Circulation December, 03, 2019 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 Dr Greg Hundley, associate editor from
the Pauley Heart Center in Richmond, Virginia, from VCU Health.


Dr Carolyn Lam: You know what, Greg, I may have a hoarse voice
today and I'm a little bit scratchy, but my goodness, I couldn't
be more excited about this issue. It's the TCT issue.


Dr Greg Hundley: Well Carolyn, I cannot wait to discuss with our
listeners the feature article that compares Apixaban and a P2Y12
inhibitor without Aspirin, versus regimens with Aspirin in
patients with AFib who have ACS, whether managed medically or
with PCI, or also those undergoing elective PCI that experience
regimens that include vitamin K antagonists, aspirin, or both,
but more to come later. Carolyn, should I start with my first
discussion article and we grab a cup of coffee?


Dr Carolyn Lam: You bet, Greg.


Dr Greg Hundley: So my first article is from Seung-Jung Park from
the Asan Medical Center at the University of Ulsan College of
Medicine. So Carolyn, here's our first quiz question. In terms of
Ticagrelor, have studies been performed in those from Asia
evaluating bleeding risk?


Dr Carolyn Lam: You know, I have to admit, Greg, I'm not totally
familiar with the literature, but I do know that it's a very
important question for us practicing in Asia. We have a
perception that the bleeding risk, especially intracranial
bleeding, may be higher in Asians.


Dr Greg Hundley: Absolutely. Well, in this multicenter trial, 800
Korean patients hospitalized for acute coronary syndromes with or
without ST elevation, and intended for invasive management, were
randomly assigned to receive in a one to one ratio, Ticagrelor
with a 180 milligram loading dose, and then 90 milligrams twice
daily, or Clopidogrel with a 600 milligram loading dose and 75
milligrams daily thereafter, and the primary safety outcome was
clinically significant bleeding, which was a composite of major
bleeding or minor bleeding according to the PLATO outcomes
criteria at 12 months.


Dr Carolyn Lam: Oh, so what did they find?


Dr Greg Hundley: Well Carolyn, at 12 months, the incidence of
clinically significant bleeding was higher in the Ticagrelor
group than in the Clopidogrel group. So it was 11.7% versus 5.3,
and that included major bleeding and fatal bleeding. They were
also higher in the Ticagrelor group. The incidents of death from
cardiovascular causes, myocardial infarction or stroke, was not
significantly different between the Ticagrelor group and the
Clopidogrel group, although there was a strong trend toward a
higher incidence in the Ticagrelor group with a P value of 0.07.
So consequently, Carolyn, these results identified safety
concerns regarding bleeding complications of standard dose
Ticagrelor in East Asian, Korean patients with acute coronary
syndromes, and therefore large adequately powered randomized
trials are needed to determine the optimal antithrombotic regimen
in this patient population.


Dr Carolyn Lam: Very important data for our patients, as is this
next paper, which really examines the cost effectiveness of
transcatheter mitral valve repair versus medical therapy in
patients with heart failure and secondary mitral regurgitation.
Now, these are results from the COAPT trial. As a reminder, the
COAPT trial demonstrated that edge-to-edge transcatheter mitral
valve repair using the MitraClip resulted in reduced mortality
and heart failure hospitalizations and improved quality of life
when compared with maximally tolerated guideline directed medical
therapy in patients with heart failure and three to four plus
secondary mitral regurgitation.


In the current paper, first author Dr Baron from Lahey Hospital
and Medical Center in Burlington, Massachusetts and St. Luke’s
Mid America Heart Institute in Kansas City, as well as
corresponding author Dr Cohen from University of Missouri, Kansas
City, and their colleagues used data from the COAPT trial to
perform a formal patient level economic analysis of the COAPT
from the perspective of the US healthcare system, and they found
that although the follow up costs were lower with the MitraClip
compared with guideline directed medical therapy, and lower by
more than $11,000 per patient. However, the cumulative two year
costs remain higher by about $35,000 per patient with the
transcatheter mitral valve repair, and this is all due to the
upfront costs of the index procedure. Now when in trial survival,
health, utilities, and costs were modeled over a lifetime
horizon, transcatheter mitral valve repair was projected to
increase life expectancy by 1.13 years, and quality adjusted life
years, or QALYs, by 0.82 years at a cost of $45,648, yielding a
lifetime incremental cost effectiveness ratio, or ICER, of
$40,361 per life year gained, and $55,600 per QALY gained.


