Circulation February 04, 2020 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 Centre and Duke National University of Singapore.


Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley
Heart Center at VCU Health in Richmond, Virginia.


Dr Carolyn Lam: Greg, this issue is full of super interesting
papers, many of which were presented as late-breaking
presentations at the American Heart Association, like the feature
paper that sacubitril/valsartan across the spectrum of ejection
fraction in heart failure, where this was really analyzed across
the landmark PARADIGM and PARAGON trials. I'm sure everyone's
looking forward to hearing about it, but before we talk about
that, I want to share some more very interesting results from a
very important trial, the REDUCE-IT trial.


So, as some background, some trials have found that patients from
the United States derive less benefit than patients enrolled
outside the United States. And this was the reason that there was
a pre-specified subgroup analysis of the REDUCE-IT trial, which
really is the reduction of cardiovascular events with icosapent
ethyl-intervention trial, and this analysis was conducted to
determine the degree of benefit of icosapent ethyl in the United
States.


So, Greg, do you remember what the REDUCE-IT trial was about?


Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized
8,179 statin-treated patients with triglycerides between 135 and
500 milligrams per deciliter and LDL cholesterol levels between
40 and 100 milligrams per deciliter and a history of
atherosclerosis or diabetes to Icosapent Ethyl, four grams per
day or placebo. And the primary endpoint, I believe, was
cardiovascular death, nonfatal myocardial infarction, non-fatal
stroke, coronary revascularization or hospitalization for
unstable angina. Hah!


Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had
a cheat sheet answer.


Dr Greg Hundley: All right, Carolyn, tell us now what did
REDUCE-IT USA find?


Dr Carolyn Lam: This was from a corresponding author, Dr Deepak
Bhatt, from Brigham and Women's Hospital Heart and Vascular
Center, and his colleagues and they found that in the United
States Icosapent Ethyl at four grams a day produced large and
significant reductions in multiple ischemic endpoints including
cardiovascular death, myocardial infarction, stroke, coronary
revascularization, and hospitalization for unstable angina.
Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl
provided a statistically significant 30% relative risk reduction
and a 2.6% absolute risk reduction in all-cause mortality. The
risk benefit profile of Icosapent Ethyl was highly favorable with
an overall safety and tolerability profile virtually identical to
placebo.


Dr Greg Hundley: Wow, Carolyn. So, this does have important
implications for us in the US, very nice. Thank you for that
lovely quiz. So, Carolyn, I'm going to switch now and talk about
a paper from Roddy Walsh from Amsterdam in the Netherlands. In
this study, the investigators defined the frequency of rare
variation in 2,538 patients with dilated cardiomyopathy across
protein-coding regions of 56 commonly tested genes and compared
this to both 912 confirmed healthy controls and a reference
population of 60,706 individuals to identify clinically
interpretable genes robustly associated with dominant monogenetic
dilated cardiomyopathy.


Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they
find?


Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12
genes potentially explain 17% of cases in the outpatient clinical
cohort representing a broad range of adult patients with dilated
cardiomyopathy and 26% of cases in the diagnostic referral cohort
enriched in familial and early onset dilated cardiomyopathy. And
so, practically speaking, by analyzing two dilated cardiomyopathy
cohorts with distinctive patient profiles, the authors were able
to comprehensively evaluate the genetic basis of dilated
cardiomyopathy and identify variant classes that were
particularly associated with early-onset disease. By restricting
analyses to validated and interpretable genes and variant
classes, the authors hoped in this study to increase the accuracy
and reduce the uncertainty associated with genetic testing in
dilated cardiomyopathy.


Dr Carolyn Lam: Very nice, very practical information. Well, my
next paper is, I have to admit a super favorite topic of mine,
and that is sex differences in heart failure. Now as a reminder
to everybody, women represent over half of patients with heart
failure with heart failure preserved ejection fraction, and there
are multiple effective drug and device therapies for HFrEF, or
heart failure reduced ejection fraction, but none approved for
HFpEF. Thus, there is a greater so-called failure therapeutic
deficit in women compared to men. So, does the recently presented
PARAGON trial provide answers?


Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON
trial. Maybe tell us a little bit about that first to help us get
oriented.


Dr Carolyn Lam: I would love to. So PARAGON compared
sacubitril/valsartan with valsartan in patients with HFpEF. The
primary outcome was a composite of first and recurrent
hospitalizations for heart failure and death from cardiovascular
causes, and the trial overall narrowly missed this primary
outcome. However, an intriguing result in PARAGON was a
significant sex-by-treatment interaction. And this was explored
further in the current pre-specified subgroup analysis of
outcomes by sex, which was reported by John McMurray from
University of Glasgow and his colleagues.


Dr Greg Hundley: Ah, so I'm interested. What was this
interaction?


