Circulation February 26, 2019 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 Carolyn
Lam, associate editor from the National Heart Center and Duke
National University of Singapore.


Dr Greg
Hundley:            
And I'm Greg Hundley, associate editor and director of the Pauley
Heart Center from VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
So, Greg, are we any closer to the holy grail of safe ED
discharge for acute heart failure based on a risk score? Well,
we're going to be discussing that coming right up after Greg and
I share about the papers that we'd like to discuss today. Lovely
issue, isn't it?


Dr Greg
Hundley:            
Yup, and time to get your coffee and bring it up. My first paper,
Carolyn, is from Michael Chu from London Health Sciences Center,
and is really investigating the surgical management of thoracic
aortic disease, and looking at the impact of gender or sex
related differences. Sex related differences have not been
thoroughly studied. This group looked at a total of 1653
patients, 30% were women, who underwent thoracic aortic surgery
with hypothermic circulatory arrest between the years of 2002 and
2017 across Canada in 10 institutions.


                                               
Well, women underwent less aortic root reconstruction, including
aortic root replacement, Ross procedures, or valve sparing root
operations. But, even with less invasive, the women experienced
higher rates of mortality, 11% versus 7%, stroke, and that
composite of the thoracic surgeons' adverse events. On multi
variable analysis, female sex or women was an independent
predictor of overall mortality, stroke, and those comorbidities.


Dr Carolyn
Lam:               
Greg, you know how much I love these papers, so I'm going to
repeat that. You're saying the women received less ominous
procedures and yet had worse outcomes, and this was independent
of the clinical covariances, right?


Dr Greg
Hundley:            
Absolutely. Putting all this together, women underwent thoracic
aortic surgery a little bit older, and with larger index aortic
aneurysm size than men. Intraoperatively, women undergo fewer
concomitant procedures, such as the aortic root repairs, and
things that you just mentioned. But nevertheless, women
experience significantly worse outcomes identified as an
independent predictor of mortality, stroke, and that composite
endpoint for mortality, morbidity, after multi variable analysis.


                                               
What should we think about this? Well, sex specific
considerations are important when considering thoracic aortic
surgery and future research should focus on the development of a
personalized approach to thoracic aortic surgery with respect to
gender. For example, utilization of maybe lower size thresholds
for women for aortic aneurysms should be considered, and for
earlier interventions, and improved outcomes.


                                               
Carolyn, tell me about one of your papers.


Dr Carolyn
Lam:               
All right, so I chose a paper looking at the stroke outcomes in
the COMPASS trial. Now, let's remind everybody that the COMPASS
trial, where patients with stable coronary artery disease or
peripheral artery disease, and randomly assigned to receive
aspirin 100 milligrams daily, rivaroxaban five milligrams twice
daily, or the combination of rivaroxaban 2.5 milligrams twice
daily plus aspirin. Patients requiring anticoagulation with a
stroke within a month had a previous lacunar stroke or
intracerebral hemorrhage were excluded.


                                               
Now, in the current paper, and this is from Dr Sharma from
Population Health Research Institute, and their colleagues,
basically they looked at a detailed analysis of the stroke by
type, predictors, and anti-thrombotic effects in the key
subgroups. They found that the combination of low dose
rivaroxaban and aspirin prevented stroke and disabling stroke
better than aspirin in patients without atrial fibrillation and
with stable vascular disease, and without an increasing risk of
hemorrhagic stroke; which is really important. This effect was
consistent across subgroups of baseline risk, and particularly
marked in those with a history of previous stroke.


Dr Greg
Hundley:            
Carolyn, what about that rivaroxaban five milligrams twice daily
alone?


Dr Carolyn
Lam:               
There was no significant difference in the occurrence of stroke
in the rivaroxaban alone group compared with aspirin. But all of
this simply says perhaps low dose rivaroxaban and aspirin may be
a really important new anti-thrombotic option for primary and
secondary stroke prevention in patients with clinical stable
atherosclerosis.


