Circulation November 03, 2020 Issue

This week’s episode features author Karolina Szummer and
Associate Editor Emmanouil Brilakis as they discuss the article
"Comparison Between Ticagrelor and Clopidogrel in Elderly
Patients with an Acute Coronary Syndrome: Insights from the
SWEDEHEART Registry."


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, Director of the Pauley
Heart Center at VCU Health in Richmond, Virginia. Carolyn, this
week's feature article, we're going to investigate antiplatelet
therapy use, but in older patients, as opposed to those that are
middle-aged, and have sustained a prior acute myocardial
infarction. But, before we get to that, how about we grab a cup
of coffee and jump into the other papers in the issue?



Dr Carolyn Lam: Absolutely, Greg. I've got my coffee right here,
and I really want to start with a paper that adds to our
understanding of, guess what, the sodium=glucose cotransporter 2
inhibitors, SGLT2 inhibitors, and their diuretic and natriuretic
effects in combination with loop diuretics. Of course, a
clinically really important question since now we know that SGLT2
inhibitors improve outcomes in patients with heart failure in
whom they are likely to be co-prescribed with a loop diuretic.
So, Professor Chim Lang from University of Dundee and his
colleagues performed the RECEDE-CHF trial, which was a randomized
double-blind placebo-controlled crossover trial of 23 patients
with type 2 diabetes and HF REF taking regular loop diuretics who
were randomized to the SGLT2 inhibitor empagliflozin 25
milligrams once daily or placebo for 6 weeks with a 2-week
washout period. The primary outcome was change in 24-hour urine
volume from baseline at week 6.



Dr Greg Hundley: So, empa versus placebo. What did they find?



Dr Carolyn Lam: In patients with heart failure and type 2
diabetes taking a regular loop diuretic, empagliflozin caused a
significant increase in urine volume at both day 3 and week 6,
compared to placebo, as well as empa also caused a significant
increase in electrolyte-free water clearance. Though there was a
small non-significant increase in natural uresis with
empagliflozin at day 3, this was absent by week 6. These results
suggest that empagliflozin may have an advantageous diabetic
profile in patients with type 2 diabetes and heart failure in
addition to loop diuretics, with only a short transient
natriuresis.



Dr Greg Hundley: Very nice, Carolyn. Great information.
Diuretics, heart failure reduced ejection fraction, and
empagliflozin. Well, my clinical paper comes from Dr Renato Lopes
from Duke University Medical Center, and this is a sub study from
the ISCHEMIA trial that evaluates whether an initial invasive
strategy in patients with stable ischemic heart disease and at
least moderate ischemia improves outcomes in patients with a
history of heart failure or left ventricular dysfunction when the
EF is greater than 35%, but less than 45%.



Dr Carolyn Lam: Aw, that mid-range ejection fraction. Favorite
topic. So, Greg, what did they find?



Dr Greg Hundley: Those with heart failure and left ventricular
dysfunction randomized to the invasive versus the conservative
strategy had a lower rate of the primary outcome, 17% versus 29%.
Whereas those without heart failure and left ventricular
dysfunction did not, 13% versus 14%. A similar differential
effect was seen for the primary outcome, all-cause mortality and
cardiovascular mortality, when invasive versus conservative
strategy associated outcomes were analyzed with LVF as a
continuous variable for those with and without prior heart
failure.



Dr Carolyn Lam: Wow, that is clinically important, Greg. So, can
you summarize our take home message?



Dr Greg Hundley: Well, Carolyn, ischemia trial participants with
stable ischemic heart disease and at least moderate ischemia with
a history of heart failure or LV dysfunction, were at increased
risk for the primary outcome. And in this small high-risk
subgroup with heart failure and an ETF between 35% and 45%, an
initial invasive approach was associated with a better event free
survival. This result should really be considered for hypothesis
generation and future studies.



