Circulation November 1, 2022 Issue

This week, please join authors Kevin Roedl and Sebastian
Wolfrum, as well as Associate Editor Mark Link as they discuss
the article "Temperature Control After In-Hospital Cardiac
Arrest: A Randomized Clinical Trial."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary,
and backstage pass to the Journal and its editors. We are your
cohosts. 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, Associate Editor and Director of the
Pauley Heart Center at VCU Health in Richmond, Virginia. Well,
Carolyn, this week's feature, very interesting, a randomized
clinical trial of temperature control after in-hospital cardiac
arrest. But before we get to that exciting study, let's grab a
cup of coffee, and jump in and discuss some of the other articles
in the issue. Carolyn, would you like to go first?


Dr. Carolyn Lam:


Yes. Starting with a great quiz. So Greg, which is better? How
about this? It's multiple choice. Is it A; transradial, or B;
transfemoral access, in terms of post-procedural mortality?


Dr. Greg Hundley:


I'm going to go with transradial. It has been, hopefully, I'm
okay on this. It just seems so many fewer complications.


Dr. Carolyn Lam:


But that's exactly that we need to meta-analyze the studies that
have been done. Exactly what this paper did, led by Professor
Valgimigli, from USI in Lugano, Switzerland. So what they did is,
they performed an individual patient data meta-analysis of 21,600
patients, enrolled in seven multi-center randomized control
trials, comparing the transradial with transfemoral access, among
patients undergoing coronary angiography with or without PCI. And
they found that transradial access was associated with a lower
incidence of the primary outcome of all-cause mortality, and the
co-primary outcome of major bleeding at 30 days, compared to
transfemoral access.


There was also evidence for reductions in major adverse cardiac
and cerebral vascular events, net adverse clinical events,
vascular complications, excess site bleeding, and blood
transfusion. MI, stroke, and stent thrombosis, did not differ.
And crossover was higher in the transradial access group.


At predefined subgroup analysis, the authors confirmed that the
benefit observed the transradial group was generally consistent
across the majority of pre-specified subgroups, except for those
with significant baseline anemia. Patients with baseline anemia
appear to derive a substantial mortality benefit with transradial
access rather than transoral access, compared to those with mild
or no anemia.


So, the authors concluded, that the meta-analysis provides
evidence that transradial access should be considered the
preferable access site for PCI, in patients with acute coronary
syndrome, supporting most recent recommendations on the
preferential use of this radial approach. So you were right,
Greg.


Dr. Greg Hundley:


Very nice, Carolyn. A really important piece of science to
disclose to our listeners, in that hurried state, and moving
quickly door to balloon times, et cetera. And here we find
another positive outcome in study result for transradial
approaches.


Well Carolyn, as we know, my next paper, it's really going to
come to us from the world of preclinical science. And it pertains
to hypertension, which is a common cardiovascular disease, and is
related to both genetic and environmental factors. But the
mechanisms linking the interplay between the domains of genetics
and the environment have not been well studied.


Now, DNA methylation, a classical epigenetic modification, not
only regulates gene expression, but is also quite susceptible to
environmental factors. Thereby, linking environmental factors to
genetic modifications. So therefore, Carolyn, these authors,
including Professor Jingzhou Chen, from Fuwai Hospital, National
Center for Cardiovascular Diseases, and the Chinese Academy of
Medical Sciences, and the Peking Union Medical College, and their
colleagues, felt that screening differential genomic DNA
methylation, in subjects with hypertension, would be important
for investigating this genetic environment interplay in
hypertension.


So this study, Carolyn, like many from the world of preclinical
science and circulation, incorporated both human and animal model
subjects. Methodologically differential genomic DNA methylation
in hypertensive, pre-hypertensive, and healthy control
individuals, was screened using the Illumina 450K BeadChip, and
then verified by pyrosequencing. Plasma oviduct glycoprotein 1,
or OVGP1 levels, were determined using an enzyme-linked
immunosorbent assay. And OVGP1 transgenic and knockout mice were
generated to analyze the function of OVGP1.


Dr. Carolyn Lam:


Wow. Nice approach, Greg. And what did the authors find?


Dr. Greg Hundley:


Right, Carolyn. These authors found a hypomethylated site at
cg20823859 in the promoter region of OVGP1, and the plasma OVGP1
levels were significantly increased in hypertensive patients.
This finding indicates that OVGP1 is associated with
hypertension.


