Circulation January 29, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the Journal and its editors. We're your
co-hosts of Circulation on the Run. I'm Dr Carolyn Lam, associate
editor from the National Heart Center and Duke National
University of Singapore.


Dr Greg
Hundley:            
And I am Greg Hundley, also associate editor from VCU Health
Systems in Richmond, Virginia.


Dr Carolyn
Lam:               
So, have you ever wondered in patients with atrial fibrillation
and stable coronary artery disease beyond a year of coronary
stenting, can you safely just continue on oral anticoagulation
without antiplatelet therapy? Well, if you've ever wondered that
... I sure have. I'm sure you have too, Greg. Our feature paper
this week does discuss this, so you have to stay tuned. But for
now, Greg, what are your picks from this week's issue?


Dr Greg
Hundley:            
I've got a couple to discuss. The first is Patrick Hsieh from
Taipei, Taiwan, and really is evaluating the gut microbiota and
how that affects cardiac repair after myocardial infarction. I
mean, who would've thought to chase an idea like this? But what
this investigative team did is they had mice, so this was a basic
science experiment, and they treated them seven days prior to
ligation of their left anterior descending artery that would
induce a myocardial infarction. They treated them seven days
prior with ampicillin, metronidazole, neomycin, and vancomycin.
What were they trying to do? Totally obliterate any bacterial
load within their GI system. Then, they ligated that coronary
artery, and at 21 days, they looked at histopathologically what
was happening.


                                               
And you know what they found? Those where they wiped out the
bacterial load, they had increased cardiovascular events. And
importantly, myocardial rupture was very high in this group of
mice. Also those mice, they had reduced heart rate, and
mechanistically what had occurred is there was a reduction in our
immune monocytes that were trying to infiltrate the peri-infarct.
They weren't there. They were not in those peri-infarct zones.
And so, the thought here is that removal of the favorable
microbiota in the gut can actually be harmful in the setting of
myocardial infarction.


Dr Carolyn
Lam:               
Fascinating. So, microbiome as our pals. But wait a minute. I
mean, how can you say it's from elimination of the microbiome
versus some kind of effect of the antibiotics itself?


Dr Greg
Hundley:            
Yeah, that's a great question, Carolyn. The way they did this is
they took another group of animals, and they supplemented them
with lactobacillus probiotic, like the stuff we get in the
grocery store. And those animals, they did not suffer any of the
adverse cardiovascular effects. So, it really points to an
important role of our gut microbiota. You know, and what do they
do? They basically ferment these carbohydrates that we ingest,
and produce short chain fatty acids that are a substrate for
these mononuclear cells to help infiltrate those infarct zones.
So, really exciting basic science question that this group
examined.


Dr Carolyn
Lam:               
I love that you picked a basic science paper, and I love that you
made even me understand it so well. Okay, but what I have is a
clinical trial. So, it's the REDUCE-MVI trial, which is the first
randomized trial comparing maintenance treatment with ticagrelor
or prasugrel after a primary PCI. So, this is from Dr van Royen
and colleagues. They're from Radboud University Medical Center in
the Netherlands. Basically, they figured that despite successful
restoration of epicardial vessel patency with primary PCI,
coronary microvascular injury does occur in a large proportion of
STEMI patients, and of course, adversely affects outcomes. Now,
ticagrelor has been reported to increase plasma adenosine levels,
which may have a protective effect on the microcirculation. So,
the authors randomize 110 STEMI patients following
revascularization to maintenance therapy with ticagrelor versus
prasugrel, with the primary outcome being microvascular injury at
one month as determined by the index of microcirculatory
resistance in the infarct related artery.


                                               
What they found was that there was no difference in the extent of
microvascular injury and in the extent of infarct size by cardiac
MRI at one month after the primary PCI. The attributed
pleiotropic benefits of ticagrelor through the adenosine
metabolism pathway actually could not be confirmed in the STEMI
population, as plasma adenosine levels were actually not
increased in the patients treated with ticagrelor.


Dr Greg
Hundley:            
So, what does this mean for the use of adenosine and its role?


