Circulation August 2, 2022 Issue

This week, please join authors Paul Ridker and Eric Van
Belle, editorialist Robert Harrington, and Guest Editor Allan
Jaffe as they discuss the original research articles "Effects of
Randomized Treatment With Icosapent Ethyl and a Mineral Oil
Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein,
Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine,
Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A
REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During
Transcatheter Aortic Valve Replacement: A Prospective Magnetic
Resonance Imaging Cohort” and the editorial "Trials and
Tribulations of Randomized Clinical Trials."


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.


Dr. Carolyn
Lam:            


It's double feature time Greg. We've got two totally unique and
interesting papers that we'll be discussing. The first, a
biomarker substudy from the REDUCE-IT trial, that is looking at
the effects of randomized treatment with icosapent ethyl, versus
a mineral oil comparator, on inflammatory biomarkers. Now, don't
use roll your eyes at me, because I'm telling you, this has
results that you may not expect, and very, very important
clinical implications, and implications for clinical trials.


The second paper, very much up your alley, Greg, is a prospective
MRI study of cerebral microbleeds during TAVR. But okay, enough
now to whet your appetite, let's now just first grab coffees, and
discuss the other papers and the issue, shall we?


Dr. Greg
Hundley:          


You bet, Carolyn. And how about if I go first?


Dr. Carolyn
Lam:            


Please.


Dr. Greg
Hundley:          


So, Carolyn, my first paper comes from a group of investigators
led by Dr. Araz Rawshani from the Institute of Medicine, and it
included 715,143 patients with diabetes, registered in the
Swedish National Diabetes Register, and compared them with over
two million match controls, randomly selected from the general
population, to determine the role of diabetes in the development
of valvular heart disease, and particularly, the relation with
risk factor control.


Dr. Carolyn
Lam:            


Huh? Interesting, diabetes and valve disease. All right. What did
they find, Greg?


Dr. Greg
Hundley:          


Right, Carolyn. So they found, that individuals with type one and
two diabetes, have greater risk for stenotic lesions. Whereas,
risk for valvular regurgitation was lower in type two diabetes.
Patients with well controlled cardiovascular risk factors,
continued to display higher risk for valvular stenosis, without a
clear stepwise decrease in risk between various degrees of risk
factor control. So Carolyn, diabetes and a link with valvular
heart disease.


Dr. Carolyn
Lam:            


Wow. Really interesting, Greg. Thanks. Well, the next paper is a
preclinical study with really interesting clinical implications.
Now, we know the human heart has limited capacity to regenerate
new cardiomyocytes, and that this capacity declines with age.


Now, because loss of cardiomyocytes may contribute to heart
failure, it is important to explore how stimulating endogenous
cardiac regeneration, to favorably shift the balance between loss
of cardiomyocytes and birth of new cardiomyocytes, occurs in the
aged heart.


Now, these authors, Doctors Rosenzweig, from Massachusetts
General Hospital, and Dr. Lee from Harvard University and
colleagues, previously showed that cardiomyogenesis can be
activated by, guess what? Exercise in the young adult mouse
heart. However, whether exercise also induces cardiomyogenesis in
aged hearts, however, is not yet known. So in today's paper, the
authors aim to investigate the effect of exercise on generation
of new cardiomyocytes in the aged heart. And here, we're talking
about 20 month old mice, who were subjected to an eight week
voluntary running protocol, and age matched sedentary animals who
served as controls.


Dr. Greg
Hundley:          


Wow, Carolyn. Really interesting evaluation of exercise on
cardiomyogenesis. So what did they find?


Dr. Carolyn
Lam:            


Endogenous cardiomyogenesis can be stimulated by exercise in aged
hearts. Comparative global transcriptional analysis further
revealed, that exercise and age specific changes occurred in gene
programs. The regulator of calcineurin RCAN1.4 was specifically
found to be induced with exercise in aged hearts, and was
accompanied by reduced calcineurin activity. So what's a
take-home message? Exercise induced cardiomyogenesis may counter
the increased cardiomyocyte loss and reduced cardio myogenic
capacity in elderly patients.


