Circulation September 19, 2017 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.


                               
Today we will be discussing the cost effectiveness of statin use
guidelines for the prime and prevention of coronary heart disease
and stroke. Comparing the 2013 American College of Cardiology
American Heart Association guidelines with the adult treatment
panel three guidelines. A very important and current discussion
that you don't want to miss. All coming up right after these
summaries.


                               
The first original paper in this week's journal is the largest
study yet reported that assessed the long term outcome of
Takayasu's Arthritis. First author, Dr. Comarmond, and
corresponding author Dr. Saadoun and colleagues from Hospital
Pitie-Salpetriere in Paris performed a retrospective,
multi-centered study of 318 patients from the French Takayasu
network including patients with Takayasu Arthritis fulfilling the
American college of Rheumatology and/or Ishikawa criteria. They
found that, firstly, 50% of  Takayasu arthritis patients
relapse and experienced a vascular complication at ten years.
Secondly, male sex, elevated CRP, and carotidynia were
independently associated with relapse and with a two-fold higher
risk of relapse. And thirdly, patients at high risk for vascular
complications could be identified according to presence of two or
more of the following risk factors: progressive clinical course
diagnosis, thoracic aortic involvement, and or retinopathy. In
summary, these factors identify patients with a high risk of
relapse or vascular complications and may therefore serve to
adjust more aggressive management and close follow up in
Takayasu's Arthritis.


                               
The next study provides experimental evidence for a pathogenic
role of the transcription factor interferon regulatory factor
five or IRF-5 in atherosclerosis. In this study from co-first
authors, Dr. Seneviratne and Dr. Edsfeldt, corresponding author
Dr. Monoco from Kennedy Institute of Rheumatology in Oxford,
United Kingdom, and colleagues. The authors showed that
atherosclerosis prone apple-E negative mice who were also
deficient in IRF-5 showed reduced atherosclerosis lesions and
necrotic core formation. They found that the development of the
lesion necrotic core was controlled by IRF-5 through impairment
of macrophage dead cell removal, or spherocytosis. They further
demonstrated that the CD-11C gene was a direct target of IRF-5 in
macrophages and that IRF-5 was important in maintaining CD-11C
positive macrophages in atherosclerotic lesions. In summary IRF-5
was shown to be a potential therapeutic target since its
inhibition could reduce plaque inflammation and necrotic core
size, thus potentially promoting a stable plaque phenotype with a
lower risk of acute clinical complications.


                               
The next study is the first to assemble a transcriptomic
framework of multiple cardiac cell populations during post natal
development and following injury, thus enabling comparative
analysis of the regenerative or new natal state, compared to the
non regenerative or adult state. In this study from first author
Dr. Quaife-Ryan and co- corresponding authors Dr. Porrello from
the Royal Children's Hospital and Dr. Hudson from the University
of Queensland, Australia. The authors isolated cardiomyocytes,
fibroblasts, leukocytes and endothelial cells from infarct and
non infarct neonatal and adult mouse hearts. The then performed
RNA sequencing on these cell populations to generate the
transcriptome of the major cardiac cell populations during
cardiac development, repair and regeneration. They further,
surveyed the epigenetic landscape of cardiomyocytes during post
natal maturation by performing deep sequencing of assessable
chromatin regions. This comprehensive profiling of cardiomyocytes
and non myocyte transcriptional programs uncovered several injury
responsive genes across regenerative and non regenerative time
points. The majority of transcriptional changes in all cardiac
cell types resulted from development maturation from neo natal
stages to adulthood. Rather that activation of a distinct
regeneration specific gene program. Furthermore, adult leukocytes
and fibroblasts were characterized by the expression of a
proliferative gene expression network following infarction, which
mirrored the neonatal state.


                               
But in contrast cardiomyocytes failed to reactive the neonatal
proliferative network following infarction which was associated
with loss of chromatin accessibility around cell cycle genes
during post natal maturation. In summary these findings are
significant because they defined a regulatory program
underpinning the neonatal regenerative state and identified
chromatin modifications in adult myocytes that could restrict
cardiac regenerative potential after birth and may need to be
overcome to facilitate cell cycle re entry in adults.


