Circulation January 22, 2019 Issue

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly
podcast summary and backstage pass to the journal and it's
editors. We're your co-hosts of Circulation on the Run and if you
don't know what this show is about, well, you have to listen to
the previous episodes in January please.


                               
I'm Dr Carolyn Lam, associate editor from the National Heart
Center and Duke National University of Singapore.


Greg Hundley:   I'm Greg Hundley from the Pauley Heart
Center at VCU Health in Richmond, Virginia.


Dr Carolyn Lam: So Greg, before we pick up our coffees and begin
discussing a couple of the paper, let's just tell everyone that
this feature paper, they have to listen to because it is the
results of the cardiac amyloidosis section, or sub-set of the
APOLLO study. Have to listen to this one. But how about the other
papers in today's issue Greg?


Greg Hundley:   Right Carolyn, the first one I'm going
to start with is from Alexander Fanaroff at Duke University and
the DCRI. And basically, this particular paper was looking at the
procedural volume and how that might affect outcomes with those
that are performing PCI. So they divided the cohort into those
individuals that had less than 50 PCIs per year, 50 to 100 and
then greater than 100 PCIs per year. So, this is looking at our
national cardiovascular data registry within the United States,
and of course, as you know, that's linked to Medicare claims data
for those that are over 65 years in age. So they had 723,644 PCIs
performed by 8,936 operators. And the surprise in this study was
that those low volume operators, less than 50 PCIs per year had a
one year rate of 15.9% of MACE as opposed to those that were high
volume operators that had 16.9% MACE rates. That was significant
at a P value of .004.


Dr Carolyn Lam: Wait a minute, this seems different from prior
reports. Are you saying that those with low volume operators
actually had lower mortality?


Greg Hundley:   Yeah, exactly. And you've pointed out
something, cause previously what's been shown is that high volume
operators have lower 30 day and in-hospital mortality rates. And
that was actually confirmed in this study. But out of a year it
was really the low volume operators in unadjusted results had
lower rates of all MACE.


                               
A very nice editorial by Dharam Kumbhani from UT Southwestern
points out that high volume operators do tend to take on more
serious cases, those with higher numbers of cardiovascular risk
factors. And so, when they did adjustments and accounted for all
those risk factors, actually the event rates were the same. Still
though, they're the same. And so what could be going on? And the
editorialist and also the authors of the paper point out, "Hey,
maybe we shouldn't just be focusing on PCI volume per operator,
but other quality metrics to look at outcomes. And so this really
builds in to the whole quality discussion. Adherence to therapy
with the patients in your health care system. What about operator
longevity? An operator that may have been doing this for 10 years
but has a lower volume, maybe that could come into play. So
future studies I think, certainly all over the world in this
field, this paper's going to direct us to focus more on other
quality issues and not just procedural volume.


Dr Carolyn Lam: So, quality versus quantity. Interesting.


                               
Well switching gears to a paper that I thought was nice, it is
from Dr Lubitz from Massachusetts General Hospital in Boston and
colleagues, and they sought to answer the question of whether
refining a phenotypic classification of heart failure would
facilitate genetic discovery. So, to do that, they defined all
cause heart failure among almost 500,000 participants in the UK
bio-bank and performed a GWAS study and then later refined the
heart failure phenotype by classifying individuals with left
ventricular dysfunction but without coronary artery disease as
having nonischemic cardiomyopathy and then repeated the GWAS. And
basically they found that the GWAS in the all cause heart failure
yielded multiple genetic signals for known heart failure risk
factors, such as coronary artery disease and atrial fibrillation.


                               
However, after refining the heart failure phenotype to a
nonischemic cardiomyopathy sub-set, this enhanced the detection
of genetic loci associated with dilated cardiomyopathy, which
appeared to operate independent of the traditional heart failure
risk factors. So that was pretty interesting.


Greg Hundley:   So where do we go from here with that
Carolyn? I mean, what is this telling us and how are we going to
move forward with this information?


Dr Carolyn Lam: I think the clinical implications are first that
common genetic variants associated with both clinical and
sub-clinical heart failure, because they looked at left
ventricular dysfunction, these genetic variants may be leveraged
to improve heart failure risk prediction and prevention. But
obviously future studies are warranted to investigate the
prognostic and therapeutic implications of these findings.


