Oct 17, 2016
Carolyn:
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 Centre and Duke National
University of Singapore. Have you ever wondered what the clinical
implications of very brief episodes of device-detected atrial
tachyarrhythmias are? Well, we will be discussing this with novel
data from the RATE registry in just a moment. First, here's your
summary of this week's journal.
The first study provides the first evaluation of the Sweden
nationwide abdominal aortic aneurysm screening program. Of almost
303,000 men invited for screening, 84% attended. The prevalence of
screening detected abdominal aortic aneurysm was 1.5%. After a mean
of 4.5 years, 29% of patients with aneurysms had been operated upon
with a 30-day mortality rate of 0.9%. The introduction of screening
was associated with a significant reduction in aneurysm-specific
mortality. The number needed to screen to prevent 1 premature death
was 667, while the number needed to operate on to prevent 1
premature death was 1.5.
Furthermore, the authors showed that their screening program was
highly cost-effective in the contemporary setting in Sweden. These
findings confirm results from earlier randomized controlled trials
in a large population-based setting, and may be important for
future healthcare decision-making. This and the diverse
requirements for efficient population screening for abdominal
aortic aneurysm, from program management to maintaining skills in
open repair are discussed in an excellent accompanying editorial by
Dr. Cole from Imperial College London.
The next study looks at thoracic epidural anesthesia and suggests
that caution may be needed in patients with or at risk for right
ventricular dysfunction. You see, thoracic epidural anesthesia
involves blockade of cardiac sympathetic fibers, which may affect
right ventricular function and interfere with the coupling between
the right ventricle and right ventricular afterload. Dr. Wink and
colleagues from the Leiden University Medical Center therefore used
combined pressure volume conductance catheters to study the effects
of thoracic epidural anesthesia on right ventricular function and
ventricular pulmonary artery coupling in 10 patients scheduled for
lung resection.
Thoracic epidural anesthesia resulted in a significant reduction in
right ventricular contractility, stroke work, dP/dt max and
ejection fraction. This was accompanied by a reduction in effective
arterial elastance such that ventricular pulmonary coupling remain
unchanged. Clamping of the pulmonary artery increased right
ventricular contractility but decreased ventricular pulmonary
coupling. These effects of increased afterload were the same before
and after thoracic epidural anesthesia. In conclusion, therefore,
thoracic epidural anesthesia impaired right ventricular
contractility but did not inhibit the native positive ionotropic
response of the right ventricle to increase afterload. These
findings are clinically relevant for daily practice in
cardiothoracic surgery because pulmonary hypertension is frequently
encountered, and right ventricular function is an important
determinant of early and late outcomes.
The next study suggests that the use of point of care hemostatic
testing may have a place in the management of patients undergoing
cardiac surgery. Dr. Karkouti and colleagues of the Toronto General
Hospital hypothesized that point of care hemostatic testing within
the context of an integrated transfusion algorithm would improve
the management of coagulopathy in cardiac surgery, thereby reducing
blood transfusion. They therefore conducted a pragmatic
multi-center stepped-wedge cluster randomized controlled trial of a
point of care based transfusion algorithm in 7,402 consecutive
patients undergoing cardiac surgery with cardiopulmonary bypass in
12 hospitals in Ontario, Canada. They found that the trial
intervention reduced rate of red cell transfusion with an adjusted
relative risk of 0.91 and a number needed to treat of 24.7.
The intervention also reduced rates of platelet transfusion and
major bleeding but had no effect on other blood product
transfusions or major complications. These findings that point of
care testing improved management of coagulopathy in cardiac surgery
support the consideration of their broader adoption in clinical
practice.
The next study provides experimental evidence that brings us one
step closer to therapeutic targeting of arterial leukocyte
recruitment in the context of atherosclerosis. In this study from
first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein
and colleagues from LMU Munich, authors focus on cathepsin G, which
is stored in neutrophil and azurophil granules and discharged upon
neutrophil activation. They studied site-specific myeloid cell
behavior after high-fat diet feeding or TNF stimulation in the
carotid artery, the jugular vein, and cremasteric arterioles and
venules in APOE E and Cathepsin G-deficient mice.
