Circulation January 15, 2018 Issue

Dr Carolyn
Lam:               
Hello. We're here at the American Heart Association meeting in
Chicago where circulation has 19 simultaneous publications this
year. And that is a huge increase from six in the past to 19, all
thanks to the man next to me.


                                               
But first, let me introduce myself. I'm Dr Carolyn Lam. I'm
associate editor from the National Heart Center and Duke National
University of Singapore. I'm the voice you hear on 'Circulation
On the Run'.


                                               
I'm so pleased to be here in person today with Dr Dharam
Kumbhani. He's associate editor from UT Southwestern and he also
leads the simultaneous publications for this journal. So big
applause for this amazing bonanza this year.


Dr Dharam Kumbhani:   Thank you.


Dr Carolyn
Lam:               
Next to him, we have Dr Sana Al-Khatib and she's from the Duke
University. And finally, Dr Gabriel Steg from University of
Paris. Wow! Okay, we've got 19 papers to chat about. No, I'm just
kidding. We're going to talk and focus on the seven simultaneous
publications that were late-breaking science.


                                               
Why don't you start us off, Dharam. We will first start with the
interventional trials, and there were three of them. I'd love you
to chat about the first of them, but even before that, maybe,
tell us what it's like to get a simultaneous publication. Because
I think people underestimate the amount of work it takes to do
that.


Dr Dharam Kumbhani:   Thanks a lot, Carolyn. I think
under Joe's leadership the whole space of simultaneous
publications in late paying clinical science has really been a
big endeavor for him and for the journal. We just have an amazing
team that's able to work on this in very quick order. So, for the
viewers, I think it's a very involved process, but it's a very
gratifying process.


                                               
We work very closely among the associate editors, the senior
editors, and then the circ staff, and we have very rapid
turnaround time. So we owe a lot of gratitude to our reviewers
who frequently will turn these reviews in within 48 hours. Our
goal has been that we respond back with a decision usually within
five to seven days. So it's been very gratifying.


                                               
Then it moves onto the next set of revisions, et cetera. But even
among the papers that we are unable to accept for circulation,
it's just a quick turnaround time for the authors so they haven't
lost as much time and can potentially look elsewhere.


                                               
It's been a really gratifying process. It's been a great, great
team effort. I appreciate everything you said, but really I don't
deserve all that credit. It's been a great team effort.


Dr Carolyn
Lam:               
No, it's been rumored there's a lot of lost sleep on your end, so
thank you, thank you Dharam for this. And maybe you could open
with the ISAR-TEST 4, that's been [crosstalk 00:02:47].


Dr Dharam Kumbhani:   Yeah, well thank you. I think we
had some really interesting interventional trials and Dr Steg
will discuss a couple of them as well.


                                               
ISAR-TEST 4 was a very interesting trial. It is one of the first
10 trials that gets to the 10-year mark, so this is just the
10-year follow-up results of that. It was about a 2500 patient
trial. It was done in Germany, multiple centers. Really they were
trying to assess the space that they were trying to ... Or the
knowledge gap that they were trying to fill was the durability of
the bioabsorbable polymer stents.


                                               
Specifically, they were looking at a bioabsorbable polymer
sirolimus-eluting stent, the Yukon stent, and then they compared
that with durable polymer stents including Xience or the
everolimus-eluting stent and then Cypher, which is no longer
available in the U.S., but that's a permanent polymer
sirolimus-eluting stent.


                                               
The primary results were published and presented a long time ago.
There was really MACE events at one year and it showed
non-inferiority for this bioabsorbable polymer stent back then.
So, then they had, incredibly, 83% of the cohort that they were
able to follow-up out of 10 years. And what they showed is that
... I don't want to necessarily get into the numbers and the
details as much, but what they showed is that this bioabsorbable
polymer sirolimus-eluting stent tended to have similar outcomes
to Xience, which we accept as state of the art current generation
stent, permanent polymer. And it did better than the Cypher
stent, both in terms of MACE events and stent thrombosis.


                                               
So suggesting that, the big advance in the field for this is ...
This is a long-term follow-up of the stent. It suggests that
outcomes may be similar in this patient population. Although only
12% were really enrolled with an MI in this patient population.
Most of them were stable or less sick ACS patients. And they show
fairly good outcomes out of 10 years, comparable to Xience and
better than Cypher.


                                               
I think it was interesting. Gabriel, what is your take [crosstalk
00:04:57].


Dr Gabriel
Steg:               
I think it's important. There's been a tremendous interest in
international community on trying to tease out which are the best
types of stents and beyond brands, try to understand the type of
stent, the coating, the drug that you put on it, whether the
polymer is durable or not durable. I think these types of fairly
well done, large randomized trials with long term flow are
critical.


