Circulation January 17, 2023 Issue

Please join author Pieter Martens and Associate Editor
Justin Grodin as they discuss the article "Decongestion With
Acetazolamide in Acute Decompensated Heart Failure Across the
Spectrum of Left Ventricular Ejection Fraction: A Prespecified
Analysis From the ADVOR Trial."


Dr. Greg Hundley:


Welcome listeners to this January 17th issue of Circulation on
the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart
Center at VCU Health in Richmond, Virginia.


Dr. Peder Myhre:


And I'm Dr. Peder Myhre from Akershus University Hospital and
University of Oslo, in Norway. And today, Greg, we have such an
exciting feature paper. It comes to us from the ADVOR trialists.
And the ADVOR trial examined the effect of acetazolamide in acute
decompensated heart failure. And in this paper we're going to
discuss how that treatment effect was across the left ventricular
ejection fraction, across the spectrum. Greg, what do you think?


Dr. Greg Hundley:


Oh, wow. Sounds very interesting. But we might have some other
articles in the issue. How about we grab a cup of coffee and
Peder maybe this week, I'll go first and we'll start with
preclinical science. How about that?


Dr. Peder Myhre:


Let's do preclinical science, Greg.


Dr. Greg Hundley:


Well, Peder, this particular paper focuses on the relationship
between cardiac fibroblasts and cardiomyocytes. Remember that
myocytes sit on a lattice of network of fibroblasts. And when the
myocytes die, the fibroblasts then proliferates, secrete collagen
and form this thick scar. Now, if we're going to try to
regenerate, how are we going to get myocytes to get back into
that thick scar when there's really a complete absence?


And so as adult cardiomyocytes have little regenerative capacity,
resident cardiac fibroblasts synthesize extracellular matrix,
post myocardial infarction to form fibrosis, leading to cardiac
dysfunction and heart failure. And therapies that can regenerate
the myocardium and reverse fibrosis in the setting of a chronic
myocardial infarction are lacking. Now, these investigators led
by Professor Masaki Ieda from University of Tsukuba, were going
to evaluate this process. The overexpression of cardiac
transcription factors, including Mef2c, Gata4, Tbx5, Han2, all
combined as MGTH. They can directly reprogram cardiac fibroblasts
into induced cardiomyocytes and improve cardiac function in and
under the setting of an acute myocardial infarction. However, the
ability of an in vivo cardiac reprogramming to repair chronic
myocardial infarction with established scars, well, that is
really undetermined.


Dr. Peder Myhre:


Oh, what a wonderful introduction, Greg. And the way you
described to us how cardiomyocytes and fibroblasts interact was
really fascinating. Thank you. And now let's hear what the
authors found and don't forget the clinical implications.


Dr. Greg Hundley:


Thanks, Peder. So these authors developed a novel transgenic
mouse system where cardiac reprogramming and fibroblasts lineage
tracing could be regulated spatiotemporally with tamoxifen
treatment to analyze in vivo cardiac reprogramming in the setting
of chronic MI. Then with this new model, the authors found in
vivo cardiac reprogramming generates new induced cardiomyocytes
from resident cardiac fibroblasts that improves cardiac function
and reduces fibrosis in chronic myocardial infarction in mice.
Wow.


And additionally, they found that overexpression of cardiac
reprogramming factors converts profibrotic cardio fibroblasts to
a quiescent state, and that reverses fibrosis in chronic
myocardial infarction. And therefore, Peder, direct cardiac
reprogramming may be a promising therapy for chronic ischemic
cardiomyopathies and heart failure. Really exciting work,
converting scar tissue to actual functional cardiomyocytes.


Dr. Peder Myhre:


That was such a fantastic summary, Greg, and a very interesting
paper. And I'm now going to take us back to clinical science and
epidemiology. Because Greg, we all know that social and
psychosocial factors are associated with cardiovascular disease
risk. But the relative contributions of these factors to racial
and ethnic differences in cardiovascular health has not been
quantified. So these authors, led by the corresponding author,
Nilay Shah from Northwestern University Feinberg School of
Medicine in Chicago, used data from NHANES to examine the
contributions of individual level social and psychosocial factors
to racial and ethnic differences in population cardiovascular
health. And that was measured by something called the
cardiovascular health score, CVH score, which ranges from zero to
14, and it counts for diet, smoking, physical activity, body mass
index, blood pressure, cholesterol, and blood glucose.