Their studies revealed a crucial role for Cathepsin G in arterial
leukocyte adhesion, an effect that was specific for the arteries
and not found during venular adhesion. Consequently, Cathepsin G
deficiency attenuated atherosclerosis but not acute lung
inflammation. Mechanistically, Cathepsin G was immobilized on
arterial endothelium, where it activated leukocytes to firmly
adhere, engaging endocrine clustering, a process of crucial
importance to achieve effective adherence under high-sheer
flow.
Therapeutic neutralization of Cathepsin G specifically abrogated
arterial leukocyte adhesion without affecting myeloid cell adhesion
in the microcirculation. Repetitive application of Cathepsin
G-neutralizing antibodies really allowed the inhibition of
atherogenesis in the mice. Taken together, these findings presented
evidence of an arterial-specific recruitment pattern centered on
Cathepsin G adhesion, thus representing a potential novel strategy
and target for the treatment of arterial inflammation. Well, that
wraps it up for the summary of this week's journal. Now, for our
featured discussion.
Our feature paper for today discusses the clinical implications of
brief device-detected atrial tachycardias and really novel findings
from the RATE registry. I'm so happy to be here with the first and
corresponding author, Dr. Steven Swiryn from Feinberg School of
Medicine, Northwestern University. Hi, Steven.
Steven:
Good morning.
Carolyn:
We also have with us Dr. Mark Link, associate editor from UT
Southwestern. We all know that prolonged episodes of atrial
tachycardia or atrial fibrillation are associated with increased
risk and that if we anticoagulate those with a high CHA2DS2–VASc
score, we can lower the risk of stroke. Now, the European Society
of Cardiology guidelines also say that recent data reinforced the
assumption that even brief episodes of silent atrial fibrillation
may convey an increased risk of stroke. We also know that prior
studies have looked at device-detected atrial fibrillation. Steven,
I'd really love if you could start by telling us what makes your
study different. What was the main thing you were trying to look
at?
Steven:
Well, one reason it's attractive to use the device population,
patients with pacemakers or defibrillators, to look at these issues
is because devices have a very high likelihood of detecting
episodes of atrial fibrillation whereas symptoms or single 12 EKGs
miss a lot of atrial fibrillation, so the sensitivity is much
higher, although not perfect. The problem is that very brief
episodes of atrial fibrillation are very poorly detected by
devices. The specificity of automatic detection is very low, such
that all previous studies until the RATE registry have excluded any
episode of atrial fibrillation detected by a device less than 5
minutes in duration because they're unreliable. A lot of them turn
out to be false positive detections. Our study was designed to
evaluate whether even very brief episodes of an atrial
tachyarrhythmia might also be associated with risk of clinical
events and might or might not warrant anti-coagulation.
Carolyn:
Ah, that's interesting, so you really helped to answer how brief is
"brief" when we need to talk about device-detected atrial
fibrillation. Could you expand on how you actually defined "short
episodes" here?
Steven:
Right. A short episode for the purpose of the RATE registry was
defined as an episode where the electrogram that we scrutinized had
both the onset and the offset of the episode within the same
electrogram tracing, so although we can't put a specific time
duration on it because that wasn't part of the criterion, it's
typically less than 20 seconds or so, although not always, whereas
a long episode was defined as an electrogram where either the onset
and/or the offset was not captured by the device memory and
therefore we don't know the duration. Some of those may not have
been very long, and some of those may have been extremely prolonged
episodes. That allows us to actually scrutinize the electrogram. We
looked at 37,530 individual electrograms using 8 teams of
adjudicators, each with a physician and a field clinical engineer
from the device company so that we could actually say definitively,
"Yes, this was atrial fibrillation," or, "No, it wasn't."
Carolyn:
This is the first study to really look under that 5-minute limit of
atrial tachycardias. What did you find?
Steven:
Well, we found that in contrast to prolonged episodes, short
episodes of atrial tachyarrhythmias were not associated with an
increased risk compared to those without atrial fibrillation of
pre-defined clinical events, including death from any cause, heart
failure, stroke, hospitalization for atrial fibrillation, and a few
other smaller events.
Carolyn:
This was over a 2-year follow-up period, is that right?
Steven:
The median follow-up was slightly less than 2 years, that's
right.
Carolyn:
What I really was struck with was also the second finding, the
propensity to develop longer episodes. Could you expand on
that?