Now Carolyn, in OVGP1 transgenic mice, OVGP1 over expression
caused an increase in blood pressure. Also, dysfunctional
vasoconstriction, and vasodilation, remodeling of the arterial
walls, and increased vascular superoxide stress and inflammation.
And these phenomenon were exacerbated by angiotensin II infusion.


In contrast, OVGP1 deficiency, attenuated angiotensin II induced
vascular oxidase, stress, inflammation, and collagen deposition.


Now pull down, and co-immunoprecipitation assays showed that
myosin heavy chain 2A, or MYH9, interacted with OVGP1. Whereas,
inhibition of MYH9 attenuated OVGP1 induced hypertension and
vascular remodeling.


Dr. Carolyn Lam:


So Greg, let me try to summarize, is that okay? So
hypomethylation, at that specific site in the promoter region of
the OVGP1 gene, is associated with hypertension, and induces its
upregulation. The interaction of this OVGP1 with myosin heavy
chain 2A contributes to vascular remodeling and dysfunction. And
so, OVGP1 is a pro hypertensive factor, that promotes vascular
remodeling by binding to this myosin heavy chain. So, really cool
stuff. Thanks for teaching us.


Dr. Greg Hundley:


Very good.


Dr. Carolyn Lam:


Well thanks so much, Greg. And we go back to the clinical world
now, and ask the question, what is the efficacy and safety of
prophylactic full dose anticoagulation and antiplatelet therapy,
in critically ill COVID-19 patients? So I'm going to tell you the
results of the COVID-PACT trial. And this was a multi-center,
two-by-two factorial, open label, randomized controlled trial,
with blinded endpoint adjudication in 390 ICU level patients. So,
severely ill patients with COVID-19, from 34 US centers. Patients
were randomized to a strategy of full dose anticoagulation, or
standard dose prophylactic anticoagulation. And in the absence of
an indication for antiplatelet therapy, patients were
additionally randomized to either clopidogrel or no antiplatelet
therapy.


Dr. Greg Hundley:


Ah, Carolyn. So what did they find?


Dr. Carolyn Lam:


Full dose anticoagulation substantially reduced the proportion of
patients experiencing a venous or arterial thrombotic event, and
there was no benefit from treatment with clopidogrel. Severe
bleeding events were rare, but numerically increased in patients
on full dose versus standard dose prophylactic anticoagulation,
without any fatal bleeding events, GUSTO moderate or severe
bleeding was so significantly increased with full dose
anticoagulation, but with no difference in all-cause mortality.


So in summary, in a population of critically ill patients with
COVID-19, a strategy of prophylaxis with full dose, versus
standard dose prophylactic anticoagulation, but not the addition
of clopidogrel, reduced thrombotic complications, with an
increased risk of bleeding, driven primarily by transfusions in
hemodynamically stable patients, with no apparent excess in
mortality.


Dr. Greg Hundley:


Very nice, Carolyn. What a important piece of information, as
many of us around the world are taking care of critically ill
patients with COVID-19.


Well, how about we see what is in the mail bag this week? So
first, Carolyn, there's a Frontiers piece by Dr. Packer,
entitled, “Critical Reanalysis of the Mechanisms Underlying the
Cardiorenal Benefits of SGLT2 inhibitors, and Reaffirmation of
the Nutrient Deprivation Signaling Autophagy Hypothesis.”


Next, there's a Research Letter, from Professor Airaksinen
entitled, “Novel Troponin Fragmentation Assay to Discriminate
Between Troponin Elevations in Acute Myocardial Infarction and
End-stage Renal Disease.”


Carolyn, there's another Research Letter, from Professor Solomon,
entitled, “Aptamer Proteomics for Biomarker Discovery in Heart
Failure with Reduced Ejection Fraction.”


Also, Carolyn, [a] wonderful Cardiovascular News summary from
Tracy Hampton, reviewing three articles. First, “Mechanisms
Behind Cannabis Effects on Heart Health.” The second, “Exercise
Inducible Metabolite Suppresses Hunger.” And then lastly, “Piezo1
Initiates the Cardiomyocyte Hypertrophic Response to Pressure
Overload.”


Dr. Carolyn Lam:


Cool. There's also an exchange of letters between Doctors Jha and
Borlaug on latent pulmonary vascular disease in therapeutic
atrial shunt.


And finally, an On My Mind, by Dr. David Kass entitled, “What's
EF Got To Do, Got To Do With It.” I love it. You must read it.
It's so, so cool. All right. But now, let's go on to our feature
discussion, shall we?


