Circulation December 6, 2022 Issue

This week, please join author Sean Pokorney and Associate
Editor Shinya Goto as they discuss the article "Apixaban for
Patients With Atrial Fibrillation on Hemodialysis: A Multicenter
Randomized Controlled Trial."


Dr Carolyn
Lam:              


Welcome to Circulation on the Run, your weekly podcast summary
and Backstage Pass of the journal and its editors. We're your
cohost. 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, Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn,
this week's feature, very interesting topic. In patients that
have end stage renal disease that require dialysis, questions
emerged should we anticoagulate them to prevent stroke, but of
course, there's a risk of excess bleeding. Well, this feature
discussion today is a study comparing apixaban and warfarin for
anticoagulation in exactly this patient population. But before we
get to those results, how about we grab a cup of coffee and go
through some of the other articles in the issue? Would you like
to go first?


Dr Carolyn
Lam:              


Absolutely, Greg. So my first paper is a pre-specified analysis
of the Paradise MI trial and knowing you'll likely ask me what
that was about, Greg, at least to summarize for everyone, the
Paradise MI trial compared sacubitril/valsartan with ramipril and
its effect on reducing heart failure events after an MI in more
than 5,600 patients with an acute myocardial infarction
complicated by LV systolic dysfunction, pulmonary congestion, or
both. Now in today's paper, what Dr. Mehran and colleagues found
was that among patients with a recent AMI and LV systolic
dysfunction, heart failure are both, sacubitril/valsartan
decreased the risk of coronary related events by 14% as compared
with ramipril over a median follow-up of 22 months. The reduction
in coronary events occurred with a favorable safety profile.


Dr Greg
Hundley:           


Wow, Carolyn, very interesting. Another indication perhaps for
sacubitril/valsartan, especially relative to ACE inhibitors. So
what does this mean for us clinically?


Dr Carolyn
Lam:              


Well, the results really cause us to consider if in addition to
antiplatelets and lipid lowering therapies, sacubitril/valsartan
may be explored as a potential agent to mitigate the residual
risk in survivors of AMI. Of course, dedicated studies are
necessary to confirm this finding and elucidate its mechanism.


Dr Greg
Hundley:           


Oh, very nice, Carolyn. Well, my first paper comes to us from the
World of Preclinical Science and Carolyn, this study evaluated
the scavenger receptors stabilin-1 and stabilin-2, proteins that
are preferentially expressed by liver sinusoidal endothelial
cells. Now, they mediate the clearance of circulating plasma
molecules controlling distant organ homeostasis. And studies
suggest that stabilin-1 and stabilin-2 may impact
atherosclerosis. So in this study, the investigative team led by
Professor Cyrill Géraud from the University Medical Center and
Medical Faculty in Mannheim, Heidelberg comprehensively studied
how targeting stabilin-1 and stabilin-2 affects atherosclerosis.


Dr Carolyn
Lam:              


Huh. All right, nicely explained. And so what did they find,
Greg?


Dr Greg
Hundley:           


Right, Carolyn. So inhibition of evolutionary conserved class H
scavenger receptors, stabilin-1 and stabilin-2, reduced aortic
plaque burden in preclinical models and athero protection was
mediated likely through down regulation on transcriptional factor
ERG1 in monocytes by multifaceted plasma protein changes. And
then finally, Carolyn transforming growth factor beta induced
periostin, reelin, and they are novel ligands of stabilin-1 and
stabilin-2 and are implicated in the development of
atherosclerosis.


Dr Carolyn
Lam:              


Okay. Wow. Could you give us a take home message, please Greg?


Dr Greg
Hundley:           


Right. Carolyn, I knew you had asked me this. So here we go.
Monoclonal, anti-stabilin-1 and anti-stabilin-2 antibodies
provide a novel approach for the future treatment of
atherosclerosis. And in the future, perhaps the plasma proteome
composition may serve as a predictive factor, biomarker or
surrogate parameter for cardiovascular disease in patients.