Dr Greg
Hundley:            
Very interesting. I'm going to follow your lead and go into
another sort of anticoagulant-related topic on iliofemoral deep
vein thrombosis. This paper is by Suresh Vedantham from the
Washington University of St. Louis.


                                               
Let's talk about just what is the definition? This is a DVT that
involves the iliac and/or the common femoral vein with or without
involvement of additional veins. It basically obstructs the
outflow of the veins. These patients are phenotypically distinct
from patients with cath or femoral popliteal DVT because that
totally obstructs flow, and they have more frequent recurrence of
venous thromboembolic events, and more frequent post-thrombotic
syndrome. Well, that's a horrible condition because of that
obstruction, it leads to calf muscle dysfunction, edema,
subcutaneous fibrosis, tissue hypoxia, and ulceration.


Dr Carolyn
Lam:               
Great background. What did this study show?


Dr Greg
Hundley:            
This is a sub-study of the ATTRACT trial. The ATTRACT trial
basically is looking at anticoagulation plus perhaps mechanical
intervention, or direct catheter directed thrombolysis therapy
versus just anticoagulation alone. This sub-study is 391 patients
with acute DVT involving just the iliac or the common femoral
veins, and following these individuals for 24 months to compare
short and long-term outcomes.


                                               
What did the study show? Well, this interventional group did have
a reduction in leg pain and swelling, and improvement in quality
of life related to that lower extremity. But, no overall
difference in overall quality of life, and very importantly, no
difference in the occurrence of this post thrombotic syndrome.


Dr Carolyn
Lam:               
That's kind of disappointing. I understand that the ATTRACT study
is not the first to look at this, though. That was in an
editorial discussing this. Could you tell us about that?


Dr Greg
Hundley:            
Yeah, Carolyn. Jay Giri from University of Pennsylvania just had
an incredible editorial. I think if you have an opportunity,
listeners, to take a look at that, I highly recommend it. He
reminded us of the CaVenT trial, which is basically performed as
an open label randomized control trial of 209 patients across 20
hospitals in Norway.


                                               
What was different in the CaVenT trial is that at 24 months of
follow up, the intervention with thrombolysis and systemic
anticoagulation improved iliofemoral patency. It reduced the
incidence of this post thrombotic syndrome. In ATTRACT, in this
sub-study, it was intravenous thrombolysis, systemic
anticoagulation, and mechanical intervention on the vein versus
in the other study from Norway, CaVenT, just the inter vein
thrombolysis and the systemic anticoagulation.


                                               
What Dr Giri points out is that maybe something related to
intervention in that vein when you're stripping out thrombus, et
cetera, are we damaging the veins in the vessel that prevents
reflux, et cetera?


                                               
I think really moving forward, you're going to have to
personalize this decision in individual patients until we have
more data on this subject.


Dr Carolyn
Lam:               
Great learning. I learned a lot from this next paper, too,
because I actually chose a basic science paper. This is a paper
that uncovers a new fine tuning factor that modulates myocardial
infarction induced inflammation. That is a small GTPase called
RhoE.


                                               
In this study, Drs Chang from Texas A&M University College of
Medicine, and Song from Fuwai Hospital in Beijing used three
genetic mouse model lines. Those are the global knockout, the
cardiomyocyte specific RhoE heterozygous mouse, and the
cardiomyocyte specific RhoE over expression mouse. With this
combination, they showed that RhoE deficiency causes excessive
inflammatory response in infarct animal heart, resulting in
enlarged heart, decreased contractility, and increased mortality.
The mechanism is that RhoE binds to P65 and P50, which impedes
their dimerization and blocks these two proteins from nuclear
translocation. Now, over expression of cardiac RhoE inhibits
NF-κB, restrains post MI inflammation, and improves cardiac
function and survival.


                                               
Importantly as you always say, Greg, there is human data. They
found that the expression of RhoE was elevated in the infarct
patient heart and that patients with a higher expression of RhoE
exhibited a better prognosis and better cardiac function
recovery.


