Circulation November 2, 2021 Issue

Please join author Ole Fröbert
and Associate Editor Dharam Kumbhani as they discuss the
article "Influenza Vaccination After Myocardial Infarction: A
Randomized, Double-Blind, Placebo-Controlled, Multicenter
Trial."


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 Lam, associate editor from the National
Heart Center in Duke National University of Singapore.


Dr. Greg Hundley:


I'm Dr. Greg Hundley, associate editor, director of the Poly
Heart Center at VCU health in Richmond, Virginia. Well,
listeners, this week we've got a really hot feature topic
pertaining to flu vaccines, which are coming in the US, North
America, South America, coming up soon, and their relationship to
myocardial infarction. But before we get to that feature
discussion, let's grab a cup of coffee and jump in to some of the
other articles in this issue. Oh, wait a minute. Our first
article, we've got a co-author here. Carolyn, something about the
VICTORIA trial, which you were a part of. Can you tell us a
little bit about this?


Dr. Carolyn Lam:


I would love to, and first of all, I'm doing this on behalf of a
big team, and I want to really, really call up first Dr. Paul
Armstrong who's the senior author from University of Alberta. But
let me tell you first about the VICTORIA study. VICTORIA
evaluated vericiguat, a soluble guanylate cyclase stimulator,
compared to placebo, in patients with heart failure with reduced
ejection fraction with a recent worsening heart failure event and
the primary result was actually a significant reduction in the
primary composite outcome of cardiovascular death or heart
failure hospitalization with vericiguat compared to placebo.


Dr. Carolyn Lam:


Now, interestingly though, in VICTORIA, we found that anemia
occurred more often in patients treated with vericiguat at a rate
of about 7.6% compared to placebo, which was 5.7%. Now, although
earlier studies of another soluble guanylate cyclase stimulator
like riociguat was found to be associated with anemia. The
etiology really remains unknown. In the current paper, we
explored the relationship between markers of anemia and
vericiguat versus placebo in VICTORIA. We further explored the
changes in hemoglobin and hematocrit over the course of the trial
and their relationships with the primary composite outcome.


Dr. Greg Hundley:


Carolyn, this is such an important new study heart failure
therapy for those with reduced ejection fraction, and again, an
important topic related to anemia. What did they find?


Dr. Carolyn Lam:


Thanks, Greg. First, approximately a third of patients in
VICTORIA had anemia at randomization, and this is using the
standard sex-based definitions. With a lower hemoglobin indeed
predicting a higher risk for cardiovascular death, heart failure
hospitalization, all-cause mortality. As I had already mentioned,
we found more anemia with vericiguat than with placebo. The
interesting thing though is after 16 weeks, no further decline in
hemoglobin occurred over the remaining and over 96 weeks of
follow up, and the ratio of hemoglobin to hematocrit remained
constant. Now, overall, the adverse event of anemia occurred in
7.1% of the patients.


Dr. Carolyn Lam:


Importantly, the lower hemoglobin was not related to the
beneficial effect of vericiguat over placebo on the primary
outcome. Now, I know all of that may be more descriptive and
reassuring than really understanding the mechanism by which it
occurred. Further mechanistic studies are certainly warranted to
better understand the basis of the anemia development, and it's
of principle importance because as you said, vericiguat I think
it's going to be an important new medication that we can consider
in high-risk patients with recent worsening heart failure with
reduced ejection fraction.


Dr. Greg Hundley:


Thanks so much, Carolyn, especially the perspective of being an
author on this particular study. Well, Carolyn, my next study is
going to come to us from Dr. Zhao Wang from University of Texas
Southwestern Medical Center, and it's really about the integrated
stress response, and that's an evolutionary conserved process to
cope with intracellular and extracellular disturbances.
Myocardial infarction is a leading cause of death worldwide.
Coronary artery perfusion is the most effective means to mitigate
cardiac damage resulting from myocardial infarction. However,
that can cause, as we know, additional reperfusion injury. This
study aim to investigate the role of the integrated stress
response in myocardial ischemia reperfusion injury.


