Circulation June 09, 2020 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 Dr Greg Hundley associated editor from
the Pauly Heart Center at VCU health in Richmond, Virginia. Well
Carolyn, this week's feature investigates the compass trial and
is going to examine the role of combination antiplatelet and
anticoagulation therapy in patients with diabetes and
cardiovascular disease. But before we get to that feature
discussion, how about we grab a cup of coffee and jump in and
discuss some of the other papers in the issue?


Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and
I'd like to start by talking about paclitaxel containing devices.
You may already know this, but it was nice to revise that these
significantly reduce re intervention in patients with symptomatic
femoral, popliteal, peripheral artery disease, as we may expect.
However, a recent aggregate data meta-analysis reported increase
late mortality in pad patients treat it with these paclitaxel
containing devices. Thus today's authors, Dr Rocha-Singh from
Prairie Heart Institute of Illinois at St. John's hospital and
their colleagues performed an individual patient data
meta-analysis to evaluate mortality using data from eight
randomized controlled trials of FDA approved paclitaxel coated
devices using de identified data that was provided by
manufacturers.


Dr Greg Hundley: Well, Carolyn, what did they find?


Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight
paclitaxel coated device trials with a four year median
follow-up, there was a 4.6% absolute risk of increased mortality
associated with paclitaxel coated device use compared to balloon
angioplasty at a median of four years follow up, significant loss
to follow up and withdrawal rates of 24% and 23% in balloon
angioplasty and paclitaxel cohorts respectively through five
years were observed. Recovery of lost vital status data reduced
the observed paclitaxel device associated mortality rate. And
there was no paclitaxel drug dose mortality relationship
identified.


Dr Greg Hundley: Oh, Carolyn, I think this is really an important
finding, and we have a nice editorial, don't we? So what was the
take home message?


Dr Carolyn Lam: Yeah. In fact, this was discussed in an important
editorial by doctors Royce, Chakraborty and Dao from the USFDA.
Now listen up. So based on the prior aggregate data meta-analysis
and subsequent FDA review, FDA had already communicated that
clinicians should consider the increased rate of long-term
mortality when making treatment recommendations. They had also
implemented updated labeling for this device class to communicate
the risk. So in this editorial, the FDA commended the authors of
the current individual patient data meta-analysis for providing
important information towards signal refinement, and also commend
at their collaboration with device manufacturers to work together
with a shared goal of patient safety. Now, there are still many
unanswered questions, including the mechanism for the observed
increase in late term mortality associated with these devices and
how the benefit risk profile of these devices may shift across
various patient populations.


Dr Greg Hundley: Well Carolyn, my paper comes from Professor
Antje Beling from Charité – Universitätsmedizin Berlin in Berlin.
And it investigates heart specific immune responses in an animal
model of auto immune related Meyer carditis mitigated by an
immuno proteasome inhibitor and a genetic ablation. So Carolyn,
this study used mouse models to understand mechanisms involved in
immune checkpoint inhibitor related Maya carditis, a phenomenon
that we can observe in 5% to 10% of patients that are receiving
these checkpoint inhibitors for treatment of their cancer.


Dr Carolyn Lam: So what did they find, Greg?


Dr Greg Hundley: Several things, Carolyn. All immuno proteasome
deficient strains of mice showed mitigated auto-immune related
cardiac pathology with less inflammation, lower pro-inflammatory
and chemo tactic cytokines, less interleukin 17 production and
reduced fibrosis formation. The auto-immune signature during
experimental proponent I auto immune carditis with high immuno
proteasome expression, immunoglobulin G deposition, interleukin
17 production in heart tissue, and troponin I directed humeral
auto immune responses was also present in two cases of immune
mediated related my carditis. Thus demonstrating the activation
of heart specific autoimmune reactions by this checkpoint
inhibitor related myocarditis therapy. So Carolyn, perhaps by
reversing heart specific auto immune responses, immuno proteasome
inhibitors applied to these mouse models demonstrated their
potential to, in the future, aid in the management of auto-immune
bio carditis in humans, possibly including cases with immune
mediated myocarditis heart-related specific auto-immunity.


Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a
quiz? Remember what desmoplakin is Greg?


Dr Greg Hundley: I think this is going to do something with right
ventricular cardiomyopathy.


Dr Carolyn Lam: Very nice. Desmoplakin is the primary force
transducer between cardiac desmosomes and intermediate filaments.
And mutations in Desmoplakin indeed cause an arrhythmogenic form
of cardiomyopathy that has been variably associated with
arrhythmogenic right ventricular cardiomyopathy. Clinical
correlates of desmoplakin cardiomyopathy have been limited to
small case series. Today's paper, by Dr Helms from University of
Michigan and colleagues is the largest series of desmoplakin
mutation carriers reported to date.


