Circulation January 25, 2022 Issue

Please join authors Christopher Granger and Anthony
Carnicelli, as well as Associate Editor & Editorialist Shinya
Goto as they discuss the article "Direct Oral Anticoagulants
Versus Warfarin in Patients With Atrial Fibrillation:
Patient-Level Network Meta-Analyses of Randomized Clinical Trials
With Interaction Testing by Age and Sex" and accompanying
Editorial "Patient Level Meta-Analysis: End of the Era for DOAC
Developmental Trial in AF Patients?"


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Nam, 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
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, I'm so excited about our feature discussion today. It is
about DOACs versus warfarin in patients with atrial fibrillation,
a really important patient-level network meta-analysis of
randomized control trials with interaction testing by agent six.
So you can already tell something very, very clinically relevant
and important discussed by not only the authors, but our dear
associate editor and editorialist.


Dr. Carolyn Lam:


Okay. You just got to tune in, but first I'm going to start us
off with some coffee, as well as a description of this first
paper in today's issue. The 2018 AHA ACC multi-society
cholesterol guidelines states that statin therapy may be withheld
or delayed among intermediate risk individuals in the absence of
coronary artery calcium.


Dr. Carolyn Lam:


However, two traditional cardiovascular risk factors associate
with incident atherosclerotic cardiovascular disease events among
individuals with zero coronary artery calcium over the long term?
Well, this is the question that investigators decided to answer
in today's paper and they're led by Dr. Virani from Baylor
College of Medicine in Houston, Texas.


Dr. Carolyn Lam:


They studied 3,416 individuals with coronary artery calcium score
of zero at baseline from the MESA study, which is a prospective
cohort study of individuals free of clinical atherosclerotic
cardiovascular disease at baseline. Among these individuals with
zero coronary artery calcium, cigarette smoking, diabetes and
hypertension were found to be independently associated with
incident atherosclerotic cardiovascular disease events over
long-term follow up.


Dr. Greg Hundley:


Ah, very interesting. Another piece of information relating to
how we might use coronary artery calcium scores in, it sounds
like, a high-risk patient population. So, Carolyn, what's the
take-home message here?


Dr. Carolyn Lam:


Well, even if individuals have a coronary artery calcium of zero,
if they are current smokers, if they have diabetes melitis or
hypertension, initiation and long-term use of statin therapy,
along with a heart healthy lifestyle and risk factor modification
may still be warranted as part of the patient/clinician risk
discussion.


Dr. Greg Hundley:


Very interesting Carolyn. Well, I've got a clinical study to tell
you about. And, Carolyn, as you know, obesity and diabetes are
associated with a higher risk of heart failure and the inner
relationships between different measures of adiposity, including
overall obesity, central obesity, fat mass, and diabetes status
for heart failure risk, are not well established.


Dr. Greg Hundley:


And so this investigative group, led by Dr. Ambarish Pandey, from
UT Southwestern Medical Center, looked at the ARIC, the visit
five in ARIC and CHS, the visit one, and cohorts together, and
they were obtained from the NHLBI BioLINCC. They were harmonized
and pooled for the present analysis, excluding individuals with
prevalent heart failure.


Dr. Greg Hundley:


So using multi-variable adjusted fine-grade model models were
created to evaluate the associations of body mass index, waist
circumference, and fat mass with risk of heart failure in the
overall cohort, as well as among those with, versus without,
diabetes at baseline.


Dr. Greg Hundley:


And the population attributable risk of overall obesity with BMI
greater than 30 kilograms per meter squared, abdominal obesity
with waist circumference greater than 88 and 102 centimeters in
women and men, respectively, and high fat mass above the
sex-specific median for incident heart failure, was evaluated
among participants with and without diabetes.


Dr. Carolyn Lam:


Ooh, I'm so in interested in this topic. So what did they find,
Greg?


Dr. Greg Hundley:


Right, Carolyn. So a large study, it included 10,387
participants, about 53% from ARIC, 25% had diabetes, and the
median age was 74 years. And higher levels of each adiposity
measure were significantly associated with higher heart failure
risk. The population-attributable risk percentage of overall
obesity, abdominal obesity, and high fat mass for incident heart
failure was higher among participants with diabetes versus those
without diabetes.


Dr. Greg Hundley:


And so, Carolyn, we can conclude from this research that higher
BMI, higher waist circumference and higher fat mass, are strongly
associated with greater risk of heart failure among older adults,
particularly among those with prevalent diabetes.


Dr. Carolyn Lam:


So, so nicely done. Thank you, Greg. Well, the next paper talks
about common ancestry-specific ion channel variants and how they
predispose to drug-induced arrhythmias. Now, we know that
multiple reports associate the cardiac sodium channel gene Scn5a
variants, and these are the specific variants, S1103Y and R1193Q,
with Type 3 congenital long QT syndrome and drug-induced long QT
syndrome.