Dr. Carolyn Lam:


Oh, very interesting. What were the results?


Dr. Greg Hundley:


Right, Carolyn. The authors found that the integrated stress
response is activated by ischemia reperfusion injury in the
heart, and the perk branch of the integrated stress response
protects the heart from ischemia reperfusion injury through
inhibition of protein synthesis. Also, Carolyn, mitochondrial
complex proteins are selectively suppressed and oxidative stress
is reduced by the integrated stress response. Carolyn, the
takeaway is that this integrated stress response is
cardioprotective against cardiac ischemia reperfusion injury.
Perhaps pharmacological stimulation of the integrated stress
response at reperfusion, well, that may reduce heart damage and
improve cardiac outcomes after ischemia reperfusion injury.


Dr. Carolyn Lam:


Cool. Thanks, Greg. Well, I've got one more paper, and this deals
with coronary microcircuitry dysfunction and acute rejection
after heart transplantation. Co-corresponding authors, Doctors
Lee and Choi from Heart Vascular Stroke Institute in Samsung
Medical Center sought to evaluate the prognostic implications of
coronary microcircuitry dysfunction assessed by the index of
microcircuitry resistance or IMR for the risk of acute cellular
rejection after heart transplantation. They did this by
prospectively enrolling 154 heart transplant recipients who
underwent scheduled coronary angiography and invasive coronary
physiological assessment one month after transplantation.


 


Dr. Greg Hundley:


Very interesting, Carolyn. What did they find here?


Dr. Carolyn Lam:


IMR measured early after heart transplantation was significantly
associated with the risk of acute cellular rejection, and an IMR
above or at 15 was highly predictive for the recurrence of acute
cellular rejection during two years of follow up following heart
transplantation. Adding IMR to the prediction model with clinical
variables significantly increase discriminant and
reclassification ability for the risk of acute cellular
rejection. In addition to surveillance endomyocardial biopsy, the
implications are that early stratification using IMR could be a
clinically useful tool to identify patients at higher risk of
future acute cellular rejection after heart transplantation, and
this is discussed in an editorial by Doctors Fearon and Valentine
from Stanford University.


Dr. Greg Hundley:


Very nice, Carolyn.


Dr. Carolyn Lam:


Great. Greg, before we go to the exciting feature discussion,
let's round it up by just a quick tour of what else there is in
today's issue. There is an exchange of letters between Doctors
Pappone Leor on atrial fibrillation as a cardiomyopathy, global
rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr.
Tsai on grouped beating following acute inferior myocardial
infarction, and a research letter by Dr. Salem on
electrocardiographic manifestations of immune checkpoint
inhibitor myocarditis.


Dr. Greg Hundley:


Great, Carolyn. Well, I can't wait to get to this next feature
discussion and learn a little bit more about the relationship
between flu vaccines and future myocardial infarction.


Dr. Carolyn Lam:


Today's feature discussion was a really hot topic at the ESC
2021, and in fact, a simultaneous publication. It is about
influenza vaccination after myocardial infarction, a very
important topic and a very novel paper. We are so pleased to have
the first and corresponding author, Dr. Ole Fröbert from Orebro
University in Sweden to discuss this paper, as well as our
associate editor, Dr. Dharam Kumbhani, from UT Southwestern.
Welcome, gentlemen. Only if I could start with asking you to
describe the rationale for why you did this study, and then
perhaps quickly summarize the results.


Dr. Ole Fröbert:


Yeah, thank you so much, Carolyn. The background of the study was
that during influenza epidemics, more people die from
cardiovascular causes, and out in the literature, there are
numerous observational studies suggesting a protective effect
from influenza vaccination on cardiovascular events. There are
also three smaller single-center randomized trials supporting
these registered findings. Currently influenza vaccination
carries a Class I, Level of Evidence B recommendation in both
American and European secondary prevention guidelines, but uptake
is low and vaccination timing is unclarified. Our aim was to
determine whether influenza vaccination improves clinical
outcomes in patients with a recent myocardial infarction or with
high risk corona artery disease.