Dr Greg
Hundley:            
Carolyn, tell me a little bit about the clinical significance of
this.


Dr Carolyn
Lam:               
You just wanted to ask me a tough question. I can see it on your
face. Basically, I think this is really exciting because RhoE may
serve as a new potential biomarker for the assessment of
myocardial infarction in patients, and manipulation of RhoE could
be a potential therapeutic approach for MI. There.


Dr Greg
Hundley:            
Very good.


Dr Carolyn
Lam:               
That's all the time we have for our little discussion here. Now,
let's go onto the feature paper. ...


                                               
Over 80% of emergency department patients with acute heart
failure are admitted to the hospital. Now, contrast this with the
fact that over 80% of all emergency department visits result in
discharge. So, why is that many other emergency department based
cardiovascular disease processes like for acute coronary syndrome
have evolved from high rates of admission to timely and safe
discharge whereas decision making in acute heart failure has not
experienced a similar evolution. Do we need perhaps a better
acute heart failure prognostic score that's validated?


                                               
Well, guess what? We're going to talk about this right now in our
feature discussion, and a beautiful feature paper that we're so
proud to have the corresponding author, Dr Douglas Lee from
University of Toronto right here to discuss; along with the
managing editor, Dr Justin Ezekowitz, who's associate editor from
University of Alberta, and the editorialist, Dr Sean Collins from
Vanderbilt University Medical Center. Welcome everyone, and Doug,
please, could you just start by telling us about this great
paper?


Dr Douglas
Lee:                
We validated, and it's a tool, decision making tool, for acute
heart failure patients in the emergency department. We, in this
study, wanted to prospectively validate a decision making
prognostic tool called the Emergency Heart Failure Mortality Risk
Grade, or EHFMRG for short, to see how well it performed in the
real world busy emergency department hospital setting.


                                               
We studied just under 2,000 patients who came to emergency
departments at multiple centers, and asked physicians to rate
their prognostic estimation of what's going to happen to that
patient in the next seven days. We compared that with the EHFMRG
model, which predicts outcomes of seven days and 30 days. We were
very careful to ask physicians to provide their prognostic
estimates. This is their intuitive guesstimation of the risk of
the patient before calculating the score because we didn't want
the physicians to be influenced by the score.


                                               
What we found was that when we looked at how well physicians'
estimates performed, they actually performed quite well. The
c-statistic for physician estimated risk was around .7, which is
a reasonable discrimination. However, the physicians' estimates
were not as good as the EHFMRG risk score, which had a C greater
than .8. The mathematical model seemed to do better in terms of
predicting what's going to happen to the patient than physicians'
estimates.


                                               
Interestingly, when we combined the physicians' estimates with
the EHFMRG risk score, the c-statistic improved by another 1%, so
there's some additive value of having both factors combined.


                                               
The other interesting finding was that patients in the lowest
risk groups had 0% mortality at seven days, and 0% mortality at
30 days. We may be able to identify, using the score, patients
who have a very low risk of events in that seven to 30 day period
after emergency department presentation.


Dr Carolyn
Lam:               
Thanks so much, Doug. I have to tell you, I am a fan of the
EHFMRG score. In fact, we're trying to study how well it performs
in our local situation even here in Singapore.


                                               
Justin, you've been thinking a lot about this. I would love for
you to share the reactions that we got when we discussed this
among the editors.


Dr Justin Ezekowitz:        We
had a lot of good discussion about this from a number of
different aspects. First, it's an in-practice assessment, a
physician-based risk assessment, as we survey hundreds of
physicians in the ER, which is a busy environment, and get these
types of information. That's a very unique piece of this study
where, in addition to the just under 2,000 patients and
collecting the other data in a robust way, this really does have
a potential to contribute to the literature.


                                               
A lot of the discussion was about how data rich this is, and that
this is an area where unlike acute cardiovascular disease where
there are good risk assessment tools and other therapies, it's a
really need of a scoring system that was well validated, can be
replicated, and both in clinical practice as well as in selective
cohorts. Doug, my congrats to your and the other parts of the
team that's helped put this together.