                                               
A lot of the focus in the interventional community originally was
on lumen size, late loss, angiographic parameters short term. And
now the field has matured, and we've moved to clinical outcomes,
patient-oriented outcomes, long term follow-up. And it's
important because we've learned from long term trials such as
PROTECT that the result at one year may not predict what happens
at five years, and sometimes you have surprises.


                                               
So, it's really important. We owe it to our patients because
these are irretrievable devices. Once you've implanted them, they
are there. We talked about Cypher being out of the market, but
there are more than a million patients who walk every day on this
plant with a Cypher in their coronary artery, so we better know
what the long-term follow-up is.


Dr Dharam Kumbhani:   Yeah, that's a great point.


Dr Carolyn
Lam:               
Wow. And then thanks also for the discussion that allows me, as a
noninterventionist, to realize ... It's hard to keep track of
what's happening with all the different types of stents and
polymers and so on. But could you then summarize for the field,
does that mean that these biodegradable ones are now ... Do I
sound ignorant when I say that? That they are now really in the
game. Is that what it does?


Dr Dharam Kumbhani:   This whole bioabsorbable field,
there are nuances. So this really is testing a bioabsorbable
polymer where -


Dr Carolyn
Lam:               
Oh!


Dr Dharam Kumbhani:   So, with every stent you have a
stent, you have the polymer, and then you have the drug.


Dr Carolyn
Lam:               
Thank you.


Dr Dharam Kumbhani:   And so, the polymer and the drug
go away, and then you're left behind with a bare metal stent. And
that's this Yukon stent.


Dr Carolyn
Lam:               
Got it.


Dr Dharam Kumbhani:   The one that has been in the
press a lot more is the bioabsorbable scaffold where the stent
and the polymer and the drug, everything in theory should be gone
at a certain period of time. So this is ... It's an important
distinction though. Because I know that it's very confusion when
you just say bioabsorbable and it's unclear if you're talking
about the polymer or you're talking about the stent, itself. But
this really was a bioabsorbable polymer issue, so you're left
behind with a bare metal stent at the end of it.


Dr Carolyn
Lam:               
Got it, crystal clear, and thank you. That's cool. That's super.


Dr Sana
Al-Khatib:           
I agree, for an electrophysiologist too.


Dr Carolyn
Lam:               
But now, let's go into the AMI field. There were two trials that
really spoke to acute management patients coming in with an AMI
and with cardiogenic shock, for example. Gabriel, could you tell
us a little bit about the IABP-SHOCK II trial, as well as the
really talked about a door-to-unload IMPELLA Trial.


Dr Gabriel
Steg:               
The IABP II trial is a randomized trial looking at the benefit,
or lack thereof, of intraaortic balloon pump in patients with
cardiogenic shock and acute MI. It's been standard practice since
the '60s to offer IABP pumping to patients with cardiogenic
shocks and AMI.


                                               
So, literally more than a million patients have been implanted
with IABP, but the reality is when we look at the randomized
trial evidence of benefit there was none. They were very small
trials, inconclusive, underpowered. Professor Thiele from Germany
and his colleagues deserve enormous credit for having had the
courage to really do what needed to be done. A proper randomized
controlled trial, of course open label.


                                               
And what they found in IABP II, which they already reported a few
years ago, was that there was no acute benefit of IABP on
survival short term, or for that matter on many of the secondary
clinical outcomes looked at in this trial. They subsequently
reported one year mortality.


                                               
What they did here is they gathered follow-up on almost all of
the cohort at more than six years. And they found that the long
term survival is identical for patients who received an IABP and
those who did not. So I think this nails the issue. But there's
another thing we learn. The mortality at six years is staggering,
it's close to 60%. And although a large fraction of the patients
die in the first 30 days, you still have an additional 10% of
patients who die between the first year and six years.


                                               
So there still remains a very sick patient population for whom we
need to investigate new strategies. I don't think it's going to
be necessarily mechanical. We have to think of all of the
strategies we do to prevent and mitigate cardiogenic shock to
build up. And that's gets us to the second trial that I'll talk
to you about in a minute.


Dr Sana
Al-Khatib:           
I have a quick question about this. Did they provide any
information about modes of death in these patients?


Dr Gabriel
Steg:               
Yes. They did capture information about that. Off the top of my
head, I'm unable to provide information, but yes they did capture
that. The German system allowed them to retrieve information
about causes of death and it's a closed system. It's a national
trial, so they were able to get enormous follow-up.


Dr Sana
Al-Khatib:           
Because this information can help us inform what interventions
are needed next.