Dr Greg Hundley: Very interesting. So how do we interpret these
results for clinical practice?


Dr Carolyn Lam: Ah, good question. So in order to place this in
context, perhaps the most comparable case is the use of
transcatheter aortic valve replacement, or TAVR. So based on the
partner 1B trial, the ICER for TAVR, compared to medical therapy,
was $61,889 per QALY gains. So this is very similar to what you
just heard as the ICER for the transcatheter mitral valve repair.
The cost effectiveness is also comparable for other commonly used
treatments such as the implantable cardiac defibrillators for
biventricular pacing, and was interestingly substantially more
than the cost effectiveness of continuous flow LVADs, for
example, and this is really discussed in a beautiful editorial by
Dr Bonow, Mark, and O'Gara, and in this editorial, I think it's
really important that they say the cost effectiveness projections
really need to be placed in the context of continuing
uncertainties regarding the interpretation of COAPT compared to
that of the MITRA-FR trial, which reported no benefit of
transcatheter mitral valve replacement compared to medical
therapy, and so they warn that the current cost effectiveness
analysis is not a carte blanche for interventional cardiologists
to dramatically escalate their use of MitraClip procedure, and
the data do support the thoughtful and deliberate use of this
potentially life lengthening procedure in carefully selected
patients and under very careful circumstances. You've got to read
their editorial.


Dr Greg Hundley: That sounds excellent, Carolyn. I really like
that, putting that editorial that puts that data in perspective.
Well, my next study really emanates from the ABSORB III trial,
and it's from Dr Dean Kereiakes at the Christ Hospital Heart and
Vascular Center. The manuscript addresses the long-term
cardiovascular event rates among bioresorbable vascular scaffolds
and drug eluting metallic stents.


Dr Carolyn Lam: Greg, remind me, what were the results of the
original ABSORB trial?


Dr Greg Hundley: Right, Carolyn. So the ABSORB III trial
demonstrated non-inferior rates of target lesion failure, cardiac
death, target vessel myocardial infarction, or ischemia driven
target lesion revascularization at one year with the
bioresorbable vascular scaffolds compared with cobalt chromium
everolimus-eluting stents, but between one year and three years,
and therefore the cumulative to 3 year time point, the adverse
event rates, particularly for target vessel myocardial infarction
and scaffold thrombosis, were increased with this bioresorbable
vascular scaffold.


Dr Carolyn Lam: Ah, I see. Okay, so this current study evaluated
the outcomes from three to five years beyond the implantation?


Dr Greg Hundley: Exactly. So what this study did is they looked
at an interval of time between three and five years out, and they
found reductions in the relative hazards for the bioresorbable
vascular scaffolds compared to the common coated stents, and that
particularly occurred for target lesion failure, either cardiac
death or target vessel MI or ischemia driven target
revascularization when compared to the earlier zero to three year
time period. So therefore Carolyn, the authors conclude that
improved scaffold design and development techniques to mitigate
that zero to three year bio resorbable vascular scaffold risk may
enhance the late benefits that one sees in this three to five
year time point, because of the complete bioresorption.


Dr Carolyn Lam: So that's interesting Greg. Well, my next paper
is kind of related. It is the first report of a randomized
comparison between magnesium based bioresorbable scaffold and
sirolimus-eluting stent in this clinical setting of STEMI with
one year clinical and angiographic follow-up. So this study is
from the Spanish group, Dr Sabaté and colleagues from the
Interventional Cardiology Department and Cardiovascular Institute
in Barcelona in Spain, and they found that at one year when
compared to the sirolimus-eluting stent, the magnesium based
bioresorbable scaffold demonstrated a higher capacity of vasal
motor response to pharmacological agents, either endothelium,
independent or dependent, at one year. However, the magnesium
based bioresorbable scaffolds were also associated with a lower
angiographic efficacy, a higher rate of target lesion
revascularization, but without thrombotic safety concerns.


