Circulation October 4, 2022 Issue

This week, please join authors Jonas Oldgren and Signild
Åsberg as they discuss the article "Early Versus Delayed
Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute
Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based
Randomized Controlled Noninferiority Study."


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 and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Today's featured paper is a very important discussion, and in
fact, the first study to compare early versus delayed NOACs after
acute ischemic stroke in patients with atrial fibrillation. The
timing study. You're not going to want to miss this, but you're
going to have to wait for it, because we're going to discuss all
the papers in today's issue. Can I start, Greg? Because I want to
start, or is it too early to start with a Greg quiz? With the
quiz question being, what is cell-free DNA?


Dr. Greg Hundley:


Oh, thank you Dr. Lam. I really appreciate your wonderment into
the world of preclinical science. So something maybe short DNA
fragments, but I'm not sure.


Dr. Carolyn Lam:


Aw, you're absolutely right. It's circulating DNA fragments
predominantly from mononuclear zones that represent cell injury
and/or turnover. So what we know is elevated total cell-free DNA
concentration has been associated with worse prognosis in a
variety of conditions such as sepsis, trauma, malignancy. In
addition, and this may be where a lot of us have heard of
cell-free DNA, it's become clinically relevant as a noninvasive
marker of solid organ transplant rejection as well as a tool for
genotyping and surveillance in oncology.


However, in today's paper, given the parallels in the
pathogenesis of pulmonary artery hypertension, two of the
diseases I've talked about before that are characterized by
increased cell proliferation and turnover, like the cancers and
inflammatory mediated tissue injury. Now this particular study
sought to determine if plasma cell-free DNA concentrations were
elevated in pulmonary artery hypertension, and if those levels
would correlate with disease severity or predict outcomes.


Dr. Greg Hundley:


Oh wow, Carolyn, this sounds really informative. So what did they
find?


Dr. Carolyn Lam:


Well, this study from corresponding authors, Dr. Solomon from NIH
Clinical Center and Dr. Agbor-Enoh from NHLBI in Bethesda and
their team found that circulating cell-free DNA is elevated in
patients with pulmonary arterial hypertension compared to healthy
controls. In two independent PAH patient cohorts, cell-free DNA
concentrations increased with severity of disease and predicted
transplant free survival in the larger of the two cohorts.


Interestingly, methylation patterns revealed increased cell-free
DNA originating from biologically plausible sites including
erythrocyte progenator and myeloid lineage inflammatory cells,
vascular endothelium, and cardiac myocytes. So the implications
are that in pulmonary arterial hypertension, cell-free DNA
concentrations could serve as a non-invasive biomarker of
underlying disease activity, may add prognostic value to
currently use risk scores, and may provide a unique noninvasive
window into its pathogenesis.


Dr. Greg Hundley:


Wow, Carolyn. So another interesting technique and
pathophysiologic study highlighting the utility of circulating
cell-free DNA. Wow. Well, Carolyn, how about I start in with my
first study and it comes to us from the world of clinical science
and refers to the paradise MI echocardiographic substudy. So
Carolyn, the prospective RNE versus ACE inhibitor trial to
determine superiority in reducing heart failure events after
myocardial infarction.


So the Paradise MI echo study tested the effect of
Sacubitril/Valsartan compared to Ramipril on LV function and
adverse remodeling following high risk acute myocardial
infarction. So this substudy included 544 Paradise MI
participants that underwent echocardiography at randomization,
and then again later at eight months. Patients were randomized
within a half to seven days of their presentation with their
index, myocardial infarction, to receive a target dose of
Sacubitril/Valsartan of 200 milligrams or Ramipril five
milligrams twice daily.


Dr. Carolyn Lam:


All right. So the Paradise MI echo substudy, what did they find?


Dr. Greg Hundley:


Right Carolyn, so treatment with Sacubitril/Valsartan compared to
Ramipril following acute myocardial infarction did not result in
changes in left ventricular ejection fraction or left atrial
volume at eight months. Patients randomized to
Sacubitril/Valsartan had less LV enlargement and greater
improvement in filling pressure, and thus there are new insights
here in that treatment with Sacubitril/Valsartan compared to
Ramipril early following acute myocardial infarction may
beneficially impact LV size and diastolic properties possibly due
to reductions in LV filling pressure.


Dr. Carolyn Lam:


Oh, very nice, Greg. Thank you. Another clinical study here, and
this time a paper aimed to evaluate the influence of sex on the
effects of empagliflozin in patients with HFpEF enrolled in the
Emperor Preserved trial.


Dr. Greg Hundley:


Ah, Carolyn, two of your favorite things, sex differences and
SGLT2 inhibitors. So Carolyn, remind us, what did Emperor
Preserved show us?