Dr Gabriel
Steg:               
Yes. That's really important.


Dr Dharam Kumbhani:   To your point about ... You use a
very interesting word, the last nail. That's actually how Dr
Hochman addressed her editorial. She wrote a really nice
editorial-


Dr Gabriel
Steg:               
The leading expert in the field.


Dr Dharam Kumbhani:   And so, I'm interested in your
thoughts. The use of balloon pumps for shock, there's a
discrepancy between the American guidelines and the European
guidelines. Last year the European guidelines were updated. It is
really such a practice changing guideline in that it now lists
routine use of balloon pumps in cardiogenic shock-


Dr Gabriel
Steg:               
Class III.


Dr Dharam Kumbhani:   -as a class III indication. Going
through training, that was all you had when someone came in with
shock, you would throw in a balloon pump. So that's really quite
a practice changing event.


Dr Gabriel
Steg:               
Yeah. These investigators are embarking on new studies with ECMO
and I think it's going to be fascinating to see whether ECMO,
which also gets increasingly used worldwide, whether there is
evidence to acutely support or not whether this is useful. I
think they are doing the proper thing. They are doing the right
thing, randomized trials. And we could commend them because these
are really difficult trials.


Dr Carolyn
Lam:               
Absolutely.


Dr Gabriel
Steg:               
In the acute MI setting, shock patients, ECMO, IABP, that's
really difficult. They are brave investigators, they are good
investigators, and I think they provided the community with a
clear answer.


Dr Carolyn
Lam:               
And exactly the kind of papers that we like publishing at
circulation, isn't it? Now what about the door-to-unload?


Dr Gabriel
Steg:               
That is actually a good segue with door-to-unload because if we
can't properly treat shock once it's there, can we do something
to prevent shock? Can we do something to preserve myocardium? One
of the experimental findings that is very clear is that if you
unload experimental myocardial infarction, if you unload the left
ventricle you reduce infarct size.


Dr Gabriel
Steg:               
So, investigators have been trying to translate this experimental
finding into the clinical arena using the Impella device. There's
enormous interest, particularly in North America for Impella use
in acute MI patients with larger infarcts with the idea that if
you can unload the left ventricle, you might be able to mitigate
the extent of the myocardial infarction, and therefore avoid
cardiogenic shock and probably improve prognosis.


                                               
Although this is a very attractive theoretical concept, it still
deserves to be tested. And so, if you want to test it you have to
unload the ventricle as soon as possible, ideally before
reperfusion, which means that you're going to have to delay
reperfusion for the time of implanting the device and unloading
the ventricle. And so what the investigators did in this trial is
to study whether delaying proposedly by 30 minutes reperfusion,
to unload the ventricle for 30 minutes prior to reperfusion, was
feasible and reasonably safe.


                                               
It's a small trial. It's really a pilot trial. By no means does
it test the proof of concept of the device or the theoretical
issue, but it shows that it's feasible. There doesn't seem to be
a massive increase in total time to reperfusion because just by
change the group that was not delayed had a longer time to PCI,
so eventually things are sort of evening out.


                                               
They looked at MRI size of infarcts at follow-up. There was no
obvious difference, but of course it could still be tied to
errors. We're not totally sure about this, but it certainly paves
the way for doing a proper proof of concept randomized trial,
testing unloading versus no unloading with a true control group.
And I think that's what investigators are looking forward, but I
understand there's immense interest for this concept in
international community, particularly in the United States and
I'm quite curious to see what this future trial will look like
and what the results will be.


Dr Carolyn
Lam:               
Yeah, indeed. Gabriel, I noticed you were very careful to frame
it, to say what the trial was trying to address and what it
wasn't. And there's been quite a bit of buzz after that.


                                               
Do you agree with everything Gabriel has said and what have you
heard?


Dr Dharam Kumbhani:   I think he was incredibly
eloquent in outlining the premise of the trial and what it really
showed. I think the one thing that ... And this was brought up in
the very nice editorial by Dr Patel from Duke as well, is it
would've been really nice to have a control arm which didn't have
any unloading. Because these are not patients with shock, that
just directly had primary PCI. And then comparing infarct size.


                                               
So, I think that was one of the pieces of information that
would've been helpful to then put this in perspective. When you
have an infarct size of 8% or 10%, how does that compare in the
same patient population in their testing? You're absolutely right
about the need to do difficult trials like this, where a lot of
times it's just assumed to be true and is embraced in clinical
practice.


                                               
As I gave the example about the balloon pump earlier, where as a
Fellow you saw someone in shock and your reflex was to put in a
balloon pump. And so, I think testing these very difficult
patient scenarios, as well as just in terms of trial execution,
it's amazing to have two trials on that.


