Circulation April 18, 2023 Issue

This week, please join authors Marc Sabatine and Prakriti
Gaba, as well as Associate Editor Amit Khera, as they discuss the
article "Association Between Achieved Low-Density Lipoprotein
Cholesterol Levels and Long-Term Cardiovascular and Safety
Outcomes: An Analysis of FOURIER-OLE."


Dr Greg Hundley:


Welcome listeners, to this April 18th issue of Circulation on the
Run and I am Dr. Greg Hundley, Associate Editor, Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr Peder Myhre:


And I'm Dr. Peder Myhre, Social Media Editor from Akershus
University Hospital and University of Oslo.


Dr Greg Hundley:


Peder, today's feature discussion, very interesting. We're going
to evaluate the association between what's achieved with LDL
cholesterol lowering, and then also long-term cardiovascular and
safety outcomes. But before we get to that, how about we grab a
cup of coffee and discuss some of the other articles in the
issue? Would you like to go first?


Dr Peder Myhre:


Yes, Greg. I would love to. And the first paper is from the World
of Preclinical Science and it comes to us from corresponding
author, Jan Magnus Aronsen from University of Oslo in Norway. And
perhaps, as you know, Greg, cardiomyocyte contraction and
relaxation depend on the activity of the sarcoplasmic reticulum
CA+2 ATPase 2, abbreviated SERCA2, and lowered levels or reduced
activity of SERCA2, as seen in chronic heart failure, weakens
contractile force and delays relaxation and no available therapy
involves direct manipulation of the SERCA2 activity. And Greg,
phosphodiesterase 3A is proposed to be present in the SERCA2
interactome limit SERCA2 activity and disruption of
phosphodiesterase 3A from SERCA2 might thus be a strategy to
develop SERCA2 activators. And in this study, the authors
investigated and mapped SERCA2 and phosphodiesterase 3A and
assessed this in experiments assessing the binding between these
two in cardiomyocytes and in vesicles.


Dr Greg Hundley:


Wow Peder, sounds very interesting. So what did they find and how
about the clinical implications of the findings?


Dr Peder Myhre:


So Greg phosphodiesterase 3A bounded directly to SERCA2 in the
cardiomyocyte. So that's the first finding. Second, they
demonstrated that SERCA2 phosphodiesterase 3A disruption
increased SERCA2 activity independently of the catalytic activity
of phosphodiesterase 3A in both normal and failing
cardiomyocytes. And third, SERCA2 activity by the optimized
SERCA2 phosphodiesterase 3A disruptor peptide OPT F reduced
mortality and improved contractility after aortic binding in
mice. So the clinical implication is that direct targeting of
phosphodiesterase 3A binding to SERCA2 could be a novel approach
to increase SERCA2 activity and thus cardiac contractility in
patients with heart failure.


Dr Greg Hundley:


Very nice Peder. What a great new finding in the world of
preclinical science. Well my paper is going to delve into the
world of clinical science and involves patients with stroke. So
Peder in this study led by corresponding author, Dr. Dileep
Yavagal from University of Miami Miller School of Medicine
performed a survey in 75 countries through the Mission
Thrombectomy 2020+ Global Network between November of 2020 and
February of 2021 to determine the availability of mechanical
thrombectomy for large vessel occlusion in patients with stroke.
Now Peder, the primary endpoints were the current annual
mechanical thrombectomy availability, the mechanical thrombectomy
operator availability and the mechanical thrombectomy center
availability. All of these availabilities were defined as the
proportion of estimated large vessel occlusion for patients
receiving mechanical thrombectomy in a given region annually.


Dr Peder Myhre:


Okay, Greg, so this is really an access question. So in essence,
what is the availability of mechanical thrombectomy worldwide? So
what did they find?


Dr Greg Hundley:


Right, great Peder. So what they found, the authors received 887
responses from 67 countries and low-income countries had 88%
lower mechanical thrombectomy availability compared to
high-income countries. The global mechanical thrombectomy
operator availability was 16.5% of optimal, and the mechanical
thrombectomy center availability was only 20.8% optimal. And with
these results, the authors indicate that global cooperation and
targeted region-specific public health interventions, including
all stakeholders involved in stroke care delivery, are really
needed to rapidly increase access to this brain-saving and
disability-sparing treatment with mechanical thrombectomy really
worldwide.


Dr Peder Myhre:


Oh wow. What a beautiful summary, Greg. Thank you so much. And we
also have some other interesting papers in the mailbag today. We
have an exchange of letters between Dr. Yang and Dr. O'Donoghue
regarding the article “Long Term evolocumab in Patients with
Established Atherosclerotic Cardiovascular Disease.”


