Circulation October 1, 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 Greg Hundley, associate editor at Circulation and
director of the Pauley Heart Center at VCU Health in Richmond,
Virginia. Carolyn, have you ever wondered about instead of coding
a stent, coding balloons with paclitaxel? Well, the feature
article day is going to look at mortality assessments of
paclitaxel-coated balloons in a meta-analysis from the ILLUMENATE
clinical program, the three-year outcomes. Do you have a paper
you want to start us off?


Dr Carolyn
Lam:               
I sure do. First of all, we know that diabetes impairs
atherosclerosis regression following cholesterol lowering in both
humans and mice. Now in this process of plaque regression, what's
the role of functional high density lipoprotein or HDL, which is
typically low in patients with diabetes?


                                               
Well, this first paper that I chose looks just at that and it's
from Dr Fischer from New York University School of Medicine and
colleagues, who aimed to test if raising functional HDL levels in
diabetic mice prevents monocytosis, reduces the quantity and
inflammation of plaque macrophages and enhances atherosclerosis
regression following cholesterol lowering. So to do this, the
authors used aortic arches containing plaques, which were
developed in LDL receptor null mice, and these were transplanted
into either wild type or diabetic wild type or diabetic mice
transgenic for human APL lipid protein A1, which have elevated
functional HDL.


Dr Greg
Hundley:            
So Carolyn, what did they find in this interesting study?


Dr Carolyn
Lam:               
Well, diabetic wild type mice had impaired atherosclerosis
regression, which was normalized by raising HDL levels. The
benefit was linked to suppressed hyperglycemia-driven
myelopoiesis, monocytosis and neutrophilia. Increased HDL
improved cholesterol efflux from bone marrow progenitors,
suppressing their proliferation and monocyte neutrophil
production capacity. ACL also suppressed the general
recruitability monocytes to inflammatory sites and promoted
plaque macrophage polarization to the M2 phenotype, which is an
atherosclerosis resolving state. There was also a decrease in
plaque neutrophil extracellular traps or nets, which are
atherogenic and increased by diabetes. So raising apolipoprotein
AI and functional levels of HDL promoted multiple favorable
changes in the production of monocytes and neutrophils and in the
inflammatory environment of atherosclerotic plaques in diabetic
mice after cholesterol lowering. And this may represent a novel
approach to reduce cardiovascular risk in patients with diabetes.


Dr Greg
Hundley:            
Really interesting, Carolyn. Well, I'm going to talk to you a
little bit about a large study in patients with valvular heart
disease and it's a contemporary presentation and management study
and it's from the Euro Observational Research Program Valvular
Heart Disease II, Roman numeral two, survey. And the
corresponding author is Professor Bernard Iung from Bichat
Hospital. So the VHDII survey was designed by the Euro
Observational Research Program of the European Society of
Cardiology to analyze actual management of valvular heart disease
and compare practice with guidelines.


                                               
Now in short, patients with severe and native valvular heart
disease or previous valvular intervention were enrolled
prospectively across 28 countries over a three-month period in
2017. Indications for intervention were considered concordant if
the intervention was performed or scheduled in symptomatic
patients corresponding to class one recommendation specified in
the 2012 ESC and in the 2014 American Heart Association American
College of Cardiology valvular heart disease guidelines.


Dr Carolyn
Lam:               
Wow. So what did they find, Greg?


Dr Greg
Hundley:            
Okay, so there's 7,247 patients. 4,483 were hospitalized, and
2,764 were outpatients, and they were included across 222
centers. The median age was 71 years and 1,917 patients were over
the age of 80, and 3,400 were women. Now, aortic stenosis was
present in 2,000 plus patients, aortic regurgitation in 279,
mitral stenosis and 234, mitral regurgitation in 1,114. And
multiple left-sided valvular heart disease was present in 1,297,
right-sided valvular heart disease in 143, and 2,028 patients had
prior vascular intervention.


