Circulation October 12, 2021 Issue

Please join author Milton Packer and Associate Editor
Justin Ezekowitz as they discuss the Perspective "Heart Failure
and a Preserved Ejection Fraction: A Side-by-Side Examination of
the PARAGON-HF and EMPEROR-Preserved Trials."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the Journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center.


Dr. Greg Hundley:


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


Dr. Carolyn Lam:


Greg, it really is so great to be back with you chatting about
the papers here in the Journal. Thank you for going solo and for
just being the greatest partner on earth. Thank you for that. For
everyone listening in, we are back with some gusto and especially
with this feature discussion today. You are not going to want to
miss it. We are talking to Dr. Milton Packer as well as Dr.
Justin Ezekowitz. We are going to compare PARAGON and
EMPEROR-Preserved trials in heart failure with preserved ejection
fraction. A really interesting discussion you're not going to
want to miss, but now let's start with some papers in today's
issue. I'd like to start, please.


Dr. Greg Hundley:


You bet.


Dr. Carolyn Lam:


Greg, you know the optimal duration of antiplatelet therapy in
patients with high bleeding risk with or without oral
anticoagulation after coronary stenting? Well, that still remains
a question. Today's paper is a pre-specified subgroup analysis of
the MASTER DAPT trial and reports on the outcomes of patients
with or without an oral anticoagulation indication in this study.


Dr. Greg Hundley:


Right, Carolyn. Remind us. What was the MASTER DAPT trial? What
did it test?


Dr. Carolyn Lam:


Ah. MASTER DAPT investigated an abbreviated or one-month versus a
non-abbreviated or three to 12-month dual antiplatelet therapy
and a stopping of antiplatelet therapy at six months strategy
after coronary stenting in an all-comer population at high
bleeding risk.


Dr. Greg Hundley:


Carolyn, what did this subgroup analysis of outcomes in patients
with and without oral anticoagulation show?


Dr. Carolyn Lam:


At 12 months of follow-up, ischemic and net risk did not differ
with abbreviated versus non-abbreviated anti-platelet regimens in
both subgroups, although significantly fewer clinically relevant
bleeding events occurred in the group without an oral
anticoagulation indication. Whereas only numerically fewer
bleeding events occurred in the group with an oral
anticoagulation indication that did not reach statistical
significance. This subgroup analysis from the MASTER DAPT trial
really adds additional evidence that dual antiplatelet therapy
beyond one month in patients with or without an indication for
oral anticoagulation really has no benefit and only increases
bleeding risk.


Dr. Greg Hundley:


Oh, very important finding, Carolyn. Great research. Well,
Carolyn, how the extracellular matrix microenvironment modulates
the contractile phenotype of vascular smooth muscle cells and
confers vascular homeostasis really remains elusive. Thus, these
investigators led by Professor Wei Kong at Peking University
applied protein-protein interaction network analysis to explore
novel extracellular matrix proteins associated with the vascular
smooth muscle cell phenotype.


Dr. Carolyn Lam:


Huh. Interesting. What did they find, Greg?


Dr. Greg Hundley:


Right, Carolyn. By combining an in-vitro and an in-vivo genetic
mice vascular injury model, they identified nidogen-2, a basement
membrane glycoprotein, as a key extracellular matrix protein for
maintenance of vascular smooth muscle cell identity. Nidogen-2
exerted its protective function via direct interaction and
modulation of Jagged1-Notch3 signaling.


Dr. Carolyn Lam:


Wow! Nidogen-2 and Jagged1-Notch3. I always learn so much. What
are the clinical implications, Greg?


Dr. Greg Hundley:


Right, Carolyn. Perhaps targeting nidogen-2 to precisely modulate
Jagged1-Notch3 signaling, well, that may provide novel
therapeutic strategy for atherosclerosis and post-injury
restenosis.