Dr. Carolyn Lam:


These variants are, however, two common in ancestral populations
to be highly arrhythmogenic at baseline. The S1103Y allele
frequency, for example, is 8.1% in Africans and the R1193Q is
6.1% prevalent in East Asians. So the investigators, led by Dr.
Roden from Vanderbilt University Medical Center in Nashville,
Tennessee, and colleagues, determined the effect of the S1103Y
variant on QT intervals among 1,479 Africans from a large
electronic health record with no confounding medications or
diagnosis of heart disease.


Dr. Carolyn Lam:


Now, while both the specific variants generated increased late
sodium current, baseline action potential durations in
cardiomyocytes from induced pluripotent stem cells carrying these
variants were unexpectedly normal. The re-polarizing potassium
current, IKR, was markedly increased in these induced pluripotent
stem cells with the variants, accounting for normal baseline
action potential duration but, with exposure to an IKR blocker,
they displayed exaggerated action potential duration prolongation
and after depolarizations.


Dr. Greg Hundley:


Wow, Carolyn, interesting. So tell us, what are the clinical
implications of this really exciting research?


Dr. Carolyn Lam:


Yeah. So here's the take-home message. These common
ancestry-specific variants do not affect baseline
re-polarization, despite generating an increased late sodium
current. So the authors propose that increased re-polarizing
potassium current, IKR, serves to maintain normal
re-polarization, but increases the risk of manifest QT
prolongation with IKR blocking in these variant carriers. So we
need to be aware of that and, further, these findings highlight
the need to include ancestral diversity in genomic and
pharmacogenomic studies.


Dr. Greg Hundley:


Oh, wow. Beautifully described, Carolyn. I really appreciate
that. Just excellent discussion. Well, Carolyn, my next paper
comes to us in an investigation regarding doxorubicin or
anthracycline-associated induced cardiotoxicity. So, Carolyn,
multiple pharmacogenetic studies have identified the synonymous
genomic variant rs7853758 and the intronic variant rs885004 and
SLC28A3 as statistically associated with a lower incidence of
anthracycline-induced cardiotoxicity.


Dr. Greg Hundley:


However, the true causal variant, or variance, of this
cardioprotective mechanism at this locus, the role of SLC28A3 and
other solute carrier transporters in anthracycline-induced
cardiotoxicity and the suitability of solute carrier transporters
as targets for cardioprotective drugs has not been investigated.


Dr. Carolyn Lam:


Wow. Got it. So what did these investigators do and find, Greg?


Dr. Greg Hundley:


Right. So Paul Burridge and his colleagues at Northwestern
University found that the patient-specific cardiomyocytes
recapitulate the cardioprotective effect of the cGAS-identified
SLC28A3 locus, and the authors functionally confirmed for the
first time, the role of SLC28A3 in doxorubicin-induced
cardiotoxicity.


Dr. Greg Hundley:


And a novel genetic variant, the rs11140490, is the potential
causal variant in the SLC28A3 cardioprotective locus. And
finally, Carolyn, the solute carrier transporter inhibitor
desipramine protects against doxorubicin-induced cardio toxicity
through decreasing the intracellular uptake of doxorubicin into
the heart.


Dr. Carolyn Lam:


Wow. That is a lot of data. Could you summarize it for us, Greg?


Dr. Greg Hundley:


Right, Carolyn. So these investigators provide two potential
therapeutic options to attenuate doxorubicin-induced
cardiomyopathy, either repurposing FDA-approved desipramine, or
therapy with long non-coding RNA SLC28A3-AS1. Also, Carolyn, they
propose that a simple clinical test to detect the presence of
rs11140490 can be used to predict that a patient will be less
likely to experience doxorubicin-induced cardiomyopathy, and
that, perhaps with future clinical trials, it may be possible for
these patients to be treated with a longer duration, that is a
higher accumulative dose of doxorubicin, to enhance the efficacy
of their chemotherapy.


Dr. Carolyn Lam:


I love the way you took that home for us. Thank you, Greg. Well,
also in today's issue is a Research Letter by Dr. Chen on
multifaceted spacial and functional zonation of cardiac cells in
an adult human heart.


Dr. Greg Hundley:


Right, Carolyn. And Professor Constantine has a Letter to the
Editor entitled Pravastatin Versus Placebo in Pregnancies at High
Risk of Term Preeclampsia. Well, Carolyn, how about we get onto
that feature article and learn about DOACs versus warfarin in
this very large network meta-analysis?


Dr. Carolyn Lam:


Yes, yes, yes. Let's go, Greg. Thanks.


