Circulation October 27, 2020 Issue

This week’s episode includes author John McMurray and Associate
Editor Brendan Everett as they discuss the effect of
dapagliflozin on outpatient worsening of patients with heart
failure and reduced ejection fraction.


TRANSCRIPT BELOW:



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 Dr Greg Hundley, Associate Editor,
Director of the Pauley Heart Center, VCU Health in Richmond,
Virginia. Well, Carolyn, I hear you might have an interesting
feature paper?



Dr Carolyn Lam: Oh, yes. I think everyone's going to look forward
to this one, because we cannot get enough of the DAPA-HF study.
This is another very important prespecified analysis, looking at
the effect of dapagliflozin on outpatient worsening of patients
with heart failure with reduced ejection fraction. Very important
stuff coming right up, but first, I've got two papers looking at
congenital heart disease that I'd like to share with you, Greg.
Have you got your coffee?



Dr Greg Hundley: Yeah, I do. Let's get going.



Dr Carolyn Lam: Well, as you know, the mechanisms of congenital
heart disease associated right ventricular dysfunction are not
well-understood. And so, in this first paper, Dr Reddy from
Stanford University and colleagues assessed lipid peroxidation, a
potent form of oxidative stress, as well as mitochondrial
function and structure, in right ventricular myocardium,
collected from patients with and without right ventricular
failure.
And what they found, was that right ventricular failure was
characterized by increased oxidation of membrane phospholipids,
known as lipid peroxidation and its products, such as
4-hydroxynonenal, or 4-HNE. Now, 4-HNE binds to metabolic and
mitochondrial proteins, and was associated with decreased
myocardial energy generation and mitochondrial structural
disruption with increasing severity of right ventricular
hypertrophy and right ventricular failure. Mechanistically, the
authors showed that 4-HNE was sufficient to decrease energy
generation by inhibiting electron transport chain complex
activities and mitochondrial dynamics.



Dr Greg Hundley: Dr Carolyn, a lot of mechanism here. So
clinically, what are the implications?



Dr Carolyn Lam: I thought you'd ask. Well, since standard heart
failure therapies, such as ACE inhibitors and beta blockers, are
ineffective in the treatment of right ventricular failure,
developing therapies focusing on new targets, such as what we
talked about, the lipid peroxidation, could improve right
ventricular function in
congenital heart diseases by improving mitochondrial energy
generation and cardiomyocyte survival.



Dr Greg Hundley: Ah, very interesting, Carolyn.



Dr Carolyn Lam: Thank you. The next paper, also very interesting,
this time focusing on Tetralogy of Fallot, the most common
cyanotic congenital heart disease. Now, this is from Dr Marijon
from Hôpital Européen Georges-Pompidou in France and colleagues
who highlighted, first, that sudden cardiac death represents an
important mode of death in these patients with Tetralogy of
Fallot, yet data evaluating the ICDs in these patient population,
really, has remained scarce. And so, they use the nationwide
French registry to include 165 patients with Tetralogy of Fallot
with an ICD initiated in 2010 by the French Institute of Health
and Medical Research. 63%, by the way, of these ICDs, were used
for secondary prevention.



Dr Greg Hundley: Ah, Carolyn, I can't wait to see. What did they
find?



Dr Carolyn Lam: So during a median follow-up of 6.8 years, 47% of
patients received at least one appropriate ICD therapy. The
annual incidence of the primary outcome was 10.5% overall, 7.1%
in the primary prevention, and 12.5% in the secondary prevention
cohorts, respectively. 43% of patients presented with at least
one ICD complication, and, importantly, QRS fragmentation was the
only predictor of appropriate ICD therapies.
So, even before you asked me, Greg, the take home message is,
patients with Tetralogy of Fallot and an ICD, experience high
rates of appropriate therapies, including those implanted for
primary prevention. The considerable long-term burden of
ICD-related complication, however, underlines the need for
careful candidate selection. A combination of easy-to-use
criteria, including QRS fragmentation, might improve our risk
prediction.



Dr Greg Hundley: Oh, very nice summary, Carolyn. Learned a lot
there. Well, I'm going to steer us to two other papers in the
issue, and the first one is from the world of basic science, and
it's from Dr John Cooke from the Houston Methodist Research
Institute. So Carolyn, the angiogenic response to ischemia
restores perfusion, so as to preserve tissue. Something we all
know. A role for mesenchymal to endothelial transition in the
angiogenic response is controversial, and this study utilized a
murine model of hindlimb ischemia and an in vivo Matrigel plug
assay, together with lineage tracing studies and single-cell RNA
sequencing, to examine the transcriptional and functional changes
in fibroblasts in response to ischemia, to determine if resident
fibroblasts contribute to angiogenesis.



