Circulation April 17, 2018 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. Does NT-proBNP-guided
therapy improve outcomes in acute decompensated heart failure?
Well the Prima II trial results are coming right up after these
summaries.


                               
Is hospital volume a good structural metric assessing the quality
of care in heart failure? Well, in the first original paper this
week from Dr. Kumbhani and colleagues at UT Southwestern Medical
Center, authors determined the relationship between admission
volume, process of care metrics, and short and long-term outcomes
admitted with acute heart failure in the Get With the
Guidelines-Heart Failure registry, which has linked Medicare in
patient data at 342 hospitals.


                               
They found that lower volume hospitals had worse adherence to
important heart failure process measures, than higher volume
hospitals. There was no association between risk adjusted
in-hospital mortality and hospital heart failure admission volume
among older adults.


                               
After adjusting for adherence with process measures at discharge,
annual heart failure admission volume had a minimal association
with mortality, and readmissions up to six months post-discharge.
Thus, rather than focusing solely on hospital volume, hospital
profiling efforts should perhaps focus more on participation in
quality improvement initiatives, adherence to process metrics,
and risk standardized outcomes.


                               
The next study describes the association between air pollution
and heart disease mortality in the United States, with a focus on
whether the association differs by race and ethnicity. First and
corresponding author Dr. Jennifer Parker from the National Center
of Health Statistics Centers of Disease Control and Prevention
and her colleagues use data from the 1997 to 2009 National Health
Interview Survey linked to mortality records through December
2011 and the Annual Estimates of Fine Particulate Matter or PM2.5
as an index of air pollution.


                               
They found that the association between air pollution and heart
disease mortality in this national sample was elevated and
similar to estimates found in prior studies. After controlling
for social demographic and geographic factors, the associations
between air pollution and heart disease mortality for
non-Hispanic black and Hispanic adults were not statistically
significantly different from that of non-Hispanic white adults.


                               
Thus, this study supports the application of findings from prior
studies of air pollution and mortality, albeit largely from
non-Hispanic white adults, but to other races and ethnicities in
the United States.


                               
The next study suggests that large cardiac muscle patches
engineered from human induced pluripotent stem cells may be a
reality. First author Dr. Gao, corresponding author Dr. Zhang
from University of Alabama at Birmingham generated human cardiac
muscle patches of clinically relevant dimensions of 4 x 2
centimeters and they did that by suspending cardiomyocytes,
smooth muscle cells, and endothelial cells that had been
differentiated from human-induced pluripotent stem cells in a
fibrin matrix and culturing this construct on a dynamic platform.


                               
The results from in vitro assessments of calcium transience,
action potential propagation, and forced generation, as well as
the presence of intercalated disc-like structures, suggested that
cardiomyocytes matured in these human cardiac muscle patches.
During the 7-day dynamic culture period. When transplanted onto
infarcted swine heart, measurements of cardiac function, infarct
size, wall stress all improved with no increase in arrhythmias.


                               
Changes in the expression profile of myocardial proteins
indicated that the human cardiac muscle patch transplantation
partially reversed abnormalities in sarcomeric protein
phosphorylation. Collectively, these observations indicate that
human cardiac muscle patches can be successfully generated and
may improve recovery from ischemic myocardial injury.


                               
Does a second arterial conduit improve outcomes after multivessel
coronary artery bypass grafting? Well, in the next study from
first author Dr. Goldstone, corresponding author Dr. Woo, from
Stanford University and their colleagues used a clinical registry
including all 126 non-federal hospitals in California to compare
all-cause mortality, and rates of stroke, myocardial infarction,
repeat revascularization, and sternal wound infection between
propensity score matched cohorts, who underwent primary isolated
multivessel coronary artery bypass grafting with the left
internal thoracic artery, and who received a second arterial
conduit or a venous conduit between 2006 and 2011.


                               
The authors found that receipt of a second arterial conduit was
associated with lower mortality, and at first cardiovascular
events, compared with receipt of a venous conduit. The survival
benefit associated with the use of a second arterial conduit
extended to patients up to 78 years old. As a second arterial
conduit, the right internal thoracic artery offered no benefit,
compared with the radial artery, but it was associated with an
increased risk of sternal wound infection.


