Circulation June 5, 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, associated editor from the National Heart Center and Duke
National University of Singapore. This week's feature paper
reports results of the SWAP-4 study, which is the first study to
evaluate the pharmacodynamic impact of the timing and dosing of
clopidogrel administration when de-escalating from ticagrelor
therapy. Extremely important take-home messages for clinicians
looking after patients with coronary artery disease and a must
listen to. Coming up right after these summaries.


                                               
In the first original paper this week, chondroitin sulfate, well
known in the context of the monogenic disease
mucopolysaccharidosis type 6 may actually represent a novel
therapeutic approach for the treatment of general heart failure.
First author Dr Zhao, corresponding author Dr Foo, from Genome
Institute of Singapore studied changes in myocardial chondroitin
sulfate in non-mucopolysaccharidosis failing hearts and assessed
its generic role in pathological cardiac remodeling. They found
that failing human hearts display an abundant accumulation of
chondroitin sulfate proteoglycans in the extracellular matrix
largely localized to fibrotic regions.


                                               
The main component of chondroitin sulfate glycosaminoglycan
chains in human hearts was chondroitin 4 sulfate. TNF alpha was a
direct binding partner of glycosaminoglycan chains rich in
chondroitin 4 sulfate. Modification of the chondroitin sulfate
chain with the recombinant human arylsulfatase B, which is an
FDA-approved treatment for mucopolysaccharidosis type 6 that
targets chondroitin 4 sulfate, actually ended up reducing
myocardial inflammation and overall fibrosis in vivo. In two
independent rodent models of pathological cardiac remodeling,
this recombinant human arylsulfatase B treatment prevented
cardiac deterioration and improved functional recovery. Thus,
targeting extracellular matrix chondroitin sulfate represents a
novel therapeutic approach for the treatment of heart failure.


                                               
The next paper focuses on the subcutaneous ICD, which is an
entirely subcutaneous system that does not require
intra-procedural vascular access or endovascular defibrillator
leads or coils. Now the subcutaneous ICD has a novel mechanism of
defibrillation and is associated with an increased energy
requirement for defibrillation when compared to traditional
transvenous ICDs. Thus, ventricular fibrillation or VF conversion
testing at the time of subcutaneous ICD implantation is a class 1
recommendation.


                                               
Yet, what is the current adherence to this recommendation? Well,
today's paper addresses this question from first and
corresponding author Dr. Friedman from Duke Clinical Research
Institute. He and his co-authors studied first time subcutaneous
ICD recipients between 2012 and 2016 in the National
Cardiovascular Database Registry ICD Registry to determine the
predictors of use of conversion testing, predictors of an
insufficient safety margin during testing and in-hospital
outcomes associated with the use of conversion testing.


                                               
Results show that use versus non-use of VF conversion testing
after subcutaneous ICD implantation in the US was more related to
physician preference than patient characteristics. The study also
identified several patient characteristics associated with an
insufficient defibrillation safety margin. That included
increased body mass index, severely decreased ejection fraction,
white race, and ventricular pacing on the pre-implantation ECG.
Use of VF conversion testing after subcutaneous ICD implantation
was not associated with a composite of in hospital complications
or death. These data may inform ICD system selection and a
targeted approach to conversion testing.


                                               
We know that elderly patients are at elevated risk of both
ischemic and bleeding complications after an acute coronary
syndrome and display higher on clopidogrel platelet reactivity as
compared to younger patients. Does prasugrel at five milligrams
compared to clopidogrel reduce ischemic events without increasing
bleeding in the elderly? Today's paper addresses this question
from corresponding from corresponding author Dr Savonitto from
Manzoni Hospital Italy and his colleagues.


                                               
These authors performed a multicenter randomized open label
blinded end point trial comparing a once daily maintenance dose
of prasugrel five milligrams with the standard clopidogrel 75
milligrams in patients more than 74 years old with acute coronary
syndrome undergoing percutaneous coronary intervention. The
primary end point was a composite of mortality, myocardial
infarction, disabling stroke and re-hospitalization for
cardiovascular causes or bleeding within one year. Enrollment was
interrupted due to futility for efficacy according to
pre-specified criteria after a planned interim analysis when
1,443 patients had been enrolled with a median follow-up of 12
months.


                                               
At this point of interruption, there was no difference in the
primary end point between reduced dose prasugrel and standard
dose clopidogrel. The results of this Elderly ACS 2 study
therefore could not show overall clinical benefit of prasugrel
five milligrams versus clopidogrel in elderly ACS patients
undergoing early PCI.


                                               
The final study is the first to define the cellular and molecular
mechanisms of cardiac valve inflammation and fibrosis occurring
in the setting of systemic inflammatory disease. First author Dr.
Meier, corresponding author Dr Binstadt from University of
Minnesota used T-cell receptor transgenic mice which
spontaneously developed systemic auto antibody associated
autoimmunity leading to fibro inflammatory mitral valve disease
and arthritis.


