Circulation January 17, 2017 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. Dr.
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore.


                                               
In today's episode, we are discussing very important new data
regarding stroke risk stratification in patients with atrial
fibrillation. First though, let me give you the highlights of
this week's journal.


                                               
The first paper provides mechanistic evidence that
endothelial-derived microparticles may play a key role in the
development of endothelial dysfunction following acute coronary
syndrome. In this paper from first author, Dr. Abbas,
co-corresponding authors, Dr. Toti and Morel from the University
of Strasbourg in France, authors expose core sign coronary artery
endothelial cells to microparticles shed from senescent cells, or
circulating microparticles from patients with acute coronary
syndrome.


                                               
They showed that exposure to these microparticles induced
increase senescence-associated beta-galactosidase activity,
oxidative stress, and early phosphorylation of MAP kinases and
AKT, and upregulation of p53, p21 and p16. Depletion of
endothelial-derived microparticles from acute coronary syndrome
patients reduced the induction of senescence.


                                               
On the other hand, pro-senescent microparticles promoted
endothelial cell thrombogenicity. These microparticles exhibited
angiotensin-converting enzyme activity and upregulated AT1
receptors and ACE in endothelial cells. Losartan and AT1 receptor
antagonist and inhibitors of either MAT kinases or PI3-kinase
prevented the microparticle-induced endothelial senescence. 


                                               
In summary, these findings indicate that endothelial-derived
microparticles from acute coronary syndrome patients induce
premature endothelial senescence and thrombogenicity suggesting
that targeting endothil-derived microparticles and their
bioactivity may be a promising therapeutic strategy to limit the
development of endothelial dysfunction post-acute coronary
syndrome.


                                               
The next study is the first large and prospective study showing
that NT-proBNP is associated with cardiovascular events in
patients with adult congenital heart disease independent of
multiple clinical and echocardiographic variables.


                                               
This is a study from first author, Dr. Bekan; and corresponding
author, Dr. Roos-Hesselink and colleagues from the Erasmus
University Medical Center in Rotterdam, the Netherlands. The
author studied 595 clinically stable patients with adult
congenital heart disease who attended the outpatient clinic
between 2011 and 2013.


                                               
All patients underwent clinical assessment, electrocardiography,
echocardiography and biomarker measurement, including NT-proBNP,
high-sensitivity troponin T and growth differentiation factor 15.
Patients were prospectively followed over a median of 42 months
for the occurrence of cardiovascular events including death,
heart failure, hospitalization, arrhythmia, thromboembolic events
and reintervention.


                                               
They found that of the three evaluated biomarkers, NT-proBNP was
most strongly associated with cardiovascular events. Importantly,
patients with a low-risk of death and heart failure could be
accurately identified with a high negative predictive value.


                                               
In patients with elevated NT-proBNP, elevations of high
sensitivity troponin T and growth differentiation factor 15
identified those patients at highest risk of cardiovascular
events.


                                               
In summary, these biomarkers may play an important role in the
monitoring and management of patients with adult congenital heart
disease.


                                               
The next study describes heart failure stages among older adults
in the community. Dr. Shah and colleagues from the Brigham and
Women's Hospital in Boston Massachusets classified more than
6,000 participants in the atherosclerosis risk and community
study into heart failure stages. These were stage A; asymptomatic
individuals with heart failure risk factors, but no cardiac
structural or functional abnormalities. Stage B; asymptomatic
individuals with structural abnormalities such as left ventricle
hypertrophy, dilation, dysfunction, or valve disease. Stage C1;
clinical heart failure without prior hospitalization. Stage C2;
clinical heart failure with prior hospitalization.


                                               
They found that only 5% of examined participants were free of
heart failure risk factors or structural heart disease. 52% were
categorized as stage A, 30% stage B, 7% stage C1, and 6% stage
C2. Worst heart failure stage was associated with a greater risk
of incident heart failure hospitalization or death at a median
follow up of 608 days.


                                               
Left ventricular ejection fraction was preserved in 77% of stage
C1 and 65% of stage C2 respectively. In corporation of
longitudinal strain measurements and diastolic dysfunction into
the stage B definition, reclassified 14% of the sample from stage
A to B.


                                               
Abnormal LV structure, systolic function, whether based on
ejection fraction of longitudinal strain, and diastolic
dysfunction, were each independently and additively associated
with the risk of incident heart failure hospitalization or death
in stage A and B participants.


                                               
The authors concluded that the majority of older adults in the
community are at risk of heart failure, appreciably more compared
to previous reports in younger community-based samples. The study
also highlighted the burden of heart failure with preserved
ejection fraction in the elderly and provided evidence that left
ventricular diastolic function and longitudinal strain provide
incremental prognostic value beyond conventional measures of LV
structure and ejection fraction in identifying patient at risk of
heart failure hospitalization or death.