Dr Carolyn Lam: Ah, so here is how the interaction work. Now,
remember this was multi-variably adjusted significant in a
pre-specified large subgroup of PARAGON. And what we found was
that as compared with valsartan, sacubitril/valsartan seem to
reduce the risk of heart failure hospitalization more in women
than in men. Now, while the possible sex-related modification of
this effect of treatment has potential explanations, the current
study really cannot provide a definitive mechanistic basis for
this finding.


Dr Greg Hundley: Very interesting. So, perhaps then, in heart
failure preserved ejection fraction, sacubitril/valsartan could
be very helpful in women.


Dr Carolyn Lam: Yes, and perhaps especially those with each
ejection fraction in the lower ejection fraction range. And that
is coming up in our future discussions, so let's not preempt it.
You got another paper, Greg?


Dr Greg Hundley: Absolutely, Carolyn. My next paper is from
Professor Irene Lang at the Medical University of Vienna, and
it's related to microvascular disease and chronic thromboembolic
pulmonary hypertension and hemodynamic phenotyping and
histomorphometric assessments. So, Carolyn, pulmonary
endarterectomy is the gold standard for treatment of patients
with operable chronic thromboembolic pulmonary hypertension.
However, persistent pulmonary hypertension after PEA or
endarterectomy remains a major determinant of poor prognosis.


Dr Carolyn Lam: Ah, so are there any possible solutions to this?


Dr Greg Hundley: Well, Carolyn, today it is thought that a
concomitant small vessel arteriography in addition to major
pulmonary artery obstruction may play an important role in the
development of persistent pulmonary hypertension and survival
after pulmonary endarterectomy. One of the greatest unmet needs
in the current preoperative evaluation is to assess the presence
severity of small vessel arteriopathy.


Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the
authors do? What they find?


Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with
49 of them receiving lung wedge biopsies for validation. So, in
analyses incorporating receiver operating characteristic curves,
pulmonary vascular resistance measures and larger arterial
upstream resistance beds predicted persistent pulmonary
hypertension after pulmonary endarterectomy, and certain values
identified patients with poor prognosis after endarterectomy.
Therefore, perhaps this form of analysis could be helpful in
establishing prognosis in these patients and perhaps suitability
for future interventions.


Dr Carolyn Lam: Wow, very interesting. Well, we were saying this
issue's full of very important papers, and that also includes
research letters. There's a research letter by Dr Cannon talking
about evaluating the effects of canagliflozin on cardiovascular
and renal events in patients with type 2 diabetes and chronic
kidney disease according to baseline HbA1c, including those with
an HbA1c less than 7%. And these are very interesting results
from the CREDENCE trial that was also presented at the American
Heart Association.


There's a research letter by Dr Jackevicius on the population
impact of generic valsartan recall in Ontario, Canada, that
really highlights the potential burden and risks associated with
recalls of chronic oral medications used by large populations.
And in Cardiology News, Bridget Kuehn talked about cardiovascular
risk biomarkers, high-sensitivity cardiac troponin T and
NT-proBNP and talked about how these two biomarkers may help
clinicians stratify which patients may benefit the most from
therapies for hypertension or diabetes. And this was according to
a pair of studies presented, again, at the American Heart
Association.


Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've
got just a couple more papers to discuss. There's a perspective
piece from Dr Ben Levine and colleagues from UT Southwestern that
discusses whether a simple physical exam and maneuvers could
actually supplant tilt-table testing. He provides arguments as to
whether we should continue with tilt-table testing given the high
rate of false positives. And then lastly, from the Mailbag, Dr
Shuyang Zhang from Peking Union Medical College Hospital and the
Chinese Academy of Medical Sciences provides a letter to the
editors regarding a prior publication on the clinical
applicability of the awareness of androgen-deprivation therapy's
effects on ventricular repolarization. And Dr Joe-Eli Salem from
Vanderbilt University provides his response.


Well, Carolyn, how about onto that feature?


Dr Carolyn Lam: Let's go. Our feature discussion today is all
about left ventricular ejection fraction. Ah, that measure we
both love and hate in the world of heart failure, I think. And
this paper is truly remarkable, in my opinion. It is the look at
the effect of sacubitril/valsartan across the spectrum of left
ventricular ejection fraction in the PARADIGM and PARAGON trials.
And I'm just so pleased to have none other than the first and
corresponding author, Dr Scott Solomon, from Brigham and Women's
Hospital and Harvard Medical School, as well as our Senior
Associate Editor, Dr Biykem Bozkurt, from Baylor College of
Medicine as well.


Scott, could you start by telling us about this analysis and why
the opportunity to do such a special analysis in this paper?


Dr Scott Solomon: This was a really fantastic opportunity
because, as you know, we did these two trials, PARADIGM and
PARAGON, not at the same time but essentially in series. PARADIGM
was a trial of patients with heart failure reduced ejection
fraction, so ejection fraction of 40%, and PARAGON was a study of
patients with heart failure with preserved ejection fraction. And
the interesting thing is that, with the exception of ejection
fraction, the criteria for enrolling patients in these trial was
virtually the same.