Dr. Carolyn Lam:


Ah, so Emperor Preserved studied the sodium glucose cotransporter
2 or SGLT2 inhibitor empagliflozin in patients with HFpEF, which
is an ejection fraction above 40%, and showed a significant
reduction in the risk of cardiovascular death or heart failure
hospitalization. In the current paper, corresponding author Dr.
Javed Butler from University of Mississippi Medical Center and
colleagues found that empagliflozin reduced the risk of the
primary outcome of cardiovascular death or hospitalization for
heart failure to a similar degree in both women and men with
HFpEF irrespective of baseline left ventricular ejection
fraction.


Empagliflozin produced comparable benefits for the pre-specified
secondary outcomes of total heart failure hospitalizations,
cardiovascular death, and all-cause mortality, as well as
physiologic measures and health status. The pattern of the
effects of empagliflozin and HFpEF in both sexes in EMPEROR-
Preserved stands in contrast to the influence of sex on the
response to neprilysin inhibition. So very interesting paper. I
encourage everyone to pick it up, of course, because it's two of
my favorite topics.


Dr. Greg Hundley:


Very nice, Carolyn. Well, my next paper comes to us from the
world of pre-clinical science, and it's from Dr. Chunyu Zeng from
Diping Hospital, the third military medical university. Carolyn,
adverse environmental exposure during the prenatal period can
lead to diseases in offspring, including hypertension. Now
whether or not the hypertensive phenotype can be
trans-generationally transmitted is really not new.


Dr. Carolyn Lam:


Wow, that's interesting. So what did this paper find?


Dr. Greg Hundley:


Carolyn, this was really interesting. So these authors in a rat
model, they found that prenatal lipopolysaccharide exposure can
impair the ability to excrete a salt load and induce hypertension
from the first to the third generations, with the fourth and
fifth generations inducing salt-sensitive hypertension. And
Carolyn, really interestingly, and based on these findings, they
treated lipopolysaccharide exposed pregnant rats with the
reactive oxygen species scavenger temple, which successfully
prevented hypertension in the first-generation offspring and the
transgenerational inheritance of hypertension.


So Carolyn, these findings show that adverse prenatal exposure
induces transgenerational hypertension through an epigenetic
regulated mechanism. And these findings identify potentially
preventive and therapeutic strategies for this form of
generationally transmitted hypertension. Really interesting.


Dr. Carolyn Lam:


Wow, that sounds wild. Very, very interesting. Well, let's go
through the other things that are in today's issue. There's a
research letter by Dr. Moayedi on anteroposterior pacer pad
position is more likely to capture than anterolateral for
transcutaneous cardiac pacing.


Dr. Greg Hundley:


Great, Carolyn. And I've got a research letter from Professor
Porrello entitled, “Defining the Fetal Gene Program at Single
Cell Resolution in Pediatric Dilated Cardiomyopathy.” And then
lastly, there's an ECG Challenge from Dr. Chen entitled, “A Shark
Thin Electric Cardiogram in the Intensive Care Unit.” Well
Carolyn, how about we get onto that featured discussion and learn
more about non-vitamin K antagonists after acute ischemic stroke?


Dr. Carolyn Lam:


Yep. In patients with EF, here we go.


Today's feature discussion is all about atrial fibrillation, how
it's a risk factor for stroke, but also about how we've never
known really how soon after an acute stroke can we start oral
anticoagulation to prevent recurrent strokes? Today we're going
to talk about the timing study. It's the first randomized
controlled study to evaluate the efficacy and safety of
initiation of treatment with NOACs within 10 days of acute
ischemic stroke in patients with atrial fibrillation.


Wow. What an exciting study, and also how exciting that we have
two co-first authors. We have Dr. Jonas Oldgren and Dr. Signild
Åsberg from Uppsala University in Sweden, and this represents a
partnership between neurology and cardiology. I mean really
unique in many aspects as well as the way this study was
performed, which is truly, truly a feat in itself. May I ask you
both please to tell me the story of how this study came to be in
the first place?


Dr. Signild Åsberg:


Well, we like to mention the late Professor Gesteruen student who
actually was the first to bring this question to the table.
Together we talked with the cardiology department and Jonas
Oldgren to see if we can collaborate to solve this important
question for us that works with stroke patient, because it's on a
weekly or even a daily basis, troublesome question.


Dr. Jonas Oldgren:


My background is as a cardiologist and professor of coagulation
research. I've been very interested in anticoagulants,
antithrombotic treatments, and had the pleasure and privilege to
be part of the development of the novel oral anticoagulants. And
in all those pivotal trials, we excluded patients with a recent
stroke at least seven days from the stroke, sometimes even 30
days from the acute stroke we excluded them from the studies.


