Circulation October 29, 2019 Issue

Dr Carolyn Lam:  Welcome to Circulation On The Run, your
weekly podcast summary and backstage pass to the journal and it's
editors. I'm Dr Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg Hundley:  I'm Greg Hundley, Associate Editor from
the Pauley Heart Center at VCU Health in Richmond, Virginia.
Well, Carolyn, our feature article today involves bleeding and
new cancer diagnosis in patients with atherosclerosis and it
emanates from Dr John Eikelboom from McMaster University who
addresses the question of whether incident GI or GU bleeding when
treating cardiovascular disease with anticoagulation is
associated with incident cancer. Now, that's a common occurrence
that we see frequently clinically, and I'm really interested to
hear those results.


Dr Greg Hundley:  How about we start with our articles. And
Carolyn, maybe I'll go first this time and my first paper is on
mapping and ablation of ventricular fibrillation associated with
early repolarization syndrome and it's from Professor Nademanee
from Chulalongkorn University. Carolyn, this multicenter study
evaluated mapping and ablation of ventricular fibrillation
substrates and VF triggers in early repolarization syndrome, also
called ERS or J wave syndrome, JWS, among 52 ERS patients for
women who are averaged age 35 years with recurrent ventricular
fibrillation episodes. Ablations were performed on one. VF
substrates defined as areas that had late depolarization
abnormalities characterized by low-voltage fractionated late
potentials and two VF triggers.


Dr Carolyn Lam:  So... What did they find?


Dr Greg Hundley: So first there were two phenotypes of ERS/JWS.
Group one included those with late depolarization abnormalities
with the underlying mechanism of high-amplitude J wave elevation
that predominantly resided in the right ventricular outflow tract
and the right ventricular inferolateral epicardium. They served
as excellent targets for ablation. And two, the other was with a
pure ERS devoid of VF substrates, but with VF triggers that are
associated with Purkinje sites. The catheter ablation of the
arrhythmogenic substrates with late depolarization abnormalities
was very effective in preventing VF recurrence in group one
patients and ablation of VF triggers emanating from the Purkinje
system was effective in treating the group two patients.


Dr Carolyn Lam:  Wow, thanks Greg. My first paper is a first
randomized double-blind placebo-controlled trial examining the
early effects of SGLT2 inhibitors on clinically important
endpoints in patients with heart failure and reduced ejection.
Recall that outcome trials in patients with type 2 diabetes have
demonstrated reduced hospitalization for heart failure with SGLT2
inhibitors. However, few of these patients had heart failure and
those that did were not really fully well characterized.


Dr Carolyn Lam:  So DEFINE-HF was an investigator-initiated
multicenter randomized controlled trial of heart failure patients
with left ventricular ejection fraction less than 40, New York
Heart Association Class II to III, GFR above 30, and elevated
natriuretic peptides. This DEFINE-HF was published by Dr
Kosiborod from St. Luke's, Mid America heart Institute and
colleagues. In total, 263 patients were randomized to
dapagliflozin 10 milligrams daily or placebo for 12 weeks. There
was a dual primary outcome and the first was mean NT-proBNP and
the second proportion of patients with a five or more point
increase in heart failure disease specific health status on the
Kansas City Cardiomyopathy Questionnaire or KCCQ overall summary
score or a 20% or more decrease in NT-proBNP.


Dr Carolyn Lam:  So here's what they found. There was no
significant difference in average six and 12 weeks adjusted
NT-proBNP with dapagliflozin versus placebo. However, for the
second dual primary outcome of a meaningful improvement in KCCQ
overall summary score or NT-proBNP, significantly greater
proportions of patients treated with dapagliflozin experienced
clinically meaningful improvements in heart failure-related
symptoms, functional status, and quality of life or natriuretic
peptides compared to placebo, and these results were consistent
among patients with or without type 2 diabetes.


Dr Greg Hundley:  Wow, Carolyn, another sort of feather in
the cap for SGLT2 inhibitors. What are the clinical implications
specifically for this study?


