Circulation January 23, 2018 Issue

Dr. Carolyn
Lam:              
Hello from the American Heart Association meeting in Anaheim. I'm
Dr. Carolyn Lam, associate editor from Circulation at National
Heart Centre in Duke National University of Singapore and I'm so
pleased to be here with the Circulation team led by editor in
chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior
editor from Brigham and Women's Hospital, and Dr. Dharam
Kumbhani, associate editor from UT Southwestern. Boy, we've got
lots to discuss. I mean, I want to just first start with
congratulating you, Joe. We have got quite a number of
simultaneous publications here at the AHA.


Dr. Joseph
Hill:                 
I appreciate that, Carolyn. Don't congratulate me. We have a team
that is a privilege to work with. One of the initiatives that we
launched right from the start was a desire to foster and shine a
bright light on emerging science at the major meetings around the
world. Often, that involves simultaneous publication.


                                               
I'm proud to say that we have 11 simultaneous publications, a
record for us here at AHA. Most of them are clinical trials. A
few are clinical science, and two of them are young investigators
who are competing in the various different competitions. We
reached out to them a few weeks ago and offered them the
opportunity to submit to us, of course with no guarantees, and
our standard remains the same, but we promised that we would
provide them with an external peer review. Two of them made it
through the process and they will be simultaneously published
with their presentations here in Anaheim.


Dr. Carolyn
Lam:              
Wow, well you heard it. A record 11 simultaneous publications.
We've got a lot to talk about. Let me just maybe group the topics
a little bit. Let's start with talking about peripheral artery
disease. I think there are at least three papers around that
area, and then we'll talk about coronary artery disease, and
almost focusing more on implementation science, papers, there are
two there, and then of course we have to talk about heart
failure. Dharam, could you start? Tell us about the FOURIER PAD
trial.


Dr. Dharam Kumbhani:  Yeah. It's very exciting to have
clinical trials in the PAD realm. FOURIER PAD is certainly really
well done sub-study of the FOURIER trial. As you remember, this
was a landmark trial, which compared a PCSK9 inhibitor Evolocumab
in two doses, two placebo. The overall trial was done in about
27,000 patients who were followed for a median of 2.2 years. In
this trial, Marc Bonaca and investigators, they looked at the PAD
subset, which were about 13% of the total cohort. Now, they
specifically set out to look at how patients with PAD, during
this trial and very gratifyingly, they also specifically assessed
how patients with PAD did as far as limb events, not just
cardiovascular events.


                                               
At the outset, not surprisingly, patients with PAD had a higher
risk of cardiovascular events by, I think it was about 60% higher
for the primary end point compared with patients who did not have
PAD. There was really no, in fact, modification by PAD in that
the benefit of Evolocumab that we saw in the overall trial was
preserved among the patients with PAD as well as those without
PAD. However, because patients with PAD had higher event rates,
the absolute risk reductions were higher in patients with PAD.


                                               
Then, these investigators looked specifically at the incidents of
major adverse limb events, which is a composite of acute limb
ischemia, urgent revasc, and major amputations. What they show is
that in the overall cohort, there is a 42% reduction in the risk
of these major adverse limb events with Evolocumab compared with
placebo. Obviously, the effect is significantly higher in
patients with PAD. Although the benefit wasn't noted in the PAD
subset specifically, the overall p-value for interaction was
negative.


                                               
One of the really exciting things about this paper is that just
like investigators have shown a monotonic reduction in
cardiovascular event rates with LDL reduction, similarly, the
investigators show a reduction in limb events, which is dose
related and the same way in a monotonic fashion with Evolocumab.
I think this is really exciting and I think this will be a very
important paper for the field.


Dr. Carolyn
Lam:              
Yeah. Dharam, that was beautifully summarized but once you start
talking about the peripheral artery disease and this lack of
interaction on effects and so on, I think of the CANVAS trial
results that were reported at this meeting too. If I could maybe
briefly summarize what the authors did in this circumstance, they
looked at the more than 10,000 patients in the CANVAS trial who
were randomized into Canagliflozin versus placebo in diabetic
patients but this time they looked at whether or not there was a
difference in effect with the primary prevention cohort versus
the secondary prevention.


                                               
Primary prevention meaning those adults who had diabetes and risk
factors but no established cardiovascular disease and the
secondary prevention were those with peripheral artery disease,
for example, and other established cardiovascular disease. The
same thing, a lack of interaction, which I think is really
important because it was the same sort of idea that the overall
risk of cardiovascular events was lower in the primary prevention
group. Looking at them as a subgroup alone, you didn't get the
p-value that crossed the limit because the power was less in a
lower risk group, but the lack of statistical interaction really
gives us additional information, I think, that Canagliflozin and
maybe the SGLT2s in general may be effective for primary
prevention in diabetic patients. What do you think?


