Circulation December 7, 2021 Issue

Please join Guest Host Mercedes Carnethon along with
first author Connie Hess and Guest Editor
Gregory Lip as they discuss the article
"Reduction in Acute Limb Ischemia With
Rivaroxaban Versus Placebo in Peripheral Artery Disease After
Lower Extremity Revascularization: Insights From VOYAGER
PAD."


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 Poly
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, our feature discussion is on a really important topic,
peripheral artery disease. So important, so rampant, not talked
about enough. And it's really insights from the VOYAGER-PAD trial
telling us about the reduction in acute limb ischemia with
Rivaroxaban versus placebo in peripheral artery disease after
lower extremity revascularization. But before we get into all
that, I want you to get your coffee while I tell you about my
picks of today's issue. Should I start?


Dr. Greg Hundley:


Very good.


Dr. Carolyn Lam:


Okay. So the first paper deals with the residual ischemic risk
following coronary artery bypass grafting surgery. We know that
despite advances, patients following CABG still have significant
risk. So this paper refers to a subgroup of patients from the
REDUCE-IT trial with a history of CABG, which was analyzed to
evaluate the efficacy of icosapent ethyl treatment in the
reduction of cardiovascular events in this high risk patient
population. Now, as a reminder, the REDUCE-IT trial was a
multicenter, placebo controlled, double blind trial, where statin
treated patients with controlled LDL cholesterol and mild to
moderate hypertriglyceridemia were randomized to four grams daily
of icosapent ethyl or placebo. They experienced a 25% reduction
in risk of a primary efficacy endpoint, which was cardiovascular
death, MI, stroke, coronary revascularization, or hospitalization
for unstable angina. Now the current report tells us about the
subgroup of patients from the trial with a history of CABG.


Dr. Greg Hundley:


Ah, Carolyn. So what did they find in this subgroup of patients?


Dr. Carolyn Lam:


So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a
history of CABG with 897 patients randomized to icosapent ethyl
and 940 to placebo. Baseline characteristics were similar between
the treatment groups and randomization to icosapent ethyl was
associated with a significant reduction in the primary endpoint,
as well as in key secondary endpoint and in total ischemic events
compared to placebo. This yielded an absolute risk reduction of
6.2% in first events with a number needed to treat of 16 over a
median follow up time of 4.8 years. So, Greg, I think you'll
agree, icosapent ethyl may be an important pharmaco-therapeutic
option to consider in eligible patients with a history of
coronary artery bypass grafting surgery.


Dr. Greg Hundley:


Very nice, Carolyn. What an excellent summary. So Carolyn, for my
first paper... And this study comes to us from Professor Judith
Haendeler from the Leibniz Research Institute for Environmental
Medicine. So Carolyn, this is a new type of quiz question. And as
you listen to the presentation, help us predict the clinical
implications. Okay, here we go.


Dr. Greg Hundley:


All right. So Carolyn, telomerase, also called terminal
transferase, is a ribonuclear protein that adds a species
dependent telomere repeat sequence to the three prime end of
telomeres. And Carolyn, just to refresh our memories, a telomere
is a region of repetitive sequences at each end of the
chromosomes of most eukaryotes. And telomerase was discovered
interestingly by Carol Greider and Elizabeth Blackburn in 1984.
And together with some others, including Jack Szostak, they were
awarded the 2009 Nobel Prize in physiology and medicine for
discovery.


Dr. Greg Hundley:


So Carolyn, telomerase is active in gamuts and most cancer cells,
but is normally absent from or at very low levels in most somatic
cells. And the catalytic subunit of telomerase called telomerase
reverse transcriptase or trt has protective functions in the
cardiovascular system, particularly in regard to ischemia
reperfusion injury. And interestingly trt or telomerase reverse
transcriptase is not present in the nucleus, but also in
mitochondria. However, for us in cardiovascular medicine, it is
unclear whether nuclear or mitochondrial trt is responsible for
the observed protection.


Dr. Carolyn Lam:


Wow, fascinating. So what did today's paper find?


Dr. Greg Hundley:


Right, Carolyn. So it was mitochondrial, but not nuclear
telomerase reverse transcriptase that was found critical for
mitochondrial respiration during ischemia reperfusion injury. And
mitochondrial telomerase reverse transcriptase improves complex 1
subunit composition. And trt is present in human heart
mitochondria and remote ischemic preconditioning increases its
level in these organelles. Also, Carolyn TA65 was found to have
comparable effects ex vivo and improved migratory capacity of
endothelial cells and myofibroblast differentiation. So Carolyn,
with this summary, can you help speculate on the clinical
implications of this paper?


