Circulation June 18 Issue

Dr Gregory Hundley:       Welcome
everyone to the June 18th edition of Circulation on the Run. I am
Dr Greg Hundley, Professor of Internal Medicine and Director of
the Pauley Heart Center at VCU Health in Richmond, Virginia.


                                               
In today's issue we're deviating from our common format due to
some scheduling difficulties. So, rather than our traditional
coffee chat in this program I'm going to have a large gulp of
coffee and present results from several exciting papers. Then
we'll turn over the second half of our program to Dr Carolyn Lam
for our feature discussion.


                                               
Now, I promise this is a one-time deviation and we will return to
our common chat format in early July. But, before I launch into
my presentations I did want to introduce what will transpire with
Carolyn. She will be discussing an exciting paper from the
Adelaide Medical School at the University of Adelaide in
Australia.


                                               
Some have wondered whether the persistence of a patent arterial
venous fistula post-kidney transplant may contribute to ongoing
maladaptive cardiovascular remodeling. To address this issue
Carolyn will be discussing with authors whether ligation of this
AV fistula may reverse this maladaptive remodeling. And like you,
I'm excited to listen to that discussion. But before that let me
review several of the other distinctive papers on this issue.


                                               
The first one is entitled “Individual Treatment Effect Estimation
of Two Doses of Dabigatran on Stroke and Major Bleeding in Atrial
Fibrillation.” They are the results from the RE-LY trial. The
corresponding author is Professor Frank Visseren from the
University Medical Center of Utrecht in Utrecht University.


                                               
The study emanates from the randomized evaluation of long-term
anticoagulation therapy or the RE-LY trial. In which high dose
dabigatran, that's 150 milligrams twice daily, was found more
effective in prevention of ischemic stroke and systemic embolism
than low dose dabigatran which is 110 milligrams twice daily.


                                               
But this occurred at that expense of an increased risk of
gastrointestinal bleeds. Importantly however, the absolute
treatment effect of dabigatran in both doses, likely differs
between individuals. And therefore, individual treatment effect
estimation has the potential to identify patients who have a
favorable trade off and absolute benefit and harm from dabigatran
compared with no treatment, and to select the optimal dose for
each individual patient.


                                               
So in this study, the investigative team derived and validated a
prediction model for ischemic stroke and systemic embolism and
major bleeding in patients with atrial fibrillation from three
treatment arms of the RE-LY study. They had 11,955 individuals in
the derivation cohort and 6,158 in the validation cohort. And
they evaluated the patient characteristics of sex, age, smoking,
anti-platelet drugs, prior vascular disease, diabetes, blood
pressure, estimated glomerular filtration rate, and hemoglobin.


Dr Gregory Hundley:       Well,
what were the results? Well the five-year absolute risk
reduction, for ischemic stroke and systemic embolus minus the
five-year absolute risk increase for major bleeding, when
comparing the high to the low dose of dabigatran yielded a net
benefit in 46% of patients. And therefore, the authors conclude
that the absolute treatment benefits and harms of dabigatran in
atrial fibrillation can be estimated based on readily available
patient characteristics.


                                               
And perhaps down the road such treatment effect estimations can
be used for shared decision making before starting dabigatran
treatment and to determine its optimal dose of administration.
Well, how 'bout that? And let's go on to the second paper
entitled “Empagliflozin and the Risk of Heart Failure
Hospitalization in Routine Clinical Care: A First Analysis from
the Empagliflozin Comparative Effectiveness and Safety, or
EMPRISE Study.


                                               
And the corresponding author for this study is Elisabetta Patorno
from Brigham and Women's Hospital in the Harvard Medical School.
So, as a background in a different study to this, the EMPA-REG
OUTCOME trial showed that Empagliflozin an SGLT2 inhibitor was
found to reduce the risk of hospitalization for heart failure by
35% on top of standard of care in patients with Type 2 diabetes
and established cardiovascular disease.


