Circulation October 26, 2021 Issue

Please join author Jonathan Newman and Associate Editor
Sandeep Das as they discuss the article "Outcomes of Participants
With Diabetes in the ISCHEMIA 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 and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor, Director of the
Pauley Heart Center at VCU health in Richmond, Virginia. Well,
Carolyn, this week's feature, a couple of weeks ago, we had that
feature forum on the ischemia trial. Now we're going to explore
some of the outcomes in patients with diabetes, from the ischemia
trial in the feature discussion today. But, before we get to
that, let's grab a cup of coffee and start in on some of the
other articles in this issue. So, how about if I go first, this
time? This particular paper, Carolyn, we're going to start on one
of your topics. I know you're a fan of diet related
interventions. So high intake of added sugar is linked to weight
gain and cardio-metabolic risk. And in 2018, the U S National
Salt and Sugar Reduction Initiative proposed government supported
voluntary national sugar reduction targets.


Dr. Greg Hundley:


This intervention's potential health and equity impacts and cost
effectiveness are unclear. And so Carolyn, these authors, led by
Dr. Renata Micha from Tufts University, incorporated a validated
micro-simulation model - CVD Predict coded in C++, and used it to
estimate incremental changes in type two diabetes, cardiovascular
disease, quality adjusted life years, cost and cost effectiveness
of this national policy. The model was run at the individual
level and the model incorporated national demographic and dietary
data from the National Health and Nutrition Examination Survey
across three cycles spanning from 2011 to 2016, added sugar
related diseases from meta-analysis and policy costs and
health-related costs from established sources and a simulated
nationally representative us population was created and followed
until age 100 years or death with 2019 as the year of
intervention start and findings were evaluated over 10 years and
a lifetime from healthcare and societal perspectives.


Dr. Carolyn Lam:


Ooooh, You so got my attention, Greg, a very important topic and
so, what did they find?


Dr. Greg Hundley:


Right, Carolyn. So achieving the NSRI sugar reduction targets
could prevent 2.48 million cardiovascular death related events,
0.5 million cardiovascular disease deaths, and three quarters of
a million diabetes cases, gain 6.7 million quality adjusted life
years, and save $160.8 billion in net cost from a societal
perspective over a lifetime. The policy became cost-effective,
defined as less than $150,000 for quality adjusted life years at
six years and highly cost-effective at seven years with a cost
savings noted at nine years. And therefore, Carolyn, implementing
and achieving the NSSRI sugar reformation targets could generate
substantial health gains, equity gains, and cost savings.


Dr. Carolyn Lam:


Wow, thanks Greg. So, moving from a very publicly health focused
paper to this paper that really focuses on hypoplastic left heart
syndrome with very, very scientifically significant findings.
Now, first, we know hypoplastic left heart syndrome is the most
common and severe manifestation within the spectrum of left
ventricular outflow tract obstruction defects occurring in
association with ventricular hypoplasia. The pathogenesis is
unknown, but hemodynamic disturbances are assumed to play a
prominent role. Authors led by Doctors Moretti and Laugwitz from
Technical University of Munich in Germany, as well as Dr. Gruber
from Yale University School of Medicine, and their colleagues
combined whole exome sequencing of parent offspring, trios,
transcriptome profiling of cardiomyocytes from ventricular
biopsies and immuno-pluripotent stem cell derived cardiac
progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as
well as single cell gene expression analysis to decode the
cellular and molecular principles of hypoplastic left heart
syndrome phenotypes.


Dr. Greg Hundley:


Wow, Carolyn, there is a lot of data, very complex preclinical
science here. So what did they find?


Dr. Carolyn Lam:


Indeed, Greg. As I said, scientifically incredible and rigorous,
and they found that initial aberrations in the cell cycle
unfolded protein response, autophagy hub led to disrupted cardiac
progenator lineage commitment, consequently, impaired maturation
of ventricular cardiomyocytes limited their ability to respond to
growth cues. Resulting in premature cell cycle exit and increase
apoptosis under biomechanical stress in 3D heart structures.
Together, these studies provide evidence that the hypoplastic
left heart syndrome pathogenesis is not exclusively of
hemodynamic origin, and they revealed novel potential nodes for
rational design of therapeutic intervention.


Dr. Greg Hundley:


Wow, Carolyn, we really need research in this topic and this is
great preclinical science that we're getting here in our journal.
Congratulations to the authors and what a great presentation of
that by you. Well, Carolyn and my next paper there remain major
uncertainties regarding disease activity within the Retain Native
Aortic Valve, as well as bioprosthetic valve durability,
following transcatheter aortic valve implantation. And these
authors led by Doctor Jacek Kwiecinski, from the Institute of
Cardiology, aimed in a multi-center cross-sectional observational
cohort study to assess native aortic valve disease activity and
bioprosthetic valve durability in patients with TAVI in
comparison to subjects with bioprosthetic surgical aortic valve
replacement or SAVR.


