Circulation May 07, 2019 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:            
And I'm Greg Hundley, Associate Editor as well, at Circulation,
and Director of the Pauley Heart Center in Richmond, Virginia at
BCU Health.


Dr Carolyn
Lam:               
Now, we've heard of the PIONEER heart failure trial and that is a
sacubitril/valsartan in acute decompensated heart failure. A very
important trial, but was powered on the surrogate outcomes. Now,
in today's issue though, we're going to hear a little bit more
about the clinical outcomes from the PIONEER heart failure trial,
a very important paper, a very important discussion coming right
up. Greg, what paper do you have to start us off?


Dr Greg
Hundley:            
Carolyn, I've got another favorite of our little discourse, your
next Carolyn's Quiz. Except this time it's essay format, so it's
open ended questions. And so here's my question to you. What
paper addresses an important issue related to hookah inhalation.
So Carolyn, do you know a little bit of the origins of hookah and
then how does its use compare to e-cigarettes or conventional
cigarettes?


Dr Carolyn
Lam:               
Oh, okay. Well at least the quiz wasn't asking if I smoke hookah.
Okay, so hookah, that water pipe smoking pipe, fun stuff. I
think, is it a Middle Eastern origin? And frankly I don't know of
any data to say whether it is better or worse than cigarette
smoking.


Dr Greg
Hundley:            
Yeah, you're exactly right. Hookah, it's a longstanding practice,
primarily confined to men from the Middle East. But in the 1990s
it was introduced with fruit flavored pre-packaged tobacco
products and that ignited a sharp uptake of hookah smoking by
young women and also men in the Middle East, and then a migration
to our western culture. Now, believe it or not, in the United
States and in the United Kingdom, hookah has a prevalence of 15%
to 25% among university students. And today, twice as many
secondary school children smoke hookah as they do cigarettes, and
more adults have tried or currently use hookah than electronic
cigarettes.


                                               
So, what does this article discuss? Well, it focuses on hookah
inhalation byproducts, because the charcoal traditionally is used
to heat the hookah tobacco in the water pipe, hookah smoke
delivers tobacco toxicants and nicotine plus charcoal combustion
products, not only carbon rich nanoparticles and oxidants that
may destroy nitric oxide and impair endothelial function, but
also large amounts of carbon monoxide, a putative vasodilator
molecule that will dilate the arteries independent of endothelial
dysfunction.


                                               
So, this study enrolled three groups of patients. First, there
were 30 26-year-old hookah smokers. Second, there were 20 in
which the flavored hookah tobacco product was heated
electrically, not by the charcoal. And then finally, 15 age
matched cigarette smokers who smoked one cigarette.


Dr Carolyn
Lam:               
Wow, what was the result?


Dr Greg
Hundley:            
Unfortunately, nicotine levels increased similarly with all types
of smoking. Now, flow-mediated arterial dilation, a marker of
endothelial function, did not become impaired after smoking
charcoal heated hookah, but instead increased by about 43%. In
contrast, flow-mediated arterial dilation decreased by 27% after
smoking electrically heated hookah, compared to the decrease
after cigarettes smoking. For hookah smokers, vasodilation
increased 138% times more than in the other two groups.
Therefore, the acute endothelial dysfunction was masked by those
high levels of carbon monoxide that are generated from the
charcoal. Remember, carbon monoxide is a very potent vasodilator.


                                               
What do we take away from this, Carolyn? With respect to large
artery endothelial function, smoking hookah is not as harmless as
discussed by an excellent editorial by Naomi Hamburg from the
Whitaker Cardiovascular Institute at Boston University School of
Medicine.


Dr Carolyn
Lam:               
Oh wow.


Dr Greg
Hundley:            
You know, importantly, the carbon monoxide is blocking our
ability to appreciate endothelial dysfunction with traditional
measures. So Carolyn, what about your article?


Dr Carolyn
Lam:               
Going from smoking to exercise, this one looking at intensity of
exercise that should be performed after heart transplantation.
This is a study from Dr Nytrøen and colleagues from Oslo
University Hospital in Norway, and they performed a multicenter
prospective randomized controlled trial of 81 patients at a mean
of 11 weeks only after a heart transplantation. And these
patients were randomized to either nine months of high intensity
training, which is a four by four minute intervals at 85% to 95%
of peak effort, or to moderate intensity continuous training
defined as 60% to 80% of peak effort. And the primary outcome was
the effect of high versus moderate intensity exercise on the
change in aerobic exercise capacity assessed as VO2 peak.


Dr Greg
Hundley:            
So, what did they find here?


Dr Carolyn
Lam:               
First, it's important to note that it is the first study to test
this and to show that the effect of nine months of high intensity
training in de novo recipients of heart transplants produced a
clinically meaningful, significantly larger increase in peak VO2
and muscular exercise capacity compared to moderate intensity
continuous training. Importantly, the study also showed that the
approach was safe with high adherence and high completion rates.
96% of patients completed the study, during which time the
exercise adherence for both groups was 81% and there were no
serious exercise related adverse events.


