Circulation September 13, 2016 Issue

 


Carolyn:
Welcome to Circulation on the Run. Your weekly podcast summary
and backstage pass to the journal and it's editors. I'm Dr.
Carolyn Lam, Associate Editor from The National Heart Center and
Duke National University of Singapore. Have you wondered which
anti-platelet agent you should use in your patients with diabetes
and coronary artery disease? Well, our feature paper deals with
just this topic, so stay tuned, I'll be write back with it's
author and associate editor. First, here's your summary of this
week's journal: The first paper unravels novel peptides involved
in atrial extracellular matrix remodelling in atrial
fibrillation. This is work from first author Dr.
Barallobre-Barreiro, corresponding author Dr Mayr from King's
College London, and colleagues. They used novel mass spectrometry
methods to analyze extracellular matrix in human atrial
appendages from patients undergoing coronary artery bypass
surgery.


 
 
Now, previous proteomic studies have examined the cellular
proteome, but this is the first study to comprehensively
characterize extracellular matrix proteins in human cardiac
tissues, including the identification of glycosylation sites.
They found extensive cleavage in the protein core of decorin
which is a small leucine-rich proteoglycan that regulates
collagen fibrillogenesis and a variety of other extracellular
matrix cell signalling molecules. Decorin processing differed
between human ventricles and atria and was altered in disease.
It's C-terminus which is important for the interaction with
connective tissue growth factor was predominantly detected in
ventricles compared to atria. In contrast, atrial tissues from
patients in persistent atrial fibrillation had higher levels of
full length decorin, but also harbored a unique cleavage site
that was not found in atrial appendages from patients in sinus
rhythm. This unique cleavage site preceded the M-terminal domain
of decorin and altered the binding capacity for myostatin, this
altering muscle growth.


 
 
The cleaved decorin peptide antagonized myostatin, such that
myostatin expression was decreased in atrial appendages of
patients with persistent atrial fibrillation and in hearts of
decorin-null mice. Furthermore, a synthetic peptide corresponding
to this decorin region, those dependently inhibited the response
to myostatin in cardiomyocytes and in perfused mouse hearts. This
is clinically important because mystatin inhibition has been
implicated as a substrate for atrial fibrillation. This study
therefore provides first evidence that peptides generated from
the cleavage of extracellular matric proteins such as decorin,
constitutes a local regulatory mechanism for growth factors in
human cardiac tissue.


 
 
The next study looked at therapeutic hypothermia in patients with
out of hospital cardiac arrest, and questioned if it may be most
effective when induced early during cardiopulmonary resuscitation
or CPR, in contrast to prior trials that looked at therapeutic
hypothermia induced only after return of spontaneous circulation
and hospital admission. This is the RINSE trial from Professor
Bernard and colleagues from Ambulance Victoria Australia, which
was a multi center randomized controlled trial which assigned
adults with out of hospital cardiac arrest undergoing CPR to
either a rapid intravenous infusion of up to two liters of cold
saline, or standard care. The primary outcome measure was
survival at hospital discharge. Secondary end points included
return of spontaneous circulation.


 
 
The trial was unfortunately closed early at forty-eight percent
of the recruitment target, due to changes in temperature
management protocols at the major receiving hospitals. Still, a
total of one thousand, one hundred and ninety-eight patients were
randomized. Six hundred and eighteen to therapeutic hypothermia
during CPR, and five hundred and eighty to standard pre-hospital
care. Overall there was no difference in outcomes at discharge.
In patients with an initial shockable cardiac rhythm there was
lower rate of return of spontaneous circulation in patients who
received cold saline compared with standard care. Thus, although
this trial was stopped early, the data suggests that induction of
mild therapeutic hypothermia using a rapid infusion of large
volume intravenous cold saline during CPR did not affect outcomes
at hospital discharge and may in fact cause harm in the subset of
out of hospital cardiac arrest patients who present with
shockable rhythm.


 
 
The last study provides the first generalizable risk score for
sudden cardiac death among American adults from the general
population without a history of cardiovascular disease. This
large study from Dr. Deo of University of Pennsylvania, and
colleagues, derived a sudden cardiac death prediction model using
the Atherosclerosis Risk in Communities or ARIC cohort, and
validated it in the Cardiovascular Health Study or CHS cohort.
They found that the twelve independent risk factors in the ARIC
study included age, male sex, African American race, current
smoking, systolic blood pressure, use of [anti-hypotensive
00:06:00] medication, diabetes, serum potassium, serum albumin,
HDO, estimated GFR, and QTC interval. Over a ten year follow up
period this model combining these risk factors showed good to
excellent discrimination for sudden cardiac death risk. In fact
the model slightly outperformed that of the 2013 ACC AHA pooled
cohort risk equations.


