Circulation May 15, 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 Centre and
Duke National University of Singapore.


                                               
Our featured discussion today is really a very important message,
that hospitals have the capacity to influence a patient's
adherence to secondary prevention and thereby potentially
impacting long-term patient outcomes. Much more on this important
paper coming right up.


                                               
Higher physical activity is known to be associated with lower
heart failure risk. However, what is the impact of changes in
physical activity on heart failure risk? The first paper in this
week's journal, by first author Dr. Roberta Florido,
corresponding author Dr. Ndumele from Johns Hopkins Hospital,
provides us some answers. These authors evaluated more than
11,350 participants of the Atherosclerosis Risk in Communities,
or ARIC, study who were followed for a median of 19 years during
which there were 1,750 heart failure events.


                                               
They found that, while maintaining recommended activity levels
was associated with the lowest heart failure risk, initiating and
increasing physical activity even in late middle age were also
linked to lower heart failure risk. Augmenting physical activity
may, therefore, be an important component of strategies to
prevent heart failure.


                                               
The next paper highlights the importance of bystander automated
external defibrillator use. First author Dr. Pollack,
corresponding author Dr. Weisfeldt from Johns Hopkins University
School of Medicine sought to determine the association of
bystander automated external defibrillator use with survival and
functional outcomes in shockable observed public out-of-hospital
cardiac arrests.


                                               
From 2011 to 2015, the Resuscitation Consortium prospectively
collected detailed information on all cardiac arrests at 9
regional centers. The exposures were shock administration by a
bystander applied automated external defibrillator in comparison
with initial defibrillation by emergency medical services. The
primary outcome measure was discharged with near or normal
functional status as defined by a modified ranking score of two
or less.


                                               
The authors found that among 49,555 out-of-hospital cardiac
arrests, 8% were observed public out-of-hospital cardiac arrests,
of which 61% were shockable. Overall bystanders shocked a
remarkable 19% of shockable observed public out-of-hospital
cardiac arrests. Bystander automated external defibrillation in
shockable observed public out-of-hospital arrest was associated
with an increased odds of survival with full or nearly full
functional recovery compared to emergency medical services
defibrillation.


                                               
The benefit of bystander automated external defibrillation use
increased as the arrival of emergency medical service was
delayed. Thus, efforts to increase the availability and use of
automated external defibrillators in public locations are likely
the most promising immediate ways to improve survival from
out-of-hospital cardiac arrests.


                                               
The next paper suggests that the complement pathway may contain
the secret to a successful cardiac regeneration. First author Dr.
Natarajan, corresponding author Dr. Lee from Harvard University,
and their colleagues performed a cross-species transcriptomic
screen in 3 model organisms for cardiac regeneration, the
axolotl, neonatal mice, and zebrafish, all of which underwent
apical resection.


                                               
RNA-seq analysis showed that genes associated with inflammatory
processes were found to be upregulated in a conserved manner.
Complement receptors were found to be highly upregulated in all 3
species, particularly the induction of gene expression for
complement 5a receptor 1. Inhibition of this particular
complement receptor attenuated the cardiomyocyte proliferative
response to heart injury in all 3 species.


                                               
Furthermore, following left ventricular apical resection, the
cardiomyocyte proliferative response was abolished in mice with
genetic deletion of complement 5a receptor 1. These data,
therefore, identified the complement pathway activation as a
common pathway for a successful cardiac regeneration.


                                               
The final study sheds light on the association between hyperoxia
exposure after resuscitation from cardiac arrest and clinical
outcomes. First author Dr. Roberts, corresponding author Dr.
Trzeciak from Cooper University Hospital performed a prospective
multicenter protocol directed cohort study that included 280
adult postcardiac arrest patients.


                                               
They found that early hyperoxia exposure, defined as a partial
pressure of oxygen of above 300 millimeters mercury during the
first 6 hours after return of spontaneous circulation, was an
independent predictor of poor neurologic function at hospital
discharge even after adjusting for a potential baseline and
postcardiac arrest confounders.


                                               
That brings us to the end of our summaries. Now, for our featured
discussion.


