Circulation May 27, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and it's editors. We're your
co-hosts, 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 for Circulation and
director of The Pauley Heart Center at VCU Health in Richmond,
Virginia.


Dr Carolyn
Lam:               
Guess what Greg? Right after this we have a double feature
discussion. It is all about dapagliflozin with some really,
really important self-analyses from the DECLARED-TIMI 58 trial
and about heart failure in Type 2 Diabetes with dapagliflozin.
But, all of that coming right up only after we have our chat. So
Greg, what do you have for us today?


Dr Greg
Hundley:            
My first article is going to be from Dr Mintu Turakhia at the VA
Palo Alto healthcare system at Stanford University and is going
to discuss the practice variation in anticoagulation prescription
and outcomes after device-detected atrial fibrillation. It's a
study that has insights from the VA Health Administration. This
study evaluated the relationship between oral anticoagulant
prescription practice variation in response to new device
detected atrial fibrillation and the association to outcomes.


                                               
As you know Carolyn, there are no clearly defined thresholds of
AF burden, for which to initiate oral anticoagulation.


Dr Carolyn
Lam:               
Interesting, so what did they find, how did they do this?


Dr Greg
Hundley:            
Carolyn, the investigators performed a retrospective cohort
analysis using data from the Veterans Health Administration
linked to remote monitoring data that included day level AF
burden. They included patients with cardiac implantable
electronic devices and remote monitoring from the years 2011
through 2014. A CHA2DS2-VASc score of greater or equal to 2, and
no prior stroke or oral anticoagulant receipt in the preceding 2
years. They determined the proportion of patients prescribed oral
anticoagulants within 90 days following new device-detected AFib
across a range of AFib thresholds. Greater than or equal to 6
minutes, all the way up to greater than 24 hours. And they
examined sight variation in oral anticoagulation prescription.


Dr Carolyn
Lam:               
And so? What did they find?


Dr Greg
Hundley:            
Well, you ask among 10,212 patients with defibrillators,
proportion receiving oral anticoagulation varied based on device
detected AF burden. For example, for those greater than or equal
to 6 minutes, it was roughly 13% of individuals, for those
greater than 24 hours, 27% of individuals received oral
anticoagulants. Importantly, there was a substantial sight
variation in oral anticoagulation prescription after
device-detected atrial fibrillation, for example, greater than
one hour. The median was 16%, but it ranged from as low as 3% up
to highs of 67%. And so, in adjusted models, oral anticoagulant
prescription after device-detected AFib of greater than 24 hours
was associated with reduced stroke risk and has a ratio of 0.28,
p-value's 0.02, although, the propensity adjusted model was
significant when AFib lasted at least 6 minutes.


                                               
So, in conclusion, among veterans with implanted devices,
device-detected atrial fibrillation is common. There is large
practice variation in 90-day oral anticoagulation initiation
after new device-detected AFib with low rates of treatment
overall, even for episodes greater than 24 hours. Remember, we
said that rate was 27%. The strongest association of oral
anti-coagulation with reduction in stroke was observed after
device-detected Afib of greater than 24 hours. And what this
study shows, is that randomized trials are needed to perform
these observational findings.


                                               
So, Carolyn, how about your next study?


Dr Carolyn
Lam:               
Well, from anti-coagulants to anti-hypertensives. I'm going to
tell you about the 6-month results if the RADIANCE Hypertension
Solo Trial.


Dr Greg
Hundley:            
Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you
remind us?


Dr Carolyn
Lam:               
Glad you asked. So the trial was the one that demonstrated a
greater reduction in daytime ambulatory systolic blood pressure
at 2 months by endovascular ultrasound renal denervation compared
with a sham procedure among patients who were not treated with
anti-hypertensive medications. So the current paper, led by
Michel Azizi from Université Paris-Descartes and colleagues, now
report the 6-month results following the addition of a
recommended, standardized, stepped-care anti-hypertensive
treatment to the randomized endovascular procedure under
continued blinding to the initial treatment.