So when we found the exciting results with at least as good
efficacy as warfarin and at least as good safety as warfarin and
the tremendous reduction in intracerebral or intracranial bleeds,
that was a finding which was not evaluated in acute stroke
patients with atrial fibrillation. And when Signild approached me
with this idea, I said, "Well this is absolutely a very important
question and why hasn't it been resolved earlier?"


And the problem is, of course, that these are patients who are in
a sensible setting earlier after the acute ischemic stroke, and
when are we able to safely start an effective treatment?


Dr. Carolyn Lam:


Oh, I couldn't agree more with you about how important that is. I
mean, when we have an acute stroke patient, we just don't know
whether we should start the NOAC early or delay it and we
definitely need that evidence gap filled. But I'm also so
intrigued with the way you did it with the Swedish Stroke
Register. I mean, what a powerful way to look at important
questions like this. Could you tell us a bit more about the
method used?


Dr. Jonas Oldgren:


Yeah, so in cardiology we started rather early by using our
national health registries for doing randomized controlled
trials. We did a lot of observational studies in our registries,
both in stroke and in cardiovascular medicine, otherwise in every
other area of medicine. But in the end we realized that we could
at best be hypothesis generating, but we still needed to add
randomized controlled studies to have the last piece of the
puzzle to provide good evidence.


And then we ran a lot of studies in cardiologists, especially in
myocardial infarction patients, by just adding to simplify, by
adding a randomization module, and then follow the patients in
the registries because we know that we have high quality data in
the registry. For instance, in the stroke registry. So we anyway
collect every important data on each and every patient in the
register. So by adding a randomization module, we can facilitate
the conduct of a clinical study.


Dr. Carolyn Lam:


Wow. The way you say it, you make it sound so simple, but I can
tell you what you have there in Sweden is like the envy of the
whole world, and everybody's thinking about how to do a registry
based trial like that. So maybe after you tell us the results,
you could also share a little bit of how difficult and
challenging it can be as well. But would either of you like to
share the results?


Dr. Signild Åsberg:


Well, the major result from our trial is that initiating NOAC
within four days is non-inferior to starting in a delayed phase
of up to 10 days. So that's our key finding. But equally
important is that we didn't have any patients explaining as
symptomatic and terrible hemorrhage, and that is extremely good
news for us who worked with these patients.


Dr. Carolyn Lam:


That is such an important message. The early initiation was
non-inferior. Could you expand on non-inferior in terms of what
primary outcome?


Dr. Jonas Oldgren:


Yeah, so the primary outcome was really a clinically important
outcome we think, both from the cardiac perspective but also from
stroke specialists. So we had a combination composite of
symptomatic intracerebral hemorrhages, ischemic strokes and
death. And this is what matters to patients and to doctors. We
would like to avoid strokes, and it doesn't matter if it's an
ischemic stroke or if it's a hemorrhagic stroke. We would like to
avoid them. And of course we would not like to have an increased
mortality as well.


So it's a relevant endpoint. And when we designed the study, the
main drug used was warfarin, and there we knew that there was a
lot of hemorrhagic transformations and a lot of intracerebral
hemorrhages. So we designed the trial to look at these three
endpoints to prevent ischemic strokes, but to avoid hemorrhagic
strokes. And that is why we choose to have a non-inferiority
design, because we also have the advantage of starting early if
we can make the decision to start with the stroke specialists
sometimes in collaboration with the cardiologist, and then we can
have the patient step down unit earlier if the treatment is
already started.


So that was the choice of a non-inferiority design. We of course
also tested for superiority, but unfortunately we didn't meet
that superiority testing endpoint. But as Signal mentioned, I
think thrilling results is to have no symptomatic intracerebral
hemorrhage in any of the groups. That really speaks in favor of
the safety of this drug or these drugs that we used, but also the
concept to start early. We can also note that we had some ... I
mean there were numerically lower rates of both ischemic strokes
and deaths in the early group, albeit not meeting the
significance for superiority, but it's important. And as we see
also the events tend to occur very early. So we really gain with
treating our patients earlier with this intervention.


Dr. Carolyn Lam:


Oh indeed. And to all the listeners, do pick up the paper because
if you look at the Kaplan-Meier curves, they're really
impressive, exactly like you said, numerical differences,
although the trial did demonstrate non-inferiority and could not
demonstrate the superiority. But have a look at those figures.
And if I could just clarify the comparator arm, notice that we've
been saying NOACs, not a particular NOACs. So could you expand on
that a bit?