Dr. Greg Hundley:


Wow, really interesting, Peder. So what did they find here?


Dr. Peder Myhre:


So Greg, among males, the mean cardiovascular health score was
7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic
black, and 7.6 in non-Hispanic white adults. And the authors
found that the education explained the largest component of
cardiovascular health differences among males. And now what about
females? In females, the mean score was 8.0 in Hispanic, 9.3 in
non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in
non-Hispanic white adults. And for women, education explained the
largest competence of cardiovascular health difference in
non-Hispanic black. And place of birth, and that is US born
versus born outside the US, explained the largest component of
cardiovascular health difference in Hispanic and non-Hispanic
Asian females. So Greg, the authors conclude that education and
place of birth conferred the largest statistical contributions to
the racial and ethnic differences in cardiovascular health among
US adults.


Dr. Greg Hundley:


Very nice, Peder. What a beautiful description and outline that
so well highlighting the differences in men versus women. Well,
now we're going to turn back to the world of preclinical science,
listeners. And we will continue with the paper by Dr. Amit Khera
from Verve Therapeutics. Now, Peder, VERVE-101, this is an
investigational in vivo CRISPR base editing medicine designed to
alter a single DNA base in the PCSK9 gene. And that permanently
turns off hepatic protein production and thereby, durably lowers
LDL cholesterol. In this study, the investigators tested the
efficacy, durability, tolerability, and potential for germline
editing of VERVE-101 in studies of non-human primates and also in
a murine F1 progeny study.


Dr. Peder Myhre:


So more on PCSK9s, and this time CRISPR technology. Very
exciting. Greg, what did they find?


Dr. Greg Hundley:


Right, Peder. So VERVE-101 was well tolerated in non-human
primates and led to, listen to this, an 83% lower blood PCSK9
protein and 69% lowering of LDL-C with durable effects up to 476
days following the dosing. These results have supported
initiation of a first inhuman clinical trial. That's what needs
to come next in patients with heterozygous familial
hypercholesterolemia and atherosclerotic cardiovascular disease.
Wow.


Dr. Peder Myhre:


Even greater reductions from this therapy on PCSK9 than the
previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we
go from one fascinating study to another. And this time we
actually have the primary results from a large randomized
clinical trial, Greg. Isn't that exciting?


Dr. Greg Hundley:


Yes.


Dr. Peder Myhre:


And this paper describes the primary results of a trial testing
in Indobufen versus aspirin on top of clopidogrel in patients
undergoing PCI with drug-eluting stent DES who did not have
elevated troponin. So that is patients without mycardial
infarction. And in fact, fact, this is the first large randomized
control trial to explore the efficacy and safety of aspirin
replacement on top of P2Y12 inhibitor in patients receiving PCI
with death. And Greg, I suppose you like I wonder what Indobufen
is, and I just learned that that is a reversible inhibitor of
platelet Cox-1 activity and it has comparable biochemical and
functional effects to dose of aspirin. And previous data indicate
that Indobufen could lessen the unwanted side effects of aspirin
and that includes allergy intolerance and most importantly,
aspirin resistance, while it retains the antithrombotic efficacy.


Dr. Greg Hundley:


Wow, Peder. Really interesting and great explanation. Indobufen.
So how did they design this trial and what were the primary
results?


Dr. Peder Myhre:


So Greg, the investigators of this trial, called OPTION, led by
corresponding authors, Drs. Ge, Quian, and Wu from Fudan
University in Shanghai, randomized 4,551 patients from 103 center
to either indobufen based DAPT or conventional, and that is
aspirin based DAPT for 12 months after DES implementation. And
the trial was open label and with a non-inferiority design, which
is important to keep in mind. And the primary endpoint was a one
year composite of cardiovascular death, non-fatal MI, ischemic
stroke, definite or probable stent thrombosis or bleeding,
defined as BARC criteria type 2, 3, or 5.