Dr Carolyn
Lam:               
I suppose you're also asking, you know, is the adenosine
hypothesis really out here? This is a study that really suggests
we have to question it, but there are some limitations that we
perhaps should keep in mind when we think about this. So first,
before primary PCI, all patients were loaded with ticagrelor
because this was standard of care in the participating centers.
That, of course, could have modified microvascular injury already
at the index event. Now, a second important thing is that the
study may have been underpowered. There was a greater than
anticipated variability in that primary outcome of index on
microcirculatory resistance.


                                               
The relatively low rates of risk factors, the small infarct size,
the preserved ejection fraction could all have influenced this
IMR values, as well as the potential effects of the
pharmacological intervention. And furthermore, the natural
recovery of microvascular dysfunction over time may have diluted
the positive effects. And of course, selection bias is inevitable
in a trial. And so, you know, although this really questions the
adenosine hypothesis, there are still caveats to these results.


Dr Greg
Hundley:            
Very good. So, Carolyn, I've got another study to sort of go
over, and this is from Dan Modin from the University of
Copenhagen. And it's really addressing this issue. We all in the
fall, do we all get our flu shots? And could that be helpful in
patients with heart failure? You know, the ACC, the AHA, and the
ESC all suggest flu shots, but there's actually no guideline to
recommend. So, what did these investigators do? They looked in
Denmark, and from the period of January of 2003 to June of 2015,
they identified 134,048 subjects. And they looked at the
vaccination status for those with a diagnosis of heart failure
that were greater than 18 years in age. 55% percent of these were
men. And then, they also looked at ICD-10 codes for
cardiovascular events.


                                               
Now, they examine the dates of when you had your vaccination, how
frequently, what were your comorbidities cardiovascular-wise,
medication use, etc. And what they observed is that those
individuals that had more than one vaccination ... So, basically
annual vaccinations for a three year period, they had an 18%
reduction in all death, and a 19% reduction in cardiovascular
death.


Dr Carolyn
Lam:               
So, is this all heart failure patients? Are there specific
subgroups that we should be targeting?


Dr Greg
Hundley:            
At our institution, they really get on us. If we don't have our
flu shots in September, I mean, they threaten to withhold
everything, or maybe October. Well, interesting that you asked
that question. Those individuals that had flu shots in the
September to October window did much better than those
individuals that had their vaccination November, December, or
actually later in January. And the second group that benefited
were the individuals that actually had annual vaccinations. So,
if periodically you say, "Oh, I'm going to get it this year, but
then I'm not going to get it two years from now." Not so good. It
was those individuals that had those vaccinations annually.


Dr Carolyn
Lam:               
You know, Greg, it's making me question too, because here I am in
a tropical island. We actually don't have seasons. So, what does
that mean for us? That's one thing. And then, do we need even
randomized trials now?


Dr Greg
Hundley:            
Yeah, I think you're right there, Carolyn, because first of all,
you know the investigators targeted this because 50% of heart
failure exacerbations are actually triggered by some sort of
respiratory infection. So, that was kind of the thought behind
this. But we do have to be careful about looking at this
longitudinal data and making predictions or developing
guidelines. A couple of reasons why. It could be that those that
come in for annual vaccinations at the time points, well, maybe
they also come in for more frequent heart failure visits with
their doctor. So, it's not cause and effect.


                                               
And in fact, there was another study, Get with the Guidelines
heart failure study, and it actually showed no association. So,
more work really needs to be done in this area. And just to point
out quickly, there is a current randomized trial going on called
Invested, and it's looking at different types of vaccinations,
trivalent versus quadrivalent. They're underway in those with
heart failure. And so, there's a lot more work in this area. But
it was interesting getting it that old "get your flu shot," and
it looks like at least longitudinally in cohort studies could be
beneficial. And if you are going to do it, do it every year and
get that September, October. So, Carolyn, what about your next
paper?


