Circulation March 7, 2023 Issue

This week, please join author Xuerong Wen, Associate
Editor Sandeep Das, and Guest Host Mercedes Carnethon as they
discuss the article "Comparative Effectiveness and Safety of
Direct Oral Anticoagulants and Warfarin in Patients With Atrial
Fibrillation and Chronic Liver Disease: A Nationwide Cohort
Study."


Dr. Carolyn Lam:


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


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, associate editor, Director of the Poly
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, I'm so excited about today's feature paper. It deals with
the important condition where atrial fibrillation exists in
patients with chronic liver disease and what do we do for
anticoagulation in these patients. It's a comparative
effectiveness and safety study of direct oral anticoagulants
compared with warfarin in these patients. A huge, wonderful,
important study that we're going to discuss. But before we get
there, I'd like to tell you about some papers in this issue and
I'd like you to tell me about some too. You got your coffee?


Dr. Greg Hundley:


Absolutely.


Dr. Carolyn Lam:


All right. I'll go first In this paper that describes a
quantitative prognostic tool for the mitral valve prolapse
spectrum and it's derived from the new mitral regurgitation
international database quantitative or MIDA-Q registry, which
enrolled more than 8,000 consecutive patients from North America,
Europe, Middle East. And these were patients all diagnosed with
isolated mitral valve prolapse or MVP in routine clinical
practice of academic centers, all of which also did prospective
degenerative mitral regurgitation quantification. The MIDA-Q
score was calculated based on characteristics collected in
routine practice combining the established MIDA score, which
integrated guideline based markers of outcomes like age, New York
Heart Association status, atrial fibrillation, LA size, pulmonary
artery pressure left ventricular and systolic, I mentioned, and
ejection fraction. Integrating that with scoring points based on
the degenerative mitral regurgitation quantitation that is
measuring effective regurgitant orifice and volume.


Dr. Greg Hundley:


Very interesting Carolyn. So a scoring system that combines
clinical information with what we might assess with
echocardiography like regurgitant volume or regurgitant orifice
area. So how well did this mortality risk score perform?


Dr. Carolyn Lam:


So the new score was associated with an extreme range of
predicted survival under medical management and that ranged from
97% to 5% at five years for the extreme score ranges. And it was
strongly, independently and incrementally associated with
long-term survival over all the markers of outcomes. So the
authors concluded, and these by the way were authors led by Dr.
Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These
authors concluded that the score should allow integrated risk
assessment of patients with mitral valve prolapse to refine
clinical decision making in routine practice and ultimately
reduce degenerative mitral regurgitation under treatment.


Dr. Greg Hundley:


Wonderful description Carolyn. Well I'm going to switch to the
world of electrophysiology, Carolyn. And so as you know, the
Brugada syndrome is an inherited arrhythmia syndrome caused by
loss of function variants in the cardiac sodium channel gene
SCN5A and that occurs in about 20% of subjects. And these authors
led by Dr. Dan Roden at Vanderbilt University School of Medicine
identified a family with four individuals diagnosed with Brugada
syndrome, harboring a rare missense variant in the cardiac
transcription factor, TBX5, but no SCN5A variant. And upon
identifying these individuals, their objective was to establish
TBX5 as a causative gene in Brugada syndrome and to define the
underlying mechanisms by which it would be operative.


Dr. Carolyn Lam:


Oh wow. So a new gene variant. So what was the relationship?


Dr. Greg Hundley:


Right Carolyn? So using induced pluripotent stem cell derived
cardiomyocytes from members of the affected family, multiple
electrophysiologic abnormalities were detected in these
cardiomyocytes including decreased peak and enhanced late cardiac
sodium current. In these cells these abnormalities were entirely
corrected by CRISPR/Cas9 mediated editing of that TBX5 variant
and transcriptional profiling and functional assays in unedited
and edited pluripotent stem cell derived cardiomyocytes showed
direct SCN5A down regulation caused decreased peak sodium current
and that reduced PDGF receptor expression and blunted signal
transduction to phosphoinositide-3-kinase. And interestingly,
PDGF receptor blockade markedly prolonged normal induced
pluripotent stem cell derived cardiomyocyte action potentials.