                                               
Well, the current study, The Empagliflozin Comparative Effective
and Safety or EMPRISE Study was designed to assess
empagliflozin's effectiveness, safety, and health care
utilization in routine care from the period of time between
August of 2014 through September of 2019. And the author's report
on the first interim analysis in which they investigated the risk
of hospitalization for heart failure among Type 2 diabetic
patients initiating empagliflozin vs. sitagliptin.


                                               
The investigators used two commercial and one federal Medicare
claims data source from the U.S. and identified a one-to-one
propensity score matched cohort of 16,443 pairs of Type 2
diabetes patients that were greater than 18 years of age
initiating empagliflozin or sitagliptin. The average age of the
participants was approximately 59 years.


                                               
And almost 54% of the participants were males and approximately
25% had records of existing cardiovascular disease. So compared
to sitagliptin the initiation of empagliflozin decreased the
hospitalization for heart failure risk by 50% over a mean
follow-up of 5.3 months. And the results were consistent in
patients with and without baseline cardiovascular disease for
both the empagliflozin 10 milligram or 25 milligram daily dose.
Or analysis comparing empagliflozin vs. dipeptidyl peptidase-4
inhibitor class all comers.


                                               
Thus, in conclusion, in this first interim analysis from EMPRISE,
the investigative team showed that compared with sitagliptin the
initiation of empagliflozin was associated with a decreased risk
of hospitalization for heart failure among patients with Type 2
diabetes as treated in routine care with and without a history of
cardiovascular disease.


Dr Gregory Hundley:       Well, now
we're going to turn our attention to red meat. And this next
study was entitled, The Consumption of Meat, Fish, Dairy
Products, Eggs, and Risk of Ischemic Heart Disease. It's a
Perspective study of 7,198 incident cases among 409,885
participants in the Pan European Epic Cohort. And the
corresponding author is Professor Timothy Key from The University
of Oxford.


                                               
Some of the background here, met analysis of previous prospective
studies have suggested that intake of processed meat maybe
associated with a higher risk of ischemia heart disease whereas,
unprocessed red meat might not. For dairy products and eggs,
systematic reviews of prospective studies have reported no
consistent evidence that higher intakes are associated with a
higher risk of ischemic heart disease.


                                               
Other studies have shown that fatty fish consumption may reduce
the risk of ischemic heart disease, it is a rich source of long
chain N3 fatty acids. And meta-analysis has suggested even an
inverse association between overall fish consumption and
mortality from ischemic heart disease.


                                               
So, hear in this cohort: we're going to evaluate all of these.
Accordingly Key, and his co-authors report the relationships of
these foods with risk of ischemic heart disease in the European
prospective investigation into cancer and nutrition, the EPIC
study, and that again is a cohort of a half million men and women
from nine European countries followed for 12 years to examine the
association between the intake of animal foods and the occurrence
of ischemic heart disease.


                                               
The author's found that higher consumption of red, unprocessed
and processed meat was positively associated with the risk of
ischemic heart disease. None of the other animal foods examined
were positively associated with this risk. And intakes of fatty
fish, yogurt, cheese and eggs were modestly, inversely associated
with the risk.


                                               
In addition, the red and processed meat were associated with
plasma non-HDL cholesterol and systolic blood pressure. And this
finding is of interest as possibly these other variables could
serve as mediator of the association between red or processed
meat and future ischemic heart disease. It is important to note
that while these results are of interest to those concerned with
the future adverse cardiovascular effects related to the
consumption of red meat, one cannot infer causality and other
studies would need to be designed to address causal
relationships.


                                               
The last paper that I'm going to present during the coffee gulp,
emanates from the basic science arena. And it is entitled The
“Shear-Induced CCN1 Promotion of Atheroprone Endothelial
Phenotypes and Arthrosclerosis. And the corresponding author is
Dr Fan-E Mo from the National Cheng Kung University College of
Medicine.


