Circulation December 15, 2020 Issue

This week's episode features author Adnan Kastrati and Associate
Editor Dharam Kumbhani as they discuss ticagrelor or prasugrel in
patients with ST-segment-elevation myocardial infarction
undergoing primary percutaneous coronary intervention.


TRANSCRIPT BELOW:


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
cohosts. 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 and Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Well,
Carolyn, this week's feature Ticagrelor Prasmul in patients with
ST segment elevation myocardial infarction undergoing primary
PCI. More on that story later, though. How about we grab a cup of
coffee and look at some of the other papers in the issue. Would
you like to go first?


Dr. Carolyn Lam:


I would. And actually, I'm going to talk about two papers and
they're all about BET, BET or promo domain, an extra terminal
epigenetic reta proteins. And in particular, this one called
BRD4. Now these proteins have emerged as potential therapeutic
targets in a number of pathological conditions, including cancer
and cardiovascular disease. Small molecular BET protein
inhibitors, such as JQ1 have demonstrated efficacy in reversing
cardiac hypertrophy and heart failure in preclinical models. Yet
genetic studies elucidating the biology of BET proteins in the
heart have not been conducted. Well, at least until this week's
issue where we have not one, but two papers, both elegantly using
mouse genetic studies.


Dr. Carolyn Lam:


In the first from Dr. Srivastava from Gladstone Institute of
Cardiovascular Disease in San Francisco and Dr. Jain from Perlman
School of Medicine in Philadelphia and their colleagues, they
found that BRD4, that particular BET epigenetic reader protein,
forms a transcriptional regulatory module with GATA4, a lineage
determining transcription factor in cardiomyocytes. This BRD4
GATA4 module was a critical orchestrator of mitochondrial
bioenergetics in the adult heart.


Dr. Greg Hundley:


Well Carolyn, that is a wonderful summary. What are the clinical
implications?


Dr. Carolyn Lam:


Identification of this new BRD4 interaction partner, such as
GATA4 could provide new insights into developing epigenetic based
therapies for heart failure. And the second paper is from Dr.
Joseph Hill and Thomas Gillette from University of Texas
Southwestern Medical Center and their colleagues. And what they
found was that BRD4 was essential to the maintenance of
mitochondrial electron transport chain function via
transcriptional regulation of a nuclear mitochondrial gene
network. BRD4 heterozygous deletion resulted in delayed heart
failure, whereas pharmacological BRD4 inhibition using JQ1
induced modest changes in mitochondrial genes suggesting
potential cardiac toxicity in targeting BRD4 at baseline.


Dr. Greg Hundley:


So what does this mean for us clinically, Carolyn?


Dr. Carolyn Lam:


As more potent and specific inhibitors are developed targeting
BRD4 for clinical settings in oncology and other diseases, we
must carefully monitor bezel cardiac performance for functional
and mitochondrial deterioration. Important clinical message
there.


Dr. Greg Hundley:


Great job, Carolyn. Well, my first paper is entitled "An
Association Between Immune Checkpoint Inhibitors with
Cardiovascular Events and Atherosclerotic Plaques" And it comes
to us from Dr. Tomas Neilan and his colleagues at the Mass
General Hospital. The study was situated in a single academic
medical center. And Carolyn in this paper, there are actually
three studies described. First, there's a primary analysis that
evaluated whether exposure to an immune checkpoint inhibitor
during treatment for cancer was associated with atherosclerotic
cardiovascular events among 2,842 patients versus 2,842 controls
that were matched by age, a history of cardiovascular events and
cancer type.


Dr. Greg Hundley:


In the second study, a case crossover analysis was performed with
an at risk period defined as the two year period after, and the
control period as the two year prior to treatment. The primary
outcome was a composite of atherosclerotic cardiovascular events
including myocardial infarction, coronary revascularization, and
ischemic stroke. And secondary outcomes included the individual
components of that primary outcome.


Dr. Greg Hundley:


Finally, in the third study in this paper, there's an imaging
stub study of 40 individuals, and it looked at the rate of
atherosclerotic plaque progression compared from before and after
starting the immune checkpoint inhibitor. All study measures and
outcomes were blindly adjudicated in this third study.


Dr. Carolyn Lam:


Wow, a three in one. That really sounds novel. So what did they
find, Greg?