Dr Carolyn Lam: Ah, it's so interesting. Do fibroblasts
contribute to angiogenesis? What did they find, can't wait?



Dr Greg Hundley: Yeah, Carolyn. So, in both mice and
human-isolated fibroblasts, these author studies indicated the
presence of subsets of tissue fibroblasts, which seemed poised to
contribute to the angiogenic response. And the expansion of these
subsets with ischemia was dependent upon activation of innate
immune signaling, and this signaling contributed to recovery of
perfusion and preservation of ischemic tissue. Really interesting
findings. Didn't suspect the fibroblasts as being the
contributors here.



Dr Carolyn Lam: Very nice, Greg. Thank you. You've got another
one.



Dr Greg Hundley: Yes. So the next study is from Professor
Phillips Tsao from Stanford University School of Medicine. Well,
Carolyn, this is a genome-wide association study, and it's from
the Million Veteran Program, testing 18 million DNA sequence
variants in patients with abdominal aortic aneurysms. In the
study, they identified 7,642 cases and 172,172 controls in
veterans of European ancestry, with independent replication and
another study in 4,009 72 cases and 99,858 controls.



Dr Carolyn Lam: Wow.



Dr Greg Hundley: So it's nice, they have a replication study. The
authors then use Mendelian randomization to examine the causal
effects of blood pressure on abdominal aortic aneurysms. And they
examine the association of abdominal aortic aneurysm risk
variants with aneurysms in the lower extremity, cerebral, and
iliac arterial beds, and lastly, derived a genome-wide polygenic
risk score to identify a subset of the population at greater risk
for disease.



Dr Carolyn Lam: Wow. So a GWA study with replication to identify
those at risk for abdominal aortic aneurysms in huge cohorts.
What did they find?



Dr Greg Hundley: Well, Carolyn, this study was managed by one of
our experts in GWA studies, Dr Wendy Post, and through GWAs, the
authors identified 14 novel loci, and there were already 10, so
it brings the total number of significant abdominal aortic
aneurysm loci to 24. So a new finding there. And in their
Mendelian randomization analysis, they demonstrated that a
genetic increase of 10 millimeters of mercury in diastolic blood
pressure, as opposed to systolic blood pressure, likely had a
causal relationship with the future development of abdominal
aortic aneurysms. They observed that 19 of those 24 aortic
aneurysm risk variants associate with aneurysms in at least one
other vascular territory. And then lastly, a 29 variant polygenic
risk score was strongly associated with abdominal aortic
aneurysms, independent of family history and smoking risk
factors.
So Carolyn, in conclusion, the authors in this study identify
novel abdominal aortic aneurysm genetic associations with
therapeutic implications and identify a subset of the population
at significantly increased genetic risk of abdominal aortic
aneurysms, independent of their family history. And their data
suggests that perhaps extending current screening guidelines to
include testing for those with high polygenic abdominal aortic
aneurysm risk, would significantly increase the yield of many of
our current screening algorithms, as you know, that predominate
based on smoking and age.



Dr Carolyn Lam: Wow. Very, very impressive and convincing data.
Thanks, Greg. Let me tell you about other papers in today's
issues. There's a research letter by Dr Tiburcy on inhibition of
prolyl-hydroxylase domain enzymes, and how that protects from
reoxygenation injury in the engineered human myocardium. There's
another research letter from Dr Ohbe, entitled, The Risk of
Cardiovascular Events after a Spouse's ICU Admission. And, one
more from Dr Ganatra, on chimeric antigen receptor T cell
therapy-associated cardiomyopathy in patients with refractory or
relapsed non-Hodgkin lymphoma.



Dr Greg Hundley: You know, Carolyn, our research letters, they
really pack a punch. Such very interesting research, in a nice
concise format. I've got some other publications. So first,
there's an On My Mind piece from our own Charlie Loewenstein, and
also Dr Solomon from Boston, Massachusetts, involving, Severe
COVID-19 as a Microvascular Disease, does endothelial exocytosis
drive COVID-19? And next, there's a case series entitled, ECMO
Therapy for Cardiac Lymphoma, and it's from Dr Oscar Cingolani.
And then finally, Carolyn, a very nice ECG challenge from Dr
Bansal, related to identifying the location of an AV block. Well,
Carolyn, I'm really excited to get onto your feature discussion.



Dr Carolyn Lam: Let's go, Greg. Today's feature discussion looks
at a prespecified analysis of DAPA-HF. My goodness, I don't think
we can get enough of the data from DAPA-HF, and we have none
other than be corresponding author, Dr John McMurray from
University of Glasgow, to discuss this exciting paper, as well as
our associate editor, Dr Brendan Everett from Brigham and Women's
Hospital in Boston, Massachusetts. So John, today's feature
paper, all about outpatient worsening of heart failure. Could you
please start by defining what we meant by that, and why is it so
important?



