Circulation May 19, 2020 Issue

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


Dr Greg Hundley: And I'm Greg Hundley, associate editor and
Director of the Pauley Heart Center at VCU Health in Richmond,
Virginia.


Dr Carolyn Lam: We've got a juicy, juicy feature discussion
coming up. It's on a pre-specified analysis of the ODYSSEY
OUTCOMES randomized clinical trial, this time to ascertain
whether PCSK9 inhibition reduces the risk of peripheral arterial
disease events or venous thromboembolism after acute coronary
syndrome. And, also to answer, these effects are related to
levels of lipoprotein(a) or LDL cholesterol. I'm going to keep
everyone guessing, as we get on our coffee chat and talk about
the other papers in this issue.


And I want to go first, because the first original paper I want
to discuss is really quite related to the feature discussion too.
And it asks the question, what is the relationship between
cholesterol levels and risk of venous thromboembolism? And, what
is the effect of PCSK9 inhibition on the risk of venous
thromboembolism? So this is from Dr Marston from the TIMI Study
Group, Brigham and Women's Hospital, Harvard Medical School in
Boston, Massachusetts, and colleagues who performed a post hoc
analysis of the FOURIER trial, testing whether evolocumab reduces
the risk of venous thromboembolic events. That is, deep venous
thrombosis, a pulmonary embolism. The authors then looked at data
from FOURIER and the ODYSSEY OUTCOMES trial and combined them in
a meta-analysis to assess whether there was a class effect of
PCSK9 inhibition on the risk of venous thromboembolism. As a
reminder, the ODYSSEY OUTCOMES trial tested alirocumab as the
PCSK9 inhibitor.


Dr Greg Hundley: Well, Carolyn, what did they find?


Dr Carolyn Lam: Well, first Greg, remember, this is the first
study to demonstrate a significant reduction in venous
thromboembolism with PCSK9 inhibition. Interestingly, the
reduction in venous thromboembolism was associated with the
degree of lipoprotein(a) lowering and not LDL cholesterol
lowering, suggesting that lipoprotein(a) may be the mediator of
venous thromboembolic risk. More coming up in our feature
discussion.


Dr Greg Hundley: Wow, Carolyn. Well, I'm going to go into the
world of PCSKs, but talk about PCSK6. So this study involves a
secretome analysis of cardiomyocytes as novel players in cardiac
remodeling after myocardial infarction and the corresponding
author is Dr Florian Leuschner from Heidelberg University. So
Carolyn, we know that acute occlusion of coronary artery results
in swift tissue necrosis and bordering areas of the infarcted
myocardium may also experience impaired blood supply and reduced
oxygen delivery leading to altered metabolic and mechanical
processes. While transcriptional changes in hypoxic
cardiomyocytes are well-studied, little is known about the
proteins that are actively secreted from these bordering cells.


So in this study, the authors established a novel secretome
analysis of cardiomyocytes by combining stable isotope labeling
and click chemistry with subsequent mass spectrometry analysis.


Dr Carolyn Lam: Wow, sounds like very advanced methods and what
did they find?


Dr Greg Hundley: Okay. Carolyn lots of results here. They found
that PCSK6 expression was elevated in hearts of mice, following
three days of ligation of the left anterior descending artery, a
finding confirmed by immunohistochemistry. ELISA measurements and
human serum also indicated distinct kinetics for PCSK6 in
patients suffering from acute myocardial infarction with a peak
on day three post infarction.


One of these beautiful studies combining basic science and human
subjects in the same paper. In addition, adeno-associated virus
nine mediated cardiomyocyte specific overexpression of PCSK6 in
mice resulted in increased collagen expression and cardiac
fibrosis as well as decreased left ventricular function after MI.
So Carolyn, this study demonstrates how novel mass
spectrometry-based approach allows the investigation of the
secretome of primary cardiomyocytes. That's a first for that
technique. And then analysis of hypoxia-induced secretion led to
the identification of PCSK6 to be crucially involved in cardiac
remodeling after MI, demonstrating increased collagen expression
and cardiac fibrosis in those border zones.


