Circulation August 13, 2019 Issue

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
cohosts. 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 from the Poly Heart Center
at VCU health in Richmond, Virginia. Carolyn, oh, this is going
to be an exciting featured article today, and we're going to
discuss the combination of agents or their administration et al
that are best suited for managing both anticoagulation and
antiplatelet therapy and those with coronary disease, peripheral
arterial disease and heart failure. And, we'll speak with Dr
Kelley Branch from the University of Washington.


Dr Carolyn
Lam:               
And me!


Dr Greg
Hundley:            
Yes. How am I going to interview you? And, we'll discuss the
utility of Rivaroxaban with or without aspirin in patients with
heart failure or peripheral arterial disease from the compass
trial.


Dr Carolyn
Lam:               
Well, I'm not going to let you get there until I tell you about
this first basic paper I've chosen because it focuses on the
unfolded protein response.


Dr Greg
Hundley:            
What's that?


Dr Carolyn
Lam:               
Well, Greg, I was really hoping you'd ask. The unfolded protein
response is a cellular adaptive process to cope with protein
folding stress. Now, approximately 40% of human proteins are
predicted to be either transmembrane or secretory. The synthesis,
the folding, the cellular transportation and location of these
proteins rely on proper functioning of this secretory pathway.
Numerous studies have established that the unfolded protein
response plays versatile roles during development and under
physiologic and pathophysiologic conditions. However, the role of
this unfolded protein response in the regulation of cardiomyocyte
growth is unclear.


Dr Greg
Hundley:            
That's fantastic, Carolyn. I've already learned something here.
So, what did this paper show?


Dr Carolyn
Lam:               
This is from Dr Wang and colleagues from UT Southwestern, and
basically, they use both gain and loss of function approaches to
genetically manipulate spliced X-box binding protein one or XBP1,
which is the most conserved signaling branch of the unfolded
protein response in the heart. In addition, primary cardiomyocyte
cultures were employed to address the role of XBP1S in cell
growth in a cell autonomous manner. They found that XBP1S
expression was reduced in both human and Rhode and cardiac
tissues with heart failure deficiency of XBP1S lead to
decompensation and exacerbation of heart failure progression
under pressure overload. On the other hand, cardiac restricted
over expression of XBP1S prevented the development of cardiac
dysfunction. Mechanistically, they found that XBP1S stimulated
adaptive cardiac growth, your activation of mechanistic target of
rapamycin or MTOR signaling which is mediated via the FK-506
binding protein 11, which is a novel transcriptional target of
XBP1S. So in conclusion, this study really showed a critical role
of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in
coupling the unfolded protein response and cardiac cell growth
regulation.


Dr Greg
Hundley:            
Boy Carolyn, you explained that so well, and I learned a lot from
that. I hope I can do as well with this next article from
Professor Johann Backs from the University of Heidelberg. Now
paradoxically, some glucose lowering drugs have been shown to
worsen heart failure, raising the question of how glucose
mediates protective versus detrimental cardiac signaling, and
this study from his group focused on one of the class two histone
deacetylases or HDAC's namely HDAC-4, which functions as an
important epigenetic regulator by responding to upstream stress
signals, and linking them to downstream gene regulatory programs
involved in among other things, metabolic regulation.


Dr Carolyn
Lam:               
Very interesting. So what did they find?


Dr Greg
Hundley:            
What they found is that HDAC4 acts as an important maintenance
factor of cardiac function in diabetes and
O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the
production of cardio-protective HDAC F-end terminal fragment and
attenuates cardio detrimental Cam kinase two mediated
phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase
two mediated phosphorylation of HDAC4 at searing 632 attenuates
HDAC-4 n terminal production. Thus, these findings lay the ground
for the development of novel therapeutic strategies for diabetic
patients with heart failure by inhibiting Cam kinase
phosphorylation at CIHR 632 or enhancing o-glycine and escalation
at searing 642.


Dr Carolyn
Lam:               
Fascinating, Greg. Well, my next paper is a subgroup analysis of
EUCLID and is the first to assess acute limb ischemia in the
context of a large-scale clinical trial studying a primary
peripheral artery disease population.


Dr Greg
Hundley:            
So Carolyn, reminded us what was the EUCLID trial.