                                               
One of the questions that came up when we were discussing it was
the risk textiles and buckets were very important for people to
think about the very low risk, as you mentioned, 0% all the way
up through much higher percents for seven day mortality, but how
discrepant the risk was of the physicians versus the mathematical
model; and a very good reminder of the inaccuracy of sometimes
our assessments of risk in practice, especially in acute care.


                                               
I wonder if you could comment on what your fence was from the
physicians who participated in the study, and then the data of
those, the most striking findings of that piece about where
physicians make judgements on risk in for that seven-day
mortality. Just any comments you may have?


Dr Douglas
Lee:                
We didn't know what to expect because there haven’t been many
studies of this type before. What we found in our study was that
physicians tended to overestimate the risk of lower risk
patients. They thought bad things would happen to healthier
patients, just to put it very simply. Physicians also
underestimated the risk of the highest risk patients. They
thought that the highest risk patients would do well.


                                               
We were surprised about that finding, but also, we were not
surprised in the fact that it seems to explain some of our
earlier findings that in our earlier work, we found that low risk
patients are hospitalized, and we think it's probably that
physicians are admitting those patients because they want to
ensure that they're making a safe decision; and no harm will fall
in the patient. Maybe physicians are erring on the side of
admitting those patients, even though they know they're a little
bit low risk.


                                               
At the other extreme, physicians underestimated risk in the
highest risk patients. We think it might explain the observation
that we made previously that sometimes high risk patients are
discharged home, and they die at home after discharge. That may
be because patients who look well to physicians, I think there's
great value in the clinical experience of a seasoned physician
looking at a patient and knowing that, that patient is sick or
not sick. But in certain cases, patients may look relatively
well, but their numbers would indicate that they're actually
higher risk. I think it's that group where we found they're
higher risk, but physicians thought that they were healthier than
they were. It seems physicians' estimations really have great
value, but it seems that they can be improved.


Dr Carolyn
Lam:               
Sean, you discussed this beautifully in your editorial. Share
with us your thoughts, and especially thoughts on the question
you posed: are we any closer to the holy grail of safe emergency
department discharge based on acute heart failure risk rules?


Dr Sean
Collins:                
Doug, kudos to you. Nearly 2,000 patients, nine different
hospitals, prospective data collection, as Justin said. I don't
think this can be overstated. From a data cleaning perspective,
this is truly a labor of love, and to get this done,
congratulations to you and your team.


                                               
I think the most interesting part of this is this exact
disconnect of patients look well who are high risk, and patients
may look a little bit unwell who may be low risk, ironically.
That's where a risk tool is much needed, as Carolyn said in her
introduction to sort of change the dynamic of 80 to 90% of
patients are admitted to the hospital. If we even chipped away at
10 to 15% to able to be discharged, it would be a huge win for
partly for management for an emergency department perspective.


                                               
I think that the importantly, the next steps will be now looking
at implementing this in some sort of a randomized manner,
somewhat like what you did with asking physicians gestalt about
what their level of risk is, but really finding out how does a
physician gestalt when it comes to nuance and heart failure. A
relative amount of congestion, even when the tool says the
patient may be low risk, can they go home? I think that will be
the crucial next step to find out how much does this augment
and/or detract from physician decision making? We have a long way
to go, as Carolyn said. It's just the complete opposite at almost
every other disease process, including chest pain, from a
discharge perspective. Even a little bit improvement would be
great, so I'm looking forward to seeing the next steps, and I'm
wondering what your thoughts are about the next steps, Doug.


Dr Douglas
Lee:                
There's actually great value in physicians' clinical judgment.
It's been, I think relatively understudied. I'm hopeful that
future studies where decision tools or prognostic tools are
validated, we can see more potentially, more comparisons with
clinicians because we don't have a real great understanding, I
think, of how doctors think, especially in an acute setting. More
research in this area, I think would be really helpful,
especially as we ... As more and more clinical decision tools
being published, it would be great to see how well they hold up
against good clinician judgment.