Dr Gabriel
Steg:               
If I may come back to this?


Dr Carolyn
Lam:               
Yes.


Dr Gabriel
Steg:               
It's funny because we've been using the IABP for years, thinking
this is what we should do in shock. Now our German colleagues
have proven that IABP doesn't work. So a lot of investigators
have reverted, saying "Well, we should use Impella." But where is
the evidence showing that Impella is beneficial?


Dr Dharam Kumbhani:   That's right.


Dr Carolyn
Lam:               
That's right.


Dr Gabriel
Steg:               
We have none, so I think that's a trial that deserves to be done.


Dr Dharam Kumbhani:   And ECMO. Yeah, exactly.


Dr Carolyn
Lam:               
Yeah, ECMO. Exactly. And, you know, going back to door-to-unload,
it's important to prove safety in order to go to the next step,
which is exactly how you frame-


Dr Gabriel
Steg:               
I think it shouldn't be over interpreted.


Dr Carolyn
Lam:               
That's how it should be, exactly, received by the community. So
that's great. Now let's switch gears a bit.


                                               
Sana, in EP world, the EP guided noninvasive radio ablation of
VT. Fascinating stuff. What are your thoughts?


Dr Sana
Al-Khatib:           
I absolutely agree, definitely. This was a phase two study that
the authors did. They enrolled 19 patients, so it was a small
study, but it was really helpful. Remember, there's a major
clinical need there. These are patients who have an ICD, who have
recurring ventricular tachycardia, that have been treated with at
least one antiarrhythmic medication, at least one catheter
ablation procedure, and then what do you do with those patients?
This is actually a clinical scenario that comes up frequently and
we absolutely need to be looking for more therapies for those
patients.


                                               
So that's what that study was about, trying to explore new ways
to treat these patients. To be able to do it noninvasively, I
think is fascinating. That's what ... They enrolled these
patients. Patients had to have failed these treatments,
antiarrhythmic medications, prior catheter ablation, and they
underwent noninvasive imaging to really localize the source of
the ventricular tachycardia, where it's coming from, and then
they subjected them to stereotactic body radiotherapy to ablate
those sources of ventricular tachycardia.


                                               
And, of course, the results were fascinating because they showed
on the effectiveness side that this seemed to be very effective
because if you look at the reduction in the burden of ventricular
tachycardia, and a couple of their patients actually had
significant PVCs and PVC induced cardiomyopathy, there was a
significant reduction in the rates of these arrhythmias in these
patients with this intervention, which was great to see.


                                               
In fact, to be specific, about 94% of these patients, so 18 out
of the 19, had significant benefit. And in about 89% of the
patients there was more than 75% reduction in the arrhythmia. So
these are actually really interesting findings, especially in a
patient population where we really don't have other options. Now
of course you're going to ask me about the safety. What are the
safety concerns?


                                               
Of course, this was a primary endpoint for the authors. They did
look at safety up to 90 days and they found that there were two
significant adverse events that occurred in those 90 days. One
was heart failure and one was pericarditis. The concern, of
course, with radiation is what else can we expect especially if
you follow the patients longer? So certainly we need more data.
The authors acknowledged that beautifully and I think their
intent is to launch a multi-center randomized clinical trial. I
don't know if it will be randomized, but at least a multi-center
clinical trial to see if they can replicate those findings. So
that was very interesting to see.


Dr Carolyn
Lam:               
Yeah it was. Thanks, that was really exciting.


                                               
So, some exciting trials in my world of cardiometabolic disease
too, and I want to highlight two. The CARMELINA trial and the
CAMELLIA-TIMI 61.


                                               
First the CARMELINA trial. This was a secondary analysis of
CARMELINA and this was ... CARMELINA, if I can remind everyone,
is a cardiovascular outcomes trial, randomizing about 7000
patients with type 2 diabetes and atherosclerotic cardiovascular
disease, and/or chronic kidney disease. Randomizing them to the
DPP-4 inhibitor linagliptin 5 mg a day versus placebo, following
up for a median of about two years.


                                               
We know that type 2 diabetic patients are at risk of heart
failure and there's always been a bit of a question mark when it
comes to DPP-4 inhibitors and their risk for heart failure. And
so this secondary analysis looks specifically at the
hospitalization for heart failure and related events in
CARMELINA. The important thing is that all these were
prospectively centrally adjudicated events, and this was a
pre-specified post hoc analysis.