And now Greg, the primary endpoint occurred in 101, that is 4.5%
of patients in the indobufen based DAPT group compared to 140,
that is 6.1% patients, in the conventional DAPT group. And that
yields an absolute difference of 1.6%. And the P for
non-inferiority was less than 0.01. And the hazard ratio was 0.73
with confidence intervals ranging from 0.56 to 0.94.


And Greg, the occurrence of bleeding was particularly interesting
and that was also lower in the indobufen based DAPT group
compared to the conventional DAPT group. And that was 3.0% versus
4.0% with the hazard ratio of 0.63. And that was primarily driven
by a decrease in BARC type two bleeding.


So Greg, the authors conclude that in Chinese patients with
negative cardiac troponin undergoing DES implementation,
indobufen plus clopidogrel DAPT compared with aspirin plus
clopidogrel DAPT significantly reduced the risk of one year net
clinical outcomes, which was mainly driven by reduction in
bleeding events without an increase in ischemic events.


Dr. Greg Hundley:


Very nice, Peder. So another reversible inhibitor of platelet
COX-1 activity, indobufen. And seems to be very, have high
utility in individuals of Chinese ethnicity and Asian race. Well,
perhaps more to come on that particular drug. Peder, how about we
dive into some of the other articles in the issue? And I'll go
first. So first, there's a Frontiers article by Professor Beatty
entitled “A New Era and Cardiac Rehabilitation Delivery: Research
Gaps, Questions, Strategies and Priorities.” And then there's a
Research Letter by Professor Zuurbier entitled, “SGLT-2
inhibitor, Empagliflozin, reduces Infarct Size Independent of
SGLT-2.”


Dr. Peder Myhre:


And then Greg, we have a new ECG challenge by Drs. Haghighat,
Goldschlager and Oesterle entitled, “AV Block or Something Else?”
And then there is a Perspective piece by Dr. Patrick Lawler
entitled, “Models for Evidence Generation During the COVID-19
Pandemic: New Opportunities for Clinical Trials in Cardiovascular
Medicine.” And Greg, there's definitely so much to learn from all
the research that has been done through the pandemic. And
finally, we have our own Molly Robbins giving us Highlights from
the Circulation Family of Journals. And first, there is a paper
describing the characteristics of postoperative heart block in
patients undergoing congenital heart surgery described in
Circulation: Arrhythmia Electrophysiology. Next, the impact of
socioeconomic disadvantages on heart failure outcomes reported in
Circulation: Heart Failure. Then there is social and physical
barriers to healthy food explored in circulation, cardiovascular
quality and outcomes. And then there is the association of
culprit-plaque morphology with varying degrees of infarct,
myocardial injury size reported in Circulation: Cardiovascular
Imaging. And finally, the impact of optical coherence tomography
on PCI decisions reported in circulation cardiovascular
interventions.


Dr. Greg Hundley:


Fantastic, Peder. Well, how about we get off to that feature
discussion?


Dr. Peder Myhre:


Let's go.


Dr. Mercedes Carnethon:


Well, thank you and welcome to this episode of the Circulation on
the Run Podcast. I'm really excited today to host this show. My
name is Mercedes Carnethon. I'm an associate editor at
Circulation and Professor and Vice Chair of Preventive Medicine
at the Northwestern University Feinberg School of Medicine. I'm
really excited to learn from the lead author of a new study on
decongestion with Acetazolamide and acute decompensated heart
failure across the spectrum of LV ejection fraction. And I've got
the lead author with me today, Pieter Martens, as well as my
colleague and associate editor Justin Grodin, who handled the
paper. So I'd love to start off with just welcoming you, Dr.
Martens.


Dr. Pieter Martens:


Thank you for having me. It's a pleasure to be here today.


Dr. Mercedes Carnethon:


Yes. And thank you so much for submitting your important work to
the journal, Circulation. I'd love to start to hear a little bit
about what was your rationale for carrying out this trial and
tell us a little bit about what you found.


Dr. Pieter Martens:


So the ADVOR trial was a double blind placebo controlled
randomized trial, which was performed in Belgium. And it set out
to assess the effect of acetazolamide in acute decompensated
heart failure and this on top of standardized loop diuretic
therapy and patients with heart failure. And the goal of the
current analysis was to assess whether the treatment effect of
acetazolamide in acute heart failure differs amongst patients
with a different ejection fraction at baseline at randomization.
So we looked specifically at patients with heart failure,
reduced, mildly reduced and preserved ejection fraction to
determine whether acetazolamide works equally well in those
patients.