Dr. Carolyn Lam:


Very nice. Well, in the next paper, we discuss inflammation in
heart failure. We know that inflammation contributes to the
pathogenesis of heart failure, but there is limited understanding
of inflammation's potential benefits. Interesting, huh? Well,
these authors, Dr. Wollert and colleagues from Hannover Medical
School in Germany, identified an adaptive crosstalk between
inflammatory cells and cardiomyocytes that protects against
persistent afterload stress-induced heart failure in mice.
Monocytes and macrophages produced myeloid-derived growth factor
in the pressure overloaded myocardium to augment SERCA2a
expression in cardiomyocyte's calcium cycling and contractility.
Myeloid-derived growth factor plasma concentrations were also
found to be elevated in patients with aortic stenosis and to
decline after aortic valve implantation indicating that pressure
overload also triggers myeloid-derived growth factor release in
humans.


Dr. Greg Hundley:


Carolyn, really informative preclinical science, but what are the
clinical implications?


Dr. Carolyn Lam:


Ah. These observations molecularly defined a feature of the
inflammatory response to hemodynamic overload that protects
against heart failure development. Inflammation's beneficial
trade therefore need to be considered when developing
inflammation as a therapeutic target in heart failure. All of
this is really discussed in a lovely editorial entitled
Inflammation and Heart Failure: Friend or Foe? That's by Drs.
Hajjar and Leopold.


Dr. Greg Hundley:


Great job, Carolyn. Well, my next paper focuses on resistant
hypertension. Carolyn, although lifestyle modifications generally
are effective in lowering blood pressure among patients with
unmedicated hypertension or those treated with one to two
antihypertensive agents, the value of exercise and diet for
lowering blood pressure in patients with resistant hypertension
is unknown. To address this, Professor James Blumenthal and
co-authors at Duke University Medical Center enrolled 140
patients with resistant hypertension with an average age of 63
years, 48% women, 59% black, 31% diabetes, and 21% with chronic
kidney disease and randomly assigned them to A, a four-month
cardiac rehab center-based program of lifestyle modification.
We're going to call that C-LIFE, consisting of dietary
counseling, behavior and weight management, and exercise. Or
number 2 or the B, a single counseling session providing
standardized education and physician advice. We'll call that
SEPA.


Dr. Greg Hundley:


The primary endpoint was clinic measured systolic blood pressure.
Secondary endpoints included 24-hour ambulatory blood pressure
and selective cardiovascular disease biomarkers including
baroreflex sensitivity to quantify the influence of baroreflex on
heart rate; high-frequency heart rate variability to assess
vagally-mediated modulation of heart rate; flow-mediated dilation
to evaluate endothelial function; and pulse wave velocity to
assess arterial stiffness; and then finally left ventricular mass
to characterize left ventricular structure and remodeling.


Dr. Carolyn Lam:


Wow! That is a very, first of all, important clinical question.
Then also, just very intricate methodology in assessing this.
What did they find?


Dr. Greg Hundley:


Right, Carolyn. Between-group comparisons revealed that the
reduction in clinic systolic blood pressure was greater in C-LIFE
compared with SEPA. Next, 24-hour ambulatory systolic blood
pressure also was reduced in C-LIFE with no change in SEPA. Then
next, compared with SEPA, C-LIFE resulted in greater improvements
in baroreflex sensitivity, high-frequency heart rate variability,
and flow-mediated dilation. There was no between-group
differences in pulse wave velocity or LV mass.


Dr. Greg Hundley:


Carolyn, diet and exercise can lower blood pressure in patients
with resistant hypertension. When delivered in a cardiac
rehabilitation setting, a four-month program of diet and exercise
as adjunctive therapy, results in a significant reduction in
clinic and ambulatory blood pressure, and improvement in selected
cardiovascular disease biomarkers.


Dr. Carolyn Lam:


Wow! Really nice, Greg. Okay. Well, looks like we're all going to
round up already with what else there is in today's issue. Let me
start. There's an exchange of letters between Drs. Fang and
Vinceti regarding the article Blood Pressure Effects on Sodium
Reduction: Dose-Response Meta-analysis of Experimental Studies.