Dr Carolyn Lam:  Yeah, I couldn't agree with you more Greg,
and these findings in particular suggest that dapagliflozin may
have a favorable effect on improving disease-specific health
status after 12 weeks of treatment in patients with heart failure
and reduced ejection fraction. These beneficial effects of
dapagliflozin may potentially extend to patients with or without
type 2 diabetes. Interesting that the first primary outcome of
NT-proBNP was not significantly different. I'm sure we'll hear
more.


Dr Greg Hundley:  Very good. Well, my next paper comes from
Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center and
it really relates to therapeutic modulation of the immune
response in arrhythmogenic cardiomyopathy. Carolyn, inflammation
is a prominent feature of arrhythmogenic cardiomyopathy, but
whether it contributes to the disease phenotype is not really
known. So in this study, the authors sought to define the role of
inflammation and the pathogenesis of arrhythmogenic
cardiomyopathy by characterizing NF kappa beta signaling in ACM
models both in vitro and in vivo and in cardiomyocytes from
patient-induced pluripotent stem cells.


Dr Carolyn Lam: Wow, that sounds like a lot of work. So what did
they find?


Dr Greg Hundley:  First they found that NF kappa beta
signaling is activated in cardiac myocytes in arrhythmogenic
cardiomyopathy. Second, BAY 11-7082, a small molecule inhibitor
of NF kappa beta signaling prevented development of major
features of the disease phenotype. And third, cardiac myocytes
express large amounts of inflammatory cytokines and chemotactic
molecules in arrhythmogenic cardiomyopathy, reflecting activation
of an innate immune response in the heart.


Dr Greg Hundley:  So Carolyn, clinically important features
of ARVC or arrhythmogenic cardiomyopathy, myocardial injury and
arrhythmias are driven by activation of an immune response in the
heart. And the results of this study suggest that
Anti-inflammatory drug therapy should be studied to determine if
it could be an effective mechanism-based strategy to reduce
myocardial damage and risk of sudden death in patients with
arrhythmogenic cardiomyopathy.


Dr Greg Hundley:  So Carolyn, how about the other articles
in this issue? Can you tell us a little more about them?


Dr Greg Hundley:  Oh, I would love to. We have a primer from
Dr Weissgerber entitled Reveal, Don't Conceal Transforming Data
Visualization to Improve Transparency, and this primer really
outlines strategies for selecting the correct type of figure
based on a study design, sample size, and type of variable. It
examines techniques for making effective dot plots, box plots,
and violin plots and illustrates how to avoid sending mixed
messages by aligning the figure structure with the study design
and statistical analysis. A really nice primer.


Dr Greg Hundley: We also have a perspective from Dr Verma
entitled More Credence for SGLT2 Inhibition. Talk about even more
feathers in the SGLT2 inhibitor cap.


Dr Greg Hundley: There's an On My Mind article from Dr Godier on
specific antidotes for direct oral anticoagulant reversal. Is it
a case closed or a cold case? Dr Godier really concludes with
saying that the availability of specific antidotes provides in
itself reassurance, but whether DOAC reversal translates into
clinical improvements remain unknown and this leaves clinicians
in kind of an awkward position and the case is not closed. Read
more. It's a very nice piece.


Dr Greg Hundley: We also have a research letter from Dr Mills
very interestingly showing that endothelial progenitor cells do
not are originate from the bone marrow. Very interestingly, Dr
Mills systematically studied the origin of endothelial progenitor
cells in people with sex-mismatched bone marrow transplantation
using two complimentary methods and found that all the clones
formed from single cells were actually derived from the recipient
rather than from the donor bone marrow, thus suggesting that
endogenous neovascularization in the heart is driven by tissue
resident endothelial progenitor cells without a direct
contribution from bone marrow cells. A very important piece
because it goes against prior pieces and it's consistent with
others, so do read this research letter.


Dr Greg Hundley: Finally, there's a cardiovascular key series
from Dr Uriel and title It's All About the Tissue and it's a rare
case of acute cardiogenic shock.


Dr Greg Hundley: Wow, Carolyn, what great summaries and articles
we have in this issue, but how about now we go and learn a little
bit more about that GI tract in our feature article?


Dr Carolyn Lam: You bet, Greg.