Dr. Dharam Kumbhani:  Yeah. I mean, I think certainly, very
interesting findings along those lines. As you pointed out, the
event rates are much lower in the primary prevention cohort. All
the confidence intervals overlap one, but because all the
p-values for interaction for the three-point maze, the four-point
maze, et cetera, one would say that there really isn't a
difference between the primary and the secondary prevention
subgroups. You would potentially have the same benefit in that
subgroup as well.


Dr. Carolyn
Lam:              
Fortunately or unfortunately, in that same study, they looked at
the risk of amputations and there was a lack of interaction too
for that meaning there was a higher risk of amputations with
Canagliflozin versus placebo. That of course is a really hot
topic now, isn't it? I just wanted to point out though, when you
look at it in the primary prevention group, there are only 33
events. What do you think? It spells caution but further look
needs to be done? Yeah. Contrast that with the EMPA-REG outcome
PAD analysis. You want to tell us about it?


Dr. Dharam Kumbhani:  Yeah. Once the Canagliflozin CANVAS
findings came out showing a high rate of amputations with
Canagliflozin, the Empagliflozin, the EMPA-REG outcome’s
investigators went back and looked at the PAD subset in EMPA-REG
outcomes. This was about 20% of the total cohort. I will say that
unlike FOURIER, which we just discussed, the ascertainment of
amputations was not prospectively defined for this trial and it
was really obtained from the CRF forms.


                                               
However, having said that, it did not appear that amputation
rates were higher with Empagliflozin. They did not break it down
by the different doses but one assumes that the benefit is
consistent between the two doses that they study. One would
imagine the PAD patients would have a higher rate overall, which
it was, but even in that group, it was about 6% over three years
and there was really no difference between the patients who
received Empagliflozin versus those who got placebo.


Dr. Carolyn
Lam:              
That EMPA-REG outcome paper, I mean, interestingly, it was a
research letter. Joe, you've been watching this whole field
unfold right now and our journal has published so many good
papers, including CVD REAL, all in this space. Could you comment
on that a little bit and the research letter concept and the fact
that we're publishing so many of these interesting papers in this
topic?


Dr. Joseph
Hill:                 
Well, Carolyn, as you inferred, this field is evolving very
rapidly. Now, the interface between metabolic disease and
diabetes and heart disease is blurring. Some of these diabetic
drugs are really emerging as heart failure drugs, it looks like
and so there's a great deal of interest in exploring that and
trying to find underlying mechanisms. It's an incredibly exciting
time. In parallel with that, we are publishing research letters
now for papers where, again, our bar starts with validity. Our
bar doesn't change but if it's a story that can be communicated
with really one multi-paneled figure and an 800word text, then
that is a nice bite-size piece of information that we can get out
to our readership. We're publishing one or two a week now.
Overall, it appears to be well received and I think it's an
effective vehicle for conveying certain types of our content.


Dr. Carolyn
Lam:              
Frankly, it's such a delight to read, isn't it? It's hard to
write. I think the shorter, the harder to write but this just
goes to show how equally important they are.


Dr. Joseph
Hill:                 
Absolutely.


Dr. Carolyn
Lam:              
That we're discussing it here. Well, let's go on to the next
topic then, coronary artery disease. Regionalization of the care.
I'll say that again, regionalization of the care. Would you like
to comment on the two papers that are simultaneously being
published? One would be the ACCELERATOR-2 trial. That's in the
U.S. Then, a second from New Zealand, the ICare-ACS trial.
Slightly different but-


Dr. Joseph
Hill:                 
Well, that's exactly right. Often, we know what to do but we
don't do what we know we need to do in medicine. The
implementation of what we already know is an area of hot research
and is an area that's evolving rapidly. These two studies,
ACCELERATOR-2 here in the United States, focused on
regionalization of the interface between EMS systems and EDs, how
to get patients identified in the hospital to their device,
whether it's a stent or a balloon pump or whatever it is. The
first medical contact to device was the metric and by
implementing what we already know, the AHA mission lifeline
principles, these investigators were able to optimize this
regionalization, so there wasn't so much variability across these
12 metropolitan regions. As a consequence, the time to first
medical contact to device was shortened, and there was in fact a
striking, maybe even surprising, mortality benefit.


Dr. Carolyn
Lam:              
Exactly. That was striking to me too.


Dr. Joseph
Hill:                 
From the street to the lab, another paper from New Zealand that
you referred to called ICare-ACS focused on doing a better job in
the emergency department with serial ECGs and serial high
sensitivity troponins, risk stratification algorithms and they
found that, again, by developing these clinical pathways within
the ED, they were able to shorten the length of stay in the ED
and the length of stay in the hospital.


Dr. Carolyn
Lam:              
Yeah. I thought those were amazing and then also from different
parts of the world, really strong public health messages as well.
Laura, you take care of these ACS patients right on there. What
did you think of these papers?