                                               
The next study sheds light on the association of the LPA gene,
ethnicity and cardiovascular events. First author, Dr. Lee;
corresponding author Dr. Tsimikas and colleagues from University
of California San Diego studied 1,792 black, 1,030 white, and 597
Hispanic subjects all enrolled in the Dallas Heart Study. They
measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized
phospholipids on apolipoprotein B100.


                                               
These individuals were also followed for a median of 9.5 years
for major adverse cardiovascular events. The authors found that
the prevalence of LPA snips and apolipoprotein A isoforms were
very different across ethnic groups. LPA snips that were
associated with elevated LP(a) in whites were associated with low
LP(a) in Hispanics mainly due to differences in apoliproprotein A
isoforms size.


                                               
After multi-variable adjustment, LP(a) and oxidized phospholipids
on apolipoprotein B were both predictors of major adverse
cardiovascular events. Conversely, LPA snips and apolipoprotein A
isoforms did not add predictive value to models and did not show
clinical utility in this study.


                                               
These data suggests that much of LP(s) mediated major adverse
coronary events is driven by oxidized phospholipids. Importantly,
elevated LP(a) and oxidized phospholipids on apolipoprotein B
must be recognized as important predictors of major adverse
cardiovascular events across racial groups.


                                               
The final study addresses the question of the optimal
antithrombotic regimen for longterm management of patients with
symptomatic peripheral artery disease, or PAD, with a history of
limb revascularization. To answer this question, Dr. Jones and
colleagues from Duke Clinical Research Institute looked at the
EUCLID trial, or examining use of ticagrelor in PAD trial, which
randomized patients with PAD to treatment with ticagrelor 90
milligrams twice daily, or clopidogrel 75 milligrams daily.


                                               
As a reminder, patients in EUCLID were enrolled based on a normal
ankle-brachial index of less .8, or a prior lower extremity
revascularization. The current paper really focus on the subset
of 7,875 patients who were enrolled based on a prior lower
extremity revascularization criterion.


                                               
The authors found that after adjustment for baseline
characteristics, patients enrolled based on prior
revascularization for PAD had higher higher rates of myocardial
infarction and acute limb ischemia with similar composite rates
of cardiovascular death, myocardial infarction and stroke when
compared with patients enrolled based on the ankle brachial index
criterion.


                                               
Overall, there were no significant differences between ticagrelor
and clopidogrel for the reduction of cardiovascular or acute limb
events.


                                               
Those were your highlights. Now, for our featured discussion.


                                               
On today's podcast, we are discussing the very, very important
issue of stroke risk in patients with atrial fibrillation. Most
of us use the international guidelines for anticoagulation in
atrial fibrillation that mostly suggest that we use the CHADS
VASc scoring system to determine the stroke risk in a particular
patient and then determine whether or not this patient meets the
threshold for anticoagulation.


                                               
This assumes that the CHADS VASc score corresponds to a fixed
stroke rate. Today, in our journal, we have very, very
interesting results from a paper with corresponding author, Dr.
Daniel Singer who really suggest that we may need to rethink
that. Dr. Daniel Singer joins us today from Massachusets General
Hospital.


                                               
Welcome Daniel.


Dr. Daniel
Singer:            
Thank you for having me.


Dr. Carolyn
Lam:              
Great. Today, we also have Dr. Sana Al-Khatib who's the associate
editor from Duke University who managed this paper. Welcome Sana.


Dr. Sana Al-Khatib
:         Thank you Dr.
Carolyn, I'm happy to be here.


Dr. Carolyn
Lam:              
Daniel, could we start by you letting us know what you sought to
do in your study and what you found?


Dr. Daniel
Singer:            
We all know that anticoagulants are extraordinarily effective at
preventing stroke in patients with atrial fibrillation, but they
also raise the risk of bleeding, and sometimes that bleeding
could be quite serious and even fatal. As a result, for that past
10, 15 years, we have used a risk-based approach to the decision
about whether to start a patient on anticoagulation, and that
risk is the stroke risk that a patient faces if they weren't
taking anticoagulants. Then we figured that anticoagulants will
reduce it by about two-thirds.


                                               
There are formal decision analysis and then a more informal sense
that a patient has to face an anticoagulated risk of stroke of
about 2%, some people might say 1% to 2% before anticoagulation
results in an expected net clinical benefit that the effect in
reducing ischemic stroke will exceed the risk of increasing
bleeding.


                                               
While the CHADs VASc score has been widely accepted as the basis
for estimating that risk, it became apparent to us as we looked
across the studies that were underlying that assumption, that the
risk that were associated with various CHADs VASc scores were
extremely variable. Many of these risks actually were less than
that 1% or 2% threshold for anticoagulation.