                               
The final study reports results of two studies investigating the
pharmicokinetic and clinical outcomes of a new drug coated
balloon to treat femoral popliteal disease. The first study is
the Illuminate pivotal study in which 300 symptomatic patients
were randomized to stellarex drug coated balloon or standard
angioplasty. The primary safety outcome was freedom from device
and procedure related death through 30 days and freedom from
target limb major amputation and clinically driven target lesion
revascularization through 12 months. The primary effectiveness
endpoint was primary patency through 12 months. The second study
was the illuminate pharmicokinetic study in which paclitaxel
plasma concentrations were measured after last balloon deployment
and at pre specified times until no longer detectable. In this
report my first in corresponding Dr. Krishnan from Mount Sinai
Medical Center in New York. In the pivotal study the primary
safety endpoint and the primary patency rate was significantly
higher with the drug coated balloon. The rate of clinically
driven target lesion revascularization was significantly lower in
the drug coated balloon cohort. pharmicokinetic outcomes showed
that all patients had detectable Placitexal levels after drug
coated balloon deployment that declined within the first hour.


                               
In summary these findings demonstrate the safety profile and
superior patency of the stellarex drug coated balloon for femoral
popliteal disease compared to standard angioplasty. This
therefore suggests that this drug coated balloon may be a
valuable treatment option for patients with superficial femoral
and popliteal artery disease.


                               
Well those were your summaries now for our feature discussion.


                               
Today we are discussing the highly relevant and also highly
controversial issue of Statins for primary prevention of
cardiovascular disease and when do we start a statin. How cost
effective is it, and of course all this discussion really began
with the 2013 ACC/AHA guidelines that expanded the recommended
statin use. I am so pleased because this week’s journal actually
provides, for the first time, some cost effectiveness data that
may help us in making this decision and in facing our patients. I
can't tell you the number of times I've had an individual patient
come to me and just want to discuss all the pros and cons of
starting a statin for primary prevention and I'm sure, listeners
out there you identify with this. Well hang because today we have
the corresponding author of today's feature paper Dr. Kirsten
Bibbins-Domingo from University of California, San
Francisco  as well as the editorial list on this wonderful
paper, Dr. Rodney Hayward from University of Michigan and VA Ann
Arbor. Welcome Kirsten and Rod.


Dr. Kirsten
Bibbins:         
Thank you.


Dr. Rodney Hayward:     Great to be here.


Dr. Carolyn
Lam:              
Kirsten, could you please tell us the top line results of what
you found in this paper, it's such an important paper.


Dr. Kirsten
Bibbins:          We
use simulation modeling to compare three approaches to giving
Statins for primary prevention. The older guideline in the US
called ATP-3, the one that you mentioned in your introduction the
ACC/AHA guideline that broadened the use of Statins to many many
more people and then an even broader strategy where we don't look
at cardiovascular risk, and in each of these approaches we found
that the use of Statins for primary prevention was very effective
and in fact cost saving, when we did a cost effectiveness
analysis. And regardless of the assumptions that we made about
more side effects then we had known from the literature or could
anticipate or regardless of the parameters that we put into the
model we found that, pretty much that the broad use of these
medications is effective and, in fact, cost saving.


Dr. Carolyn
Lam:              
Could you give us an idea of what you used in that simulation
model, what population was it, how applicable is it to people
outside the US, for example.


Dr. Kirsten
Bibbins:         
Simulation modeling is a way to take the evidence that we have
from multiple types of studies and to try to synthesize that
evidence and apply it to, in this case, the population of the US.
So our simulation model uses the demographics of the US and takes
the primary studies and the effect rises that we know from those
studies and using that model we found that each of these three
approaches had both health benefits and cost saving benefits.
It's applicability might be somewhat variable if this were
applied to a different population, but the effects are pretty
substantial and so it suggests that Statins are likely to be
beneficial using these approaches in a broad array of
populations.