                                               
Medication nonadherence is a common problem worldwide and,
indeed, the very topic of our featured discussion today. Our
featured paper is so interesting because it tells us that
hospitals may have the capacity to influence a patient's
adherence to secondary preventive cardiac medications, thereby,
potentially impacting long-term patient outcomes, and there are a
lot of implications of that.


                                               
I'm so pleased to have with us the first and corresponding
author, Dr. Robin Mathews, from Duke Clinical Research Institute,
as well as the editorialist for this paper, Dr. Jeptha Curtis
from Yale University School of Medicine, and our associate
editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.


                                               
Robin, could you perhaps start by telling us what made you look
at this issue of nonadherence and what did you find?


Dr Robin Mathews:        
The issue of medication adherence has been something that I think
we've been dealing with in healthcare for some time now and,
traditionally, we looked at factors that, on a patient level, you
sort of also have an idea that maybe they might provider level
factors that contribute to nonadherence, so we started thinking
about this, what's the health system's role in adherence and is
there a role? Do hospital and do providers have more of a role in
promoting adherence than we acknowledged in the past?


                                               
We are fortunate to have a lot of great clinical data sources
available, and the one that we used for this study is the
ACTION-Get With The Guidelines Registry, and this is a quality
improvement registry that's been around for some time. It's a
great source of research and observational studies that has
produced a lot of data over the years.


                                               
ACTION is a voluntary registry; there are several hundred
hospitals that participate, and it gives us very good data,
detailed data on the patient experience in the hospital for
patients who come in with acute coronary syndrome, so we looked
at patients who were enrolled in ACTION over the course of 3
years, from 2007 to about 2010, and looked at the typical patient
level factors, medications that were given on admission, how they
were treated and what medications they went home on.


                                               
What ACTION doesn't give us is longitudinal data, which is really
what we were trying to get at here, so we were able to link this
clinical data set using CMS data, which is administrative data,
claims data, in order to ascertain longitudinal adherence, so we
ended up, after exclusions of about 19,500 patients or so, and
this spanned about 347 hospitals, of patients that we followed up
to 2 years out, and our objectives of the study were 2-fold, one
to assess adherence at 90 days for cardio vascular medication,
secondary prevention medications that are typically used, so, in
this case, we looked at beta blockers, ACE inhibitors, ARB,
phenoperidine, and statins.


                                               
We looked at 90-day adherence, and then the question we had
specifically was does adherence vary among hospitals? The second
thing we wanted to knowledge was, if adherence does vary among
hospitals, is there a relationship between hospital adherence and
cardiovascular outcomes at 2 years, so we looked at MACE, which
is MI, revascularization, readmission, stroke. We also looked at
death and all-cause readmission, and also mortality.


                                               


                                               
What we found is that the adherence actually did markedly vary
within the medication classes, but also among hospitals, and once
we divided these groups into essentially high adherence
hospitals, low adherence hospitals, and moderate adherence
hospitals, there were these typical differences in terms of
patient characteristics that one would expect in terms of
comorbidity, socioeconomic status. Patients who were in the high
adherence hospitals were more likely to be from ... to have a
less comorbidity burden. They had higher income based on ZIP
code, and they were more often represented from non-southern
hospitals in the United States.


                                               
When we then correlated these two outcomes, what we found is
pretty interesting. Patients who were in the low adherence
hospitals were more likely to have the outcomes that I mentioned
earlier. That's not too surprising, yeah, because I had mentioned
that the patient mix in terms of the ... their case mix varied
among these hospitals, so the logical question as well, maybe the
hospitals that are ... have low adherence have low adherence
because the patients are generally just sicker.


                                               
We know that there are certain high-risk groups and we know that
the patients who are treated at some hospitals might be sicker
than others, so we did our best to adjust to these, so we did a
multivariable model. We adjusted for various patient differences,
and we also looked at hospital-level differences, the best that
we can ascertain based on the ACTION Registry. That was sort of
where the interesting finding was the rates of major adverse
cardiac events and death at readmission were mitigated somewhat
closer to the null, but they remained significant.


Dr Carolyn
Lam:               
What a detailed summary. Thanks so much.