Dr. Ole Fröbert:


The study was international, multi-centers investigator
initiated, double-blind randomized control trial, and we enrolled
patients at 30 centers across eight countries in both the
Northern and the Southern Hemisphere, Sweden, Denmark, Norway,
Latvia, Scotland, Czech Republic, Bangladesh and Australia. We
enrolled patients between October 2016 and March 2020. We had
quite broad inclusion criteria. We included hospitalized patients
with STEMI or non-STEMI, or high-risk stable patients over 75
years of age undergoing an angio or PCI. We excluded patients
already vaccinated or intending to be vaccinated during the
current season. We also included, of course, patients if they had
allergy to X or influenza vaccine, if they had infection or if
they were immunosuppressed or previously randomized in the trial.


Dr. Ole Fröbert:


Over these four years of inclusion, we enrolled a total of 2,571
participants. The primary outcome was a composite of all-cause
death, MI and stent thrombosis. This outcome occurred in 67
participants assigned influenza vaccine and 91 assigned placebo
corresponding to a reduction of the primary endpoint of 28% with
a P value of 0.04. Also, rates of all-cause death and of
cardiovascular death were reduced and both with a hazard ratio of
0.59 corresponding to a reduction of 41% in all-cause death and
cardiovascular death. Based on these results, we think that this
trial and what we know from previous smaller trials should be
sufficient to establish influenza vaccination as a new standard
of care as part of in-hospital treatment after an MI.


Dr. Carolyn Lam:


Heartfelt congratulations, Ole. What an elegant intervention in a
very frankly challenging situation that the trial obviously
carried on through COVID as well, multinational. May I just
double check? Was it investigator-led? Because-


Dr. Ole Fröbert:


Yes, this was-


Dr. Carolyn Lam:


That's amazing.


Dr. Ole Fröbert:


... an idea that just popped up, and then yeah, we did it, but it
was seven years of work.


Dr. Carolyn Lam:


Wow. Hard work as I can just imagine. First, heartfelt
congratulations. Very impactful results. Dharam, could I invite
you to put those results in context and why we single this out?


Dr. Dharam Kumbhani:


Yeah. No, thank you, Carolyn. Ole, I want to amplify or
recapitulate the amazement and wonder that Carolyn just
articulated. I think this is a huge endeavor. It's a very
important topic. It's "a fairly simple intervention." It's
vaccination, and you've just really shown that even in the acute
setting, that A, this is as feasible, B, it is safe, and three,
it is effective. I think it's potentially ... Given the magnitude
of influenza in the world, I think this has tremendous public
health ramifications. I really want to congratulate you and your
investigators for pursuing this important question and then just
executing this, I'm sure despite multiple challenges over a long
period of time.


Dr. Ole Fröbert:


Thank you very much.


Dr. Dharam Kumbhani:


Yeah, no. I guess you already alluded to the fact that this may
influence guidelines. As you mentioned, it's a 1B. Maybe get your
thoughts, I suppose this may move the needle towards becoming
perhaps a little stronger on the recommendation front, both in
the US and the European guidelines?


Dr. Ole Fröbert:


Yeah. I think what has been the challenge until now is that many
places, of course, you commend patients to take a flu jab when
treatment is over in the hospital. But then the responsibility is
diffused. Who should take care of that? Is that up to the patient
or the primary care physician? Who is in charge? One important
finding of this study is, as you said, it's safe. There were no
differences, adverse events between the two groups. It's safe and
it could be given early. I think a take-home factor from the
study is that it should be given at the hospital and it's a
responsibility of the cardiologist.


Dr. Dharam Kumbhani:


Yeah, I really like that. Actually, I'm sure this would resonate
across the board in the cardiology community. We've taken
ownership for starting from statin and now SGLT-2 inhibitors,
which kind of ... All of these medications have come from
non-cardiology realms, so to say. But now we prescribe those
medications. We know they have clear cardiovascular benefits. I
suppose you could make a case to say we, the cardiology
community, has to adopt this. The implementation gap that exists
for a lot of these therapies, that also comes to us and for us to
move that forward. It's thought provoking. I certainly felt very
strongly after your study. I don't know how you feel about that.
We should really be the ones driving this and help with more
widespread immunization in these patients.


