Circulation April 14, 2020 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: I'm Greg Hundley, associate editor from the VCU
Pauley Heart Center in Richmond, Virginia.


Dr Carolyn Lam: Greg, amyloid cardiomyopathy is the rage. I
cannot tell you the number of discussions I've had on the topic.
Of course, it was tafamidis, the amazing results with that trial
that really made us realize we need to pick this up. But have you
ever thought about the cost effectiveness of tafamidis for
amyloid cardiomyopathy? Well, guess what? We're going to have a
whole feature discussion just about that. But first let's go to
our summary, shall we?


Dr Greg Hundley: You bet, Carolyn. Well, let me get started. I'm
going to talk about regulation of cell cycle growth as well as
division in regard to cardiac regeneration. My first paper comes
from Dr Lior Zangi from the Mount Sinai School of Medicine. Well,
Carolyn, have you ever wondered why the adult mammalian heart has
limited regenerative capacity?


Dr Carolyn Lam: All the time, Greg.


Dr Greg Hundley: Well, of course you have. It's mostly due to
postnatal cardiomyocyte cell cycle arrest. In this study the
investigators evaluated the effect of pyruvate kinase muscle
isozyme 2 and cardiomyocytes through models of loss, that is
cardiomyocyte specific PKM2 deletion during cardiac development
or gain using cardiomyocytes specific PKM to modified mRNA to
evaluate PKM to function and regenerative effects post-acute or
chronic MI in mice.


Dr Carolyn Lam: Nicely described. What did they find, Greg?


Dr Greg Hundley: What they found is that PKM2 is expressed in
cardiomyocytes during development and immediately after birth,
but not during adulthood. Using cardiomyocytes PKM to modified
RNA, they found that cardiomyocyte targeted strategy following
acute or chronic MI resulted in increased cardiomyocyte cell
division, enhanced cardiac function, and improved long-term
survival. They found that PKM2 regulates the cardiomyocyte cell
cycle and reduces oxidative stress damage through anabolic
pathways and beta-catenin.


Dr Carolyn Lam: Cool, Greg. Man, this cardiac regeneration
really, really is a hot area.


Dr Greg Hundley: Carolyn, that is so insightful because these
results really impact research toward unlocking pathways that
could be involved in induction of myocyte cell division and
regeneration in those sustaining MI or conditions like MI.


Dr Carolyn Lam: Nice. Well, Greg, I'm going to change tones here
and ask you, can we prevent atrial fibrillation with treatments
for diabetes? Well, guess what? We have a paper next. It's from
Dr Wiviott from the TIMI Study Group and his colleagues who
really reason that since atrial fibrillation is associated with
hypertension, obesity and heart failure in patients with diabetes
and SGLT2 inhibitors have been shown to lower blood pressure,
reduce weight, and reduce hospitalization for heart failure in
these patients, perhaps SGLT2 inhibitors may also reduce the risk
of atrial fibrillation. They explored the effect of Dapagliflozin
on the first and total number of atrial fibrillation and atrial
flutter events in patients from the DECLARE-TIMI 58. As a
reminder, they had type two diabetes with either multiple risk
factors for or known atherosclerotic cardiovascular disease.


Now importantly, atrial fibrillation events were identified by a
search of the safety database using these MedDAR preferred terms.
Now what they found was Dapagliflozin reduced the risk of atrial
fibrillation events during follow-up as well as the total number
of atrial fibrillation events in patients with type two diabetes.
These reductions were consistent across major subgroups including
sex, presence of atherosclerotic cardiovascular disease, history
of atrial fibrillation, history of heart failure, history of
ischemic stroke, HBA1C groups, body mass index groups, blood
pressure or EGFR. They looked at all these subgroups because
these are all clinical factors, well established, with
associations with the risk of atrial fibrillation.


Dr Greg Hundley: Wow, Carolyn. Another sort of feather in the cap
for the SGLT2 inhibitors. What does this mean for clinical
practice?


Dr Carolyn Lam: Ah. I'm not going to answer it here. I am going
to say everybody has to read the excellent editorial by Dr
Granger from Duke University and Dr Mahaffey from Stanford
University School of Medicine. But what I will tell you is their
concluding sentences. They said, "This report provides evidence
that Dapagliflozin appears to reduce atrial fibrillation events
in patients with diabetes and coronary disease and multiple risk
factors. It also raises the issue of how to determine when
effects on a secondary outcome, particularly one collected
without the rigor of systematic collection using perspective
definitions and case report forms, whether or not these are
reliable." So must read.