                                               
They identified a critical population of CD301b/MGL2 expressing
mononuclear phagocytes that orchestrated mitral valve
inflammation and fibrosis in this mouse model. They further
demonstrated an analogous cell population was present in human
inflammatory cardiac valve disease. Finally, they defined key
inflammation molecules that drove mitral valve disease in this
model, thus providing multiple potential therapeutic targets that
are required for mitral valve inflammation and fibrosis.


Dr Carolyn
Lam:               
That wraps it up for your summaries. Now for our feature
discussion.


                                               
Searching between different classes of P2Y12 inhibitors including
de-escalation from ticagrelor to clopidogrel commonly occurs in
clinical practice. However, what are the pharmacodynamic profiles
of this strategy? Well, today's feature paper is going to provide
a lot of insights. I am so pleased to have the corresponding
author of the SWAP-4 study, Dr. Dominick Angiolillo from
University of Florida College of Medicine Jacksonville, as well
as our associate editor Dr. Gabriel Steg from Hôpital Bichat in
Paris, France. Dominick, now this is SWAP-4. That means there was
a SWAP 1, 2, 3. Could you just paint the background and rationale
for SWAP-4 and tell us what you found?


Dr Dominick Angiolillo:   We performed this study on
the background of a line of research that we've been conducting
over the past number of years of switching antiplatelet
therapies. There's so many different types of switches that can
occur and one of them is that which is defined as a de-escalation
which is that from a more potent P2Y12 inhibitor to a less potent
and one of those that occur frequently in clinical practice is
the switching from a ticagrelor to clopidogrel and this was
essentially the rationale for conducting the SWAP-4 study.


                                               
Now I want to start off with saying that the reason for doing
this study is not to advocate switching because we always
recommend that individuals follow guideline recommendations but
we performed this study because we wanted to provide clinicians
with some additional insights that if you're going to switch
particularly from ticagrelor to clopidogrel, which would be the
modality which is associated with, put it this way, with the
smoothest transition one drug to another.


                                               
This is the rationale. What we did was do a pharmacodynamic,
conduct a pharmacodynamic study taking patients who were on
standard treatment with dual antiplatelet therapy aspirin and
clopidogrel and they had a run-in phase with ticagrelor. And the
reason why we took patients on the back part of aspirin and
clopidogrel is because we then wanted to look at the effects
after switching to compare it with a baseline. There have been
some discussions about drug-drug interactions. And patients were
randomized to either continue with treatment with ticagrelor to
switch with a loading dose of clopidogrel, 600 milligrams 12
hours after last dose of ticagrelor. 24 hours after last dose of
ticagrelor or directly switch with a maintenance dose. So, the
randomization was into four groups.


                                               
Essentially to keep a long story short, what we observed was that
when de-escalating from ticagrelor to clopidogrel we did see an
increase in platelet activity obviously as expected. But the use
of a loading was not able to mitigate this increase but there
were no differences according to timing of administration of the
loading dose clopidogrel 12 or 24 hours. We had anticipated in
our study design that with the administration of the loading dose
24 hours after last maintenance dose we could have achieved a
smoother transition, but this was not the case.


                                               
Nevertheless, the overall conclusions of our study are supported
by the pharmacodynamic data in terms of you still achieve a
better transition when you give a loading dose than without a
loading dose. I was also want a little bit cautious and I think
during the review process of the journal and feedback from the
editors we kind of phrased in a very cautious way the suggestion
for a drug-drug interaction, in fact we suggested because there
are other ways to look into this phenomenon in more detailed
manner. For example, doing some specific pharmacodynamic analysis
which was not done in this study. Nevertheless, the take-home
message from a clinical perspective remains unchanged.


Dr Carolyn
Lam:               
Thanks so much, Dominick. That was a very important framing of
the paper that you gave us at the start that this trial was not
designed to try to say who should be de-escalated or not and that
should be in line with the guideline recommendations and yet such
an important just take-home message that if there is a need that
the 600-milligram loading dose of clopidogrel should be used. You
know, Gabriel, you've thought a lot about this and especially the
drug-drug interaction question. What are your thoughts there?


Dr Gabriel
Steg:               
Yeah, well first of I think this is an extraordinary, important
study even though it's a pharmacodynamic study, which many
clinicians might look at and then quickly read the abstract and
turn the page I think this is actually one of the most
interesting papers we've published in recent months. The reason
for this is this is tackling a very common clinical scenario,
which is having or desiring or wanting to de-escalate the
intensity of platelet therapy after a PCI or ACS from a potent
agent such as ticagrelor to a less potent agent such a
clopidogrel. And as nicely explained in the paper, there are
multiple reasons why this can occur.


