Circulation December 11, 2018 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. What are the long-term effects
of oxygen therapy in patients with suspected acute myocardial
infarction? Well, to find out, stay tuned for our discussion of
our feature paper this week, coming right up after these
summaries.


                                               
The first two original papers demonstrate that, similar to
neonatal mice, one day old and two-day old neonatal pigs are
capable of mounting a cardiac regenerative response following
myocardial infarction, which is characterized by restoration of
contractile function, cardiomyocyte replenishment, and minimal
fibrosis. Now, interestingly, this regenerative capacity is lost
after the first two days of life.


                                               
The first paper is from co-corresponding authors, Drs Yeh and
Cook from National Heart Research Institute of Singapore and
National Heart Center, Singapore, and the second from
co-corresponding, authors Drs Zhang and Zhu from the University
of Alabama at Birmingham.


                                               
These authors report collectively that proliferation of
preexisting cardiomyocytes appear to be the primary source of
cardiomyocyte replenishment in neonatal pigs with markers of
cardiomyocyte mitosis, sarcomere disassembly, and cytokinesis
elevated following injury in the one day and two-day old hearts,
but not at later time points.


                                               
Furthermore, cardiomyocyte DNA synthesis was increased following
neonatal pig myocardial infarction. Cardiomyocyte proliferation
significantly decreased after this two-day window, which was
associated with a marked reduction in telomerase activity.


                                               
Heart failure with preserved ejection fraction may look different
in the young compared to that in the elderly. First author, Dr
Jasper Tromp, corresponding author, myself, Carolyn Lam from the
National Heart Center, Singapore and Duke National University of
Singapore, and our colleagues from the Asian Heart Failure
Registry studied more than 1,200 patients with HEF PEF from 11
Asian regions and found that 37% of our Asian HEF PEF population
was under 65 years of age. Younger age was associated with male
preponderance, a higher prevalence of obesity, and less renal
impairment, atrial fibrillation, and hypertension. Left
ventricular filling pressures and the prevalence of left
ventricular hypertrophy was similar in the very young of less
than 55 years and elderly HEF PEF of more than 75 years of age.


                                               
Compared to age matched controls from the community without heart
failure, the very young HEF PEF patients had a three-fold higher
death rate and twice the prevalence of left ventricular
hypertrophy. Thus, young and very young patients with HEF PEF
display similar adverse cardiac remodeling as their older
counterparts, but very poor outcomes compared to controls without
heart failure.


                                               
Obesity may be a major driver of HEF PEF in a high proportion of
HEF PEF in the young and very young.


                                               
How important is hospitalization for heart failure as a
complication of diabetes? In the next paper from first and
corresponding author, Dr McAllister from University of Glasgow,
the authors examined the incidents and case fatality of heart
failure hospitalizations in the entire population age 30 years
and older resident in Scotland during 2004 to 2013.


                                               
Over the 10-year period of study, among 3.25 million people, the
coot incidence rates of heart failure hospitalization were 2.4
per thousand-person years for those without diabetes, 12.4 for
those with type two diabetes, and 5.6 for those with type one
diabetes. Heart failure incidents had fallen over time for people
with and without diabetes, but remained around two times higher
in people with diabetes than those without diabetes. Heart
failure case fatality was higher in people with type one
diabetes. Duration of diabetes and glycated hemoglobin was
associated with increased risk of heart failure in type one and
type two diabetes. Thus, clinicians should be aware of the
importance of heart failure and diabetes, especially in type one
diabetes where this is under appreciated.


                                               
What are epigenetic mechanisms contributing to ischemia
reperfusion injury? Co-first authors Dr Yu, Yang, and Zhang,
co-corresponding authors, Dr Xu from Nanjing Medical University,
Dr Sun from Fudan University, and Dr Ge from Fudan University,
and their colleagues evaluated the potential role of
megakaryocytic leukemia one, or MKL 1, as a bridge linking
epigenetic activation of NAD pH oxidases, or NOX, to reactive
oxygen species production and cardiac ischemia reperfusion injury
in mice. They found that genetic deletion of pharmaceutical
inhibition of MKL 1 attenuated cardiac ischemia reperfusion
injury in mice. MKL 1 levels were elevated in macrophages, but
not in cardiomyocytes in vivo, following cardiac ischemia
reperfusion injury.


                                               
MKL 1 recruited the histone acetyltransferase, MOF, to activate
NOX transcription in macrophages. Pharmaceutical inhibition of
MOF attenuated cardiac ischemia reperfusion injury in mice, and
pharmaceutical inhibition of NOX one or four attenuated cardiac
ischemia reperfusion injury as well.


                                               
These findings provide a novel link between MKL 1-mediated
epigenetic regulation of gene expression in macrophages and
ischemic heart disease. This opens the door to small molecule
compounds targeting the MKL 1 MOF NOX access as a novel
therapeutic strategy against ischemic heart disease.