Dr Greg Hundley: So Carolyn, what did they find here?


Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin
mutations and 81 patients with pathogenic Plakophilin-2 mutations
as a comparison cohort, they found compelling evidence that
desmoplakin cardiomyopathy is a distinct form of cardiomyopathy
marked by a high proclivity for left ventricular hypertrophy and
arrhythmias and associated with intermittent myocardial
inflammatory episodes that appear clinically similar to
myocarditis or sarcoidosis. Furthermore they found that
diagnostic and risk stratification variables that performed well
for Plakophilin-2 associated ARVC exhibited poor accuracy for the
diagnosis and risk assessment of desmoplakin mutation carriers.
So these results strongly indicate that a genotype specific
management approach is essential for desmoplakin cardiomyopathy.


Dr Greg Hundley: Wow, Carolyn. Lots of great science in this
issue. Well, just like last week, we have got a lot of other
papers in this issue. So let me tell you about a few that I've
had a chance to preview. The first is a research letter by our
own Dr Hesham Sadek from UT Southwestern Medical Center involving
the homotypic fusion generates multi nucleated cardiomyocytes in
the murine heart. Next is an ECG challenge. It's from Dr G. Neil
Kay at the University of Alabama at Birmingham, and really
reviews an ECG in a patient that presents with pulmonary
embolism. Next, there's a case series from Dr Nil Uriel from
Columbia University Medical Center regarding the variety of
cardiovascular presentations of COVID-19. Next there's an on my
mind piece that comes to us from Dr Ersilia DeFilippis from
Columbia University College of and Physicians and Surgeons. And
it involves cardiopulmonary resuscitation during this COVID-19
pandemic.


And it presents a view from trainees on the front lines. Next,
Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic
provides an informative white paper on the description and
proposed management of acute COVID-19 cardiovascular syndromes.
Next is a paper from Dr Francine Marquez from Monash University,
and it's a perspective piece on the impact, strategies and
opportunities for early and mid-career cardiovascular researchers
during the COVID-19 pandemic. So many studies have been stopped
and this very nice article highlights the new opportunities in
this pandemic. Next, Dr Anabel Volgman from Rush University
Medical Center has a piece on the seniors on the sidelines, and
it's a call to action. And then finally, Dr Andrew Chapman from
University of Edinburgh and professor Christian Mueller from the
University Hospital of Basel exchange letters to the editor
regarding a prior article of high sensitivity cardiac troponin,
and the universal definition of myocardial infarction.


Dr Carolyn Lam: Nice. There's also a research letter by Dr
Sandoval and colleagues who described the transition to using
high sensitivity troponin T in a United States regional
healthcare system, namely the Mayo Clinic enterprise. And they
really showed that a small increase in MI diagnosis in part due
to an increase in type two MI diagnosis occurred without an
overall increase in hospital admissions or resource utilization
using the high sensitivity cardiac troponin T implementation. And
if I may mention, there is also a beautiful white paper by Dr
Sana Al-Khatib, whom I was very lucky to coauthor with. And it's
on the advancing research on the complex interrelations between
atrial fibrillation and heart failure. This a report from the
National Heart Lung and Blood Institute virtual workshop. Wow. A
bonanza of an issue. Thanks so much, Greg. Let's move on to our
feature discussion now.


Dr Greg Hundley: Look forward to it.


Dr Carolyn Lam: Today's feature discussion was in fact a late
breaking clinical trial presentation at the American College of
Cardiology meeting this year, 2020. And it's all about the
compass trial, this time focusing on diabetes. I'm so, so pleased
to have with us, the corresponding author Dr Deepak Bhatt from
Brigham and Women's Hospital, as well as Dr Gregory Lip from
University of Liverpool who was not only the guest editor, but
also an editorialist for this paper. So welcome gentlemen.
Deepak, could I start with you? This was an incredible
presentation that was very well discussed. ACC not virtually, but
I'm just so glad that we can have you on this podcast to tell us
again, please, the rationale, the key findings and why this paper
is just so important.


Dr Deepak Bhatt: So the background really is that prior studies
and particular registry studies, the reach registry, for example,
have shown that patients with concomitant CAD and/or PAD, that is
coronary artery disease and/or peripheral artery disease, plus
diabetes, are folks that are extremely high risk of future
ischemic events. This is true even if they are apparently stable
outpatients. At any rate in the compass trial, these sorts of
patients with CAD or PAD, stable patients, both with and without
diabetes who are enrolled 27,000 plus patients randomized. And
there were three arms in this study, aspirin alone, rivaroxaban
alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice
a day.