Dr Greg Hundley: Wow, Carolyn, very interesting, and Dr Lorenz
Räber and Yasushi Ueki wrote a very nice editorial on this whole
topic of bioresorbable scaffolds, and they wonder about some of
the unfulfilled prophecies. Great for our readers to put these
two articles together. Now, how about in that mailbox, Carolyn?
What have you got in there?


Dr Carolyn Lam: First there's a research letter by Dr Kimura
entitled Very Short Dual Antiplatelet Therapy After Drug-eluting
Stent Implantation in Patients with High Bleeding Risk, and
that's insights from the STOPDAPT-2 trial. There's another
research letter by Dr Lopes entitled The Hospitalization Among
Patients with Atrial Fibrillation and a Recent Acute Coronary
Syndrome, or PCI, Treated with Apixaban or Aspirin, and that's
insights from the AUGUSTUS trial. A very interesting perspective
piece by Dr Rob Califf entitled The Balanced Dysfunction in the
Health Care Ecosystem Harms Patients, a really, really
interesting read, especially those working in the U.S. healthcare
system. An ECG challenge deals with fast and slow, long and
shorter. I would love to give you a clue to what it is. It's got
to do with the atrial ventricular nodes, but I'll let you take a
look and test yourself. There’re highlights from the TCT by Drs
Giustino, Leon, and Greg Stone, and finally there's Highlights
from the Circulation Family of Journals by Sara O'Brien.


Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a couple
reviews. Richard Whitlock in a primer provides a nice historical
review of anticoagulation for mechanical valves. How do we get
here in anticoagulating this particular patient population? Next,
Dr Mark Brzezinski from Brigham Women's Hospital in the Harvard
Medical School in an on my mind piece provides very elegant
figures, beautiful figures, demonstrating inadequate angiogenesis
within the fibrous cap of atherosclerotic plaques, and indicates
this could be a source or thought of as a contributing factor
toward plaque rupture. What an issue, and I can't wait to get
onto that featured discussion.


Dr Carolyn Lam: For our featured discussion today, it is a
super-hot topic, and a question that comes up again and again in
clinical practice. What is the right antithrombotic therapy in
patients with atrial fibrillation and acute coronary syndrome,
not just those treated with PCI, but also in those treated
medically? Well guess what? We're going to have answers right
here. I'm so pleased to have with us Dr Renato Lopes, who's a
corresponding author from Duke Clinical Research Institute and
our associate editor, Dr Stefan James from Uppsala University in
Sweden. Wow. Very, very important question here. Renato, could
you just start by outlining what is the AUGUSTUS trial?


Dr Renato Lopes: The AUGUSTUS trial was basically one of the four
trials trying to give an answer, or help answering about the
antithrombotic therapy in patients with anti fibrillation and/or
NACS and/or PCI. So in other words, this combination of patients
undergoing PCI who require antiplatelet therapy and also patients
with AFib who requires anticoagulation therapy, and in summary,
what the AUGUSTUS trial did was randomize patients to Apixaban
versus VKA, or aspirin placebo in a double blind fashion, and
this was a two by two factorial design. So these were basically
the two questions that we wanted to answer. Is Apixaban better
than VKA, and is it safe to drop aspirin from this treatment
strategy? Remembering that everybody received a P2Y12 inhibitor
for at least eight months. So this was basically the design of
the AUGUSTUS trial, trying to answer two questions in the same
study, a two by two factorial design.


Dr Greg Hundley: Very, very nice. And Renato, if I could, I mean
I said it in the intro, but may I make sure I got it right. This
is the only trial in the field that included patients with ACS
that was managed medically. So that's a very important group of
patients that we still don't know what the best regimen is, is
that right?


Dr Renato Lopes: That is correct. The other trials, the PIONEER,
the RE-DUAL PCI and the VPCI, they only included patients
undergoing PCI, and when we designed the trial, we thought that
it would be important to also include the whole spectrum of ACS,
including not only the PCI treated patients, but also the
medically managed patients.


Dr Greg Hundley: Well, super. So could you tell us now what were
the results?


