Circulation August 30, 2022 Issue

This week, please join author Rod Stables and Associate
Editor Nick Mills as they discuss the article "Routine Pressure
Wire Assessment Versus Conventional Angiography in the Management
of Patients With Coronary Artery Disease: The RIPCORD 2
Trial."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast, summary
and backstage pass through 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... Very interesting. There is
a lot of information about using fractional flow reserve during
contrast coronary angiography. But how does that compare to just
reviewing the angiograms when managing patients with coronary
artery disease?


Well, we are going to hear some results from the RIPCORD 2 trial,
and they may surprise you a little bit. But, before we get to
that interesting feature discussion with authors and editors, how
about we grab a cup of coffee and dive into some of the other
articles in the issue?


Dr. Carolyn Lam:


Yeah, let's do that, Greg. Do you have a paper to share first?


Dr. Greg Hundley:


Oh, thanks Carolyn. Sure.


So Carolyn, as we know, Apolipoprotein B or apoB, provides an
integrated measure of atherogenic risk. But whether apoB levels
and apoB lowering hold incremental predictive information on
residual risk after acute coronary syndromes, beyond that
provided by low density, lipoprotein cholesterol, or LDLC, that's
uncertain. So Carolyn this study emanates from the Odyssey
Outcomes trial, which compared the Proprotein Convertase
Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in
18,924 patients with recent ACS and elevated atherogenic
lipoproteins despite optimized statin therapy. Now the primary
outcome was major adverse cardiovascular events. So MACE was
coronary heart disease, death, nonfatal myocardial infarction,
fatal non-fatal ischemic stroke, and hospitalization for unstable
angina. And associations between baseline ApoB or ApoB at four
months and MACE were assessed in adjusted Cox proportional
hazards and propensity score matched models over median of 2.8
years.


Dr. Carolyn Lam:


Oh, right. So what were the results, Greg?


Dr. Greg Hundley:


Right, Carolyn so impatience with recent ACS and elevated
atherogenic lipoproteins, MACE increased across baseline ApoB
strata, and now evolocumab reduced MACE across all strata of
baseline ApoB, with larger absolute reductions in patients with
higher baseline levels. Lower achieved ApoB was associated with
lower risk of MACE, even after accounting for achieved LDLC or
Non-HDLC indicating that ApoB provides incremental information.
And therefore, Carolyn, if it is modified achievement of an ApoB
level less than or equal to 35 milligrams per deciliter may
reduce lipoprotein attributable residual risk after ACS. Isn't
that interesting?


Dr. Carolyn Lam:


Yes. Very nice, Greg. Thank you. This next paper is a
pre-specified analysis of the EMPEROR-Preserved trial, looking at
patients with and without diabetes.


Dr. Greg Hundley:


So remind us, Carolyn, what was the EMPEROR-Preserved trial and
what did it show?


Dr. Carolyn Lam:


Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor
reduced risk of the composite of cardiovascular death or heart
failure hospitalization, as well as first and recurrent heart
failure hospitalizations and slowed renal function decline in
patients with heart failure and an ejection fraction greater than
40%. So the current paper sought to determine if effects were
consistent in patients with, and without diabetes, of the almost
6,000 patients enrolled, 49% had diabetes. The risk of adverse
outcomes, first of all, was higher in patients with diabetes. Now
the treatment effect of Empagliflozin was however, similar in
that Empagliflozin reduced the rate of the primary outcome and
total heart failure hospitalization, irrespective of diabetes
status. The effect of Empagliflozen falls into attenuate GFR
decline, however, was also present in patients with, and without
diabetes, although more pronounced in patients with diabetes. Now
across all these three endpoints, the effect of Empagliflozen did
not differ in patients with prediabetes or normal glycemia. And
importantly, there was no increased risk of hypoglycemic events
in either subgroup compared with placebo. So a very nice paper
there. And that was from Dr. Gerasimos Filippatos from Athens
University Hospital Attikon and colleagues.


Dr. Greg Hundley:


Wow, Carolyn, just really interesting information coming out of
the world of SGLT2 innovation. Well, Carolyn, my next paper comes
to us from the world of preclinical science and it's from Dr.
Kunhua Song from the University of Colorado Anschutz Medical
campus. So Carolyn, abnormalities of calcium homeostasis are
closely associated with cardiac arrhythmias and heart failure and
conditions that cause death of millions of people every year.
Now, Carolyn Triadin physically interacts with the Ryanodine
receptor 2 and plays an important role in releasing calcium from
the sarcoplasmic reticulum to increase the free intracellular
calcium concentration in cardiomyocytes.


Now alternative splicing of a single Triadin gene produces
multiple Triadin isoforms, the predominant cardiac Triadin
isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons
from one to eight. In humans, mutations in the Triadin gene that
lead to a reduction in Trisk 32 levels in the heart cause cardiac
dysfunction, cardiac arrhythmias and sudden death. Decreased
levels of Trisk 32, in the heart, are also common in patients
with heart failure. However, mechanisms that regulate alternative
splicing of the Triadin gene to maintain levels of cardiac
Triadin protein in the heart, remains somewhat elusive.