Dr. Greg Hundley:


Right, Carolyn. I've got a few things in the mail bag. First,
Professor Anker has a Research Letter regarding the Kidney
Function After Initiation and Discontinuation of Empagliflozin in
Heart Failure Patients With and Without Type 2 Diabetes: Insights
From the EMPERIAL Trials. Dr. Gerstenfeld has an ECG challenge
entitled Atrioventricular Block with Narrow and Wide QRS: The
Pause That Refreshes. Then lastly, Dr. Donald Lloyd-Jones has an
AHA update regarding the American Heart Association's focus on
primordial prevention. Well, Carolyn, I can't wait to hear this
fantastic feature discussion with you and Dr. Packer. How about
we jump to that?


Dr. Carolyn Lam:


Great. Let's go, Greg.


Dr. Carolyn Lam:


Because side-by-side exam of PARAGON and EMPEROR is like
side-by-side of...


Dr. Justin Ezekowitz:


You can compare our new and our old prime minister much like your
paper did.


Dr. Milton Packer:


Yeah, yeah.


Dr. Justin Ezekowitz:


There are [crosstalk] and it could be viewed until they perform
in the broader world how it goes. You don't quite know.


Dr. Milton Packer:


The only problem is you can't do a head-to-head comparison of the
old prime minister and the new prime minister.


Dr. Justin Ezekowitz:


That is true except that the head-to-head comparison includes
excellent care by both the new and the old. I think that
comparison's going to be pretty equal. I think we can
case-control that one.


Dr. Carolyn Lam:


I really liked that that was politically correct because we are
recording. Everybody, welcome to the feature discussion. I am
here with Dr. Milton Packer from Baylor and he really needs no
introduction. We're discussing heart failure with preserved
ejection fraction. As well as our associate editor, Dr. Justin
Ezekowitz from University of Alberta. Hence, in case anybody's
wondering, we were talking about the Canadian elections. Let's
just launch straight into it, a side-by-side comparison of
PARAGON and EMPEROR-Preserved. Dr. Packer... Milton, if I may,
what in the world drove you to do this?


Dr. Milton Packer:


My God. Oh, my God. Yes.


Dr. Carolyn Lam:


Tell us about what drove you to do this and please, if you could
just summarize the results.


Dr. Milton Packer:


Well, let me just say from the outset that this was a commentary,
not an original research article.


Dr. Carolyn Lam:


Yes.


Dr. Milton Packer:


The commentary was motivated by two very straightforward
observations. We had two large scale outcome trials of two
different drugs in heart failure with a preserved ejection
fraction. I was privileged to serve as you were, Carolyn, on the
leadership committees of both trials. It's not as if we have
involvement in only one trial. We have involvement in both trials
and we are very proud of that involvement.


Dr. Milton Packer:


One trial came in with a effect size of about 13% on its primary
endpoint with a borderline P-value. A second trial,
EMPEROR-Preserved, came in with a 21% reduction and its primary
endpoint with a really small and persuasive P-value. The two
patient populations in the two trials were really amazingly
similar. We wanted to understand why it was 21% in one trial and
persuasively so and why it appeared to be smaller in the PARAGON
trial with sacubitril/valsartan. We thought, well, maybe that
difference was related to how endpoints were defined or maybe
that difference was related to the influence of ejection
fraction. The reason we got excited about that was that as almost
everyone knows, PARAGON found an influence of ejection fraction
on the effect of sacubitril/valsartan in patients with HFpEF. We
found an influence of ejection fraction on the effect of
empagliflozin in HFpEF in EMPEROR-Preserved. We wanted to
understand whether that influence was similar in the two trials.


Dr. Milton Packer:


Just to make life simple, PARAGON had created certain cut points
for ejection fraction. They had presented and previously
published in Circulation endpoints based on those cut points of
ejection fraction. All we did was we used their endpoints and
their cut points, and we put the two trials side by side. We did
not do a statistical comparison of the effect size. There're
actually no P-values in the whole commentary. But what we wanted
to see was: Was the shape of the ejection fraction influence
relationship similar or different in the two trials? Well, very
simple. In PARAGON, as has been reported, there was a linear
relationship: as ejection fraction increased, the effect of
sacubitril/valsartan got smaller. In EMPEROR-Preserved, there was
also an attenuation at a highest ejection fraction, but the
relationship wasn't linear. It was like a hockey stick. It was
flat and then went up at an ejection fraction over 62.5, which
was the cut point that PARAGON used.