 
 
Finally, they also showed in the echocardiographic sub-cohort
that a left ventricular ejection fraction less than fifty percent
was present in only 1.1 percent of these participants and did not
enhance sudden cardiac death prediction. This study importantly
contributes to the distinguishing of sudden cardiac death risk
across the general population, and the results can help target
future strategies aimed at sudden cardiac death prevention for
the highest risk subgroups in the American general population.
That does it for the summaries. Now for our feature paper.


 
 
For our feature paper today we are discussing the super important
issue of anti-platelet therapy in type 2 diabetes with coronary
artery disease. Joining me today are the corresponding author,
Dr. Dominick Angiolillo from the University of Florida College of
Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate
Editor from Paris, France. Welcome gentlemen.


 
Dominick:
Thanks for having us.


 
Gabriel:
Hello.


 
Carolyn:
Dominick, I'd really like to start with you. Your paper entitled
the OPTIMUS-4 Study, is really a study of the pharmacodynamic
comparison of Prasugrel versus Ticagrelor in these patients with
type 2 diabetes and coronary artery disease. The whole question
is, what was the rationale to look at the pharmacodynamics?


 
Dominick:
As the title of the study says, OPTIMUS-4, it means that there
was an OPTIMUS-1, 2 and 3 in the past, which means that there's a
lot of thought that went into this and a lot of background
information. The rationale for this specific study was that we're
all well aware of the fact that patients with diabetes have high
platelet reactivity, which may be one of the reasons why they
have a higher risk of recurrent atherothrombotic events.
Therefore, the need to define ways to optimize their
anti-platelet effects, their levels of platelet inhibition. In
this specific study we took an approach of looking at the novel,
although we cannot call them novel nowadays, but the newer P2Y12
receptor inhibitors Prasugrel and Ticagrelor. Looking at them in
a head to head comparison from a pharmacodynamic standpoint to
see if one drug would be superior than the other, again, in terms
of a platelet inhibitory effect.


 
 
This is the rationale, and just to expand a little bit on this,
there's been a perception, again I want to underscore a
'perception' that based on subgroup analysis of the larger
clinical trials, that Prasugrel is a superior drug for patients
with diabetes. We do know that there's a benefit also with
Ticagrelor compared with Clopidogrel, although the absolute risk
reductions in the studies led to a perception that Prasugrel
would be a better drug. We said to ourselves, "Well, we're never
going to have a large scale head to head clinical comparison, why
don't we do a head to head pharmacodynamic comparison to see if
there are any differences?" This was the overall rationale for
conducting this specific study.


 
Carolyn:
That really sets a background perfectly. Tell us about the main
findings.


 
Dominick:
The main finding was as follows, we conducted a very detailed
pharmacodynamic study, this was a prospective randomized
double-blind double-dummy crossover study, with all patients on
the background of aspirin therapy. We looked at platelet
reactivity, using a variety of assays, I like to say it in every
possible salsa that you can imagine. The primary end point which
is platelet reactivity at one week into two drugs, using an [ADP
00:10:00] specific assay, actually showed that Ticagrelor was
superior to Prasugrel in terms of platelet inhibitory effects.
That was the only time point where it was shown, but the study
was actually designed to show the opposite, so it was a very
interesting finding, while with all the other time points there
were no differences between the platelet inhibitory effects
between the two drugs.


 
 
The other thing that we did look at, which gives a little bit of
a novelty to this study is, we went beyond just looking at ADP
induced effects, which is the target for these two drugs, we
looked at other signalling pathways which one would not believe
to be necessarily affected by P2Y12 inhibitors, and we found
these also to be reduced by both drugs to a similar extent.


 
Carolyn:
Fascinating. I'm going to get to your second point a bit later.
First, that first finding that surprisingly Ticagrelor appeared
to perform better using one of the specific assays and so on, I'd
really like Gabriel's opinion there. What do you think is the
overall clinical implications or what was the message that the
editorial board was hoping to get across to the audience? Because
I noticed you invited an editorial as well, a beautiful one
written by Dr. [Star-ee-an 11:36] Parker. What was the thinking
behind that?