                                               
So the decision for intervention was concordant with class one
recommendations in symptomatic patients with severe single
left-sided valvular heart disease in 79.4% of those with AS, 77%
with aortic regurgitation, 68.5% for mitral stenosis, and 71% for
primary MR. Valvular interventions were performed in 2,150
patients during the survey. Of them, 47.8% of the patients with
single left-sided native valvular heart disease were in New York
Heart Association class three or four, and transcatheter
procedures were performed in 38.7% of the patients with AS and
16.7% of those with MR.


Dr Carolyn
Lam:               
Wow, Greg. So what are the take home messages? That was a lot of
numbers.


Dr Greg
Hundley:            
Yep. Lots of data there. And so couple things. First,
recommendations for interventions in symptomatic patients with
severe valve disease are better applied today in this paper than
in the previous European survey conducted in 2001, particularly
for those individuals with aortic valve disease. Second,
multi-modality imaging is now more frequently used, but stress
testing remains underused in asymptomatic patients. And finally,
transcatheter therapies are now widely used in patients with
stenotic valve disease, and we would expect that, particularly
for the use in the elderly.


Dr Carolyn
Lam:               
Great, Greg. So what are the clinical implications?


Dr Greg
Hundley:            
Okay, so Carolyn, first, late referral for intervention shows the
need for increasing awareness of valvular heart disease by
general practitioners and cardiologists. Second, the high burden
of elderly patients highlights the need for multidisciplinary
heart team approaches to assess the risk benefit ratios of the
different modalities of valvular interventions. And finally,
number three, echocardiographic quantification of regurgitation
should be more accurate and pay more attention to quantitative
measurements. Those are the main take homes from this large
registry analysis.


Dr Carolyn
Lam:               
Nice. Thanks, Greg. My next paper is the characterization of the
first transgenic mouse model of ARVC 5. Now, that is the most
aggressive form of arrhythmogenic right ventricular
cardiomyopathy caused by a specific mutation in transmembrane
protein 43. So this paper's from co-corresponding authors, Dr
Lara-Pezzi from CNIC in Madrid and Dr Garcia-Pavia from Hospital
Universitario Porto de Hero in Madrid, and with their colleagues,
they generated transgenic mice over expressing transmembrane
protein 43 in either it's wild type or that specific mutant form
in postnatal cardiomyocytes under the control of alpha-myosin
heavy chain promoter.


                                               
And they found that these transgenic mice expressing the specific
mutant in transmembrane protein 43 showed fibro fatty replacement
of the myocardium and died at a young age. The model confirmed
that transmembrane protein 43 is mostly localized at the nuclear
membrane and provides new information regarding the
pathophysiological mechanisms underlying ARVC five. One of them
is that the GSK3 beta signaling pathway plays an important role
in this disease.


Dr Greg
Hundley:            
So that's great, Carolyn. Sounds like we have a new model that's
been created by this group and certainly this disease has spread.
It's something we definitely worry about. Do you see any
therapeutic implications for their work?


Dr Carolyn
Lam:               
Great question, and indeed the authors tested two new therapeutic
approaches for ARVC five. In the first they found that targeting
fibrosis really had no beneficial effect. But in the second, they
found that inhibition of GSK3 beta improved cardiac function and
survival, thus opening the way to a new therapeutic approach
focused on GSK3 beta inhibition in patients with ARVC five.


Dr Greg
Hundley:            
Very good. So we look forward to seeing what the results of that
study will be. How about now we talk about some of the other
articles in this issue?


Dr Carolyn
Lam:               
I love that. I think it's a great idea to tell everybody about
this amazing issue. So we start with an article from our Global
Rounds, and this time from Argentina, so a great status update
and future strategies for cardiovascular disease in Argentina. We
also have a perspective paper and that's on the new World
Symposium on Pulmonary Hypertension guidelines, really
questioning some of the cutoffs that we've taken for granted and
asking, "Should 21 be the new 25?" Intrigued? Well, you really
need to pick this one up and read it.