                                               
Is the time from last hospitalization for heart failure to
placement of a primary prevention ICD associated with patient
outcomes? First and corresponding author Dr Ambrosy from the
Permanente Medical Group in San Francisco performed a post hoc
analysis of Medicare beneficiaries enrolled in the national
Cardiovascular Data Registries implantable cardioverter
defibrillator, or ICD registry, all with a known diagnosis of
heart failure and an ejection fraction of less than 35%,
undergoing a new ICD placement for primary prevention.


                                               
They found that older patients, currently or recently
hospitalized for heart failure, undergoing initial ICD placement
for primary prevention, experienced a higher rate of
periprocedural complications and were at increased risk of death
compared to those receiving an ICD without recent heart failure
hospitalization. Additional prospective real world pragmatic
comparative effectiveness studies should be conducted to define
the optimal timing of ICD placement.


                                               
The final original paper presents result of the VERDICT trial, a
large scale randomized controlled trial evaluating the value of
very early invasive strategy conducted within 12 hours of
diagnosis on long term clinical outcomes in patients with non-SD
elevation acute coronary syndrome. First and corresponding author
Dr Kofoed from University of Copenhagen and colleagues studied
2,147 patients who were randomized and found that an invasive
strategy performed within 4.7 hours after diagnosis was not
associated with improved outcomes, compared to an invasive
strategy conducted within two to three days.


                                               
However, in the pre-specified subgroup of patients with a GRACE
risk score of more than 140, a very early invasive treatment
strategy did appear to improve outcomes, compared to a standard
invasive treatment strategy. And that wraps it up for our
summaries. Now, for our feature discussion.


                                               
For our feature discussion today, we are talking about oxygen
therapy for patients with suspected acute myocardial infarction.
Something that seems so benign, something we've taken for
granted, and yet now we now question since the Detox AMI trial.
Well, for today's feature paper, we have a follow-up of this
trial, and I'm so pleased to have actually our associate editor,
but also author of this paper, Dr Stefan James from Uppsala
Clinical Research Center, and the guest editor for this paper, Dr
David Morrow, who's from Brigham Women's Hospital and Harvard
Medical School. So, thank you both for being here.


                                               
Stefan, could I just ask you to start by taking us back. How was
Detox AMI first conceived? What made you even question oxygen
therapy? And then, perhaps then, tell us about what this new
paper adds.


Dr Stefan
James:             
I think that's so interesting because I think we all learned in
medical school that for myocardial infarction, you should always
deliver oxygen. That's sort of the first choice. And the other
sort of first choice that we learned was morphine. Some of the
other important things that we learned was to give not only
oxygen but morphine, and nitroglycerin, and perhaps aspirin. And
by those four, only aspirin is really the agent that has been
proven beneficial to patients.


                                               
But we thought for many years actually about this oxygen
hypothesis, or we were interested in trying to understand, is it
really helpful to give patients oxygen? Or are we in fact harming
patients? Because there is, as you may know, there is a
metanalysis performed long ago with small trials on the
fibrinolysis era that showed actually a threefold increased risk
of dying in those patients who had received oxygen in randomized
various small trials, and their animal experience actually
suggesting that oxygen is also hazardous. You don't think about
that so often, but it's really an agent that constricts arteries,
and so as the arteries close by a clot in myocardial infarction,
there is no way the oxygen that you breathe in your nose can
reach the suffering myocardium. It actually contracts the
arteries, and may make the infarct larger than it would be
otherwise.


Dr Carolyn
Lam:               
I love that explanation. Alright, so what did you find in the
current analysis of longer term results?


Dr Stefan
James:             
So, we performed this, the main oxygen trial that we call Detox.
We built it upon our national registries, and so we decided to
include not only MI patients, but patients who were suspected of
MI, in order to be able to enroll patients before the diagnosis
was clear. We didn't want to wait for troponins, so we enrolled
patients in the ambulances, in the emergency departments, in the
cath labs, or in the wards, patients who had suspected myocardial
infarction.


                                               
Most of them, eventually, did have myocardial infarction, but a
proportion did not have myocardial infarction. They had other
diseases that resembles MI and have breathing problems. And we
selected the cut point of 90%. We said if they are below 90%,
they're hypoxic, and it would be unethical to withdraw oxygen, if
you were hypoxic. So, we sort of arbitrarily selected the cut
point of 90%. And then, we randomized patients to receive oxygen
or do not receive oxygen.


                                               
We considered to do double blind, but in order to do a double
blind, you need to provide air on a mask. And air is not
available in ambulances or in the emergency department. We cannot
put a mask without anything in it because then it will feel more
difficult to breathe. So, we had actually oxygen versus nothing,
and we enrolled all patients coming to the cath labs, and
emergency departments, and ambulances in Sweden. And thanks to
the infrastructure that we have built on the national registries,
we were able to enroll these to conduct this large trial, larger
than any other trial, 6,600 patients.