In other words, we enrolled patients with signs and symptoms of
heart failure, some elevation in natriuretic peptides, and we
followed them. So it's really an extraordinary dataset of 13,195
patients in whom we can look at heart failure across that full
spectrum of ejection fraction. We haven't been able to do this
really since the CHARM study, which enrolled about 8,000 patients
across the spectrum of ejection fraction. And it gave us an
opportunity to look at a number of things including the effect of
sacubitril/valsartan across that full spectrum of ejection
fraction.


Dr Carolyn Lam: Great. And, Scott, you want to tell us what you
found?


Dr Scott Solomon: When we pooled 13,195 patients, and by the way,
this was a pre-specified analysis that we had decided to do prior
to unblinding PARAGON. We see that if we put them all together,
all these patients together, and just treat them as one group, we
see that for every endpoint that we looked at, whether heart
failure, hospitalization and cardiovascular death, cardiovascular
death, all-cause mortality, whether we look at the time to first
event endpoints or the total number of heart failure
hospitalizations, we see a significant benefit in patients
receiving sacubitril/valsartan compared to patients receiving
either enalapril in the PARADIGM study or valsartan in the
PARAGON study.


Now, what we also saw though, and this is probably most
important, is that there appears to be an attenuation of the
treatment effect as ejection fraction rises. Now we know that
patients with higher ejection fractions tend to have a lower
frequency of these events such as heart failure, hospitalization
and cardiovascular death. But we also see here that as ejection
fraction goes up that the benefit of sacubitril/valsartan appears
to wane, especially when you get over about 60, an ejection
fraction of about 60%. We've looked at this in categorical ways
and also looking at a continuous spline analysis throughout the
entire spectrum.


Dr Carolyn Lam: Yeah, I love that, and I just need to point every
listener right now to figures 3 and 4 of your paper. I have a
feeling we're going to be seeing these figures in a lot of talks
and cited everywhere. Biykem, could I bring you in on this? What
are the implications of something like this?


Dr Biykem Bozkurt: The interesting findings from the pooled data
are, first, support of what we had seen in PARADIGM, meaning the
lower the EF, the more the benefit or the higher the benefits.
And as we had seen in PARAGON, which did not show an improvement
in the combined endpoint with treatment with sacubitril/valsartan
in patients with heart failure with preserved ejection fraction.
In the pooled analysis as the EF got higher, there didn't seem to
be any benefit, but the interesting, perhaps group of patients
that the pooled analysis allowed us to have a deeper dive into
was heart failure with mid-range EF. And we can crudely perhaps
define this as ejection fraction between 40 and 50%. And by
certain analyses, which again this is in the post-hoc and also in
a continuous analysis and a specific analysis and a cubic spline
analysis, it appeared that the benefit extended into those
individuals with mid-range ejection fraction.


Again, we need to keep several points in consideration. One is
ejection fraction can vary over time and is not a very precise
measurement. There's definitely inter-reader as well as
intra-reader variability and is not a good mayor of contractile
performance. And we tend to actually have a significant amount of
a specific infiltrative cardiomyopathies in that EF range, which
tend to be excluded from usual clinical trials. And with that
caveat, having kept this in mind, it's also important to
recognize from cohorts and population-based studies, about 10 to
20% of our patients currently reside in that have HeFmrEF or
heart failure with mid-range EF status. And thus the findings are
intriguing, hypothesis generating and also encouraging that we
may see perhaps benefits with RAS antagonism in individuals that
do have LV systolic dysfunction.


And probably, if this is persistent and a clear reflection of a
phenotype that reflects itself as reduced ejection fraction,
probably the patient may benefit. Again, these results may need
to be supported by future studies, and also we need to keep in
mind that infiltrative cardiomyopathies, such as amyloidosis or
sarcoidosis or others, were not included in these studies.


Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott.


Dr Scott Solomon: Carolyn, I agree with many of Biykem's points.
I think that this middle range, and you and I kind of coined that
term, heart failure with mid-range injection fraction, a number
of years ago. The problem, of course, is knowing where that range
exactly is, and I think that some people believe it's 40 to 50%,
but we know that these are very arbitrary cutoffs. The data from
the pooled analysis in PARAGON, in particular, do suggest that
the patients who have evidence of some degree of left ventricular
dysfunction seem to benefit from sacubitril/valsartan. Now, this
is not a completely novel finding because we saw that in patients
who received candesartan in the CHARM study and in patients who
received spironolactone in the TOPCAT trial that the greatest
benefit was observed in the patients in that middle range of
ejection fraction, again, below what we would normally consider
the normal range. Normal might be 55% or 55% in men and women.