Dr Renato Lopes: So first, in terms of the breakdown, we found
that the breakdown of the PCI, ACS versus elective PCI, was
really nice. We had about 60% of the trial being ACS patients,
and about 39%-40% elective PCI, and then within the PCI, I think
that our results pretty much reflect practice in a lot of parts
of the world, which was about 39% medically managed and about 61%
PCI treated patients. So to begin with, I think a very nice
breakdown that gives us power to look at these three separate
groups: ACS medically managed, ACS PCI treated, and also elective
PCI, which allows us to understand the whole spectrum of coronary
disease in patients also with AFib, and in summary, what we
showed for the primary endpoint, which was clinical major or
relevant non-major bleeding. Let's start with the Apixaban versus
VKA comparison, and we show that Apixaban was safer than VKA in
all three groups, in the ACS medically managed, in the PCI
treated patients, and also in the elective PCI patients.


There was no significant direction for those three subgroups,
although it was borderline 0.052, just showing maybe a little bit
less pronounced results in the elective PCI group, but
nonetheless, I would say that in general, very consistent, and in
terms of Aspirin for the primary endpoint, also no difference, no
interaction among those three groups. In other words, as we
increase substantially the risk of bleeding about two folds in
all the three groups, ACS medically managed, PCI treated
patients, and elective PCI patients, with about again, two fold
increase in bleeding compared to placebo. If we go to ischemic
events, again, that's our hospitalization and other that are
ischemic events. In terms of Apixaban versus VKA, the results
were very consistent with the overall trial among these three
groups, and in terms of as ACS versus placebo, the results also
for the ischemic events were also similar among the three groups.
So again, reassuring that the main results of the trial were very
consistent, regardless how patients were managed in terms of the
ACS, medically or through PCI, and also included in the elect PCI
group.


Dr Carolyn Lam: Thank you for explaining that so well. Stephan, I
would love for you to take us under the hood. What were the
editors thinking when we saw this paper, why we're highlighting
it now, and what do you think are the implications?


Dr Stefan James: The AUGUSTUS trial was unique in many aspects. I
think Renato highlighted a few of them. As he told, there have
been several similar trials without the other DOAX, factor 10A
inhibitors and the dabigatran, but the AUGUSTUS trial was larger.
It includes, as you mentioned previously, patients with ACS and
medical management, and it also was designed as a two by two
factorial design. So it actually asks two different questions and
made two different randomizations, both anticoagulation with the
two different agents, Warfarin versus Apixaban, but also Aspirin
versus placebo, and so it's possible from this trial to
understand more of the different aspects of treating patients,
these complex patients with atrial fibrillation, NACS or PCI, and
gave the study group and us an opportunity to better understand
all these complexities. So with that, I'd like to turn to Renato
and try to, with that background that I just outlaid, and you
just try to make us understand what are the clinical implications
of these aspects of the trial and the treatment of Apixaban and
Aspirin in these patients?


Dr Renato Lopes: I think we were in the area that we desperately
needed randomized data, because basically until five years ago,
the standard of care of treating these patients was the classic
triple therapy with Aspirin, Clopidogrel, and Warfarin, and this
was based on no randomized trials and all observational data, and
we know how problematic this is, and this field has evolved
tremendously almost year after year since the PIONEER trial,
since the RE-DUAL trial, and this year, we had AUGUSTUS and
ENTRUST and I think now, as Mike Gibson used to say, that we have
about 2.8 million different combination of antithrombotic
strategies to treat these patients because we have different
anticoagulants, different anti-platelets, different doses,
different durations, different types of stents, which makes it
really impossible for physicians or for any guidelines to
contemplate all these options. So we really needed a few trials
to at least try to give a few options that are evidence based and
not just based on low quality of data, and I think now, if you
look at the Augustus results, and the totality of the data from
all these trials, which now is about almost 11,000 patients all
together, actually almost 12,000 patients all together.


I think that what we know today is that yes, the initial period
in hospital for some time it's important to use Aspirin. I think
this is an important point to highlight, Stephan, that Aspirin
still needs to be used for the acute treatment, and I would say
at least for the first few initial days while patients are still
in the hospital, but then by the time of discharge, which
sometimes might be five days, six days, seven days, I think that
now the totality of data show that it's reasonable to drop
Aspirin for most patients.


