Circulation October 18, 2022 Issue

This week, please join author Sunil Rao and Guest Editor
and Editorialist Gregory Lip as they discuss the article "A
Multicenter, Phase 2, Randomized, Placebo-Controlled,
Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral
Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular
Outcomes After Acute Myocardial Infarction" and the editorial
"Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic
Strategy for High-Risk ACS Patients?"


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. I'm 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 Director of the Pauley
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, today's feature paper is about the factor XI inhibitor
asundexian. It's the trial that we've been waiting for the
PACIFIC-AMI trial. You really have to listen to it because these
factor XI inhibitors are super interesting. What? We're going to
tell you about the other papers in today's issue first. Aren't
we, Greg? Do you want to go first?


Dr. Greg Hundley:


You bet, Carolyn. Thank you so much. Carolyn, did you ever
consider the genetic underpinnings of venous thromboembolism?
Well, as you know, venous thromboembolism is a complex disease
with environmental and genetic determinants. And in this study,
this large investigative team represented by Dr. Nicholas Smith
from the University of Washington in Seattle, and their
colleagues present new cross-ancestry meta-analyzed genome-wide
association study results from 30 studies with replication of
novel loci and their characterization through in silicone genomic
interrogations.


Dr. Carolyn Lam:


Wow. Sounds like a really large effort, Greg. What did they find?


Dr. Greg Hundley:


Right, Carolyn. In the author's initial genetic discovery effort
that included 55,330 participants with venous thromboembolism:
47,000 were European, 6,000 African, and a little over 1000
Hispanic ancestry. They identified 48 novel associations of which
34 are replicated after correction for multiple testing. In their
combined discovery replication analysis, so that's 81,669 venous
thromboembolism participants and ancestry stratified
meta-analyses from the European, African and Hispanic ethnic
groups. They identified another 44 novel associations, which are
new candidate venous thromboembolism associated loci requiring
replication. And many of the replicated loci were outside of
known or currently hypothesized pathways to thrombosis. Carolyn,
in summary, these findings from this very large GWAS analysis
highlight new pathways to thrombosis and provide novel molecules
that may be useful in the development of anti-thrombosis
treatments with reducing the risk of bleed.


Dr. Carolyn Lam:


Wow. Super interesting and very related to that feature paper
that we just discuss. But nonetheless, this next paper I love as
well, if I may say so myself. It deals with frailty and as we
know, frailty is increasing in prevalence. And because frail
patients are often perceived to have a less favorable benefit
risk profile, they may be less likely to receive new
pharmacological treatments. And so, we and led by Professor John
McMurray from the University of Glasgow, decided to investigate
the efficacy and tolerability of dapagliflozin according to
frailty status in the DELIVER trial.


Dr. Greg Hundley:


The DELIVER trial. Carolyn, tell us about the DELIVER trial?


Dr. Carolyn Lam:


Sure. In deliver dapagliflozin compared to placebo, reduced the
risk of worsening heart failure events or cardiovascular death
and improved symptoms in more than 6,000 patients with heart
failure and mildly reduced and preserved ejection fraction, so
ejection fraction above 40%. Now in this pre-specified analysis,
we examine the efficacy and safety of dapagliflozin according to
frailty status. That was determined using the Rockwood cumulative
deficit approach.


And so, what we found was that greater frailty was associated
with more impairment of health status and worse clinical outcomes
in patients with heart failure and ejection fraction of 40%. The
beneficial effects of dapagliflozin compared to placebo on
clinical outcomes were consistent regardless of frailty class.
But interestingly, the improvement in symptoms, physical function
and quality of life were larger in the frailest patients. Adverse
events were not more common in individuals randomized to receive
dapagliflozin compared to placebo irrespective of frailty class.
And so, the take home message is the benefit risk balance related
to frailty in patients with heart failure with mildly reduced and
preserved ejection fraction is favorable for dapagliflozin. And
so, these findings should challenge any clinical reluctance to
introduce dapagliflozin in patients perceived to be frail.


Dr. Greg Hundley:


Wow. Carolyn, really interesting. You could see with the diuretic
effect in someone that's frail, the potential hesitancy, but very
interesting study results in this world of frailty and the use of
dapagliflozin. Well, Carolyn, this next study is very interesting
and it comes to us from the world of preclinical science that
takes a very interesting approach to a scientific question. Now,
as you may know, RNA-binding proteins or RBPs are master
orchestrators of genetic expression regulation. They regulate
hundreds of transcripts at once by recognizing specific motifs,
thus characterizing RBPs targets is critical to harvest their
full therapeutic potential. However, such investigation has often
been restricted to a few RBP targets, thereby limiting our
understanding of their function.