Dr Gregory Hundley:       The
matricellular protein CCN1 has been implicated in arthrosclerosis
based on its expression in arterial segments with evidence of
arthrosclerosis. And this study evaluated the relationship
between sheer stress, both laminar and oscillatory at the site of
atherosclerotic liaisons and molecular markers of
pathophysiologic process involved in the progression of
arthrosclerosis.


                                               
The authors found that sheer induced CCN1 and its receptor
integrin, alpha six, beta one, instigate atheroprone phenotypic
changes in endothelial cells via activating NF kappa beta.
Because the activation of NF kappa beta further up regulates the
expression of CCN1, alpha six, and beta one, atheroprone flow
creates a positive feedback to sustain atherogenesis.


                                               
In addition, disrupting CCN1, alpha 6 beta one engagement by a
specific CCN1 mutation, or by a peptide antagonist unhindered
atherogenesis in mice. So what are the clinical implications of
these findings? That's something Carolyn would ask me. Well, it
appears that CCN1 alpha 6 beta one engagement represents a novel
therapeutic target for arthrosclerosis.


                                               
These data demonstrate a causative role of CCN1 in
atherosclerosis via modulating endothelial phenotypes. And CCN1
binds to its receptor integrin alpha 6 beta one to activate NF
kappa beta, thereby instigating a vicious cycle to persistently
promote atherogenesis. Perhaps in the future T1 me medics may
further be optimized to treat arthrosclerosis.


                                               
Well everyone, that concludes the first portion of this June 18
edition of Circulation on the Run and now it's time to move on to
Carolyn's discussion of our featured paper.


Dr Carolyn
Lam:               
Cardiovascular disease remains the major cause of death in kidney
transplant recipients. And today's featured paper has important
implications for the management of this cardiovascular risk
following kidney transplantation. I'm so excited to be discussing
it, and I'm going to let the corresponding author Dr Toby Coates
from Royal Adelaide Hospital tell us all about it, and so happy
to also welcome our editorialist Dr Patrick Mark from University
of Glasgow.


                                               
Toby, could you please tell us what inspired you to do this
remarkable study?


Dr Toby
Coates:               
We're very interested in obviously our patients surviving as long
as they possible can after kidney transplantation. And we noticed
that many of them having had a successful kidney transplant,
still had functioning AV fistulas. Now of course the AV fistula,
is a connection between the artery and the vein that enabled us
to access the circulation after hemodialysis. Which around the
world is probably the most, is the most common form of dialysis
practice performed.


                                               
So many of these patients sustained 20 years down the track after
successful transplants still had these very large functioning
left to right shunts, on the basis of their dialysis history. So
we had a couple of patients who developed quite severe cardiac
failure and we noticed that when we ligated the AV fistula, their
back got dramatically better.


                                               
So, as a consequence of that, we went to look at the ligature and
we couldn't find any randomized control trial that told us what
the best thing was to do, post-transplant with these fistulas. So
we decided that what we would do be use the state of the art
cardiac magnetic resonance imaging, or cardiac MRI to assist the
cardiac function with myocardium thickness in our patients and
then randomize a group of stable transplant patients to ligation
or not.


                                               
And then follow that up with cardiac MRI six months down the
track to see what happened. And so that was the basis of the
study that we performed. The first randomized controlled trial of
the effect of ligation of the AV fistula on the left ventricular
mass, that was the prominent one for trial.


Dr Carolyn
Lam:               
You know, Toby, just to let you know right there, I thought it
was so incredibly novel. So I'm a heart failure specialist and we
know that shunts are associated with high output cardiac failure,
and yet, I personally had never questioned this, so I thought
this is incredibly novel and it's important. But please, tell us
all about the results.


Dr Toby
Coates:               
We were delighted to say that there was a very significant
reduction in the left ventricle mass. In fact, the main decrease
was 22.1 grams compared to the control arm in whom the cardiac
mass actually went up 1.2 grams. So, then we mobilized the body
surface area, the reduction of the left ventricular mass index
dropped by 11.8 grams per metered square.