Dr Carolyn Lam: Wow, fascinating, Greg. Well, I want to switch
tracks here. Maybe ask, when you're choosing between
antithrombotic therapies for patients with atrial fibrillation
and a recent acute coronary syndrome, have you ever wondered what
is the tradeoff of risk? Risk of bleeding and benefit that would
be in terms of prevention of ischemic events over time? Well,
guess what, I'm not going to put you on the spot here because our
next paper addresses this very question. And it's from
corresponding author, Dr Alexander from Duke Clinical Research
Institute and colleagues who performed a post hoc analysis of the
AUGUSTUS trial.


Dr Greg Hundley: Okay, Carolyn. I'm going to digress for just a
minute here. We have this wonderful producer, Augie Rivera, and
he's just fantastic and we should give him accolades because he
really helps put all these together. Now I'm not going to ask him
this time, but maybe in one of our future discussions, we may
need to bring him into one of these because of his expanded
knowledge of all of science, but getting back, Carolyn, can you
remind us what is the AUGUSTUS trial?


Dr Carolyn Lam: All right, so in the AUGUSTUS trial, patients
with AF and a recent ACS and/or PCI taking a P2Y12 inhibitor had
less bleeding and rehospitalization with apixaban, than vitamin K
antagonists and less bleeding with placebo than aspirin. The
composite of death or hospitalization was also reduced with
placebo compared to aspirin. However, the risk of several
recurrent ischemic events, including stent thrombosis, where
numerically higher in patients assigned placebo. Further analysis
of the stent thrombosis outcomes suggested that most of the
increase in risk was early within 30 days of randomization.


And hence the objective of the current paper, which is a post hoc
analysis to explore the balance of risk and benefit using a
variety of composite outcomes between randomization and 30 days
and between 30 days and six months over time comparing apixaban
versus vitamin K antagonists and aspirin versus placebo. So,
here's what they found. Apixaban caused fewer ischemic and
bleeding events than warfarin in the first 30 days after ACS
and/or PCI and similar or fewer ischemic and bleeding events from
day 30 to six months. Use of aspirin acutely, and for up to 30
days, resulted in an equal tradeoff between an increase in severe
bleeding and reduction in severe ischemic events. However, after
30 days aspirin continued to increase bleeding without
significantly reducing the ischemic events. So these results
really informed shared patient-centric decision making regarding
the ideal duration of use of aspirin after an ACS and/or PCI in
patients with AF already receiving oral anticoagulation.


Dr Greg Hundley: Very nice, Carolyn. You know, lots of data
coming out about how we perform anticoagulation, the
administration of aspirin, both an atrial fibrillation, ischemic
events, those with stents and this is just another piece of
important data that we're so fortunate to have published in
circulation. Well in the rest of the issue Carolyn, there's a lot
of information. I want to talk about a research letter from Dr
Armand Killick from the University of Pittsburgh, and he
describes the outcomes of the first 1300 adult heart transplants
in the United States following a policy change in the U S related
to allocation of hearts.


In an EKG challenge, Dr Nobuhiro Takasugi from Gifu University
and colleagues reviewed the etiology of wide complexes. Are they
aberrantly conducted supraventricular beats? Are they premature
ventricular complexes or intermittent ventricular prereq citation
in an individual 70 years old presenting with symptoms of
palpitations? Then Carolyn, in one of our COVID-19 articles,
there's an in-depth piece by Dr Kevin Clerkin and associates from
Columbia University. And they review coronavirus disease that is
caused by severe acute respiratory syndrome, coronavirus 2 or
SARS-CoV-2, which invades cells through the angiotensin
converting enzyme or ACE-2 receptor. Among those with COVID-19,
they note there is a higher prevalence of cardiovascular disease
and more than 7% of patients suffer myocardial injury as evidence
from elevated cardiac troponin values from the infection and in
22% of those that were critically ill.