                                               
Now, remember these were patients with uncontrolled combined
systolic and diastolic hypertension who were initially off
medications for two months following randomization. Now, between
two and five months, if the monthly measured home blood pressure
was more than 135/85, the stepped-care antihypertensive treatment
approach was recommended and consisted of sequential addition of,
for example, amlodipine 5mg a day, then a standard dose of an
angiotensin-converting-enzyme inhibitor, or an ARB, and
hydrochlorothiazide at 12.5mg a day, followed by sequential
uptitration of the hydrochlorothiazide and amlodipine.


                                               
So, what did they find? At 6 months, 65% of the patients in the
original renal denervation group were being treated by this
stepped-care approach, versus 84.5 in the sham group. And the
average number of antihypertension medications and defined-daily
doses were all less in the renal denervation group than the sham
group.


                                               
Now, despite less intensive antihypertensive treatment, the renal
denervation group had reduced daytime ambulatory systolic blood
pressure to a great extent than the sham group. Importantly,
there were no major adverse events in either group through 6
months. The blood pressure lowering effect of endovascular
ultrasound renal denervation was maintained at 6 months with less
prescribed antihypertension medications compared with the sham
control. And what this means is if safety is maintained in larger
studies with longer follow-up, renal denervation could be a
promising adjunct therapy for patients with hypertension.


Dr Greg
Hundley:            
Wow, so we're getting back toward renal denervation? How about
that?


                                               
Carolyn, my next paper jumps into the world of basic science.
This is a study from Kari Alitalo at the University of Helsinki,
and it involves endothelial cells and how they regulate
physiological cardiomyocyte growth versus VEGFR2 mediated
paracrine signaling. The study evaluates the role of
bidirectional endothelial cells and cardiomyocyte cross-talk via
cardiokine and angiocrine signaling as it pertains to the
regulation of cardiac growth and homeostasis in pathological
cardiac hypertrophy. The expansion of the cardiac vasculature to
maintain adequate supply of oxygen and nutrients is a key
determinant of whether the heart grows in a physiological
compensated manner, or a pathological decompensated manner.


                                               
Understanding how an excess of angiogenesis induces cardiac
hypertrophy and how endothelial cells regulate cardiomyocyte
homeostasis, could provide novel therapeutic targets for heart
failure.


Dr Carolyn
Lam:               
Ah, this is something very close to my heart. So Greg tell us,
how did they establish the link between the endothelial cells and
cardiomyocytes?


Dr Greg
Hundley:            
The investigators demonstrated that both endothelial cell
deletion of vascular endothelial growth factor receptor 1 and
AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or
BGIF, into the myocardium increased the coronary vasculature and
induced cardiomyocyte hypertrophy in adult mice.


                                               
The resulting cardiac hypertrophy was a physiological as
indicated by preserved cardiac function and exercise capacity and
lack and pathological gene activation. Also, the investigators
demonstrated that the reported changes were mediated by increased
VEGF signaling via endothelial VEGFR2 and found that the notch
and ERBb pathways are involved in transducing signals for
endothelial cell cardiomyocyte cross-talk in response to
angiogenesis.


                                               
So clinically, the relevance of the findings are highlighted
nicely in an editorial by professor Issei Komuro at the
University of Tokyo Hospital. First, he emphasizes that
cross-talk between the endothelial cell VEGFR2 and cardiomyocyte
ErbB signaling pathways coordinates cardiomyocyte hypertrophy
with angiogenesis and contributes to physiological cardiac
growth. And understanding whether factors could modify this
process may impact the treatment down the road of pathologic
hypertrophy.


Dr Carolyn
Lam:               
Oh interesting! Well you know what, Greg, I've got a preclinical
one for you too, and this time looking at the role of
inflammation in atherosclerosis and specifically at the role of
the adaptive immune response and T-cells.


                                               
So, Greg, let me remind you that when we looked at CANTOS and
Canakinumab we were actually looking at the role of the innate
immune response. And here is where I had planned this very nice,
complicated quiz for you, Greg, about the innate versus the
adaptive immune response in the various cells. Would you like to
take the quiz?


