Circulation July 7, 2020 Issue

Dr Carolyn Lam: Well, the 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 Centre and Duke National University of Singapore.


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


Well, Carolyn, this week's feature involves the Compass trial,
and we'll be talking about a comparison of low-dose rivaroxaban
plus aspirin compared to aspirin alone in patients with chronic
vascular disease. But before we get to that, how about if we
break away and discuss a few other papers. And I'll go first this
time, because this week we're going to introduce another new
feature in addition to Carolyn's Quiz.


Dr Carolyn Lam: Wait a minute. This was not on the script. What's
going on, Greg?


Dr Greg Hundley: It's on the script!


Carolyn, let me get to my first paper. It's from Professor
Junling Liu from Shanghai Jiao Tong University School of
Medicine, and it involves branched-chain amino acid catabolism
and how that may promote thrombosis risk by enhancing
tropomodulin-3 propionylation in platelets.


But first, we've got a new feature to add to Carolyn's Quiz. It's
called Way or No Way.


Dr Carolyn Lam: Just so everybody knows. This was a one-way
decision to add this new component of Carolyn's Quiz, but okay,
I'm all for it. Go, Greg!


Dr Greg Hundley: Okay. All right. It's a fast, quick question
where our listeners seek your guidance regarding an important
scientific discovery from one of our published manuscripts. Are
you ready?


Dr Carolyn Lam: No.


Dr Greg Hundley: Okay. Here's your question. Do branched-chain
amino acids promote arterial thrombosis. Way or no way?


Dr Carolyn Lam: Maybe?


Dr Greg Hundley: Okay, Carolyn.


Dr Carolyn Lam: I have a feeling you're going to tell us yes,
although I wouldn't have guessed that straight away.


Dr Greg Hundley: Okay. Remember that branched-chain amino acids
are essential nutrients, including leucine, isoleucine, and
valine, and they serve as a resource for energy production and
the regulator of important nutrient and metabolic signals.


In this study, the activity of human platelets from healthy
subjects before and after ingestion of branched-chain amino acids
were measured. PP2Cm-deficient mice were used to elucidate the
impacts of BCAA catabolism on platelet activation and thrombus
formation.


Dr Carolyn Lam: Now okay, okay. So what did they find? Way or no
way?


Dr Greg Hundley: Ingestion of branched-chain amino acids
significantly enhanced the activity of platelets in response to
agonists and increased the risk of arterial thrombosis. The
branched-chain amino acid catabolic pathway-driven propionylation
of tropomodulin-3 at K255 was found to be an important mechanism
underlying the branched-chain amino acid-facilitated platelet
activation, and elevated levels of branched-chain amino acids and
enhanced expression of positive regulators of branched-chain
amino acid catabolism in platelets were found probably
responsible for the high platelet activity in type 2 diabetes
mellitus.


Dr Carolyn Lam: Very interesting. So yes, it is possible. And
what is the clinical implications?


Dr Greg Hundley: Right, Carolyn. Branched-chain amino acids, or
their catabolites, enhance the risk of arterial thrombosis in
small animals, and perhaps future human subject studies, that
restrict branched-chain amino acid intake or target
branched-chain amino acid catabolism may serve as a novel
strategy for anti-thrombosis therapy.


Dr Carolyn Lam: Interesting. Okay, Greg. Here you go. Question
for me. Have you heard of Home Time?


 


Dr Greg Hundley: Home Time? Yes. Home Time. It's not like time
out for our kids, but we've been having a lot of Home Time in
this COVID-19 with our families.


Dr Carolyn Lam: All right. Touché. Touché. Home Time! Did you
know it is a patient-centered outcome measure that accounts for
rehospitalization mortality and post-discharge care? In the paper
I want to talk about, Dr Pandey from UT Southwestern and
colleagues aim to characterize risk-adjusted 30-day Home Time in
patients with acute myocardial infarction as a hospital-level
performance metric, and to evaluate associations with
risk-standardized readmission rates. The study included almost
985,000 patients with AMI hospitalization across almost 2,400
hospitals between 2009 and 2015 derived from a hundred percent of
Medicare claims data. And they found that 30-day home time for
patients with AMI can be assessed as a hospital-level performance
metric using Medicare claims data. It varied across hospitals,
was associated with post-discharge readmission and mortality
outcomes, and meaningfully reclassified hospital performance
compared with the 30-day readmission and mortality metric.


Dr Greg Hundley: Very nice, Carolyn. Well, I'm coming back at you
again with another quiz. But first, this paper is from Kamal
Khabbaz from Beth Israel Deaconess Medical Center and the Harvard
Medical School, and it's going to assess whether left atrial
appendage closure or exclusion during bypass surgery has impact
on short-term outcomes.