And that gets me to the other thing that I think is really worth
mentioning here, which is that we found that the range of
benefits does vary by sex, so that women seem to derive greater
benefit to a higher ejection fraction than men. We can see that
here in figure 4, looking at these two curves that there really
does appear to be a difference between men and women. Women
overall derive greater benefit in the PARAGON study, it appeared
than in men. So I think that the fact that there's biologic
plausibility here that patients with cardiac function that is not
normal seem to benefit from therapies that we know benefit
patients with heart failure with reduced ejection fraction, that
patients with ejection fraction that was in this middle range
also do appear to benefit from sacubitril/valsartan as we think
they did in other studies of other agents that we know work in
patients with lower ejection fraction.


Dr Carolyn Lam: Indeed, Scott. You've just pointed out my
favorite figure of all, that figure 4. You know how I feel about
sex differences and pointing them out. I would love to ask for
Biykem's thoughts on it.


But in the meantime, just to emphasize how important findings
like these are because it makes us question the cutoffs that we
use to define heart failure groups, makes us question is midrange
more mildly reduced ejection fraction like we're also writing
about. And I think really makes us question, for example, the
2016 ESC Guidelines that say that mid-range ejection fraction
should be treated like preserved ejection fraction. Well, maybe
this could be really game changing here in that we actually think
now this group should be treated more like reduced ejection
fraction. So, really, congrats on this incredible paper.


Biykem, what do you think of those sex differences? I have to
point out, I love your editorial, which everyone should read.


Dr Biykem Bozkurt: It's very intriguing, very interesting point.
The benefits from sacubitril/valsartan was interestingly similar
for both sexes at lower EF levels. Women's benefit compared to
men's benefit for low EF was comparable; they were not different.
But women seem to confer a benefit at higher EF ranges and by
this continuous analysis all the way up to the 50 to 60% range,
which is very, very interesting. And as to what were the
phenotypes of the women compared to men at that range, women were
older, had more obesity, less CAD, and of course, at all ranges
they usually tend to have a higher baseline EF.


And, interestingly, even though we may state that maybe women may
have more systolic dysfunction at higher EF quantification ranges
or may have a different phenotype than men for HFpEF, maybe a
more clear or pure heart failure phenotype, heart failure with
preserved EF phenotype than men. The interesting things were the
NT-proBNP levels were lower for women, though the symptoms were a
little bit higher, and the benefit seemed to be higher even
though the KCCQ scores were not different. So, even though we did
have lesser sort of filling pressures for women and perhaps other
surrogates for improvement did not seem to differ, and also
biological metabolites, such as urinary cyclic GMP to creatine
ratios, were not different in women.


So, if we were to think of whether there were biological
differences, whether there were differences in NT-proBNP levels
or delta changes over time or the urinary cyclic GMP levels, they
were not different in women versus men. So, we still have many
other substrates for neprilysin. I mean there could be other
substrates, such as adrenomedullin or bradykinin or substance P
that may be differentially metabolized for women compared to men,
and we don't have the data on those. But again, it's very
interesting to see this upper scale of EF benefit being higher in
women compared to men. So, we don't have any other either
biological or other surrogate markers for benefit for women,
either for the HFpEF or HFrEF being than different than men.


Dr Carolyn Lam: Biykem, I just love the way you so carefully
dissected that, and it's so reflected in that editorial that you
and Justin Ezekowitz wrote entitled Substance and Substrate. So
I'm going to make sure all readers look for it. We could go on
forever. I mean I just was struck, that figure 4, also is really
similar if we look at what normally ejection fraction is for
women versus men with increasing age. We also see that women are
supposed to have higher ejection fractions as they age compared
to men at any age. So it's just intriguing to me, but you're
right. I think hypothesis generating.


Scott, I'm going to give you the last word.


Dr Scott Solomon: I'm pretty confident that there are biologic
differences between men and women. I just don't necessarily know
what they are with respect to heart failure, preserved ejection
fraction, but I think we're going to be spending a lot of time
and effort trying to sort this out. We're pretty confident that
the finding of a weighing of benefit with ejection fraction is a
real one and that the benefit in this middle range is an
important one to pay attention to because I agree with what you
said, Carolyn. If we had been thinking about heart failure with
reduced ejection fraction as something that went up to a higher
level 25 years ago, we would probably have treated a lot more
patients with therapies that we now know to benefit patients with
heart failure with reduced ejection fraction. So, I think this
data helps us rethink how we parse up heart failure and
hopefully, ultimately will lead to changes how we treat patients.


Dr Carolyn Lam: Well, listeners, you heard it right here on
Circulation on the Run. Thank you so much, Scott and Biykem, for
joining us, and don't forget to tune in again next week.


Dr Greg Hundley: This program is copyright The American Heart
Association 2020.