Dr Greg
Hundley:            
You know what? I think I'm going to pledge that I'm already going
to get a D or an F, so why don't you enlighten us?


Dr Carolyn
Lam:               
Now alright, remember that the CD4 T-cells are assumed to be
activated by our antigens derived from modified proteins such as
oxidized LDL, and these are presented via MHC class II molecules
in the context of cytokine signaling, remember those? What I
didn't realize is that it hadn't been assumed that
atherosclerosis involves a loss of tolerance against these
modified self-antigens, generated in response to
hypercholesterolemia and that presentation of such antigens on
these MHC class II cells, then lead to activation of
proatherogenic Th1 cells. So, that was the assumptions, but this
was really studied in detail by the authors, Dr Wigren from
Scania University Hospital and Lund University in Sweden and
their colleagues, who addressed the role of CD4 T-cells in a real
novel, unconventional way. And they did this by crossing MHC
class ii deficient mice with atherosclerosis-prone ApoE-deficient
mice.


                                               
Now the result of these double deficient mice was almost complete
void of CD4 T-cells. However, despite the lack of these T-cells
and inflammation, these mice developed larger atherosclerotic
lesions in the aortic root area of the heart than their
ApoE-deficient counterparts. Cell transfer and blocking antibody
studies also, then supported these findings and suggested that
loss of regulatory T-cells is the most important cause of
aggravated atherosclerosis in the double-deficient mice.


                                               
So, overall these observations demonstrate that deficiency of
activation of the adaptive immune responses through MHC class ii
is associated with increased development of atherosclerosis, and
the findings have important implications for our understanding
the possible risks and benefits of immunosuppressive therapy in
patients with cardiovascular disease. Now this is discussed in a
beautiful editorial by Dr Slütter and Kuiper and they are from
Leiden, the Netherlands.


                                               
So, Greg, interesting stuff, huh?


Dr Greg
Hundley:            
You bet! Let's go on and here a little bit more about diabetes.


Dr Carolyn
Lam:               
And dapagliflozin coming right up.


                                               
Today's feature discussion is all about SGLT2 inhibitors both in
heart failure and atherosclerotic disease. A huge discussion
because we have two papers, and they're all coming from the
DECLARE-TIMI 58 trial. I am so pleased to have the corresponding
author, Dr Stephen Wiviott from the TIMI study group at Brigham
Women's hospital in Boston, Massachusetts, as well as the first
author of one of the papers, and that is Dr Eri Kato, who was at
the TIMI study group and is now at Kyoto University, as well as
the editorialist for these two papers, Dr Subodh Verma from
University of Toronto, and our deputy editor, Dr Darren McGuire
from UT Southwestern.


                                               
All-star cast, all-star papers. So, Steve, could you start by
telling us about the DECLARE-TIMI 58 trial, just to set the
background please?


Dr Stephen Wiviott:        So
DECLARE, for people who don't know, was a large, randomized trial
of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor
dapagliflozin to placebo. And the patients could be enrolled if
the patients had either an established cardiovascular disease,
meaning secondary prevention, or simply risk factors for
cardiovascular disease with primary prevention.


                                               
Patients that were treated with dapagliflozin or placebo were
followed for a period of just over 4 years and there were
co-primary endpoints. Those were cardiovascular death and
hospitalization for heart failure, and the second co-primary
endpoint was MACE, major adverse cardiovascular events, a
combination of cardiovascular death, MI, or stroke.


                                               
And what we saw, initially, this was a safety trial to
demonstrate the safety of this diabetes agent according to
worldwide guidelines. We saw that there was certainly
non-inferiority for MACE, so it was safe with regard to MACE, but
we did see a statistically significant reduction in
cardiovascular death and hospitalization for heart failure driven
predominantly by a large reduction in hospitalization for heart
failure, and we also saw consistent with the other SGLT2
inhibitors, a significant reduction in the progression of renal
disease. And so we had the opportunity to follow up with a couple
of important papers that were published in circulation.