And despite ACE-2 serving as a portal for infection, the role of
ACE inhibitors or angiotensin receptor blockers requires further
investigation. And right now, as you know, in your field is a
heart failure expert, they are not recommendations to consider
discontinuation for those drugs. And then lastly, in a
prospective piece, Professor Gianluigi Condorelli from Humanitas
University in Milan, presents critical organizational issues for
cardiologists in this COVID-19 outbreak, including prioritization
of unstable patients with cardiovascular disorders by postponing
visits, and in this situation they did so by 80%, reorganizing
clinical activities in terms of ward, ICU beds and outpatient
visits, using a hub-and-spoke model to prioritize management
acute MI, and then finally rapidly acquiring and training
physicians and staff in the correct use of PPE. All very valuable
lessons from Italy that was so hard hit by this devastating
disease.


Dr Carolyn Lam: Indeed, and you know what, Greg, I just want to
tell everybody about our circulation YouTube channel, where we
have frontline interviews with people dealing with this from all
over the world. Thank you to Augie and his team for making all of
this happen. Let's go on to our future discussion, shall we?


Dr Greg Hundley: Absolutely.


Dr Carolyn Lam: Patients with acute coronary syndrome are at risk
of peripheral artery disease events and venous thromboembolic
events. Now we've heard a lot about PCSK9 inhibitors in patients
with acute coronary syndrome, but what is the effect of PCSK9
inhibition on the risk of PAD or venous thromboembolic events?
Well, we're about to find out. The feature paper is a pre
specified analysis of the ODYSSEY OUTCOMES trial. And I'm so
pleased to have the first and corresponding author, Dr Greg
Schwartz with us from the University of Colorado, School of
Medicine, as well as our guest editor, Dr Erin Michos from Johns
Hopkins School of Medicine. So welcome. And Greg, could I ask you
to start us off. Tell us why you looked at this in ODYSSEY
OUTCOMES and what you found.


Dr Gregory Schwartz: All of our patients or nearly all of our
patients with acute coronary syndrome have had an
atherothrombotic event and most of them also have a heightened
inflammatory state. These factors are also thought to have a role
in the pathogenesis of peripheral artery disease events, and
perhaps also venous thromboembolism. We typically think of the
risk factors for peripheral artery disease as being diabetes and
smoking, and less so dyslipidemia, although dyslipidemia may play
a role in PAD events as well. And although the association of LDL
cholesterol levels with PAD events has been inconsistent in the
literature, there's more consistency actually with levels of
lipoprotein(a) and the risk of PAD events.


And that kind of makes sense because we think that Lp(a) has both
atherogenic and pro-inflammatory and perhaps also prothrombotic
properties. So elevated levels of that lipoprotein might promote
the risk of PAD events. Now statins, which are obviously the
mainstay of our treatment of patients with atherosclerosis, lower
levels of LDL cholesterol, but they don't affect the levels of
Lp(a). In contrast, inhibitors of PCSK9 lower the levels of both
of those key lipoproteins. So we looked at the relationship of
baseline and on treatment levels of both LDL cholesterol and
lipoprotein(a) on the risk of PAD events and also venous
thromboembolism, which has been associated with lipoprotein(a) in
some observational studies.


Dr Carolyn Lam: Nice. So, could you tell us what were the
results?


Dr Gregory Schwartz: So first, we used data from the ODYSSEY
OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab
with placebo in nearly 19,000 patients with a recent acute
coronary syndrome. And as you mentioned, Carolyn, those patients
may be at elevated risk for other types of arterial and venous
atherothrombotic or thrombotic events. We had three goals in our
analysis. First, we looked at the relationship of PAD and venous
thromboembolic events to the baseline levels of lipoprotein(a)
and LDL in the trial cohort. Second, we looked at the effects of
randomized treatment on both of those types of events, PAD
events, and venous thromboembolism. And lastly, we determined the
relationship of treatment effects on lipoproteins to the risk of
those events in the alirocumab active treatment group. What we
found are four principle findings. First, although this was an
acute coronary syndrome cohort, and there were only four percent
of the trial cohort who had a prior history of PAD, there was
nonetheless a substantial risk of PAD events. About two percent
of the placebo group suffered a PAD event during the trial and
about one percent had a venous thromboembolic event.