Greg Hundley:   Very good. Well I'm going to take us
back into the cath lab again and we're going to address
fractional flow reserve. And remember, typically, we get
fractional flow reserve measures using guide wires, and that's
kind of a tough thing to do sometimes in terms of adding links to
the procedure, etc. So what these investigators did, they had 10
centers in the United States, Europe and Israel. And this was
William Fearon from Stanford University who did this study. And
they looked at 301 subjects and they had 319 evaluable vessels.
Now what did they compare? They looked at guide wire derived
fractional flow reserve versus angiographic derived. Simply, just
when you're doing the injections, looking at how quickly that
contrast flows down the coronary arteries.


                               
And so, in this study the mean fractional flow reserve value was
0.81 and 43% of the vessels they studied had an FFR less than or
equal to that magic number of 0.8. Interestingly, the
angiographic obtained FFR measures were 94% sensitive and 91%
specific for identifying the guide wire derived FFR. That's
really incredible. And importantly, the accuracy of this contrast
measure was 87% for FFR values between 0.75 and 0.85, that
magical threshold.


Dr Carolyn Lam: Well that is impressive, suggesting that we don't
need guide wires. I mean, is that true for all patients? All
vessels?


Greg Hundley:   Right, so that's sort of the kick here,
this is really interesting new data but let's look at the
patients that they studied. First of all, they were relatively
stable I would say. They had either angina or maybe even unstable
angina and non-ST elevation MIs. But no ST elevation MIs. The
average stenosis by angiography that they looked at was about 63%
and then, very importantly, you have to look at the exclusion
criteria. So things that, other conditions within the heart that
are going to impact FFR were excluded. So, all their patients had
an EF greater than 45%. Nobody had a CABG. Nobody had a chronic
total occlusion. Nobody had a heart transplant, aortic stenosis,
no heart valve surgery, no left main. It couldn't have had a
recent stent within 12 months. It couldn't have had severe
diffused disease, no collaterals, no in-stent thrombosis or
stenosis. So this technique I think could be useful when you've
got that patient perhaps with stable angina, single vessel
disease, stenosis severity of 50 to 60% and none of these other
conditions, preserved EF etc. But for many of the patients that
we send to the cath lab, this technique, we still need a little
bit more development. We don't know its utility. You've got
another paper?


Dr Carolyn Lam: I've got another few papers because I'm going to
drag you out of the cath lab right now and into the ICU. And
we're talking about cardiogenic shock and it's really nice that
we have these three papers in today's issue. One's an original
paper and two are On my Mind articles. Now the original paper
talks about the randomized shock cool trial. This is from Dr
Thiele from the heart center Leipzig in University Hospital in
Germany. And it is an un-blinded, randomized trial of 40 patients
with cardiogenic shock undergoing primary percutaneous coronary
intervention. And without a classical indication from mild
therapeutic hypothermia, but randomized one-to-one to mild
therapeutic hypothermia for 24 hours versus control. And
basically the mild therapeutic hypothermia did not show a
substantial beneficial effect on the primary outcome of cardiac
power index at 24 hours or on any other of the hemodynamic
parameters. And there was also no difference in the short and
long term outcomes. So a neutral trial.


                               
But taking a step back and just talking about these patients with
cardiogenic shock and all the different ways that we have now to
keep them alive, I really want to highlight these two On My Mind
papers. One is by Drs Gill, Grunau and MacRedmond from University
of British Columbia. And they really talk about the need to
define limits for extracorporeal cardiopulmonary resuscitation.
In a very similar vein, Drs Mulaikal, Nakagawa and Prager from
Columbia University also wrote a beautiful piece on ECMO, ECMO as
a bridge to no recovery. And when is enough enough? So really,
really interesting conversations and discussions regarding what
is death, when do we have to put a time limit perhaps to these
therapies? And yet not limit the potential life-saving effects of
these. I really strongly encourage our listeners to read these
papers and also to stay tuned because coming right up, a very
important paper on the APOLLO study in our feature discussion.


                               
For today's feature paper we're discussing the results of a
sub-study of the APOLLO study. Now this deals with cardiac
amyloidosis, a super, super hot subject. And we have super, super
hot guests today on the show. The first our corresponding author,
doctor Scott Solomon from Brigham and Women's Hospital as well as
our associate editor doctor Justin Ezekowitz. Welcome both, and
let's just plunge straight into it. So Scott, tell us, tell us
about this APOLLO sub-study.