Dr. Carolyn Lam:


Wow. I am always learning from these cool papers. Thanks Greg. So
what were the results?


Dr. Greg Hundley:


So Carolyn, the investigators found several things. First, the
cardio MyoSite specific long non-encoding RNA or link RNA Triadin
AS is essential for maintenance of cardiac function, exercise
capacity and normal lifespan and Triadin AS knockout mice were
found predisposed to cardiac arrhythmias in response to
catecholamine challenge. And finally Carolyn, Triadin AS
controls, levels, of cardiac Triadin isoforms, by regulating the
splicing of the Triadin gene.


Dr. Carolyn Lam:


Oh, wow. All right. So could you bring it home for us, Greg? What
are the clinical take home messages?


Dr. Greg Hundley:


Right, Carolyn. So cardiac explants from human heart failure
patients as well as patients with cardiac arrhythmias,
demonstrate reduced expression of Triadin AS and Triadin. And
then next the mechanism of the Triadin AS and Triandin AS
mediated alternative splicing of the Triadin gene to specifically
control levels of cardiac isoforms of Triadin in the heart,
provides a potential strategy for the treatment of cardiac
arrhythmias and heart failure.


Dr. Carolyn Lam:


Wow. Thank you, Greg. Well, let's talk about what else is in
today's issue. There's a Research Letter by Dr. Agarwal on
Chlorthalidone for resistant hypertension and advanced chronic
kidney disease.


Dr. Greg Hundley:


And Carolyn, I've got a perspective piece by Professor Cowie
pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs.
Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn,
how about we get onto that feature discussion and review the
utility of fractional flow reserve measurements, in patients
undergoing contrast coronary angiography.


Dr. Carolyn Lam:


Great, let's go.


Dr. Greg Hundley:


Welcome listeners to this August 30th feature discussion. And we
have with us this afternoon, Dr. Rod Staples from Liverpool and
our own associate editor, Dr. Nick Mills from Edinburgh,
Scotland. And gentlemen, welcome, Rod we'll start with you. Can
you describe for us the background information that went into the
preparation of your study and what was the hypothesis that you
wanted to address?


Dr. Rod Staples:


Okay, well thanks very much for hosting today. I'm very grateful
to be working circulation on this. I'm working with my co-lead
investigator Professor Nick Harrison from Southampton, who's been
doing an enormous amount of work on coronary physiology. He
actually did the original RIPCORD study, what I suppose we'd now
call RIPCORD 1, but it was called RIPCORD in the early days, an
observational study that showed that systematic use of fractional
flow reserve at the time of diagnostic angiography. Assessing the
functional significance measured in each of the major coronary
vessels, appeared in an observational study to have a dramatic
effect on the subsequent management plans allocated to patients.
And we decided to test this in a prospective randomized trial.


Dr. Greg Hundley:


Very nice. And so the exact hypothesis that you were going to
test was what?


Dr. Rod Staples:


At the time of coronary angiography, a strategy of systematic
measurement of fractional flow reserve in each and every coronary
vessel, large enough to be considered for revascularization,
would improve outcomes compared to a strategy based on
angiographic assessments alone.


Dr. Greg Hundley:


Very nice. And so you mentioned a randomized trial. Can you
describe further your study design and then which study
population did you include?


Dr. Rod Staples:


Well, this is a classic multicenter randomized trial performed in
the UK. We actually recruited in 17 different UK centers. We
asked them to assess patients who were scheduled for invasive,
currently angiography for participation against some very minimal
inclusion and exclusion criteria, trying to keep the trial
generalizable with good external validity. I think one important
point to note is that we did allow the inclusion of both patients
being assessed with elective angiography for stable symptoms, but
in the end half of the population were recruited in the context
of a stabilized acute coronary syndrome, a Non-ST-elevation event
a day or so down the line.


Dr. Greg Hundley:


And just a quick breakdown, how many men, how many women?


Dr. Rod Staples:


Well, it's in that respect, the population is very, very typical
for this type of cardiovascular trial. A 70, 30 split an age in
the midsixties, a diabetic population in the high teens. So a
very typical population we've seen in all this kind of trial
environment.


Dr. Greg Hundley:


Very nice. And so about 1100 patients. And then what were your
study results?


Dr. Rod Staples:


Well, I think there was a very good adherence to the study
protocol, very, very few crossovers. And also we were pleased to
see that our investigators stayed true to the protocol in that
the median number of epicardial vessels assessed by FFR in that
randomized arm was four. So there was a good assessment by FFR.
The trial was interesting in another respect, in that we assessed
an economic outcome based on all NHS hospital costs over the
following year and a patient reported outcome based on quality of
life using the WHOQOL, and interestingly we found no significant
differences either in total subsequent hospital costs from
randomization for a year, or indeed in patient reported quality
of life by WHOQOL or Angina symptoms by the Canadian
Cardiovascular Society classification.