So based on the AUGUSTUS results, what we show is that if you're
going to use anticoagulation as Apixaban at the dose that is
approved for stroke preventions in atrial fibrillation, combined
with a P2Y12 inhibitor without Aspirin after the initial period,
you have the best outcomes in terms of lower rates of bleeding,
lower rates of hospitalizations, and we don't have to pay a cost
in terms of ischemic events when we actually drop Aspirin and
keep only the NOAC, in this case was Apixaban, plus a P2Y12
inhibitor, which most of the time was Clopidogrel, and here with
AUGUSTUS, we basically show that this is true for patients with
AFib and ACS, irrespective of the management with medical
managing, with medical therapy, or with PCI. So I think that's an
additional piece that that is true irrespective of how we're
going to treat your ACS patient, or if the patient basically
underwent elective PCI, and I think we learned today that the
classic treatment therapy of VKA plus Aspirin plus P2Y12
inhibitor, so in other words, the triple classic triple therapy
should generally be avoided.


Dr Stefan James: Thank you Renato. I think that that was a very
complete answer in this complex arena. I'd like just to mention
that of course the AUGUSTUS, as well as the other trials, have
their limitations, as all trials. Although it was large, it was
powered for safety, for bleeding events, and it was not powered
for ischemic events. Having said that, we still want to look at
ischemic events and clinical outcomes, and to what degree do you
think we can do that? What conclusions can we draw from an
ischemic point of view because of the fact that the trial was
underpowered for that interpretation?


Dr Renato Lopes: That is a great question, Stephan, and in fact,
if we look at events like stent thrombosis, they are very rare,
and if you really want to attack a significant difference between
Aspirin versus placebo in patients having stent thrombosis, we're
really going to need a trial with about 30-40,000 people, which
would be not feasible and not doable. So we need to be cautious
when we analyze those events in the power trial for ischemic
events. Nonetheless, there was a signal, if you look at all
trials, and even in the meta-analysis that we published recently,
that dropping Aspirin probably increased the risk of ischemic
events, not in a statistically significant fashion, but
nonetheless, this trend exists. The signal exists. So probably
keeping Aspirin, add some protection for ischemic events,
primarily stent thrombosis and myocardial infarction. The problem
is a tradeoff. The problem is that the cost of adding aspirin is
too high.


So now the question to us, Stephan, is to look further into our
data and in the combined data sets that we're trying to work with
the other authors and try to identify, okay, Aspirin really
increased the risk of bleeding, but is there a group of patients
who might benefit from a little bit longer Aspirin? So that's the
first question. Who are those patients? May be complex PCI, maybe
bifurcation lesions, maybe multiple lesions, multiple stents, and
second, if we decide to give Aspirin longer, how much longer
should we give? Because again, the cost is very high in terms of
bad bleeds. So we are trying now to identify what is the trade
off, and who most benefit from keeping Aspirin longer, and for
how long in a way the cost might be worth it to pay in exchange
of potentially save some ischemic events? And with that, we can
further refine the treatment that I think I highlighted before.
For most patients, I think what I said before is probably
reasonable. We can drop Aspirin by the time of discharge after a
few days, but for a few patients, for some patients, it might be
wise to keep Aspirin a little bit longer, and we are trying now
to identify first, who those patients are and second, form how
much longer should we keep Aspirin, since the 40,000 patient
trial is very unlikely to happen.


Dr Stefan James: I like his interpretation, Renato, although I
wanted to highlight that there are limitations, I think this
trial is extremely informant for clinicians. We learned a lot how
to treat these very complex patients with complex treatments.


Dr Carolyn Lam: No, I couldn't have agreed more. I mean quoting
Mike Gibson, 2.8 million combinations. Well, at least we've
talked about some of them here and had a very clear take home
message, although with the caveats that we were discussing. Thank
you so much, Stefan and Renato. This was really a great
discussion, and thank you audience for joining us today. You've
been listening to Circulation on the Run. Don't forget to tune in
again next week. This program is copyright American Heart
Association 2019.