Circulation August 23, 2016 Issue

 


Carolyn:
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.


 
 
In just a moment, we are going to be discussing the feature paper
on results of the RE-LY trial in patients with valvular heart
disease. Yes, you heard me right, this means dabigatran versus
warfarin in patients with atrial fibrillation and valvular heart
disease. You need to listen to this discussion with first author
Dr. Michael Ezekowitz, but first here is a summary of this week's
issue.


 
 
In the first study, Dr. Norby and colleagues from the School of
Public Heath University of Minnesota assessed trajectories of
cardiovascular risk factors and the incidence of atrial
fibrillation over 25 years in the ARIC study or the
Atherosclerosis Risk in Communities Study. They first assessed
the trajectories of cardiovascular risk factors in more than
2,400 individuals with incident atrial fibrillation and more than
6,400 matched controls. Next, they determined the association of
those risk factor trajectories with the incidence of new atrial
fibrillation among more than 10,500 individuals free of atrial
fibrillation at baseline.


 
 
The main finding was that stroke, myocardial infarction and heart
failure risk increase steeply during the time close to diagnosis
of atrial fibrillation. All cardiovascular risk factors were
elevated in atrial fibrillation cases compared to controls more
than 15 years prior to the diagnosis. A trajectory analysis
showed not only the presence of the risk factors such
hypertension and obesity, but also their duration which was more
informative in determining the risk of atrial fibrillation
compared to a one time clinical measurement.


 
 
Finally, they identified diverse and distinct trajectories for
the risk factors findings that carry implications for the
different roles of different risk factors in the pathogenesis of
atrial fibrillation. The findings of this very significant study
also highlight the need to establish preventive strategies that
address risk factors decades before atrial fibrillation
diagnosis.


 
 
The next study is by first author Dr. van der Valk and
corresponding author Dr. Strauss from the Academic Medical Center
in Amsterdam. These authors aimed to better understand the
underlying mechanisms responsible for atherogenicity of
lipoprotein a or LPa. The authors achieved this aim by a
combination of three approaches. First, in vivo magnetic
resonance imaging using 18F-FDG PET/CT and SPECT to measure
atherosclerotic burden, arterial wall inflammation and monocyte
trafficking to the arterial wall. Secondly, ex vivo analysis of
monocytes using facts analysis, inflammatory stimulation assays
and trans endothelial migration assays. Third, in vitro studies
on monocytes using an in vitro model for trained immunity.


 
 
Their main findings were that, firstly, individuals with elevated
LPa had increased arterial wall inflammation in vivo. Secondly,
that monocytes from these individual remain in a long lasting
activated state ex vivo, and finally, that LPa elicited a
pro-inflammatory response in healthy monocytes in vitro, an
effect that was markedly attenuated by removing or inactivating
oxidized phospholipids on LPa.


 
 
In summary, this study nicely shows that LPa induces monocyte
trafficking to the arterial wall and mediates pro-inflammatory
responses through its oxidized phospholipid content. The clinical
implications are therefore, that oxidation's specific epitope
targeted therapy using for example specific antibodies as single
gene antibodies may bear clinical potential to modulate the
arthrogenic impact of LPa.


 
 
The final study is from first author Dr. Mazen, and corresponding
author Dr. Ouzounian from Toronto General Hospital and University
of Toronto in Ontario, Canada. These authors sought to compare
the long term outcomes of patients undergoing the Ross procedure
compared to mechanical aortic valve replacement in a propensity
match cohort study of 208 pairs followed for a mean of 14 years.


 
 
They found long term survival and freedom from re-intervention
were comparable between the Ross procedure and mechanical aortic
valve replacement. Of note however, the Ross procedure was
associated with improved freedom from cardiac and valve related
mortality, as well as a significant reduction in the incidence of
stroke and major bleeding. This paper provides important evidence
that supports continued used of the Ross procedure in properly
selected young adult patients in specialized centers.


 
 
What this means is having experienced surgical teams dedicated to
mastering the technique and committed to carefully following up
the patients for possible late complications. This and more is
discussed in a provocative editorial by Dr. Schaff from Mayo
Clinic Rochester, Minnesota who provocatively entitled his
editorial 'The Ross Procedure: Is it the Preferred Procedure or
Double, Double Toil and Trouble?'


 
 
Those were all summaries, now for our featured paper.


 
 
I am so excited to be joined from all over the world to discuss
the featured paper today, and that is on the comparison of
dabigatran versus warfarin in patients with atrial fibrillation
and valvular heart disease. To discuss this first we have, first
and corresponding author, Dr. Michael Ezekowitz from the Sidney
Kimmel Medical College at Thomas Jefferson University and
Lankenau Medical Center in Philadelphia, as well as from the
Cardiovascular Research Foundation in New York. Welcome Michael.


 
Michael:
Thank you very much.


 
Carolyn:
Michael, you're calling from South Africa aren't you?


 
Michael:
I am indeed.


 
Carolyn:
That's wonderful. We're very honored to have Dr. Shinya Goto
Sensei, Associate Editor of Circulation from Tokai University
Japan. Hello Shinya.


 
Shinya:
Hello Carolyn, thank you very much for your invitation to such an
excited podcast. I enjoy podcast every week.


 
Carolyn:
I love this and it is extremely exciting and the most global
discussion that we have had so far, with calling in Japan and
Singapore and South Africa. Indeed it's because we're discussing
a very important problem globally. Michael first, when we talk
about the RE-LY trial and the NOAC trials, we're always
associating them with non-valvular atrial fibrillation, and yet
your topic is discussing valvular heart disease from RE-LY. Can
you please start by clarifying that?