                                               
And then there's a white paper, and this is a report from the
2018 NHLBI workshop that really talks about unlocking the secrets
of mitochondria in the cardiovascular system and asking if this
may be a path to cure in heart failure. We also have a research
letter, and I love these. They're so succinct and really contain
an important message. And this one talks about the evolution of
Medicare formulary coverage changes for antithrombotic therapy
after the guideline update. So very topical subject.


Dr Greg
Hundley:            
Very good, Carolyn. So I've got a couple. There's a Paths to
Discovery article that John Rutherford did discussing with Paul
Zimmet regarding reflections of the evolving global diabetes
epidemic. Second, there is a very nice On My Mind piece from
Samuel Tretheway from Birmingham, England who discusses medical
misinformation, kind of like medical fake news. And he discusses
how this occurs and it depends on the motivation of both authors
and publishers, and he reviews responsibilities of all of us, how
to avoid generating this type of material. And then finally, a
really interesting Cardiology News piece by Bridget Kuehn, who
discusses diet and microbes in heart failure, and with that
there's a very nice piece of artistry work that would be great
for your office. So that's all included in the journal.


Dr Carolyn
Lam:               
Oh, you got us all curious. Finally, I just want to highlight, we
have a section called Highlights from Major Meetings, and this
time from my part of the world with Dr Aijun Sun and Dr Junbo Ge
summarizing the 13th Oriental Congress of Cardiology takeaways.
Cool issue, isn't it?


Dr Greg
Hundley:            
Absolutely. So how about onto our feature discussion?


Dr Carolyn
Lam:               
You bet, Greg.


Dr Greg
Hundley:            
Welcome everyone to our feature discussion. And this afternoon or
this morning, wherever you may be, we are going to have an
opportunity to discuss the utility of paclitaxel-coated balloons
in terms of management of patients with peripheral arterial
disease. And our article today comes to us from Bill Gray and
colleagues from Mainline Health in Philadelphia, Pennsylvania.
And we have our own Josh Beckman, associate editor from
Vanderbilt, who will be joining us in the discussion. Bill,
welcome to Circulation. We really appreciate you sending us this
article. Can you tell us a little bit about the background of why
you wanted to perform your study and also, what was your study
design, study population?


Dr William
Gray:              
The study was really prompted by a prior report by Katsanos et al
in JAHA about nine months ago. When we started this study, it was
much more fresh. And what we did was we realized we had data from
multiple studies using the Stellarex drug-coated balloon that we
could use to address some of the issues raised with the Katsanos
paper. Just to review that briefly, the Katsanos paper suggested
that there was a significant mortality signal in patients who
were randomized to drug-coated balloons using paclitaxel versus
PTA or patients randomized to drug eluting stent versus PTA or
other stents. That signal was seen late at two years and at five
years, and so we sought a given the data, the tightly controlled
and well-reported data and this experience to see if we could see
a signal as well.


                                               
The study design really involved taking all the data from the
randomized trials, and there were two, which comprised an
aggregate of about 600 patients, unequally randomized, about 400
in the drug-coated balloon arm and about 170 or 200 patients in
the PTA arm. And then we also looked at all the poolable data,
which was controlled data, so we had two randomized control
studies I mentioned just a minute ago, as well as three single
arm studies in one registry. Now, these had quality oversight and
data reporting. And then those data were adjudicated for adverse
events, including death, by a blinded third party CEC, and then
those data reported out by Kaplan–Meier estimates as well, and
then we do a multi-variable analysis looking at predictors of
death, and then I can talk about that in a moment. Importantly,
the data here has followed out to three years. As I mentioned
before, the original paper which incited the concern had reported
unequal deaths at two and five years, so we're somewhere
splitting that difference. That's the genesis of the study and
the study design.


Dr Greg
Hundley:            
So Bill, tell us now about the results.