                               
These findings therefore suggest that surgeons should perhaps
consider lowering their threshold for using arterial grafts and
that the radial artery may be the preferred second conduit.


                               
That wraps it up for our summaries. Now for our future
discussion.


                               
NT-proBNP and natriuretic peptides in general, have really become
mainstay in management of heart failure, in the diagnosis, in the
prognostication, but questions still remain regarding
NT-proBNP-guided therapy. We heard about the guided trial in
chronic heart failure just reported last year, and this year, in
fact this week, in this week's journal, we're about to hear about
PRIMA II trial in acute heart failure.


                               
And how NT-proBNP was tested as a potentially guiding strategy
for the management of acute heart failure. I'm so pleased to have
the corresponding author with us, Dr. Wouter Kok, from University
of Amsterdam, as well as our Senior Editor Dr. Biykem Bozkurt
from Baylor College of Medicine. So welcome both of you, and
Wouter may I just jump straight in it?


                               
PRIMA II means that there was a PRIMA I trial, so could you just
briefly tell us a bit about PRIMA I and the rationale for PRIMA
II?


Dr Wouter Kok: Well the PRIMA II was an in-hospital guiding
therapy that was preceded by the PRIMA II, it was a chronic heart
failure patient population and one of things that we noticed in
PRIMA I was the lack of effect of trying to reach a percentage
drop in chronic heart failure patients. Why is that? Is that
because there is a long time before you can achieve a therapy
adjustment? Or is it something else? And shouldn't we start
before patients are discharged from hospitals?


                               
So the idea was born to do an in-hospital guiding study instead
of chronic heart failure patients study.


Dr Carolyn
Lam:               
Interesting. And could you tell us briefly, the design of PRIMA
II and your findings?


Dr Wouter Kok: So the PRIMA II was designed based on the previous
publication of several authors indicating that a 30% reduction in
NT-proBNP would be a good target for heart failure therapy. Now,
we first asked ourselves the questions, whether we should put
this target in front of the hospital admission, so in the first 2
days or perhaps at the end of the hospital admission? And the 30%
reduction was validated only for discharge purposes, so but we
also tried to establish whether we could precede this date a
little bit before discharge, but it appears that you cannot
precede it too much.


                               
So you cannot do it at day 3 or day 4, when patients are not
stable. Because then you may expect a rise in proBNP again before
discharge, and then you already ran the rise patients to
discharge. So we decided to do it at discharge. At least 1 or 2
days before discharge, when patients would be clinically stable.
And this definition of clinical stability was important because
there should be one guideline for doctors to say, OK this patient
has been treated well, or not.


Dr Carolyn
Lam:               
Interesting. And so patients were randomized only after clinical
stabilization, though in hospital after an acute decompensation,
right? And then maybe the randomization arms, and the results
please?


Dr Wouter Kok: Yeah, so the patients were randomized about day 7
or 8 after clinical stabilization, and day 3, but also patients
at day 9, but when they were stable, they were randomized. And
then the proBNP was measured, and when it was not reduced more
than 30% they were guided. And when they were reduced more than
30% they were not guided but they were made ready for discharge.


                               
So this was the randomization group. And the conventional group,
the NT-proBNPs were measured at the randomization, and also at
discharge, but nothing was revealed to the doctors. So it was
only as a comparison for example, in the number of days necessary
to wait before discharge, if this would influence the results.


                               
The main finding is that the end point was negative for total
mortality after 6 months, in combination with heart failure
readmissions. So there were about 36% end point in both groups.


Dr Carolyn
Lam:               
Yeah Wouter, you know, we've just come from the guided trial that
was so soon neutral and infect, ended early and that was in the
chronic heart failure setting so very different from what you
tested in PRIMA II. Congratulations first of all for a
beautifully done study.


                               
But may I just ask, because in guided it was mentioned repeatedly
that perhaps even the control arm was treated so well because
these were such specialized centers. So what kind of centers took
part in PRIMA II?


