Circulation September 25, 2018 Issue

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.


                                               
Ticagrelor has shown superior efficacy to clopidogrel in the
management of acute coronary syndromes. But what about in
patients undergoing PCI for stable coronary artery disease? Well,
our feature paper this week gives us answers to this question but
you're going to have to wait to the feature discussion to hear
these answers. That's coming up right after these summaries.


                                               
Our first original paper this week shows that RBM20 mutation
carriers have an increased risk of arrhythmias. You may recognize
RBM20 as that splicing factor which targets multiple pivotal
cardiac genes such as Titin and Calcium/Calmodulin-Dependent
Kinase 2 Delta or CAMK2D. In today's paper first author Dr van
den Hoogenhof and co-corresponding authors Dr Pinto and Creemers
from Academic Medical Center Amsterdam, compared the clinical
characteristics of RBM20 and Titin mutation carriers and used
RBM20 knock out mice to investigate the downstream effects of
RBM20 dependent splicing. They showed that loss of RBM20
disturbed calcium handling and led to more pro-arrhythmic calcium
releases from the sarcoplasmic reticulum. Patients that carried a
pathogenic RBM20 mutation had more ventricular arrhythmias
despite a similarly depressed left ventricular function compared
to patients with a Titin mutation.


                                               
Targets of RBM20 splicing were enriched for calcium and ion
handling genes, most notably CAMK2D and type 2 Ryanodine
receptor. Loss of RMB20 induced an increased L-Type Calcium
current density, intracellular calcium overload, increased
sarcoplasmic reticulum calcium content and increased spontaneous
calcium releases which all could be attenuated with treatment
with an L-type calcium channel blocker. Furthermore, these
results suggest that RBM20 mutation carriers should be closely
monitored for potential electrical disturbances and cardiac
arrhythmias even in the early stages of disease.


                                               
Echocardiographic quantitation of degenerated mitral
regurgitation is recommended in clinical guidelines but is it
really scalable to routine clinical practice? First author
Antoine, corresponding author Sorano from Mayo Clinic Rochester
Minnesota and their colleagues looked at more than 3900 patients
diagnosed with isolated mitral valve prolapse between 2003 and
2011 and to any degree of mitral regurgitation quantified by any
physician or sonographer in routine clinical practice. They found
that in multi-variable analysis routinely measured effective
regurgitant orifice area was associated with mortality
independent of left ventricular ejection fraction and systolic
diameter symptoms or age and comorbidities. Furthermore, compared
with general population mortality excess mortality appeared for
moderate mitral regurgitation with an effective regurgitant
orifice area above 20 squared millimeters and became notable with
an effective regurgitant orifice area above 30 squared
millimeters which then steadily increased with even higher levels
of above 40. Thus, quantitation of degenerative mitral
regurgitation is scalable to routine clinical practice with
strong independent prognostic power when performed routinely by
multiple practitioners.


                                               
The next study identifies a novel mechanism of lipid homeostasis
that is linked to a pseudo gene associated with the recently
discovered apolipoprotein known as APOO. Co-first authors
Montasser and O'Hare, corresponding author Dr Mitchell from
University of Maryland School of Medicine in Baltimore, performed
an array based association analysis in more than 1100 Amish
subjects and identified a variant strongly associated with LDL
cholesterol levels. They identified a founder haplotype on
chromosome 5 which was associated with a 15 mg/dl increase in LDL
cholesterol after recombination mapping, the associated region
contained eight candidate genes. Using a zebra fish model to
evaluate the relevance of these genes to cholesterol metabolism
they found that the expression of the transcribed pseudo gene
APOOP1 increased LDL cholesterol and vascular plaque formation.
Thus, based on these data the authors proposed that APOOP1 
regulates levels of LDL cholesterol in humans and represents a
novel mechanism of lipid homeostasis.


                                               
The Orion-1 trial demonstrated that inclisiran which is a small
interfering RNA therapeutic that targets PCSK9 MRNA with
[inaudible 00:05:42] produces significant LDL reduction. In
today's study from Dr Ray from Imperial College London and
colleagues, the authors described in detail the effect of
inclisiran on prespecified secondary lipid and lipoprotein
outcomes over time for up to 210 days and also described the
individual variation and response in these measures. They found
that a single 300 milligram dose of inclisiran  lowered
non-HDL cholesterol at day 180 by 35% and a second dose at day 90
resulted in a 46% reduction at day 180. Similarly a single dose
of 300 milligrams of inclisiran  reduced apolipoprotein B by
31% at day 180 and a second dose of 300 milligrams administered
in day 90 reduced apolipoprotein B by 41%. Significant reductions
in all atherogenic lipoproteins measured were sustained through
today 210. Furthermore, every individual had a reduction of
apolipoprotein B and non-HDL cholesterol at 180 days with the 300
milligram two-dose regimen of inclisiran. Thus, inhibiting the
synthesis of PCSK9 through small interfering RNA may be a viable
alternative to monoclonal antibodies with respect to effects on
atherogenic lipoproteins and that brings us to the end of our
summaries. Now for our feature discussion.