Dr William
Gray:              
It turns out the baseline characteristics were largely similar
between these trials and the patient arms, even though they
weren't strictly speaking the same trials, except that the
drug-coated balloon arm was a bit younger and smoked more
frequently, so they were at a little bit more risk. In the
randomized control analysis, which was done first, there was no
difference in all-cause mortality between the PTA patients and
the patients who received paclitaxel drug-coated balloons. That
was true at one year, two years and three years. When we looked
at the pooled analysis, which included not only the drug-coated
balloon randomized trial patients, but also all the single arm
studies and registries, we also found that there was no
differences between those treated with drug-coated balloons in
those additional studies and the control group of 170 patients in
the randomized trial arm of PTA alone.


                                               
Interestingly, when we started to look at the multi-variable
analyses, we did something that we ordinarily would not do, but
because of the pressing issue around paclitaxel mortality, we
actually did a standard covariate analysis looking at predictors
and then we forced drug and drug dose into the model to see if
they would come up positive as a predictor of outcome. As you
might expect, not surprisingly, we found that age, congestive
heart failure, diabetes and renal insufficiency were the four
major predictors of mortality in a group of patients who were
largely claudicates with significant peripheral vascular disease.
No surprise there. We all know the patients don't die of
claudication, they die of cardiovascular disease, and this I
think bears that out.


                                               
When we force drug into the model, in point of fact, not a dose
nor the presence of drug had any impact on death rates in the
model, so there was no predictive value there whatsoever. Those
are the results. Again, they're out to three years, and I think
one of the important things that we have to recognize is that the
numbers are relatively small and the follow-up is relatively
limited and by itself, although it doesn't show any signal, it
probably doesn't stand on its own to refute a larger
meta-analysis, but does I think contribute to the dataset that is
becoming more evident that the individual analysis do not appear
to show mortality effects.


Dr Greg
Hundley:            
Very good. So this is Dr Josh Beckman at Vanderbilt University.
Josh, could you talk to us a little bit and put this paper in
perspective relative to the prior published literature in terms
of how you manage patients with peripheral arterial disease?


Dr Joshua Beckman:        I
have to say first, I'm really glad that we're able to publish
this paper from Bill Gray and his group. We are, and I'm going to
put this in really muted terms, in extraordinary times. I have
never seen what is going on now happen with any other technology
or really even medical therapy in the 20 plus years I've been a
practicing physician. I think for the audience, it's really
important to understand what is going on right now because if you
don't pay attention to this space, you may not realize what's
really been happening. Bill did a nice job at telling you why he
did the study, which was this Katsanos aggregate level
meta-analysis that was published in JAHA back in December.


                                               
On the basis of this paper, there has been a rapid development of
worry and concern that these devices may be associated with late
mortality. This concern has spread to the Food and Drug
Administration, which has now put out three letters to healthcare
professionals, each of them basically suggesting that you should
choose non drug-coated either balloons or stents first, and if
you want to use these, you have to have an extended conversation
with the patients discussing the risks. And so in response to
this aggregate level meta-analysis, which had an extensive number
of lost to follow-up patients and didn't account for crossovers
and the usual problems with this kind of information, I have been
really impressed by the community of people who are interested in
this topic and work with these kinds of devices.


                                               
And by that, I mean, the response has not just been a series of
editorials. The response has really been, "Let's find every
single piece of data that we can find to see whether or not this
signal holds up," because as evidence-based physicians, we take
one piece of data and say that it is one piece of data, and then
we have to put it into the context of all of the other pieces of
data that were published. And so I know that Dr Gray is old
enough to remember 10 years ago when these devices were being
used in the coronary arteries with drug eluting stents. And as
far as anybody can tell with studies that were two to three times
larger or meta analyses two to three times larger than the study
published in December, there was no mortality signal.


                                               
It should be made clear that in doses that dwarf the doses from
these devices, when these medications are given to pregnant women
who have breast cancer, not only is the mother fine but the fetus
is fine. And so I think paper that we are discussing this morning
in particular, but the group of investigators in the space has
really stepped forward to publish as much data as possible to
fill out our understanding and place the original study in the
correct context. And so when you understand what's happening in
the community, and there's been a significant reduction in the
use of these devices on the basis of that one publication at the
expense of patients for whom these devices are really much better
at limb outcomes, then you can understand why we were so
interested in the paper by Dr Gray.


