Circulation October 11, 2022 Issue

This week, please join author Michelle O'Donoghue and
Associate Editor Parag Joshi as they discuss the article
"Long-Term Evolocumab in Patients With Established
Atherosclerotic Cardiovascular Disease."


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, 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 and Director of the
Poly Heart Center at VCU Health in Richmond, Virginia. Well,
Carolyn, very interesting feature this week. Evolocumab, another
application for that in patients with established atherosclerotic
cardiovascular disease. But before we get to that feature
discussion, how about we grab a cup of coffee and discuss some of
the other very interesting articles in this issue?


Dr. Carolyn Lam:


Oh, I'd love that. And I'd like to go first, because Craig, have
you heard of hybrid debranching repair? I know, I know. I had
that same look, and can I tell you about it? Because I found it
so interesting.


Dr. Greg Hundley:


Absolutely.


Dr. Carolyn Lam:


Now, the management of complex aortic aneurysmal disease
involving the visceral vessels is challenging due to its very
high morbidity and mortality. After four decades of experience in
open repair, only a few centers worldwide report laudable
results. And numerous factors limit total endovascular repair,
including the access to devices, experience in deploying them,
and several anatomical restrictions. So, hybrid debranching
procedures were introduced for those patients who are unfit for
the open or endovascular excluded patients. And while these have
been developed, small series have only been done and revealed a
wide range of short term results. So, today's paper is very
important, and it's from Dr. Oderich from UT Memorial Herman
Texas Medical Center and colleagues.


It's a large multi-institutional study, which contains the five
year outcomes in 200 patients offering greater clarity in the
usefulness and limitations of these hybrid debranching repair
procedures. What they found was that hybrid aortic debranching
had a low early mortality when done in lower risk patients, but
mortality remained very elevated in high risk patients. And so,
this suggests that deep branching could be a good alternative in
patients adequate for traditional open repair, although pulmonary
complications are quite common. The bypass grafts to the visceral
vessels had very good patency with a five year primary patency of
90%. Permanent spinal cord injury occurred in 6%, suggesting that
deep branching in experienced centers may offer outcomes
comparable to centers of excellence for open thoracoabdominal
aortic aneurysm repair.


Dr. Greg Hundley:


Wow, Carolyn, very nice and so beautifully explained.


Dr. Carolyn Lam:


You know what, Greg? I'm on a roll and I'd like to tell you about
one more, this time a preclinical study. First, a little bit
about the background. You see, transplantation with pleuripotent
stem cell derived cardiomyocytes, as we know, represents a very
promising therapeutic strategy for cardiac regeneration. We even
have first clinical studies in humans, but yet little is known
about the mechanism of action underlying graft induced benefits.
So in this paper from Dr. Weinberger from University Medical
Center Hamburg in Germany and colleagues, they explored whether
transplanted cardiomyocytes actually actively contribute to heart
function by injecting these cardiomyocytes with an optogenetic
off on switch in a Guinea pig cardiac injury model.


Dr. Greg Hundley:


Wow, Carolyn, this is so interesting. So what did they find?


Dr. Carolyn Lam:


So, light induced inhibition of endo-grafted cardiomyocyte
contractility resulted in a rapid decrease in left ventricular
function in about 50% of the animals that was fully reversible
with the offset of photo stimulation. So in conclusion, this
optogenetic approach demonstrated that transplanted
cardiomyocytes can actively participate in heart function,
supporting the hypothesis that the delivery of new force
generating myocardium can serve as a regenerative therapeutic
strategy.


Dr. Greg Hundley:


Oh wow, Carolyn. That was just fascinating. Such incredible
preclinical science in our journal. Well, Carolyn, this next
paper comes to us from the world of myocarditis. And Carolyn, it
involves a population based cohort of 336 consecutively recruited
patients with acute myocarditis enrolled in both London and
Maastricht. And the authors, led by Dr. Sanjay Prasad from Royal
Brompton Hospital, investigated the frequency and clinical
consequences of dilated cardiomyopathy and arrhythmogenic
cardiomyopathy genetic variants in this population based cohorts
of patients with acute myocarditis. Now, Carolyn, all
participants underwent targeted DNA sequencing for well
characterized cardiomyopathy associated genes and their
comparison to healthy controls, of which they had 1,053 that were
sequenced on the same platform. Case ascertainment of their
outcomes in England was assessed against their national hospital
admission data, and the primary outcome was all cause mortality.


Dr. Carolyn Lam:


So what did they find, Greg?


Dr. Greg Hundley:


Right, Carolyn. So these authors identified for dilated
cardiomyopathy or arrhythmogenic cardiomyopathy associated
genetic variants in 8% of patients with acute myocarditis. This
was dominated by the identification of desmoplakin truncating
variants in those with normal LVF, and then titin truncating
variants in those with a reduced LVF. So Carolyn, importantly,
these variants have clinical implications for treatment, risk
stratification, and family screening. Genetic counseling and
testing would be considered in patients with acute myocarditis to
help reassure the majority of individuals that don't have one of
these genes, while improving the management of those that do have
one of the underlying genetic variants. Very interesting findings
from the world of myocarditis.