Carolyn, these investigators led by Dr. Grégoire Ruffenach from
UCLA were interested in assessing pulmonary arterial hypertension
and they turned to the world of cancer research. Carolyn, in
cancer, the RNA-binding protein hnRNPA2B1, and we're going to
abbreviate that as A2B1, promotes a pro proliferative
anti-apoptotic phenotype. The same phenotype is present in
pulmonary arterial smooth muscle cells and is responsible for the
development of pulmonary arterial hypertension. However, the A2B1
function that's never really been investigated in pulmonary
arterial hypertension.


Dr. Carolyn Lam:


Oh, Greg, that's not only fascinating, but so beautifully
described. Thank you. What did they find?


Dr. Greg Hundley:


Right, Carolyn. These authors found that A2B1 expression and it's
nuclear localization are increased in human pulmonary arterial
hypertension, pulmonary arterial smooth muscle cells. Using
bioinformatics, they identified three known motifs of A2B1 and
all mRNAs carrying them and demonstrated the complimentary
non-redundant function of A2B1 motifs as all motifs are
implicated in different aspects of the cell cycle. In addition,
they showed that pulmonary arterial smooth muscle cells and A2B1
promote the expression of its targets. Additionally, in vivo A2B1
inhibition in the lungs rescued pulmonary hypertension in rats.
And so, Carolyn, through the integration of computational and
experimental biology, this team study revealed the role of A2B1
as a master orchestrator of pulmonary arterial smooth muscle
cells in pulmonary hypertension and that phenotype and its
relevance as a therapeutic target in pulmonary arterial
hypertension.


Dr. Carolyn Lam:


Wow, that's super, Greg. Thanks. Shall we go through what else is
in today's issue?


Dr. Greg Hundley:


You bet, Carolyn. There's a Research Letter from Professor
Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium
Current versus Calcium Calmodulin‐dependent Kinase II.”


Dr. Carolyn Lam:


There's also an exchange of letters between Doctors Omarjee and
Diederichsen regarding vitamin K2 and D in patients with aortic
valve calcification: [an] absence of evidence might not be
evidence of absence? And finally, there's an On My Mind paper by
me and Scott Solomon and it's entitled, “Delivering Therapeutic
Efficacy Across the Ejection Fraction Spectrum of Heart Failure.”
But let's go on now to talk about the Factor XI inhibitor, shall
we, Greg?


Dr. Greg Hundley:


You bet. Well, listeners, welcome to this feature discussion on
October 18th at a very special article today. And we have with us
the lead author, Dr. Sunil Rao from NYU in New York City and also
our associate guest editor as well as editorialist, Dr. Gregory
Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with
you. Can you describe for us some of the background information
that went into the preparation of your study and what was the
hypothesis that you wanted to address?


Dr. Sunil Rao:


Yeah, great. Thanks so much, Greg. It's a real pleasure to be
here with you. The background of the PACIFIC-AMI study is really
rooted in the fact that patients who have acute myocardial
infarction are really at risk for recurrent thrombotic events,
even after their event. And this risk continues despite the fact
that we have evidence based therapies that are really around
targeting the platelet as well as aspects of the coagulation
cascade. There have been studies that have looked at the use of
dual antiplatelet therapy plus an anticoagulant or single
antiplatelet therapy plus an anticoagulant. And those studies
have shown a benefit. However, their clinical use is limited
because of the bleeding risk.


Factor XI is an interesting target, because factor XI is likely
involved in the amplification of thrombin generation after plaque
rupture. But it really doesn't play much of a role in hemostasis.
And so, as a target in reducing events after acute coronary
syndrome, activated factor XI is a very attractive one. And so,
the hypothesis of this study was that a highly bioavailable oral,
direct, selective activated factor XI inhibitor called asundexian
would be safe and effective in the treatment of patients who
experience acute coronary syndrome at reducing adverse events.
Now, this is a phase two study, so it really wasn't powered for
clinical events. It was really a dose-finding study, so it was
really looking at adverse events and sort of bleeding
complications.