Dr Greg Hundley: Welcome everyone to our feature discussion and
today we're going to meet with Dr John Eikelboom from McMaster
University in Ontario, Canada and our own associate editor, Dr
Shinya Goto from Tokai University School of Medicine in Kanagawa,
Japan. The feature discussion paper focuses on the development of
lower gastrointestinal bleeding or genitourinary bleeding that
may occur in patients with cardiovascular disease that are
receiving anticoagulant therapy.


Dr Greg Hundley: So first John, I was wondering, could you tell
us a little bit about the hypothesis and why you wanted to
conduct this study?


Dr John Eikelboom:  Intriguingly, we set out to do a trial
of antithrombotic therapy in cardiovascular disease and our
intent originally was not to look at cancer specifically in
relation to bleeding. In fact, normally in our cardiovascular
trials we don't even collect cancer. But the background story is
that there is a hypothesis and there are data that aspirin
protects against gastrointestinal cancer and in the COMPASS trial
we were testing a regimen that omitted aspirin. So we were
concerned that by omitting aspirin this might lead to an increase
in cancer. So as a safety measure we very carefully collected all
types of cancer during this trial. We were very much reassured
that none of the antithrombotic regimens were associated with an
increase in cancer, but then we noticed there was a very high
rate of cancer diagnosis, about 4% during the course of the
trial, and cancer was as common as cardiovascular events. This
observation prompted a secondary analysis to see who was having
the cancer and in particular with our interest in bleeding where
the bleeding identified patients who were subsequently diagnosed
with cancer.


Dr Greg Hundley: Can you tell us a little bit about the design of
your study and your study population?


Dr John Eikelboom:  The COMPASS trial was designed to test
whether an antithrombotic regimen containing rivaroxaban might be
more effective than aspirin in preventing cardiovascular events.
We included people with chronic coronary artery disease or
peripheral artery disease who were randomized to one of two
rivaroxaban regimens or aspirin. The results of this main
analysis have been previously published the rivaroxaban regimen
was associated with more bleeding than aspirin and in particular
more gastrointestinal bleeding. Of course, it was more effective
than aspirin in reducing the composite of cardiovascular death,
stroke, or myocardial infarction. So in this analysis, we then
drilled down on the bleeding story and in particular on the
gastrointestinal or genitourinary bleeding because bleeding into
a hollow viscus has previously been identified as a marker of
cancer risk.


Dr Greg Hundley: And who did you include in this study?


Dr John Eikelboom:  We included people with chronic coronary
or peripheral artery disease, that is people who were some time
away from an acute event. They were more or less stable, although
the term chronic is probably better. They were on effective
secondary prevention strategies. They'd be your typical patient
that a cardiologist, an internist, a vascular specialist, or a
neurology would see in their outpatient clinic, an ambulatory
patient, where the focus of the clinician would be on
cardiovascular prevention.


Dr Greg Hundley: And how many subjects were in your study? Was
this a large study?


Dr John Eikelboom:  The study included 27,395 patients from
33 countries and 602 centers, so yes, a large study with a very
broad inclusion criteria. This result therefore also is very
widely applicable to the secondary prevention cardiovascular
populations.


Dr Greg Hundley: So what did you find? What were your results?


Dr John Eikelboom:  We found that there are several
highlights. The first, as I've already alluded to, new cancer
diagnosis was found in one of 25 people of comparable frequency
to the composite of cardiovascular death, MI, or stroke. So
that's the first finding. The second funding was that bleeding
was very common, that is any bleeding, major or minor, about 10%
of the population during an average of two years of follow-up.
Then the third and the most relevant finding to our report is
that bleeding was a powerful predictor of a new cancer diagnosis.


To describe that a little bit more carefully, among those with
bleeds about 10% were diagnosed with a new cancer of any type.
And then when we look specifically at gastrointestinal bleeding,
it's again around the same proportion of those with GI bleeding
who are diagnosed with gastrointestinal cancer but compared with
those who did not have gastrointestinal bleeding, those with
gastrointestinal bleeding had a twentyfold increased hazard. In
other words, the GI bleeding was a very powerful predictor of
news GI cancer diagnosis.