So, Carolyn, here's your quiz. Do you think that patients
receiving CABG with atrial fibrillation should undergo ligation
of their left atrial appendage?


Dr Carolyn Lam: Well, I think there's definitely equipoise there.
On the one hand, you're already in a surgery. Why not just ligate
it? It's not like we need a left atrial appendage. And then on
the other hand, I suppose it extends the surgery, it involves
some risk, and we don't know if it actually prevents further
events. Did I answer that right?


Dr Greg Hundley: Yes. Quite the politically correct answer, I
think. Now, the objective of this study was to evaluate the
impact of left atrial appendage exclusion on short-term outcomes
in patients with atrial fibrillation undergoing isolated coronary
artery bypass graft surgery. The study analyzed 250,287 CABG
patients, of whom 7% received left atrial appendage closure. Only
patients with a history of atrial fibrillation were included in
the analysis, and the primary outcome was 30-day readmissions
following discharge. Secondary outcomes included hospital
mortality and stroke. And to assess the postoperative outcomes,
the team utilized multivariable logistic regression models, and
they adjusted for clinical and demographic co-variables.


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


Dr Greg Hundley: Okay. Couple of conclusions. First, left atrial
appendage exclusion was associated with a greater risk of
postoperative respiratory failure, acute kidney injury, but it
did not significantly change the rate of blood transfusions or
the occurrence of cardiac tamponade. Second, left atrial
appendage exclusion was associated with a nonsignificant
reduction in stroke, no difference in in-hospital mortality, and
a greater risk of 30-day readmissions. Number three, after
adjusting for these co-variables, left atrial appendage ligation
remained a significant predictor of this 30-day readmissions. And
so, Carolyn, in this study, it looks like left atrial appendage
exclusion during isolated CABG in patients with AFib is
associated with a higher rate of 30-day readmissions.


Dr Carolyn Lam: Thanks, Greg. Well, let me talk about what else
is in this issue. First is a pair of letters, one from Kai Wu
regarding the article, "Effects of Sacubitril-Valsartan Versus
Valsartan in Women Compared to Men With HFpEF: Insights From
PARAGON-HF" and the response from Dr John McMurry. There are also
two On My Mind pieces, one entitled "COVID-19 Arrhythmic Risk and
Inflammation: Mind the Gap" by Dr Lazzerini, and another
entitled, "Obesity, A Risk Factor for Severe COVID-19 Infection:
Multiple Potential Mechanisms" by Dr Naveed Sattar.


There are two perspective pieces, "Establishment and Management
of Mechanical Circulatory Support During COVID-19 Pandemic" by Dr
Pham, and "The COVID-19 Pandemic: A Global Natural Experiment" by
Dr Blake Thomson. There's an in-depth paper entitled "The Science
Underlying COVID-19: Implications for the Cardiovascular System"
by Dr Peter Liu. This is important. This one's an editor's pick,
so don't forget to read this.


There's an ECG challenge by Dr Praveen Gupta on "Chest Pain with
ST Elevation: Looking Behind the Masquerade." In Cardiology News
by Tracy Hampton, she reviews the literature and highlights three
papers, one, "A Cardiovascular Disease-Linked Gut Microbial
Metabolite Acts via Adrenergic Receptors" in Cell 2020; two,
"Noninvasive Localization of Cardiac Arrhythmias Using
Electromechanical Wave Imaging" in Science and Translational
Medicine 2020; and three, "Somatic Gene Editing Ameliorates
Skeletal and Cardiac Muscle Failure in Pig and Human Models of
Duchenne Muscular Dystrophy", and that in Nature Medicine 2020.


For the President's Page, we have a piece by Keith Churchill,
who's the Executive Vice President and CEO of Yale New Haven
Hospital entitled "The Compelling Need to Address Uncertainty,
Anxiety, and Financial Peril for Patients".


There's Highlights from Circulation Family of Journals by Sara
O'Brien, including "Factors Associated With Large Improvements in
Health-Related Quality of Life in Patients with Atrial
Fibrillation: Results From the ORBIT-AF" from Circulation
Arrhythmia and Electrophysiology. There's "Association Between
Sleep Disordered Breathing and Left Ventricular Function: A
Cross-Sectional Analysis of the ECHO-SOL Ancillary Study" from
Circulation Cardiovascular Imaging. There's also "The Impact of a
10 Rules Protocol on COVID-19 Hospital-Related Transmission:
Insights from Padua University Hospital in Italy" from
Circulation Cardiovascular Interventions. There's "The
Association of an AMI Readmission-Reduction Program with
Mortality and Readmission" from Circulation Cardiovascular
Qualities and Outcomes. And finally, "Treatment Differences in
Chronic Heart Failure Patients with Reduced Ejection Fraction
According to Blood Pressure" in Check HF, and that's in
Circulation Heart Failure.


Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a few
Research Letters that I reviewed. First is from Professor Puck
Peltenburg, and the Research Letter involves children and
adolescents from Brugada syndrome families in which only the
SCN5A mutation carriers develop a type one ECG pattern induced by
fever. And the second research letter is from Dr David Saadoun,
and this evaluates the long-term outcome and prognosis factors
associated with isolated aortitis. And then finally, Carolyn,
there's a very nice piece related to the current status of
cardiovascular medicine in Israel from Professor Ran Kornowski at
the Rabin Medical Center.


Well, Carolyn, what a packed issue we have, and how about now we
get on to that feature discussion?


Dr Carolyn Lam: Let's go, Greg.


Dr Greg Hundley: Well, listeners, we have a wonderful feature
discussion for you in this next segment. We have Professor Keith
Fox from Edinburgh and our own associate editor, Professor Stefan
James from Uppsala. And we're going to discuss anticoagulation
and antiplatelet therapy and rivaroxaban and aspirin and results
from the COMPASS trial.


Keith, could you tell us what was the background information and
what was the hypothesis that you wanted to test with your study?


Professor Keith Fox: The hypothesis was whether the combination
of a very small dose, a quarter of the dose tested here, of a
NOAC alongside an antiplatelet would be superior to aspirin
alone, or we also tested a half dose of the NOAC by itself. And
the overall trial showed that the quarter dose of rivaroxaban
plus aspirin was substantially superior to aspirin alone in
preventing cardiovascular death, MI, and stroke, with its biggest
impact on strokes and cardiovascular death. So that's the trial
as a whole.


But our specific goal here was to look at the question of net
clinical benefit because clinicians are challenged by any therapy
that has a balance of both potential hazard, like bleeding risk,
and benefit. So what we analyzed here were the pre-specified
characteristics of net clinical benefit in terms of
life-threatening and major bleeding into a critical organ, plus
cardiovascular death, MI, and stroke. And I asked the question,
what was the net clinical benefit?


Dr Greg Hundley: Net clinical benefit. Now, tell us a little bit
about what population you were looking to understand net clinical
benefit, and then what was the study design?


Professor Keith Fox: This is the whole of the COMPASS trial
without the arm that tested rivaroxaban alone, because that did
not show significant benefit. So this is the remaining 18,000
patients, double-blind randomized trial. And the trial, as a
whole, was stopped early on the recommendation of the DSMB
because it met the criteria for benefit by four standard
deviations. Now, what's unusual about this is the population of
our patients and vascular risk. So these are people who in the
past would just be treated with aspirin. So they're not post-MI.
They are people with chronic vascular disease, either peripheral
or coronary. And in the past, on top of standard secondary
prevention care, they would only have got aspirin.


Dr Greg Hundley: And what were the results?


Professor Keith Fox: There was a 20% reduction in terms of the
net clinical benefit favoring the combination of rivaroxaban and
aspirin, and that net clinical benefit being the combined impact
of cardiovascular death, MI, stroke, fatal bleeding, or bleeding
into a critical organ.


Dr Greg Hundley: And did you find the same results in, for
example, older versus some of the younger patients? Or were there
any other high-risk subgroups, those with impaired renal function
or those with heart failure where you saw particular differences?


Professor Keith Fox: Yes, Greg. This is a really important issue.
If one looked at the whole trial, the number needed to treat to
prevent one of these adverse events, N equals 52. But then if we
looked at some of the higher-risk cohorts, which we defined
prospectively ... For example, these were the risk factors like
polyvascular disease, impaired renal function, ambulant heart
failure, or diabetes. And if you had all four risk factors, the
number needed to treat was nine. If you had three risk factors,
it was 12. Two risk factors, 31. So I think there's clearly a
message for clinicians to be able to identify people with a
combination of these risk factors, one or more, in order to get
the most benefit and the least hazard.


Dr Greg Hundley: Very interesting. Any speculation on mechanism?


