may be difficult to
apply these sutures post hoc. So the sutures that we apply during
a TAVR procedure and what we use in this trial, this is the
so-called preclosure technique. So you apply the sutures after
gaining access. Then you insert your large-bore sheaths through
the procedure. And then the sutures are already there and you can
close the access site, usually without problems. Which is
difficult, if you obtain access, for example, with an ECMO or an
Impella. And then after a couple of days, you need to close it.
So the sutures are not yet in place. In this particular scenario,
it may be beneficial to use a plug afterwards. Or as a bailout
device as previously Mentioned.


Dr. Greg Hundley:


Very nice well listeners. We want to thank Dr. Mohamed Abdel
Wahab from Leipzig Germany for bringing us this study indicating
that among patients treated with transfemoral TAVR, this pure
plug based vascular closure technique using the MANTA VCD was
associated with a higher rate of access site or access related
vascular complications. Well, on behalf of Carolyn and myself, we
want to wish you a great week and we will catch you next week on
the run.


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 AHA journals
dot org.