                                               
Ticagrelor has superior efficacy to clopidogrel in the management
of acute coronary syndrome but it has not really been assessed in
patients undergoing PCI for stable coronary artery disease. For
our feature paper today it's going to shed some light and help us
with this question and these are the results of the STEEL-PC
trial. I'm so pleased to have with me right now the corresponding
author Dr Robert Storey from University of Sheffield in the UK as
well as our associate editor who managed this none other than Dr
Stefan James from Uppsala University. Thank you.


                                               
Rob, could you tell us what is the issue you tried to address and
because your study is not that simple, we're not used to thinking
about these pharmacodynamic and kinetic studies so could you
explain a bit of what you did?


Rob
Storey:                       
Well it's quite a few concepts that we assessed in this study.
We've got data from a number of studies showing that Ticagrelor
both at doses of 90 mg twice daily and 60 mg twice daily is more
reliable and superior P2Y12 inhibitor compared to clopidogrel.
We've got this issue of very variable response to clopidogrel
with some poor responders and some high responders and a range in
between. That's fairly well established and part of this study
was to get more data on the 60 mg dose of Ticagrelor in these
stable CAD patients undergoing PCI and get some pilot data on
clinical efficacy obviously this study was not part of clinical
outcomes.


                                               
But, there's another issue in terms of adenosine uptake so
Ticagrelor has a relatively weak effect on adenosine uptake into
red cells and other cells and this may or may not explain some of
its clinical effects including some adverse effects such as
dyspnea. We wanted to get a better idea of the impact of
Ticagrelor at both these doses on adenosine uptake.


Dr Carolyn
Lam:               
Could I ask ... Okay this may be naïve. I'm not an interventional
cardiologist but why would you expect something different in an
acute coronary syndrome compared to stable coronary artery
disease? Is there an underlying hypothesis there?


Rob
Storey:                       
Well there can be changes to their differences in platelet
reactivity although those aren't particularly great and
overwhelmed really by P2Y12 inhibitor like Ticagrelor which gives
such reliable inhibition of the P2Y12 receptor. But, there have
been a limited number of groups that have looked at adenosine
uptake and so we wanted to get independent confirmation or not of
whether Ticagrelor therapeutic concentrations impacting on
adenosine uptake and get some ideas of whether it's affecting
circulating adenosine levels. That's an important question in
terms of understanding the mechanisms and actions of Ticagrelor.


Dr Carolyn
Lam:               
Got it. Thanks for breaking it down so nicely. So what did you
find?


Rob
Storey:                       
What we found was surprisingly that we saw no impact of
Ticagrelor at either dose and at any time point within a month
after PCI on adenosine uptake. That is the circulating levels of
adenosine and the rate at which adenosine is taken up by cells in
the blood mainly red blood cells. The explanation for that really
is that the therapeutic levels of Ticagrelor that you see are not
sufficient to impact on adenosine uptake because it's a very weak
inhibitor of the adenosine uptake pathway known as the MT1. The
therapeutic levels are just not getting up to a high enough
concentration to have a significant impact on that.


Dr Carolyn
Lam:               
Stefan, you've thought a lot about this. What did you think of
the findings?


Stefan
James:                   
I think it's very interesting. Of course, the pharmacodynamic
effects that you can measure by pretty simple means, the level of
platelet inhibition, it should be similar in ACS and stable
coronary artery disease and I think it's sort of confirming what
Rob has been showing in other populations with ACS ... we have
been very interested in trying to understand the additional
mechanisms of action of Ticagrelor... try to understand the
mortality rate without the benefit for Plato, for example. Was it
only -- platelet  inhibition or were there other mechanisms?
And, there is a specific Ticagrelor related side effect, dyspnea,
which we would have been interested in understanding... is this
a  mechanism of action? We can't really explain that. 
There are other mechanisms and other effects that we have seen
can also be explained by adenosine, so I thought it was very
interesting and important to understand more about these
mechanisms.  


Dr Carolyn
Lam:               
Yeah.


Stefan
James:                   
But I would like to ask you, Rob. Do you think this adenosine
hypothesis now, is dead, or should we still try to explore this?