Dr. Carolyn Lam:


Great. And a great clinical take home message. Thank you, Greg.
Well, this next paper sought to investigate the influence of age
on the diagnostic performance of cardiac troponins in patients
presenting with suspected myocardial infarction. Dr. Atul Anand
from the BHF Center for Cardiovascular Science and University of
Edinburgh and colleagues did this by performing a secondary
analysis of the high stakes stepped wedge cluster randomized
control trial that evaluated the implementation of a high
sensitivity cardiac troponin ISA in consecutive patients
presenting with suspected acute coronary syndrome.


Dr. Greg Hundley:


Oh wow. Carolyn. Super interesting, and very applicable
clinically. So what did they find here?


Dr. Carolyn Lam:


In older patients presenting with suspected MI, the majority of
cardiac troponin elevations are explained by acute or chronic
myocardial injury or type two MI. The specificity and positive
predictive value of high sensitivity cardiac troponin to identify
myocardial infarction decreases with age and is observed, whether
applying sex specific or age adjusted 99th percentile diagnostic
thresholds or a rolling threshold for the triage of patients at
high probability of myocardial infarction. Serial troponin
testing incorporating an absolute change in troponin
concentration increased the discrimination for myocardial
infarction in older adults.


Dr. Greg Hundley:


Oh wow, Carolyn. Such clinically applicable findings in this
particular study, particularly when managing our aging
population. Well, Carolyn, how about we discuss some of the other
articles in this issue. And there's a very nice In-depth piece by
our own Sami Viskin entitled “Arrhythmogenic Effects of Cardiac
Memory.” And then, there's an exchange of letters by Drs.
Giannitsis and Mueller regarding the article, “Unexpected
Sensitivity Issue of Three High Sensitivity Cardiac Troponin
I-Assays in Patients with Severe Cardiac Disease and Chronic
Skeletal Muscle Diseases.”


Dr. Carolyn Lam:


Nice. There's also a Research Letter by Dr. Szendroedi on
“Impaired Mitochondrial Respiration in Humans with Prediabetes: A
Footprint of Prediabetic Cardiomyopathy.” And there's a CV case
series by Dr. Kalra on very high cholesterol mimicking homozygous
familial hypercholesterolemia. Interesting case. Well, I suppose
that wraps it up. Let's go on to the feature discussion, shall
we, Greg?


Dr. Greg Hundley:


You bet.


Evolocumab. Welcome listers to this feature discussion on October
11th, and we're very fortunate today. We have with us Dr.
Michelle O'Donoghue from Brigham Women's Hospital and Dr. Parag
Joshi from UT Southwestern, the Associate Editor for this paper.
Well, Michelle, can you describe for us some of the background
information that went into the preparation of your study, and
then what was the hypothesis that you wanted to address?


 


Dr. Michelle O'Donoghue:


Sure. Happy to do so, and thank you for having me. So by way of
background, the Fourier study, which was previously published in
the New England Journal, compared Evolocumab to placebo in 27,000
plus patients with established atherosclerotic cardiovascular
disease, and Evolocumab significantly reduced the risk of major
adverse cardiovascular events. But, the follow up duration was
relatively short. Median follow up was 2.2 years. So this was now
an open label extension study to Fourier known as the Fourier OLE
study that allowed an additional median follow up time of five
years, during which time all patients were now treated with open
label Evolocumab. T.


He primary hypothesis that we were testing in this extension
study was primarily to look at long term safety. We had limited
data to really assure us of the safety of PCSK9 inhibitors over
the course of several years. And so, safety was the primary
hypothesis that we were testing, but also of course of key
interest, during the parent Fourier study, we know that the
benefit for cardiovascular risk reduction appeared to grow over
time. So this was also an opportunity to see that pattern and to
see whether or not there was in fact legacy effect for patients
who were treated earlier with Evolocumab versus placebo.


Dr. Greg Hundley:


Very nice, Michelle. And so, sounds like we have a substudy of
the Fourier trial. Can you describe for us a little bit more, for
this substudy, your study population and your study design?


Dr. Michelle O'Donoghue:


Sure. So the patients enrolled in the open label extension were a
subset of those who participated in the parent study. So as I
previously mentioned, more than 27,000 participated in Fourier.
It was a global study. For the open label extension, it was more
than 6,500 patients who participated, and those were patients who
were at sites in Europe and United States. And so, those patients
were then followed on average for a meeting of five years. So
that means that all together, patients who had been randomized to
Evolocumab in the parent study had potentially more than eight
years of drug exposure for us to examine safety.


Dr. Greg Hundley:


Very nice. And so, what did you find?