Dr. Milton Packer:


When we compared patients between the low 40s and the low 60s,
the effect size in empagliflozin appeared to be larger than the
effect size of sacubitril/valsartan in that ejection fraction
group using the same endpoints. In fact, for hospitalizations for
heart failure, which is really what SGLT2 inhibitors do, it was
twice as great with empagliflozin in EMPEROR-Preserved than with
sacubitril/valsartan in PARAGON-HF. We thought this was really
interesting. We put the pictures up side by side. We wrote a
commentary and Circulation was so kind to accept it.


Dr. Carolyn Lam:


Oh, but Milton, you were very, honestly as always, very clever to
have done this analysis. But if I could reiterate a few things
for the audience, which is very important. First of all, as you
rightly first pointed out, it's a perspective piece. It is not a
head-on comparison with P-values. It could not be. Let's just
also give the audience a bit of background in that PARAGON
included patients with an ejection fraction of 45% and above.
EMPEROR-Preserved was above 40. PARAGON looked at total heart
failure hospitalizations and cardiovascular death as a primary
outcome. EMPEROR looked at first cardiovascular death or heart
failure hospitalization.


Dr. Carolyn Lam:


Let's just remember the designs were different. Of course in the
comparison, PARAGON compared sacubitril/valsartan versus
valsartan. I like the way you very carefully wrote in your study
that it was more a study of neprilysin inhibition since it's
sacubitril/valsartan against valsartan and it was empagliflozin
versus placebo. We know that it's important to state that as a
basis. Then really important to say to everybody out there, pick
up our journal. You must look at this bigger. I myself have
already cited it at least twice already, Milton, because people
will just naturally ask that. "Are the results different because
of ejection fraction or different endpoints?" What you did there
in that beautiful figure is that you tried as best as you can to
match it up in terms of ejection fraction bins and match it up in
terms of hospitalizations. There. I just wanted to state those
few things, but I'm really-


Dr. Milton Packer:


Oh, no. No. Carolyn, you're 100% right. That's why there are
couple of things. I just want to underscore what you said because
I think your points were spot on. First of all, we really lined
up the endpoints and the ejection fraction. We tried our best to
compare apples and apples. It would not have been a useful
exercise for us to compare different endpoints and different
ejection fraction subgroups. But I just want to make sure that
everyone understands: I'm a big fan of sacubitril/valsartan and
I'm a big fan of neprilysin inhibition. As you know, both
PARADIGM-HF and PARAGON-HF weren't really tests of
sacubitril/valsartan; they were tests of neprilysin inhibition.
They were great tests at that. PARAGON in particular was a great
test of that. We're comparing neprilysin inhibition and SGLT2
inhibition.


Dr. Milton Packer:


But here's my most important point: we do not want people to
choose one over the other. That was not the intent. We think that
there are data in patients with certain ejection fractions, let's
say between 40 and 60, I'm just creating a range, where both
interventions are appropriate. Now I understand there are cost
considerations and I don't want to minimize that, but we are not
suggesting that anyone prefer one drug over the other. All we
wanted to do was we wanted to ask the question: Since the effect
size in one trial seemed to be different than the effect size in
the other trial, what were the ejection fraction subgroups that
represented that difference? We found that the patients with
ejection fractions greater than 60, 65% did not contribute to
that difference. It was the patients with lower ejection
fractions that contributed to the difference. I hope that's
helpful.


Dr. Carolyn Lam:


Ah. That's wonderful. Justin, have you recovered from the talk
about the Canadian elections?


Dr. Justin Ezekowitz:


Oh. I have indeed.


Dr. Carolyn Lam:


I'm on swinging.


Dr. Justin Ezekowitz:


I have indeed. Thanks for recognizing that Canada just had a
major election we carried out in six weeks. But, Milton, I really
enjoyed reading this. Maybe I can just ask you about two elements
within this perspective piece, which is number 1, what's
incredibly concordant is a lack of difference across
cardiovascular death for both agents in both trials regardless of
the trial differences and the potential differences in patient
populations recruited; that's number 1. It's incredibly flat for
cardiovascular death.


