Circulation April 28, 2020 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.


Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley
Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn,
our feature article today looks at the use of Apixaban versus
Warfarin, so a trial between the two in patients with atrial
fibrillation and advanced kidney disease. But before we get to
that, how about if we break away, grab a cup of coffee and go
through some of the other important papers in this issue?


Dr Carolyn Lam: Yeah, and why not start with talking about our
gut and fiber in the diet. Now, we know that a diet poor in fiber
is associated with the prevalence of hypertension, but what are
the underlying mechanisms? Well, this first paper I want to talk
about is from Dr Marques from Baker Heart and Diabetes Institute
in Australia and colleagues who basically performed a nice series
of mouse experiments and found that a diet lacking prebiotic
fiber led to a gut microbiome that was pro hypertenenogenic
facilitated the development of cardiac hypertrophy in germ free
mice.


Even in the absence of fiber, gut metabolites called short chain
fatty acids usually produce from the fermentation of prebiotic
fiber by the gut microbiota, but they were able to protect
against the development of hypertension, cardiac hypertrophy and
fibrosis in a preclinical model. This cardioprotection involved
short chain fatty acid receptors, and a decrease in the ratio of
sodium to potassium excretion and changes in genome white
methylation that supported higher levels of T regulatory cells.


Dr Greg Hundley: Oh my goodness, Carolyn. So I need to know what
I eat for lunch? What's the take home message here?


Dr Carolyn Lam: Lots of fiber and definitely not the low fiber
westernized diet, which may underlie hypertension. And how?
Through deficient short chain fatty acid production and thus the
take home is maintaining a healthy, short chain fatty acid
producing microbiome is important for the cardiovascular health.


Dr Greg Hundley: Wow, Carolyn. I love that article because it
really helps provide some perspective on all the diet information
that we've been receiving lately. Well, my paper is from doctor
... another Carolyn, but this is Carolyn Ho from Brigham and
Women's Hospital-


Dr Carolyn Lam: I love her.


Dr Greg Hundley: ... And it involves hypertrophic cardiomyopathy
and left ventricular systolic dysfunction. So Carolyn, the term
end-stage has been used to describe hypertrophic cardiomyopathy
with left ventricular systolic dysfunction. And that's defined
when someone has hypertrophic cardiomyopathy and the LVEF is less
than 50%. The prognosis of patients with this condition has been
reportedly poor, but it's very rare in occurrence and therefore,
the natural history really remains incompletely characterized. So
what did the authors do in this study? They evaluated more than
500 patients from 11 high volume hypertrophic cardiomyopathy
specialty centers comprising the international Sarcomeric Human
Cardiomyopathy Registry or SHaRe registry. And they were used to
describe the natural history of patients with hypertrophic
cardiomyopathy and left ventricular systolic dysfunction.


Dr Carolyn Lam: Interesting. So what did they find, Greg?


Dr Greg Hundley: Number one, first overall, this group of
patients, hypertrophic cardiomyopathy with left ventricular
systolic dysfunction occurs in about 8% of those with
hypertrophic cardiomyopathy. Although the natural history of left
ventricular systolic function and hypertrophic cardiomyopathy is
variable, 75% of those that have this condition experience
adverse events including 35% experiencing a death equivalent at a
medium of 8.4 years after developing their systolic dysfunction.
In addition to clinical features, the genetic substrate appears
to play a role in both prognosis, so there are multiple
sarcomeric variants, and in the risk for incident development of
left ventricular systolic function with hypertrophic
cardiomyopathy due to variance in the thin filaments within those
myocytes.


Dr Carolyn Lam: Nice. Thanks for that Greg. My next paper is a
really interesting secondary analysis if you may, of the EXSCEL
study. As a reminder, the Exenatide Study of Cardiovascular Event
Lowering or EXSCEL assessed the impact of once weekly exenatide
versus placebo in patients with type two diabetes and showed
non-inferiority but not superiority for the primary MACE outcome.


Now, during this trial, while aiming for glycemic echo-poise, a
greater drop-in of open label glucose lowering medications
occurred in the placebo group, thus prompting the current
authors, which is Dr Rury Holman from University of Oxford and
their colleagues to really explore the possible impact of
unbalanced open labeled drop-in of glucose lowering medication on
EXSCEL outcomes. To our modern diabetes trial, they used three
methodologies. One, drop-in visit, right censoring. Two, inverse
probability for treatment waiting. And three, applying drug class
risk reductions. Now, Greg, I could either quiz you on these
methods or summarize the results, which would you prefer?