Dr Greg
Hundley:            
Wow. So it looks like we've been hearing about that in training
and athletes. Are there any caveats?


Dr Carolyn
Lam:               
Yeah, and that's an important question. High intensity training
in this study required one to one interaction with physical
therapists, and of course that's not feasible in most cardiac
rehabilitation programs. It also requires motivated, medically
stable patients who can maintain high exercise intensity ranges.
So further research is really required to determine if these
initial improvements at peak VO2 and muscular endurance persist
in the long-term period post heart transplantation and, of
course, whether they're associated with favorable clinical
outcomes. All this is discussed in a beautiful editorial entitled
"Can a Hit Result in a Home Run?" by Mark Haykowsky, Wesley
Tucker, and Peter Brubaker.


Dr Greg
Hundley:            
Carolyn, that's fantastic. In my next study, I'm going to switch
over and discuss diabetes and the age of diagnosis of type two
diabetes and its association with cardiovascular mortality and
risk findings from the Swedish National Diabetes Registry. The
study was conducted between 1998 and 2012 and the analysis cohort
comprised 318,083 patients with type two diabetes mellitus
matched with just under 1.6 million controls. Participants were
followed for total mortality, cardiovascular mortality, coronary
heart disease, acute myocardial infarction, stroke, heart
failure, and atrial fibrillation.


Dr Carolyn
Lam:               
Huge study. Important question. What did it show?


Dr Greg
Hundley:            
Over a median follow up of about five and a half years, patients
with type two diabetes diagnosed under the age of 40 years had
the highest excess risk for the most common cardiovascular
related outcomes. All risk attenuated progressively with each
increasing decade. By the time type two diabetes was diagnosed at
an age greater than 80 years, adjusted hazard ratios for
cardiovascular disease and non-cardiovascular mortality were all
less than one. In addition, survival for those diagnosed beyond
80 years was the same as controls, whereas it was more than a
decade less when type two diabetes was diagnosed in adolescence.


Dr Carolyn
Lam:               
Okay, so Greg, what does this mean for us clinically?


Dr Greg
Hundley:            
The observations of this study amplify support for preventing and
delaying type two diabetes onset in younger individuals and
raises questions as to diagnostic strategies, as to whether we
should even screen or implement management strategies for those
individuals that are diagnosed with diabetes beyond the age of 80
years.


Dr Carolyn
Lam:               
Interesting. Well, for my last paper, I have a basic science
paper and this one really provides insights into endothelial
dysfunction. It looks at
S-Adenosylhomocysteine, which is a precursor of homocysteine, and
elevated levels of these are positively associated with the risk
of cardiovascular disease and with development of
atherosclerosis, but its role in endothelial dysfunction has been
unclear. So authors Dr Ling from Sun Yat-sen University in
Guangzhou, China and Dr Ke from Shenzhen Center of Disease
Control and Prevention in Guangzhou, China, these
co-corresponding authors and their colleagues performed a series
of elegant mouse experiments and showed that the inhibition of
S-Adenosylhomocysteine hydrolase resulted in elevated plasma
levels of S-Adenosylhomocysteine, which then induced endothelial
dysfunction via epigenetic upregulation of the p66Shc-mediated
oxidative stress pathway.


                                               
Furthermore, plasma S-Adenosylhomocysteine levels were positively
associated with oxidative stress levels and inversely associated
with flow-mediated dilation and methylation of p66Shc promoters
in patients with coronary artery disease and healthy controls.
So, this study really provides a novel molecular insight into
mechanisms by which this molecule, S-Adenosylhomocysteine, may be
associated with endothelial injury and contribute to the
development of atherosclerosis. So that brings us to the end of
our summaries, Greg. Let's move on to our feature discussion.


Dr Greg
Hundley:            
Welcome everyone to the second half of our presentation where we
have an outstanding interview with David Morrow from Brigham and
Women's Hospital and Dr Justin Ezekowitz from Edmonton to discuss
a letter that we've received, "The clinical outcomes in patients
with acute decompensated heart failure randomized to
sacubitril/valsartan or enalapril in the PIONEER HF trial. David,
can you remind us just a little bit about, first, your New
England Journal study, and then how this letter adds to the prior
findings?


Dr David
Morrow:           
I think it's first worthwhile to place a little bit of context in
that paradigm heart failure trial, which was a preceding trial in
patients with chronic heart failure, who were ambulatory
patients, who had to be tolerating a stable dose of an ACE
inhibitor or an ARB, and could not have had a current acute
decompensation of their heart failure, were randomized to
sacubitril/valsartan versus enalapril with a significant
reduction in major clinical cardiac events with
sacubitril/valsartan. And that finding from that trial has led to
changes in guidelines and clinical practice for patients with
chronic heart failure with reduced ejection fraction.