Dr Carolyn
Lam:               
Thanks, Steve. And at this point I would love to invite Eri to
tell us, because we just heard that the heart failure
hospitalization signal is very strong. What did you do in your
analysis?


Dr Eri
Kato:                        
So previously, SGLT2 inhibitors including dapagliflozin have
shown to reduce hospitalization for heart failure, now we wanted
to take a step further and explore those who are at high risk.
So, the aim of our study was to evaluate whether the clinical
benefit of dapagliflozin is greater in patients with HFrEF, heart
failure with reduced ejection fraction, compared with patients
without HFrEF.


                                               
So, we used data from the DECLARE-TIMI 58, which you just heard,
which included a broad spectrum of patients with Type 2 diabetes,
and was also unique that it is the only SGLT trial to date that
has detailed the information of these ejection fractions. So, for
this study, for our study trying to find patients by the presence
or absence of HFrEF, which was defined as having ejection
fraction less than 45%, which is pre-specified ejection fraction
couplings, and the key outcome in each was cardiovascular death
or hospitalization for heart failure, its components, and of
course, mortality. But we also additionally looked at MACE and
renal composite endpoints.


                                               
There are several interesting findings. First, is that
dapagliflozin reduced the risk of hospitalization for heart
failure regardless of ejection fraction, including those with
preserved ejection fraction.


                                               
Second, is we have observed lower rates of cardiovascular death
in all-cause mortality with dapagliflozin in patients with HFrEF,
but not in those without HFrEF.


                                               
So, in patients with HFrEF, there was a significant 45% reduction
in cardiovascular death, and 41% reduction in all all-cause
mortality with dapagliflozin. And I'd like to highlight that
these were achieved on top of high-proportional use of
conventional evidence-based heart failure therapies, and that it
did not increase any adverse events.


                                               
And third, and finally, there were lower rates of renal composite
endpoints with dapagliflozin regardless rejection fraction, and
once again, it improves patients with preserved rejection
fraction.


                                               
So, to summarize, our results showed a robust mortality benefit
in patients with HFrEF, but also showed that dapagliflozin is
beneficial in full spectrum patients with diabetes, regardless of
ejection fraction.


Dr Carolyn
Lam:               
Thank you Eri, that's beautifully summarized, but could I just
clarify? These were patients not just with a reduced ejection
fraction, but with heart failure? And how was that determined?


Dr Eri
Kato:                        
We collected data at the baseline and the heart failure was
collected based on the medical record.


Dr Carolyn
Lam:               
So, I just wanted to clarify that it wasn't just rEF, but HFrEF,
but the HF part was a medical record. So, Darren, I know you
thought a lot about this stuff, so what do you think? Is there
still equipoise for these heart failure trials, or how do you
think this adds?


Dr Darren McGuire:       
First, as deputy editor of Circulation, I'm thrilled that were
attracting these excellent diabetes-related publications, we've
had a track record of several years now of capturing many of the
key analyses and certainly these two papers we're talking about
today qualify among the very best we've had, and I've also had
the privilege of working with these investigators on the
executive committee at DECLARE. And to the investigators and the
credit of the sponsor, we observed these heart failure signals in
other trials as DECLARE was ongoing, and we actually made a
modification during the trial to begin to collect as much as we
could pre-randomization ejection fraction data. And we were able
to capture on roughly one-third of the patients, pre-trial EF
data and we took any way it was measured and any time of when it
was measured, and there are some limitations to that, but this
now represents the largest data set where we can stratify the
outcomes by some measure of ejection fraction.


                                               
And I have to say I was really surprised by these results; that
the cardiovascular death benefits were amplified in patients with
heart failure with reduced ejection fraction, but not in those
with heart failure with preserved ejection fraction, as these
medications are relatively modest, diuretic agents I anticipated
the opposite, honestly, that heart failure would preserve
ejection fraction that is much more volume-sensitive may have
incremental benefits from these medications.