                                               
Now, this is quite remarkable for me doing the study because I've
never seen an intervention, I've never seen an intervention where
every single patient improved with the ligation, every single
patient there was an improvement in the cardiac parameters. Never
seen anything like it in the pre and post of the ventricular mass
it really came down. So that was quite remarkable.


                                               
And the second thing that really impressed me at the time, was
the improvement in the BMP's, and we measured the brain maturated
peptide, and being a methodologist that's clearly something
that's of interest to us and we saw a substantial reduction. It's
statistically significant reduction in BMP as well.


                                               
The patient themselves, some of them recorded quite significant
improvement in exercise tolerance afterwards. And we had, as I
mentioned before in a couple of patients, not in the study but
outside of the study, subsequently when they're presented with
profound right heart failure, the ligation of the AV fistula made
a huge difference to them symptomatically.


                                               
So that was sort of confirming all of the things that we thought
along the way. Pleasingly we didn't see any change in kidney
function. So, we were concerned that there might have been on the
basis of some non-controlled studies in the past, that there
might have been a deterioration in the estimated glomerular
filtration rate, or eGFR. We didn't see that.


                                               
And we didn't see any significant change in the blood pressure
either. Which is some of us have previously reported. Closing the
fistula itself, is a very trivial procedure. It's usually done as
an outpatient, so a day procedure. So it's not resulting in
coming to the hospital. And the only complications, really were
lots of local redness and some pain, potentially from the fistula
where in the ligated.


                                               
So, we thought this was remarkable. An outpatient procedure that
could significantly reduce the left ventricular mass by 22.1
grams over the six month period that was associated with minimal
side effects and complications. And when you think about that,
that's sort of equivalent really to taking an anti-hypertensive
medication for six months. That magnitude of reduction with
ventricular mass which clearly from the patient's point of view
is much preferable to adding more medication to an already
over-burdened tablet loading in your patients with kidney
transplants. So we were very pleased with that result altogether.


Dr Carolyn
Lam:               
Thank you Toby, and we in turn were very pleased to be publishing
this in Circulation. Likewise, Patty, if I may, I love your
editorial. First, let me tell everybody who's listening out
there. Go pick up the editorial and look at the figure. It is so
cool. It shows pros and cons of arterial venous fistula ligation
in these patients. But could you please share some thoughts
Patty? I mean you covered the perspective just so well.


Patrick
Marks:                  
I must give the credit to my co-author who actually drew the
figure himself. So Chris Eaves rather myself. We were really
impressed with the study and we're really delighted to write an
editorial for it. It's just one of those studies that I have to
say, you know, you kick yourself and you wish you'd done it. With
all the world of observational data showing that creation of a
fistula appears to be associated with an increase in LV mass
obstruction by echo and angio and bicartic MR in smalls studies.


                                               
But it's taken a long stat to move from that to actually doing a
randomized control of ligating the fistula in people with you
know, stable functioning transplants. We were really, really
impressed with Toby and his team for undertaking this study. And
until we'd gone through the results, they're really very
impressive.


                                               
The magnitude of reduction LV mass is very impressive and also
the changing BMP was really nice to see. One of my comments of
the study were, was interesting because as methodologists we are
aware of the idea arteriovenous fistula as being the axis for
dialysis. And we sometimes feel uncomfortable by ligating this
because we know if the transplant was to fail, how much patients
need a functioning fistula. And that's the one thing I'm still
curious, like and I still offered some comments in the editorial
were, that while there's doubt that the cardiovascular benefits
demonstrated by Toby's study are really very impressive.


                                               
I wondered about the implications out with the study came down
the line, you know would there be some of these patients whose
kidney transplant function would decline? And there may be regret
of losing the access. We mentioned there is some inconvenience,
it is an operative procedure to loosen the fistula. So there are
some things to think about in the study, but overall, I can't
help saying just how impressed I am that they managed to do this
trial in a proper randomized, controlled trial form. It's really,
really impressive in using the cardiac MR endpoint is it seems
quite a secure way of assessing this.


Dr Carolyn
Lam:               
Those are great points, Patty. Toby, any response to that.