Dr. Carolyn Lam:


Oh, Greg. You set it up so nicely. So I would speculate that the
clinical implications are that an increase in the mitochondrial
telomerase reverse transcriptase or trt would be able to help
with cardioprotection in ischaemic reperfusion injury, or at
least that's what we hope and that's where we should be going
with this. Am I right?


Dr. Greg Hundley:


Absolutely, Carolyn. So in the future, this research showing that
trt and cardioprotection... Maybe we increase this and it could
serve as a therapeutic strategy. Excellent job, Carolyn.


Dr. Carolyn Lam:


Thank you, Greg. All right. My next paper is a preclinical paper.
I will spare you of difficult quizzes and maybe... This is just
so neat. Let me tell you about it. So the study really provides
novel insights into the mechanisms underlying smooth muscle cell
phenotypic modulation that contributes to the development of
vascular diseases like renal atherosclerosis and restenosis after
angioplasty. So very important. Dr. Jiliang Zhou from Medical
College of Georgia and colleagues basically used an in silico
approach to probe unbiased, proprietary, and diverse, publicly
available bulk RNA-Seq and scRNA-Seq datasets to search for
smooth muscle cell specific long non-coding RNAs or lncRNAs.


Dr. Carolyn Lam:


The search ended up identifying CARMN, which stands for cardiac
mesoderm enhancer-associated non-coding RNA, CARMN. As a highly
abundant, highly conserved smooth muscle cell specific lncRNA,
CARMN was recently reported to play roles in cardiac
differentiation and was initially annotated as a host lncRNA for
the microRNA, the MIR143145 cluster, which is the best
characterized microRNAs in regulating smooth muscle cell
differentiation and phenotypical modulation.


Dr. Carolyn Lam:


But in the current study, the authors confirmed the expression
specificity of CARMN using a novel GFP knock-in reporter mouse
model, and discovered that CARMN is downregulated in various
vascular diseases. They further found that CARMN is critical for
maintaining vascular smooth muscle cell contractile phenotype,
both in vitro and in vivo by directly binding to the smooth
muscle cell specific transcriptional cofactor known as myocardit.


Dr. Greg Hundley:


Okay. Carolyn, what a beautiful summary here. So what's the take
home message here?


Dr. Carolyn Lam:


So these findings collectively suggest that CARMN is a key
regulator of vascular smooth muscle cell phenotype, and therefore
represents a potential therapeutic target for the treatment of
smooth muscle cell related proliferative diseases.


Dr. Carolyn Lam:


Well, Greg, thanks for letting me to tell you about that one. But
let me tell you also about other papers in today's issue. There's
an exchange of letters between Dr's Lee and Chew on high rates of
coronary events in the rapid troponin T0 one hour protocol. Is it
a reality or illusion? There's an ECG Challenge by Dr. Liu on
“Acute Inferior Wall Myocardial Infarction. What is the Culprit
Artery? In Cardiology News, Bridget Kuehn writes on persistent
heart effects of COVID-19 and how that emphasizes the need for
prevention.


Dr. Greg Hundley:


Very nice, Carolyn. Well, I've got a Research Letter to tell you
about from Professor Huang, entitled “High Prevalence of
Unrecognized Congenital Heart Disease in School-Age Children in
Rural China: A Population-Based Echocardiographic Screening
Study.” Well, Carolyn, what a fantastic issue. And how about we
get onto that feature discussion now and learn more out lower
extremity revascularization and insights from the VOYAGER-PAD
study?


Dr. Carolyn Lam:


Let's go, Greg.


Dr. Mercedes Carnethon:


Good morning, everyone. Welcome to this episode of Circulation on
the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair
of Preventive Medicine at the Northwestern University Feinberg
School of Medicine and associate editor of the journal. Really
excited today to hear from one of our authors of a particularly
interesting piece that we'd like to discuss today about
peripheral artery disease after lower extremity
revascularization.


Dr. Mercedes Carnethon:


And we have with us today, the lead author, Dr. Connie Hess from
the division of cardiology at the University of Colorado School
of Medicine in Aurora. And we have Dr. Gregory Lip with us. So
welcome to the both of you.


Professor Gregory Lip:


Hello there.


Dr. Connie Hess:


Thank you for having me.