Scott Solomon: APOLLO is a study of patients with hereditary
transthyretin amyloidosis and, as you know, that hereditary
transthyretin amyloidosis is an inherited disease caused by
mutations of the transthyretin gene and these mutations cause the
transthyretin protein to misfold and then accumulate as amyloid
fibrils which go to the nerves and go to the heart. And we know
that this can cause severe polyneuropathy and cardiomyopathy,
partly depending on which mutation the patients have. And we, as
cardiologists, are aware that when amyloid infiltrates the heart
it can increase cardiac wall thickness, it can cause increase in
chamber stiffness, it can result in severe diastolic dysfunction
and these patients, often with cardiac involvement of amyloid,
have a really markedly reduced life-span and really poor quality
of life.


                               
The APOLLO study was a study of a new agent that is designed to
reduce transthyretin, it's a transthyretin knock-down agent. It's
basically an RNAi therapeutic, it basically is a small,
interfering RNA that basically blocks the production of
transthyretin and this is one of several approaches that are
currently being considered for amyloid disease. And APOLLO is
primarily designed as a study to look at neuropathy. The primary
end-point was a neurologic scale to look at neuropathy, but it
was also designed to secondarily look at some cardiac end-points,
especially in the patients who were felt to have cardiac
involvement.


Dr Carolyn Lam: Cool. And so your current paper deals with that
cardiac amyloidosis sub-set, but it was pre-specified, it was
planned, right?


Scott Solomon: Yeah, it was a pre-specified sub-group. In fact,
what we did is we actually did echocardiograms on everybody in
the study and then defined a pre-specified cardiac sub-population
that was comprised of patients who had a very high likelihood of
having cardiac amyloid involvement, and so this was patients who
had a baseline left ventricular wall thickness of 13mm or greater
and no history of either aortic valve disease or hypertension.
And so this was a group that we thought most likely had evidence
of cardiac involvement. And just so it's clear, we did
echocardiography on everybody in the study and in this paper we
reported in both everybody and in the pre-specified cardiac
sub-population. So we looked a number of things in these patients
including various measures of cardiac structure function
including wall thickness, left ventricular mass, ejection
fraction, cardiac output, atrial size, volumes and myocardial
strain which, as you know, has been particularly useful in
assessment of patients with amyloidosis. And we also looked at
reduction or improvement in Anti-proBNP which, as you know, is a
very good measure of the severity of heart failure in patients.


                               
And so, of the 225 patients who enrolled overall in the APOLLO
study, 126 were part of this pre-specified cardiac
sub-population. And in this group of patients, we've observed a
reduction in left ventricular wall thickness of about a
millimeter. And this was statistically significant in the
patients who were treated with patisiran compared with placebo.
We also saw an improvement in global longitudinal strain and
improvement of cardiac output and an increase of left ventricular
end-diastolic volume. In this case an increase in end-diastolic
volume is actually a good thing because these patients often
start out with smaller end-diastolic volumes because of the
increased wall thickness. Those improvements in echocardiography
were really paralleled by dramatic improvements in Anti-proBNP
and we started out with patients with abnormal Anti-proBNPs in
the range of about 800. These were significantly reduced, highly
significantly reduced with a P value of about seven times 10 to
minus eighth at both nine and 18 months, so pretty dramatic
relative reduction in Anti-proBNP in the patisiran group compared
to placebo.


Dr Carolyn Lam: Super exciting, and it really adds to mounting
evidence isn't it? That we're sort of reaching a really effective
treatment for these patients and who knows how common they are.
But Justin, you've been thinking a lot about this, what are your
thoughts?


Justin Ezekowitz: This is a terrific paper, and this is a
groundbreaking therapy. Scott, this really has something for
everybody, for example functional Anti-proBNP and
echocardiographic measures of improvement and also less
deterioration which I think is also holding it in its tracks. The
question is, if you have 126 patients in the cardiac sub-group,
whether or not this is really prime for clinical integration, as
to start using this therapy broadly or do we need to really
broaden the scope and do larger outcome studies with this therapy
for these patients, recognizing some of the gaps in any clinical
trial design and implementation. So what are your thoughts on
that?


Scott Solomon: First of all, it's important to remember that the
APOLLO study was designed primarily to look at the neurologic
outcomes, not the cardiac outcomes. The cardiac outcomes were
technically considered exploratory and, in fact, although really
pretty impressive in this group, this wasn't really how the study
was designed. And so the current indication for this particular
therapy. Patisiran is for the improvement in the neurologic
outcomes, not for the cardiac. So I think that there will need to
be additional studies that will look more specifically at the
cardiac effects, although I think these are among the most
impressive findings we've seen with any agent that is interfering
with transthyretin. And just to put this in context, there are a
variety of ways in which amyloid can be affected and one of the
other approaches to this disease has been not to reduce the
production of transthyretin but to stabilize transthyretin.