Dr. Carolyn Lam:


Oh, very interesting. And what were the results?


Dr. Greg Hundley:


An interesting comparison, Carolyn. So in patients with TAVI,
native aortic valves demonstrated 18 F sodium fluoride uptake
around the outside of the bioprosthesis that showed a modest
correlation with the time from TAVI. Next, 18 sodium fluoride
uptake in the bias prosthetic leaflets was comparable between
SAVR and TAVI groups. Next, the frequencies of imaging evidence
of bioprosthetic valve degeneration at baseline were similar on
echo cardiography 6 and 8% respectively, CT, 15 and 14%
respectively, and with PET scanning. Next, baseline 18 F sodium
fluoride uptake was associated with subsequent change in peak
aortic velocity for both TAVI and SAVR. And on multi-variable
analysis, the 18 F sodium fluoride uptake was the only predictor
of peak velocity progression. And so Carolyn, therefore, in
patients with TAVI, native aortic valves demonstrate evidence of
ongoing active disease and across imaging modalities, TAVI
degeneration is of similar magnitude to bioprosthetic SAVR
suggesting comparable midterm durability.


Dr. Carolyn Lam:


Very nice, important stuff.


Dr. Carolyn Lam:


Well, thanks, Greg. Let's tell everyone about the other papers in
today's issue. There's an exchange of letters between Doctors
Baillon and Blaha regarding the article very high coronary
artery, calcium and association with cardiovascular disease
events, non-cardiovascular outcomes and mortality from MESA.
There's an ECG challenge from Dr. Bell Belhassen on a left bundle
branch block, tachycardia following transcatheter aortic valve
replacement. And On My Mind paper by Dr. Neeland on
cardiovascular outcomes trials for weight loss interventions,
another tool for cardiovascular prevention, another Research
Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono
therapy in heart failure, patients with atrial fibrillation and
stable coronary artery disease. So insights from the AFIRE trial,
and finally, a Research Letter from Dr. Kumoro three-dimensional
visualization of hypoxia induced, pulmonary vascular remodeling
in mice.


Dr. Greg Hundley:


Great, Carolyn, and I've got an in-depth piece from Professor Jia
Sani entitled breadth of life, heart disease, linked to
developmental hypoxia.


Dr. Greg Hundley:


Well, Carolyn, how about we get onto that feature discussion and
learn more about results from the ischemia trial?


Dr. Carolyn Lam:


Let's go Greg.


Dr. Carolyn Lam:


Well, we all know how important diabetes is as a risk factor for
atherosclerotic coronary disease. And we know it's a very common
comorbidity among patients with chronic coronary disease, but the
question is do patients with diabetes and chronic coronary
disease on top of guideline directed medical therapy and
lifestyle interventions, of course, do they derive incremental
benefit from an invasive management strategy of their coronary
disease? Well, we are going to try to answer that question today
in our feature discussion. Thank you so much for joining us
today. The first author and corresponding author of today's
feature paper, which tells us about results from the ischemia
trials. And that's Dr. Jonathan Newman from New York university
Grossman School of Medicine. We also have associate editor
Sandeep Das from UT Southwestern. So welcome both of you. And if
I could please start with Jonathan reminding us, perhaps, what
were the ischemia trials and then what you tried to answer and do
in today's paper,


Dr. Jonathan Newman:


Of course, Carolyn, and thank you so much for having me and for
the discussion with Sandeep. It's a pleasure to be here. So sure
has a little bit of background, as you indicated, the ischemia
trials basically enrolled and for the purposes of this discussion
and this analysis, I'm referring to both the main ischemia trial
and the ischemia chronic kidney disease trials. So ischemia CKD
under the umbrella of the ischemia trials. Ischemia stands for
the international study of comparative health effectiveness with
medical and invasive approaches. And the purpose of the trial was
to test to see whether a routine invasive approach on a
background of intensive guideline directed medical therapy for
high risk patients with chronic coronary disease and at least
moderate ischemia and obstructive coronary disease documented on
a blinded CCTA or computed coronary tomography angiography prior
to randomization was associated with benefits for a
cardiovascular composite. And we looked in this analysis at
whether or not there was appreciable heterogeneity of treatment
effect or a difference in treatment effect for patients compared
without diabetes in the ischemia trials, in ischemia and ischemia
CKD.