                                               
Jeptha, I love your editorial that accompanied it. Could you put
the study into context a bit for all of us? Why are these finding
so impactful?


Dr Jeptha
Curtis:              
It's rare that you get to review and editorialize a paper that
has so many implications both from a clinical practice and policy
standpoint, so I think they really hit on a understudied area,
and really this paper should cause people to reflect on what's
going on in their practice and at the institutions that they
practice in.


                                               
I would say that adherence is just such a challenging problem
that, as Robin articulated, has been refractory to change over 15
years. We've been studying this for a long time, and we know that
the numbers had not improved over time.


                                               
What's different about this paper is that it really suggests a
completely different approach to addressing nonadherence among
patients, and if this is ... if their findings are true, if
nonadherence is really actionable at the hospital level or
attributable to the hospital level, it really opens up new
avenues both for research as well as for quality measurements.


                                               
As I read this paper for the first time, I was really struck by
thinking about how invisible adherence is to frontline
clinicians. We just don't have the information to tell us are our
patients taking their medications on a day-to-day basis, and we
know that most of them are not because the research has
consistently shown that a large proportion failed to take their
medication, and Robin's paper showed that yet again, but I can't
say that there's any steps that our hospitals are really doing to
address that in a systematic fashion.


                                               
All of our efforts for quality improvement have really been
towards making sure that patients are prescribed the medication
on discharge, and in the setting of readmission and trying to
prevent readmission to our hospitals, we are now having follow-up
phone calls with patients to assess failures to taking
medications and follow-up, but it's really ... That's it. There's
really no systematic way that we're trying to ... if an
individual patient or a group of patients are adherent to their
medications, so this is really a whole new avenue.


                                               
What we don't know is how to improve it, right? I think that the
first implication of this paper is that there are differences at
the hospital level. Some hospitals seem to be doing this better
than others. That could be driven by differences in case mix, but
it could also be driven by differences in hospital practices, and
I think this is a wonderful opportunity for future direction of
research perhaps using positive deviance methodologies to go to
those hospitals that have high adherence rates in really trying
to understand what differentiates their practices from those of
other hospitals.


Dr Carolyn
Lam:               
Indeed, Sandeep, I remember some of the conversations we had as
editors about this paper. We, too, were struck by the novelty,
and you've mentioned before, Sandeep, that the novelty of perhaps
nonadherence or adherence as a new performance measurement. Would
you like to comment on that?


Dr Sandeep
Das:              
Yeah, first thing, what was kind of interesting about the
discussion surrounding this paper, there were some people who
read it and just sort of read it as the message being
nonadherence associated with worst outcomes, and I thought like
that was pretty established, known, but then there were some
people like Jeptha and Erica who really got it, who really
understood what was novel and interesting about this, and I also
congratulate Robin on a fantastic paper.


                                               
One thing I think that's really interesting, in my day job, I
wear a couple of quality hats. I am the cardiology division
quality officer, and health system quality officer for UT
Southwestern, so I spend a lot of time thinking about quality,
and I'll tell you there's quite a bit of metrics that he ...
there's just a lot of things that now you feel they're not
particularly substantive and they're very difficult to change,
you have, you know, if aspirin on discharge, as Robin mentioned
discharge adherence, aspirin on discharge is 99% and getting
people to document the last 1% rather than fail to document it,
there's not really a fulfilling challenge where you think, "I'm
really impacting patient endpoints."


                                               
I was really struck by the opportunity here. We know that from
studies like MI FREEE that adherence to medications even at a
year is probably about a third of patients are not adherence, so
it's really kind of interesting to take that as an opportunity.
We should fixate on what are these therapeutic option or not
therapeutic option can move the needle by a fraction of a
percent, but these are medications that are proven to prevent MI
and change lives, and there's a massive delta here that we can
address. The concept that this is addressable on the hospital
level is fascinating, and I'm a big fan of coming up with sort of
systems level approaches to addressing problems.


Dr Carolyn
Lam:               
Congratulations once again on this great paper. Just tell us what
do you think of the next steps and what would your message be to
those of us who practice outside of the US?