                               
And you may be aware of the ATTRACT trial which was presented at
ESC and published in the New England Journal, which was actually
an outcomes trial in patients with cardiomyopathy secondary
amyloid and they used a drug which is a TTR stabilizer and showed
a significant reduction in cardiac events and mortality. And I
think that in the context of that study, this is extremely
exciting as well because it says that there are multiple
potential approaches to affecting transthyretin and potentially
improving outcomes in patients with cardiac amyloidosis. There
are other approaches that also are being tested. In fact, another
therapy that works in a similar way to patisiran is atersin which
is an agulo nucleotide anti-sense molecule. And so, I think that
it's such an exciting time now in this field because there almost
certainly will be several different approaches to transthyretin
amyloidosis.


                               
So, I think, Justin, to succinctly answer your question I don't
think we're quite ready yet with patisiran but stay tuned because
there will be more trials for sure. The other thing that we have
to realize is that this study was done in mutant or hereditary
amyloidosis but there's a very broad group of patients out there
with wild type amyloidosis and there's no reason to think that a
therapy like this won't work there as well. So that has to be
tested too.


Justin Ezekowitz: I think, Scott, that's a true way to put it. I
think one of the other questions is the substantial difference
between the trials and sub-groups of the trial between the three
major therapies you just described about wild type versus
hereditary. It does make you wonder if either one individual
therapy or a combination of the therapies might give the right
way to precisely manage these individuals according to their
phenotype, neurologic status or cardiac status.


So, I maybe just want to draw you on one other point which is
that you used global longitudinal strain as one of your outcomes
and it sounds like, and from all the data we've seen, it looks
like GLS will be the way to go for earlier phase two and other
types of studies. What are your thoughts based on experience?


Scott Solomon: Well in general I'm a big fan of global
longitudinal strain because I think it is, in many respects, more
robust than our standard measures of cardiac function like
ejection fraction, it's not volume dependent the way ejection
fraction is. In particular in amyloid heart disease, as you know,
global longitudinal strain can be quite abnormal and,
interestingly, it can be quite abnormal in a very specific
pattern. And patients with amyloid is typically sparing at the
apex, so the apical strain is relatively normal compared to the
strain at the base of the heart. And this is kind of interesting
and we've certainly been looking at this as well in amyloid heart
disease but I agree that this global longitudinal strain as a
measure of potential benefit for a therapy has a lot of
potential.


Dr Carolyn Lam: You know, that's just so amazing. I just have one
last question for both of you. Where do you think the field is
going? Do you think it's going to be a race to treatment or a
race to diagnosis? I shudder to think of the number of cases
we're missing, what do you think Justin?


Justin Ezekowitz: Carolyn you just brought up a great point which
is, one is our diagnostics need to improve and be broadly
applicable and implementable in any health care system, so I
think that race has to speed up and become more cost-effective
and efficient to know who indeed we need to screen closer. That's
point number one but number two is the therapies ... the race has
to be focused around what will be the best way to treat patients
rather than the cost-effectiveness initially, but then once we
identify the three or four different agents that work with
different groups and how you can combine them, then the
consideration has to be how we can apply these more broadly to
the groups that really haven't had a therapy that has had a
meaningful impact trajectory.


Dr Carolyn Lam: Scott, what do you think?


Scott Solomon: Well I would add that one of the most exciting
things I think in this area, Carolyn, and this is going to
interest you I think because of your own interests, is that
there's probably a lot of amyloid out there that we don't know
about. Especially in these patients that we're currently calling
heart failure with preserved ejection fraction. There's some data
from Mayo clinic and from groups in Europe suggesting that 15 to
20% of patients with HFpEF, might actually have wild type
transthyretin amyloid. And that means that we've got to get
better at making this diagnosis, especially where our suspicions
are high. Because we might all of sudden have a targeted therapy
for some of these patients, so I think that's one area where
things are really exciting. And then with respect to which of
these therapies is going to be beneficial, I mean I think that
we're still in the early stages, it's very possible as Justin
said that even a combination of TTR stabilizers and knock-down
agents are going to provide the best benefit. But I think we're
going to see a lot of very interesting studies in the next
several years in this field. It's really great to have a
potential molecular target, and targeted therapy for a type of
cardiomyopathy and I think this is one of the really few areas
where we have that as this point. So I'm extremely excited.


Dr Carolyn Lam: Thank you so much for publishing your paper with
us in Circulation.


                               
Well audience you heard it right here on Circulation on the Run.
Don't forget to tune in again next week.


                               
This program is copyright American Heart Association 2019.