Dr. Greg Hundley:


You bet, Carolyn.


 


Welcome listeners, to our feature discussion today, and really
delving into the world of in-hospital cardiac arrest, and how we
manage those patients. And we have with us today, Dr. Kevin Roedl
from Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck,
Germany, and our own associate editor, Dr. Mark Link from
University of Texas Southwestern in Dallas, Texas. Welcome
gentlemen. Kevin, we're going to start with you. Can you describe
for us, some of the background information that went into the
construct of your study, and what was the hypothesis that you
wanted to address?


Dr. Kevin Roedl:


Thank you, Greg. We thank you for the kind invitation to this
podcast. We're very likened to do this podcast with you. And so,
talking about the background of hypothermia in-hospital cardiac
arrest, we have to go back like two decades almost, because there
were two studies in New England Journal of Medicine published
2002, who introduced mild therapeutic hyperthermia to the
treatment in post cardiac arrest. Primary, these two studies show
the benefit of the therapy in this kind of patients. And then,
2003, it was introduced in also the international guidelines.
However, these studies only addressed out-of-hospital cardiac
arrest patients, and also, only shockable rhythms. And so, the
question arised over the years, what about other patients like
non shockable rhythms, or also in-hospital cardiac arrest?


And so, that's basically was the primary aim of our study to
address this special population. Because when you see the states,
the numbers, there are 290,000 in-hospital cardiac arrests a
year. So it's actually, a very large population. And there's no
randomized control trial to show any benefit, or maybe harm, in
this group. There were some observational studies, 2016 in China
published. From China, in this group, they looked at the Get With
The Guidelines registry, and actually, they saw that there was
probably a negative influence of hypothermia in the study.
However, it was only observational. So actually, there were no
randomized control trials. And that primary hypothesis was, that
we wanted to know actually, does thus mild therapeutic
hyperthermia work in this group of patients in the in-hospital
cardiac arrest setting? And what is the outcome? Is it like in
the out-of-hospital cardiac arrest setting, or not?


Dr. Greg Hundley:


Wonderful, Kevin. And so, can you describe for us then, your
study population and your study design?


Dr. Kevin Roedl:


Yes, of course. We did a randomized control trial. There were
over 1000 people screened, and overall, we included 242. So you
see how hard it is to get people in there. And actually, in terms
of hypothermic temperature control, we are 120 about, and long
term at 118, and the final others of the endpoints. And when we
look at the baseline characters of these patients, they were well
balanced actually, about 72 years. When we look at the initial
cardiac arrest rhythm, that's interesting because about 70%
non-shockable rhythms, and 25% shockable rhythms. And probably
also interesting, the location of the cardiac arrest. Medical
boards about 50%, and ICU or ED was 22%. So that's probably
summed up the baseline characteristics of our study.


Dr. Greg Hundley:


Perfect. And so Kevin, can you describe for us what was the
hypothermic target for the group that was going to have their
temperature recused?


Dr. Kevin Roedl:


Yes, hypodermic target was 32 degrees to 44. And so two degrees
Celsius, basically the same target like in earlier trials.


Dr. Greg Hundley:


Very nice. Well listeners, now we're going to turn to our second
co-author, Dr. Sebastian Wolfrum. And Sebastian, can you share
with us the study results?


Dr. Sebastian Wolfrum:


Yes, Greg. Thank you very much for the opportunity to participate
in this podcast. Only wanted to include unconscious patients, and
therefore, we took a time and took 45 minutes after their cardiac
arrest, to let the patients get away if they did so. We also
excluded patients that had severe functional deficit before the
cardiac arrest; since we could not really define the neurological
outcome if we would've included those. And we didn't see any
differences. Neither in mortality, not in the functional outcome,
either when they're treated with 33 degrees Celsius, or whether
normothermia was used.


The death rate after six month was in a range which is comparable
to other in-hospital cardiac arrest studies, and higher than
those performed in the out-of-hospital cardiac arrest studies. It
was about slightly over 70% in both groups. And the number of
patients with the good functional recovery after six months was
23% of the patients in the hypothermia group, and 24% of the
patients in the normothermia group.


And if we look at only the survivors, we see that the ones which
are worse functional outcome, were most of them dead after six
months. We then also focused on the temperature curves in our
patients, and to see whether we have achieved our goal. And we
saw that we have reached the target temperature within four and a
half hours after cardiac arrest in our hypothermia group. Which
is not as fast that we had expected, but still in the range,
which is comparable to other studies on this field. And we also
saw that our control group was about 37 degrees, within the first
12 and 48 hours. So we truly avoided fever, which has not been
done in every previous study on cardiac arrests.


