Circulation August 21, 2018 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and it's editors. I'm Dr
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore.


                                               
Can we get better at predicting clinical benefit of PCSK9
inhibition based on the severity and extent of coronary artery
disease? Well coming right up after these summaries we have an
important discussion of an analysis from the FOURIER trial, so
stay tuned.


                                               
The first original paper this week suggests that targeting
visceral adiposity may be the crucial step to limit age-related
cardiac remodeling and to promote healthy cardiac aging. Co-first
authors Drs Sawaki and Czibik, corresponding author Dr Derumeaux,
from INSERM France, and their colleagues, hypothesize that since
aging induces cardiac structural and functional changes, linked
to increase deposition of extracellular matrix proteins including
osteopontin, well osteopontin may play a role in myocardial
aging.


                                               
To test this hypothesis, they studied osteopontin-deficient mice
and their wild-type litter mates at two and 14 months of age in
terms of cardiac structure, function, histology and key molecular
markers. They found that during aging, visceral adipose tissue
represented the main source of ostepontin and altered heart
structure and function via its profibrotic secretome.
Furthermore, interventions targeting osteopontin, such as
visceral adipose tissue removal and osteopontin deficiency,
rescued the heart and induced a selective modulation of
fibroblast senescence. This work uncovers ostepontin's role in
the context of myocardial aging and suggests that osteopontin may
be a potential new therapeutic target for a healthy cardiac
aging.


                                               
The next study shows that higher triglyceride rich lipoprotein
cholesterol may be a risk factor for cardiovascular disease and
potential therapeutic target. First author Dr Vallejo-Vaz,
corresponding author Dr Ray from Imperial College London, and
their colleagues assess the relationship between
triglyceride-rich lipoprotein cholesterol and cardiovascular risk
and whether this risk was modifiable among patients receiving
statins in the TNT trial. They found that higher levels of
triglyceride rich lipoprotein cholesterol were associated with a
significantly higher rate of cardiovascular events among coronary
patients treated with statins. Statin therapy reduced
triglyceride-rich lipoprotein cholesterol and to a greater extent
among those treated with a higher statin dose.


                                               
Based on their post hoc analysis of the TNT trial, they found
that more intensive statin therapy with atorvastatin 80
milligrams, compared to atorvastatin 10 milligrams, resulted in a
significantly greater cardiovascular risk reduction among
patients with higher triglyceride-rich lipoprotein cholesterol.
These results were consistent for higher triglycerides and
directionally concordant for non-HDL cholesterol. A higher
percentage reduction in triglyceride-rich lipoprotein cholesterol
was associated with lower cardiovascular risk independent of LDL
cholesterol reduction. Thus, these findings suggest that
triglyceride-rich lipoprotein cholesterol is not only a
cardiovascular risk marker, but also potentially a therapeutic
target.


                                               
Late gadolinium enhancement on cardiac magnetic resonance imaging
represents fibrosis and is seen in 60% of adult patients with
hypertrophic cardiomyopathy. However, what about in children and
adolescents with hypertrophic cardiomyopathy? First author Dr
Raja from University of Copenhagen in Denmark, corresponding
author Dr Ho from Brigham and Women's Hospital in Boston, and
their colleagues looked at cardiac magnetic imaging data from 195
children and adolescents with hypertrophic cardiomyopathy. Late
gadolinium enhancement was present in 46% of patients with overt
hypertrophy as opposed to 60% typically represented in an adult
population of hypertrophic cardiomyopathy. On the other hand,
late gadolinium enhancement was not seen in mutation carriers
without left ventricular hypertrophy.


                                               
In patients who underwent serial imaging, increases in late
gadolinium enhancement, left ventricular mass, and left atrial
size were detected over two and a half years. Thus these findings
in children provide additional insights into the biology and
natural history of hypertrophic cardiomyopathy and confirmed that
fibrosis is a significant part of the disease process in both
children and adults.


                                               
Whether the adult mammalian heart harbors cardiac stem cells for
the regeneration of cardiomyocytes is an important yet
contentious topic in the field of cardiovascular regeneration.
This week's paper adds to the growing knowledge in this area.
First author Dr Li, corresponding author Dr Zhou from Chinese
Academy of Sciences and their colleagues developed a new genetic
lineage tracing system to label all nonmyocyte populations that
contain putative cardiac stem cells. Using dual lineage tracing
system, they assessed if non-myocytes generated any new myocytes
during embryonic development, adult homeostasis and after
myocardial infarction. Skeletal muscles were also examined after
injury and acted as internal controls.


                                               
By using this stem cell marker free and dual recombinases
mediated cell tracking approach, the author showed that new
myocytes arose from nonmyocytes in the embryonic heart, but not
in the adult heart during homeostasis or after myocardial
infarction. As positive controls, the same lineage tracing system
detected new myocytes derived from nonmyocytes in the skeletal
muscle after injury. Thus, this study provides in vivo genetic
evidence for non-myocyte to myocyte conversion in the embryonic
but not the adult heart. This study also provides a new genetic
strategy to identify endogenous stem cells, if any, in other
organ systems for tissue repair and regeneration.


