Nov 2, 2020
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.