Dr Carolyn Lam: Greg, for the next paper, do you remember
hydrogen sulfide? The stuff we learned about in school. It's the
gas with that characteristic foul odor of rotten eggs. Well,
guess what? This whole paper is about hydrogen sulfide, and in
the body, it actually has antihypertensive and anti-inflammatory
effects, and its endogenous generation key enzyme is
cystathionine gamma lyase, or CSE, and that's expressed in CD4+ T
cells. So today's paper provides insights into how all of these
players work together in the development of hypertension.
To investigate the pathophysiological relevance of this CSE
hydrogen sulfide system, co-corresponding authors, Doctors Geng
and Cai from Fuwai hospital and Chinese Academy of Medical
Sciences, Peking University Medical College, as well as Dr Xu
from Peking University Health Science Center in Beijing. Well,
they and their coauthors performed elegant experiments involving
peripheral blood lymphocytes, isolated from hypertensive patients
or spontaneously hypertensive rats. They also looked at mice with
CSE-specific knockout in T cells, and CD4 null mice.



Dr Greg Hundley: Well, Carolyn, what did they find?



Dr Carolyn Lam: Well, they found that endogenous cystathionine
gamma lyase, or CSE, and hydrogen sulfide, but not cystathionine
beta-synthase, in lymphocytes, responded to blood pressure
changes. Deleting CSE in CD4+ T cells exacerbated
angiotensin II-induced hypertension by reducing circulatory and
renal T regulatory numbers. Hydrogen sulfide from CSE
self-hydrates, liver kinase 1, thereby activating the AMP kinase
energy pathway to promote TReg differentiation and proliferation,
which then attenuates the vascular and renal immune inflammation,
and thus, prevents hypertension.



Dr Greg Hundley: Carolyn, this sounds like a very thorough study.
What are the clinical implications?



Dr Carolyn Lam: Endogenous CSE hydrogen sulfide in lymphocytes
may be both a potential biomarker of hypertension, or its
complications, or hydrogen sulfide donor may be a therapeutic
approach to lower hypertension.



Dr Greg Hundley: Great, Carolyn. Well, my next paper comes from
Professor Goo Taeg Oh from Ewha Women's University, and it really
involves the world of inflammation. So Carolyn, as you know,
macrophages produce many inflammation-associated molecules
released by matrix metalloproteinases, such as adhesion
molecules, as well as cytokines, which play a crucial role in
atherosclerosis. In this paper, the authors investigated the
relationship between Ninjurin-1, or nerve injury-induced protein
1, a novel MMP9 substrate expression, and atherosclerosis
progression.



Dr Carolyn Lam: Ninjurin-1? Interesting. So, what were the
results?



Dr Greg Hundley: Well, Carolyn, Ninj1 expression and
atherosclerosis progression were assessed in atherosclerotic
aortic tissue and serum samples from coronary artery disease
patients and healthy controls, as well as athero-prone,
apolipoprotein E-deficient, or APOE -/- wild type mice. Two
important findings, Carolyn.
First, the authors in vivo results conclusively showed a
correlation between Ninj1 expression in aortic macrophages and
the extent of human and mouse atherosclerotic lesions.
Ninj1-deficient macrophages promoted pro-inflammatory gene
expression by activating mitogene-activated protein kinase, or
MAP kinase, and inhibiting the phosphoinositide 3-kinase
signaling pathway. Whole-body and BM-specific Ninj1 deficiencies
significantly increase monocyte recruitment and macrophage
accumulation in atherosclerotic lesions through elevated
macrophage-mediated inflammation. Now, in addition and secondly,
macrophage Ninj1 was directly cleaved by MMP9 to generate a
soluble form that exhibited anti-atherosclerotic effects, as
assessed both in vitro and in vivo.
Treatment with the sNinj1-mimetic peptides, ML56 and PN12,
reduced proinflammatory gene expression in human and mouse
classically activated macrophages, thereby attenuating monocyte
transendothelial migration. Moreover, continuous administration
of mPN12 alleviated atherosclerosis by inhibiting the enhanced
monocyte recruitment and inflammation characteristics of the
disorder in mice, regardless of the presence of Ninj1.
So in summary, Carolyn, Ninj1 is a novel MMP9 substrate in
macrophages, and sNinj1 is a secreted athero-protective protein
that regulates macrophage inflammation and monocyte recruitment
in atherosclerosis.