Dr. Greg
Hundley:          


Great, Carolyn. Well from the mail bag, there's an exchange of
letters to the editor from Professor Zhou and Veith regarding a
prior letter to the editor from Professor Jin and associates,
pertaining to the previously published article “SPARC, A Novel
Regulator of Vascular Cell Function in Pulmonary Hypertension.”
And also, there's a Perspective piece, from Professor Mentz
entitled, “Catastrophic Disruptions in Clinical Trials.”


Dr. Carolyn
Lam:            


There's also a Research Letter by Dr. Kumar on [entitled] “von
Willebrand Factor Is Produced Exclusively by Endothelium, Not
Neointima, in Occlusive Vascular Lesions in Both Pulmonary
Hypertension and Atherosclerosis.” There's also this beautiful
tour of Cardiology News from the literature, from Tracy Hampton,
which ranges from a study linking COVID-19 to higher long term
cardiovascular risks, which was published in Nature Med, to
uncovering alternative metabolic pathways involving cell fate
transitions, published in Nature, to designing an autonomous
biohybrid fish, from human stem cell derived cardiac muscle
cells, that was published in Science. Wow. Isn't that amazing,
Greg? Well, let's get on now though, to our two feature papers.
Shall we?


Dr. Greg
Hundley:          


You bet.


Welcome listeners, to these two feature discussions on this
particular day. And our first feature today, we have with us Dr.
Paul Ridker, from Brigham and Women's Hospital in Boston,
Massachusetts. Dr. Bob Harrington, from Stanford University in
California. And also, Dr. Allan Jaffe, from Rochester, Minnesota.
Welcome to you all.


And Paul, we're going to start for you. Can you describe for us,
the background information that really went into the construct of
your study, and what was the hypothesis that you wanted to
address?


Dr. Paul Ridker:


Sure, Greg. So first of all, my thanks to the AHA and the
Circulation for publishing this paper, we always want to support
the AHA, and we're delighted to be here today for these podcasts.


The field of omega-3 fatty acids has been a complicated one for a
long time. Epidemiology suggested that, fish consumption would
lower cardiovascular risk, and there was a number of trials done.
And my friend and colleague here at the Brigham, Deepak Bhatt,
was the lead of a very big trial, called REDUCE-IT. Some 8,000
plus patients who received EPA alone, and they got a terrific
result. A 25% reduction in their primary endpoint. And this was a
New England Journal paper, back in 2019 or so. But another friend
of mine, Steve Nicholls, ran another large trial of a combination
of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid
that's DHA called STRENGTH. And that one showed, really, no
benefit. And so, there's been some controversy out there.


In any event, when Deepak and his colleagues published their
original paper, they said it's interesting, because they got this
big risk reduction, but it wasn't apparently due to the
triglyceride lowering of the drug. And so, my interest, as many
people know, has largely been in inflammation biology. And so we
said, well maybe we should just do a test. Well, we said, we'll
measure a number of biomarkers that we know were associated with
atherosclerosis, some inflammatory, some with coagulation. And
so, that was the core hypothesis, was simply to look at some
other markers, and see what we might learn. And sometimes, you
learn things that you didn't expect. And I think, that goes to
the heart of what complicated clinical trials are all about. And
I'd also say perhaps, what the roles of surrogate endpoints are,
as compared to hard clinical endpoints, and things that make this
whole field kind of interesting.


Dr. Greg
Hundley:          


Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a
little bit more for your study. What was the study population,
and what was your study design?


Dr. Paul Ridker:


We were fortunate enough to work with REDUCE-IT investigators, to
use their biobank. They had put together, again, it's 8,000 plus
patients. I think, it was two thirds secondary prevention, one
third primary prevention. And when they received the combination
of EPA and DHA, as I said earlier, they had about a 25% reduction
in the risk of their primary endpoint, which was cardiovascular
death, nonfatal AMI, nonfatal stroke, coronary revascularization,
and the like.


What we did is, we basically said, "Okay, since the mechanism was
uncertain, why don't we go ahead and measure a series of
biomarkers?" Things that a lot of us are interested in,
homocysteine, LPLa, oxidized LDL, my own interest in
inflammation. We measured, IL-1β, we measured, IL-6, we measured
CRP. We measured another molecule, Lp-PLA2, that people have been
interested in.