Dr. Greg Hundley:


Very nice. And then, what about clinical events? Did you examine
those as well?


Dr. Rod Staples:


We did. And again, just a little caveat here, the trial is again
interesting in that, what is often in the UK these days called a
lean efficient methodology. Whereby, rather than individually
contacting individual trial participants or scouring medical
records, we interrogated the central national NHS digital
repository of all hospital admissions. And we examined
electronically a download of every hospitalization event for
every patient using algorithms based on diagnostic and procedural
codes to define events. And again, we found a very credible
representative rate exactly at incidents and events we would've
predicted, but again, no difference between the randomized
groups.


Dr. Greg Hundley:


Very nice, well listeners, now we're going to turn to our own
Associate Editor, Dr. Nick Mills. And Nick, again, you see many
papers come across your desk. What attracted you to this
particular manuscript? And it's very interesting study results.


Dr. Nick Mills:


Thanks, Greg. Firstly, it addresses an important clinical
question. Going beyond that, what appealed to me was it was
investigator initiated. It was managed by independent trials
unit. It recruited a target, it reported the registered outcomes
and it was thoughtfully interpreted. And the fact that it didn't
prove the hypothesis was irrelevant because it addresses a really
important clinical question. And I think it requires some
context, and that is that from the previous randomized trials The
FAME series, we have been chastised as interventional
cardiologists for not using FFR for relatively low use of FFR
clinical practice. It's always around one in 20 patients in most
series, given the evidence that FFR guided intervention improves
outcomes. But actually what FFR is good at is discouraging you
from stenting patients with stable Coronary Disease.


And so, I think a pragmatic trial that addresses that, the
fundamental question, should we be doing more FFR more broadly in
both acute and stable disease to guide revascularization with a
definitive message that we shouldn't, it doesn't improve quality
of life. It doesn't alter costs. Clinical outcomes are similar,
but there are more complications associated with routine pressure
wire use, gives us a very clear steer for the future. So this is
a really important trial addressing a fairly fundamental clinical
question.


Dr. Greg Hundley:


Very interesting. Well, Rod, we're going to turn back to you with
Nick's comments and how we're really seeing an evolution in
thought processes regarding both diagnostic angiography, and then
also the use of functional testing. What do you see is the next
study, really in this sphere of research that would be performed?


Dr. Rod Staples:


Well, I agree with Nick in a way that this raises important
philosophical points about the use of intelligence, selective
employment of tests or interventions, and that perhaps we need to
reflect this in the way we conduct our future studies. I think
we're all aware that fractional flow reserve and other measures
of functional significance are tremendously valuable in certain
clinical settings. And that value's been proven in randomized
trials, but in PRECORD 2, for example, if a patient randomized to
angiography only was an acute coronary syndrome patient, who had
inverted their T waves in their anterior leads, had an associated
troponin rise, an echocardiogram had shown some Hypokinesia in
the anterior territory. Then I think the potential value of PCI
in the LAD does not necessarily require FFR confirmation, and
hence that patient will have an equivalent outcome in the
angiography group. Similarly, high quality pre-angiography
preparation in the elective population with functional testing,
stress testing, other forms of imaging mean that we can reserve
the use of invasive fractional flow reserve, tight indices to
more selective use.


Dr. Greg Hundley:


And Nick, turning to you, what do you think is the next research
study that could be informative in this space?


Dr. Nick Mills:


I think our whole philosophy by how to manage stable coronary
disease is changing. In part because of some other landmark
trials that the Ischemia trial and some of the key secondary
analyses of the Ischemia trial that tells the Pathoma burden, low
attenuation plaque, other aspects of chronic disease are vitally
important in predicting major events in the future. And that
leaves us with the role for FFR or CT FFR, primarily to manage
symptoms. And I think we're getting increasingly good evaluating
patients before they get to the Cathflow, optimizing their
medical treatment. And so for me, the trial that we really need
to help us, is a CT FFR trial to understand the role of Ischemia
testing plus anatomical testing and how they dovetail in guiding
treatment decisions before they get to the cath lab. I think we
need to move this before the lab, always going to be a role for
intelligent FFR testing in selected patients once we get to it.
But I think that the question probably needs to be addressed
before they get to the cath lab.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank, Dr. Rod Staples from
Liverpool and Dr. Nick Mills from Edinburgh, Scotland for
bringing us this very interesting study, highlighting that a
strategy of systematic FFR assessment, when compared to
angiography alone, did not result in a significant reduction in
cost or improvement in quality of life.


Well, on behalf of Carolyn and myself, we want to wish you a
great week and we will catch you next week On the Run.


This program is copyright of the American Heart Association,
2022. 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, please visit
ahajournals.org.