                                               
But there were several important aspects that still left gaps for
our clinical care, in that because of a run in period in that
trial, so a period where patients had to tolerate
sacubitril/valsartan, the stability of the patients that I just
described, it often left practitioners in the position of caring
for patients who might not meet those inclusion criteria,
particularly those patients who are hospitalized where there is
an opportunity, often, to update their care to be consistent with
current standards and current guidelines. And so we designed the
PIONEER heart failure trial with that in mind, to study
specifically patients with acute decompensated heart failure, all
patients with heart failure with reduced ejection fraction. And
they were randomized within hospital initiation after an initial
period of stabilization to either sacubitril/valsartan or
enalapril in a double blind, double dummy design.


                                               
The primary endpoint for the PIONEER heart failure trial was a
biomarker, so NT-proBNP, and we saw that there was a
significantly greater reduction in
NT-proBNP by four to eight weeks as an average endpoint, by 29%
more with the sacubitril/valsartan versus enalapril. And we also
saw that the adverse events, the tolerability of the two regimens
was similar and the event rates did not differ in the
sacubitril/valsartan group.


                                               
And so that was the primary result of the trial that was
published in the New England Journal of Medicine. We had, in
addition, some exploratory clinical end points, one of which was
a broad composite which included all-cause mortality, the need
for an LVAD implantation, referral for transplantation, heart
transplantation, as well as rehospitalization for heart failure.
And so, what was new in the letter that we have published in
Circulation, is that we specifically looked at the clinical end
points and additional exploratory end points, looking at the
harder composite of cardiovascular death and rehospitalization
for heart failure. And we had particular interest in that because
it's being used as a primary end point that was consistent with
the paradigm heart failure trial that I described in chronic
heart failure. That was really the reason for undertaking this
additional analysis.


Dr Greg
Hundley:            
So how did you define rehospitalization for heart failure and
what did you find?


Dr David
Morrow:           
Rehospitalization for heart failure, we actually used the same
clinical endpoint committee as for the paradigm heart failure
trial and used the same definition, which requires that patients
had clinical evidence of heart failure, which could include both
symptoms as well as biomarker values and evidence of congestion
on physical exam. We needed graphic evidence of pulmonary edema.
Together, they had to have a clinical presentation that was
consistent with heart failure, and then also who have been
hospitalized for the management of that decompensation.


                                               
And so what we found overall was that there was a significant
reduction in cardiovascular death or heart failure with the
sacubitril/valsartan over the eight week double blind study
period, such that it was a 42% reduction in that end point and an
absolute 6% reduction in cardiovascular death or
rehospitalization for heart failure with sacubitril/valsartan
compared with enalapril.


Dr Greg
Hundley:            
And David, looking at these fantastic figures, for listeners,
please take a look at this letter, it looks like the two groups
separated early. Can you suggest a mechanism for why that
might've occurred?


Dr David
Morrow:           
We agree that it does appear that the separation begins early on.
We did not have sufficient statistical power to test individual
hypotheses much earlier time points, but the relative risk
reduction appears homogeneous over that period. And when we look
specifically at 30 days, for example, the relative risk
reductions are comparable. So we do think that observation you
just made is correct and consistent.


                                               
And I think that there's evidence of support for rather early
effects on hemodynamic stress. So we have the primary end point
with NT-proBNP where we saw that there was separation between the
groups that was actually statistically significant on that
continuous end point of a natriuretic peptide value already by
one week of therapy, which was quite remarkable to us. We had
planned as our primary end point the four to eight weeks period
where we had expected, based on previous work, that there would
likely be a reduction in this slightly different population. But
in fact we saw those curves in NT-proBNP separate already by one
week. We've also had subsequent work that we presented in
abstract form looking at other biomarkers such as troponin and
soluble SD2, so biomarkers of wall stress and myocardial injury,
and also seeing reductions in those markers that appear also to
occur early on.


Dr Carolyn
Lam:               
Justin, can we bring you into this conversation here right now?
What do you think are the clinical implications of this
particular research letter and then perhaps of PIONEER in
general?


Dr Justin Ezekowitz:       
Thanks Carolyn, and my compliments to Dr Morrow and the team for
putting this together as a research letter because that's often a
challenge to get to the core information from the study. And I
would, again, draw the listeners to get a look at the figures
that they put together and especially the way in which they
separate early out. And we did ask to be cautious with
statistical power about rehospitalization, but it's quite a
driving factor for the overall end point and one that shouldn't
be lost, because that has the biggest probably clinical
implications, that the curves separate early between the groups
on an ACE inhibitor versus to sacubitril/valsartan. And given
they separate early, one of the clinical implications is, why
wait? So why wait for when people have been outside the hospital
to change the medication but instead use that as an opportunity
when they're in front of you as a clinician to consider switching
them over to a newer therapy and consider what they’ve been on
from the majority of patients being on an ACE inhibitor or an
ARB, but it is the right time when you have them in observation.