And the hypothesis, of course, was to see what the drug did, as
compared to the comparator did. And the findings were interesting
to us, in that, to simplify them, the actual icosapent ethyl arm
didn't do much to most of those biomarkers, very little change.
But the mineral oil comparator arm had some small to modest
effects on all those biomarkers, all of which went up again. Now,
some of these effects are pretty small, two to 3% for things
homocystine, LPLa. Others were moderate, 10 to 20% increases in
oxidized LDL, Lp-PLA2. And the inflammatory markers went up about
25%, sometimes, even a little more. So it's complicated.


It's important to point out, that these changes on an absolute
scale are relatively small. On a percent scale, they're
different. The REDUCE-IT investigators themselves, to their
credit, had earlier published that, they saw some increase in LDL
cholesterol as well, about 10, 11% in those who had received the
mineral oil comparator. So it's not exactly what we thought we
were going to find, I guess, is the simplest way to express it.


Dr. Greg
Hundley:          


Very nice. And so, describe for us just a little bit more, any
differences in men and women, and what about age? Or for example,
premenopausal, postmenopausal women.


Dr. Paul Ridker:


No, the effects were quite consistent across all various
subgroups. It's a very large study. There were, again, 8,000
patients, lots of blood samples been drawn. And I should again,
commend the REDUCE-IT investigators, for allowing us to do this
work with them. And again, as I point out, sometimes you find
things out that weren't what you expected. And the hard part, I
was glad this got tossed over with Dr. Harrington, is sort to
figure out well, what's it really mean? Because again, as a
clinical trial list, I will say, my instincts are to trust the
primary endpoint of the trial. That's what they did. They're
going to go out and lower heart attacks and strokes. And then,
here we are a couple years later, trying to figure out what the
mechanism might be, and just came across some puzzling results.


Dr. Greg
Hundley:          


Very nice. Well, next listeners, we're going to turn to the
editor that actually processed this manuscript, Dr. Allan Jaffe.
Allan, what drew you to this particular article?


Dr. Allan Jaffe:  


Well, I was asked to be a guest editor this week, by the Journal,
because of some conflicts that were intrinsic to the editorial
board. And since I have an interest in biomarkers, and had for a
long time, it made perfect sense for me to become involved. I was
particularly interested in this particular area, because I was
aware that there were these two trials that had found different
endpoints, and that there were some controversy as to what the
mechanisms might be by which these effects could occur. And so I
was pleased to get involved. And I think it's a compliment to the
REDUCE-IT investigators, and to Dr. Ridker, that they were
willing to put the data out there so that everybody could see it.
And we could then begin to look.


So it was of interest to me. I thought it was important to the
field, to get really good reviewers who would be, make sure that
the data that would eventually be published was clear, so that
readers would understand it. And so that, at the end, we'd be
able to at least, come to some conclusions that we could end up
having an expert in clinical trials. And I thought about Bob
Harrington, right from the beginning, might be able to comment
on.


Dr. Greg
Hundley:          


Very nice. Well, Bob he's setting you up here nicely, both Paul
and Allan, to really help us put these results in perspective
with other studies that have been performed in this space. What
are your thoughts?


Dr. Robert Harrington:  


So first off, Greg, thanks for having me. And Allan, thanks for
inviting me to review and comment on the paper. As both Allan and
Paul have indicated, that I've spent the last 30 plus years doing
clinical trials of all sizes. Very small, where we try to
understand mechanisms, and very large, where what we're trying to
understand is clinical outcomes. And I've been intrigued in this
field, because of the inconsistency of the data across the field.
Where in some trials, Paul had indicated this STRENGTH, there
seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT,
there was quite a pronounced effect of the test agent. And so,
when one sees discordance in a field, one tries to understand,
well, why might that be? And so in the editorial, I took the
position that, well, what are we trying to do in clinical trials?