Dr. Carolyn Lam:


Great, thanks for lining that up so nicely. So what,


Dr. Jonathan Newman:


So the results of our analysis really highlighted a couple of
things that I think you touched upon initially, the first thing
that I would highlight is that diabetes was very common in this
high risk cohort with chronic coronary disease, over 40% of
participants in the ischemia trials, 43% with obstructive
coronary disease and moderate to severe, you may have had
diabetes. Perhaps not surprisingly patients with diabetes had
higher rates of death or MI than those without diabetes. And the
rates were highest among those patients that required insulin,
had insulin treated diabetes, but using really robust methods to
assess for heterogeneity using a Bassen assessment of
heterogeneity of treatment effect accounting for violation of
proportional hazards. The fact that there was an upfront hazard
and a late benefit, we really saw no difference in death or MI,
between the invasive or conservative strategies for patients
with, or without diabetes over about three years of follow-up.


Dr. Jonathan Newman:


And the results importantly were consistent for ischemia and
ischemia CKD and provided the rationale for us when we started by
looking to see if the distribution of risk and characteristics
allowed the trials to be combined. The study really confirms this
higher risk of death or a MI for chronic coronary disease
patients who have diabetes extends these findings for those
patients with moderate or severe ischemia. And I think really
notably also adds information about chronic coronary disease
patients with diabetes and CKD. That's sort of the overall
findings. And I'm happy to talk in more detail about that.


Dr. Carolyn Lam:


I love the way you explain that Jonathan and especially, going
into detail on what was so different about the paper and the
really important statistical methods that made these findings
robust, very important and impactful findings. If I could ask
Sandeep to share your thoughts.


Dr. Sandeep Das:


Thanks, Carolyn. You know, I am just a big fan of everything
that's come out of the ischemia group. One of the things that I
really most enjoy as a consumer of the literature is when well
done studies give me results that are unexpected. And I know it's
become fashionable now to say that everybody knew that all along
that this is what going to be the result. But honestly, I think
we all sort of are many of us thought that there's going to be a
subgroup somewhere that's really going to benefit from an
invasive approach in terms of preventing heart outcomes. I think
the key here that really jumped out at me was that this is
identifying what we typically think of is a very high risk
subgroup. You know, patients with diabetes patients with
multi-vessel coronary disease patients with insulin dependent
diabetes.


Dr. Sandeep Das:


And we did see the association with mortality across the
increased disease severity and the increased severity of diabetes
as expected. But really we didn't see a signal that
revascularization, routinely revascularizing patients, even the
higher risk patients led to clinically relevant heart outcome
benefits. So I thought that that was a really interesting top
line finding and really that's kind of. I mean, it would have
been interesting if it was the other way too, but it was, it
really was kind of the hook that got me into the paper.


Dr. Sandeep Das:


I actually have a question for Jonathan, one of the things that I
think we spend a lot of time as an editorial group thinking about
and talking about, and we bounce back and forth with the authors
a few times was the idea that relatively few of these patients
with multi-vessel CAD ended up having CABG. So, you would
typically think of diabetes multi-vessel CAD as being a pretty
strong signal for patients that may benefit in terms of mortality
from having bypass surgery. And here it was a relatively small
group about a third, or maybe even less than a third. And I
realized up front, they excluded the left main and the patients
that had angina had a CTA, et cetera. But what I'd be curious as
to your thoughts about, the benefits of bypass surgery and
diabetes, which have been established in other trials.


Dr. Jonathan Newman:


It's a great question. And I think we really appreciated the
questions from you and from the editors to try and get at some of
the nuance with this issue. As you indicated in the ischemia and
ischemia CKD trials overall, and the patients in the invasive
treatment arm, it was about 25% or so 26% and 15% were
revascularized with CABG. Part of the issue here is that it gets
a little tricky with the use of CCTA of pre randomization CTA to
define coronary artery severity, which was not required in the
CKD population due to impaired renal function. But what we can
say is among the patients with diabetes and multi-vessel coronary
disease, 29% were revascularized surgically in their combined
analysis, which is comparable to the 30% in Bery 2d that were
revascularized via bypass surgery, as we've discussed. And as you
know, the decision for surgical versus percutaneous
revascularization in ischemia, as in Barry 2d was non-randomized
though we might want to, we really tried to be very, very
cautious in terms of comparing revascularization strategies on
outcomes for patients with diabetes and multi-vessel CAD, which
has you suggested.


Dr. Jonathan Newman:


And as we pointed out, the proportion with multi-vessel CAD was
more common amongst in patients with diabetes compared with those
patients without diabetes. The other thing I would sort of say in
the framework of, the revascularization and strategies for
revascularization, comparing, let's say ischemia to Barry 2d or
to freedom. Basically we have very little data about
revascularization approaches for those patients with creatinine
with impaired renal function and, patients with the crediting
greater than two were excluded from Barry 2d. So while we had
about 15% or so that had severe CKD. So in the GFR, less than 30
are on dialysis. And we know that's an extremely high risk group
of patients with diabetes and chronic coronary disease. And we
don't have great evidence on which strategy for revascularization
if at all provides additional benefit. So I think it's a really a
tough question to answer, and we tried to be as judicious as
possible in our comments about revascularization approaches,
given the nature of the trial design.