And that was the winner, that combination sometimes referred to
as dual pathway inhibition significantly reduced the schemic
events versus aspirin alone, a significant reduction in
cardiovascular death MI stroke, as well a lower rate
significantly so of cardiovascular death, and even all-cause
mortality was lower. So the overall trial was positive, but what
we wanted to examine in this analysis was specifically how to
patients with diabetes fare, knowing that they're a higher risk
group in general across multiple registries and studies? And
indeed we found that they were higher risk, those with diabetes
versus those without diabetes and compass, and indeed, though
their relative risk reductions were similar, those patients with
diabetes had numerically larger, absolute risk reductions than
those without diabetes with this regimen of low dose rivaroxaban
plus aspirin versus aspirin alone.


Dr Carolyn Lam: Thanks Deepak. And I just have to refer the
listeners to those beautiful figures in your paper. I mean, just
one look at it really explains exactly what you were saying and
really highlights that patients with diabetes are at higher risk
of adverse events and also in one of the graphs of bleeding.
Greg, could I bring you in here? You mentioned that in your
editorial as well, that there has to be importantly acceptable
bleeding risks. Could you expand on that?


Dr Gregory Lip: The compass crowd was a game changer and in this
high-risk subgroup, as Deepak elegantly has described. These are
diabetic patients, and then we also have the subgroups we call
with or without PCI. And those would be so of course, being the
higher risk group of patients. Nonetheless, the comparison was
basically a dual pathway inhibition, but a combination
rivaroxaban plus aspirin compared to aspirin alone. But a high
cardiovascular risk and high bleeding risk tend to track each
other.


So it was important that we certainly want to reduce the adverse
outcomes of cardiovascular endpoints, we should certainly
individualize our assessment of our patients and make sure that a
patient is not an excessive high bleeding risk. I think overall,
the study is very reassuring because there was no significant
access in the overall population of the subgroup, at least in
relation to fatal bleeding, critical organ bleeding or
intracranial hemorrhage by dual path inhibition. But I think we,
as physicians, just need to assess the patient in front of us
just to make sure that particular patient is not at high risk
particularly of bleeding, given that high risk of bleeding also
generally is high cardiovascular risk as well.


Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some
words from you about this sort of risk benefit ratio? How do you
see it? How do we apply these results?


Dr Deepak Bhatt: I totally agree with everything Dr Lip said.
Really, the key message when we're talking about antithrombotic
numbers, something Dr Brunwald had said in this context, that is,
there's no free lunch. When it comes to antithrombotics, there's
always bleeding risks. There's just no way around that. In any
trial that is adequately powered long enough, we'll find that,
and that can include bad bleeding. Now, fortunately there was no
significant excess and failure endocranial bleeding within the
trial or within the subgroup of patients with diabetes. But
nonetheless one needs to be cautious because these of course are
carefully selected patients at low bleeding risk to get into the
trial. There was a run in period. So when applying to real life,
of course, there's the potential for bleeding. So we need to be
really cautious about that. And it's also not a stat. So if we
were talking about secondary prevention, either with or without
diabetes, CAD, PAD, both of them together, of course, all those
patients should be on Statin assuming they don't have a real type
of contraindication.


So that's kind of a no brainer. That's a matter of implementation
science. A lot of patients that should be on Statin aren't, but
that's not an issue of science. We already know the answer there.
Here, it's not the case of everyone that is like this who has
diabetes, or even who doesn't, who has CAD or PAD should be on
this regimen. It needs to be carefully selected patients,
patients that are a low bleeding risk. And sometimes doctors ask,
"Well, how do you tell that?" Well, it's not always easy, but for
sure there's some things that predict future bleeding risks such
as prior bleeding. So prior bleeding, anemia, those are powerful
predictors of future bleeding. And one would want to be really
cautious in these largely stable outpatients that we're talking
about in the compass trial in intensifying their antithrombotic
regimen. But in the right patients, I think it's a really
effective way of reducing important future vascular risk, whether
that's cardiovascular risk consisting of MI related end points,
stroke, peripheral ischemic end points, including amputation,
which was significantly reduced in the trial, and within the
subgroup of those with diabetes.


So it's a matter of balancing those, but I do think with careful
decision-making on the part of the physician, with discussion
with the patient, with their understanding of the risks and
benefits of intensifying the antithrombotic regimen beyond
aspirin, there are a substantial number of patients who could
benefit.