                                               
In the main study, we found no benefit, and fortunately, no harm
of providing oxygen for our primary end point, which was all
caused death. But we realized that we were little bit
underpowered actually to really clearly rule out that there was
any benefit on the primary endpoints. And so, we said, we
probably need a longer follow-up, and we probably also need other
important measures such as heart failure. Because we thought that
oxygen may, if it works, it may reduce the infarct size and may
result in a lower risk of heart failure in the long-term. We
don't believe that we will reduce the risk of re-MI because we're
not interfering with atherosclerosis or plaque ruptures, but we
may interfere with the development of heart failure.


                                               
So, in this particular paper, we said, longer follow up in order
for patients to possibly develop heart failure and increase their
risk of heart failure hospitalizations. So, in this paper, we
used as a primary endpoint of this analysis, death or
hospitalization for heart failure, post MI. And with this way of
calculating events, we are more sure that we are not underpowered
for this evaluation.


Dr Carolyn
Lam:               
Right. And the results?


Dr Stefan
James:             
The results were completely neutral. There was no benefit at all
in any sub group. It doesn't matter if you were ST elevation MI,
or no ST elevation MI, or no MI, or high risk prior MI, prior
heart failure, respiratory disease, there is no benefits and no
harm, which is good. And those results are supported by our
findings on troponin levels. So, we checked troponins repeatedly.
I shouldn't say top troponin, but the highest measured, we did
not find any difference between the two groups in Troponin
elevations. And we did not find any difference in LVEF and in
Echo performed during the initial hospitalization.


                                               
So, I think both of those results support the primary endpoint of
death and repeat hospitalization for heart failure.


Dr Carolyn
Lam:               
So David, you've thought a lot about this, and also framed it so
nicely when we were just talking a little bit earlier. What do
you think is the real significance of this paper on so many
levels?


Dr David
Morrow:           
Yeah, I think there are many levels. I think it's such important
work because it takes something that we are still doing in many
hospitals every day for patients and is difficult to study
because it's become part of standard of care, as Dr James pointed
out, and so the authors are to be congratulated for being able to
study this intervention. And I think in additionally because it
is a therapy that's not associated with high cost, has been part
of our care for so long, it's not one where there is the support
for a large type of randomized trials. So, the ability to perform
this with relatively low costs by nesting it in a registry is
important, not only for this particular test, but also as a model
for future research of so many interventions that we make right
now where they started in a time where our threshold for a need
for data was much less.


Dr Carolyn
Lam:               
Yeah. Indeed. That's wonderfully put. I am also really struck.
It's the importance of the message, but also especially about how
you do a pragmatic registry-based randomized trial. The ability
of Sweden to do this, it's just rock the world, right? Because we
really need solutions like that for our clinical trial world,
which has to be sustainable somehow. Could you maybe take us
behind the scenes a little bit? I mean you did already in your
description. I didn't realize there were so many considerations
when you're planning this, but how easy or difficult is it to do
a trial like this?


Dr Stefan
James:             
We call the entity RRCT. We call it registry based randomized
trial, but being aware that there is no strict definition of what
is a registry based randomized trial. So, sometimes for some
simple interventions like strategies, we can use only the
registry for collection of baseline variables, procedure
variables, and also outcomes. The registry can really do
everything. The only thing we need to add is a randomization, so
then we just program into the registry, which is used live in
front of the patients.


                                               
So, when I enter a patient in the registry, the personal
identification number collects me to the population registry that
supports directly back to me name and gender of the patient, and
then I enter all the baseline characteristics anyway in the
registry. And then, there is a question that comes up that
screens my patients. So, the system proposes to me to randomize
patients who are eligible because I programmed the
inclusion/exclusion criteria. So, it proposes to every doctor in
the country, this is a patient that is eligible potentially for
this trial and just click randomize, and that's the trial.
Everything is completed by that. No extra tests, no visits, no
follow up, no telephone calls.


                                               
That's the basic, very simple format that can only be used for a
strategy, like a device or a strategy. But many of the questions
we have in medicine are really regarding strategies. How long
should you treat? How often do you need to come back? Sort of
strategies. Then, when we've tried to expand this to
pharmaceutical agents, and oxygen was the first pharmaceutical
agent that we wanted to try. You may not consider oxygen as a
pharmaceutical agent, but it is in fact. But it's not
manufactured by any companies, and we are still, in this trial,
wanted to keep all-cause mortality as the primary end point
because that's very reliable. That's indisputable, and in our
country it's absolutely 100% correct. If they registered dead,
they are dead. There's no question.