                                               
In terms of next steps and implementation, when we talk to our
emergency colleagues, they have brought up an issue about it's
great that patients are low risk, and that we could potentially
discharge them from hospital; but where is the receptor to take
that patient and to care for that patient once they've left the
hospital? Are they going to get good care once they leave the
hospital? Are there structures in place?


                                               
We're now embarking on testing this in the clinical trial where
we will be comparing two strategies. The first strategy will be
using the risk score at a hospital-wide level, and then
discharging home patients who are in the lower risk categories,
and having them follow up, and receive their care in a rapid
ambulatory follow up clinic within two to three days after
discharge from the emergency. This will be compared to the
control, which is not using the risk score, and having usual
follow up care. This trial is called the Comparison of Outcomes
and Access to Heart Failure Trial, or the COAHFT trial. It is
currently ongoing.


Dr Sean
Collins:                
Great point, Doug. As Carolyn suggested with chest pain and heart
failure as the interesting dichotomy is that unlike chest pain,
when we safely rule somebody out and send them home, we're sort
of done with that acute episode. Heart failure, it doesn't end.
We've found that they're safe enough to go home, but now they
need great collaboration and outpatient support with their heart
failure provider, which may be as equally heavy lift as
externally validating the EHFMRG score. You bring up a great
point, which is we need to have outpatient follow up and
collaboration for this to be successful. Thanks.


Dr Carolyn
Lam:               
Awesome comments, guys. Could I switch tracks a bit and maybe
just ask Justin to round up by sharing? Circulation, we get a lot
of papers about risk scores and so on. There's a bit of fatigue,
I think, about scores in all kinds of things. Now, could you
maybe tell us, Justin, what makes us look at a paper twice, and
in fact, feature this one with a good editorial? I mean it's
clearly very clinically applicable. Could you share some thoughts
there?


Dr Justin Ezekowitz:       
Yes, that's a great point. The things that make a risk score like
this kind of elevated into kind of a circulation level of
manuscript is A) the data quality has to be excellent. There has
to be lots of completeness of data, but also capture of elements
that we think are quite important. Two, the data science about
how it's analyzed and put together, and interpreted, it has to be
to the bar that we feel would be robust, and be able ... if
somebody could repeat it and replicate it without an obvious
challenge to the quality.


                                               
The third, I think is the clinical applicability. It's okay to
write a data model and come up with all these great risk scores,
but if they haven't been thought through about how either a
patient will be seeing this, or clinicians behave, or the
environment that it has to be deployed in that, that isn't
necessarily going to be something that is going to be
implemented. Then, the question is: why would somebody do the
study in the first place?


                                               
Now, it's okay if somebody's forward thinking and saying, 'Look,
EMRs are coming, or other EHRs around, so this could be
implemented if there was enough impetuous and it's a good enough
quality.' That's actually okay, but in the reverse where if you
try to implement a model that is too complex, and it's in a
hand-off to the environment, it just won't work. We just want to
make sure people have thought that next knowledge translation and
dissemination approach through.


                                               
The final part is things that have a very local impact are, that
are very unique to the environment they're in, such as it only
would work in your hometown or your own country because of some
environment, that's okay. But under that, the much more global
focus that, that is, it could be picked up and trans located to
any major city, providence, state, or country, because vis vises
are global. Those things have a much greater impact because the
circulation leadership is global. The patients are global. The
clinicians who care for them are also global. People are all
looking for very similar situations and can adapt to their own
environments.


Dr Carolyn
Lam:               
Awesome, Justin. I don't think any of us could have said it
better. Those are the reasons that we're so grateful that you
publish with us, Doug. Thank you so much, Sean, for your
excellent editorial, too.


                                               
Thank you, listeners, for joining us today. You've been listening
to Circulation on the Run. Don't forget to tune in again next
week.


                                               
This program is copyright American Heart Association 2019.