Rob
Storey:                       
Well of course in this study what we didn't look at was the
adenosine kinetics in the tissue level which is where we
hypothesize the dyspnea may arise from stimulation of C5 is in
the lung tissue so we're missing that piece of information. It's
still conceivable that very weak levels of ENT-1 inhibition may
impact from adenosine levels in the tissue. We're not seeing a
strong ENT-1 inhibition sufficient to raise circulating levels or
something that we can pick up on this in vitro assay.


                                               
I think it still remains an open question. We've got this sort of
contradictory information from drugs like cangrelor and other
drugs in development like Elinogrel  where we don't see an
impact on adenosine but they still may cause dyspnea.  So I
think it's a very open question still.


Stefan
James:                   
Do you think that your paper gives us additional strength to the
hypothesis that the mortality benefit for ticagrelor as seen in
Plato is explained by the platelet inhibition and the balance
between the reduction in ...


Rob
Storey:                       
Well I think what we see really in all these studies is that
Ticagrelor is a fantastically effective PTY12 inhibitor. It gives
you the best level of platelet inhibition during maintenance
therapy out of all the available PTY12 inhibitors. And clearly
having such more reliable PTY12 inhibition than clopidogrel could
still be driving a mortality benefit in high risk patients so we
can't exclude the adenosine pathway contributing to some of the
clinical effects but I think this sways me a little bit more to
the position of thinking this is most of the benefits through
platelet inhibition.


Dr Carolyn
Lam:               
Interesting. So you're on the cutting edge of this. What's the
next step then?


Rob
Storey:                       
Clearly we can see that very effective and reliable P2Y12
inhibition is important and leads to clinical benefits and I
think we need to implement that wherever we're using P2Y12
inhibitors. We need to take that message and use a more
consistent therapy rather among those with associated with
variable response which doesn't seem to make sense. I think this
stable PCI population, their risk has fallen. And we see that in
this study, quite a number of patients report a response to
clopidogrel but no stent thrombosis.


                                               
That really reflects, I think improvements in stent design and
implantation techniques, so the implication is that maybe aspirin
alone is enough to prevent stent thrombosis with modern
techniques if you get a good result but in the higher risk
patients particularly the ACS patients it's likely you need much
more reliable platelet inhibition and that's why Ticagrelor
really provides this security.


Dr Carolyn
Lam:               
So, Rob there is one thing you tested two doses and they seemed
to be equivalent at least in antiplatelet inhibition, right? So
what does this mean? Should we maybe preferentially use the lower
dose from now on, is there still room for the higher dose? Could
you share some insights there?


Rob
Storey:                       
Well I think one has to be cautious in not jumping to adopt a
dose just on the basis of pharmacodynamic data but clearly what
we show is that the 60 mg dose of Ticagrelor offers a very
reliable and consistent level of PTY12 inhibition and that's
likely to be very effective in preventing stent thrombosis in
combination with aspirin. We also show signals that were also
shown in the Pegasus study that the 60 mg dose may be better
tolerated such as with lower levels of dyspnea.


                                               
So, there is the option for off label use of the lower dose of
Ticagrelor in those who cannot tolerate the high dose due to
dyspnea because certainly they'll have better platelet inhibition
down titrating from 90 to 60 and if they were to switch to
Clopidogrel. So I think our study offers some comfort in terms of
that aspect. The only caveat is that you have to be careful not
to use strong CYP3A inducers such as some epilepsy drugs with
Ticagrelor cause that can increase the metabolism and we did have
one case of high platelet reactivity with strong CYP3A inducers
so using a higher dose initially I think is a good idea. The
label says 90 mg for 1 year following ACS and the 6 is licensed
beyond one year as a down titration predominantly.


                                               
Our study certainly gives some comfort that down titrating
earlier if a patient can't tolerate the 90 for whatever reason,
seems to be a justifiable thing. And the other thing is the
European guidelines support the use of Ticagrelor off label in
elective PCI and our study certainly gives some comfort that off
label use and the low risk elective PCI patients of the 60 mg
dose can be justified at least from a pharmacodynamic point of
view.


Dr Carolyn
Lam:               
Well, thank you because that's exactly what our audience is
loving to hear. How do these findings translate into the clinical
practice - Would you have any other take home messages for the
clinicians listening in?


Rob
Storey:                       
Well I think one thing we looked at also was troponin release
which is very common after PCI. We didn't see an impact of PTY12
inhibition high levels on troponin  release and I think that
sort of caveat in terms of that's not going to be the best
measure in terms of surrogate for efficacy in the PCI population.
The other question really is, how much of the platelet inhibition
and how much of the adenosine effects of Ticagrelor influence the
clinical outcomes and clearly the studies sways towards the
platelet inhibition very consistent high level of platelet
inhibition explaining most of the benefits.


Carolyn
Lam:                     
You've been listening to circulation on the run, don't forget to
tune in again next week.