Circulation January 14, 2020 Issue

Dr Greg Hundley: Welcome listeners. This is Dr Greg Hundley from
the VCU Pauley Heart Center in Richmond, who is in the second of
his two-week stint without his dear friend, Dr Carolyn Lam who
will be returning in a week or two. Our feature article this week
is from Dr Mikhail Kosiborod from Saint Luke's Mid America Heart
Institute and the Georgia Institute for Global Health, and
University of New South Wales. And we'll review the effects of
dapagliflozin on quality of life and other metrics in patients
with heart failure and reduced ejection fraction. But first,
let's have a look at the other articles in this issue and just
like last week we've got four other original manuscripts. The
first two are sort of clinically related and that very first
article comes from Dr Ben Levine from University of Texas
Southwestern and he serves as the corresponding author and he's
examining future predictors of the development of heart failure
and preserved ejection fraction or HFpEF.


His team tested the hypothesis as to whether patients with LVH
and elevated cardiac biomarkers would demonstrate elevated LV
myocardial stiffness when compared to healthy controls as a key
marker for future HFpEF. The team recruited 46 patients with LVH.
The LV septum was greater than 11 millimeters and elevated
cardiac biomarkers, so the NTproBNP was greater than 40 or the
cardiac troponin T was greater than 0.6. And they were recruited
along with 61 age and sex-matched cohort of healthy controls. To
define LV pressure volume relationships, right heart
catheterization and 3D echocardiography were performed while
preload was manipulated using lower body negative pressure and
rapid saline infusion. They found that the left ventricle was
less distensible in the LVH patients relative to the controls,
that is they had a smaller volume for the same filling pressure.
When preload was expressed as transmural filling pressure or
wedge pressure minus right atrial pressure left ventricular
myocardial stiffness was nearly 30% greater in the LVH group
compared to the controls.


The author's note that although LV myocardial stiffness of LVH
patients was greater than that of the healthy controls at this
relatively early stage, further studies are required to clarify
whether interventions such as exercise training to improve LV
compliance may prevent the full manifestation of the HFpEF
syndrome in these high-risk individuals.


Well, the second paper comes from Professor John McMurry of the
British Heart Foundation Cardiovascular Research Center at the
University of Glasgow in the United Kingdom. And the paper is
somewhat similar to our feature article because it emanates from
the DAPA Heart Failure dataset that we will hear about later. So
in this paper, the authors examined the effects of Dapagliflozin
according to age, given potential concerns about the efficacy and
safety of therapies in the elderly in the prior trial. A clinical
trial that as we know, demonstrated that a reduced risk of
mortality and heart failure hospitalizations occurred in patients
with HFrEF.


So in this current study, a total of 4,744 patients that were 22
to 94 years of age were randomized. 636 were less than 55 years
of age, 1,242 we're 55 to 64 years of age 1,717 were 65 to 74,
and finally 1,149 were greater than 75 years of age. Consistent
benefits were observed for the components of the primary outcome
of all-cause mortality and symptoms across all the age groups.
Although the adverse events and the study drug discontinuation
increased with age, neither was significantly more common with
Dapagliflozin across any of the age groups. There was no
significant imbalance and tolerability or safety events between
Dapagliflozin and placebo, even in the very old population group.
So we'll have more to discuss later in the feature discussion
with a second paper that really looks also at the DAPA-HF study.


The next original article comes from our world of Basic Science
and it reports that the deficiency of circulating monocytes
ameliorates the progression of myxomatous valve degeneration in
the Marfan syndrome. And this paper comes from Dr Katherine
Yutzey from Cincinnati Children's Medical Center. Well, first is
some background, leukocytes comprised primarily of macrophages
have recently been detected in myxomatous valves, but the timing
of the presence and the contributions of these cells in
myxomatous mitral valve degeneration is not known. So the authors
found in this study that Marfan syndrome mice recapitulated the
histopathologic features of myxomatous valve disease by two
months of age, including mitral valve thickening, increased
leaflet cellularity and extracellular matrix abnormalities
characterized by proteoglycan accumulation and collagen
fragmentation.


Concurrently, disease mitral valves of the Marfan syndrome mice
exhibited a marked increase of infiltrating and resident
macrophages along with increased chemokine activity and
inflammatory extracellular matrix modification. Likewise, mitral
valve specimens obtained from gene-edited Marfan syndrome pigs as
well as human subjects exhibited increased monocytes and
macrophages detected by immunofluorescence. So remarkably
deficiency of monocytes was protected against mitral valve
disease progression resulting in a significant reduction of
macrophages, had minimal leaflet thickening and preserved mitral
valve integrity. So the authors identify for the first time in
this interesting study from the world of basic science that
monocytes are a viable candidate for targeted therapy in
myxomatous valve degeneration.