Dr. Carolyn Lam:


Gee, thanks so much, Jonathan, for explaining that. So, well, I
actually have a related question now, referring to the medical
therapy. Can I, sort of ask you about the fact that, these days
that the rage is all about GLP one receptor agonist, for example,
that are known to reduce the risk of atherosclerotic
cardiovascular disease and diabetes. So these ischemic trials, I
assume, did not have a high usage of these medications. And what
do you think would be the impact, if anything, I suppose even
more for guideline directed medical therapy. Huh?


Dr. Jonathan Newman:


Yeah. So it's a great question, Carolyn. As you know, in strategy
trials and clinical trials in general, that take a while it's
always a real challenge to keep the trial contemporary with
current clinical practice, whether it's revascularization
strategies or changes in medical therapy. And as you indicated,
the real revolution and glucose lowering therapies with profound
cardiovascular benefit for patients with diabetes, we worked hard
to try and stay up to date and encourage sites around the world
with the use of best SGLT2 inhibitors and GLP ones. The rates
were very, very low and we don't actually given the fact that the
ischemia trials were conducted a real multinational and is really
an international trial is over 330 sites worldwide. So we really
had to balance the data that we could get from sites with the
reality of collecting and running this trial across the whole
world.


Dr. Jonathan Newman:


So we don't actually know. We know insulin use or non-use or oral
medication use or non-use or no medication use or non-use, but
not much more than that. From what, as, you know, unfortunately,
even after now, six going on seven years of impressive data for
the benefit of these agents, uptake remains low for patients with
diabetes, whether it's with coronary disease or heart failure.
And there was certainly the case with the trial, which started
back in 2015, or sorry, before 2015, even before the results of
EMPA-REG. So the rates of those agents were low. I would expect
as you indicated that if we did have greater use of these
beneficial therapies. Medical therapy may have performed even
better and potentially given an added boost potentially for our
high risk, even higher risk subgroups that we'd looked at that
were available in these trials.


Dr. Carolyn Lam:


Oh, thanks again. I wish we could go on forever, but we've got
just a little bit of time left. So I'd like to ask you both for
your quick take home messages for the audience. Could I start
with Sandeep and then Jonathan?


Dr. Sandeep Das:


Yeah. You know, I think a key take home from this is that,
although it may be naively intuitive that a very aggressive
invasive strategy would be superior, especially in high risk
patients. You know, the data are very, very convincing that it's
not. And so therefore I think in an absolute minimum, you have
plenty of time and ability to think about these patients
carefully, to select who, if anybody would be a great candidate
for revascularization, more aggressive therapy and more invasive
therapy, but the most patients will do well with conservative
management.


Dr. Sandeep Das:


And I think that that's the, that's a real key take home here.
And I think that the points that Jonathan raised about, you know,
poor uptake of GLP one RAs and SGLT 2 inhibitors in the community
as they're so far are key, right? So we have great medicines that
we just under used, and that to me is the other sort of clarion
call here is that if in the context of a nice trial, that you can
see similar result for invasive conservative approaches, then
lets, let's get our medical therapy where it needs to be to
provide our patients the best outcomes we can


Speaker 3:


Love it, Jonathan.


Dr. Jonathan Newman:


Yeah. So I'm really glad that Sandeep brought up the issue of
medical therapy in the trial. And maybe I can take a minute to
sort of frame what San kind of build off of what Sandeep just
said, you know, we, in the context of this clinical trial, you
know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the
co-chair and I, we worked very hard with optimizing medical
therapy across the trials, for all participants. So really
getting patients on the maximum tolerated doses of high-intensity
statins, lowering patient's LDL as aggressively as possible
evolving our systolic blood pressure targets. And it was
extremely challenging. And at the end of the day, we see that
patients with diabetes were more likely than those without to get
to our LDL goal. We used a threshold problematic concept that
that still may be to some extent, but they were less likely to
achieve their systolic blood pressure goals.


Dr. Jonathan Newman:


And I think Sandeep was exactly right. We have a way to go with
implementing existing therapies, existing medical therapy. There
may be a benefit for as demonstrated in Dr. S. for patients that
remain highly symptomatic to derive symptom benefit with
revascularization. The other context I would sort of add with the
medical therapy issue is that despite really aggressive medical
therapy, and we really did as much as we could, patients with
diabetes still had, a 40, 50% greater risk of death or MI than
those without diabetes. So there's still this idea of kind of
residual risk. And these were patients with diabetes that were
very well managed from a medical and glycemic control
perspective. So we still have a lot of work to do. And I think
understanding ways we can benefit our patients is really that
challenge.


Speaker 3:


Thanks so much, Jonathan, and thank you Sandeep for joining us
today.


Speaker 3:


And thank you audience for listening from Greg and I. This has
been "Circulation On The Run", please 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 AHJjournals.org.