Dr. Mercedes Carnethon:


Well, thank you so much. Tell me a little more. What did you
find? Did your findings surprise you?


Dr. Pieter Martens:


All patients that were randomized in the ADVOR trial, we
registered a baseline left ventricular ejection fraction at
baseline. And what we saw was at the multiple endpoints that we
collected in the ADVOR trial, that randomization towards
acetazolamide was associated with a pronounced and preserved
treatment effect. And different endpoints that we looked at was a
primary endpoint which was successful, which is an important
endpoint, which we all strive towards in acute decompensated
heart failure. And we saw that irrespective of what your baseline
ejection fraction was, that randomization towards acetazolamide
was associated with a higher odds ratio for having successful
decongestion.


And also looking at other endpoints which we find important in
the treatment of patients with acute compensated heart failure,
such as renal endpoints such as the diuresis, the amount of urine
that they make, or the natruresis, the amount of sodium that they
excrete, we again saw that randomization towards acetazolamide
was associated with a higher treatment effect, so more diuresis,
more natruresis, which was not effective, whether you had heart
failure, reduced, mildly reduced or preserved eject fraction. We
did see a slight increase in the creatinine, which was a little
bit more pronounced in patients with heart failure with reduced
ejection fraction.


Dr. Mercedes Carnethon:


Thank you so much for that excellent summary. I'm an
epidemiologist, so I'm certainly aware that of the cardiovascular
diseases and their changes over time, heart failure is one that
is going up over time and affecting more of the population. So I
know I really enjoyed hearing about an additional therapy that
helps to improve quality of life and improve clinical outcomes in
individuals who are experiencing heart failure. And I'm really
curious as I turn to you, Justin, what attracted you to this
particular article and why did you find it to be such a good fit
for our audience here at Circulation?


Dr. Justin Grodin:


Well, Mercedes, I mean, I think you hit the nail on the head with
your comment. And clearly when we look at Medicare beneficiaries
in the United States, hospitalization for decompensated heart
failure is the number one or most common cause for
hospitalization. And up to this time, we really haven't had any
multi-center randomized control clinical trials that have really
informed clinical care with a positive result or a novel strategy
that says, "Hey, this might be a better way to treat someone in
comparison with something else."


And so when we have a clinical trial like ADVOR, one of the
crucial things that we want to understand is how does this work
and does it work for everybody? And now when we look at the
population hospitalized with heart failure, we know that
approximately half of them have a weak heart or low ejection
fraction, and the other half have a stiff heart, a normal
ejection fraction. And so since we've got this 50/50 makeup, it
is a crucially important question to understand if we have an
important study like ADVOR, does this apply? Are these benefits
enjoyed by all these individuals across the spectrum?


Dr. Mercedes Carnethon:


Thank you so much for really putting that in context. And I
believe you had some additional questions for Dr. Martens.


Dr. Justin Grodin:


Yes. Yeah, thank you. So Pieter, I mean obviously this was a
terrific study. One question I had for you guys is, you and your
colleagues and the ADVOR research team is whether you had
expected these results. Because we know at least historically,
that there might be different cardiorenal implications for
individuals that have a weak heart or heart failure with reduced
ejection fraction in comparison with a stiff heart or heart
failure with preserved ejection fraction.


Dr. Pieter Martens:


Thank you for that comment. And thank you also for the nice
feedback on the paper. I think we were not really completely
surprised by the results. I think from a pathophysiologic
perspective, we do wonder whether heart failure with reduced
ejection fraction from a kind of renal perspective is different
from heart failure with preserved ejection fraction. Clearly,
there are a lot of pathophysiological differences between heart
failure with reduced, mildly reduced and preserved ejection
fraction. But when it comes to congestion and acute heart
failure, they seem to behave, or at least similarly in terms of
response to acetazolamide, which was very interesting. We do
think there are neurohormonal differences between heart failure
reduced ejection fraction, preserved ejection fraction. But at
least how acetazolamide works seems relatively unaffected by the
ejection fraction.