Dr. Michelle O'Donoghue:


Well, first, looking at the first hypothesis of safety, we saw no
evidence that there was any increased risk of any adverse events
of interest when it comes to PCSK9 inhibitors as a drug class, or
achieving very low levels of LDL cholesterol. So there was no
uptick in terms of neurocognitive events, the risk of diabetes.
We do know that there was an increased risk of injection site
reactions with the PCSK9 inhibitors, but not one that appeared to
persist over time. So first was the safety, but importantly, I
think that the more interesting results perhaps were those for
MACE, for cardiovascular risk reduction. So we saw, even though
all patients were being treated with open label Evolocumab during
the extension phase, the benefit that was seen during the parent
study persisted.


So there was a 15% reduction in the primary outcome, a broad
composite of cardiovascular events. There was also a 20%
reduction in the triple composite of cardiovascular death, MI, or
stroke. And then perhaps of the most interest to your listeners
is that there was a 23% reduction in cardiovascular mortality,
and that was not something that was seen in the parent study. It
really took time for that mortality benefit to emerge.


Dr. Greg Hundley:


Very nice. Michelle. Just a couple quick clarification points.
Did you see these effects in both men and women? And then was
there any impact of age on those results?


Dr. Michelle O'Donoghue:


Great questions. Some of those subgroup analyses are still
ongoing, but no, we did not see any evidence of effect
modification at first pass. But again, we'll be continuing to dig
into all potential subgroups.


Dr. Greg Hundley:


Very nice. Parag, I know you have many papers come across your
desk. What attracted you to this particular manuscript?


Dr. Parag Joshi:


Yeah, thanks. And congratulations again, Michelle. It's a really
phenomenal study, and the findings, as you highlighted, are just
really impactful for the field. I think for our journal at
circulation, this is a really high impact finding in terms of
extending out, giving us a rigorous way to look at long term
follow up for people on PCSK9 inhibitors and really reassure that
there is safety there. And as you highlighted, a sustained
reduction in LDL cholesterol, other compounds in the space,
Bococizumab in particular, that there were induced antibodies
against the monoclonal antibody, and that sustained response was
not there. So I thought that was also really reassuring, that
over the course of eight years, we see sustained LDL reduction.
And with that, really reaffirming the idea that the longer you
can reduce LDL, there's an associated reduction in events.


And as you highlighted, the initial Fourier, there was some
question about why there wasn't a CV death mortality signal while
there was in the Odyssey outcome study and slightly different
patient populations of course, but just really needed more time
to start to tease that out. So all of this, I think this is the
first that we're seeing this kind of long-term data on this
impactful class of medications that really made this a fantastic
manuscript for us at Circulation.


Dr. Greg Hundley:


Wow. Boy, Parag, I don't know that you could have stated that any
better. So Michelle, looking forward, what is your group
thinking? And then maybe just as your comment on the field in
general, what do you think is the next study or series of studies
that needs to be performed in this sphere of research?


Dr. Michelle O'Donoghue:


Well, I think he started to touch upon the areas of interest to
us, is that I think that there are still many opportunities to
answer more questions even within this existing data set. In
particular, there was a dedicated neurocognitive substudy that
was built into the parent study. And we also have that now
through the extension period. So, that was a sort of more
rigorous assessment of neurocognitive outcomes. And so, that's
another analysis that we're going to be pursuing in the near
future and I think is of potential key interest. And then beyond
that, I think that the PCSK9 inhibitor class in general is just
so interesting. There are additional compounds that are under
study, such as small interfering RNA, so different mechanisms of
getting to the PCSK9 protein. And I think it'll be reassuring to
see whether or not they are consistent results, regardless of how
you lower PCSK9, whether it translates into similar types of
clinical benefit. So I think it's an exciting field. And then
stay tuned. I think there'll be more to come.


Dr. Greg Hundley:


Parag, do you have anything to add? What do you see really as the
next series of studies that might be performed here in this area
of research?


Dr. Parag Joshi:


Yeah, I think Michelle hit the nail on the head that seeing
confirmatory evidence here would be great. And then really,
what's so exciting about this space is there's so much interest
in ways to address this protein, including gene editing,
vaccination against it. And now you're getting the necessary
evidence that, hey, you can really suppress these levels in
patients for years without concerning safety signals, at least
from what we've seen so far. So that's more excitement as to long
term ways to address cardiovascular risk.


Dr. Greg Hundley:


Wow. Well, listeners, we've been very fortunate today to have
with us Dr. Michelle O'Donaghue from Brigham and Women's
Hospital, and Dr. Parag Joshi from UT Southwestern as the
Associate Editor of Circulation to really bring us these exciting
results, highlighting that long term LDL-C lowering with
Evolocumab was associated with persistently low rates of adverse
events over eight years that did not exceed those observed in the
original placebo arm during the parent Fourier study, and led to
further reductions in cardiovascular events compared with delayed
treatment initiation.


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.