                                               
And the summary of it all is that linagliptin was not associated
with an increased risk of hospitalization for heart failure or
the composite of cardiovascular death in hospitalization or the
related outcomes. Importantly, the authors did also sensitivity
analyses and interaction analyses to show that the results were
consistent whether or not patients had a history of heart
failure, which was in 27% of patients, regardless of the baseline
ejection fraction that was measured within a year of starting the
drug, and also regardless of renal function. So EGFR or urinary
albumin to creatinine ratio.


                                               
This is really important because this trial adds to the growing
perhaps understanding of DPP-4 inhibitor heart failure risk. The
whole question mark actually came with SAVOR TIMI and that was
saxagliptin. But since then there's been three other trials that
have showed no heart failure risk. EXAMINE, TECOS, and now
CARMELINA. So, an important addition and I think it should
reassure us.


                                               
And then from diabetes and heart failure risk, which is always
very hot, but now obesity. The CAMELLIA-TIMI 61 trial looked at
renal outcomes in this trial. Now what was this trial? It was
actually testing lorcaserin, and that is a selective serotonin 2C
receptor agonist, in about 12,000 obese or overweight patients.


                                               
Basically, the primary results showed that it did not increase
any ... It met it's CV safety outcomes with weight loss and so
on. But this time they looked at renal outcomes. Because obesity
has been known to be associated with hyperfiltration of the
kidneys, you get albuminuria and it's apparently worsening of
kidney disease. So what we need to know is pharmacological weight
loss going to be associated with improved renal outcomes?


                                               
And basically, that is what CAMELLIA-TIMIA 61 showed. Their renal
outcomes were new or persistent albuminuria and then the standard
doubling of EGFR or end-stage renal failure, renal transplant or
renal death. And that was improved by lorcaserin. Along with
that, there was the anticipated reduction in weight, HbA1c, and
BP. It does look like, from these late breaking results that we
have another tool in our toolbox.


Dr Sana
Al-Khatib:           
And for the clinicians out there, which patients should they be
thinking to use this medication in? What kind of obesity are we
talking about? At what point do you introduce that?


Dr Carolyn
Lam:               
This is common garden, just defined by BMI that was above 27. And
I don't think they're saying to use it in patients with renal
dysfunction, but to sort of say to look and see whether weight
loss also associates with renal function improvement, and it
does. It's reassuring.


Dr Sana
Al-Khatib:           
Yeah, okay.


Dr Carolyn
Lam:               
And then ... Okay, let's round up with that last trial. A very
interesting one because it's pragmatic mobile health and
wellness. Tell us.


Dr Dharam Kumbhani:   It's really a monumental effort.
This is ... I'll be brief, but it's really a phenomenal trial
from an epi standpoint and implementation standpoint. This is
from India. It was coordinated by the Center for Chronic Disease
Control and the Public Health Foundation of India where, as
everyone knows, India is now the diabetes capital of the world
and chronic diseases have very quickly overtaken other infectious
causes as the number one cause of mortality and morbidity.


                                               
This was a big undertaking, really collaboration from three
continents, but it was a community based plus a randomized trial.
They had 40 community health centers and what they were trying to
see is primarily for hypertension and diabetes. That if you
implemented a structure and typically using this mWELLCARE tool,
which is basically an electronic medical records storage facility
and then it also has inbuilt clinical decision support.


                                               
And really for hypertension and diabetes management, but also,
they had tobacco and alcohol screening, abuse screening, and also
for depression. So what they really wanted to do ... A very
ingenious endeavor and they try to see if doing this
systematically on a clustered randomized fashion if that would
actually influence patient outcome. They had a little over 3000
patients and they followed them for 12 months.


                                               
Unfortunately, the trial, itself, as far as the primary endpoint,
which was change in systolic blood pressure and hemoglobin A1c,
they had pretty significant reductions in both arms, about 12 to
13 millimeters, which is amazing from a population health
standpoint, in both arms not statistically significant, and in
hemoglobin A1c also by 0.5% in both arms.


                                               
Just suggesting that having this more frequent interactions with
the medical health system, itself, was driving a lot of this
benefit. So although the trial, itself, was negative for the
primary endpoint, I think it's a huge step forward for the
management of chronic disease epidemiology and burden in
developing countries.


Dr Gabriel
Steg:               
Neutral.


Dr Carolyn
Lam:               
Ah, true.


Dr Dharam Kumbhani:   Fair point.


Dr Carolyn
Lam:               
We've discussed this whole array of seven trials and they are
difficult trials. I mean, talk about another difficult type of
trial to do, cluster randomized pragmatic trial. It's amazing the
breadth of simultaneous publications we've had this year. Thanks
again to everyone for introducing this and thank you for joining
us today.