                                               
What I mean is that the stroke risk associated with CHADs VASc
score of one, or two, which is the basis for the guideline
threshold for anticoagulation actually corresponded to risk less
than 1% in many of these very large studies. We have conducted a
systematic review just to be sure that we were capturing the
overall evidence base for this, and that's what we report in our
paper.


Dr. Carolyn
Lam:              
Perhaps you could start by letting us know exactly how far off
are we in our stroke risk estimation.


Dr. Daniel
Singer:            
We looked at 34 studies that were quite large and then we zeroed
in on the largest one. If you looked at the rate for stroke
overall, they varied enormously in terms of the overall stroke
rate. Then when we focused down on CHADs VASc score of 1, or 2,
we found that the majority of these studies, actually, for CHADs
VASc 1, was less than 1% per year. For CHADs VASc 2 score was in
the majority these studies less than 2% per year.


                                               
Both of those stroke risks have raised us the question where are
these patients could gain in that clinical benefit from being
anti-coagulated, because those stroke risk, if they were reduced
by two-thirds, would really be a very small reduction in risk and
yet they'd still face the bleeding risk.


                                               
Among the most interesting findings actually is that we found
that a Swedish national database and the large Danish national
database came up with threefold difference in their estimate of
stroke rates. The Swedish database produced lower risk, and the
Danish database produced substantially higher risk.


                                               
If you think about it, there are probably no two countries in the
world that are more similar in terms of gene, social
environmental, medical care systems, and that raises the specific
question of, "Is it underlying rates that vary across different
cohorts and different geographies, or is it a different in
methodology?"


                                               
We think a lot of the differences are due to methodologic
difference, and that we need to standardize these differences
together, better handle on what the real stroke rate is among
patients with these low CHADs VASc scores.


Dr. Carolyn
Lam:              
The variability that you pointed on your paper is really
striking, but another possibility, do you think, is that maybe
stroke risk isn't static.


Dr. Daniel
Singer:            
Yeah. If that's the case, we face a great difficulty in
developing predictions rules of what the stroke risk could be. I
think most people feel it's the function of their age, and
whether they've had a prior stroke, and whether they have the
comorbidity, hypertension, and diabetes, and so on, that are
incorporated into the various stroke risk scores, in particular,
CHADs VASc.


                                               
We tend to think that that's pretty fixed until you get older or
until you accumulated another comorbidity. I think the striking
difference is that, one, that we actually anticipated in the
beginning, was that the stroke rates in people with atrial
fibrillation were also coming down. The stroke rates in general
have been dramatically decreasing for decades now.


                                               
One issue is whether that applies as well to atrial fibrillation
associated stroke. There is a suggestion of that, but the
variability across the cohorts is so great that you can't pick up
a strong signal in terms of calendar time. Although I suspect
that there is a strong calendar effect. Exactly why that is, we
could speculate. I suspect a lot of it is control of blood
pressure, but that's speculation.


Dr. Carolyn
Lam:              
Daniel, congratulations again for that fascinating and really
very sobering findings.


                                               
Sana, you managed this paper. It's very important paper. In fact,
important enough that you invited an editorial. Could you please
share some of your thoughts?


Dr. Sana Al-Khatib
:         Oh, yeah.
Absolutely. First, I'd like to start by congratulating Daniel and
his team on conducting this really important study. I enjoyed
reading it and managing it. Definitely, congratulations.


                                               
A couple of thoughts that I have. I completely agree with this
really important finding, that there is a lot of variability in
the rates of stroke that come from different patient populations
and databases. As you pointed out Daniel, I think this is indeed
largely due to differences in methodology in terms of how the
information was selected, how certain things were defined.


                                               
I agree with you there. You called for standardization of this,
and I wonder if you have any thoughts about how we can go about
doing that. I also want to bring up some of the newer studies now
that are showing some significance in terms of biomarkers. Is
that really adding significantly to the predictive ability of
risk prediction models? I wanted to get your thoughts on that as
well.


Dr. Daniel
Singer:            
Let me address your last question, which is simply you state that
the CHADs VASc score, the CHAD score and so on, are based on very
simple clinical features, and it would be unusual for them to be
highly predictive. In fact, they're only mediocrely predictive,
and the addition of biomarkers high-sensitivity troponin proBNP,
now, people have suggested the imaging biomarkers like magnetic
resonance to asses fibrosis in the left atrium. These are all
very, very promising in terms of getting better models.


                                               
The problem is to do that on a very scale such that we can get
precise and well-calibrated predictions. We've found when we're
analyzing to pair risk scores, we found that the most important
issue is the underlying risk, so that, yes, you can get a great
model, but if you have high variability in the underlying rate,
you can have a problem specifying an individual with a stroke
risk.