And in outcomes trials, we're trying to figure out what matters
to patients. Do they live longer? Do they feel better? Do they
avoid bad stuff happening to them? Like having to undergo
revascularization procedure. So you're trying to do things that
are really clinically meaningful, but that doesn't say that
you're also not trying to understand mechanism. And as Allan
said, there have been some questions raised. And so, trying to
understand mechanism in the edit in trials can be quite useful,
not just to understand that trial results, but to really form
hypothesis for a field going forward. And so, I took the approach
of, we learn things from different trials, and sometimes we learn
things in the same trial. Meaning that, there's mechanistic work
embedded in the large trial. One of the most famous examples of
this, in the GUSTO trial 30 years ago, we learned through the
mechanistic substudy, that it was rapid reprofusion TIMI-3
establishment of TIMI-3 flow, that really explained the
difference between TPA and streptokinase. So I was very intrigued
by how we might use these data to explore the results.


And I find the findings fascinating, as Paul said. It is
complicated, but it raises a really fundamental issue in clinical
trials. There's an assumption in a placebo control trial, that
because randomization is allowing you to balance everything,
except for the randomized treatment groups, and therefore, that
comparison has causal information in it. There's an underlying
assumption that's really important. And that is, that the placebo
is inert. That it has no biological effect of its own. Well, that
assumption was violated here. The placebo is not inert in this
clinical trial.


Now, the investigators, I think to their credit, have said,
"Well, this is small, probably doesn't matter." And that might be
right, but it also may be wrong. And you can't just say, well, it
doesn't matter, these are small effects. As Paul said, some of
the effects are small, some are medium, some are large. So what
explains it? And I made a point in the editorial, you could model
all of this. If you get 5% of this, and 10% of this, and 20% of
this, you could make some assumptions and say, well, the
magnitude of the benefit was so great that it couldn't have been
overcome by this. But that's just modeling, and there's
uncertainty. So for me, as a trialist, and somebody who really
believes in using evidence to guide practice and to guide public
policy, I think there's uncertainty here.


It's likely that the treatment effect is not as large as was
observed, but how large is it? And how large is important? And
how large might we want to consider to put into our practice
guidelines? I think all of those open questions, particularly in
a field where there is inconsistency across trials, in terms of
the observation of the outcome. So my conclusion is, we need more
work. We need another trial, if we really want to understand
this. And we need to use an inert placebo, to really understand
what the contribution was. I'd like nothing better to see that it
didn't matter. But I can't say that it doesn't matter because I
don't know.


Dr. Greg
Hundley:          


Well, listeners, boy, we've got kind of some interest here in
that an unexpected result. So Paul, it's nice doing an interview
like this listeners, because each speaker sets up the next one.
Paul, Bob is saying, well, what should we do next to clarify the
results here? So maybe we'll go through each of you, and start
with Paul. Just describe for us, what do you think is the next
study that we need to perform?


Dr. Paul Ridker:


Well, Greg, it's a really interesting issue. We saw it, as
authors, to write as neutral a paper as we could possibly write,
and sort of do our academic job and say, here are the data. And I
think we did it that way because, we don't really know what the
interpretation should be. On the one hand, you have a very big
beneficial result, which is great for patients. And there's a
prior clinical trial called JELIS, which was open label, the same
drug, and also got a large benefit. And we were trying to figure
out mechanism. That being said, as Bob pointed out, I think what
we stumbled into is some level of uncertainty. And the question
is, how uncertain would it be, and does it matter in the big
picture?


Allan was interesting, because the Journal asked us to use the
word comparator, rather than placebo. Now this was designed as a
placebo controlled trial, but our paper uses the word comparator,
because of the possibility, that as Bob Harrington points out, it
may not be totally inert. So the writing of this was quite
carefully done. I think, at the end of the day, my REDUCE-IT
colleagues, who I have great respect for, and really worked
terribly hard to do the main trial, understandably feel, that the
trial would've showed, and I have a lot of sympathy for that,
because it's the hard endpoints we should go with.


On the other hand, I have sympathy with the idea that it never
hurts to have more data. And if there could be a way to have a
second trial, and I might change the population a little bit,
maybe I'd do it in true primary prevention. This was one third
primary prevention. My colleague, Joanne Manson had done her, she
had a trial where they showed some potential benefit in the black
populations. Maybe you might over sample some minority groups.
But just the pragmatic issues here, make it tough to have a
second trial. And so, uncertainty is just part of what we, as
physicians, have to learn to live with.