Dr. Mercedes Carnethon:


Thank you both for joining us. This is really exciting. I know
that when I read this piece, I was really excited to think about
the implications that these study findings from this clinical
trial will have for a very important clinical problem of
peripheral arterial disease and those complications. So, Connie,
would you be willing to start by telling us a little bit about
what you found in this study?


Dr. Connie Hess:


Yeah, absolutely. I think maybe a good place to start first is,
if that's okay, is just a little bit of the background and why we
looked at this and thought to look at this. I think as you're
both probably aware, peripheral artery disease is a very highly
prevalent condition. It affects a lot of people, but there's not
a lot of awareness about it. It's in some ways the forgotten
manifestation of atherosclerosis. And so acute limb ischemia in
particular is a very feared complication of peripheral artery
disease. And unlike things like ST elevation, myocardial
infarction, and stroke about which patients and providers have a
lot of knowledge and understanding, many people don't know about
acute limb ischemia. And in particular ALI, acute limb ischemia,
is a complication of peripheral revascularization that many of us
as proceduralists are very concerned about.


Dr. Connie Hess:


And so what we wanted to do was use this very unique clinical
trial and dataset to look at acute limb ischemia, to describe it,
to better understand it, especially after a peripheral
revascularization. And then also to look at the effect of
Rivaroxaban plus aspirin versus aspirin alone on this feared
outcome. We're lacking therapies to effectively prevent ALI.


Dr. Connie Hess:


And so if I just briefly review the trial, VOYAGER-PAD randomized
6,564 patients undergoing peripheral revascularization, both
surgical or endovascular to Rivaroxaban, 2.5 milligrams twice
daily versus placebo on top of aspirin. And then providers could
use prochidagril for up to six months per their discretion. Now,
the primary outcome for VOYAGER-PAD was very unique. This was a
five point composite that looked at acute limb ischemia, major
amputation of vascular etiology, myocardial infarction, ischemic
stroke, or cardiovascular death.


Dr. Connie Hess:


And so in this trial in the primary results, Rivaroxaban plus
aspirin versus aspirin alone was highly effective in reducing the
primary endpoint, that five point composite I just described. And
so we were excited to look specifically at the effect of this
combination therapy on acute limb ischemia alone. What we found
to begin with, I think in terms of describing acute limb ischemia
is important. So the three year cumulative incidence in the
patients assigned a placebo was about 8% for ALI. So this is not
an uncommon problem. And in fact, we found that there was
incidents of ALI occurring quite early after the procedure and
that the risk persisted, even three years out.


Dr. Connie Hess:


And Rivaroxaban plus aspirin versus aspirin alone was very
effective in reducing ALI by about 33%. Beyond that, we also
looked at ALI in terms of severity of these complications. And we
found that about a third of patients had a very severe ALI event
that we defined as ALI followed by death, major amputation, or
requiring a prolonged hospitalization with time in the intensive
care unit. And for those patients, Rivaroxaban plus aspirin was
even more effective with almost a 55% reduction.


Dr. Connie Hess:


Lastly, I think we also looked at just the patients who are at
risk for ALI after peripheral revascularization. And we did
identify some patient and procedural factors that might help us
identify these patients. For example, having a prior lower
extremity revascularization, having more severe PAD as indicated
by a low ankle brachial index, undergoing surgical
revascularization, and having longer target lesions. So I think
we were able to describe ALI in a way that some other trials and
datasets have not been able to do. And then also beyond that to
provide some evidence for effective therapy to prevent this
complication.


Dr. Mercedes Carnethon:


All of that is so exciting. And for somebody coming to this
outside of the initial field, I can certainly see a lot of
innovations that you describe in what you've done and the
importance to the population of people who experience this very
debilitating illness. So it's really wonderful to see this in
print. So tell me, Greg, what excited you as the editor about
this particular paper? So what made it really stand out in your
mind?


Professor Gregory Lip:


Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a
really nice paper. And I think that it's really important because
many cardiologists tend to neglect looking at and managing
peripheral artery disease, especially with the medical therapies.
And I think VOYAGER-PAD was an important advancement of how we
can have... You could say, dual blockade, both with low dose
anticoagulation plus antiplatelets should improve the outcomes.


Professor Gregory Lip:


So I think it really brings to the forefront how we should
optimize medical therapy and peripheral disease. It's not simply
a matter of surgery or just intervention with stenting. And I
think maybe the other important aspects in regard to this study,
this trial is when you combine an antiplatelet with an
anticoagulant, it's worth flagging up the potential for added
risk of bleeding. And it's therefore the fact that your analysis
included to identify the patients at high risk of acute limb
ischemia, then we will actually facilitate risk stratification so
that we can perhaps target the very high risk patients where that
balance in terms of the net benefit for the combination therapy
compared to aspirin alone would be there because you're balancing
the thrombotic and limb ischemic outcome versus the potential for
bleeding.