In the placebo group. We found that there was a very strong
association between baseline lipoprotein(a) concentration and the
risk of PAD events. So to put that in a quantitative framework,
if we compared the highest quartile of baseline lipoprotein(a)
with patients in the lowest quartile of baseline lipoprotein(a),
there was a more than twofold elevated risk of PAD events. And by
that, I mean, critical limb ischemia, revascularization, or
amputation for ischemia, more than a twofold elevated risk in the
highest quartile of baseline lipoprotein(a). There was a
non-significant relationship of venous thromboembolic events to
the baseline concentration of lipoprotein(a). The patients who
were treated with alirocumab, the PCSK9 inhibitor, achieved the
expected approximately 50 percent reduction in LDL cholesterol
and a median 23 percent reduction in lipoprotein(a)
concentration.


And those effects were associated with significant reduction in
PAD events, a hazard ratio of point six nine, and a nearly
significant peak, well point zero six reduction in the risk of
venous thromboembolic events with a hazard ratio of point six
seven. And incidentally, in the same issue of circulation, there
is a companion paper from the FOURIER study, which looked at the
risk of venous thromboembolic events with another PCSK9
inhibitor, evolocumab. They found something very, very similar.
And again, the results of that trial individually were kind of on
the margins of statistical significance, but putting the two
trials together in their analysis, there was a highly significant
reduction in the risk of venous thromboembolic events with PCSK9
inhibition, compared with placebo. They also related those
effects to lipoprotein(a), but not to LDL cholesterol levels.


So we found that the magnitude of the reduction in lipoprotein(a)
was related to the reduced risk of PAD and VTE events, but a
similar relationship between the magnitude of LDL cholesterol
reduction and the risk of those events was not found. So to put
it all together, lipoprotein(a) may be the stone that we haven't
turned over, but should, when we encounter patients with PAD
events or VTE events that we can't otherwise explain. And
although these two trials were not purposed primarily to look at
PAD events, the findings certainly suggest that treating elevated
levels of lipoprotein(a) might be an effective strategy to reduce
risk of PAD events and VTE.


Dr Carolyn Lam: Wow. Congratulations, Greg, that was beautifully
summarized. A novel on at least two levels, right? One is the
PCSK9 inhibition effects on these two outcomes that we never
thought of before. And second, that role of lipoprotein(a). Erin,
could I bring you into this discussion? You were guest editor
when this paper came across your desk. Could you tell us what
were the considerations and frame how novel these findings are
for us?


Dr Erin Michos: Oh, Carolyn excited to be the associate editor
for this paper. People who know me know; I love all things
lipids. So as a preventive cardiologist, I'm very excited to have
drugs like PCSK9 inhibitors in my toolbox. They are certainly
known for their powerful LDL lowering effects, but also further
lipoprotein little a reducing effect who these combined data show
the PCSK9 inhibitors, not only reduced incident major adverse
cardiovascular events and PAD events, but potentially can reduce
VTE events as well in patients prescribed this therapy. So I
thought it was really interesting and this new analysis from
ODYSSEY, that it was the levels of lipoprotein little a, but not
LDL cholesterol that predicted the risk of future PAD event and
we saw a similar trend with VTE. And then furthermore, on
treatment with alirocumab. It was the magnitude of Lp(a) little a
reduction, but not LDL reduction that was associated with reduced
PAD and VTE events.


And so this suggests that the reduction of PAD events is mediated
by the lipoprotein little a lowering and not the LDL lowering.
You know, lipoprotein(a) is a particularly risky type of LDL.
It's strongly inheritable it's atherogenic similar to LDL, but
prothrombotic, so it's this double whammy of badness due to its
structural homology with plasminogen competes with berberine
binding and inhibits tissue plasminogen activator and ultimately
inhibits fibrinolysis. And so that's why lipoprotein(a) may be a
mediator of this apparent effect of PCSK9 inhibitors with PAD and
VTE incidents. So how do I put this in practice? Prior to PCSK9
inhibitors, we really didn't have any lipid modifying therapies
to actually lower lipoprotein little a, except niacin, which we
don't really use. This was mentioned by Greg, statins don't
really lower lipoprotein(a) and they actually increase
lipoprotein little as levels.