Dr. Greg Hundley:


Right, Carolyn. In the matched cohort study, there was a
three-fold higher risk for cardiovascular events after starting
an immune checkpoint inhibitor. There was a similar increase in
each of the individual components of the primary outcome. In the
case crossover study, there was also an increase in
cardiovascular events from 1.37 to 6.55 per hundred person years
at the two year time point.


Dr. Greg Hundley:


And then lastly, Carolyn, in the imaging study, the rate of
progression of total aortic plaque volume was three fold higher
after immune checkpoint inhibitors from 2.1% per year to 6.7% per
year after receiving these agents. The association between immune
checkpoint inhibitor use and increased atherosclerotic plaque
progression was attenuated with the concomitant use of statins or
corticosteroids.


Dr. Carolyn Lam:


Wow, Greg. So I suppose what all this shows is that we need to be
aware of the cardiovascular risk prior to, during and after
treatment with immune checkpoint inhibitors and perhaps, you
know, optimize these cardiovascular risk factors. Thank you,
Greg.


Dr. Greg Hundley:


You bet. Well, Carolyn, my next paper is from Dr. George
Vlachojannis from University Medical Center at Utrecht. These
authors conducted a randomized control multi-center trial in the
Netherlands enrolling STEMI patients planned to undergo primary
PCI. Now patients were randomly allocated to receive in the
ambulance before transfer a 60 milligram loading dose of
Prasugrel, either being crushed or as integral tablets. The
independent primary end points were thrombolysis in myocardial
infarction, TIMI three flow in the infarct related artery at
initial coronary angiography, and complete greater than they go
to 70% ST segment resolution one hour post primary PCI. The
safety end points were TIMI major and bleeding academic research
consortium, or BARC, greater than three bleedings and secondary
end points included platelet reactivity and ischemic outcomes.


Dr. Carolyn Lam:


Nice trial design. So what did they find?


Dr. Greg Hundley:


Well, Carolyn, a total of 727 patients were assigned to either
crushed or integral tablets of Prasugrel. The median time from
study treatment to wire crossing during primary PCI was 57
minutes, and the primary end point of TIMI three flow in the
infarct related pre primary PCI artery occurred in 31% in the
crushed group versus 32.7% in the integral group. No difference,
P .064. Complete ST segment resolution one hour post primary PCI
was present in 59.9% in the crush group and 57.3% in the integral
group. Again, no difference, P equals .055. Platelet reactivity
at the beginning of primary PCI measured as the P2Y12 reactivity
unit, differed significantly between the groups. Crushed was 192
versus integral was 227 and the P value was less than 0.01. TIMI
major and BARC greater than three bleeding occurred in 0% in the
crushed group and 0.8% in the integral group and in 0.3% in the
crushed group versus 1.1% in the integral group respectively. So
there were no differences observed between groups regarding
ischemic events at 30 days.


Dr. Greg Hundley:


So Carolyn, in conclusion, prehospital administration of crushed
Prasugrel tablets does not improve TIMI three flow in the infarct
related artery, pre primary PCI or complete SD segment resolution
one hour post primary PCI in patients presenting with STEMI
planned for primary PCI.


Dr. Carolyn Lam:


Interesting and interesting stuff with platelet reactivity and
bleeding. Thank you, Greg. Well, there are other papers in
today's issue. There's an in-depth paper by Dr. Katsanos on
stroke prevention in atrial fibrillation, looking forward.
There's a research letter by Dr. Berger on myocardial injury in
adults hospitalized with COVID-19 and another by Dr. Hacker on
again, immune checkpoint inhibitor therapy and how that induces
inflammatory activity in large arteries.


Dr. Greg Hundley:


Well, Carolyn, I've got a couple other papers to talk about in
this issue. There's a On My Mind piece from Dr. deFilippi
entitled "Navigating Testing for COVID-19." There's a Perspective
from Dr. Ridker entitled "Equipoise Trust and the Need for
Cardiologists to Randomize Patients into Anticoagulation Trials
in the Time of COVID." There's an ECG challenge from Dr. Arias
entitled, "A Paced Tachycardia." And then finally, there's an
exchange of letters from Drs. Liu regarding a prior publication
entitled "Branched-Chain Amino Acid Catabolism Promotes
Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in
Platelets." Well, Carolyn, how about we get to the world of
anti-platelet therapy, ticagrelor prasugrel in patients with ST
segment elevation myocardial infarction, shall we?