Dr. Greg Hundley:


Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can
you describe for us your study design and then maybe a little bit
more about the study population, how many subjects?


Dr. Sunil Rao:


Sure. Again, this is a phase two study. It was a randomized,
double-blind, parallel-group design where patients, who were
admitted with acute coronary syndrome were randomized to three
different doses of asundexian and or placebo in a one-to-one to
one-to-one fashion. Patients who met criteria for enrollment
were: patients who were admitted with a diagnosis of acute MI; if
they were older than or equal to 45 years of age; they were
hospitalized in acute coronary syndrome that did not occur in the
context of revascularization, so it was not a type 4 event; and
they were planned to be treated with dual antiplatelet therapy
after hospital discharge.


Dr. Greg Hundley:


Sunil, thank you for describing this very interesting study
design. Now, how many subjects did you include and could you just
describe for us the study population?


Dr. Sunil Rao:


We had a total of 1,601 patients that were randomized at 157
centers in 14 countries between June 2020 and July 2021. And in
order to be eligible for enrollment into the study: patients had
to be admitted with a diagnosis of acute MI, they had to be
greater than or equal to 45 years of age, and be hospitalized
with that acute MI that did not occur in the context of
revascularization, so type 4 MIs were excluded. The other
inclusion criteria was that they had to be planned to be treated
with dual antiplatelet therapy after hospital discharge. Now, we
allowed randomization up to five days after hospital admission
and randomization occurred after patients were clinically
stabilized and any planned PCI was performed. We included both
patients with STEMI as well as non-ST segmental elevation ACS,
but we capped the number of patients with STEMI that were
included to no more than 50%. Now, the main exclusion criteria
were things that you would expect for a phase two trial.
Obviously, hemodynamic instability at the time of randomization,
active bleeding or bleeding dialysis, severe renal dysfunction,
planned use of full-dose anticoagulation.


Dr. Greg Hundley:


Very nice. And so, we have several doses of this new factor XI
inhibitor. Describe for us your study results?


Dr. Sunil Rao:


Again, this was a phase two trial that was really looking at
safety and adverse events as you would expect. The study groups
were pretty balanced across all of the dosing arms. When we
looked at the pharmacokinetic and pharmacodynamic data, we found
something really interesting, which was that there was a dose
relationship between the dose of asundexian and the factor XIa
activity. Factor XIa is activated factor XI. The higher the dose,
the more suppression of factor XI activity. In fact, the highest
dose nearly eliminated factor XI activity. The drug clearly works
in the way that it was intended. Now again, the clinical data, it
wasn't powered for clinical data. But when we look at the
bleeding results, we found that there was in fact an increase in
bleeding as the dose of asundexian increased. The overall rate of
bleeding in the highest dose of asundexian was in 50 milligrams
was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about
9.02%. Again, the efficacy outcomes, very, very low rates of
overall events. Again, not powered to show a difference.
Essentially, very similar across all the arms.


Dr. Greg Hundley:


And did you find the same results for the men and the women? And
what about older individuals and younger individuals?


Dr. Sunil Rao:


Yeah. We did look at some subgroups. And you had to be a little
bit cautious because again, the trial itself is relatively small.
I mean, we didn't notice any significant patterns across these
subgroups. And the overall interaction p-values were really
non-significant. But I think what this does show is like a phase
two trial that the drug works as in the way that it's intended.
Overall, safety was as expected. And I think it really sets up
data for a larger study.


Dr. Greg Hundley:


Well, listeners, what a fantastic presentation. And now, we're
going to turn to our guest editor and editorialist, Dr. Gregory
Lip from Liverpool. Greg, I know working for circulation, you
have many papers come across your desk. What attracted you to
this particular paper? And then maybe secondly, can you help us
put the results of this study in the context of other studies
that have been evaluating these factor XI therapies?


Dr. Gregory Lip:


Thanks, Greg. Well, I think this is an important paper, because
it is a phase two trial with a novel, orally bioavailable
inhibitor factor XI. And this is intriguing because factor XI
efficiency in humans and experimentally in animals is associated
with a reduced risk of thrombotic events like stroke or venous
thromboembolism. But spontaneous bleeding is rare and also
bleeding in response to trauma or surgery is much milder. Really
it's the holy grail of trying to get an anticoagulant that
reduces thrombosis but doesn't cause an excess of bleeding. Now,
this was the quest with different anticoagulants.