 
Gabriel:
I think this is really a very important paper and I'm delighted
that Dominick Angiolillo and his team submitted it to
Circulation, in fact to be frank, we invited that paper after
seeing his presentation at the ACC earlier this year. The reason
that paper caught everybody's attention in the editorial board
was that it's addressing a frequent and deadly disease, diabetes,
that kills really patients with cardiovascular disease. There's a
critical issue in the treatment because of the limitations of
Clopidogrel because of the increased platelet reactivity in
diabetics, and there's tremendous interest in the novel P2Y12
inhibitors Prasugrel and Ticagrelor, and of course any hint of
differences between these agents has major clinical implications.
In addition, I think I can state that Dominick's team is really
one of the premiere international teams looking at this exact
issue, platelet reactivity in diabetics. What they did was really
state of the art rigorous clinical investigation by a highly
skilled team, looking rigorously at a double blind crossover
designed four different assays looking at platelet function and
platelet response, looking both at the effect of a loading dose
and the maintenance dose.


 
 
To me, the message is not a minute difference between the
treatments, in fact I think that even though it's the primary
outcome and it does show a slightly greater response with
Ticagrelor than with Prasugrel, the overall most of the other
assays at the other time points show a consistent good response
with both agents. To us, and to me, the message is that the novel
agents are clearly superior to Clopidogrel as we've seen in the
clinical trials, but they are fairly consistent in their benefit,
and it's reassuring to see this not in healthy volunteers but in
actual patients with stable coronary artery disease. I think it
was really important to show that. Certainly platelet reactivity
doesn't summarize entirely the effects of any drug, and there
might be platelet independent effects of Ticagrelor mostly and
possibly Prasugrel, but I think on the platelet side, I think
that this paper really nails it.


 
Carolyn:
I read that editorial and really agree that that puts everything
in perspective really well. I particularly like the figure that
accompanied the editorial. In case any of our listeners out there
don't really remember all the different pathways and how
Prasugrel and Ticagrelor and Clopidogrel are metabolized
differently, I'd really refer everyone to that figure as well.
Just want to pick up on one of the points that both of you
mentioned, and that is the non ADP induced platelet reactivity
that Prasugrel and Ticagrelor both seem to have an affect on and
so on, and if they're so effective, Dominick, is there still a
role for aspirin co-administration with these new anti-platelet
agents?


 
Dominick:
The study clearly puts a little bit more beef, let's put it this
way, to some of the ongoing clinical studies looking at whether
we need aspirin in the patients treated with one of these newer
P2Y12 receptor inhibitors. There are a series of ongoing studies
out there. There's a laundry list, so I'm not going to go into
the details. It does highlight that maybe when you have ultimate
P2Y12 blockade, which is a key signalling pathway and blocks
other responses by virtue of the fact that there's an interplay
between this pathway and others, maybe you do not need this
additional anti-platelet agent such as aspirin, which we know
there's associated with potential bleeding particularly
gastrointestinal side effects.


 
 
Having said that, this is not something that I'm advocating at
time, but what I am saying is that we'll need to look into the
results of the clinical trials. I believe that this study is an
additional piece of evidence from an ex vivo standpoint to prior
in vitro studies showing that aspirin is not associated with
additional platelet inhibitory effects, at least not substantial
platelet inhibitory effects. One can say that you may get away
with just one of these newer agents. Again, this is based on
pharmacodynamic findings, let's just wait for the clinical trial
results.


 
Carolyn:
I think that's so fairly put, and I learnt so much just listening
to this conversation. Thank you so much for joining me today. Any
last words from Gabriel?


 
Gabriel:
Yeah, I'd like to make a couple of points as an Associate editor
for Circulation. The first one is, this paper was picked up when
we saw Dominick's team's presentation at the ACC, and I think it
exemplifies that we really want to pick up the best science from
the meetings, either before the meetings and publish it
simultaneously as much as possible, but sometimes also at the
meetings, so expect to see Circulation Editors at your
presentations and maybe you'll seduce them enough with your
science that we'll get good science submitted to the journal. The
other aspect to it is also that I think with the new editorial
board there's really a focus on trying to make the journal very
international in it's approach, and I think it's fitting that I
am Associate Editor from Europe and I think there's no more
international a scientist than Dominick Angiolillo who's not only
a good friend but also has been trained in Italy, has practiced
in Spain, and now works in the US. I think he embodies how
science transcends boundaries and borders. I think there's a
definite international outlook to Circulation, and we're looking
for great science from anywhere in the world, not solely the US.


 
Carolyn:
Thank you so much Gabriel. Thank you so much Dominick. Thank you
listeners for listening today, you've been listening to
Circulation on the Run. Don't forget to join us next week for
more summaries and highlights.