Dr. Laura
Mauri:               
No, I agree. I think that we've, in the past, focused on science
and focused on clinical trials but ultimately, none of that
matters if we don't deliver the healthcare to the patient. I
think this is just a growing field and I'm glad that we're
emphasizing it in circulation.


Dr. Carolyn
Lam:              
Absolutely. If we would now go to another area that is really
increasing in prevalence throughout the world. Heart failure, and
of course, heart failure with preserved ejection fraction.


Dr. Joseph
Hill:                 
Your favorite topic.


Dr. Carolyn
Lam:              
Congratulations, Laura on the paper that you're presenting, that
is being presented at this meeting, the REDUCE LAP trial. Could
you tell us a little bit more about that?


Dr. Laura
Mauri:               
Sure. Yes, as you know, it's a really challenging field, heart
failure with preserved ejection fraction. There aren't a lot of
therapies that we have. We really don't have great medical
therapy. This study actually looks at a medical device to treat
patients. It really is a feasibility study, so it's a relatively
small trial, just over 90 patients but it's randomized. We know
in the device arena, as in all trials, how important
randomization is but also blinding. This was actually a
sham-controlled blinded trial really designed to look at this
interatrial shunt device in patients who have an elevated wedge
pressure.


                                               
The REDUCE LAP stands for reduce left atrial pressure. That was
the primary endpoint, was pulmonary capillary wedge pressure.
This was not only looked at the safety, which showed that the
device placement was very safe, but at the same time also looked
at the proof of concept that by placing the shunt device, there
was actually a reduction in wedge pressure over a period of
exercise. It needs to be followed on. It's certainly just the
first phase of trials but a pretty good standard with the sham
control.


Dr. Carolyn
Lam:              
Yeah, well, congratulations again. I mean, this follows … There
was a previous publication of the single arm trial and now, this
is the first randomized sham-controlled, and the results are
consistent. It's a very difficult trial to carry out. HFpEF
patients are notoriously difficult to recruit. Could you tell us
a little bit about what it was like successfully completing this
trial?


Dr. Laura
Mauri:               
Yeah. Well, we had very enthusiastic centers and principal
investigators, Ted Feldman and Sanjiv Shah. I think what it
really required in this early phase was sites that were committed
to characterizing the exercise physiology. The next stage of
rolling this out to a broader number of sites and a larger number
of patients to see if there's a clinical effect will really be
more focused on the clinical endpoints and quality of life
because ultimately that's the goal, is to improve symptoms in
these patients.


Dr. Carolyn
Lam:              
What I love about the design and the whole concept, it's so
simple and elegant. We almost sometimes forget that HFpEF is
heart failure, which means that by definition, there's raised
filling pressures. It's hemodynamic at the end and this is just a
simple concept of offloading the left atrium. That's so beautiful
but it does come with some questions. Every time you mention this
to someone, they go, “What about, I don't know, Eisenmenger's
syndrome developing later?” The right side, volume overload,
pulmonary hypertension, what about atrial fibrillation down the
line? How about the safety parts of it?


Dr. Laura
Mauri:               
Right, so the procedural safety was excellent but then I think
you raise really important questions and these patients are still
in follow-up but looking at the report here at this meeting,
there was no pulmonary hypertension in excess in the shunt
treated arm. The patient selection was towards patients who had
higher wedge compared with right atrial pressure and among those
patients, there was no evidence of RV overload. At least at this
stage things look good to go on to the next step.


Dr. Carolyn
Lam:              
That's wonderful and exciting. We definitely need a therapy for
HFpEF. Joe, would you like to highlight any other trial? We have
11. We've discussed six.


Dr. Joseph
Hill:                 
Tonight at the editorial board meeting, we will be saluting these
two young investigators who are presenting their work in this
competition and simultaneously publishing their work. We've
invited these young investigators and their mentor and they will
present a short talk to the editorial board dinner. It's an
effort to salute and recognize these early career investigators,
to congratulate them on outstanding work. We're pleased and
privileged to publish it, so I'm particularly excited about that.


Dr. Carolyn
Lam:              
Wow, Joe. That is great. Thank you. I didn't know that was
happening either. That's fabulous. Dharam or Laura, any other
highlights that you may want to mention in this meeting?


Dr. Laura
Mauri:               
I think that it's just been a wonderful kickoff to the meeting.
We've covered, I think, many of the really important trials so
it's really exciting to be able to see the work in print.


Dr. Carolyn
Lam:              
That’s great, and to discuss it as well.


Dr. Dharam Kumbhani:  Yeah, I agree. This is really exciting
and hopefully, we can keep growing from strength to strength
every year.


Dr. Carolyn
Lam:              
Yep. You heard it right here everyone. We are going to grow from
strength to strength under your leadership and with this great
team, so thank you very much for joining us today.