Dr Carolyn
Lam:              


Wow. Thanks Greg. My next paper is a true story of discovery. Now
I could ask you what you know about the condition hypertension
with brachydactyly type E... Greg, I love that expression. I
wouldn't be able to answer that too. So let me tell you the
story. So hypertension with brachydactyly type E is an autosomal
dominant Mendelian disease resembling essential hypertension.
Untreated patients die of stroke by the age of 50 years. Now,
these authors had previously demonstrated a gain of function
phosphodiesterase 3A gene mutations that caused the condition by
increasing peripheral vascular resistance.


They studied a large family with the condition earlier and were
puzzled that cardiac hypertrophy and heart failure did not occur
despite the decades of hypertension. And so they hypothesized
that in the heart, this phosphodiesterase 3A or PDE3A mutations
could be protective. Isn't that neat? And so corresponding
authors, Doctors Bader, Klussmann, Bähring and Hübner, all from
the Max Delbruck Center for Molecular Medicine in Berlin,
Germany. So they studied new patients as well as CRISPR-Cas9
engineered rat models of this condition of hypertension with
brachydactyly type E. And they comprehensively phenotyped all of
them with the human induced pluripotent stem cells carrying these
PDE3A mutations as well. So analyzing all of this from cells to
new patients to CRISPR-Cas9 models.


Dr Greg
Hundley:           


Wow, Carolyn, what an interesting story. So what did they find?


Dr Carolyn
Lam:              


So while in vascular smooth muscle, the PDE3A mutations caused
hypertension, in the hearts, they conferred protection against
hypertension-induced cardiac damage, hypertrophy and heart
failure. The mechanism involved long-term adaptations of mRNA and
protein expression as well as calcium cycling. Non-selective
PDE3A inhibition was a final short term option in heart failure
treatment to increase cardiac cyclic AMP and improve
contractility. So the data argued that mimicking the effect of
PDE3A mutations in the heart rather than non-selective PDE3
inhibition was cardioprotective in the long term. And these
findings could indeed facilitate the search for new treatments to
prevent hypertension-induced cardiac damage. This is discussed in
a really lovely editorial by Dr. Chiong, Houslay, and Lavandero.


Dr Greg
Hundley:           


Very nice, Carolyn. Wow. What another... we have such great
articles from the World of Preclinical Science. Beautiful
description as well. Well, we have some other articles in the
issue, particularly from the Mailbag. And we have a Research
Letter from Professor Thiagarajan entitled “Yield of Cardiac MRI
in a pre-participation cohort of Young Asian males with T-Wave
inversion.”


Dr Carolyn
Lam:              


Interesting. There's an exchange of letters between Dr. Xu and
Huang regarding the article associations of dietary cholesterol,
serum cholesterol and egg consumption with overall and
cause-specific mortality with a systematic review and updated
meta-analysis. There is a Perspective piece by Dr. Marcus on
Smart watch detected atrial fibrillation, the value in positive
predictive value. Isn't that interesting? And now onto that very,
very important question of anticoagulation in patients with
kidney disease. Can't wait. Let's go, shall we?


Dr Greg
Hundley:           


You bet. Carolyn. Welcome listeners to our December 6th feature
discussion. And we have with us today Dr. Sean Pokorney from Duke
University in Durham, North Carolina, and our associate editor,
Dr. Shinya Goto from Tokai University in Isehara, Japan. Welcome
gentlemen. Well, Sean, we're going to start with you. Can you
describe for us some of the background information that went into
the preparation of your study and what was the hypothesis that
you wanted to address?


Dr. Sean
Pokorney:        


Yeah, absolutely. Thanks for having me to discuss the renal AF
trial. And so I would say that the background information to the
study was that we know that atrial fibrillation is an incredibly
common condition in patients with chronic kidney disease. And the
decision of anticoagulation in patients with end-stage kidney
disease, on hemodialysis is really quite complex because these
patients are at high risk for stroke and they're at high risk for
bleeding. There are concerns with warfarin around calcific uremic
arteriolopathy or calciphylaxis and there have been some data
including from the original Aristotle trial that apixaban was
even more favorable in terms of bleeding reduction relative to
warfarin in patients with more advanced chronic kidney disease.