Dr Wouter Kok: We started at centers in Amsterdam, they were all
very well educated in heart failure treatments, and all were
using proBNP before the study started, so they were experienced
in interpreting proBNPs. Because we had too little centers, and
the inclusion rate was not so fast, then we asked other centers
to participate, and we asked 2 for instance in Barcelona and
Porto in Portugal, which helped us to complete the trial.


Dr Carolyn
Lam:               
Oh that's really nice. And the design is really quite special,
and I'm so appreciative that you took the time to explain that
they were randomized only when stabilized.


                               
Biykem, what do you think of that?


Dr Biykem
Bozkurt:         It's a
fascinating trial, I have to congratulate Wouter and his
colleagues. The number one very important finding I think is,
about two-thirds of the patients before randomization are able to
achieve reduction of NT-proBNP more than 30%. So subsequent to
that in the guided therapy we're able to achieve maybe an
incremental additional 15% adding to about, I think 80% of the
patients initially randomized to the NT-proBNP arm. Achieving a
reduction more than 30%. So overall, if the patient's naturally
before randomization, achieve a reduction NT-proBNP, two-thirds
of the time, pushing it further, trying to achieve a further dry
state, by randomization does not appear to make any changes in
readmission rates, or mortality at six months.


                               
So this very important finding is the majority of the patients on
conventional strategies are able to be decongested and achieve
clinical stability. Now the other important finding is, I think
about 17-20% of the patients regardless of what we do, do not
demonstrate this significant drop in their NT-proBNP levels.
Which I call as a non-responder team, which is a fascinating
group of individuals. So we have the yin-yang, individuals may
actually demonstrate that they're responsive. And when they're
responsive, then the majority of the patients do demonstrate a
reduction by more than 30%, and even if we push it further by
targeted therapies, don't make a difference in outcomes.


                               
About 17-20% regardless of what we do, do not respond, and from
former studies we know that those patients are associated with
worse outcomes. The other important finding I think, is what
changed in the study? What medications, what therapies were
changed? It was fascinating from Wouter's group to recognize that
there was a little, significant, but a little increase in the ACE
admission prescription. But there was also an interesting finding
in the guided therapy, that the beta blocker used was slightly
lower.


                               
That raises a question of if we were to just chase the numbers,
meaning try to just target therapies according to the NT-proBNP
levels, whether we would see some unintended consequences such as
reduction in medications, just because the numbers may be going
in one way or the other. This is acknowledged in Lynne Warner
Stevenson's editorial that will be accompanying the paper. And
the editorial is very nicely titled "Getting to Dry". So I found
that fascinating to recognize that the therapies, when especially
the conventional arm is treated well, did not differ.


                               
As was the case in the guided trials. When you treat the patients
very well, as was seen in this trial, there was not much of a
difference. But again trying to treat a number by targeted
therapies may not result in all the optimization that as we
envisioned to see. And the third concept is the length of stay,
of course in the U.S. is a major issue, and I do realize when
we're trying to treat a number, sometimes the length of stay may
end up being longer. And I do realize that perhaps in the
targeted therapy group, the length of stay was a little bit
longer, maybe Wouter can comment on that.


                               
But overall it didn't result in any change in outcomes, or was
not associated with any of the outcomes. So that was also an
interesting finding. Because we tend to focus a lot on length of
stay, but interestingly I guess by secondary analysis, there was
no association with the clinical outcome.


Dr Carolyn
Lam:               
Wouter, would you want to comment the length of stay concept?


Dr Wouter Kok: Well it's indeed in the guided group, and the
randomized group who were trying to attain the 30% NT-proBNP
reduction, the length of stay was longer. Something about 11
days, compared to those who did not need guiding was about 8
days. Still long compared to U.S. standards, but it was the same
in the conventional group, so about 9 days is respective of
whether they reached a 30% reduction or not.


                               
So here is the clinical experience. So the patient cannot tell
whether he is reduced more than 30%, and the doctor isn't able to
tell either. Because then the admission would have been longer
probably. But trying to lower the 30% more, has some effect.
There's little effect, but it has some effect. And then they have
to do a sort of economic analysis, is 3 days longer in hospital,
is it worthwhile to do that compared to for example reduction in
admissions that you receive? This is a small population, only
one-third of the patients who need guiding, and more than half of
them you will reach somewhat more reduction than if you don't try
at all.