Dr. Carolyn
Lam:              
Could you give us an idea of the estimated effect size, you know,
when you say cost effective, for example, how, how much and for
what. Give us everyday clinician some kind of take home of
numbers that would make sense for them.


Dr. Kirsten
Bibbins:         
One way to think about these types of cost effectiveness analysis
is that often times they give us numbers that suggest that we
have to pay a certain amount to get the type of health benefit
that we want. In this case because we found that they were cost
savings, it actually suggests that the amount that we pay for
Statins, to give Statins to a broad population of individuals
actually saves us money. It saves us money in terms of the heart
attacks that are avoided, and the other types of health care
costs that are avoided and probably a number that might be
relevant to your audience might be that the number that one would
need to treat in order get one additional year of life, through
using these Statins for primary prevention, is on the order of
about 35 individuals and so that's a small number that we would
be treating in a primary care practice in order for an additional
quality adjusted year of life.


Dr. Carolyn
Lam:              
I thought that was really one of the most remarkable figures, you
know, that the ATP-3 guidelines would result in 8.8 million more
statin users than the status quo and that was an entity of 35 per
quality of life. Was that correct?


Dr. Kirsten
Bibbns:          
That's exactly right.


Dr. Carolyn
Lam:              
Whereas the ACC/AHA guidelines could potentially result up to
12.3 million more statin users than the ATP-3 guidelines with a
marginal number needed of 68 per quality of life. So very, very
useful figures, but you know, I began by saying my individual
patient. These feel like population bases statistics, you know,
and my individual patient kind of wants to know but for me,
what's a long term risk and so on. And these are issues that you
have discussed so elegantly, Rod, in your editorial. Could you
enlighten us a bit on these considerations.


Dr. Rodney Hayward:     Sometimes decisions
that we have to make in policy are inherently population based
decisions, like putting fluoride in the water, in which the
average benefit of cost for population is what you have. Cause
you can't treat individual separately with that type of
intervention, but with a statin, the average that a population
gets is not the important thing to our patients across the room.
And it's sort of the number needed to treat for them, how likely
are they to benefit. And what I think this paper establishes very
well, and I think it's important to start with why the areas of
agreement here, this establishes that the new guidelines are a
great idea. There's no assumptions in this model that would
change that starting people on a statin between 7.5 and 10 % ten
year risk isn't a good idea. And that aspect of the paper even
some of the issues I have about some of the assumptions are not
going to be relevant, where it starts to become concerning, and
will always be controversial is how low of risk to start it at.
Do we go from 7.5 to a 5% risk? Do we start putting everyone at
age forty on a statin?


                               
And at that case, certain elements of this simulation model are
very important, the likelihood of an individual benefiting
becomes very, very small. And even a small dislike of the
medicine, would outweigh that. But also you have to assume in
this model that we know all the bad things of a statin at 20-25
years, because you're starting to put people on a daily medicine
that's biologically active for 30 years. And it's impossible
statistically, epidemiologically, to know with any degree of
certainty whether or not being on these medicines for 20-30 years
would have unheard effects. We don't have that ability,
currently, even if we had the databases so how should individuals
think about that, well my feeling is that is part of the shared
decision making of how much a patient worries about unknowns,
about being on a medicine long-term versus they worry more about
the potential for a heart attack prevention which are likely
there. I want to emphasize again these are not relevant concerns
when we're talking about the current guidelines, these are only
concerns when we start pushing it down to a 5% risk or everyone
over 40 where you're extending to tens of millions more people,
in which the population benefits would be substantial.


                               
As long as people don't mind taking a pill every day at those
ages and we know all of the harms being on a statin for 20 years.
And that's something that no one knows.


Dr. Carolyn
Lam:              
Rod that was just so eloquently stated, and listeners out there,
you just have to read this editorial. It states these things very
clearly, and I think it's really helpful in our thinking of what
to tell patients when we do see them. Kirsten, I'd love to invite
your thoughts on what Rod just said, you acknowledge this, fully
in your paper. Curious, any steps you took to maybe address this
and what you would say as a take home message for clinicians?