Dr Gregory Lip: I whole fully agree with Deepak's comments. And
we do have to bear in mind also that risk is also a fairly
dynamic process and we may well be assessing the patient as the
one off initially while we are initiating treatment. But of
course risk, whether from cardiovascular risk or whether from
bleeding risk particularly, also is influenced by increasing age
and by incident comorbidities, which really means that risk
reassessment should be performed in every patient we contact.
With bleeding risks in particular, there are modifiable bleeding
risk factors that we can mitigate. So proactive assessment or
rather reassessment of risks, whether both from cardiovascular
events and/or bleeding, is necessary as we follow up these
patients.


Dr Carolyn Lam: Thank you, both. Deepak, I'm just going to build
a bit on your analogy of no free lunch. And maybe sort of a
general question do you both, because it seems like we've got a
bonanza of a buffet now when it comes to diabetes, especially
with the new anti-diabetic drugs. So how do you think this fits
in altogether? You talked about Statins. We now talk about low
dose rivaroxaban in addition to aspirin, and you think diabetic
patients should be treated with all? Maybe Deepak first, then
Greg.


Dr Deepak Bhatt: What a terrific question. In fact, that was
asked of me by the late-breaking clinical-trial panel clinical
trial panel. They said, "Well, how does it fit in? Because these
data look terrific, but there's also other new diabetes drugs and
approaches." So for sure, I would say again, barring a real
contraindication, I would say everyone that we're talking about
here should be on a statin and preferably if they can tolerate
it, a high intensity statin.


And if that doesn't do the trick in terms of LDL goal, I would
say zetomyde. And potentially if they're in a region of the world
where it's affordable a PCSK9 inhibitor. Then beyond that, I
think we've got to pay attention to triglycerides these days, not
just LDL cholesterol and if it's some patient that's sort of like
REDUCE IT, well then, they should be on eicosapentaenoic. So we
can modify LDL related and triglyceride related risks without too
much effort or too much in the way of side effects. Then beyond
that, I would say, we've got to think about blood pressure,
inadequate control, especially in those with diabetes, but even
those without that have cardiovascular disease. And then we have
to think about glycemic control. And I don't mean the
old-fashioned way, but I mean with some of the newer drugs. SGLT2
inhibitors in particular have been found to be useful for both.


That's just the glycemia control part of things, more
importantly, cardiovascular outcomes. In particular, heart
failure and renal related outcomes. And then GLP 1 agonist as
well have been shown to be very useful once more modifying
cardiovascular outcomes, including atherosclerotic outcomes. So
there is, as you say, quite the buffet. And assuming a patient
can tolerate that polypharmacy and afford it, I do think the
majority of patients with diabetes should be treated that well.
And that's of course on top of lifestyle modification, weight
loss is particularly important, plant-based diet, et cetera.


But on top of that, then, with all those things that are being
done and a patient is still at high ischemic risk but is at low
bleeding risk, that's where I think, even in the deceptively
stable appearing outpatient, it's worthwhile just running a
mental checklist and saying, "Okay, are they on an SGLT2
inhibitor? Check. Did In someone measured their triglycerides?
Check." And then on that checklist is, "Yeah, could they tolerate
being on more than just aspirin alone in terms of bleeding risk?
And if the answer to that is yes, might they benefit from adding
this on?" And there are a lot of patients these results apply to,
and I think a proportion of those patients who are otherwise
optimally treated for their risk factors are the ones to target.


Dr Carolyn Lam: Beautifully put. And Greg?


Dr Gregory Lip: Deepak does raise an increasingly applied concept
in how we approach our patients at high risk of cardiovascular
events. That's the so called integrated or holistic approach to
management. Because we have in the past tended to just focus on
one strand of management. For example, we may well just be
putting a lot of focus when on the analytic reduction and
ignoring the rest. Well, we can't do that these days. We have to
manage the whole patient and not just the bit of the patient. And
this brings in this holistic approach, this integrated approach.
And I think Deepak summarized that very nicely. It may require a
number of medical approaches or medication-based approaches, but
we have to practically look at the comorbidities like blood
pressure reduction and also the lifestyle changes that Deepak's
already summarized. So a holistic and integrated approach to our
care of these patients. And in fact, some of the more recent
studies showed nicely how this results in better outcomes in our
patients at high cardiovascular risk.


Dr Carolyn Lam: And in fact, those were exactly the last words of
your editorial. A holistic and integrated care approach.
Beautifully done, thank you both so much for this excellent
discussion. Thank you, audience, for joining us today. You've
been listening to Circulation on the Run. Don't forget to tune in
again. Next week.


Dr Greg Hundley: This program is copyright the American Heart
Association 2020.