Dr John McMurray: Our interest in this actually started back when
we did PARADIGM and we had collected, in a not very systematic
way, information about episodes of outpatient worsening, so by
that, I mean episodes of worsening symptoms and signs, not
leading the patient to go to the emergency department or be
admitted to hospital. The sort of worsening that a patient might
tell you about in your outpatient clinic, say they're a bit more
breathless or they've got a bit more ankle swelling, and you do
something about it. And that's the critical part. You decide to
increase their dose of diuretic, add another drug.
And in PARADIGM, we find that those episodes, first of all, were
quite common, and secondly, and most importantly, we're actually
prognostically very significant. They were associated with worse
outcomes. So in that HF, we decided that we would collect these
more systematically, we would try and define them a little bit
more robustly, so we would require the investigator to report
worsening signs and symptoms, and we also wanted evidence that
additional treatment had been given and then that had been
sustained for at least a month, because, as you know, diuretic
dose can increase and decrease.
Then we prespecified, as you said, Carolyn, that we would then
incorporate those manifestations of worsening, as an additional
component to our primary composite endpoint, which was
cardiovascular death, heart failure hospitalization, worsening of
heart failure requiring intravenous therapy, so an urgent visit
for that, that would often be in an emergency department, and
then in addition to that, this further manifestation of worsening
as the extra component to this broader composite outcome that we
hoped would encompass the whole range of worsening of heart
failure that a patient might experience.



Dr Carolyn Lam: Thanks so much, John, and you actually preempted
my question of how it differed from the original primary outcome
that included urgent heart failure visits, intravenous diuretic
use, but not these nuance outpatient intensification of heart
failure therapy that I really salute you for prospectively
collecting information on. So could you summarize what you found,
please?



Dr John McMurray: Well, first comment to make, Carolyn, is that
we included those urgent visits requiring intravenous therapy,
because, as you know, in the U.S., I think there is a move to try
and avoid admission and to treat patients in the ambulatory care
setting or non-ward setting. Although, I have to say, as it
turned out, those episodes of worsening were very infrequent.
There was, I think, 33 in total in DAPA-HF, compared to almost
600 of the other episodes of worsening. The ones that we almost
feel at a brainstem reflex level when we see patients in our
clinics.
So what did we find? Well, we find that when you add those
episodes of worsening, then, of course, you considerably increase
the proportion of patients who have, from what you might call,
the most trivial manifestation, worsening the events we just
talked about, all the way through to the very worst, in other
words, death, from cardiovascular causes, in fact, so much so,
that by about two years of follow-up, the Kaplan-Meier rate for
that expanded composite endpoint was about 33%. And, as you know,
Carolyn, we're talking about a trial that enrolled patients who
were very well-treated by conventional standards and who, by and
large, had mild symptoms, but 70% were NYHA class II. And yet,
within two years, if you take into account all of these different
manifestations of worsening, we had about one-in-three people in
the placebo group that deteriorates, and we reduced the risk of
deterioration with dapagliflozin, we reduced the instance of that
expanded composite endpoint by 27%, and that was a highly
statistically significant result.
And if you like numbers needed to treat, then for that expanded
very broad composite endpoint, the number needed to treat over
the median follow-up of 18.2 months, was only 16. And by the way,
we did confirm that those outpatient worsening events were
prognostically significant as well.



Dr Carolyn Lam: Very good. Brendan, could I bring you in on this?
It's got such great implications, maybe you could share a little
bit about what the editors thought when we saw this paper?



Dr Brendan Everett: One of the key things that the editors
thought when they reviewed this, was the fact that, as you
pointed out, you collected these outpatient worsening episodes
prospectively across the trial and did so in a very rigorous and
systematic way. And I think for those of us who take care of
patients with heart failure, which of course is most
cardiologists, these kinds of episodes where your patient calls
you and their weight's gone up, or where they've gotten a little
more short of breath, then you, over the phone, intensify their
diuretic regimen, are incredibly common, and, of course,
bothersome to the patient and challenging for the clinician who's
caring for the patients too. So I think, in that sense, it's a
really important paper. That was the other aspect, I think, that
the editors were interested in. But the impact, the clinical
impact on day-to-day care of patients with heart failure, was
substantial.
The other part that I found intriguing, because of course, when
you're caring for individual patients, you don't have a sense,
necessarily, of what these episodes mean in a broader population
for those patients' overall risk of bad outcomes. So you
mentioned it right at the end when you were speaking a moment
ago, about the association of these outpatient intensifications
of oral diuretic therapy and their association with future bad
outcomes within the trial. Could you tell us a little bit about
what those were and why they ended up seeming so important, both
to patients and to you as the trialist?