Dr. Kirsten
Bibbins:          I
think that Rod's bringing out exactly the point. And, I think, we
have seen the shift from the earlier guideline to the most recent
guideline in putting more people on Statins and these medications
certainly have the benefit, but as you bring more and more people
on who have lower overall cardiovascular risk, their likelihood
of benefiting while there, is always smaller. And so then other
things do come in to play, and I think the thing that probably
was most surprising to us as we put this work together, was how
sensitive our results were to, essentially, a patients preference
as we moved down into including more of these lower risk
individuals. That means that an individual who's lower risk may
not directly benefit or their likelihood of benefiting in terms
of avoiding a heart attack is lower, and so therefore the facts
that their tolerance for taking a daily medication is in fact,
then becomes relevant in to their particular trade off for taking
this medication. And I think that is clinically important as we
think about including more and more lower risk people into these
types preventative guidelines, the threshold for any given
individuals tolerance for taking a daily medication and of
course, as Rod said, if you're doing this over many years and
decades the fact that we don't actually know what will happen
over the long term, also becomes relevant.


Dr. Carolyn
Lam:              
Just maybe one last question for both of you. What do you think
our next step is here, what more do we need?


Dr. Kirsten
Bibbins:          I
just think we still want to continue to expand our understanding
of what the long term effects and side effects of daily use of
statin therapies are, again I'd want to emphasize as you said
it's always important to understand patients preference, but, as
Rod said, our current guidelines which really have focused on
higher risk individuals, I wouldn't want it to be lost that these
medications are in fact very effective and so I think having an
understanding of the long term use of these medications and what
the potential side effects when used over a long period time are,
I think that's a critically important area. As well as really
developing continuing to develop the tools that can help doctors
and patients together engage in the conversation about the trade
off for given individual.


Dr. Rodney Hayward:     I would definitely
agree with that, but I would focus on three bits of science. That
are critically important for refining this issue. The one is
something we currently don't have and that's post marketing
surveillance of medicines long term. That when you look at the
data we have, that, most of them follow patients either a short
period of time and don't have enough continuity or their smaller
studies in which outcomes that are long term might be found. And
this is a place where big data, but also combining and sharing
data across health systems could really help us monitor. This is
not just an issue for Statins but as more medicines are
recommended for younger individuals with life expectancy we need
to work on that. Two the results are insensitive meaning that it
always looks good, for people in the current guidelines but two
elements of the model for people at a 5% risk or starting people
at age 40 are assumptions that are being made with the best
available data now, but have some considerable concerns and could
be improved.


                               
One is, we don't know the impact of a non fatal heart attack on
future outcomes, my personal opinion is the assumption in this
model, is probably an overestimate. Unimportant for the current
guidelines but would be critically important for these younger
risk people and ways to really understand the impact of non fatal
events on future risk are epidemiologically tricky and it's very
easy to pick up things that are markers that aren't causal and
then when you run your models you think you're extending life
years where you really aren't. And the other is we still don't
know how much a Statins relative benefit varies by a persons LDL
level, that might seem astounding but there's evidence on both
sides. That it is related to baseline LDL and it's not. This is a
completely solvable question, the CTT group has the data and we
really need them to publish and tell us how much the relative
risk of a statin varies by that. The current assumption in the
ACC/AHA guidelines is that it is not correlated, the assumption
in Kirsten's model is that it is.


                               
Either could be correct, my personal opinion is it's probably in
between, those two, but that would help us in terms of thinking
of extending to the lower people. If LDL is a partial factor that
probably should be considered, if it's not then only risks should
be considered. That is completely answerable for those that have
access to the RCT data and I'm hoping that this paper may
encourage that publication.


Dr. Carolyn
Lam:              
Wow, those were such insightful comments, I can't thank you
enough, Rod and Kirsten for joining us today.


                               
Listeners I'm sure you enjoyed that and learned so much just like
I did. Don't forget to join us again next week.