The second basic science original article in this issue is
entitled "Genetic IL-6 Signaling Deficiency Attenuates
Cardiovascular Risk in Clonal Hematopoiesis" and the
corresponding there is Pradeep Natarajan from the Mass. General
is background clonal hematopoiesis of indeterminate potential or
CHIP is a term that refers to clonal expansion of hematopoietic
STEM cells due to acquired leukemic mutations in genes such as
DNMT3A or TET2. In humans, CHIP associates with prevalent
myocardial infarction. In mice CHIP accelerates atherosclerosis
and increases IL-6 and IL-1 beta expression raising the
hypothesis that IL-6 pathway antagonism in CHIP carriers would
decrease cardiovascular disease risk.


So in this study, the authors observed some really exciting
results. They analyzed over 34,000 samples from the UK Biobank
and identified 1,079 individuals with CHIP, including 432 with
large clones an LV fraction greater than 10%. During a 6.9-year
median follow-up CHIP presence was associated with increased
incidents, cardiovascular disease event risk with greater risk
from large CHIP clones. IL6R attenuated cardiovascular event risk
among participants with large CHIP clones but not in individuals
without CHIP. This really exciting research results suggest that
CHIP is associated with increased risk of incident cardiovascular
disease. And among carriers of large CHIP clones, genetically
reduced IL-6 signaling abdicated this risk. Really exciting
results in an emerging area of science.


So what else is in the issue? Well, in our in depth review
feature, Professor Stephan Rosencrantz from the University of
Cologne Heart Center reviews the systemic consequences of
pulmonary hypertension with right side heart failure. And then an
On My Mind piece, our own associate editor, Dr Vlad Zaha coupled
with doctors Walter Myers and Javid Moslehi from Vanderbilt
discuss the impact of evolving immunotherapies for cancer and
their impact on the cardiovascular system. In our mailbag, Dr
Xiayan Shen from the Medical Classification Center of the
Singapore Armed Forces discusses in a research letter the
prevalence of Brugada Syndrome in a large Singaporean young male
population. In letters to the editor, Dr Muddassir Mehmood from
University of Tennessee Medical Center in one letter and Dr
Goodarz Danaei from Boston in a response letter discuss the
importance of diet relative to the development of HFpEF and how
heart failure may be coded in by the World Health Organization
when assessing global cardiovascular outcomes.


Bridget Kuhn in our cardiology news feature reports on
preliminary results from the International Childhood
Cardiovascular Cohort or i3C Consortium that was presented at the
2019 European Society of cardiology Congress. The i3C Consortium
used data on 40,000 patients who participated in seven major
longitudinal cohort studies that evaluated childhood
cardiovascular risk factors from repeated measures during
childhood and adolescence. And finally, our own Molly Klemarczyk
at Circulation gathered and combined a very nice serial update
that highlights important articles from our circulation family of
journals, including electrophysiology, imaging, heart failure,
and others.


Well, listeners, that's a summary of what's in the journal. But
let's now proceed to our feature discussion to learn more about
the rapidly emerging field of SGLT2 inhibition.


Well listeners, we are very excited for this feature discussion
we have today, Dr Mikhail Kosiborod from Saint Luke's Mid America
heart Institute and our own associate editor, Dr Justin Ezekowitz
from Alberta, Canada. And we're going to be discussing the paper
related to the effects of Dapagliflozin on symptoms, function and
quality of life in patients with heart failure and reduced
ejection fraction. They're going to be presenting results from
the DAPA Heart Failure trial. Well Mikhail, I was wondering could
you orient us a little bit to the DAPA heart failure trial. And
then what was the hypothesis that you were trying to address in
the current study?


Dr Mikhail Kosiborod: DAPA-HF was the first heart failure outcome
trial trying to answer two critical questions about the effects
of SGLT2 inhibitors in patients with heart failure and reduced
ejection fraction. We knew from prior trials, outcome trials in
patients with diabetes SGLT2 agents can effectively prevent heart
failure inpatients, overwhelming majority of which did not have
heart failure and baseline. But what we didn't know was whether
these agents can also be used as therapies for patients with
established heart failure, and specifically heart failure with
reduced ejection fraction. And they reduce death or worsening
heart failure in the patient population. And the second question
was whether that effect, if in fact this medications can
significantly improve outcomes in patients with heart failure
reduced ejection fraction. Can they do that even in patients who
do not have type 2 diabetes? Because, in a diabetes trial it
appears that that heart failure protective effect may be
completely independent on the hemoglobin AONC.