Dr. Greg Hundley:


Welcome, listeners, to our feature discussion today. And we're
very fortunate. We're going to review the utility of DOACs in
patients with atrial fibrillation. And we have with us two of the
authors of this original research, Dr. Anthony Carnicelli from
Duke University, and Dr. Chris Granger from Duke University.


Dr. Greg Hundley:


Additionally, we have with us our associate editor, Dr. Shinya
Goto, from Japan. Welcome, gentlemen. Anthony, we'll start with
you. Describe for us a little of the background information
pertaining to your study and what was the hypothesis that you
wanted to address?


Dr. Anthony Carnicelli:


Yeah, thanks so much, Greg, for having us here to discuss this. I
started working in the DOAC space when I was a resident at
Brigham and Women's Hospital with mentorship from Dr. Bob
Guigliano there, and was really fortunate to connect with Dr.
Granger when I came to Duke for a fellowship, and we had this
unique opportunity to take data out of the four largest trials of
anticoagulants in the atrial fibrillation, and take individual
patient data from these international centers and combine them to
form the combined AF database from which we did this analysis.


Dr. Anthony Carnicelli:


So a very unique opportunity here to have individual
patient-level data from over 70,000 patients, and perform this
analysis. And, really, what we aimed to do was to do the kind of
highest quality meta-analysis using network meta-analysis methods
to investigate the relative safety and efficacy of DOACs versus
warfarin and a broad and diverse, but randomized, population of
patients with atrial fibrillation.


Dr. Greg Hundley:


Very good. So you started to describe for us your study
population and your study aligns. So tell us a little bit more,
who were these patients, and then maybe specifically give us a
little bit of the outline of your meta-analysis.


Dr. Anthony Carnicelli:


Yeah, so these were, again, a very broad patient group, but from
kind of 10,000 feet, this was a population of patients with
atrial fibrillation who were at risk of stroke, from CHADS score
perspective. So there are some nuances from each of the included
studies, of course, regarding the individual risk of stroke from
one study to the next. But largely, as I mentioned, in patients
with non-valvular atrial fibrillation randomized to either DOAC
or warfarin.


Dr. Anthony Carnicelli:


And, from a method standpoint, we are fortunate at Duke and at
DCRI, to have an expert in the network, meta-analysis
methodology, whom we've worked with, Dr. Bonnie Huang, who helped
to put together the analysis here and to proceed with this kind
of network methodology.


Dr. Anthony Carnicelli:


And so, again, our goal was to evaluate the overall safety and
efficacy of DOACs versus warfarin, but then also to dive into
some specific subgroups, both from a categorical covariant
perspective, and then also to evaluate some continuous
covariants, specifically age, and to assess gender across the
entire spectrum of continuous age in our population, which, of
course is a unique opportunity in the individual patient-level
data.


Dr. Greg Hundley:


And, Anthony, you had, gosh, it looks like over 70,000 patients
in this particular analysis. Tell us a little bit about the
results.


Dr. Anthony Carnicelli:


Yeah, so interesting, actually, and I agree that the biggest
strength of our meta-analysis is the individual patient-level
data and also the profound number of randomized patients
included. So I think, from a high level, the most important
results to highlight are the fact that there is a 19% relative
risk reduction in stroke or systemic embolism among patients who
are randomized to DOACs compared to warfarin, with an 8%
reduction in all-cause death and a 55% reduction in intracranial
hemorrhage.


Dr. Anthony Carnicelli:


So a massive reduction in the most feared complications of both
atrial fibrillation and then also those associated with systemic
oral anticoagulation. We also found a trend towards less bleeding
in patients randomized to the standard-dose DOAC group, as well.


Dr. Greg Hundley:


Very good. Well, Chris, we're going to turn to you. What an
exciting discovery here, and beautiful methodology. I wonder, in
addition to what Anthony has shared with us, were there
particular outcomes that were pertinent to men versus women or
perhaps related to age?


Dr. Christopher Granger:


Yeah, Greg. So, again, we're proud of this as being really the
state-of-the-art ability to evaluate safety and efficacy in this
incredibly important population of patients with Afib and at risk
for stroke, and to be able to dive into the subgroups and to the
individual outcomes, even the less common outcomes. And one of
the most striking things, and this really reinforces prior data,
but with the greatest confidence of any study ever done, there
was this 55% at reduction in intracranial hemorrhage and 19%
reduction in total stroke and systemic embolism, really
highlighting that these drugs are clearly better than warfarin,
from reinforcing the guidelines.


Dr. Christopher Granger:


And the message with the subgroups is there was really a
remarkable amount of consistency. And specifically in the older
population where people are really concerned about
anticoagulation, there was a clear and consistent major advantage
of DOACs over warfarin. Men versus women, clear, clear,
compelling benefit of DOACs over warfarin across each of these
outcomes, including mortality, by the way, 8%. But highly
statistically significant reduction in total mortality.