Dr Greg Hundley: Absolutely. Carolyn, my next study comes and
evaluates arrhythmogenic right ventricular cardiomyopathy and is
really investigating the concept of auto immunity, looking at
associations of circulating anti heart and anti intercalated disc
auto antibodies with disease severity and family history. The
paper comes from Professor Alida Caforio from the University of
Padova. Again, looking at the role of auto antibodies in patients
with ARVC. An interesting topic.


Dr Carolyn Lam: Yeah, that's really novel. What did they find?


Dr Greg Hundley: They investigated ARVC pro bands, so those that
sort of started with the disease process in a family and noted an
increased frequency of serum organ specific anti heart
autoantibodies and anti-intercalated disc autoantibodies in a
sizeable arrhythmogenic RVC cohort as compared to controls. They
found that positive AHA status.


Dr Carolyn Lam: Anti-heart antibodies.


Dr Greg Hundley: Yep. Was associated with lower left ventricular
ejection fraction, a higher frequency of cardiac symptoms and
implantable cardioverter defibrillator implantation. Positive
AIDA was associated with lower ejection fractions in both the
right and the left ventricle.


Dr Carolyn Lam: AIDA being the anti-intercalated disc auto
antibodies. Wow. That is interesting. But what are the clinical
implications?


Dr Greg Hundley: Well, the presence of both these organ specific
AHA and AIDA antibodies provides evidence of autoimmunity in the
majority, so 85% of familiar, and almost half, 45%, of sporadic
ARVC. In programs and in effective relatives, these antibodies
were associated with the disease severity features. So really a
link with this auto immunity and ARVC.


Dr Carolyn Lam: Yeah. I never thought of ARVC as an autoimmune
disease. Very interesting. But let me also tell you what else is
in this week's issue. There are letters to the editors, one from
Dr Kaski regarding the mag STEMI randomized control trial
questioning whether improving coronary vasal motion can be
equated to restoring patient's cardiovascular health.
Interestingly with a letter in response from Dr Sabatine. There's
also a research letter by Dr Alahmad on the cardiovascular
mortality and exposure to heat in an inherently hot region and
where they were was Kuwait. They also drew some implications for
climate change. Very interesting piece. There's also an ECG
challenged by Dr Verma describing conduction abnormalities and
ischemic cardiomyopathy in an 84-year-old man.


Dr Greg Hundley: Very nice. Carolyn, in the mailbag, there's a
nice research letter from Dr Nicholas Leeper from Stanford
University School of Medicine. It's entitled “The 9p21 locus
promotes calcific atherosclerosis.” Our own Josh Beckman has an
on my mind piece regarding “The Big Mac Attack on Peripheral
Arterial Disease.”


Dr Carolyn Lam: I love that. I just love the titles Josh comes up
with.


Dr Greg Hundley: Then finally Bridget Kuehn has a very nice sort
of correspondence on Cardiovascular News regarding cardiac
imaging on the cusp of artificial intelligence. What a revolution
we have ahead, Carolyn, and I know that's a topic that's true to
your heart.


Dr Carolyn Lam: It is. I loved her paper.


Dr Greg Hundley: Okay. Carolyn, how about we get onto that
feature article? I'm waiting to hear about the cost effectiveness
of tafamidis.


Dr Carolyn Lam: Me too.


Dr Greg Hundley: Well listeners, we have got a great discussion
for our feature publication today and we have Dr Dhruv Kazi from
Beth Israel Deaconess in Boston and our own associate editor, Dr
Justin Ezekowitz from University of Alberta. Well, as we get
started, Kazi, can you tell us a little bit what was the
hypothesis that you wanted to test with this study and maybe even
before that a little bit of background with transthyretin amyloid
and tafamidis?


Dr Dhruv Kazi: Yeah. Transthyretin amyloidosis is a subgroup of
patients who present with heart failure with preserved ejection
fraction, which we know is a heterogeneous condition that has
been pretty resilient to effective guideline directed therapies
over the past decade. It's a subgroup of patients generally
presenting in their 70s with slowly declining quality of life and
a median survival of about three years. It hadn't had an
effective therapy before and so when tafamidis, which is a
stabilizer of transthyretin and prevents its deposition in the
myocardium, was developed and tested in a randomized clinical
trial that showed an improvement in survival, a reduction in
heart failure hospitalizations and a slowing of decline and
quality of life. It was viewed as a really big win for the heart
failure community.