Professor Gregory Lip:


We are also using of course, in VOYAGER-PAD low dose Rivaroxaban,
which is not the stroke prevention dose of Rivaroxaban in
everyday clinical practice. And that's worth emphasizing. So we
translate peripheral disease dosages or regimes versus what we
see in other prothrombotic situations like atrial fibrillation,
which leads to stroke. And that's probably worth emphasizing. And
I think really what is most important is that we can hopefully
identify the high risk subset of patients with peripheral artery
disease at risk of acute limb ischemia, where they're going to
particularly benefit from combination therapy. So an important
advance for medical therapy for peripheral disease. So
congratulations on this paper as well.


Dr. Mercedes Carnethon:


Yeah. I really echo that. One of the things that when we write
original research papers, we are always encouraged not to
speculate beyond the data that we're presenting. But one of the
values of this podcast is that we get a chance to really needle
the authors and challenge them to speculate about what does this
mean? What does this mean for the field? And Connie in
particular, what do you think the next steps are for patients and
providers based on what you found today in this excellent study?


Dr. Connie Hess:


Mercedes, that's a great question. Certainly we always want to
know what next? What are the implications of these findings? And
so to me, I echo both of you. I'm personally very excited as
someone in the field. And as a proceduralist, I'm very excited
that for the first time, we actually have data to support a
medical therapy post intervention. Although there's a lot of use
of things like dual antiplatelet therapy and even
anticoagulation, there's not a lot of data to support it after
peripheral revascularization. So this really is the first large
scale, high quality data to support a strategy. And so I do think
that this is something that we should adopt.


Dr. Connie Hess:


I think what I didn't mention before is that actually, when you
look at the cumulative incidence curves for ALI in the
Rivaroxaban versus placebo groups, not only do you see that there
is early risk for ALI after the procedure... And typically we
think of this as potentially technical failure that we can't
modify, but you saw a very early benefit for Rivaroxaban plus
aspirin versus aspirin alone here, suggesting that the sooner you
start, the better. Of course, it has to be when it's safe from a
bleeding perspective and when the proceduralist feels comfortable
with this. But I do think that the implications are that we
should... We proceduralists, especially in this population and as
professor Lip mentioned the high risk patients in particular,
should be starting this therapy as soon as we feel safe. And so I
think the data are there. The next step to me is really
increasing awareness, in particular among providers who are
treating these patients, but even among our other colleagues or
cardiovascular colleagues who may not treat these peripheral
artery disease patients primarily, but do see them in their
clinic.


Dr. Connie Hess:


A lot of them have cardiovascular disease and other
cardiovascular problems, but to increase awareness that this dual
pathway inhibition with low dose factor 10, anticoagulation
inhibition and low antiplatelet therapy is a viable and favorable
combination and to continue this so that when they see this,
they're not surprised and not questioning whether to stop it.


Dr. Connie Hess:


I think also of course now that we are getting more data to
understand how morbid and bad ALI is, I do think we also need to
educate patients. You both probably recall all the tremendous
efforts that were made to increase awareness in the patient
population about myocardial infarction and stroke. You have all
those campaigns and understanding the importance of timely
intervention and reperfusion. I think that actually should be
done for acute limb ischemia as well. We need to have providers
aware about this complication and understanding emergent
treatment. We also need patients to understand it so they can
come in sooner so that they're not having delayed presentation
for which primary amputation is the only treatment option. So I
think there's a lot of work to be done, but certainly very
excited that we have a better understanding of ALI as well as
preventive therapy.


Dr. Mercedes Carnethon:


I really appreciate that final word. And I really can't think of
a better way to wrap up than the final words that you provided,
Connie. Both the context that you provided around this piece and
your thoughts as well, Greg, about what makes it innovative and
exciting for our readership at Circulation are really invaluable.
So I just really want to thank you for joining us as an author
and thank you for selecting this, Greg. This is a really great
piece. I've learned a good deal.


Dr. Mercedes Carnethon:


This is me, Mercedes Carnethon, wrapping up this addition of
Circulation on the Run, following an outstanding discussion with
Dr. Connie Hess from the University of Colorado and Greg Lip, the
handling editor for the piece.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2021. 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, visit ahajournals.org.