Dr Toby
Coates:               
Look it's really very interesting as a transplant pathologist for
the last 20 years, one of the biggest, I guess it's a bit of a
misconception. When a fistula has been present for 10 or 15 years
and still there to come back and try and reuse it for dialysis
access after that period of time, in my experience anyway, also
very difficult to reuse those fistulas and the surgeons end up
having to create a new one anyway.


                                               
They frequently become quite aneurismal, they get very large and
unsightly and the volume of the shunt is significant and often we
find that as an access they don't work as well. So I personally
don't have a huge concern about closing them. Now I agree with
you, these patients were stable, longstanding and we assessed
that the risk is, we need to go back onto hemodialysis was small.


                                               
But you are absolutely right, I mean, it is possible that
something could have come out of the blue and maybe a patient
would be disappointed that that access that they'd had for so
many years was no longer available. So that is, the caveat on the
study, but thankfully so far out, some of these patients five or
six years down the track, we haven't had anybody need to go back
on dialysis, so it's been good.


Dr Carolyn
Lam:               
Yeah, it really says to me as well, that patient selection is
important exactly like you emphasized, and you, in the editorial
Patty. But from a cardiology standpoint, too, are there plans to
perhaps do studies with hard, clinical endpoints? What do you
think are the next steps? Maybe I'll let Toby go first, then
Patty.


Dr Toby
Coates:               
We think now with this study done, the next thing is to have a
larger study with significant cardiovascular endpoints. Which I
obviously would be cardiac failure and acute coronary events. So
the two things that would seem in my mind, and I think that needs
to be multi-centered, preferable international if we can.


                                               
And one of the really positive things about the highlight from
the American Heart Association is that we've had people reach out
to us from France and all around the globe saying that they'd be
interested in participating, you know in a multi-centered trial.
So, I think that's what we need to do, and clearly you don't
it’ll have to be a constant endpoint, or not. I'd be interested
in Patty's thoughts about that, right if you had some guidelines
and some suggestions.


                                               
And then obviously would be randomized, controlled trial looking
at those hard endpoints with probably some sidearms doing cardiac
MRI as well, and potentially more heart functioning tests. So
yes, I think this is just the beginning, we do need a hard
endpoint trial to really nail this completely.


Patrick
Marks:                  
Yeah, I'll just come in there and just come on to that Toby. I
completely concur with what you said. I think there's been quite
a provocative editorial a few years back, and suggesting that
while there's lots of studies in chronic kidney disease, end
stage renal disease, kidney transplant patients avoid LV mass,
really it hasn't yet been translated into actually leading
studies in the integration of LV mass and end stage renal failure
haven't really yet translated into mortality benefits.


                                               
And I think we need to move to a bigger study. It's really
beautiful that you've been able to demonstrate LV mass falls
naturally with ligation. And it's impressive that it just happens
so consistently across your population in the intervention arm.
But we need to move on to a longer trial with hard clinical
endpoints. Certainly heart failure, certainly cardiovascular
mortality, [be]cause there's plenty of reasons to believe that
producing LV mass in these patients might have benefit both for
heart failure, whether that's heart failure, heart injection
fraction, or whatever, I'll leave that to Carolyn's judgment to
help us with that.


                                               
But also, if we can reduce LV mass and then we may be able to
reduce arrhythmia burden which again is when these things we
worry about in end stage renal disease, again, your answer for
that is, that in addition to the heart endpoints you should be
able to also add in some patient afforded outcomes in a larger
study. Or something like an exercise tolerance quota of quality
of life.


                                               
All this has started has journey from the surrogate endpoint of
left ventricular mass into a bigger outcome study and I can't
wait to see how you get on with it.


Dr Carolyn
Lam:               
I can't wait either. And I'm sure the audience is sharing all our
enthusiasm as well. Thank you so much Toby and Patty. I really
learned so much. You heard it right here on Circulation on the
Run. Thank you for joining us this week. Don't forget to turn in
again next week.


                                               
This program is copyright American Heart Association 2019.