What came as a surprise though is the pricing. It was launched in
2019 at $225,000 a year. We set out to ask, given that this is a
severe disease without alternative treatments, is this price tag
generating enough value? Is this a cost-effective therapy? The
background here again is that oncologic therapies have had a long
history of very high prices for rare diseases and severe
diseases. But this is the first time we're seeing this in
cardiology. Can we think more broadly about how we're going to
tackle this issue? Not just for tafamidis but also for other
drugs that come down the pipe.


Dr Greg Hundley: Wow. $225,000 per year. Tell us what was your
study design, and how did you go about evaluating this issue?


Dr Dhruv Kazi: We started off with the one phase three trial of
the drug that has been published and simulated in a mathematical
model the population that would be eligible for this therapy,
reproduced the events, heart failure hospitalizations, debts,
quality of life that were seen in the trial for the first three
years, and then extrapolated beyond the trial based on what we
know about HFpEF and what we know about transthyretin
amyloidosis. It's a mathematical model that first reproduces what
was seen in the trial and then extrapolates beyond what we think
is the best guess of what happens to these patients. We tested a
variety of scenarios whether the drug continues to be effective,
whether the effectiveness declines over time or the effectiveness
ceases immediately after three years.


Dr Greg Hundley: What did you find?


Dr Dhruv Kazi: What we found was interesting and it surprised us
a little bit, which is that in the base case, which is assuming
that the drug stays effective beyond three years, the drug is
actually very effective in the traditional sense. It added 1.3
quality adjusted life years. For context here, this is about
twice the effect size you expect to see with Entresto, and the
HFpEF patients. So here's a drug that we've accepted and HFpEF
has part of guideline directed medical therapy. Tafamidis in that
best-case scenario is about twice as effective, but it is not
cost effective. Because you're paying $225,000 for every year
that the patient is on the medication, its incremental cost
effectiveness ratio compared with usual care was $880,000, so
well above what we would consider value for money. That's the
best-case scenario assuming that the drug is permanently
effective, if the drug's effect wanes over time, which is very
likely as these patients get older and sicker, then the drug gets
even less economically attractive.


Dr Greg Hundley: You've pointed out in your article, if you had
120,000 transthyretin patients in the United States, that would
translate to how many dollars?


Dr Dhruv Kazi: We estimate that if all of those 120,000 patients
received tafamidis, the healthcare spending would go up by $32
billion a year and most of it is towards the drug. But the caveat
is that we think 120,000 patients in the US is a very
conservative number because the diagnostic technology for amyloid
cardiomyopathy has improved substantially over the last five
years so that we no longer need biopsies. We can use nuclear
scans to diagnose the disease and we have pretty good to genetic
testing to identify the genetic variant of the disease. We think
that number is probably closer to 200,000 or even higher because
the healthcare expenditure is almost entirely driven by drug
costs. The more patients we diagnosed, the bigger the budget's
impact on healthcare spending.


Dr Greg Hundley: Oh my. Well Justin, for our listeners, Justin
resides in Canada. Justin, what do we do with these results? I
mean this is quite a sticker shock for probably an important
therapy for this patient population.


Dr Justin Ezekowitz: Greg, it's a great issue and Kazi, thank you
very much for this terrific, easily understandable manuscript
that I think everybody should read as it's very well written and
easy to understand for us non-health economists. The sticker
shock is a bit of a tricky one because we always want to do
what's best for our patients. When we look at that budget impact
analysis, the challenge is what do we think internationally? The
US is critical in terms of understanding this, but then for the
rest of the world, there's certainly almost no willingness to pay
at this threshold and with an uncertain incidence of amyloidosis
globally, but also within the US and Canada and the difficult in
diagnosis already, I think we're going to have to realize what
can we do for our patients and who benefits the most with this
drug given its importance and its efficacy?


Kazi, you mentioned another thing which I think is critical is
what happens after 30 months if the effect wanes and where does
that take us for the impact on cost and effectiveness over time
but also the budget impact analysis? Because the second drug or
third drug may very well come along that may fill that niche.