Steven:
We reasoned that in the clinic, one might be faced with a short
episode was we defined them, and then you don't know what's going
to happen for the next 2 years to bring to bear the results of our
study. We looked at if your first episode was short, what was your
likelihood over the full follow-up of the study of progressing to
longer episodes. About 50% of patients who had their first episode
as only a short episode progressed to a longer episode over the
full follow-up and therefore were in the long category for the rest
of the results. Half of them never got a longer episode.
It was, as one might imagine, if you had your first short episode
very early in the study and had a longer follow-up, you were more
likely to end up in the long category, and if you had very frequent
short episodes, you were also more likely to end up in the long
category by the time the full follow-up was over with. Having an
initial short episode is not a guarantee that you're never going to
get a long episode and that you'll never acquire a consideration of
anti-coagulation.
Carolyn:
That was a very important message to me as well because it meant
that although I can be secure or reassured by these data for very
short episodes, I needed to look out for the development of longer
episodes, at least that's what your registry showed over 2 years of
follow-up. I'm curious, Mark, what were your take-home messages
because that leaves us with a bit of a conundrum. What do we do
about anti-coagulation in these patients?
Mark:
I think this study is a big help to the practicing
electrophysiologist and practicing cardiologists. It's a very
ledger number of patients with a lot of episodes of afib. It's
reassuring to me that the shorter episodes of afib as defined by
the study, the individuals did not have a higher incidence of
stroke compared to those with no episodes, so it's reassuring and
very important clinically as I go through my practice.
I do look forward to more analyses and more data from this study
because although now we know that episodes less than 20 seconds are
in all likelihood not going to need anti-coagulation, we still
don't know about those from 20 seconds to 5 minutes. Hopefully with
more analysis of this study we'll get that answer also.
Carolyn:
Steven, do you agree with that?
Steven:
We would love to have that. At first glance, you would think that
devices would give you all of the data you needed because after
all, they're monitoring the patient 100% of the time, but there are
difficulties with that because device memory is limited, and you
don't get electrograms that go on until the termination of atrial
fibrillation even if the device were accurate in determining when
that termination was because depending on how the device was
programmed and depending on whether it was a more modern device
later in the trial or earlier and had more or less memory, it cuts
off after a limited amount of time, and you don't see necessarily
how long the duration is.
Now, you can use device-based data. The device gives you its
estimate of how long the episode is, but those are not as reliable
as adjudicating the electrograms and actually looking at them.
Those data would be a little softer than the main results if we get
there.
Mark:
That was the data that was used for all of the other studies, was
[transassert 00:14:51]. It would be comparable to those other
studies. I still think it would be very important data that I'd
love to see.
Steven:
Okay, well, I agree. I think it would be very interesting to look
at that and a number of other things. We have a number of other
things we could do with this database. There are a number of
substudies that are in progress. For example, one interesting one
is there were some instances we found, because we actually looked
at these electrograms, there's something that we termed
"competitive atrial pacing," where the device will pace at times
when we as clinicians would not want to pace. For example,
pacemaker-mediated tachycardia would be an instance of that, but
then you can pace in the atrium inappropriately. There's a rhythm
called repetitive non-reentrant ventricular atrial systole, which,
although it's exotic to all of us, actually turned out to be fairly
common where there's pacing in the atrium that occurs for various
reasons when we want it to.
We actually saw instances where the device itself induced atrial
fibrillation. It wasn't that common, but we did see it. We have a
substudy that we're working on about the subjective competitive
atrial pacing to see how much of that there was and of what, if
any, consequence that was. That's one of the things that's been
done. Because we scrutinized these so carefully, we tracked
morphology and atrial rate at least as a crude estimate, and we
have those data, so we could actually evaluate whether if something
looks very, very rapid and disorganized as opposed to more
organized electrograms at a slower rate, did that make any
difference. We don't have any results for those analyses yet. I
agree with Mark that the intermediate durations would be
interesting to look at.
Carolyn:
I agree too, and I'm really grateful for you sharing those
thoughts. Very grateful for both of you for your time today. I just
have to congratulate you. I completely agree this paper fills an
important knowledge gap, and congratulations once again.
Steven:
Thank you very much.
Mark:
Thank you.
Carolyn:
Thank you for listening. You've been listening to Circulation on
the Run. Please tune in next week.