And also Carolyn interestingly in this study they did a separate
analysis. It reviewed plasma levels of PDGF in the Framingham
Heart Study and they found that they were inversely correlated
with the QT corrected interval. And so Carolyn, these results
established decrease SCN5A transcription by the TBX5 variant as a
cause of Brugada syndrome and also reveal a new general
transcriptional mechanism of arrhythmogenesis of enhanced late
sodium current caused by reduced PDGF receptor mediated
phosphoinositide-3-kinase signaling.


Dr. Carolyn Lam:


Wow. Wow, that's significant. Thanks Greg. So this next paper is
also really important and could change the practice in the field
of cardiac resynchronization therapy or CRT. You see, it suggests
that the practice of what we do now, which is combining right
bundle branch block with intraventricular conduction delay
patients into a single non-left bundle branch block category when
we select patients for CRT, that this may not be the way to go.


So let's go back a bit and remember that benefit from CRT varies
with QRS characteristics and individual trials are actually
underpowered to assess the benefit for relatively small
subgroups. So the current authors led by Dr. Friedman from Duke
University Hospital and colleagues, therefore performed a patient
level meta-analysis of randomized trials of CRT to assess the
relationship between QRS duration and morphology with outcomes.


Dr. Greg Hundley:


Very interesting Carolyn. So another wonderful paper from the
world of electrophysiology in trying to understand optimal
mechanisms to resynchronize the ventricle in patients with
differing bundle branch blocks or intraventricular conduction
delays. So what did they find?


Dr. Carolyn Lam:


They found that patients with intraventricular conduction delays
and a QRS duration of 150 milliseconds or more, CRT was
associated with lower rates of heart failure hospitalizations and
all cause mortality. The magnitude of CRT benefit among these
patients with the interventricular conduction delay of 150
milliseconds or more and those with the left bundle branch block
of 150 milliseconds or more were similar.


In contrast, there was no clear CRT benefit for patients with a
right bundle branch block of any QRS duration, although the
authors could not rule out the potential for benefit at a
markedly prolonged QRS duration.


So they concluded that the practice of combining right bundle
branch block with intraventricular conduction delay patients into
a single non-left bundle branch block category when we make
patient selections for CRT is not supported by the current data.
And in fact, patients with an intraventricular conduction delay
of 150 milliseconds or more should be offered CRT as is done for
patients with a left bundle branch block of 150 milliseconds or
more.


Dr. Greg Hundley:


Wow, Carolyn, so really interesting point. No clear CRT benefit
for patients with right bundle branch block regardless of the QRS
duration. Well we've got some other articles in the issue. I'll
describe a couple from the mail bag. There's a Research Letter
from Professor Lassen entitled "Risk of Incident Thromboembolic
and Ischemic Events Following COVID-19 Vaccination Compared with
SARS-COV2 Infection." Also Bridget Kuhn has a wonderful
Cardiology News piece entitled "Collaborative Care Model Helps
Heart Failure Patients Meet End-of-Life Goals."


Dr. Carolyn Lam:


There's an exchange of letters between Doctors Donzelli and
Hippisley-Cox regarding that risk of myocarditis after sequential
doses of COVID-19 vaccine, there's an AHA Update by Dr.
Churchwell on continuous Medicaid eligibility, the lessons from
the pandemic. There's an On My Mind paper by Dr. Parkhomenko on
Russia's war in Ukraine and cardiovascular healthcare.


Wow, what an issue. Thanks so much, Greg. Shall we go on to the
feature discussion?


Dr. Greg Hundley:


You bet.


Dr. Mercedes Carnethon:


Well welcome to this episode of Circulation on the Run podcast.
I'm Mercedes Carnethon, associate editor of the journal
Circulation and Professor and Vice Chair of Preventive Medicine
at the Northwestern University Feinberg School of Medicine.


I'm very excited to be here today with Xuerong Wen and Sandeep
Das, my fellow associate editor here at Circulation to talk about
a wonderful piece by Dr. Wen and colleagues from the University
of Rhode Island. So welcome this morning Xuerong and thank you so
much for sharing your important work with us.


Dr. Xuerong Wen:


Thank you Dr. Carnethon. It was great meeting you all and I'm the
Associate Professor of Pharmacoepidemiology and Health Outcomes
at the University of Rhode Island. I'm happy to introduce my
study to everyone.


Dr. Mercedes Carnethon:


Well thank you so much and thank you as well Sandeep for
identifying this fantastic article and bringing it forth.


Dr. Sandeep Das:


Thanks Mercedes. It's great to be with you.