                                               
So, I was surprised by this, it was a little bit upside-down from
what I expected. I know Subodh and Carolyn you've both thought a
lot about this as well, I'd be interested in your opinions. Did
you expect that heart failure with reduced ejection fraction
would drive these clinical results?


Dr Carolyn
Lam:               
Subodh, I'm going to let you go first.


Dr Subodh
Verma:          
First and foremost, I appreciate the opportunity the circulation
gave both myself and Professor McMurray to write the editorial to
these very important pre-specified analyses from DECLARE.


                                               
I actually see the results not only as interesting and
tantalizing as you already discussed, but I actually see a lot of
consistency between the two phenotypes, if I may, in that there
is a heart failure signal or reduction in heart failure
hospitalizations that appears to be consistent between the two
groups, right? People with an EF of less than 45 with or without
heart failure and then on the other side, people without reduced
ejection fraction. They're both responsive in terms of reductions
in heart failure hospitalization, so it brings into question that
is this differences that we're seeing with respect to mortality,
a reflection of a difference in phenotypic responsiveness to an
SGLT2 inhibitor, or is this simply a reflection of increasing
placebo event rates and a response based on baseline of entry in
one group versus the other.


                                               
So, as has been nicely outlined by the authors, the placebo event
rate for CB death and heart failure and the placebo group would
have pass, if I may, was about 5 times lower than those with
heart failure with reduced ejection fraction. And it might be
that as we go up the pyramid of risk, whether that risk is
defined based on a TIMI risk score, whether it's based on a
post-MI versus stable CAV risk score, or whether it's defined
based on GFR, or whether, finally, it's defined based on the
event rates for CV death and heart failure, that the higher the
event rate, the higher the probability of demonstrating a CV
death benefit, but that old strategies are actually demonstrating
a consistent benefit on the overall driver of that outcome, which
in this case, is a reduction in heart failure.


                                               
So, that's what we sort of said in the editorial as well that we
think that it may be a bit premature at this point to reach a
conclusion that one group is responsive, and the other group is
not responsive. But, as you rightfully said, Darren, it is
entirely feasible through these analyses to hypothesize that one
of the alternative hypotheses could be that there is a greater
responsiveness in HFrEF compared to HFpEF. I actually don't
understand the mechanisms of it, if that was the pieces I would
have a difficult time explaining it based on the overall biology
and sort of current understanding of these agents.


                                               
But, I would say let’s wait: dapa heart failure is just around
the corner. That trial will enroll people with documented heart
failure with reduced ejection fraction. I think 4,774 patients
that are being randomized on top of base, on top of RNA, on top
of MRA, etc. who still have heart failure and who have a BP
that's elevated so the definitive proof for this, at least from a
rough standpoint, will be forthcoming. And then there are
numerous HFpEF studies that are ongoing. There's Emperor Preserve
and there's Deliver, and they have characterized the HFpEF
population with a little bit more granularity and clarity. And I
think we will be able to then look at, specifically, is there a
HFpEF group that has the same event rate for CV death and heart
failure, and compare that population to a HFrEF group at the same
level of risk and whether there is differences in the
responsiveness to be definitive about whether this is a matter of
risk, threshold, or whether this is a true representation
phenotypically.


Dr Carolyn
Lam:               
Subodh is a hard act to follow. So, I will answer your question
directly, but maybe not with so many words, because it's already
been said, Darren. And I'll just say I expected this benefit to
be in both, I wouldn't have said one versus the other, but
because we do know that in trials and with prospective studies
that HFpEF outcomes are lower, especially mortality is lower,
compared to HFrEF. I do wonder if it's a power issue, but the
most important message--and this is coming from me also being on
the steering on the committee of both DELIVER and EMPEROR
Preserve--that please, this doesn't mean that we don't need the
trials. I really really think that there's equipoise there still
and we need to look at the DEDICATED HFpEF trials.


                                               
But, moving on from the concept of risk stratification, I would
like to go on and talk about the next paper. About the DECLARE
sub-study of those with a prior MI. So, Steve, could you tell us,
why did you do this, and what did you find?