Dr Carolyn Lam: Wow, Greg, that was incredibly summarized. Thank
you. Let's go through what else there is in today's issue. In
cardiology news, Bridget Kuhn talks about how the pandemic
intensifies the push for home-based cardiac rehabilitation
options. There's a white paper by Dr Ho and colleagues, including
me, describing the diagnostic dilemma of HFpEF. There's a
Research Letter by Dr Gill talking about the cardiometabolic
trait sepsis and severe COVID-19, a Mendelian randomization
investigation. There's also a Research Letter by Dr Wu on the
atlas of exosomes microRNAs secreted from human iPSC-derived
cardiac cell type.



Dr Greg Hundley: Carolyn, this issue is just packed with
articles, because I've got five more to tell our listeners about.
First, it's a research letter from Professor G. Hovingh,
entitled, Inclisiran Durably Lowers LDLC and PCSK9 Expression in
Homozygous Familial Hypercholesterolemia, The ORION-2 Pilot
Study. Next, there's an ECG challenge from Dr Jason Gilge
relating to AV conduction during atrial flutter. Next, Dr Keith
Churchwell has a nice piece related to the importance of those
involved in cardiovascular care and participating in their civic
duties, including voting. Next, Professor Karthikeyan has nice On
My Mind related to overestimation of stroke risk and rheumatic
mitral stenosis and the implications for oral anticoagulation.
And finally, Carolyn, another research letter, from Dr Pieter van
Paassen, entitled, Neutrophils and Contact Activation of
Coagulation as Potential Drivers of COVID-19.
Well, Carolyn, how about we get on to our feature discussion and
review in older patients, which antiplatelet therapy may be
safest?



Dr Carolyn Lam: Let's go!



Dr Greg Hundley: Well, listeners, now we're turning to our
feature discussion, and today we'll talk about antiplatelet
therapy. And then we have with us, Dr Karolina Szummer from
Karolinska Institutet, and our own Associate Editor, Dr Manos
Brilakis from the Minneapolis Heart Institute. Welcome to you
both, and Karolina, let's start with you. Could you describe for
us your hypothesis and some of the background information that
led you to perform this study?



Dr Karolina Szummer: Thank you so much for having me here and for
sharing the ideas behind our study. Current recommendations
recommend that we use high-potent antiplatelet agents for
treating myocardial infarctions, and in particular, elderly
patients are not included. So we decided to do an observational
study to look at patients in our Swedish registries treated for
myocardial infarctions who were 80 years and older.
Dr Greg Hundley: Very nice. Can you tell us a little bit more
about your study design? And also the study population?



Dr Karolina Szummer: The startup populations are all patients who
were admitted to an acute coronary care unit for treatment of
myocardial infarctions, and they were all 80 years and older, and
they were included from 2010 to 2017. So this encompasses the
period during which treatment with ticagrelor was introduced. So
we are comparing to ticagrelor versus clopidogrel for the
outcomes during the year, following the myocardial infarction.



Dr Greg Hundley: And how many patients did you enroll in the
study? And what were your study results?



Dr Karolina Szummer: We enrolled, in total, 14,000 patients, and
these consisted of non-STEMI and of STEMI patients. The majority,
about two thirds, were non-STEMI patients. We show, in this
study, elderly patients have a lower risk of readmission for
myocardial infarction or stroke, but they have a higher risk of
having readmission for bleeding and death. So the risk-benefit
ratio seems to be skewed towards having, probably, more harm with
ticagrelor being more risky than clopidogrel in this study
population of elderly.



Dr Greg Hundley: And was this true for both men and for women?



Dr Karolina Szummer: Yes. So this was true for both men and
women. And we did a sensitivity analysis. We looked closer at
those who are younger than 80 years old, and in this patient
population, the results selected in the same way as for our
cohort of elderly, they actually did have the same benefit with a
low risk of MI, stroke, and death, and high risk of bleeding. But
in the elderly, we noticed a signal towards harm with an
increased risk of death.



Dr Greg Hundley: It sounds like with ticagrelor, did we have a
lower risk of death and a slightly lower risk of myocardial
infarction and stroke, but a higher risk of bleeding? Was that
the findings?



Dr Karolina Szummer: So for the elderly, there was a high-risk of
death and bleeding with ticagrelor compared to clopidogrel, but a
lower risk of ischemic component of MI and stroke.