Dr John McMurray: We write about these being common, in fact, in
the placebo group in DAPA-HF. I think it was 14% of patients had
one of those episodes of outpatient worsening. And again, as you
correctly identified, in the majority of cases, the therapeutic
intervention by the physician, was simply to increase the dose of
diuretic, although, actually about 40% of people also, at some
point, had the addition of another drug.
So, in terms of the significance of those events, in PARADIGM, we
find that they appeared to be associated with almost the same
impact on mortality as being admitted to hospital with worsening
heart failure. But in fact, in DAPA-HF, where we collected more
of these events, so maybe we collected, perhaps, the more severe
cases in DAPA where we collected them systematically, we find
that the prognostic impact wasn't quite as large. So for example,
if you were admitted to hospital with heart failure during
DAPA-HF, then you were six-times more likely, subsequently, to
die in that rather short follow-up period, than if you had no
manifestation of worsening.
On the other hand, if you had an outpatient episode of worsening,
then it was around a three-fold higher risk of death than if you
had no manifestation of worsening. So, my take home from this was
that these episodes really do matter to patients. Not only, of
course, do they matter because it means the patient doesn't feel
so good, but they matter because that patient suddenly is on a
different prognostic trajectory, and you can change that by
intervening.
So these events are common, they're prognostically bad news, and
fortunately, we can reduce them. And maybe the last thing to say,
which I also didn't mention, I apologize, was that, of course, if
you look at that expanded endpoint, as you can imagine, because
there's so many events now, you see the effect of treatment very,
very quickly. So by day 27 after randomization, in other words,
by day 27 after starting dapagliflozin, we had a statistically
significant reduction in the occurrence of that comp standpoint,
that then remained significant thereafter.



Dr Brendan Everett: Thanks, John. I had one other question that I
hope doesn't take us too far into the weeds, but I think as a
clinician, when you care for these patients, you try to intensify
their outpatient therapy, and when that seems to fail, the
patient then becomes admitted to the hospital. And I thought it
was very interesting and thoughtful the way that you approach
that problem, in other words, you have potentially, of this
composite endpoint, you have the outpatient worsening that comes
first, and then it's followed, in many cases, by a
hospitalization for heart failure. How did you tease those two
apart? And what analyses did you do to make sure that what you
were really measuring was the effect of the outpatient
intensification, rather than really just a prelude to a hospital?



Dr John McMurray: Very good question, Brendan. So, obviously, we
were concerned about the possibility of double counting, so we
did a primary analysis in which we built in a blanking window.
So, for example, if you had an episode about outpatient and you
or I increased the patient's oral therapy, but within 30 days,
they were admitted to the hospital, then in our analysis, that
patient only counted once, and the event that counted was the
hospital admission, not the outpatient episode of
worsening.
And then, as I said, we did a number of sensitivity analyses
where we adjusted the length of that blanking period, because we
recognized, obviously, that some people, that episode of
outpatient worsening that you intervene for, your intervention
may not work and they may still get hospitalized. So we try to,
as you obviously identified when you read our manuscript, we
tried to counter that by not double counting episodes of
outpatient worsening that were closely adjacent to the hospital
admission.



Dr Carolyn Lam: Could I end with just one quick question? You've
published many times with us at Circulation, and I'd like to
think that that's from a very good experience with us, with
working with us, and I've noticed even in this discussion, it's
just so interesting the exchange. And so, John, could you say a
few words about publishing in Circulation, and why do it?



Dr John McMurray: Well, obviously it's our leading cardiovascular
journal. As I was being trained as a fellow, it was every
fellow's aspiration to publish a paper in Circulation. So
reputationally, obviously, it's very, very important.
But why do I like Circulation other than that? Well, first of
all, you handle papers quickly and efficiently. I think you're
very fair. I really like the reviews. So I would say one of the
greatest frustrations most authors, and certainly I know that
from my own experience, is when you get poor reviews. I don't
think I get those from
Circulation, so you obviously have a much higher quality review.
I like the way the editors give you guidance about the manuscript
and how to respond to the reviewers. That's really, really
helpful, because sometimes you think, "Well, that reviewer’s
comment doesn't make sense. Do I have to really do that?" But
often, your replies to me, come with guidance about how to handle
the different reviewers’ comments. So, all in all, it's fair. I
would say that's always important. Everybody will not get every
paper accepted, but I think you get a very fair response from
Circulation. It's good. It's thoughtful. So, that's fine.



Dr Carolyn Lam: Thank you so much, John. I'm sure I'm speaking on
behalf of Brendan as well, and kudos to him because obviously he
managed this paper so well. Thank you, audience, for joining us
today on Circulation on the Run. So don't forget to tune in again
next week.



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