Although patients with creatinine clearance less than 25 were
excluded from Aristotle and really all patients with endstage
kidney disease on hemodialysis have been excluded from all trials
of atrial fibrillation in the past. And so we really wanted to
evaluate the safety of apixaban versus warfarin in patients with
end-stage kidney disease, on hemodialysis. And the hypothesis was
that apixaban was going to be non-inferior to warfarin with
respect to safety in terms of major or clinically relevant,
non-major bleeding in these patients with atrial fibrillation and
end stage kidney disease on hemodialysis.


Dr Greg
Hundley:           


Thanks so much, Sean. And you've mentioned the renal AF trial. So
could you describe for us, for your, I guess, substudy, what was
the study population? Who did you include and describe for us
also your study design?


Dr. Sean
Pokorney:        


Yeah, absolutely. So the trial included patients who had
end-stage kidney disease, and/or on hemodialysis, as well as
having concomitant atrial fibrillation. And the patients had to
have a CHA-VASc score greater than equal to two. All of the
patients had to be on hemodialysis for at least three months. So
these were chronic hemodialysis patients. And the study design
was an open label randomized trial that was 1:1 randomization
between apixaban and warfarin with blinded outcome evaluation.
And again, the primary endpoint of the study was major or
clinically relevant non-major bleeding based on ISTH definitions.
And there were secondary endpoints looking at stroke, systemic
embolism, death, medication adherence, and I think a really
important sub-study looking at PK data. And the goal was to have
50 patients where we included PK data that was going to more
represent what chronic apixaban dosing data would look like in
these patients with end-stage kidney disease on hemodialysis.


And originally the goal of the trial was to include over 700
patients. Originally we were trying to include 762 patients based
on our initial power calculations to achieve true
non-inferiority. Unfortunately, the trial enrollment was low and
so the trial was ultimately stopped prematurely at 154 patients,
although we were able to include the original targeted 50
patients in the PK substudy. The dosing that we used in the renal
AF trial was 5 mg of apixaban twice daily unless patients had a
second dose-reduction criteria in addition to chronic kidney
disease. So the fact that they had end-stage kidney disease and
were on hemodialysis counted as one dose reduction criteria and
patients that were under 60 kilograms or less were 80 years of
age or older, who had then a second dose-reduction criteria were
treated with the 2.5 mg twice daily dosage. And this was
important to note because this is different than the dosage that
was used in the AXADIA-AFNET trial.


Dr Greg
Hundley:           


Very nice. And so Sean, what did you find?


Dr. Sean
Pokorney:        


Yeah. So again, a lot of this data is really exploratory because
of the limited sample size, we weren't really able to
definitively conclude anything about the major or clinically
relevant non-major bleeding rates. I would say that some of the
key findings that we saw was that there were high rates of major
or clinically relevant non-major bleeding in both arms of the
trial and one year bleeding event rates were 25% in the warfarin
arm and 31% in the apixaban arm. And again, there was no
statistically significant difference, although again, this is
really exploratory. I would say that some of the other
interesting findings that we saw was that there were very low
rates of ischemic and hemorrhagic stroke in this patient
population. Again, there were 82 patients randomized to apixaban,
72 patients randomized to warfarin. And there was a difference in
the randomization because of the stratification by site that was
performed with the randomization.


And so within the 82 patients that were randomized to apixaban,
the patients, there was one ischemic stroke and one hemorrhagic
stroke. There were no hemorrhagic strokes in the warfarin
population and two ischemic strokes. Another key finding was the
high rates of mortality in this patient population. So 26% of the
apixaban patients experienced a mortality event, 18% in the
warfarin arm. So again, the mortality rates in these patient
populations were extremely high. I would also emphasize some of
the data from the PK analysis. So we looked at the PK analysis in
two different ways. For the patients that were treated with the 5
mg dose of apixaban, the PK data showed that there was consistent
overlap in the steady state concentration at one month compared
to patients in the Aristotle trial that had really mild to
moderate, moderate to severe and severe chronic kidney disease.