Dr Dhruv Kazi: Justin, that's a really good question. I mean the
study only goes to 30 months and that's the only one randomized
trial for tafamidis that we're working off of. So there's
substantial uncertainty about what happens to this drug beyond 30
months. It's reasonable to assume that some of the effect
persists, that as patients get older, get sicker, that
effectiveness will wane over time. Which ties very closely to the
cost effectiveness. So if the patients continue to take the drug
but it's not as effective as you can imagine, it becomes less
cost effective.


This also has implications for other drugs coming down the pike,
which may or may not be more effective than tafamidis. They may
or may not be tested head to head with tafamidis. Physicians are
going to be left with the question, very clinically relevant
question, of which drug to start with, how do you switch on them
the next generation or more expensive drugs that come down the
pike? We'll have to rely on both real-world evidence and to some
extent mathematical modeling to use our best judgment on
developing a treatment strategy for these patients. But rest
assured that our current regulatory framework means that the
drugs coming down in the future will be more expensive than
tafamidis and hence, this is a good time to have the conversation
about cost effectiveness and our willingness to pay for
innovation.


Dr Greg Hundley: What needs to happen next to help either lower
cost or develop some sort of competition in the treatment of this
disease to lower the cost?


Dr Dhruv Kazi: I can take a stab at that. Greg, I think the
findings of this particular drug in transthyretin amyloidosis is
illustrative of the challenges that lie ahead. I think there are
clinical research and policy implications. As clinicians, it's
really important for us to know that this high cost of the drug
is not a theoretical challenge. It's a practical challenge for
our patients. The majority of these patients are going to be on
Medicare part D. We estimate that the out of pocket costs is
going to be in the range of $8,000 to $9,000 a year even with
Medicare part D, which is a big amount of money for our fixed
income seniors. I encourage our clinicians to have this
conversation about out-of-pocket costs with patients, not just
when you start the therapy but throughout the year. We know that
the Medicare part D copays change over the course of the year
based on where they are in the insurance plan.


Having this conversation may help preclude costs related
non-adherence. We might be able to identify patients early or at
risk, put them into patient support programs or switch them to
alternate therapies that may not be as effective but at least are
likely to offer the patient some support.


From a research perspective, we really need to figure out what
subgroup of patients are more likely to benefit. Let's say we
have 200,000 patients with transthyretin amyloidosis in the US.
We need more research, and the company is not going to be vested
in doing this research, it's going to have to be NIH funded
research to identify subgroups of patients who benefit most from
this drug, both in the short term and over the long term.


From a policy perspective, what this drug pricing issue is
telling us is that we provided incentives for companies to
innovate in the rare disease orphan drug program. These
incentives are working. More than half of the drugs that are
coming out now or have in the past year are under this rare
disease umbrella. But these drugs, once they're approved, are
super expensive.


We need to figure out a regulatory framework where we continue to
incentivize innovation for rare diseases for orphan drugs, but at
the same time tie those incentives to the final pricing to ensure
that the patients get access to the drug and not just the wealthy
patients who can afford the copays, but all patients who would
benefit from the drug.


One of the things that comes to mind as clinicians and
researchers is that particularly in cardiology, we are obsessed
with innovating, with regards to new molecules and new
technology. I would like us as a community to focus not just on
molecules but also on markets because the innovation is not
meaningful if our patients cannot have access to them. This year
being the presidential election year, we're going to hear a lot
about drug pricing. What I hope that this example shines a light
on is that drug pricing is complicated and trying to figure out
the right framework to incentivize innovation while it's still
ensuring access is going to take thoughtful interventions,
regulatory interventions, and clinicians should very much be a
part of that process.


Dr Greg Hundley: Well listeners, we've heard a wonderful
discussion here highlighting a new therapy for a disease process
that's being increasingly diagnosed with our aging population and
new technologies, magnetic resonance, echocardiography that
identify this condition. But then how are we going to afford some
of the therapies that are moving forward and design a system that
emphasizes not only scientific discovery, but cost effectiveness?


We want to thank Dr Dhruv Kazi from Beth Israel Deaconess and
also Justin Ezekowitz from the University of Alberta. We hope you
have a great week and look forward to speaking with you next
week. This program is copyright the American Heart Association
2020.