                                               
The next level we did in the validate was a true pharmaceutical
agent manufactured by a company, [byobatterin seprin 00:18:31]. A
little bit more complex because you need to be careful about
making sure that the patients are receiving the pharmaceutical
agent in the right manner, in the right time point. We need to be
a little bit careful about collection of side effects, and
complications, and so on, but it also worked very well in that
trial. If they validated, we did actually adjudicate events
because in the primary end point we had it where it was more
complex primary endpoint, including myocardial infarction. If you
include myocardial infarction or bleeding events, that needs to
be defined in a certain way according to protocol. You need to
adjudicate. If you really need to rely on the outcome assessment.


                                               
We're not trying to take this type of study to the next level, to
use it for typical oral pharmaceutical agents. Our largest trial
now running is the spirit HFPF lactone versus no treatment in
patients with HFPF. And again, this is a pharmaceutical agent
that is a very inexpensive. There's no company that would sponsor
such a trial, but we think it's a really important question.
There's so many patients that suffer from HFPF, and in order to
do that trial, it has to be simple and inexpensive.


                                               
So, that's running. We hope to be successful. There are, of
course, many challenges. Like any other trial, it's difficult to
write a protocol. You have to be very dedicated and detailed for
any trial. So backstage, this is not easier than any other trial,
but for the investigator, it is much easier. That's the reason we
have succeeded to reach out to every hospital in the country, and
every physician seeing these patients are investigators. And many
of them have never done any trials before. They have no
experience with research, but still they should be able to
randomize and do the trials because it seems to be so easy for
them and for the patients. That's the whole idea.


Dr Carolyn
Lam:               
Yeah. I'm just enamored by the whole concept, and of course, a
lot of people I think are wishing that we could institute that in
all countries as well. Trust me, a lot of conversation has
occurred about that in Singapore, for example, where population
based capture is possible. But, as you said, it's not that easy.
It's got to be well thought out. Protocols still have to well
thought out. Investigators still need to be trained, and so on.


Dr Stefan
James:             
We want the investigators to feel that it's easy, that it's
attractive to participate. Not for money, just because it's so
easy and so interesting to be part of such an experiment.


Dr David
Morrow:           
I think testing some of those therapies that are commonplace that
they're used to, and our nature of practice is this is the
perfect type of setting than more complicated interventions where
you may need to train the investigators more in order how to
implement to them, and apply the therapy correctly. That's the
new trend, is ... I think the key issue is that in order to
reliably test things where mortality is not the acceptable
outcome that you could power adequately for, it's really the
endpoint collection in the safety collection, and because of the
robust medical record systems you have, you're able to do that.
And we're so far from being able to do that reliably in the
United States right now that it's not possible to do that. Unless
we have specific well-constructed registries, which we do in some
areas. I think we're learning, and hopefully we'll get there, but
we're far behind [crosstalk 00:21:55].


Dr Stefan
James:             
[crosstalk 00:21:55] Yeah, but even-


Dr David
Morrow:           
[crosstalk 00:21:57] Nationals-


Dr Stefan
James:             
Even if you're not able to do a registry based, I think we all
should consider in all trials to do it as easy as possible and
really try to ask ourselves, what is the most important reason
we're doing this trial? Sometimes we need to collect a lot of
extra information because we need to understand the mechanisms or
the side effects. If that's the case, I don't think at this trial
methodology is not suitable. You shouldn't perform it that way.
It needs to be the more traditional, more conservative, more
expensive and burdensome way, but for many therapies, a more
simple approach, more pragmatic approach is preferable.


Dr Carolyn
Lam:               
Well, thanks again for diving into that because it gives us a
real, to me at least, even greater appreciation for this paper
when you understand the amount of work that's gone into it. But
may I just end by saying, what do you think is the take home
message for clinicians now? David, for example, you started by
saying everyone's still doing it? I fully agree.


Dr David
Morrow:           
Yeah. I think it's a very simple message, and that we know that
oxygen is not effective in patients who have an oxygen saturation
above 90%. And there's really no rationale to use it.


Dr Carolyn
Lam:               
Perfect. Has this been put in practice in Sweden already?


Dr Stefan
James:             
It has been. One of the virtues of running these registries is
that we can also check the adherence to the results, so we can
check that this is not used anymore.


Dr David
Morrow:           
And since the investigators are your entire country, they all
learned actually from participation in these trials.


Dr Stefan
James:             
Exactly. Exactly.


Dr David
Morrow:           
There's more of an investment in it already.


Dr Carolyn
Lam:               
That's amazing. So, thank you again for sharing. Thank you for
publishing this in circulation and for helping us to do that.


                                               
You've been listening to Circulation on the Run. Don't forget to
tune in again next week.


                                               
This program is copyright the American Heart Association in 2018.