Dr Carolyn
Lam:               
Okay, so EUCLID stands for Examining Use of Ticagrelor in
Peripheral Artery Disease, and this was a randomized clinical
trial that included acute limb ischemia as an adjudicated outcome
in a primary peripheral artery disease population randomized to
ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not
superior to Clopidogrel for the prevention of cardiovascular
events in patients with stable peripheral artery disease.
However, a EUCLID subgroup analysis of patients with and without
prior limb revascularization demonstrated significantly higher
risk for acute limb ischemia hospitalization in patients with
prior low extremity revascularization.


Dr Greg
Hundley:            
So Carolyn, that's interesting. So, what did they find related in
this study that focused on the acute limb ischemia?


Dr Carolyn
Lam:               
Right. So, today's paper is from Dr Hess and colleagues at
University of Colorado School of Medicine and CPC, clinical
research in Aurora, Colorado. And, they found that acute limb
ischemia occurred in 1.7% of almost 13,900 randomized patients
with a median time to hospitalization for acute limb Ischemia of
320 days after randomization. In this population, prior lower
extremity revascularization, atrial fibrillation and lower ankle
brachial index identified patients at higher risk for acute limb
ischemia. Hospitalization for acute limb ischemia was associated
with subsequent cardiovascular and limb ischemic events. So, the
take home message is providers should monitor for signs and
symptoms of acute limb ischemia in patients with stable
symptomatic peripheral artery disease, particularly those with
prior lower extremity revascularization, atrial fibrillation, and
lower ankle brachial index.


Dr Greg
Hundley:            
That's very instructive, Carolyn. Fantastic message. So, I'm
going to ask you if you could select one lipid biomarker to
forecast future adverse cardiovascular events, which would you
select? Total cholesterol, HTLC, non-HTLC, direct and calculated
LDLC, APO-A1, or APO-B?


Dr Carolyn
Lam:               
Well, I'm traditional. I would have chosen LDL.


Dr Greg
Hundley:            
Okay. Well, the authors of this study led by Dr Paul Welsh at the
University of Glasgow attempted to answer this question by
studying participants from the UK Biobank without baseline
cardiovascular disease and not taking statins with relevant lipid
measurements. They had 346,686 participants. An incident fatal or
nonfatal cardiovascular event occurred in 6,200 participants of
which 1,656 were fatal, and they occurred over a median time of
8.9 years. So, the associations of non-fasting lipid
measurements, total cholesterol, HDLC, non HDLC, direct and
calculated LDLC, APO-a1, and APO-B with cardiovascular disease
were compared using Cox models, adjusting for classical risk
factors and predictive utility was determined by the C-index and
net reclassification index. Also, prediction was tested in 68,649
participants taking a statin with or without baseline
cardiovascular disease, and that group experienced 3,515
cardiovascular events.


Dr Carolyn
Lam:               
Okay, so drum roll. What did they find?


Dr Greg
Hundley:            
So, measurement of total cholesterol and HDLC in the non-fasted
state is sufficient or was sufficient to capture the lipid
associated risk in the cardiovascular disease prediction with no
meaningful improvement from addition of APO lipoproteins, direct
or calculated LDLC. And, similar findings were reproduced in
those taking a statin at baseline.


                                               
As such, the authors feel like calls for widespread use of APO
lipoproteins are not warranted given the negligible difference in
risk prediction beyond total cholesterol in HDLC. And, direct
LDLC is also not required for risk prediction. Non HDLC is a
cheaper or equivalent predictor of risk on and off statins
without the requirement of one of us being fasting. This is an
excellent article for our listeners to review or download.


Dr Carolyn
Lam:               
Wow, that is so cool. So, from one excellent paper to another
excellent paper in our feature discussion. Let's go, shall we?


Dr Greg
Hundley:            
Welcome everyone to discussion of our featured article. We have
Dr Kelley Branch from the University of Washington and our own
Carolyn Lam, and they're going to be discussing the compass
trial. So Kelley, could you tell us a little bit about the
rationale for compass as opposed to the previously published
commander study?


Dr Kelley
Branch:             
So, in order to understand compass and compare it to commanders,
we're going to have to go back a little bit in time here. And
recall, you know well over 20 years ago that when we used
anticoagulants in coronary artery disease, that was actually
shown to be more beneficial than aspirin alone, but because of
the excess bleeding risk, warfarin or vitamin K antagonists not
used, and aspirin won. Fast forward a number of years, and now we
have the non-vitamin K anticoagulants, and the was potentially
that we could find the goldilocks, if you will, the good balance
of benefit as well as less bleeding maybe used to these new
agents. So, the compass trial was really born from an atlas ACS
one and Atlas ACS two, which found that a low dose of, in this
case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams
VAB were shown to be beneficial in patients after acute coronary
syndrome.