Dr. Mercedes Carnethon:


Great. Well let's go ahead and get into it. There's so much here
to talk about. So Dr. Wen and colleagues studied the comparative
effectiveness and safety of direct oral anticoagulants or DOACs
and warfarin in patients with atrial fibrillation and chronic
liver disease. So this is such an important topic. Can you tell
us a little bit about what your study found?


Dr. Xuerong Wen:


So our study is a comparative effectiveness and the safety
analysis using a national health administrative data from private
health plans. So we compared the risk of hospitalized ischemic
stroke, systemic embolism and major bleeding between DOACs and
warfarin in patients with atrial fibrillation and chronic liver
disease. So we also had to had compare to these primary outcomes
between apixaban and rivaroxaban in the study population.


So our studies show that among patients with atrial fibrillation
and chronic liver disease, DOACs as a class was associated with
lower risk of hospitalization of ischemic stroke and systemic
embolism and major bleeding, compared with warfarin. And when
compared risk outcomes between individuals apixaban has lower
risks as compared to rivaroxaban. So that's our study results.


Dr. Mercedes Carnethon:


Well thank you so much. This seems like such an important
question. We hear a lot about DOACs and some of their risks as
well as their considerable benefits. I think what leaves me the
most curious is why did you choose to pursue this question and in
particular in patients with both atrial fibrillation and liver
disease. So why was the intersection of these two particular
conditions of interest to your study team?


Dr. Xuerong Wen:


That's a great question. So the liver actually plays a central
role in both the synthesis of coagulation factors and the
metabolism of anticoagulant drugs. And the clearance of the
anticoagulants in liver ranges from 20% to 100% for DOACs and
warfarin. So in clinical practice anticoagulation abnormalities
and elevated risk of spontaneous or unprovoked venous thrombotic
complications have been reported in patients with liver disease.
While these patients with cirrhosis were excluded from the
clinical trials of DOACs and also population based, the real
world experience is very limited. So that is why we initiated
this retrospective cohort study and based on the real world data
in this specific population.


Dr. Mercedes Carnethon:


Oh, thank you so much for explaining that. I definitely learned a
lot and really enjoyed reading the piece. I think it was very
well organized and well written and I know that our readership
will appreciate it. It obviously stood out to you as well,
Sandeep. Can you tell me a little bit about why you thought that
this would be an excellent piece for circulation?


Dr. Sandeep Das:


Yeah, absolutely. Thanks for the question.


So in the broad field of what we call observational comparative
effectiveness research, so basically that's using large
observational data sets to try to answer important clinical
questions and it's a really challenging thing to do. I mean we're
all very familiar with the idea of using randomized trials to
assess important clinical questions because of the structure of
that design allows you to mitigate some of the effects of
confounding. Here, it has to be done analytically. So what's the
important factor that really drives you towards a great
observational comparative effectiveness piece? So first the
clinical importance. I feel a little guilty because I'm old
enough to remember when warfarin was the only option available,
but really as a clinician, or every patient, I really prefer
DOACs over warfarin just for ease of use and lifestyle. So
there's a huge sort of importance to the question.


Second, the patients with chronic liver disease were excluded
from the larger RCTs and the DOAC trials. So really we don't have
the answer to the question already. It's an important question.
Obviously the bleeding risk is tied up with the liver, warfarin
directly antagonizes vitamin K, so there's real questions about
safety and so this is the perfect storm and then on top of it was
a really well done and well executed study. So when this came
across my desk, the very first thing I thought was not, "Is this
something that we're interested?" But rather, "How do we make it
better? How do we make it more useful to the reader?" This had me
from hello.


Dr. Mercedes Carnethon:


Well thanks so much. We rarely have the opportunity when we read
an article to be able to ask the authors questions. So Sandeep, I
know that you had mentioned that you had some follow up questions
as well.


Dr. Sandeep Das:


Yeah. So the real thought that I have then is would you argue
based on this that we know enough that we should change our
practice? And that do you feel comfortable advocating that people
now prescribe DOACs to these patients?


Dr. Xuerong Wen:


I would say yes. Okay.


Although this is not a clinical trial, but our study is actually
systematically compare the effectiveness and safety between DOAC
users and also the warfarin users. And if you look at our table
one, we compare with so many variables between these two users
and we use the propensity score adjustment and we after
propensity score weighting and the two control group almost
balanced.