Dr. Justin Grodin:


And Pieter, another question that comes to mind, and this is
getting a little bit technical, but there have been studies that
have shown that people that present to the hospital with
decompensated heart failure, that have HFpEF, have a very
different perhaps congestion phenotype where they might not have
as much blood volume expansion. And so I, for one, was pretty
curious as to how these results were going to play out. And I
wonder what your thoughts are on that, or maybe that's perhaps
more niche and less widely applicable than what you observed.


Dr. Pieter Martens:


Now, I can completely agree that when we are thinking about
congestion, the congestion itself is a sort of pressure based
phenomenon. And the pressure based phenomenon is based on what
your volume is and the compliance within your cardiovascular
system. But I think one of the important things to remember is
that how we enrolled patients in the ADVOR trial was that we
enrolled patients who had clear signs of volume overload.
Remember, we used a volume score to assess clinical decongestion
or actually getting rid of the volume. Volume assessment isn't
really necessarily a pressure based assessment. And pressures
might be the genesis of elevated pressures might be different
amongst heart failure with reduced versus preserved ejection
fraction.


But what was really clear was that all these patients were volume
overloaded. And when you think about the volume axis, then it's
really about getting rid of that additional sodium, water, and
that's where really acetazolamide works. So I do think we differ
a little bit from historical acute decompensated heart failure
trials in which they sometimes use signs and symptoms of more
congestion, a pressure based phenomenon, where our endpoint was
truly at volume endpoint. And we do believe that diuretics work
really on a volume component of heart failure.


Dr. Mercedes Carnethon:


Thank you so much, especially for explaining that in a way that
even non-clinicians such as myself can understand the potential
implications. A big picture question that I have, and I really
enjoy these discussions because they give us an opportunity to
speculate beyond what we read in the paper. And that question is
we do clinical trials and we identify effective therapies. And
one of the bigger challenges we often face is getting those
therapies out to the people who need them. Do you perceive any
barriers in uptake of the use of acetazolamide in clinical
practice?


Dr. Pieter Martens:


That's an excellent question. So one of the, I think beauties
about acetazolamide is that this drug has been on the market for
about 70 years. So I think everybody has access to it. This is
not a novel compound which needs to go through different steps of
getting marketing approval and getting a sort of reimbursement
before it becomes available in clinical practice. And in theory,
everybody should have access to this relatively cheap agent and
can use it in its clinical practice. And I think it was very
interested when we came out with the initial paper. I think
already the day afterwards, we were getting messages from across
the world that people have been using acetazolamide. So I think
it is an agent which is available in current clinical practice
and should not be too many barriers to its current implementation
and clinical practice.


Dr. Mercedes Carnethon:


Well, that's fantastic to hear. So I hope Justin, that you will
certainly help to ring the bell to get the information out about
this wonderful study. I do want to turn to you, Pieter, to find
out whether or not there are any final points that you didn't
have an opportunity to discuss with us today.


Dr. Pieter Martens:


Think some of the other end points we didn't discuss were the
effect, for instance, on length of stay. I think length of stay
is a very important endpoint because hospital admissions, like
Justin said, heart failure is the number one reason why elderly
patients are being admitted. And just shortening the length of
stay from a financial perspective might be important. So it was
also very interesting to see that the use of acetazolamide in the
study also translated into a shorter length of stay, which was
also was unaffected, whether you had heart failure, reduced,
mildly reduced or preserved ejection fraction,


Dr. Mercedes Carnethon:


Well, I certainly know people appreciate being in their own homes
and being able to discharge is certainly a major benefit. So
thank you so much for sharing that final point. I really want to
thank you so much for a stimulating discussion today. I know that
I learned a lot from you, Pieter, and the hard work of your
research team as well as from you, Justin, for putting these
findings in context and really helping our listeners and the
readers of our journal understand why this paper is so important
and how it's really moving the field forward for a clinically
important problem. So thank you both so much for joining us here
today on Circulation on the Run.


Dr. Justin Grodin:


Thank you.


Dr. Pieter Martens:


Thank you for having me.


Dr. Mercedes Carnethon:


I really want to thank our listeners for joining us today for
this episode of Circulation on the Run. I hope you will join us
again next week for more exciting discussions with our authors.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2023.
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.