Dr. Greg Hundley:


Very nice. And any differences between the hypothermia and
normothermia groups, related to the age of the patient? Or,
whether or not they had a shockable rhythm at the time of
presentation?


Dr. Sebastian Wolfrum:


We saw as a result of our study, that age is a predictive factor
for mortality. But age did not differ between our treatment
groups, and therefore, did not interfere with our results. And we
didn't see differences in the shockable or non-shockable rate in
our patients in the different treatment groups.


 


Dr. Greg Hundley:


Thank you. Well listeners, now we're going to turn to our
associate editor, Dr. Mark Link, one of our expert
electrophysiologists at Circulation. And Mark, you have many
papers come across your desk, and what attracted you to this
particular paper?


Dr. Mark Link:


There were a number of things. One, it's hard to do RCTs in
resuscitation, and I thought they did a very nice job with this
RCT. Two, the subject of hypothermia, or therapeutic temperature
management, is a very hot one in resuscitation. It's one of the
few treatments in the past that have been shown to make a
difference in outcome. And so, all of those trials were done in
out-of-hospital arrest. So to have a trial done in in-hospital
arrest was very intriguing also.


And I think we're all disappointed that it wasn't a positive
trial, but we have to take the negative trials also. And I think,
part of the reason it may have been a negative trial is because
the normal thermic group avoided hyperthermia. And I think that's
something that's coming out of a lot of these trials is avoid
fever. It may not be so important to get hypothermic targets,
actually, looks like it's probably not, but it looks like it's
very important to avoid fever.


Dr. Greg Hundley:


Very nice. Well listeners, we're going to turn back to our expert
panel here really, and start with you Kevin. Kevin, what do you
think is the next study that needs to be performed in this sphere
of research?


Dr. Kevin Roedl:


Thank you for this interesting question. Yeah, a bunch of studies
could be performed, especially maybe in the out-of-hospital
cardiac arrest study, because we don't know. This fever harmful,
we have to find certain subgroups in which this treatment works.
So maybe in this subgroups there is data on this and it could be
a benefit. So these are, I think, the two main topics that should
be done in the future.


Dr. Greg Hundley:


Thank you. Sebastian, what are your thoughts?


Dr. Sebastian Wolfrum:


As Mark said, the hypothermic treatment was, for decades, maybe
the only treatment which we could give to cardiac arrest
patients, which has been proven to reduce mortality. And all
other studies following didn't see any be benefit of hypothermia,
not even in a subgroup. Also, the TTM trials did not. So I'm
questioning myself, where is the original HACA study group that
benefits? Where did this hide in the other studies?


So I would think, to do another study in out-of-hospital cardiac
arrest patients, whether in ventricular fibrillation that had
shown in the HACA trial to reduce mortality. This should be done
in a similar way to the original study, to see whether there is
this subgroup. People who support the idea of hypothermia also
focus very much on the fast onset of their hypothermic treatment.
And they say we saw a difference in mortality in the HACA trial,
and we could very fast. And I think the other studies have to
show that they cool as fast as the HACA study. So the main focus
should be on the time calls of hypothermia after cardiac arrest,
cooling very fast to a target temperature of 33 degrees, maybe
holding on for 24, maybe 48 hours.


Dr. Greg Hundley:


Very nice, Sebastian. So focusing on the speed and the timing of
that cooling. And Mark, anything to add?


Dr. Mark Link:


Yeah, so if I sit here with my writing group hat on for the HA
and say, "What are we going to do for the resuscitation
guidelines in 2025?" I think you look at the totality of the data
for targeted temperature management. And I think, the main thing
you say, walking away from this, is avoid fever. Don't let your
patients get hot. I'm not sure you can say much more than that
right now, until we get more data.


Dr. Greg Hundley:


Very nice. Well listeners, a really interesting provocative
discussion today. And we want to thank Dr. Kevin Roedl from
Hamburg, Germany, Dr. Sebastian Wolfrum from Lubeck, Germany, and
our own associate editor, Dr. Mark Link from Dallas, Texas,
bringing us the results of this study highlighting that
hypothermic temperature control is compared with normothermia did
not improve survival, nor functional outcome, at 180 days in
patients presenting with coma after in-hospital cardiac arrest.


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.


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.