Professor Keith Fox: Yes. One of the things that we've done in
the past is we've hammered one antithrombotic pathway. Like, for
example, we've used more and more potent anti-platelets or
combination of anti-platelets. But perhaps one of the things that
we've forgotten is the fact that the platelet activation pathway
is triggered by thrombin activation and vice versa. So the
concept that was new behind the whole COMPASS study was that
augmentation of the antithrombotic effects by combining a very
small dose of a novel anticoagulant would be beneficial. And the
critical question is, would it be sufficiently beneficial without
producing a lot of bleeding? So that's why we did this particular
analysis.


Dr Greg Hundley: So lower doses of some of these drugs. Well,
Stefan, can you help us put these study results into context with
what we know today about using aspirin alone, rivaroxaban, et
cetera?


Professor Stefan James: The reason I think this study's so
important and interesting is that, first, it's a very common
population that we see now in the practice, patients with a
stable phase of atherosclerotic disease, both coronary and
peripheral vascular. And we need to take care of these patients
better. Until now, we have not had very great alternatives for
these patients. Now, we've learned what Keith said, that if you
combine a low dose of both anti-platelet and antithrombin, you
can inhibit and reduce the risk of ischemic events. And the other
important finding here is that, I think conceptually very
interesting, that if you are able to reduce their number of
ischemic complications or thrombotic complications, but not doing
that to such an extent that bleeding increases too much, not to
an extent that bleeding causes fatal events, then you can find a
nice balance between safety and efficacy that can lead to
substantial reductions and improvements in terms of the clinical
benefit.


And that's what we see here in this trial. You can see that there
is a reduction of thrombotic events, ischemic events, and there
is also some bleeding, but not to such an extent that it affects
overall survival and the overall event rate in these patients.
And particularly in patients at high risk that you pointed out,
these patients have a very high event rate. Although the relative
benefit is similar, the absolute benefit is quite impressive.


Dr Greg Hundley: Just very exciting to me. Very low doses of some
of these common drugs. What's the next study in this field,
Keith?


Professor Keith Fox: We've got a big gap because we know that
modern dual antiplatelet therapy works really well after an acute
coronary syndrome and it's highly effective. In the longer term,
we know, for example, from some of the studies with ticagrelor
that there are cohorts that do well for a period of time after
ACS, but really we don't know the bridge between this period and
the long term and what role this therapy may have after essential
dual antiplatelet therapy.


Dr Greg Hundley: Stefan, do you have any thoughts?


Professor Stefan James: I agree with Keith. This transition
period, when is patient transitioned from being an acute coronary
syndrome patient to a chronic coronary syndrome patient? When
does that happen? And then probably it differs between
individuals and type of events, and so we need to understand more
of when is this patient acutely affected and when do we need
potent dual antiplatelet therapy? And when can we transition to a
more stable phase in which we can inhibit thrombotic events,
ischemic events, but not increased bleeding to such a degree that
it affects overall survival? And so I think we need to learn a
lot more about that transition period and these subgroups of
patients of different risks and risks of ischemic events and
bleeding events.


Dr Greg Hundley: Keith, how would you go about conducting a study
in that regard?


Professor Keith Fox: I think really one of the very interesting
questions is whether the combination of the standard of care of,
for example, aspirin and ticagrelor may be better, worse, or the
same than this therapy instituted at the end of the period of
essential dual antiplatelet therapy. And we need to know that.


Dr Greg Hundley: In closing and summing up, Keith, are there any
concepts that we want to take home here?


Professor Keith Fox: I think that there are two key concepts. One
is the synergy between the anticoagulation system and the
antiplatelet system, with the potential to use very low doses, to
minimize bleeding risk, yet have the benefits. That is the first
concept. The second concept is that these chronic vascular
disease patients Stefan has described are at continuing risk of
vascular events, especially stroke, myocardial infarction, and
cardiovascular death. And these can be modified.


Dr Greg Hundley: And Stefan, any thoughts from you in closing?


Professor Stefan James: I think this paper and the work that
Keith has described is fantastic and fascinating to think about
because these populations are incredibly large, and they are not
doing well. They have a high risk of events, and we tend to
forget that, and so we need to both identify them and start
treating them now, as we have some evidence, but we'll also need
to learn more of how to identify them, how to select them
appropriately, and how to identify the transition from acute
events to chronic events or current chronic phase of the disease.


Dr Greg Hundley: Well, listeners, I want to thank both Professor
Keith Fox and our own associate editor, Professor Stefan James,
for this very interesting presentation of lower doses of
anticoagulant and antiplatelet therapy in patients with chronic
vascular disease and really being able to reduce events and
diminish bleeding.


On behalf of Carolyn and myself, we want to wish you a great week
and look forward to catching you next week. Take care.


This program is copyright of the American Heart Association 2020.