Dr Greg Hundley: And then with those under 80, those were the
ones that had the lower risk of death, lower risk of MI and
stroke, but the higher risk of bleeding?



Dr Karolina Szummer: Yes, that's correct. So really the end point
that differs most is that there is sustainment towards higher
mortality in the elderly, because in both younger and elderly,
the risk of readmission for bleeding was elevated in both.



Dr Greg Hundley: Now, let's turn to our own Associate Editor,
Manos Brilakis. Manos, can you help us put these results into
perspective, relative to other studies that evaluate the efficacy
of antiplatelet therapy, post myocardial infarction?



Dr Emmanouil (Manos) Brilakis: I would like to start by
congratulating Dr Szummer. It's a wonderful paper, and, I think,
provide some new insights on how to use the medications in the
ACS patients. And going on the background, if we look at the
guidelines, both the European guidelines, as well as the American
guidelines, what they say is that both ticagrelor, as well as
prasugrel, are preferred and recommended for patients with ACS,
both non-ST elevation ACS, as well as ST segment elevation
myocardial infarction. And actually, European guidelines say that
clopidogrel should only be used when prasugrel or ticagrelor are
not available or are contraindicated. And this is based on two
trials.
One is the PLATO trial, and the other is the TRITON-TIMI 38, that
both showed, actually, more benefit with the more intensive P2Y12
inhibitors. And this is what is extrapolated to all patient
populations. But as you've heard before, there was only a
minority of elderly patients that were included in those trials,
about 13% to 15%, and that is why the present study is important,
because it suggests that maybe we should look more carefully into
the patient's age and potentially other characteristics like
frailty or other comorbidities, that might actually alter the
risk-benefit ratio. And maybe those medications should not be
routinely given to all patients, but perhaps, elderly patients,
or at least some of them, might not require, and actually be
better off with clopidogrel.



Dr Greg Hundley: Let's turn back to Karolina. Karolina, the study
was observational. What do you see as, perhaps, a next study to
follow up the results that you've brought to us with this
study?
Dr Karolina Szummer: So the next step would definitely be to do a
randomized control trial in the elderly to explore this topic
further, to really know for sure what the safety and efficacy is,
and what's the best treatment would be for these patients.



Dr Greg Hundley: Very good. And Manos, do you have anything to
add?



Dr Emmanouil (Manos) Brilakis: One more thing. So, there was
actually a trial that compared ticagrelor as well as prasugrel
with clopidogrel in elderly patients that was called the POPUlar
AGE trial that was published last year. And actually this one,
published earlier this year, and actually this trial randomized a
thousand patients who were more than 70 years old, to either
more-intensive or less-intensive. And the results were actually
very similar to the findings from Dr Szummer's study from
SWEDEHEART, showing that there was more bleeding without any
ischemic benefit. And didn't show actually higher mortality but
didn't show any significant benefit. So that actually adds to the
data that maybe the elderly patients, the selection of
antiplatelet agent should be taken into account.
And I think for me, this also extrapolates the high bleed risk,
higher risk of bleeding, based on criteria, which we currently
use mainly for duration. We say, for example, if you're precise
DAPT score, which is a score for determining risk of bleeding, is
high, you should consider shorter duration of DAPT, but it
doesn't say anything about the type of DAPT. And for me, this
makes sense that the high bleeding risk, and age is one of the
main risk factors for high bleeding risk, should be taken into
account also for determining the type of P2Y12 inhibitor.



Dr Greg Hundley: Well listeners, we've had a great discussion
with Karolina Szummer from Karolinska Institutet, and our own
Manos Brilakis from the Minneapolis Heart Institute, really
reviewing the utility of ticagrelor versus clopidogrel in older
individuals, above the age of 80, that have sustained myocardial
infarction, and identifying that ticagrelor is associated with a
higher risk of death and bleeding, as opposed to clopidogrel,
opening the question up as to whether further studies in older
individuals need to be performed to examine the efficacy of
antiplatelet therapy.
So, on behalf of Carolyn and myself, we wish you a great week and
look forward to catching you On the Run next week. This program
is copyright the American Heart Association, 2020.