And I know right now FDA actually suggested that emulate the
trial using the large real world data to do the emulated trial.
So our study actually conducted is based on the large population
using large data and we use the propensity score weighting to
control all this potential compounding factors. Although there
are still some limitations in this study. I think we mentioned
that in the discussion section and we discussed all potential
compounding factors that still may exist.


And also there are some misclassifications and out of all this
limitations and we still found the two drugs performed
differently in this specific population. So we feel that
comfortable to say that a DOAC drug performs better than
warfarin. And also I think based on other studies that based on
the clinical trial in the general population, DOAC drug is
performs much better than warfarin and considering that the
clearance in liver for DOAC is less than warfarin. So plus all
this information together, I think DOAC may be safer than wafarin
in the patients with AF and chronic liver disease.


Dr. Sandeep Das:


Yeah, I would say that I agree that these data, even if you're
skeptical about observational CT generally, which I admit that I
tend to be, these are really reassuring data that at least the
DOACs are... There's absolutely nothing that suggests that
they're any worse than warfarin and all of the sort of soft
indications for ease of use and patient happiness really would
seem to favor DOACs. So I think this is the sort of rare
observational CT paper that may actually change my practice.


Dr. Mercedes Carnethon:


I have a follow-up question, Xuerong, related to the design and
as well your strategy to address differences between the groups.
So inverse probability weighting is certainly a standard in the
field to be able to manage differences between groups when you
have a situation where can't, where it's not a randomized trial.
Do you as well, and educate me, I admit I'm an epidemiologist
whose methodological skills are sometimes challenged. Do you have
the opportunity using this design and with inverse probability
weighting to evaluate subgroup effects? So my specific question
is were you able to determine whether or not these associations
were similar based on age and gender in particular?


Dr. Xuerong Wen:


That's a great question. We did conducted a lot of subgroup study
but not by age or gender. We conducted I think this study in a
lot of subgroups using the propensity score weighting, but the
subgroup that I think we did a subgroup like a patient with a
different chronic liver disease. So that's what we did. And we
also tested different methods inverse probability score
weighting. So we did trimming and we used a different percentage
of trimming and to see how that affect the study results. So we
have done a lot of subgroup studies. We did not check the age and
the gender, but that's a very good point. Maybe later, well I'll
ask my student to do that.


Dr. Mercedes Carnethon:


Well, you're a good mentor. So I think that is a really certainly
an appropriate approach. Sandeep, did you have additional
questions?


Dr. Sandeep Das:


No, I wish I had thought of yours before you did. I think exactly
the older age, women, racial ethnic groups that are
underrepresented historically in trials. I think that that's
really, again, the sweet spot of this observational research. We
definitely, and NH definitely working on trying to increase
enrollment of all these groups in our CTs. However, while we wait
for that, I think that's exactly what we should be doing.


Dr. Mercedes Carnethon:


Well that's great. And Xuerong, you really alluded to really, I
think what is one of my final questions related to what do you
think based on what you have observed in this study, what do you
see as the next steps in the research field for your team, your
students, or other people who are carrying out this type of work?


Dr. Xuerong Wen:


Well, that's a great question. We currently have a couple of more
manuscripts ongoing in this field, and we will continue
conducting the comparative effectiveness and analysis to compare
drugs head to head as well as developing and implementing new
methodologies to this field. And we hope our study provides real
world evidence for clinical decision making, prescribing
anticoagulants to patients with atrial fibrillation and chronic
liver disease. We also expect the physicians and researchers more
and more value the real world data studies, especially when
clinical trials are not feasible or ethical.


Dr. Mercedes Carnethon:


Well, thank you so much. That was such an excellent vision that
you provided us with and we're just very grateful that you
submitted this fantastic work to the journal Circulation. I know
that our readers will enjoy really digging in. The podcast is
meant as a teaser to bring you to the journal so that you can
read about this wonderful work by Dr. Wen and colleagues. So
again, thank you. I'm Mercedes Carnethon, joined with my
associate editor partner here, Dr. Sandeep Das. And thank you
very much for spending your time with us today, Dr. Wen.


Dr. Xuerong Wen:


Thanks for this great opportunity to disseminate my study with
us, thank you.


Dr. Sandeep Das:


Thanks Mercedes.


Dr. Mercedes Carnethon:


Thank you for joining us for this episode of Circulation on the
Run.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2023.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.