Although we do know that statins of course reduce ASCBD risk. So,
I'm checking lipoprotein little a now in all my secondary
prevention patients with established CVD and in high risk primary
prevention with those with family history. While we're all
anxiously awaiting outcome trials, such as the antisense
oligonucleotides that can lower lipoprotein(a) by 80 percent,
that therapy is not here now, we don't have that available in
practice. But we do have PCSK9 inhibitors now, which can reduce
lipoprotein little a by 20 to 25 percent and have meaningful
outcome data like the alirocumab data we see here in this ODYSSEY
OUTCOMES study.


With a 31 percent reduction of PAD, that is really meaningful. So
I'm particularly excited about PCSK9 inhibitors and my patients
with PAD who often have concomitant CAD, polyvascular disease,
and then regarding the VTE effects, I think we should point out
that the absolute risk reduction of VTE was pretty modest. We
didn't really see significance until we combined it with the
FOURIER data. So I think given the cost of the drug, it's not
warranted to prescribe PCSK9 inhibitors to the general
population, specifically for VTE prevention alone. But in
patients with ASCBD, who would be recommended for a PCSK9
inhibitor to reduce incident CBD, you know, there may be this
added special benefit of reducing risk of VTE as well.


Dr Gregory Schwartz: I just wanted to comment on a few things
that Erin said, I think we’re really important. All of these
patients were on intensive statin therapy in the background. So
although we did not see a relationship between the further
reduction in LDL cholesterol with alirocumab and the risk of
these events, it doesn't mean that lowering LDL cholesterol has
nothing to do with the risk of those events because everybody was
on background statin therapy, 90 plus percent. So, I think that's
important to point out. And I think the comment that was made
about when to check a lipoprotein(a) level is very pertinent.
And, in the European guidelines, they direct us to check
lipoprotein(a) at least once in a lifetime for everyone, even if
there's no other signs or risk factors for cardiovascular
disease.


So I think as Erin indicated, with some tools in the toolbox now,
and more tools, perhaps on the way with both the antisense, and
also there are small interfering RNA approaches to lower
lipoprotein(a), we should get more accustomed to looking at this,
to turning over that stone. Even if we're not a hundred percent
certain what to do with what we find underneath it, we should
still look because there may be some things we can do in the
interim.


Dr Carolyn Lam: Thanks, Greg. Erin, can I give you the last word?
Any take home messages?


Dr Erin Michos: I definitely think that as we move forward with
other therapies such as the small interfering RNA and the
antisense oligonucleotides, we need really more phase three
clinical trials specifically assessing VTE. And then I just want
to mention, although I didn't write an editorial for this study,
I did have the pleasure of writing an editorial for another
ODYSSEY OUTCOMES analysis that was published in December. You
know, my editorial was entitled, "Achievement, a Very Low LDL. Is
it Time to Unlearn the Concern for Hemorrhagic Stroke?" And I
mention this because one of the barriers I get in clinical
practices, people get very worried about the very low LDL levels
that we see with PCSK9 inhibitors and I think important to point
out from ODYSSEY that, with the reduction in ischemic stroke,
that there was no signal for increased hemorrhagic stroke and
that provides additional reassurance.


So I think that's important to mention, I think this PCSK9
therapy is being under-utilized in clinical practice and ASCBD
and PAD, these are really high-risk patients who have really high
risk of recurrent events and our efforts to ward off these
devastating consequences. We need to make sure that we're
appropriately utilizing this important therapy.


Dr Carolyn Lam: Thank you so much, Erin. Thank you so much, Greg.
You've been listening to Circulation on the Run. Don't forget to
tune in again next week.


Dr Greg Hundley: This program is copyright, The American Heart
Association, 2020.