Dr Greg Hundley:


Great Peder, and also Professor Perera has a Frontiers article
entitled “Unloading the Left Ventricle in Venoarterial ECMO in
Who, When and How?” and then finally there's a Research Letter
from Professor Verma entitled “Prevalence of Diabetes and
Cardiovascular Risk in the Middle East and Africa: The Primary
results of the PACT-MEA Study.” Well Peder, how about we jump to
that feature discussion?


Dr Peder Myhre:


Can't wait.


Dr Greg Hundley:


Welcome listeners to this feature discussion on April 18th and we
have with us today Prakriti Gaba and Marc Sabatine from Brigham
and Women's Hospital and our own associate editor, Dr. Amit
Khera. Welcome everyone. Well Marc, we'll start with you. Can you
describe for us some of the background information that really
helps constitute the preparation of your study and what was the
hypothesis that you wanted to address?


Dr. Marc Sabatine:


Yeah, thanks Greg and thanks for having us. So we've seen in a
variety of epidemiologic cohorts the association between LDL
cholesterol and the risk of adverse cardiovascular events like in
Framingham Heart Study and UK Biobank. But in those cohorts, in
these industrial societies, we don't have the benefit of lots of
data in individuals with very low levels of LDL cholesterol and
so we had the opportunity with the FOURIER study that was the
randomized comparison of evolocumab PCSK9 inhibitor versus
placebo to get patients down to extremely low levels of LDL
cholesterol and evolocumab. We were able to get individuals down
to about 30 mg/dL. And so in addition to all the studies we've
done showing the comparison of evolocumab to placebo, we also
then had the chance to use FOURIER, and as you'll hear from PK,
FOURIER-OLE, the open-label extension, as a cohort to then
examine patients' new baseline, if you will, their new achieved
LDL cholesterol and then it's association not only with
cardiovascular events but safety events.


And so the hypothesis is that there would be a relationship with
the lower the LDL cholesterol, the lower the risk of
cardiovascular events and we wanted to explore how far down that
went. And then the second one for safety would be that there
wouldn't be any association between low levels of LDL cholesterol
and a variety of safety outcomes that rightly or wrongly people
have ascribed to low levels of LDL cholesterol.


Dr Greg Hundley:


Thanks so much, Marc. Well listeners, now we're going to turn to
PK, the first author, on this very interesting paper and PK, Marc
mentioned to us the FOURIER-OLE study. Maybe describe for us here
your study design and then what specifically was your study
population?


Dr. Prakriti Gaba (PK):


Yeah, definitely. Thanks so much for the introduction. So the
study population included 27,564 patients with stable
atherosclerotic cardiovascular disease and LDL cholesterol levels
that were greater than or equal to 70 mg/dL or non-HDL
cholesterol greater than or equal to a 100 mg/dL on statin
therapy. The patients who then went on to the FOURIER-OLE or the
open-label extension part of the trial consisted of about 6,635
patients. And so in this study we essentially evaluated the
combination of those populations in 2 separate analyses. We then
categorized patients according to 6 pre-specified bins based on
their achieved LDL cholesterol levels at designated time points
and those ranged from LDL levels of less than 20 mg/dL all the
way up to 100 mg/dL. And then we looked at their baseline
characteristics and evaluated the cardiovascular and safety
outcomes that Dr. Sabatine mentioned earlier.


Dr Greg Hundley:


Very nice PK. Well we've got a great listening audience today and
they're anxious to hear your study results, so can you share
those with us please?


Dr. Prakriti Gaba (PK):


Definitely. So over the course of more than 77,000 patient years
of follow-up, we found that there was a monotonic relationship
between achieving lower LDL cholesterol levels down to very low
levels of less than 20 mg/dL and a lower annualized risk of the
primary efficacy endpoint, which was a composite of 5 individual
endpoints. We also found that there was a similar relationship
observed between lower LDL achieved, LDL cholesterol levels and a
lower annualized risk of the secondary efficacy endpoint, and
then when we looked at safety, there were actually no clear
monotonic trends between lower achieved LDL levels and the risk
of any of the 8 adverse events and these included things like
serious adverse events, hemorrhagic stroke or muscle related
events.


Dr Greg Hundley:


Very nice PK and I'm sure our listeners are wanting to know, did
you find any discrepancy in your results based on either age or
gender?


Dr. Prakriti Gaba (PK):


That's an excellent question, and we did look at age and gender
throughout. I think across the board the results were pretty
consistent, but additional subanalyses will further address this
question.