Dr Robin Mathews:        
Jeptha talked about where our focus should be in terms of what we
can do on a hospital level. I think the ultimate answer is
there's a lot of heterogeneity in terms of what is done, and I
think that, expanding on his point about better investigating
practices that currently exist, and whether that's surveying
things, and we have a lot of great professional societies and
registries that we can sort of reach out to these hospitals, find
out what they're doing, what makes them different from the
hospitals that are not doing those things and then really doing
some rigorous testing to figure out if in fact these specific
interventions that these hospitals have put in place are with the
high likelihood leading to the effects that we've seen, so I
think that surveying sort of what's out there, understanding what
works in a rigorous way and then being able to systematically
apply this or distribute this to other hospitals to share the
knowledge and say, "Hey, this is what we think. We've actually
done it."


                                               
Like Sandeep said, with the inpatient management of patients who
come in with acute coronary syndrome, we've done it well. I think
it sort of contributed. Our guidelines and adherence to these
guidelines and the metrics that we've used have really
demonstrated that we've sort of achieved high levels, but we sort
of reached I think the ceiling for a lot of that, and you always
have to be open to novel metrics and then the idea of focusing in
on the transition from hospital to home and what we can do once
they leave their door, once they leave the door of the hospital,
I think would be useful.


                                               
In terms of the rest of the world, I mean, the US has very unique
problems based on our payment models and access to care and
whatnot, but I think a lot of the themes that we sort of have
seen with medication nonadherence when it comes to patient-level
factors and provider-level factors are sort of universal.


                                               
At the end of the day, patients need to be empowered, and they
also need to have the tools to allow them to be successful in my
opinion. I think we've for a long time in this space often said,
"Well, this is sort of a patient that there's only so much that
we can do as providers," but I think that papers like this
highlight the possibility that there's probably more that we can
do to make these impacts.


Dr Sandeep
Das:              
One of the comments or a question that I had was the
controversial thing is to what extent hospitals should be
accountable for things that happen well after discharge? I think
readmission is one that always comes up. There's factors that are
outside our control, so one question is kind of to what extent
should we be responsible for stuff that happens forward of 6, 9
months down the road?


                                               
The second question that I had or a comment that I had was I do
think that there's going to be a generalizability to non-US
settings because there's elements of this ... For example, this
now would incentivize hospitals and discharging physicians to
make sure that patient education is substantive, right? If the
metric is, "Did you provide discharge instructions, yes or no?"
then that's sort of trivially accomplished by handing them a
piece of paper and checking a box, but, now, if we follow a
metric like this, we're really going to be accountable for making
sure people understand what they're supposed to be taking and
have a path to get it and things like that, so it makes some of
the transitions of care stuff, and that's a great point, some of
the transitions of care stuff much more substantive.


Dr Robin Mathews:        
Sandeep's point is a very good point, and it's very difficult to
come up with a clear answer for that and, like you said, the
issue with readmissions and all sort of the factors that are
involved from a social level and research level cloud that, so
... and, hence, I think something like readmission is
controversial, and I think this sort of question will generate a
lot of further questions about whether using medication adherence
and holding hospitals responsible.


                                               
I will say that when we looked at adherence sort of in the short
term at 90 days and we looked at it in the long term at a year,
we saw there was sort of a drop off, but it wasn't as substantial
it was earlier, so I think a lot of adherence in the short term
after hospital discharge continues to decline over time, but it
doesn't drop down as precipitously downstream as it does early
on, and I think that, just like with readmission, there's been
some data to suggest that near term readmission are more likely
things that "could be preventable" as opposed to maybe a
readmission toward the end of the month.


                                               
At the end of the day, it's a very difficult thing and there's a
lot more discussion that needs to be had about this topic, but I
think that with this, it gives me some hopefulness and I think
everybody else on this call that at least we wouldn't then be
able to prevent every adverse outcome that happens 2 years down
the road, but we might be able to at least affect a substantial
portion of them.


Dr Carolyn
Lam:               
Listeners, you heard it. There's lots that we can do. This paper
says a lot. Please do pick it up. Read the editorial as well.


                                               
Thank you so much for listening today, and don't forget to tune
in again next week.