Dr Stephen Wiviott:        I
think that what we've seen as a pattern across the three SGLT2
inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE,
was that there seems to be, as Subodh has said, reductions that
are relatively consistent in heart failure and renal outcomes.
But there was what appears to be ischemic outcomes, the MACE
outcomes, cardiovascular death, MI and stroke.


                                               
In fact, in a meta-analysis that we published at the same time as
the primary paper for DECLARE, we demonstrated that there was an
interaction between the primary prevention in the population,
those without established cardiovascular disease, and the
secondary prevention population as it relates to MACE, where the
benefits for MACE seem to be in the secondary prevention
population.


                                               
So, this was seen in DECLARE as well, and so we hypothesized that
the population of patients who had myocardial infarction as their
entering condition may be particularly at high risk for MACE and
it may potentially be that that was driving the benefit. And so,
what we did was we stratified the patients based on history of
prior myocardial infarction versus none, turned out that there
was about 3,500 patients in the trial who had had a prior
myocardial infarction. As would be expected from what's known
about the conditions, the event rates for those patients in the
placebo arm were much higher, about 2.5 times higher than
patients without myocardial infarction for MACE, also true for CV
death and hospitalization for heart failure.


                                               
And then what we saw when we looked at the treatment outcomes was
that there tended to be a greater reduction in MACE for patients
with prior myocardial infarction. In fact, for the MACE outcome,
we saw about a 16% reduction in MACE with patients with prior MI
compared to reduction with patients without prior MI. And so, the
combination of this higher risk, also a tendency towards a
greater relative benefit lead to a much greater absolute benefit,
where, in fact, we saw about a 2.5% reduction in MACE over the
four-year period for patients with prior MI, compared to a 0%
reduction for patients without prior MI.


                                               
And, in fact, when we broke this down to three groups: patients
with prior MI, patients with atherosclerotic cardiovascular
disease without prior MI, and then patients with no
atherosclerotic vascular disease, essentially, we saw the same
thing, which is that patients with MI were the ones who had the
greatest benefit in terms of MACE. And this was almost entirely
driven by reductions in myocardial infarction.


                                               
Now, I would say in contradistinction, as we look at heart
failure reductions, the relative benefits for heart failure were
similar among these groups, but because the risk was higher in
the patients with prior MI, and of course the absolute benefits
were greater in the MI population, and similar for renal outcome.
So, I think that this sort of extends what we have previously
known that patients with atherosclerotic cardiovascular disease
were at higher risk intended to have greater benefit with the
SGLT2 inhibitors on MACE events that the core of that appears to
be those patients with myocardial infarction.


Dr Carolyn
Lam:               
Thanks, Steve, that was just so clearly explained. Darren, in the
last couple of minutes could I ask you to give us the take-home
messages from these two studies, and maybe just, what next?


Dr Darren McGuire:        I
think the take-home message from these two studies in the context
of the overall field of SGLT2 inhibitor data, I think the
picture's becoming relatively clear and Subodh stated in
eloquently before and is reviewed in the editorial is that I
think across the board, and independent of how you define higher
versus lower risk subsets, this class of medications in general
and dapagliflozin, and these studies appear to have augmented
benefit, the greater the risk. Whether that greater risk is
defined by prior myocardial infarction, or heart failure with
reduced ejection fraction, or decreased EGFR, these are all
states where various sub studies have consistently shown across
the three compounds where we have outcomes data that the
treatment benefits are amplified in the higher risk patients.


                                               
And it's not just an absolute risk reduction that's augmented
based on baseline risk, but there appears to be an interaction
where the relative risk reduction is also amplified. And so, it's
really a remarkable field and it's providing therapeutic options
in these really high-risk subsets of patients where we've really
been handicapped up until now with these antihyperglycemic
therapies for type ii diabetes.


Dr Carolyn
Lam:               
Thank you everybody for joining us today. This was truly a
bonanza feature discussion, didn't I tell you?


                                               
You've been listening to Circulation on the Run, thank you for
listening today and don't forget to tune in again next week.


                                               
This program is copyright American Heart Association 2019