                                               
Well, that wraps it up for our summaries this week, now for our
feature discussion.


                                               
Are there subsets of patients that derive greater clinical risk
reduction with the PCSK9 inhibitors? Well we're gonna find out
about that right now with a discussion of our feature paper
entitled the “Clinical Benefit of Evolocumab by Severity and
Extent of Coronary Artery Disease.” So pleased to have with us Dr
Marc Sabatine from the TIMI Study Group, who is the first and
corresponding author of today's feature paper, as well as our
editorialist, Dr Roger Blumenthal from Johns Hopkins University.
And of course, we have a familiar voice, a very important editor
of our digital strategies and that's Dr Amit Khera from UT
Southwestern.


                                               
Welcome everyone, I think I'd really like to start with maybe
asking Roger to paint the background of the importance of this
paper. Simply because I just love the title of your editorial,
which is “Realizing the Value of PCSK9 Inhibitors: Are We Closer
to Finding the Sweet Spot?” I think that really encapsulates it.
So Roger, your thoughts?


Dr Roger Blumenthal:     As Amit Khera knows,
I'm a golfer, so when you think about the sweet spot on the club,
and we know that PCSK9 inhibitors are a great story of
translation from bench to bedside, and we also know that the high
cost of the therapy presents a challenge. So what Dr Sabatine and
colleagues did was to try to identify the sweet spot for its most
effective use and that was a pleasure to comment on Dr Sabatine's
excellent study.


Dr Marc
Sabatine:           
I think taking a step back I would say from pure biologic
perspective, we know that lowering LDL cholesterol will reduce
events and that's true and primary and secondary prevention and
so if you have therapies that were safe and inexpensive, then I
think you wouldn't need to really look for that sweet spot cause
it would be all sweet if you will to extend the analogy. But
Roger's absolutely right that when you have therapies that are
then expensive, then you have to decide, okay in which patients
will I get the biggest bang for my buck? And that's a very
legitimate question to ask.


                                               
And so in FOURIER, overall the trial was positive but as we look
for subgroups we say, "Can we find individuals who enjoy a
greater absolute risk reduction?" Because therefore the benefit
cost ratio is gonna be particularly favorable. And so we approach
that in a couple different ways. First you can look for just
predictors of baseline risk, so if someone has twice the baseline
risk and the same relative risk reduction, you should get about
twice the absolute risk reduction and therefore the number needed
to treat would be cut in half. And so based on our experience
from other TIMI trials and other datasets, we looked at three
features that have identified patients with higher baseline
risks.


                                               
Amongst those with a history of MI which is in and of itself a
heterogeneous group. And so those features were patients with a
more recent MI, those with multiple prior MIs and those with
known residual multivessel coronary disease. And all three
features in the FOURIER dataset, not surprisingly, were
predictors of risk with patients having an average about a 50%
higher baseline risk. But what was particularly nice was that the
subgroups also identified patients who had greater relative risk
reduction. And so when you couple the two, the higher baseline
risk with the greater relative risk reduction, that translated
into greater absolute risk reduction then in each of these
high-risk groups, the absolute risk reductions over three years
or for CV death, MI, and stroke was around 3% versus around 1%
for the low-risk groups.


                                               
And so that changes the number needed to treat by a factor of
three.


Dr Carolyn
Lam:               
Wow, that's so cool. Amit, do you think you could just give us a
sneak peek into the editors’ discussions when you saw this paper?


Dr Amit
Khera:                 
This was an easy one, it's clearly a very important paper and if
you step back 10,000-foot view, these drugs were initially
approved based on LDL lowering and people were using them without
knowledge of whether or not they actually lowered events. Marc's
group and others have now shown us that certainly they do lower
events, but really the next most important thing is application.
Who should we use them in and when should they be used and where
might they be most effective and I think it was said out in the
introduction of this paper, this idea of personalized medicine.
And I think this really is an important step forward, not just
for PCSK9 field but in general, how we should be thinking about
drugs, about balancing cost and benefits and who would benefit
most.


                                               
So maybe one analogy, I think PCSK9 was not prescribed as much as
they had been predicted given costs and other considerations and
maybe with analysis like this they've hit it out of the rough
back on the fairway, I threw that in for you, Roger. And I do
have one question for Marc, which is this is clearly important to
better define who would benefit the most and I guess in terms of
action abilities, the goal here to provide guidance for
clinicians where, you know, if I'm seeing a patient this morning
I would take this into account or is this something larger where
we recently saw with alirocumab, they changed pricing based on
sub-group analysis of a higher risk group. How do you think we
should move forward with this type of information?