Dr. Greg
Hundley:          


Allan, turning to you. What do you think is a next study to
perform in this space?


Dr. Allan Jaffe:  


Well, I think what Paul has said is correct. That it would be
very hard to generate enthusiasm funding for a large trial. But
it might not be nearly as difficult to begin to explore the
effects of the mineral oil comparator, versus the active agent,
versus perhaps, another potential placebo, and see over time what
happens in primary prevention patients, as a way of beginning to
put some context around what these results might mean. So for
example, it could turn out that, the active agent actually kept
the values from rising as they normally would've, and mineral oil
had no effect at all. Alternatively, mineral oil may well have
been a negative. It had a negative effect. And I think, those are
the sorts of questions that could be explored reasonably in the
short term, without doing another multimillion dollar randomized
trial.


Dr. Greg
Hundley:          


And Bob, your thoughts.


Dr. Robert Harrington:  


Well, and I mentioned this in the editorial, Greg. I didn't make
my recommendation lightly. I know that these trials are
expensive. I know these trials take a great deal of time, a great
deal of energy. And I know that the REDUCE-IT investigators
worked enormously hard over the years to get this done. So I
don't say tritely, "Oh, just do another trial."


But if you think about the magnitude of the public health issue
here, there are millions of people to who this kind of therapy
might apply globally. And so, shouldn't we be more certain than
less certain, if we want to include it, for example, in ACC/AHA
guidelines? I would say, the answer to that is yes. And so, I
think of it as, okay, let's make some assumptions. Let's assume,
that the effect that was observed in JELIS and REDUCE-IT, is the
true effect. That's ground truth.


Well, there are different study designs one might think about,
from an analytic perspective, using Bayesian statistics, as
opposed to frequency statistics. One might think about an intense
interim analysis plan, to understand where the data are going,
and be able to pull in the prior data for evaluation. I would
advise getting a smart group of people together, who spend their
lives thinking about trials in the atherosclerotic space, and the
REDUCE-IT team is pretty darn good, and say, "How could we do
this efficiently?"


I do think, there's enough uncertainty that it would be ethical,
from an equipoise perspective, to include high risk patients in a
second evaluation, because we do have uncertainty. And if we
really want to nail this down, I think we could look at high risk
patients with hypertriglyceridemia, and try to use some
interesting design issues, and some interesting analytical
issues, to try to reduce the sample size, lot of attention in
interim analyses, to try to answer the question. I'd like, as I
said, nothing better to say, "Oh look, REDUCE-IT was the truth."
This next trial is consistent. That'd be, to me, a terrific
outcome of this.


On the other hand, if you said to me, "Well, the effect's not
25%, it's more in the 15% range." Well, maybe then we think about
how we apply it to our patients a little differently, maybe a
little more cautiously. So I don't make the recommendation
lightly, as I said, but I do think that there are some
conversations that could be had, being respectful of the effort
and the expense that goes into these kind of things. To try to
answer the question efficiently.


Dr. Greg
Hundley:          


Very nice. Well listeners, we want thank Dr. Paul Ridker, from
Brigham and Women's Hospital, Dr. Bob Harrington from Stanford
University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing
us the results of a substudy of the REDUCE-IT trial, that
assessed a variety of serum biomarkers, pertaining to systemic
inflammation, and highlighting uncertainty around the mechanism
regarding the efficacy of icosapent ethyl, that's been used
previously for primary or secondary prevention of cardiovascular
events.


And next listeners, we are going to move to our second feature
discussion and review some data pertaining to microbleeds in the
central nervous system, during and after TAVR procedures.


Welcome listeners, to our second feature discussion on this
August 2nd. And we are going to explore some of the world of TAVR
and its potential complications. And we have with us today, Dr.
Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis,
from Minneapolis, Minnesota. Welcome gentlemen.


And Eric, we'll start with you. Can you describe for us a little,
the background information that you use to assemble and construct
your study, and describe, or list for us, the hypothesis that you
wanted to address?