Likewise, genitourinary bleeding was a very powerful predictor of
new genitourinary cancer diagnosis, about a thirtyfold increased
hazard. And when we separated out the urinary bleeding that was
the most powerful predictor about a hundredfold increase. And the
converse, if we look at bleeding in other areas, they was an
association with cancer, but it was much weaker, and this really
focuses the attention on bleeding into a hollow viscus, GI tract,
the genitourinary tract, and in particular the urinary tract, and
it sends up a red flag for clinicians if you bleed into these
areas there is a very great increase in the hazard of new cancer
diagnosis.


Dr Greg Hundley:  Fantastic, John. So just two quick points
and then we wanted to ask Shinya to help us put this study in
perspective. The average age of the patients, what was that in
this study, what was the gender breakdown, and then did you find
any more frequent association of cancer with genitourinary
bleeding in men versus women?


Dr John Eikelboom:  The average age was 68 and about one
fifth where women, so that is pretty typical of cardiovascular
trials, although an area of separate interest because women were
relatively underrepresented. Of course, that's another story. In
terms of cancer prediction, we didn't separately explore this in
men and women and indeed the cancers were dominated by the
urinary tract and the GI tract with far fewer genital tract
cancers. So we're not really in a position to answer that
question. I do accept that very important consideration because
clearly, we're going to investigate differently in a man compared
with a woman if they have genitourinary tract bleeding.


Dr Greg Hundley:  Well, Shinya, we appreciate having the
opportunity to speak with you as an associate editor of
Circulation. How do we implement or interpret this data in the
context of administration of both aspirin as well as other
anticoagulant strategies?


Dr Shinya Goto:  This paper is very important. I mean, that
we are cardiologists, we believe we are very away from that
cancer, but John and COMPASS group demonstrated cancer is much
commonly occurred than we expected, almost similar rate as
cardiovascular death within two year in patients recognized
coronary artery disease and peripheral artery disease. They are
on antiplatelet or anticoagulant agent aspirin, 2.5 milligram
b.i.d. of rivaroxaban, plus over 5 milligram b.i.d. of
rivaroxaban alone. So CAD/PAD patient on antithrombosis, we have
to care about cancer.


And as John beautifully pointed out, if the patient experienced
bleeding, like GI tract bleeding, we have to care seriously about
hidden GI tract cancer. If a CT scan found GU bleeding, it is an
important sign of concealed genitourinary tract cancer. We are
very close, so it's a kind of bridging discipline. Cardiology
should be close to oncology. As John pointed out, the patient at
68 average age, not so old, it's typical of age of the patient
treated by cardiologist. But you know, the message is strong: We
have to be careful about the cancer and we have to be careful
especially if we found anything in GI tract or GU, so the message
is clear.


Dr Greg Hundley:  Well, thank you Shinya. Shinya, I wanted
to ask you, what do you think is the next study to be performed
in this area of investigation?


Dr Shinya Goto:  If we conducted a cardiovascular trial, it
would be nice to add cancer as an endpoint, especially for
long-term trial.


Dr Greg Hundley:  John, do you have any perspectives? Where
do you see your research going in this area over the next five
years?


Dr John Eikelboom:  In addition to the very important point
raised by Shinya, I think there are two additional
considerations. The one is we need to better understand whether
the apparently earlier diagnosis of cancer that can be achieved
by exploring bleeding in these cardiovascular patients can
improve clinical outcome. We certainly hope that this is good
news for patients because we hope to be able to diagnose cancer
earlier. The second big question is if we were more diligent in
screening for bleeding and in particular occult bleeding in the
cardiovascular patient, would that lead or help us to diagnose
the cancer earlier?


Dr Greg Hundley:  Well listeners, we've had a great
discussion from Dr John Eikelboom from McMaster University in
Ontario, Canada, and our own Shinya Goto from Tokai University
School of Medicine in Kanagawa, Japan. They have highlighted to
us this important study result indicating an association of
detection of cancer when we observe gastrointestinal and
genitourinary bleeding after treatment with both anticoagulant
and antithrombotic therapy.


And so for Carolyn Lam and myself, Greg Hundley, we wish you a
great week and we look forward to catching you On the Run next
week.


Dr Carolyn Lam:  This program is copyright American Heart
Association 2019.