And so DAPA-HF was specifically designed to test those two
hypotheses. It enrolled about 4,800 patients with heart failure
and reduced ejection fraction about 45% of which had types 2
diabetes. And there's a majority of us, 55% did not. And the main
trial results that were published prior to risk analysis showed
that in fact dapagliflozin significantly reduced the risk of the
composite endpoint of cardiovascular death and worsening heart
failure. It was a 26% relative risk reduction and the effects
were identical in patients with or without type two diabetes. So
both of those hypothesis were proven to be correct. It was
effective therapies for established heart failure and reduced
ejection fraction, and it was equally effective regardless of
diabetes status. Now what we did in this study is really trying
to understand the effects not just on cardiovascular deaths and
hospitalization for heart failure, but on health status, which is
symptoms, physical limitations, and quality of life.


He knows that heart failure is a debilitating disease, causes
high burden of symptoms, and physical limitations, has adverse
impact on quality of lives. We know that two key goals of
managing heart failure are to; one, reduce deaths and
hospitalizations for heart failure and two to reduce the burden
of symptoms and physical limitations and improve the quality of
life. So, that was really the focus of this specific analysis
that we're talking about today.


Dr Greg Hundley: Excellent. So I understand you use the KCCQ-12,
maybe help us understand what that test is and then tell us a
little bit about your methods and your study population. Did you
use the whole study population?


Dr Mikhail Kosiborod: KCCQ stands for Kansas City Cardiomyopathy
Questionnaire and we actually in the study we use KCCQ-23 which
is the full Kansas City Cardiomyopathy Questionnaire, consists of
23 items. And it a disease-specific tools for evaluating health
status and heart failure.


So it essentially assesses four key domains, which are the
symptom burden, physical implementations, quality of life, and
social limitations. In this particular study is a primary
endpoint as a primary part of the KCCQ as KCCQ total symptom
score, which is a domain that focuses on symptoms. And the idea
behind KCCQ is that you have a debilitating disease, which is
heart failure. That disease has impact on the patient by causing
symptoms, the symptoms then translate to physical limitations.
And the combination of the symptom burden physical limitations
has an impact on quality of life and social limitation. So that's
why are this four different domains assessing these four
components of the adverse effects of the heart failure compared
to health status. And just very briefly, to mention that KCCQ has
been proven to be responsive to clinical change. It's highly for
data predictive of death and hospitalizations from heart failure.
It has been extensively validated both of them hearts failure was
reduced enters and the ejection fraction.


And so we essentially focused, or the primary focus of the paper
was really to evaluate the effect of dapagliflozin versus placebo
on a Kansas City Cardiomyopathy Questionnaire or KCCQ level
symptom score. But we also looked at other domains as well. We
looked at the clinical summary score, which includes both
symptoms and physical limitations and we looked at the overall
summary score, which includes all of the four domains that I
mentioned before.


Dr Greg Hundley: What did you find?


Dr Mikhail Kosiborod: The patients treated with dapagliflozin had
a greater improvement in health status as assessed by a KCCQ
total symptom score or for that matter KCCQ clinical summary
overall summary score as compared to patients treated with
placebo. So if you look at the mean effect, there is some
improvement in the patients taking placebo. That's what we call a
placebo effect. And it's very commonly seen in clinical trials.
We assessed health status, but there was a greater improvement
with dapagliflozin as compared with the placebo, it was
statistically significant even in four months. But as the effects
were further amplified to eight months and this differences were,
I would say favorable when you kind of compare the effect of
Dapagliflozin versus other established heart failure therapies
when you look at the effects on health status.


What I think was even more important than analysis from a
clinician standpoint, and then they think it's actually much more
meaningful clinically is what we call a responder analysis. And
that's where we look as the proportion of patients that have a
clinically meaningful improvement with one type of therapy versus
other in this case Dapagliflozin versus placebo.


So it's been previously established that at five-point difference
or a five-point change rising KCCQ is what's considered to be
clinically meaningful or minimal clinically meaningful
difference. So a 5.2 grade deterioration KCCQ means it's a
clinically important deterioration. And a five-point or greater
improvement is a clinically important improvement. And then we
also looked at the proportion of patients with moderate and large
improvements in health status as well defined as STEM point of
grade of two, or two point a great improvement. And essentially
what we found was that significantly fewer patients treated with
dapagliflozin and as compared with placebo had a clinical
importance deterioration. And significantly greater proportion of
patients treated with dapagliflozin has small, moderate, large
improvements in health status. And the numbers needed to treat to
see those differences, as the small moderate large improvements
was very favorable ranging typically between 12 and 18 and over
eight-months-treatment period.


Dr Greg Hundley: Outstanding. So both clinically relevant as well
as statistically significant findings. Now we're going to bring
in Justin, our associate editor. Justin, help us put these
results into the just our perspective in looking at SGLT2
inhibitors, particularly for treatment for heart failure.