                                               
And then, it was thought what happens if we treat these patients
with now chronic coronary disease as well as arterial disease?
And from this 27,000 patients, 47,395 patients were tested, and
our study very specifically looked at patients with a baseline or
a history of heart failure when they answered compass. Compass
were shown to be beneficial with specifically the use of aspirin
plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test
this in patients with this baseline or history of heart failure.
Now, this is in real contradistinction to what the commander
tried to do. And the reason why encompass, we actually excluded
patients with severe heart failure. This was defined as a New
York Heart Association class three or four or an ejection
fraction less than 30%. Now if you looked at patients with
commander, these patients had ejection fraction less than 40%.
That was a criteria to get in. And of course, these patients had
to have a recent hospitalization for heart failure. So, these are
very different patient populations. Well, both of them, yes, they
did have coronary artery disease, but really very different
patient populations.


Dr Greg
Hundley:            
Very good. So Kelley, tell us specifically, what were your
treatment group assignments and the doses and the outcomes that
you were going to follow, and then lead us into what did you
find? What were the outcomes of your study?


Dr Kelley
Branch:             
Sure, so compass was actually developed as a partial three by two
factorial. The arm that we're going to be talking about is the
rivaroxaban arm. There was also another arm that tested the use
of Proton pump inhibitors, and that actually was shown to not be
as beneficial as we thought to decreased bleeding. But
specifically for rivaroxaban, the baseline was aspirin, and this
was on top of guideline based medical therapy. And then patients
were randomized to either aspirin alone plus placebo or
Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at
all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5
milligrams BAD. Those were really the three treatments. Patients
were going to be followed for about three to four years. That's
what we expected to get our 2200 events , an event-driven trial.
But, because of the overwhelming benefits at 23 months median
follow up, this trial was actually stopped early, so we only had
a little over 1300 events at that time.


                                               
And with that we saw substantial reduction in major adverse
cardiovascular events, about 24% mortality was reduced 18%, and
there was a bleeding risk along with this, major bleeding, little
different way of actually measuring major bleeding, but that was
increased by about 70%, and that was the overall trial results.
So, looking at the patients with heart failure, though, there was
actually a relatively large proportion of patients, so 5,902
patients, about 22% of patients, actually had either baseline
heart failure or had a history of heart failure coming in. Now,
this was defined specifically by the PI's. These were not
rigorously defined as compared to say commander, but these were
patients where the PI said this patient has history or has
chronic heart failure. So, with these 5,902 patients, we looked
specifically at the outcomes of major adverse cardiovascular
events similar to what we saw with compass and that is
cardiovascular death, myocardial infarction, or any stroke, that
combination. And then, looked at some others exploratory analysis
like mortality.


                                               
And, what we found is that in patients with heart failure, the
baseline rate was substantially higher for a mate's. Not too
surprising because this tends to be a higher risk patient
population. But, what we found is that the hazard ratio was about
0.68, so pretty similar to what we've seen the 24% relative risk.
In this case, this was a 32% relative risk reduction in those
patients with heart failure. Now, if we looked at a patients
without heart failure, the hazard ratio is 0.79, so fairly
similar and the [conference intervals 00:16:33] overlap. No
statistical heterogeneity or no difference between those, but
what we did see if we looked at the absolute risk reduction, was
an absolute risk reduction in heart failure of 2.4% reduction.
That means a number needed to treat of about 42. If you look at
the absolute risk reduction for those patients without heart
failure, that was 0.9 to 1.0 depending on what the rounding was.
We took 1.0 so that means the number needed to treat of 103. So,
these were slightly different relative risks, but overall, what
we saw is that the hazard ratio is very consistent with the
overall effect of compass in the same direction.


                                               
Interestingly, and actually I think even for me it was
surprisingly, we actually looked at the hazard ratios for
bleeding, and when we looked at the hazard ratios for bleeding,
we fully expected that because it's the higher risk patient
population, we actually expected that to go up. What we saw is
that the bleeding actually was no difference at all, and if
anything in the heart failure population was slightly lower. And,
this was fairly surprising to us because we thought that the
patients with heart failure, the bleeding would actually trend up
because this was a higher risk patient population. So it looks
like it's something can be used and really no substantial
increase in bleeding.