Dr Marc
Sabatine:           
I’ll get back to the point I raised earlier, I do want to
underscore that I think that the true biologic notion is that all
these patients, sub-types of secondary prevention or primary
prevention all benefit from LDL lowering. So I wouldn't want
people to walk out with the notion that it's the only subset that
would benefit and really from a population level, obviously
Roger's in a better position to speak about this, but sort of
shifting the population LDL lower in general would have a huge
impact on the risk for cardiovascular disease. But to your
question Amit, looking in for a patient in front of you, I think
it's quite fair to say right now there's this kind of tug of war
back and forth between payers and clinicians.


                                               
Clinicians saying, "I have a patient in front of me, they have
known atherosclerotic cardiovascular disease, I wanna lower their
risk, I wanna manage their risk factors and I wanna get their LDL
cholesterol lower and I have a bunch of great tools in front of
me." Statin for sure is the foundation, maybe acetamide and PCSK9
inhibitors. And then payers saying, "Well wait a minute, these
are expensive drugs and so we're gonna try to restrict that and
create a lot of hoops for clinicians to jump through." And so I
would rather than wasting all that time back and forth, I think
it is logical to say, "What are the high-risk groups?" Where we
can agree there's the large enough absolute risk reduction that
for a given cost, that makes sense.


                                               
Allow there to be alignment for that and have clinicians just be
able to write a script and have it filled rather than wasting a
lot of time with preauthorization and letters back and forth.


Dr Amit
Khera:                 
That's a great point, maybe I'll just take one follow-up, which
is now trying to sift through all the high-risk groups and they
end up maybe becoming a bit of a Venn diagram. I know in Roger's
editorial he talked about the other FOURIER analysis with PAD and
there's more groups to come or do we have enough of a starting
place where we think we have enough for decision making?


Dr Marc
Sabatine:           
I would say there are a variety of groups, there is some
overlapping even in the paper then we looked at the union of
those three high-risk features, which identified about two thirds
of the patients who were enrolled in the trial with a history of
MI. But you're right, the other slices of the data that will also
identify high risk groups, PAD is a particularly good one because
most of the therapy for those patients has focused on
antithrombotic therapy, which always will have some downside for
increased bleeding, whereas risk factor modification in this case
has no downside. So that's a very high-risk group, it certainly
is important to focus on. But I think within the MI subset, this
is a great place to start the other analyses we're doing.


                                               
And probably after we've sort of finished the series of, if you
will, these kind of univariant slices, then we'll try to put that
together into a more comprehensive picture.


Dr Roger Blumenthal:     We tried to say that
we still need the formal cost-effective analyses in these
specific high-risk groups, but it seems most reasonable to focus
on engaging in shared decision making now with our patients about
PCSK9 inhibitor use and those with a recent ACS and the basis of
Odyssey Outcomes and we're awaiting the final publication of
that. Symptomatic peripheral arterial disease, which Marc
previously published in Circulation, and then looking at these
high-risk features that was the subject of this article, those
with a more recent MI within the past two years, multiple prior
MIs and residual multivessel coronary disease.


                                               
And one of the things that we especially found interesting was
among the more than 8,000 individuals without a high-risk
feature, the event rates were nearly unchanged in the evolocumab
versus placebo groups. So I think that's very important, but one
other point that we have to keep in mind is that the focus of the
last set of guidelines and probably the next cholesterol
guidelines that likely will be out in November, will have a large
component of the shared decision making and we need to see where
the cost comes down, whether these companies that make these
medications will be able to significantly lower the cost in a
reproduceable manner and patients and clinicians will have to
jointly decide what to do, do we add acetamide? Do we add a PCSK9
inhibitor?


                                               
But we finished our editorial saying that all clinicians and
patients should currently pursue a comprehensive lifestyle and
medical regimen for secondary prevention. We all have to remember
that and if a person's LDL, a high-risk individual is at least 70
with high-risk features and certainly above 100 on maximum
tolerated statin therapy, it's important to strongly consider a
PCSK9 inhibition and it'll be very interesting to see what the
final wording is when the ACC/AHA cholesterol guidelines come out
in November.


Dr Carolyn
Lam:               
Amit, would you like to add any further take-home for the
clinicians listening in?


Dr Amit
Khera:                 
I just first want to congratulate both of these discussions
today, I think the paper was so incredibly important and I think
Roger's group really helped frame it well in the field. The one
thing I'd say is this is a moving target, we have some early
guidance now that I do think is actionable, so I actually have
clinic in about an hour and I'm sure I'll be thinking about this
as I think about how to apply PCSK9. Which groups might benefit
most, so I do think this is actionable now, I think the points
that were made about cost effective analysis, how do we bundle
all these concepts or high risk patients into maybe an algorithm
and how do the guidelines interpret this as a moving target.
We'll wait to see, but I do think there's some important
actionable information even now for our clinical patients.


Dr Carolyn
Lam:               
I just love that, and you know that is just so much in line with
the ethos of what Circulation is about now. We really, really
love the papers that you have to pick up because they're of
immediate applicability to your clinical practice.


                                               
Well audience, you heard it right here. Thank you so much for
joining us this week and of course don't forget to tune in again
next week.