Dr. Christopher Granger:


A couple of the interesting ones, there was some effect
modification. In other words, some evidence of an even greater
benefit in patients who were not previously on a vitamin K
antagonist or who had lower creatinine clearance, really
important group, right? The renal impairment group.


Dr. Christopher Granger:


And then there was a greater benefit of lower risk of bleeding
for patients with low body weight. And, in fact, the younger
population, if anything, had a greater benefit with respect to
less bleeding. And the bleeding is so important, Greg and Shinya,
right? Because that's the major reason that people are not using
anticoagulation, warfarin or DOACs, for this large population of
patients who are untreated. And I hope this meta-analysis will be
viewed as evidence that have really safe and effective treatments
that are underused for this population that we're concerned about
bleeding.


Dr. Greg Hundley:


Excellent. Thanks so much, Chris. Well, Shinya, you see a lot of
papers come across your desk. What attracted you to this
particular paper? And then can you help us put these results in
the context with others that have evaluated the utility of DOACs
in patients with atrial fibrillation?


Dr. Shinya Goto:


Thank you, Greg. Let me congratulate for Anthony and Chris and
also group for conducting this great work. I mean, combine AF
with amazing success for sharing the clinical trial database. So
that all the four with a DOAC available is approved by each
country based upon individual trial. Individual trial itself,
large enough, right? Include more than 10,000 patient, but this
time the [OSA 00:19:49] accumulated all four DOAC trial database
together so that it is easy to say clinical trial data sharing
provided robust evidence.


Dr. Shinya Goto:


But it is difficult, actually, to conduct it. I really commended
OSA to conduct this success. So the data is predicted, I would
say. Individual clinical trial itself shows lower risk of
bleeding in DOAC as compared to warfarin. But this paper really
provides the first time standard dose of DOAC reduce the risk of
stroke and systemic embolism and death as compared to warfarin.


Dr. Shinya Goto:


So I really commented OSA. So this paper have a strong impact on
the medical care. DOAC rapidly change the standard of care
already. But superior efficacy was shown only in a few dose of
DOAC, like 150 milligram BID of dabigatran, 60 milligram QD
edoxaban, and five milligram apixaban. But this combined AF
provides a stronger and a trustable robust evidence DOAC is
better than warfarin.


Dr. Greg Hundley:


Very nice. Well, gentlemen, I want to turn back to you. I'll
start with Anthony and then Chris, and then Shinya. Anthony, what
do you think is the next study to be performed, really, in this
space?


Dr. Anthony Carnicelli:


Well, it may be a bit of a pitch, but I mean, we have many
opportunities in the combined AF data set to perform additional
analyses, but I think that one of the most important next steps
in this space that I'm most excited about is with respect to the
newer oral anticoagulants that are coming down the pike.


Dr. Anthony Carnicelli:


For example, the Factor 11 inhibitor space. I mean, I think that
there is another opportunity in the near future to potentially
revolutionize the systemic anticoagulation space. And I think
that data from combined AF could potentially be used to help
continue moving the ball forward, again in the development of
newer agents. So I think that's probably the thing that I'm most
excited about in this space.


Dr. Greg Hundley:


Very good. And, Chris?


Dr. Christopher Granger:


Greg, I think there's so many unanswered questions and I think,
as Tony points out, this highlights the fact that we know a lot,
but there's a lot of unanswered questions. And those, some of the
ones that I'm most interested in are low burden AFib, this AFib
that we're detecting now with smart watches and devices, and what
we do with that. And patients with renal impairment, including
all the way down to renal failure, where those are relatively
underrepresented, including in the combined AF data set.


Dr. Greg Hundley:


Very good. And, Shinya?


Dr. Shinya Goto:


Yeah. Yeah, Anthony and Chris talked about a little bit the plans
to space, but I insist there is a lot of space that also could do
with the combined AF database. We can expect a lot of
sub-analysis, like you conducted as a continuous variable in this
paper, but you can do that with eGFR as continuous variable, PMI
as continuous variable. So we can expect a lot of sub-analysis.
Probably, this is the end of publication from the individual DOAC
development trial. You change the game with the combined AF data
set.


Dr. Greg Hundley:


Very good. Well, listeners, we want to thank Dr. Anthony
Carnicelli, Dr. Christopher Granger and our own associate editor,
Dr. Shinya Goto, for bringing us this very interesting result
from the meta-analysis that, compared to warfarin, DOACs have a
more favorable efficacy and safety profile among patients with
atrial fibrillation. Well, on behalf of Carolyn and myself, we
want to wish you a great week and we will catch you next week on
the run.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2022. 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.