And so there was a consistent overlap in those steady state
concentrations between the end-stage kidney disease population on
hemodialysis and the chronic kidney disease population who
benefited from a apixaban in the Aristotle trial. Similarly, in
the 2.5 mg apixaban dose, the patient who had a second dose
reduction criteria in addition to chronic kidney disease, those
patients had consistent steady state concentrations of apixaban
relative to patients with mild to severe chronic kidney disease.


Dr Greg
Hundley:           


Very nice. Well thank you so much, Sean. And listeners, now we're
going to turn to our associate editor, Dr. Shinya Goto. Shinya,
can you, sort of, highlight for us some of the interesting
findings that you see from these study results that Sean just
presented?


Dr. Shinya
Goto:             


Thank you, Greg. Thank you, Sean for your wonderful summary of
your study. We had a great discussion with an editor for this
paper. As Sean pointed out, this is a kind of underpowered trial
or just terminated early, hypothesis was not tested in the trial.
But this population of patient clearly needs a real-world
clinical trial, patient with atrial fibrillation, end-stage
kidney disease, on hemodialysis; things a clinician could do. In
some country, nephology society defined warfarin contraindicated
in this population. As Sean pointed out, whether the development
of this trial include this high-risk population patient. So we
had a discussion whether the underpowered trial provided
something or nothing may be better than something just provided
here. Our consensus finally reached was, this limited trial still
provide something like, you have to make a decision to use the
anticoagulation. I mean, that the apixaban might be still used
due to the PK data. That is the kind of interesting point of this
trial.


Dr Greg
Hundley:           


Very nice Shinya. Well, Sean, turning back to you and Shinya with
that nice lead in really, Sean, what do you think is the next
study that needs to be performed in this sphere of research?


Dr. Sean
Pokorney:        


Yeah, absolutely. I think this is a challenging patient
population to study. And again, our trial, the renal AF trial
stopped early. Unfortunately, the AXADIA-AFNET 8 study also
stopped early, which was also looking at apixaban versus warfarin
outside the US and Europe. And so again, it is a challenging
patient population to study. But again, I also think it's a
really important population to study because one of the main
unanswered questions in this population is whether or not they
should receive anticoagulation. And so I think that ultimately
more work and additional studies trying to determine whether or
not these patients truly benefit from anticoagulation or stroke
prevention, I think is really one of the critical directions that
we need to take the field in.


Dr Greg
Hundley:           


And Shinya, do you have anything to add?


Dr. Shinya
Goto:             


Well, I fully agree with Sean. I mean, this is a very challenging
area and still raising the question whether anticoagulation is
necessary or not by your study. Maybe next generation oral
anticoagulant such as Factor XI inhibitor that is more elevated
to contact pathway may be beneficial. So we really need a good
clinical study in this very important and known answered area.


Dr Greg
Hundley:           


Very nice. Well listeners, we want to thank Dr. Dr. Sean Pokorney
from Duke University in Durham, North Carolina and our own
associate editor, Dr. Shinya Goto from Tokai University in Japan
for bringing us the results of this randomized open-label trial
of apixaban versus warfarin in patients with chronic kidney
disease on hemodialysis, revealing high rates of bleeding in both
groups, but due to low enrollment, was unable to identify its
non-inferiority endpoint. It's important to note, however, as
both our author and editorialists have identified further
research is really needed in this area to really examine the
efficacy of anticoagulation for stroke prevention in this
high-risk patient population.


Well, on behalf of Carolyn and myself, we want to wish you a
great week and we will catch you next week On The Run.


Dr. Greg
Hundley:          


This program is copyright of the American Heart Association 2022.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.