                                               
The second observation I would make from this study is that
although this was done in high quality sites and sites that know
how to do clinical research, but also those who take care of
patients that are on high quality medications, the baseline
medication rate use wasn't perfect. So there's dual opportunity
for looking at the baseline medications, which was MRAs and beta
blockers, and use it as opportunity and an implication to use all
the best medications. And in this case sacubitril/valsartan would
be an opportunity.


                                               
My final point would be, I think this study is critical from a
clinician's perspective, as we've seen many biomarker-based
studies where there's a reduction in the biomarker, but the
clinical end point doesn't seem to change so NT-proBNP is great,
but here is the judicated clinical endpoints. So for me, when I'm
treating a patient, that means more to me than the lowering of a
biomarker. We've seen other evidence where that doesn't always
pan out, and so you are confident now that that is the case.


Dr Carolyn
Lam:               
Well put, Justin. And you had a question, didn't you, for David?


Dr Justin Ezekowitz:       
Right. One of the questions I was trying to sort through, and we
couldn't squeeze this fully into the research letter, was there
were some patients who were randomized in the hospital but the
overall PIONEER program allowed for up to 10 days, and when you
look at the patients and when they were randomized and how they
were cared for beginning of the hospital, end of the hostel,
right after discharge, was there any difference that you saw
across the spectrum of outcome?


Dr David
Morrow:           
Actually, the study drug was initiated in hospital for all
patients. We did provide up to 10 days while in hospital for the
outer limits of recruitment into this study because we recognized
that some hospitalizations for acute decompensated heart failure
are quite lengthy, and we wanted to give sites the opportunity to
recruit patients who took longer to stabilize in this study than
others. So it was starting from 24 hours after hospital
presentation up to 10 days as a maximum, but all patients were
initiated in hospital.


                                               
The median turned out to be at 68 hours and at least
three-quarters of patients were recruited and randomized within
98 hours. So the vast majority were early on. Overall, when we
look at the consistency of the effects of the primary end points
of the natriuretic peptide and a broader composite, we did not
see any evidence of heterogeneity based on the timing of
randomization relative to presentation. As you pointed out
earlier, we have to recognize that the numbers do get smaller
across that tier, particularly when we get out to the later
window. Still. I would say that the primary results, almost in
any trial you should always go by the primary result, and we did
not see any heterogeneity to think that there was a different
effect in those who were enrolled early or late.


Dr Carolyn
Lam:               
David, can I just chime in and say again, congratulations on this
great work. Can I go back to one of the points that Justin made a
bit earlier? This being a research letter, could you maybe share
with the audience a bit, what's it like to write and be
constrained to such few words and a single figure?


Dr David
Morrow:           
Well, as Dr Ezekowitz said, it does present a little bit of a
challenge. You have to be very concise. We certainly were
fortunate that we could leverage the primary publication for the
majority of methods and other design elements that we didn't need
to recapitulate. And so I think for, in particular, this type of
research where there was something that we felt was quite
important scientifically with potentially important clinical
implications, but yet still was an additional exploratory end
point that we could express concisely, the research letter was a
very reasonable format to do that.


Dr Carolyn
Lam:               
I couldn't agree more. But Justin, how about from the editor's
point of view? Could you share about the research letter?


Dr Justin Ezekowitz:        My
compliments to Dr Morrow and his team, as I asked him a lot of
questions that required both expanding on the things they had to
say while constricting the number of words at the same time, and
that's a huge challenge to get findings across. So they were able
to meet that challenge. I think one of the key things was really
honing down as to what the key messages are, as Dr Morrow just
alluded to, you can refer to the main complication or a baseline
trial publication for all the other details, but what were the
core things that could be demonstrated in a publication that is
of a limited number of words, tables, or figures. And I think
that's the key is, what is the real hypothesis and question to be
answered. And that's the way we focused on all the efforts. I did
appreciate that it was not easy not to have a lengthy discussion.
So we had a ... in the written discussion we have really just
truncated this down to a few key sentences which summarize the
overall study, so the reader could pick this up and know what the
implications are without actually having to go into a lot of the
detail that we've just been speaking about.


Dr Carolyn
Lam:               
Ah, I love it. And thank you so much for this conversation too.
That helps us go under the hood a little bit. I'm sure everyone
who's listening just wants to pick this up now because it's so
concise, so beautiful to read, and just look at the figure.


                                               
Thank you everyone for joining us today. Don't forget to tune in
again next week to Circulation on the Run.


                                               
This program is copyright American Heart Association 2019.