Dr Greg Hundley: Well, Carolyn, this calls for the infamous phone
a friend. So one of the nice things we have at Circulation is a
wonderful group of statisticians that really help us go through
all the papers. But I sure would like to pick up the phone and
call one of those folks now. But I think what I'm going to do ...
maybe just give me the results of this study. That's what I
prefer.


Dr Carolyn Lam: I thought you might say that. So the EXSCEL
observed has its ratios for MACE remained robust after right
censoring or application of the literature derived risk
reductions, but the exenatide versus placebo MACE effect size and
statistical significance were increased by the inverse
probability treatment waiting approach. So I think the take home
is that effects of open label drop in cardioprotective
medications do need to be considered carefully when designing,
conducting and analyzing cardiovascular outcome trials of glucose
lowering agents. Do we have the perfect solution? Perhaps not,
but this was a really important paper to just look at and study.
So Greg, I can see that you are stats out, so I'm going to tell
you a little bit more about other papers in this week's issue.


There's a research letter by Dr Zhang on transcription factor
Kruppel-like factor 15 and how it regulates the circadian
susceptibility to ischemia-reperfusion injury in the heart.


Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple of
other papers. There's a nice in-depth piece from Dr Gregory
Marcus from the University of California, San Francisco on how we
evaluate and manage patients that have premature ventricular
contractions. Dr Mori Krantz from Denver Health and Hospital
Authority gives us an EKG challenge in someone that's had a
needle stick. And then finally, there's a nice perspective piece
from Dr Paul Armstrong from the Canadian VIGOUR Centre,
department of medicine cardiology at the University of Alberta.
And he really goes over nicely how we're going to do global
collaboration to enhance cardiovascular care. What a great issue.
And now onto that feature where we're going to hear a little bit
about Apixaban and Warfarin in those individuals with atrial
fibrillation and chronic kidney disease.


Dr Carolyn Lam: Let's go, Greg.


Today's feature paper really represents the first randomized data
on NOAC versus warfarin in a very important group of patients,
that is those with atrial fibrillation and advanced chronic
kidney disease. So happy to have with us the corresponding
author, Dr John Stanifer from Munson Healthcare, Traverse,
Michigan. As well as our associate editor, Dr Chang-Sheng Ma from
Beijing Anzhen Hospital in China. Welcome, welcome. So John,
could you tell us the inspiration if you may, or the rationale,
for doing this study?


Dr John Stanifer: This is a population that's near and dear to my
heart as a practicing nephrologist. We care for so many patients
with atrial fibrillation, particularly those on dialysis or those
with advanced kidney disease. And as other practitioners and
people taking care of this population will tell you, this is just
such a confusing and challenging clinical problem to try to deal
with. And then really this stems from that important clinical
need that we recognize almost on a daily basis.


Dr Carolyn Lam: I just love that you shared that John, because
coming from a nephrologist, and we're usually talking to
cardiologists where we think about this all the time and have no
idea what to do. So tell us about your study and what you found.


Dr John Stanifer: As you know, these were data that were taken
from the Aristotle trial that was finished in 2011, that was
really a landmark study that established the real superiority of
Apixaban compared with Warfarin and the general population.


And it happened that within the study, there were several
patients, 269 that had a creatinine clearance of between 25 and
30 milliliters per minute. We then took those data from those
patients and compared really in this study, the safety of
Apixaban compared with Warfarin within that subpopulation, and
then compared that as an interaction with the safety of Apixaban
versus Warfarin in patients with creatinine clearance of greater
than 30.


Dr Carolyn Lam: And what did you find?


Dr John Stanifer: Well, in conclusion, we really found that among
these patients with a creatine clearance of 25 to 30 MLs per
minute in atrial fibrillation that Apixaban did cause less
bleeding than Warfarin. And it appeared to be an even greater
relative risk reduction when you compare that with the safety of
Apixaban versus Warfarin and those with a less severe kidney
disease.


Dr Carolyn Lam: It's truly the first time I've seen data like
this. So congratulations John and thank you so much for
publishing this paper with us at Circulation. Chang-Sheng,
Circulation seems to be publishing a lot in the space of combined
renal and cardiac disease, which is very interesting. Why was
this paper so important to us as well?