Dr Greg
Hundley:            
Very good. Well Carolyn, as someone that's managing patients with
heart failure, what do you see are the clinical implications of
this study?


Dr Carolyn
Lam:               
That is a beautifully simple, direct question but is not as easy
to answer as I may have thought. And, that's because the
commander trial that Kelley did describe a bit earlier was
neutral on its primary outcome. And, the commander trial is what
we would traditionally think of as a heart failure trial. And
why? Because those were patients that we rigorously define heart
failure, including a naturally acid peptide inclusion criteria.
And, because we really wanted these to be severe heart failure
patients, we recruited them very close to their hospitalization
or decompensation event. So, I just want to reiterate what Kelley
has already so beautifully described that commander was neutral,
whereas this heart failure subset of compass showed very
impressive results that were consistent with the very impressive
positive results of the overall compass trial.


                                               
So, how do we reconcile all of it? Well, first of all, I have to
humbly remind myself that this heart failure subset of compass,
the entire subset was actually bigger in numbers than the entire
of the commander trials. So, this is not a small little subgroup
analysis. This is a huge subgroup analysis. And that's why a
paper like this, we're so proud to be publishing in circulation.


                                               
So, how do I apply it? Well, when I have a compass like patient,
which means it's a stable coronary artery disease or peripheral
artery disease patient who happens to have some mild heart
failure. I think of this patient as a compass patient and I think
that the combination of aspirin and low dose Rivaroxaban has been
shown to be effective in these patients. So, in such a patient, I
continue the aspirin rivaroxaban combination. However, if I have
a new patient coming in with decompensated heart failure, a very
low ejection fraction and has some coronary artery disease, by
the way, I see that as a commander patient, and I just want to
make sure that in such a patient I'm not trying to reduce their
overall mortality by treating them with a combination of aspirin
Rivaroxaban because commander has shown that I don't impact their
overall survival with this combination, even though we may still
have beneficial effects on their thromboembolic thrombotic
events.


                                               
Kelley, would you agree?


Dr Kelley
Branch:             
I would completely agree. That was actually born out very, very
well by Barry Greenberg who had a really a wonderful sub analysis
which he looked at the thrombotic events published in Jama
cardiology and really showing that yes, you can affect the
thrombotic events, but I mean really what it comes down to is we
want to save lives. We want people to be better. There's just an
overwhelming risk for these patients with heart failure that is
really non thrombotic, primarily. And so, you're really not going
to move the needle very much. You may prevent a stroke here, you
may prevent some cardiovascular death from a thrombotic problem,
but overwhelmingly pump failure, arrhythmia, et cetera. Those are
really going to be the drivers for the commander like population.


Dr Carolyn
Lam:               
But Kelley, this comes up a lot when we've chatted, but if you
have a compass patient who has heart failure and then gets
admitted with heart failure, what would you do then?


Dr Kelley
Branch:             
That's a really interesting question, right? It depends on what
the overall goal is. So, if the patient gets admitted for heart
failure, now has it decreased ejection fraction sick. So has an
MI, now decreased the ejection fraction. What's the end game?
Right? Well you know, you may not be affecting mortality in this
case because there's now competing events. However, if the goal
was to decrease stroke, we've seen that. Still this goal is to
decrease MI to some extent than we see that also. So, it would be
reasonable to continue in order to prevent those events. But,
just knowing full well that there's many other medications which
actually do much better for the patients with decreased ejection
fraction. And, those would probably be considered first line, but
it's reasonable to continue. But, I would never start it.


Dr Carolyn
Lam:               
Kelley, I couldn't agree more. And here I think the, your data
showing that the bleeding risk is not significantly increased in
this patient matters a lot. So, if I had a patient, a compass
patient who was already on the combination and then gets admitted
with heart failure, I too, if there's no additional bleeding
risk, I would continue the combination as well.


Dr Kelley
Branch:             
Couldn't agree more.


Dr Greg
Hundley:            
Well listeners, this was a fantastic discussion, and we look
forward to seeing you next week. Have a great week.


Dr Carolyn
Lam:               
This program is copyright American Heart Association 2019.