And I think it was very exciting to see this particular paper in
the patients who've had an acute coronary syndrome, because there
was a lot of interest in the use of anticoagulants, particularly
in combination with antiplatelet therapy from trials such as
ATLAS and COMPASS, where there was certainly a reduction in
adverse cardiovascular events. But a downside with those drugs
and when using combination, was an excess of bleeding by the
combination of the available anticoagulants now plus
antiplatelets. The factor XIs agents offered the possibilities we
might have combination therapy to reduce cardiovascular events
but not causing an excess of bleeding.


Dr. Greg Hundley:


Well, listeners, what a wonderful discussion that we've had here.
Let's circle back with both individuals. Sunil, we'll start with
you. What do you see as the next study to really be performed in
this sphere of research?


Dr. Sunil Rao:


I think that factor XI is a very attractive target in patients
with acute coronary syndrome. Again, the rationale for why we did
this phase two trial was to show that inhibition of activated
factor XI should result in a low rate of ischemic events without
a significant increase in bleeding. This phase two trial was
really to try and decide which doses result in potent inhibition
of factor XIa and potentially which doses should be carried
forward into a larger study. What we found in the PACIFIC-AMI
trial was that the doses of asundexian and the factor XIa
inhibitor were very, very well tolerated with a low rate of
adverse events. It resulted in a dose-dependent near complete
inhibition of factor XIa activity without a significant increase
in bleeding and a low rate of ischemic events. I think, again,
it's a very attractive target in patients with ACS and this
really provides support for a larger adequately powered clinical
trial in patients with acute coronary syndrome that is really
looking at clinical events such as MACE as well as bleeding.


Dr. Greg Hundley:


And Greg as an editorialist, what did you see with this paper?
Maybe some unanswered questions that we'd like to pursue further?


Dr. Gregory Lip:


Well, I think this does raise a lot of questions in the sense
that it'll be interesting because as a phase two trial, it's a
relatively moderate sized trial. It's not like a phase three
large outcome trial and phase two trials also testing different
doses of the novel agent. We need to see the definitive phase
three trial and to look at the magnitude of benefit versus
potential for bleeding if in the large phase three trial and
obviously, the net clinical benefit and importantly are some of
the subgroups: ST elevation, myocardial infarction, undergoing
primary PCI, for example, those with renal impairment. And I
think particularly intriguing would be looking at the patients in
this scenario who get the new antiplatelet drugs such as
ticagrelor and prasugrel. And the reason I say that is what we
have with warfarin or Coumadin and from the current DOACs or
NOACs, depending on the risk side upon. We refer to them, that's
the direct oral anticoagulants or non-vitamin K antagonist or
anticoagulants.


Well, if you give a more potent antiplatelet like prasugrel or
ticagrelor, the risk of bleeding not surprisingly is higher.
Hence, the guidelines recommend that if you use an anticoagulant
or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as
opposed to the more potent ones. If this new class of drugs, the
factor XI inhibitors can work well in combination with one of the
more potent antiplatelets without causing an excessive bleeding,
again, this is going to be a substantial advance.


Well, with these new class of anticoagulants, will be really
interesting to see the phase three trials when applied to other
chronic conditions. For example, stroke prevention and atrial
fibrillation. And the other category of patients would be those
who've had an embolic stroke of uncertain source or ESUS or in
old terminology cryptogenic stroke. With the ESUS group of
patients, they're currently treated with aspirin because the
trials which tried a NOAC or DOAC, they were not showing a
positive result. They'll be interesting again with the factor XI
inhibitors, whether we are going to see this benefit with the
reduction in recurrence stroke with no excessive bleeding.


Dr. Greg Hundley:


Very nice. Well, listeners, we want to thank Dr. Sunil Rao from
NYU in New York City and Dr. Gregory Lip from the University of
Liverpool for bringing us this study highlighting that in
patients with recent acute myocardial infarction, three doses of
asundexian when added to aspirin plus a P2Y 12 inhibitor resulted
in dose-dependent near complete inhibition of factor XIa activity
without a significant increase in bleeding and a low rate of
ischemic events. And certainly, the data from this study support
the investigation of asundexian at a dose of 50 milligrams daily
in an adequately powered clinical trial of patients following
acute myocardial infection.


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. 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.