Dr Justin Ezekowitz: This is an exciting class of medications and
we're eagerly awaiting these results because we saw the DAPA-HF
Overall results. The majority of us treat patients with a pretty
symptomatic disease and as such this quality of life is quite an
important change. There's ongoing trials we're eagerly awaiting
which are also going to be using other medications in the same
class, but I think one question that remained was, are these
simply improving symptoms by one meaning, so the total symptom
score? Or the overall quality of life? And I think you nicely,
elegantly portrayed that in the figures and you have. The one
other part maybe Mikhail, you could expand upon, which is when
you think about DAPA-HF, and the quality of life gains and across
all the three different ways of looking at quality of life, where
do you see this in terms of its relationship to other things that
we know improve quality of life? Where we send patients, for
example, CRT or put them on an RNE. Where does this fit on top of
those types of changes?


Dr Mikhail Kosiborod: Thanks Justin. I think it's a really
important question because it says think critical from a clinical
standpoint to put it in the context of other therapies that had
been previously shown to improve health status, which means
again, reduced symptoms, improve physical and patient quality of
life. And there are a number of perhaps the types of therapies on
heart failure and LVCF that have been evaluated particularly on
side this one there also have been studies with exercise training
in heart failure or and the ones that you brought up, which is
cardiac resynchronization therapy in patients with heart failure
reduced ejection fraction and left bundle branch block. And as
that perhaps, if you kind of think about it. What are some of the
most effective treatments to improve the health status? That is
ones that we typically would consider as such, which is CRT in
patients with half RAF and a left bundle branch block.


And in fact, if you look at the mean effects dapagliflozin
compares very favorably even with highly effective therapies such
as TRT. Relatively few studies have previously reported to this
responder in analysis. But if you look at Digoxin comparing those
to dapagliflozin, one of the recent ones that I can think of is
[inaudible 00:20:23], again dapagliflozin compares very favorably
when you look at this types of responder analysis where again you
look at proportion of patients, it was a clinically meaningful
change.


So I think the beautiful thing about putting the study in the
context of further studies looking at health status and also in
the original main results that were published from a DAPA-HF
early this year is that it's really kind of a full house if you
will. So as the agent reduced deaths, reduced hospitalizations
and made patients feel better and all of that, with very
favorable safety profile. So, if you kind of think about risk
benefit analysis and you look at numbers need to treat both for
clinical outcomes such as CVS and hospitalizations for heart
failure for example, where health status, it looks really
impactful from a clinical standpoint.


Dr Greg Hundley: So relevance to other therapeutic interventions
for heart failure is what this whole class of agents seems to be
showing? So briefly, what do you see is the next important study
in the field?


Dr Mikhail Kosiborod: I will waffle on this question a little bit
and say there was more than one, but my views are there kind of
two key components to this. One is that there are additional
trials going on and heart failure with reduced ejection fraction
with other agents. And so seeing what happens with those other
agents in the class in a similar patient population and whether
is this a class effect or not? Now the diabetes trials would
suggest that these may well be class effects but I think it's
nice to have validation of that. I would say that is one real
important questions that hopefully we will have additional
answers to in the coming year or so.


And the second and perhaps I would argue even more important
question is whether these agents can also be effective in
improving outcomes in patients with heart failure and preserved
ejection fraction. That's a patient population that has also very
high debilitating burden of symptoms that has poor prognosis and
for which unlike them, half rubs, there are very few, if any
medications that have been proven to be disease-modifying and
actually have shown outcomes and benefit. So I would say those in
my mind, are the two critical developments that we'll be seeing.
And the good news is, there are the trials going on with more
than one agent in a class and half to half as well. Great.


Dr Greg Hundley: And Justin?


Dr Justin Ezekowitz: Yeah, I think that there's been an explosion
of therapies and Mikhail is bang on with this is the one class
where we're excited about. I think the other groups of
medications include Omecamtiv Mecarbil we'll know in a year or
two. We'll hear more details in the spring and then there's a few
other medications that Mikhail mentioned. I think this is a real
good message though, that both HFrEF and HFpEF, it's the rise of
medications again. Because we were on a device track for a while,
but I think the medications have such more potent effect on the
underlying structure and function that it's great to see that
there's been such a development and explosion of medications that
may obviate the need for implanted devices or advanced therapies,
so we're very excited about that.


Dr Greg Hundley: Outstanding. Well, listeners, we've had the
opportunity to hear from Mikhail Kosiborod from Saint Luke's Mid
America Heart Institute and our own associate editor, Dr Justin
Ezekowitz from Alberta, Canada, and learn more about SGLT2
inhibition and its importance in improving clinically
symptomatology both in those with diabetes and heart failure, but
also those with heart failure alone.


On behalf of Carolyn and myself, we wish you a great week and we
look forward to running and having a coffee chat next week. Take
care of. This program is copyright the American Heart
Association, 2020