                                               
A common clinical scenario is that cost is a major issue. Because
of the cost patients or physicians may want to switch to
clopidogrel, a generic drug as opposed to a branded drug. Another
scenario which is fairly common is side effects. Either nuisance
bleeding or maybe dyspnea with ticagrelor may prompt some
physicians and patients to want to deescalate to clopidogrel. To
a less intensive therapy which may not have dyspnea or may not
cause as much nuisance bleeding. And finally, sometimes it's done
on purpose because some believe that within a few weeks or months
following PCI or ACS the benefits of more intensive patient
therapy is less, the risk remains the same and therefore maybe we
could proposedly de-escalate therapy to clopidogrel and get away
with it and there have been a number of randomized studies and
observational studies that suggested that this might be feasible
although these studies have weaknesses. They're often open label.
They're often fairly small and somewhat underpowered.


                                               
So, we don't have a definitive answer. Nevertheless, this happens
on an everyday basis in most large clinical centers and we don't
know exactly how to do it and what the best way to do it and I
really want to credit Dominick's team for doing a rigorous series
of investigations, including this one, which is the latest one
but not the only one in trying to really map out how exactly we
should as clinicians manipulate these agents to achieve the best
safety and efficacy for our patients. And I think the message
here is very clear. Yes, you can de-escalate but you have to be
careful on how you do it. And I think you really need to use a
loading dose, a 600-milligram loading dose of clopidogrel if
you're going to deescalate from ticagrelor to clopidogrel to
avoid a gap in protection that might be deleterious to patients.


                                               
That does not address all of the questions that are raised by
de-escalation and as I pointed out I think outcome trial data are
really of paramount importance here, but I think this really
important because it has major practical implications for
clinicians worldwide on how to do this. So, I think this is a
great study. I really want to congratulate Dominick.


Dr Dominick Angiolillo:   Thank you.


Dr Carolyn
Lam:               
You looked at the genetic status as well. Could you tell us about
your findings there?


Dr Dominick Angiolillo:   We in the spirit of trying to
perform the most comprehensive possible assessment we have also
looked at the genetic background of our patients and in
particular looking whether the presence of a loss of function
allele for CYP2C19, which is involved with clopidogrel
metabolism, could have affected the outcomes. And the reason why
we did this there've been a lot of studies clearly showing that
if you have a loss of function allele for CYP2C19 you do have
higher levels of platelet reactivity. Therefore, we want to see
if those carriers would have had even a greater increase in
platelet reactivity. And again, we did all this in the spirit of
really trying to define again this from a pharmacodynamic
standpoint, if there could be any potential safety hazards with
such an increase in platelet reactivity with the de-escalation.


                                               
When we did our analysis, we did not find any impact of a CYP2C19
on our data. However, I think it's important to underscore that
we did not have too many patients with a loss of function allele
so clearly the study was not designed or nearly closely powered
to look into this assessment. So, I think that aspect does need
to be interpreted with caution.


Dr Carolyn
Lam:               
Thanks so much, Dominick. Were there perhaps caveats that
clinicians listening in should pay attention to? For example,
this study was conducted in stable patients with coronary artery
disease. What about patients with recent acute coronary syndrome?


Dr Dominick Angiolillo:   That's a great point. The
reason why we conducted this study in a more stable setting was
largely driven by two aspects. Well first of all, we wanted to
have a run-in phase of patients switching from clopidogrel to
ticagrelor to have some sort of baseline to reference to after
the switch. And this would have been mostly ACS patients that
would be less likely to be on clopidogrel. The second is purely a
safety issue. We know that patients with acute coronary syndromes
are associated with higher levels of platelet reactivity and in
the context of a study where we do not know the pharmacodynamic
profiles associated with de-escalation or better off we don't
know the details.


                                               
And so, there was a safety consideration there which is why we
did it in stable patients. But what we can say is tied with
Gabriel's comment before in all the studies out there are not
powered or do not have the rigor of a mega trial. Although we
give our suggestions and recommendations, practical
recommendations on how to switch, there is an increase in
platelet reactivity and we stress in our manuscript that if you
are going to switch, please try to delay this as much as possible
because those increases in platelet reactivity for example, in a
patient with an ACS for example, immediately after PCI, something
that we probably would not want for our patients. I'm very happy
actually that we conducted the study in the more stable cohort
because we had less confounders. This is kind of the reason
behind all this.


Dr Gabriel
Steg:               
The last question maybe I would ask Dominick is whether he
believe that results would be different if we had the patients on
a maintenance therapy for longer with clopidogrel, do you believe
that the risk of rebound or drug-drug interaction are the same
early on after institution of therapy or later on? Is there any
reason to expect a difference?


Dr Dominick Angiolillo:   That's a great question. My
personal opinion would be that with longer duration the platelet
reactivity would have gone back down to baseline. We actually
continue to study out up to around 10 days following the switch
which we thought would have been sufficient time to get back to
baseline and it was not the case particularly in the patients
whose switch was a 75 milligram. The answer's probably yes.
Probably yes. To redesign the trial again maybe having that
30-day time point as well would have been obviously of added
value.


Dr Carolyn
Lam:               
Thank you so much, Gabriel and Dominick. This has been extremely
insightful. Fun as always.


                                               
You've been to Circulation on the Run. Don't forget to tune in
again next week.