Dr. Justin Ezekowitz:


But number 2 is there is a danger in comparing trials even
non-statistically. That's often a pitfall we get into, but we
have to put some frame of reference on that. What is the one or
two key things you think differ between PARAGON and
EMPEROR-Preserved that you say, "You really need to look at these
trials differently"? Those two questions came to mind when
looking at this great figure that you produced.


Dr. Milton Packer:


Okay. The first question is so much easier and that is that these
drugs don't reduce cardiovascular deaths. Full stop. It's really
interesting because sacubitril/valsartan reduces cardiovascular
death in people with ejection fractions of 40% or less, but not
in patients with ejection fraction greater than that. The primary
effect is heart failure hospitalizations. Empagliflozin didn't
reduce cardiovascular death even in patients with the ejection
fraction less than 40% or greater than 40%. What we're really,
really talking about two drugs where the major effect is a
reduction in heart failure hospitalizations. That comes out
whether you do the analysis as time-to-first-event or total heart
failure hospitalizations.


Dr. Milton Packer:


Of course, we're looking forward to the DELIVER trial with
dapagliflozin. My own personal expectation is they're going to
come out with a very striking effect on heart failure
hospitalizations and not on cardiovascular deaths. Cardiovascular
deaths in patients with HFpEF is really... It's a hard goal
because only half of the deaths are cardiovascular. These
patients have so many comorbidities that influence prognosis. The
other thing, which is really important, is that heart failure
hospitalizations only represented 18% of all hospitalizations in
these patients; it's really small. I think of empagliflozin as
being a treatment of the heart failure of HFpEF, not a treatment
for HFpEF. I hope that makes sense. Justin, what was your second
question?


Dr. Justin Ezekowitz:


Absolutely.


Dr. Milton Packer:


Oh, the differences between-


Dr. Justin Ezekowitz:


Yeah. Thank you, Milton.


Dr. Milton Packer:


Okay. There's always differences between two trials. As I said
before, Carol and I were involved in both trials. They were done
slightly at different times. They didn't overlap. Remember that
the cut points in the two trials, one was 40%, one was 45%,
really didn't matter to our analysis because we corrected for
that in our ejection fraction subgroups. I was actually really
much more impressed by the similarities than by the differences,
but here's the catch. HFpEF is an incredibly heterogeneous
disease. When we look at baseline characteristics, we're looking
at means, medians, percentages. We're not picking up on any
heterogeneity and there's a lot of heterogeneity. I actually
think that HFrEF is a reasonably homogeneous disease. I think
HFpEF is an incredibly diverse disease with a whole host of
different disorders. What I'm amazed by is that we actually got
an effect size that was greater than 20% in an all-comers HFpEF
analysis.


Dr. Milton Packer:


But in all honesty, Justin, it wasn't really all-comers. We
excluded people with BMIs over 45. There are a lot of patients
who are obese and had BMIs greater than 45 who have HFpEF. By the
way, especially in Texas. I didn't say that. We didn't enroll
those patients. In all honesty, if I had to do it all over again,
I would have. By the way, PARAGON didn't enroll them either.


Dr. Carolyn Lam:


Well, this is an incredible conversation. I know that we could
just do a whole hour of chatting about what this implies for the
higher ejection fraction, what this implies for how we should be
treating heart failure. I don't even dare to ask for some last
words maybe from both Justin and Milton, but recognizing that the
time is short, anything else to add?


Dr. Milton Packer:


I think Justin should do last words.


Dr. Justin Ezekowitz:


Well, let me summarize by saying there is a hockey stick. We love
hockey sticks in Canada. A simple and an excellent comparison. I
think people should really look at that figure to understand it,
but do not undertreat your patients with HFpEF and look at these
with a grain of salt. Thanks for joining us, Milton. Thanks,
Carolyn.


Dr. Milton Packer:


Thank you so much.


Dr. Carolyn Lam:


On behalf of Greg and I, you've been listening to Circulation on
the Run. Thank you so much for joining us today and don't forget
to tune in again next week.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2021.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors, or of the American
Heart Association. For more, visit ahajournals.org.