Dr Greg Hundley:


Very good. Well listeners now we're going to turn to one of our
associate editors, Dr. Amit Khera, who has helped move this
article through the process of evaluation with the editorial
team. Amit, you have many papers come across your desk, what
attracted you to this paper and then how do we put this study's
results really in the context of other studies that have sought
to dramatically lower LDL cholesterol?


Dr. Amit Khera:


Well first thanks a lot Greg for allowing me to participate
today. I want to congratulate Drs. Gaba and Sabatine on a
fantastic paper and the minute I saw it, and you know can tell
when you've done this for a while what's a great paper, and this
one certainly is and we work closely with them to try to make it
better and enhance the analyses and as a group, I think we
achieved that. I was fortunate to write an accompanying editorial
that you'll see.


So I got to take a pretty deep dive in this paper and I want to
just talk about sort of what's important here, why is this
important, and I think as Dr. Gaba mentioned, there's two sides
to this. There's the efficacy side where you talk about LDL
lowering and getting to very low levels. Now mind you, they got
to, what I call, ultra low levels, even explored for a down to a
median of 7 mg/dL, so really, really low. And first I think what
our listeners need to know when we look at guidelines, these
numbers of 70 or 55, these are completely arbitrary and they're
based on what was observed in clinical trials, what was achieved
in high intensity versus moderate intensity statins in
IMPROVE-IT.


There's no biology behind that, and I think what this study does
is reminds us there is no biology behind how low we need to go.
This group previously published their shorter-term data
approximately 2 years with this construct of lower is better and
I think that's fine, but people worry, particularly on the safety
side about extension, and we'll get to that in a minute, so where
this fits is it gives us even more reassurance that lower is
better, reminds us there's no biologic basis of that even down to
very low levels. And so what does that mean? I think that comes
back to guidelines. We have some discrepancy between European,
ACC, Multisociety Guidelines that are around 55 and so from a
guideline perspective, I think we'll see a little bit more
enthusiasm about lower cut points or lower thresholds. And from a
clinical standpoint, as a clinician it reminds me that when I see
someone that's very high risk, there's no magic to achieving a
number that if the risk is high, we need to be quite intensive
and get their LDL down as low as possible and as safely as
possible.


I do want to also acknowledge, there's not, to your point about
context, the IMPROVE-IT study also showed very low levels show
additional efficacy and there's also a lot of other data,
genetics and ecologic data supporting this. So this is... we look
at Bayesian analysis that this is consistent that we're seeing
across different platforms.


I do want to talk about safety too, Greg. That's really important
because honestly this is when it comes to patient level, the
safety part of it. We as clinicians may have comfort with very
low levels, but the safety is important. I also want to, just
from a steady design, this is post-hoc, so those that achieve
very low levels are different. You can see that in their table 1,
but these investigators did lots of things. They did pretty
extensive multi-variable analysis, they looked at time-dependent
LDLs, they looked at it multiple different ways, but as
mentioned, there really did not seem to be a safety signal. And
this is where time matters.


Safety in two years, interesting, but safety 5 to 8 years really
offers us much more reassurance. So I think that's where this
really comes in about that safety piece with the extended
analysis. So again, I think from a guideline perspective, from a
clinical perspective, there's so many implications from this
paper and I really hope people take the time to take a deep dive
and also put it in context, like you said, to the other
literature where this is not standalone, but it's corroborating
what we're seeing.


Dr Greg Hundley:


Very nice, amit. Marc, I want to come back to you, just two quick
questions thinking about the preparation of your study. One, did
you sample cognition? One thing we hear about frequently in
dramatic lowering of LDL cholesterol are questions around
cognition, particularly in the elderly?


Dr. Marc Sabatine:


Yeah, it's a great question Greg. So first of all, in the FOURIER
study itself, there was an embedded study called EBBINGHAUS that
Bob Giugliano from our group led that actually did formal
neurocognitive testing in individuals using basically a iPad-like
test. We also collected the usual neurocognitive adverse events
as part of safety collecting. So 2 ways, the general asking about
any adverse events and then the specific neurocognitive testing.
We had previously reported out the results of EBBINGHAUS that
there wasn't any relationship between evolocumab and the low LDL
cholesterol and the risk of any neurocognitive AEs. We just were
able to recently do this OLE analysis over time for the major
adverse cardiovascular events and for the general safety events
including cognition, so all that looked good. As PK indicated,
we're now digging into the EBBINGHAUS formal neurocognitive
testing, which was also extended out. So stay tuned for those
results.


Dr Greg Hundley:


Very nice. And then eligibility, maybe just walk us through that
really quickly. Patients that are going to be randomized to this
form of therapy, were they already on high-dose statins? Who
exactly did we randomize in this trial?


