Sep 20, 2016
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.