                               
So for us, that is the main result of the trial, if there is a
signal, then it is still possible to do something, and the other
remark about whether you increase or decrease medication, that's
something that was discussed in the guided study too. So what is
the best for the patient, is that the maximum medication or not,
and we see for example, that if we reduce beta blockers, in some
patients then some will improve in their functioning and also in
the BNP.


                               
So it's not always necessary to increase and increase medication.
So that was also some signal that we tried to do some more
research in. What is the target? Is the target a guideline,
saying that more medication is better? Or is the target itself
for proBNP a possibly better target than that?


Dr Biykem
Bozkurt:         And the
other interesting finding for that, there were no differences in
chemo concentration levels in the guided versus non-guided
groups. And last point that I wanted to make is the larger BNP
reduction was amongst the individuals who did not require any
guidance in successfully guided versus unsuccessfully guided,
compared to those who did not need the guidance.


                               
Those who were able to achieve the more than 30%, when you look
at the magnitude, meaning amongst the individuals who are going
to naturally respond to therapy, the natural responders, the
decrement, or the decrease in the BNP levels are larger, than
those ones we're trying to push. So that was another interesting,
fascinating ... I was almost thinking whether that in the future
we should look at responsiveness of patients, if we see they're
responders then try to target their therapy or not.


                               
So in a sense the non-responders, they now respond regardless of
what we do. Responders may be gaugeable or titratable, or maybe
with the precision respond to targeted therapies that almost have
a dichotomous approach. What do you think about that Wouter?


Dr Wouter Kok: I say yeah we made a big mistake in thinking that
more than 30% for patients who still needed guiding would be the
same as rating the more than 30% without guiding. But the
difficulty you have in reaching the 30% is already indicative
somewhat less increase in prognosis than you will reach it
spontaneously.


                               
So we have to adapt our numbers for the trial, so it is
recalculation that how many patients we would need to be
successful in our trial, and that would be 600 patients in every
arm, and then even then, you have to recalculate some of the
effects that you will have to reach them. Perhaps the mid-range
risk group is a better risk group to target than the highest risk
group. That's something that we have to think about too.


Dr Biykem
Bozkurt:         I think
we will probably need to focus on individualization, I almost
feel as though we will need to learn from the cancer trials, and
see whether we could try to target rather than you know the
population based clinical trials, trying to do the targeted
therapies. Maybe fine tune the ability to precisely target, and
of course that requires a little bit more layering of the markers
and or a signal that we're going to be profiling in the
individual.


                               
So I don't think it's the end of targeted therapies, perhaps
requiring a little bit of a more precision, and maybe
individualization. But I am fascinated by first realizing it's a
responder, and then maybe trying to accelerate and or optimize
therapy, perhaps especially when we are forced or driven by
administrative concepts such as length of stay or others. So
making sure that maybe these variables, these biomarkers may help
us recognize that maybe we haven't achieved that appropriately
dry state yet.


                               
But those all need to be determined, of course, by future trials,
so far targeted therapies both in the acute and in the chronic
does not seem to result in implementing outcomes.


Dr Wouter Kok: Well and the next step for us is to try and think
how can reduce proBNP in all patients, we tried it with
medication, but didn't do that much of catheterizations for those
who were ... there were 50% of patients who were ischemic so why
don't we do much of these catheterizations now days. So that's
something we're thinking about how can we improve these patients?
What are we missing?


Dr Carolyn
Lam:               
Yeah, if I could add my two cents. So Wouter mentioned finding
the right therapies that can effectively reduce NT-proBNP safely,
and well you mentioned choosing the right patients to use this
in. And if I may, you know, just adding perhaps the right
settings as well. Because it's well known that not all of us take
care of heart failure patients the same way. And maybe there are
settings where having a number to guide us may be more useful
than others. But what do you do? You know, we wait for more data,
but in the meantime, just congratulations. Heartfelt, heartfelt
congratulations Wouter for a beautiful study, thank you so much
for the privilege of publishing it in Circulation.


                               
Thank you for being on this podcast, and listeners don't forget
to tune in again next week.