Dr. Carolyn Lam:


Yes, let's go Greg.


Dr. Greg Hundley:


Well welcome, listeners, to our featured discussion today on this
December 15, and we are going to learn and discuss a little more,
a paper pertaining to ticagrelor versus prasugrel in patients
with ST segment elevation myocardial infarction. And our lead
author today is Adnan Kastrati from Deutsches Heart center in
Munich. And we also have our own Associate Editor, Dr. Dharam
Kumbhani from UT Southwestern in Dallas. Welcome, gentlemen.
Adnan, maybe I'll start with you. Could you tell us a little bit
about the background related to this article and what was the
hypothesis that you wanted to address?


Dr. Adnan Kastrati:


First of all, thank you very much for having me here to share
with you some thoughts. Thank you, Dharam, for handling our paper
in Circulation. We are very honored to have it published there.
About these are the ISAR REACT-5 series of studies dedicated to
optimizing the antiplatelet therapy in patients and anticoagulant
therapy in patients with acute and chronic coronary syndromes,
mostly who are undergoing a PCI procedure. We started to think
about that study immediately after the publication of the
platelet trial. We showed the superiority of prasugrel in
patients with acute coronary syndromes. These were the two new
ADP receptor antagonists at the time. And so as a physician, we
are interested to know which of them was better because there was
no direct comparison. And so that's why we decided to have an
open-label trial randomized. Most of the centers were situated in
Germany. Two centers were situated in Italy. The private end
point was adopted to the private end point of the trials in this
skill. Only one difference was there, instead of cardiovascular
death, we put all cause death in the primary end point. Why?
Because all cause death may also reflect the gradient end
bleeding between the two drugs. We wanted to have a more
integrative endpoint in this sense. So it was a combination of
all cause death, myocardial infarction, and stroke.


Dr. Adnan Kastrati:


It was a one year followup study. The study had two groups of
steady patients, which was about 40% of the patients, included in
the multicentral trial. And what we found in this trial, it was
the same results as it was found in the whole trial. The
advantages seen for prasugrel was present here also. Although we
lost the significance in the evaluation of the primary endpoint.
It was a 31% increase or 24% decrease with prasugrel in that
sense. But otherwise everything was in the same direction as in
the whole trial. And if you look also in the components of the
primary end point…, you have the chance to see that numerically,
it was the same trend for all components. Although the trial was
not powered for going to evaluate the component of the prime end
point. This was the main result.


Dr. Greg Hundley:


It sounds like you had 1,653 patients with STEMI randomized to
receive ticagrelor or prasugrel and 10% experienced the primary
end point in the ticagrelor group, but only 7.9% in the prasugrel
group. But the P value was only .10. We saw trends toward
favoring prasugrel rather than sort of a definitive difference.
Is that a correct summary?


Dr. Adnan Kastrati:


Yes, it is a correct summary. I would say this group of patients
is the most interesting subgroup of patients in ISAR 5 trial.
Why? Because the pretreatment strategy is the same. Because there
have been a lot of discussions about non-S-segment segment
elevation acute myocardial infarction due to the difference in
pretreatment. Although it was intentional, some people felt it's
different and they said you have two different strategies there.
In the STEMI subgroup, the pretreatment strategy was the same, so
it was a head to head comparison of two drugs, even according to
the same strategy. This is one.


Dr. Adnan Kastrati:


Second, you have to look back at the trials in the same
field…Both these trials, if you look closely to the results of
for STEMI patients, both of these trials haven't shown a
significant result for the STEMI subgroup. For plateau it was a P
value of 007 and for tritan it was a P value of 0014 only. Why?
Because in the tritan it was very specific. They included also
patients after fever analyzes and the significance came only from
the comparison of tritan in this group, not in the primary PCI
group. In the plateau and ISAR-5 we excluded these patients.


Dr. Greg Hundley:


Dharam, we're going to turn to you now. Adnan's really framed
this study nicely, but can you help us from your perspective, put
this study in perspective with others that have been published in
this space?