 
Michael:
I think the reason we wrote this paper is that there is a
misunderstanding of the patient populations that was studied in
all the NOAC trials because they were characterized as having
non-valvular atrial fibrillation. That's only partially true
because in all the trials, patients with mechanical heart valve
and hemodynamically significant mitral stenosis were excluded,
and yet there were many patients with valvular disease that were
included. In the RE-LY trial which is the focus of this
particular paper, 25% of the patients had some form of valvular
disease that were recruited into the study. So the term
non-valvular is misleading.


 
Carolyn:
That is such an important clarification, and it's an issue that I
see a lot in Singapore. Frankly, lots of patients with atrial
fibrillation have some valve disease even if you exclude
prosthetic valves, significant mitral stenosis or valvular heart
disease requiring intervention. We're very clear not that this is
the patient population you're referring to. Shinya, I want to
bring you into this. I see lots of these patients, how about you?


 
Shinya:
The same. Majority of patients have valvular heart disease, small
mitral regurgitation is very common. We are excluding only
clinically overt mitral stenosis and basically mechanical heart
valve in all the newest trials. As Michael pointed out, it is
very important to correct misunderstanding. Non-valvular atrial
fibrillation, we used in the clinical trial is all atrial
fibrillation except clinical overt mitral stenosis and prosthetic
for mechanical heart valve.


 
Carolyn:
Exactly. A great foundation for us to get our understand right
before we discuss the findings. Michael, could you please give us
the top line result and tell us what do the results mean for your
own clinical practice?


 
Michael:
Basically, it means that the patients with valvular heart disease
that were included in the trial, and these included patients with
mitral regurgitation with was the most common lesion, mixed
aortic valve disease, tricuspid regurgitation, and also it turned
out that there were 192 patients that had mild mitral stenosis.
Those with mitral stenosis were presumed to be rheumatic in
ideology, and they did have a profile of having rheumatic heart
disease, that there were more females, they were younger, there
was a high incidence of heart failure and a high incidence of TIA
and stroke.


 
 
The bottom line here is whether the patients had mild mitral
stenosis or the other forms of valvular disease that I just
mentioned, that they benefited in an identical fashion from the
150 milligram BID dose of dabigatran and the one 110 milligram
BID dose of dabigatran as those patients without any valvular
disease. The bottom line is that clinicians can use dabigatran
with equal confidence in these patients with valvular disease as
in patients without valvular disease.


 
Carolyn:
Thank you Michael, that was very reassuring and something that is
very clinically important. Shinya, I'm going to ask a different
question. First, maybe your take on the findings, and secondly,
what was it like handling this paper across the globe as the
Associate Editor Managing this?


 
Shinya:
That is a very important point. The past as Michael pointed out,
this paper is very important to remind the clinician of
non-valvular atrial fibrillation is not really non-valvular
atrial fibrillation, and there is no difference between valvular
atrial fibrillation except mitral stenosis and prosthetic valve.
The result is similar to non-valvular atrial fibrillation in
regard to the effect of dabigatran or by warfarin. That is the
one point I have to assure. As a part, it is very important. We
are now including many patients not limited in that North
America, Europe. We are participating a huge number of patients
from Asia. The results is applicable to the global level. We are
now leading in that global evidence-based world and RE-LY is one
of the good example for the global trial testing the hypothesis
with [inaudible 00:13:58] over warfarin.


 
 
Michael made a very good summary of that, not only limited to
RE-LY, he talked about as our trial like ARISTOTLE and the ROCKET
trial. All of the NOAC trial include patient who is valvular
heard disease, and the exclusion criteria is a little bit
different. Michael beautifully summarized that difference in the
table, in his paper.  There is a strong intention to publish
this paper integration from all the editorial of old member. This
is a very nice paper.


 
Michael:
He's been very kind, that's very nice. That's true. In fact, the
results in RE-LY were compared in an indirect fashion with the
other trials, ROCKET and ARISTOTLE, through have published
similar papers on patients with and without valvular heart
disease. Just in summary, the bottom line is that this finding in
RE-LY is highly reproducible in the other two trials so this is
an important finding that is reproducible and true of the three
novel agents that had looked at this in detail.


 
 
The other point that was raised is that there were differences in
the exclusion criteria in these trials, but at the end of the
day, the Europeans and the Americans in terms of guidelines, had
fairly similar recommendation. For instance in the United States,
it was felt that all patients with valvular disease could be
anti-coagulated with the novel agent unless they had rheumatic
mitral stenosis, mechanical or bioprosthetic heart valves, or
patients that had undergone a prior mitral valve repair. The
emphasis was that all other patients could be included.


 
 
The Europeans differed slightly and that they agreed that
mechanical prosthetic valve and moderate to severe mitral
stenosis should be excluded, but they were somewhat more global
in recommending inclusions of all other valvular conditions.
There is a slight difference then between the European and the
American recommendations and guidelines.


 
Carolyn:
On that note of looking across the world at the guidelines and
what these results mean, it really leaves me to congratulate you
Michael on such an excellent paper, and Shinya for just managing
this paper so well.


 
Michael:
Thank you.


 
Shinya:
Thank you very much for your invitation. Bye-bye.


 
Carolyn:
You've been listening to Circulation on the Run. Thank you for
joining us today.