                                               
We have to standardize and improve the quality of bringing people
into these cohorts, and of interrogating the cohorts and
databases and making sure that we have the same approach to
assessing outcomes.


                                               
This could probably be best done in very big scientific
prospective registry studies, but it's tough to get all that
information. There are some registry studies now ongoing, the
ORBIT registries, the GARFIELD registries that may help us a lot
with specifying stroke risk, but they don't have the biomarkers
embedded in them. I'm hopeful that with better message, and large
studies, and incorporating biomarkers, that we'll really get down
to very accurate and generalizable stroke risk.


                                               
I think the CHADs VASc and similar simple stroke risk scores will
be in the rear-view mirror.


Dr. Sana Al-Khatib
:         That's great.
Can I ask one other question, because I completely agree with you
looking at your numbers and the data that you presented, is that
when you look, especially at the CHADs VASc score 1 patient, the
risk seems to be pretty low.


                                               
As you very well know, the guideline documents don't really ...
At least, for the American AHA/ACC guideline document, they don't
really verbalize very definitively the need to anticoagulate
patients with a CHADs VASc score of 1.


                                               
If you look at the numbers related to a CHADs VASc score of 2,
I'm not sure that I completely agree that the risk is very low.
Certainly, there was 33% of the studies reported stroke rates of
greater than 2% per year. I think maybe different people have
different thresholds. While I completely agree with you on the
CHADs VASc score of 1 patients, I find that the findings on
patients with a CHADs VASc score of 2 a bit more concerning.


                                               
In fact, if anything, I would want based even on your data, not
on the guidelines to offer anticoagulation to patients with CHADs
VASc score of 2. What would you say to that?


Dr. Daniel
Singer:            
I'm looking at our table that has this, and a lot of the CHADs
VASc 2 scores are under 2%, but they're in mid 1%. In the North
American cohorts in particular, the rates tend to be lower. That
said, I think the heart of the problem here is that we have
focused on the threshold for anticoagulation. I think there's an
argument to be made that you lay out the risks and benefits to
the patients and engage them in a decision, particularly with
regards to these lower CHADs VASc scores.


                                               
At least you make a lot of, perhaps, even more emphasis on being
sure that the higher CHADs VASc scores, that anticoagulation is
the net benefits of anticoagulation are made very clear to the
patient, and that we don't have large fractions of patients who
can take anticoagulants not taking them.


                                               
We know from the pinnacle registry and other registries, that
even at high CHADs VASc scores, we have 40% plus of atrial
fibrillation patients who are not getting anticoagulants. I think
that's where we have a lot more assurance that the net benefit is
positive and that we can make a different both in terms of a
patient in front of us, and in terms of the overall public health
aspects of atrial fibrillation and stroke.


Dr. Sana Al-Khatib
:         I do believe
that this is really important, but it is also important to keep
in mind that with the novel novel oral anticoagulants, I think
the whole landscape has changed. Not only do patients have
different options to consider, but certainly, the risk of
bleeding, which is the other part of this equation, has gone down
significantly with the novel agents.


                                               
I think as we engage in shared decision making with patients, I
think it is really important to highlight these really very
remarkable features about the agents that have really changed the
care of patients with atrial fibrillation.


                                               
One thing to add to this whole topic is, really, all the new
advances that we're seeing in this field that has been really
life-changing for us and for our patients.


Dr. Carolyn
Lam:              
Indeed Sana. I was about to bring up the bleeding risk part, the
flip side of the coin as well. Also, the point that most of my
patients with atrial fibrillation, they really strongly value the
avoidance of stroke even more than avoidance of bleeding.
Someone, that needs to be taken into consideration as well.


                                               
Daniel, I'd love to give you the last words. You mentioned that
you like to highlight, maybe, some more of the implications of
your findings.


Dr. Daniel
Singer:            
I guess I would say there's a scientific implication, which is
what we've ben discussing, which is the importance of trying to
get these rates down correctly and accurately, and maybe we have
to get people together to say how they're doing these studies.


                                               
The second is, for the individual patient, that we should engage
them in this discussion. Maybe patients who are perfectly willing
to a novel anticoagulant and CHADs VASc score of zero. That would
come out of a discussion with the patient. That our emphasis at
this point since we're a little unsure about the threshold level,
our emphasis both at the individual patient level, and then from
the public heath perspective should be on the higher CHADs VASc
scores where we know that we can expect a net clinical benefit
from the vast majority of patients with AF.


                                               
I agree with Dr. Al-Khatib, that the novel anticoagulants post an
important advantage in the sense not so much in their overall
bleeding, but particularly in terms of their intercranial
bleeding, which is the lethal bleeding we most want to avoid.


Dr. Carolyn
Lam:              
Thank you both for joining us. Thank you listeners for joining
us. Don't forget to tune in next week.