Dr. Eric Van
Belle:          


Yes. Thanks a lot for the question. So we knew for many years,
that some of the complication of the TAVR procedure relate to the
brain. And it has been described by many others, that there were
some complication in the brain of patient undergoing TAVR. And
there was no previous investigation on potential bleeding or
microbleeding in this population.


And on the other side, there are previous publication on, of
course, initially chronic microbleeding, in patient with some of,
let's say, disease in the brain, but also, a possibility of acute
microbleeding. And especially, in some interesting population
relating to the TAVR feed, that is patient with valve disease,
patient with endocarditis, or patient with assist device.


In this population, microbleedings, acute microbleeding, have
been described. And what is interesting, if you look at all these
populations, these are population in which the Von Willebrand
factor has been impacted and modified, and could be one of the
reason of the microbleeding. And one of the similar feature of
the patient with aortic stenosis that undergo TAVI, or TAVR, that
are patient with indeed also, this kind of Von Willebrand
disease.


So if we put everything together that is previously, we only
looked at antibody complication in those population, and that Von
Willebrand disease, which is present in patient with aortic valve
stenosis, could promote a bleeding, in particular, bleeding in
the brain. We decided to look at the potential appearance of
microbleeding, in patient undergoing TAVR procedure.


Dr. Greg
Hundley:          


Very nice. And Eric, can you describe for us, your study design,
and who was your study population?


Dr. Eric Van
Belle:          


Yes. So basically, the study population is a basic population of
patient undergoing TAVI. Just to make sure that one of the
difficulty of this study, was to conduct and perform an MRI, a
brain MRI, before the procedure, and as short as possible after
the procedure, within three days, which is logistically
challenging. And also, to make sure that we keep most of the
population to undergo the MRI, we had to exclude patient with a
high risk of pacemaker, or patient with pacemaker that could not
undergo the MRI. But basically, without this, it's just a regular
population.


And if we indeed, compare to some of the previous work I was
mentioning, about describing the acute MRI, it was important for
us to make sure, or to be as sure as we could get, that indeed,
this microbleeding, if we observe them, could be related to the
procedure. And it means that, the MRI, after the procedure,
should be done as short as possible. And also, that an MRI, a
baseline MRI, should be performed. Because we know, that in this
population, you could have some microbleedings also observed
before starting the procedure.


Dr. Greg
Hundley:          


So a cohort study design where MRIs are performed before, and
then very soon after, TAVR procedures. So Eric, what did you
find?


Dr. Eric Van
Belle:          


So what we observed, the first thing that we confirmed was
indeed, that in this population of that age, that is patient
around 80 years old, when we do the baseline MRI, you find in
about one out of four patients already, some microbleedings. And
this was expected, and it is very similar to what is expected in
this kind of population.


But what was indeed more striking, that when we repeated the MRI
after three days, we observed another 23% of patient with a new
microbleedings that were observed. This is indeed the most
important observation. What was also important that, the patient
with microbleedings, and the location of the microbleedings, were
not related to the cerebellum brain, because indeed we could
observe some cerebellum arise in this population, as it is
expected. And there was no relation between the two. So it's
also, an important observation, suggesting that this
microbleeding are not hemorrhagic transformation of cerebellum
brain, for instance. And we also observed that, the risk of
microbleeding, or the chance to observe the microbleeding, was
increased when the procedure was longer. And also, when the total
duration of anticoagulation was longer, we also observed that,
when the procedure was, when we used protamine at the end of the
procedure, the risk of microbleeding was less. And also,
importantly, the status of the Von Willebrand factor, and indeed,
an alteration of the multimer of Von Willebrand factor, was also
associated with the risk of microbleeding in this population.


Dr. Greg
Hundley:          


Very nice. So in this cohort of 84 individuals, average age
around 80, undergoing TAVR procedure, and about 50/50 men and
women, you had several factors. Prior history of bleeding, amount
of heparin, absence of protamine, all indicating a higher risk of
these microbleeds. So very practical information. Well, Manos,
you have many papers come across your desk. What attracted you to
this particular paper? And then secondly, how do we put these
results really, in the context of maybe other complications that
can occur during or after TAVR procedures?