Dr Changsheng Ma: It's a very important question for a clinical
practice. The anticoagulation therapy in patient with advanced
CKD. And observation or analysis have demonstrated inconsistent
of findings regarding the net clinical benefit of warfarin in
reducing the risk for stroke in patients with advanced CKD. The
problem of Warfarin treatments in this patient group is
dramatically higher bleeding risk. The current study also show
that the bleeding risk was three- to four-fold higher in patient
with advanced CKD compared to that in patient with creatinine
clearance more than 30 milliliters per minute when treated with a
Warfarin.


So these studies are our first randomized data for NOAC compared
with warfarin in patients with advanced CKD. The results provide
important information as to the safety of Apixaban in this
special patient group with high risk of bleeding. With reduced
risk of bleeding, we may expect net clinical benefits of Apixaban
in preventing stroke in patients with advanced CKD.


Dr Carolyn Lam: Indeed. John, did you demonstrate that net
clinical benefit or could you perhaps explain if future steps are
needed to look at that a bit better?


Dr John Stanifer: Well, I think absolutely future studies are
needed. You have to keep in mind that these were pre-specified
groups within Aristotle. These are still post-trial data from
this study and that absolutely we need studies that are powered
to really compare the safety. I would add not just apixaban with
warfarin, but I would also add placebo to that.


Dr Carolyn Lam: Interesting. Changsheng, you had some questions
for John as well.


Dr Changsheng Ma: Yes. John, I had questions for you. If you take
a randomized trial for the answer for this question, how many
cases do you think?


Dr Carolyn Lam: How many cases of?


Dr Changsheng Ma: How many cases should there be for a sample
size for a trial?


Dr John Stanifer: Well, you're really putting me on the spot
here. I'll have to go back to my statistical days. Well, I think
the easy part in the design of a trial for a question like this
is that the event rates are so high. Whether that be for both
safety outcomes related to hemorrhage and bleeding risks or
primary benefit outcomes. So that would be very beneficial with
that respect. But I think the key to designing a study ... and I
know that there are several ongoing RENAL-AF and several others
that are trying to examine this very question, but I think as a
nephrologist, what we would kind of push back on a little bit is
that there's no placebo arm to these trials. And I actually think
that that would be a step forward even though that would be a
very challenging thing, I think at this point to push for ... I
think the nephrologist has kind of continued to push for that a
little bit.


Dr Carolyn Lam: So John, that was beautifully answered. If I
could ask you then, have these results influenced your practice
even now?


Dr John Stanifer: Well, prior to this, we've been a little bit
nervous with Apixaban, even though observational data may suggest
that it would be safer or potentially usable in patients with
advanced kidney disease. But part of the real conundrum and some
of the challenges that come up are really around dosing of
Apixaban. And they say, "Well, gosh, if they're in stage renal
disease, yeah, maybe it's too bad. Maybe the kidney function is
way too low and we need to kind of reduce it based just on that
one criterion as opposed to the three criteria laid out in
Aristotle." So I think that was some of the challenges. but I
think after seeing these data and seeing the safety relative to
Warfarin was really there in this patient group, yeah, it has
influenced me a little bit. I am a little more adamant about
switching patients.


Dr Carolyn Lam: Yep. Chang-Sheng, do you agree with that? What do
you think are next steps here?


Dr Changsheng Ma: Because clinical practice is different,
apparently, more evidence is badly needed to guide the future
clinical practice because the patients with creatinine clearance
even less than 25 milliliters per minute. And those in dialysis
were not included in any of the pivotal studies of NOAC.


Dr John Stanifer: Absolutely.


Dr Changsheng Ma: It is still uncertain whether this patient will
benefit from Apixaban or other NOACs. So in this study, even the
significant less measured bleeding events were observed. I think
the all-cause mortality was not different between the two groups.
So the next step we should design a new trial to confirm whether
Apixaban will really improve the prognosis of the patient with
advanced CKD and AF.


Dr John Stanifer: I will second that. For sure we want to answer
that very important efficacy question related to this class of
medications.


Dr Carolyn Lam: Efficacy and patients on hemodialysis. Wow. This
really just opens up a lot, but you're right. It's such
tantalizing information that you see in ... so thank you so much
John, for publishing this paper with us. Chang-Sheng, it's such a
great paper. I remember the discussions we had during our
editors’ discussions and it's so nice to see it out in print. I'm
telling you, audience, you have to get hold of this paper. It
will change this field I think and will lead to further trials
exactly like you've heard here, and that we've put John on the
spot to describe.


Dr Carolyn Lam: Thank you very much gentlemen for a wonderful
discussion. Thank you, audience, for joining us. You've been
listening to Circulation On The Run. Join us again next week.


Dr Greg Hundley: This program is copyright the American Heart
Association, 2020.