Dr Carolyn
Lam:               
So, Greg, my second paper is another trial. It's the radio sound
hypertension trial, this time focusing on renal denervation. In
fact, it's the first trial to compare three different techniques
and technologies for catheter-based renal denervation. It's from
Dr Lurz from Heart Center Leipzig in Germany. And what they did
is, they randomized 120 patients with resistant hypertension to
three arms. Either one, radiofrequency, renal denervation of the
main renal arteries. Two, radiofrequency renal denervation of the
main renal arteries and the side branches and accessories. Or
three, an endovascular ultrasound-based renal denervation of the
main renal artery. The primary endpoint was change in systolic
daytime ambulatory blood pressure at three months. In the end,
endovascular ultrasound-based renal denervation was the winner
over radiofrequency ablation of the main arteries, with or
without ablation of the side branches.


Dr Greg
Hundley:            
Carolyn, does this mean that renal denervation is coming back?
Are we going to actually start thinking about this as a viable
option to treat those with longstanding hypertension?


Dr Carolyn
Lam:               
Greg, this was exactly addressed by an editorialist, Dr Ram from
UT Southwestern and Apollo Hospitals and Apollo Medical College
in India. Beautiful editorial. Basically, even with the
publication of these new data, it is difficult to predict whether
renal denervation is firmly back on track. You see, some caveats
should be mentioned, including that in this trial, only patients
with large renal arteries were chosen for this study. And patient
enrollment was rather selective.


                                               
For example, out of 1,884 patients screened, only 120 patients
met the inclusion criteria. And then, importantly, in a few
patients, the reduction in systolic blood pressure was really
impressive, close to 40 millimeters mercury. But the majority of
responders had a more modest effect, and in about 30%, there was
no change in blood pressure.


                                               
So, one of the ultimate things we need to learn to do is to
identify the so-called hyper-responders from the non-responders.
So, lots more work needs to be done in renal denervation.


                                               
That brings us to a close of our little chat. Can't wait for our
feature discussion coming right up.


                                               
Our feature paper today deals with a very important topic in a
very frequently encountered group of patients. And they're the
ones with concomitant stable coronary artery disease and atrial
fibrillation. You see, these are patients at high risk of both
ischemic and bleeding events, and therefore, it's critical to
identify the right antithrombotic regimen with the optimal
benefit ratio, since this is going to be lifelong therapy. Now,
interestingly, despite recommendations in the guidelines and
consensus documents, there has been no randomized controlled
trial evaluating oral anticoagulation with and without
antiplatelet therapy in patients with atrial fibrillation and
stable coronary artery disease beyond one year of coronary
stenting. I mean, Greg, I didn't even realize that we didn't have
a randomized control trial. Did you?


Dr Greg
Hundley:            
Absolutely, Carolyn. And, you know, this is an important issue,
because we have a lot of patients coming to the cath lab that
have atrial fibrillation, and what is going to be the recommended
anticoagulant and antiplatelet combination? And so, it's really
time for a randomized trial.


Dr Carolyn
Lam:               
I know, and luckily for us, that's exactly what this issue's
feature paper does. And I'm so pleased to welcome to the show Dr
Satoshi Shizuta from Kyoto University Graduate School of
Medicine, Japan, as well as associate editor Dr Shinya Goto from
Tokai University in Japan. We're so proud to be publishing the
OAC-ALONE trial, even though we understand it was a difficult
trial. Tell us, what were the results?


Dr Satoshi
Shizuta:          
As you know, the results were somewhat inconclusive because of
pretty much a combination of patient enrollment. Initially, we
scheduled to enroll 2,000 patients during 12 months, but patient
enrollment speed was extremely slow, much slower than expected.
So, we extended the patient enrollment period from 12 months to
38 months. But finally, we could only enroll 696 patients, about
one-third of the initially planned patients. The result was
around 50% rate of primary end point during 2.5 years of follow
up. And the hazard ratio of [inaudible 00:15:01] strategy, as
compared with OAC plus APT was 1.16 with a 95 confidence interval
of 0.79 to 1.72.


                                               
So, in conclusion, our study failed to establish no inferiority
of OAC-ALONE to combination therapy of OAC plus antiplatelet
therapy in patients with AF and stable coronary artery disease
beyond one year after stenting in terms of primary endpoint of
death, MI, or stroke. So, this study was underpowered and
inconclusive. So, future larger studies require to establish the
optimal antithrombotic regimen in this same patient population.