Dr. Emmanouil Brilakis:


Yes, thanks so much, Greg. And also, congratulations Eric, for a
wonderful paper, and thanks for sending it to circulation.


I think, with increasing the number of targets, as you know, TAVR
now is becoming the dominant mode for treating severe aortic
stenosis. Safety is of paramount importance. And even though
there's been a lot of progress, we still have issues with the
safety of the procedure. So understanding how can make it safer
is very important. And I think, what was unique in this paper,
again, congratulations for creating this study, is that it opens
a new frontier. We worry about stroke. We're all very worried
about the stroke, and having the patient have a permanent
neurologic damage during the procedure. But there may be more to
it than the classic embolic stroke. And I think, this study opens
actually, a new frontier with the micro cerebral bleeds.


Now we don't completely understand, despite the study, we don't
understand the functional significance from this. And I think,
that's one of the areas that will need further research. But I
think, trying to understand what causes them, and preventing
those microbleeds, would have a very important role in the
future, for making TAVR even safer than it is.


Dr. Greg
Hundley:          


Very nice. Well, Manos, you really lead us into the kind of the
next question. So Eric, what do you see as the next study to be
performed in this sphere of research?


Dr. Eric Van
Belle:          


Again, to me, and to follow with the comment of Manos, we need to
include, I would say, to solve two questions. We have to solve
the question of, what could really impact these microbleedings.
And what would be the impact of this microbleeding on the long
term outcome of this patient? So it's means that we have to set,
as part of the studies that we will design, potentially studies
on aortic immolation. Or let's say for instance, we could
investigate the role of protamine. It has been suggested that
protamine could be something interesting, so it could be tested
as part of a randomized study. But this means that, as part of
such randomized study on the use of protamine, for instance, you
would include a last cohort of patients with MRI after the
procedure. And also, a long term follow of the neurological
complication, which indeed, is the missing part of our current
study. We would need to have a much larger cohort of patients, to
be able to reconnect the neurological outcome to the MRI outcome,
and also to include this.


So let's say, for me, one of the studies we would be interested
to perform, is to conduct a study on the use of protamine, which
is very simple, randomized, yes or no, and includes brain MRI in
this population, as a systematic investigation, which is
difficult to conduct. You have to know that it's difficult to do,
but it will be very important. And then, to look at the long term
neurological outcome.


Dr. Greg
Hundley:          


And I see, Eric, you mentioned the long term, because really in
the short term, so within six months, you really didn't see any
changes in neurological functional outcome or quality of life. So
Manos, just coming back to you. What do you see is the next study
that should be performed in this space?


Dr. Emmanouil Brilakis:


Yeah, I agree actually, with Eric. The next step is, this was an
80 patient study. Right? It's a very small preliminary data, all
that opens a new system for evaluation, we're still a very small
number of patients. So having a larger number of patients, I
think for me, the key thing is to understand the connection. Does
this actually cause neurologic symptoms? What does it mean having
a microbleed? I think right now, we're still confused on the
study. There was not really much impact on the neurologic status
of the patient.


So for me, the number one thing is, to understand how it impacts
the patient's quality of life, the neurologic status. Perhaps
more sensitive studies, neurocognitive studies, to understand
exactly how it impacts. And then after doing that, I agree with
Eric, if this is a bad, something really bad, then we can find
different ways to prevent them from happening. Protamine is one
of them during the procedure time, and not be a very feasible
one. Or it could be interesting to see if different valves, for
example, have different propensity for causing those microbleeds.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank Dr. Eric Van Belle,
from Lille, France, and also, our own associate editor, Dr. Manos
Brilakis, from Minneapolis, Minnesota for bringing this very
important study, highlighting that one out of four patients
undergoing TAVR has cerebral microbleeds before the procedure.
And then, after the procedure, one in four patients develop new
cerebral microbleeds. And then, procedural and antithrombotic
management, and persistence of acquired Von Willebrand factor
defects, were associated with the occurrence of these new
cerebral microbleeds.


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 ahajournals.org.