Dr. Dharam Kumbhani:


Yeah, thanks, Greg. And I want to congratulate Adnan and his
group for providing the field with another really well conducted
study in a very important field. The center has done some very,
very landmark trials, and I think this is another one of those.
It sort of helps us understand potentially the best treatment
mechanism or protocol for patients undergoing primary PCI for
STEMI in this case. As you nicely outlined sort of the background
for this, the only other trial that I'm aware of in this space is
directly comparing pasugrel and ticagrelor head to head was the
Prague 18 trial, which was smaller. I think it was about under
1100 patients. So even the STEMI cohort here was larger than that
trial. But that trial ended up being terribly underpowered and
unfortunately, also discontinued prematurely. So there wasn't
really any significant difference that was noted in that trial
and there was also a high crossover to clopidogrel in that other
trials.


Dr. Dharam Kumbhani:


So I think that trial, in fact, we had published a trial in
circulation as well. And I think this study sort of helps to
advance the field a little bit by providing a head to head
comparison between the two drugs. If I may extend some of the
discussion points that were brought up earlier, I think, again,
there is a couple of things that jumped out to me. One is, as you
mentioned, the semi cohort is very interesting and very
important. The p-value for interaction between the STEMI and the
non-STEMI population was not significant for the primary end
point. So that is certainly important when considering these
results.


Dr. Dharam Kumbhani:


And the second thing is the differences that were noted in the
rates of reinfarction, both spontaneous as well as PCI related.
And although that is very interesting, we certainly have to keep
that first point in mind when considering that. I think it
becomes more hypothesis generating that MI rates ended up being
higher with ticagrelor compared with prasugrel, and then sort of
trying to tease that out in terms of, was that just a play of
chance? Do we end up seeing that, is there a real biological
reason for that? All of the trials was extremely well done. There
were about 29 patients that did not have one-year follow-up and
there were about 67 or so MI events. I think it's very
interesting, and I think for at least for me, when I review this
trial, I think it brings up some very interesting hypotheses that
I think we would need to test further. Those anyway, my sort of
high-level thoughts on this excellent trial.


Dr. Greg Hundley:


Very good. Well, I'd like to ask you just in 20 seconds, each of
you, what's the next study that needs to be performed in this
field? Adnan, start with you.


Dr. Adnan Kastrati:


I don't expect trials doing the same thing that we have done in
ISAR-X5. We are planning now that ISAR-X6 trial. They are
finalizing the protocol, and it will be a large trial of 9,000
patients with acute coronary syndromes in which will test the
need for aspirin after discharge. That means all the spaces will
be with the potent P2I12 inhibitors. And one group, it will be a
placebo controlled trial. One group will have aspirin after
discharge, the other placebo. And this is now, for us, the most
important thing in this area.


Dr. Adnan Kastrati:


If I have the chance to respond to Dharam about the mechanistic
insights of this effect, I would say that we have shown
aggressive cardiology, our data about platelet function. It is
the biggest platelet function studies in this area, 600 patients.
We have tested in patients after PCI. We tested ADP in used
aggregation after ticagrelor and prasugrel. And prasugrel was
associated with a 30% reduction in platelet aggregation in these
patients. And I think that this offers the mechanistic basis also
for our results. And the results will be published shortly.


Dr. Greg Hundley:


Very nice, and Dharam.


Dr. Dharam:


Thank you for that response, Adnan. And Greg, to your question, I
agree. I think it would be hard, although the field would really
benefit from having a head to head comparison between these two
drugs again in a larger study. I do think a lot of the interest
and excitement in the ACS field is on de-escalation strategies as
the outline. And so I suppose that that's sort of where we'll see
a lot more in terms of clinical trials.


Dr. Greg Hundley:


Very good. Well listeners, this has been a wonderful discussion
and we appreciate the input from the primary author, Dr. Adnan
Kastrati, from the Deutsches Heart Center in Munich and our own
associate editor, Dr. Dharam Kumbhani from UT Southwestern.
Really reviewing prasugrel versus ticagrelor for primary PCI in
patients with STEMI only, and showing really no difference in
their primary endpoint of death, myocardial infarction, and
stroke, with however an increased risk of reinfection in the
patients receiving ticagrelor only.


Dr. Greg Hundley:


So on behalf of Carolyn and myself, we wish you a great week and
look forward to catching you next week On the Run. This program
is copyright the American Heart Association, 2020.