Dr. Signild Åsberg:


We used all the four NOACs that we have in Sweden, so that was to
the physician's discretion to choose between them. So that was
not a part of the randomization. So we only randomized the timing
to the early phase or the delayed phase.


Dr. Carolyn Lam:


I love that. And then if you could please educate the
cardiologist in me, please. There are symptomatic intracerebral
hemorrhages, and then there are all kinds of little things that
you can pick up if you image the brain and hemorrhagic
transformation and microbleeds and all these things. So I think
one of the things here was their systematic imaging and does it
matter? Could you teach us a little bit more about these
different types of bleeds?


Dr. Signild Åsberg:


We did not have a systematic imaging, but in Sweden that is
performed mostly by CT on admission. So that was for all
patients. And then on events, the imaging was performed and
reported through the registry. And yes, there were hemorrhagic
transformation actually in three patients, two in the early
phase, and one in the delayed phase, but only one before day 10.
So all blood that was seen on imaging was reported, but we used
symptomatic criteria from the stroke severity scale.


Dr. Carolyn Lam:


Thank you. That's a good clarification. And then the study aimed
for a larger number, and here perhaps if either of you could tell
us the story, the struggles, and how you ended up with these
beautiful results.


Dr. Signild Åsberg:


Yeah, struggle is the word. It was troublesome and we had long
talks. So why was this happening? Why didn't science recruit
more? But I think one issue might have been that NOACs had been
on the market for a while once we started, and even the stroke
physicians were getting used to it and had trouble not to start.
Before the timing study started, we did a observational
pre-timing study just to see how we were doing in Sweden at this
stage. Because we didn't really know that.


We know that a lot of patients were discharged with oral
anticoagulation, but we didn't really know when they started. And
so by that study we could see that in median time to initiation
was five days, already before the timing study. So one thought
was that this was for some physicians then had to delay their
start. They were getting used to start early. So that could have
been one explanation.


Dr. Jonas Oldgren:


And of course there has been a lot of observational studies
looking at the safety of NOACs or other oral anticoagulants in
the early setting after acute ischemic stroke in patients with
atrial fibrillation. And of course with the evidence from such
studies, albeit observational doctors felt perhaps more confident
starting very early despite the lack of evidence from randomized
control trials.


So we had the opportunity to follow those patients as well in the
stroke registry. Every patient with an acute stroke in Sweden
attending a stroke unit is registered. So we have in the
supplement of the paper in circulation, we have observational
data from the centers participating in stroke, but patients not
randomized in the timing study. And we also have observational
data from all stroke centers in Sweden. So we can see that many
start very earlier with NOACs based on observational data, based
on experiences.


And perhaps we're more and more reluctant to randomize the
patient in the study because as Signal says, that means there is
a 50% chance of delayed treatment by randomization. And when we
started this study, there were no evidence from randomized
controlled trials within the first 14 days. But while running the
study for a couple of years, you start to believe that there
seemed to be safety because no one saw any symptomatic
intracerebral hemorrhage. And we discussed that, of course, at
investigative meetings that this seemed to be a very good
treatment, which is bad for running a clinical study, but it's of
course good for the patients.


Dr. Carolyn Lam:


Interesting. So echo points kind of may have shifted a little bit
even during the course of the trial. So just thank you so much
all the more. Thank you for seeing this to completion in the
sense of a beautiful manuscript with very meaningful results. If
I could ask you both to each summarize just very quickly what the
take home message is for clinical practice from neurologist's
point of view and cardiologist's point of view?


Dr. Signild Åsberg:


Yeah, what I would say, it seems both safe and reasonable to
initiate NOAC earlier after an acute ischemic stroke. So I think
that's the key take home message that really to consider the
acute secondary prevention.


Dr. Jonas Oldgren:


I may bring that from another perspective. I think when there's
lack of data in collaboration, we can do a lot. So in this case,
we had a great collaboration in the student committee,
cardiologist and stroke specialists collaborating to run such a
study. And we are extremely grateful for all the sites and all
the investigators at the sites participating in the study. And
then of course grateful to circulation for publishing it because
we are very proud of this study.


Dr. Carolyn Lam:


And we are proud to be publishing this. So ladies and gentlemen,
you heard it right here in Circulation On The Run. Remember this
is about early versus delayed initiation of NOACs in patients
after an acute stroke who also have atrial fibrillation. And this
is a very, very, I think, important study that fills an important
evidence gap. We're so grateful to both of you for being here to
discuss it, and to the audience for listening today. You've been
listening to Circulation On The Run. And don't forget to tune in
again next week.


Dr. Greg Hundley:


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.