Sep 20, 2016
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.