Dr. Marc Sabatine:


Yeah, so at the get-go, as PK indicated, these are patients with
atherosclerotic cardiovascular disease, so they had a prior MI,
prior stroke, symptomatic PAD. They were to be on an optimized
lipid-lowering regimen, optimized statin therapy, so for close to
70%, that was a high-intensity statin. We had a small percentage
on ezetimibe, but that's because we hadn't yet published the
results of the IMPROVE-IT trial that Amit mentioned when we were
enrolling in FOURIER, but it was a well-treated population on
statin therapy. So these results would apply to your typical
patient with ASCVD who's on a good statin regimen.


Dr Greg Hundley:


Very nice. Well, listeners now we're going to go back to both of
our authors and investigators, as well as Dr. Khera. PK we'll
start with you. What do you see as the next study to really be
performed in this sphere of research?


Dr. Prakriti Gaba (PK):


I think that's an excellent question. I think with the data
presented here now we know that the lower the LDL, the lower the
risk of adverse cardiovascular events and that having a low LDL
is safe in the long term. I think moving forward, as Dr. Khera
mentioned, there needs to be a shift of these recommendations
into the guidelines. So I think additional studies confirming
these findings is what we need, but we do have the evidence
available.


Dr Greg Hundley:


Very nice. And Marc?


Dr. Marc Sabatine:


Yeah, and I agree with PK of course. I think there's a couple
things that we want to look at. We had looked in the parent
FOURIER trial and found some groups who were higher risk, who
seemed to have a bigger benefit early on, and those by and large
were people who had a lot of athero. But as Amit indicated that
the parent FOURIER trial was relatively short at about in two and
a quarter years median follow up, and so now we have the benefit
of an additional half decade of follow up in a subset of people
and so now we're starting to look through and see the subgroups
where we saw some differential benefit and this was a paper we
published in circulation soon after we published the primary
results of FOURIER.


Now we have the ability to go through and look at those same
subgroups and see what happens now with an additional 5 years.
And so that'll be quite interesting, I think, to see how those
groups play out now over time. I think as Amit indicated, time is
critical. We know the benefit of lipid lowering really tends to
grow with time. We saw that in FOURIER, we saw that in
FOURIER-OLE and then as Amit indicated, I think for safety also
it's now very reassuring, being able to go out to not two and a
half years, but 5, 6, 7, 8 years of safety follow up.


Dr Greg Hundley:


Very nice. Well, listeners we're next going to turn to Dr. Khera.
I'm going to put him on the spot a little bit. I don't know if
many of you know he's a cardiologist with expertise in primary
prevention. So here we've really focused today, I think, on a
very unique set of results in secondary prevention. Amit, as you
think about studies to be performed in the future, is there a
role for really lowering LDL cholesterol as a primary prevention
target?


Dr. Amit Khera:


The short answer is absolutely. I think, to be fair, you can't
necessarily directly extrapolate these results 'cause it's a
secondary prevention population, but I think if we step back for
a second, is there any reason I think this wouldn't work in
primary prevention, there's not, and I think there's tons of
genetic data, tons of other long-term data that suggests that
lower is better than primary prevention. I think the challenge,
as you know, is just from primary prevention is it's just about
the number that you need to treat and primary prevention is
pretty profound in terms of to lower events. So this is where the
trade-off comes.


I think even in their study, we do have to appreciate while lower
is better, when you have very low levels and you're going to even
lower, let's say when you go from in secondary prevention from 50
to 40, as much as that sounds valuable, that delta's pretty small
and then the absolute risk reduction is still going to be pretty
small for those individuals and that's only magnified in primary
prevention. So the short answer is I have no reason to believe
that lower is better is not applicable in primary prevention, but
I do know that the cost and what entails to get there, you don't
get as much return on investment.


I do want to say one last thing though. We're talking about lower
is better, and I know these investigators know this well, but
it's not only just how low but how long and I think that's where
primary prevention about to go to clinic and I play the long game
for primary prevention that we know we've magnified these
benefits over the long term and even a little bit early in life
can pay off long dividends. So that's how I look at it.


Dr Greg Hundley:


Very nice. Well, listeners we want to thank Dr. Prakriti Gaba,
Dr. Marc Sabatine, both from Brigham and Women's Hospital and
also our own associate editor, Dr. Amit Khera from University of
Texas Southwestern Medical Center for bringing us this study
involving patients with arteriosclerotic cardiovascular disease
indicating that long-term achievement of lower LDL cholesterol
levels down to values less than 20 mg/dL was associated with a
lower risk of cardiovascular outcomes and not and not an increase
in the risk of significant safety related events.


Well, on behalf of Peder, 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 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.