                                               
This is another brick in creating the foundation to really have a
fuller and better understanding of any possible relationship
between the use of these devices and a nonspecific increase in
mortality two to five years later, which as far as I can tell,
I've never seen something that may end up being a poison that
doesn't have a specific mechanism of causing morbidity or
mortality. And so when we got this paper, I was really happy to
be able to work with Bill and bring it to the level that it is
now so that when it's published in October, it's going to be
another really important contribution and I just want to
congratulate the authors for doing that work. I will say, and I'd
like to get Bill's perspective on how he thinks the information
that's now being published is going to help us understand what to
do with these devices.


Dr William
Gray:              
Yeah, that's a great question, and I want to emphasize something
you brought up, which I did not, which is at the aggregate level
data that Katsanos used to publish his analysis was really all he
had access to, which means that he had some numerical data from
prior published publications but did not have patient level data.
And so what Josh is referring to appropriately is the concept
that each individual holder of those data, those patient level
data, are now coming forward with their own analysis of those
data at a patient level, which allows us to look more granularly
and more clearly at the causes of death. For example, in this
study, the causes of death did not cluster around cancer. They
were largely cardiovascular, and they were not dis-equally
distributed or unequally distributed between the two groups.


                                               
So I think that patient level data, to get back to your original
question, Josh, the patient level data will be incredibly
important from each of the experiences with the various
drug-coated balloons and drug eluting stents on the market
because it does allow us to look more closely at the mechanism of
death and whether there's any putative cause that might be
assigned to paclitaxel. As you mentioned, the pharmacology of
this is not understandable. The only type of pharmacology that
would work like this was if paclitaxel was radioactive and
accumulated a hazard along the way, but we know that's not true.


                                               
I think extend your question, it's important to say that both the
FDA and other independent groups like VIVA have looked closely at
the meta analytic data both from a patient level and aggregate
level data set, and they have seen a signal at five years. The
problem with that is that data starts to winnow down very quickly
at five years. There's not a lot of numbers, so that's the first
problem, and the meta-analysis that have followed the publication
by Katsanos. The second problem is, as Josh alluded to, there's a
lot of missing data. Either patients withdrew or got lost to
follow-up, and that didn't happen at an equal distribution
between the control and the active arms, so there's some
ascertainment bias there.


                                               
And lastly, there's a crossover, that is patients who are in the
control arm crossed over near as we can tell at a rate of about
one in five or one in four to an active arm in the first year
alone, which means they need to be reassigned to a risk pool that
includes the original assignment of paclitaxel randomization. My
sense is that those data will not get any better in the near-term
future because the problems I just listed are not going to go
away anytime soon. And so we are left with these individual
patient level data and other big data, like Medicare analyses of
tens of thousands of patients or Optum insurance analyses of
again, tens of thousands of patients, which actually show no
difference between the treatment with paclitaxel in the real
world and patients treated with non-paclitaxel devices. So while
we are comfortable and happy to publish these data and we think
that are meaningful in terms of contributing to the larger
dataset, we recognize the flaws and the limitations in the
meta-analysis, which will not be solved soon or quickly.


Dr Joshua Beckman:        So,
I totally agree with what you just said. I will also say that
every time data like this is published, it adds to the picture to
make our understanding clearer. And you are responding directly
to the Food and Drug Administration, who basically said they are
not settled on this question either. It is noted, they are
worried about it, and what they've really asked for is for more
data to be published. And so when people analyze data like these,
I think it is really helpful to the rest of us to create a fuller
and more granular picture of the overall state of the field.


Dr Greg
Hundley:            
We want to thank again both Josh for his time and Bill for his
time. Hope you have a great week, and both Carolyn and I look
forward to sharing with you again next week. Take care everyone.


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