Dr Carolyn
Lam:               
Thanks so much. Shinya, you've been thinking about this, too, and
the performance of such a difficult trial. Did you have anything
to add or to ask?


Dr Shinya
Goto:               
So, first of all, I would to congratulate Satoshi and the group.
They have completed a very interesting randomizing trial. As Greg
mentioned, there is two kind of patient who lead to coronary
artery disease and atrial fibrillation, especially after, you
know, one year after stenting. So, taking a look at coronary
artery disease with atrial fibrillation, we don't have the
established standard of care yet. So, Satoshi know, it is a
long-time study. So, I understand the rich colored nature of the
patient in this kind of trial. So, what is the most difficult
point increased to encourage the patient in this long-term trial?


Dr Satoshi
Shizuta:          
We think that difficulty reflects substantial reluctance of most
cardiologists to withdraw antiplatelet therapy, single
antiplatelet therapy from stented patients, even the patients
treated with oral anticoagulation for atrial fibrillation. So,
that is the most important point.


Dr Shinya
Goto:               
You have already showed in this paper myocardial infarction
recurrence of stents thrombosis. Not a huge problem in this kind
of patient population, you know? Stroke is a bigger problem,
mortality, not including cardiovascular is also the problem. So,
you have suggested, you have a strong kind of mind, is it? And
single antiplatelet therapy necessary after stenting. Your
results are underpowered but still suggest how always you know
would be enough in stable CAD patients with atrial fibrillation.


                                               
I would congratulate you again.


Dr Satoshi
Shizuta:          
Thank you.


Dr Greg
Hundley:            
Satoshi, I have a quick question. So, in the randomization
process, how can you achieve the physicians managing the patients
to administer the anticoagulant therapy to guideline levels,
particularly when they are also prescribed antiplatelet therapy?
I noticed that in the editorial on this manuscript that was a
concern, and suggesting that in future studies that the therapy
really be defined, and not so much open label administration at
the discretion of the prescribing physician. What are your
thoughts on that?


Dr Satoshi
Shizuta:          
I agree with you, but in this kind of study, randomizing whether
or not to withdraw a drug is very difficult to conduct. Financial
support is limited, and in such situation, double blind placebo
controlled trial is very difficult to conduct. As you know,
several years ago, a loose trial was published in the Lancet. And
also in the loose trial, the study design was open level, and
also in the PCI and [inaudible 00:19:48], I think the study
design was not blinded but open. In this paper figure two, our
control level was set as a dependent based on the Japanese
guidelines. In the Japanese guidelines, target IR was set as 1.6
to 2.6, a little bit lower than Western golden standard for
elderly patients older than 50 years. And same 2.0 to 3.0 in
patients younger than 70 years.


                                               
And in that criteria, as you can see, if you get 2A of paper, the
therapeutic range was extremely high. 76% in the OAC-ALONE group,
and also 73% in the OAC plus APD group. We can clearly understand
that the intensity of oral anticoagulation was different between
the two groups. Most of the OAC-ALONE group, OAC was controlled
with ionine level higher than 2.0. On the other hand, in the OAC
plus APD group, the ionine level was mostly controlled between
1.6 to 2.2 or .5 or so. So, this is a great big limitation of the
study. But even in this limitation, the bleeding events, there
was numerical excess in the OAC plus APD group. And, regarding
the TEMI major bleeding, there was a trend toward increased major
bleeding in the OAC plus APD group. If the intensity of OAC was
the same, of course, I am convinced that even in this
underpowered sample five, the major bleeding will be
statistically higher in the OAC plus APD group.


Dr Carolyn
Lam:               
Thank you so much Satoshi for really taking us under the hood,
and showing us all the myriad of considerations that occurred to
perform this trial.


                                               
This is Greg and Carolyn. Thank you for joining us on Circulation
on the Run. Don't forget to tune in again next week.


                                               
This program is copyright American Heart Association 2019.