Dr. Ole Fröbert:


I think because not just this study, but also the previous
studies and what we know from observational findings is that this
is safe and it works. What we also saw in our study, and it has
been indicated in previous meta analysis, is that the maximum
effect is seen in the acute setting. It's the acute coronary
syndrome patients, the patients we had in our study, that benefit
the most. That's also a case for actually doing this in the
hospital and not postponing it.


Dr. Carolyn Lam:


Wow. That's amazing. Ole, I do have one question. Just for
clarification. You were careful to say that you did this during
influenza seasons, right? Coming from my part of the world in
Singapore where we don't really have influenza seasons, don't
have any seasons, frankly, what would you think? What would you
advise?


Dr. Ole Fröbert:


There is influenza seasons in all parts of the world, I'm sorry.


Dr. Carolyn Lam:


True.


Dr. Ole Fröbert:


For example, we had Bangladesh on board in our study. It's in the
Northern Hemisphere, but influenza-wise, it's in the Southern,
and their season is between May and September. But it's not as
clearly defined as the Northern Hemisphere season. It's almost
always in two waves during that season. One practical challenge
with influenza vaccine is that it's produced for the seasons.
It's difficult to say, "Yeah, we can just do it all year round,"
and also we didn't test that. I, of course, feel we should give
it all year round, but it's not available, the vaccine. Perhaps
it should be tested, but it is probably difficult to find funding
for such a study.


Dr. Carolyn Lam:


Very fair, and thanks for the correction. It's true though.
Singapore's on the Equator, so we don't have maybe weather
seasons. But yeah, we do get vaccinated for both North and South.
It's quite fascinating. But nonetheless, could I now switch
topics a little bit and just over the next couple of minutes just
ask you, could you please perhaps share with the audience what it
was like to work with Circulation, to do this simultaneous
publication? You see, our associate editor, Dharam Kumbhani,
really leads this effort to get simultaneous a fast-track
publication from major conferences, and it means a lot to us that
investigators like you chose us. Could you share a bit?


Dr. Ole Fröbert:


Yeah, thank you very much. Overall, it was a pleasure. Of course,
we were ... With every study of this size, you are under stress,
you get the results late, and there's a conference coming up, and
you would like your paper to come out at the same time across to
maximize impact and attention. What I really like with working
with Circulation was turnaround time was ultra fast, really
extremely fast. Of course, we had a lot of questions to our
study, but these were ... Some of them of course were quite
difficult, but they were fair. In a way, they were also helpful
in a way that made it easier to address the questions in a more,
you could say, collaborative way. It was very smooth. No hiccups.


Dr. Carolyn Lam:


Thank you. Dharam, any final responses to that?


Dr. Dharam Kumbhani:


No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure
to work with you on this. I think we all recognize that this was
an important study and wanted to make sure that we were able to
accomplish the goal of simultaneous publication. Thank you for
working with us on that. I just want to put a pitch in, I think
this, for Joe, Dr. Hill and the rest of the editorial team,
having a robust simultaneous publication program has been very,
very important. We are very committed to working with
investigators and authors on this. We are really blessed with our
team on the backside that works seamlessly with us nights,
weekends, just to get these things done. I just want to end with
that to say this is very important for us, and we look forward to
the opportunity to work with Ole and others on future papers as
well.


 


Dr. Carolyn Lam:


I love that. Thank you both for being on this podcast today.
Today I want to especially call out David Rivera, a wonderful
managing editor who really, really is part of leading this entire
group that supports us, but also even this very podcast. You've
been listening to Circulation on the Run. Thank you, from both
Greg and I, for joining us today, and don't forget to tune in
again next week. Thank you.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2021.
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, visit ahajournals.org.