This week we speak with Ohio State ACHD fellow Andrew Freddo MD, PhD about a recent large single center study he conducted assessing the cardiovascular drugs that adult Fontan patients are taking and whether they might offer us insights into general well-being. Are there agents that are associated with worse outcomes? If so, is this a situation of the agent causing harm or is it a possible marker of illness? Are there agents associated with improved outcomes? These are amongst the questions reviewed with Dr. Freddo this week.
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Speaker 1 (00:16):
Welcome to Pdheart Pediatric Cardiology Today. My name is doctor
Robert Pass and I'm the host of this podcast. I
am Professor of Pediatrics at the Icon School of Medicine
at Mount Sinai, where I am the chief of Pediatric Cardiology.
Thank you for joining me for this three hundred and
sixty first episode of Pdheart. I hope everybody enjoyed last
week's episode, in which we discussed the new Renata minimum stent.
(00:38):
For those of you interested in interventional pediatric cardiology, I'd
certainly recommend you tech to listen to last week's episode.
As I say most weeks, if you'd like to get
in touch with me, my email is easy to remember.
It's pdheart at gmail dot com. This week we move
into the world of adult congenital heart disease. The title
of the work we'll be reviewing is Cardiac medication prescription
(01:01):
pattern and Association with Transplant free Survival in the adult
Fontaine population. The first author of this work is Andrew
Fredo and the senior author Sumt Veikunth. And the authors
of this work come to us from the University of Pennsylvania.
When we're done reviewing this paper, doctor Fredo has graciously
agreed to speak with us about it. Therefore, let's move
(01:22):
straight onto this article and then a conversation with its
first author. The work starts with some general comments about
the fontine operation and the large numbers of adults who
now live with fontine circulation, and the authors bemoan the
absence of true guideline directed medical therapy based on high
level evidence, as is the case with acquired heart disease,
and they explain that this means that there's going to
(01:44):
be wide variability regarding how medications are prescribed in this
fontane patient group. They reference the few prospective trials in
fontine patients, specifically the Fontine fuel Trial and Rubato trials,
but these are few and far between. With this as
a background, the authors explained that the goal of this
work was to describe medications prescribed to patients with fontane
(02:06):
circulation at the University of Pennsylvania's ADHD Center to explore
the relationship between medication prescriptions and adverse outcomes. This was
a retrospective cohort analysis that reviewed fontanne patients at their
center between January two thousand and nine and December twenty
twenty three who had at least one patient encounter in
(02:26):
the outpatient ADHD center in that timeframe. If there were
greater than an equal to eighteen years of age at
the time of the visit, the outcome of interest was
transplant free survival and the author's review how all sorts
of data regarding these patients were obtained, including things like
liver assessments and a arrhythmias status for each patient. Medication
history was collected in non cardiac meds. Inpatient medications, and
(02:49):
pulmonary vase of dilators that were used for erectile dysfunction
were all removed from analysis. The authors explained that the
relationship of each cardiac med and transplant FARRE survival from
the first ADHD encounter was assessed, and then a sensitivity
analysis performed to assess the potential influence of several confounders
on the medication effect in a multi variable model and
(03:12):
onto the results. There were four hundred and twenty nine patients,
of which fifty five percent were male and fifty percent
had a single l V morphology, with a median age
of twenty four years at the time of the first
clinic visit. The median follow up time was four years,
with an intercortel range of one and a half to
seven years. The most common diagnosis was tricuspidatrecia in twenty
(03:32):
seven percent, and most common type of fontaine was a
lateral tunnel seen in fifty nine percent. And so what
was the most commonly prescribed medication in this cohort? It
was an antiplatelet agent and seventy five percent or three
hundred and twenty of the patients, followed by ACE inhibitors
in fifty two percent, and then loop diuretics in forty percent,
followed by metopolol and thirty two percent, and minerali corticoid
(03:55):
receptor antagonists or MRAs in thirty two percent. And what
happened to these patients?
Speaker 2 (04:01):
While the outcome of interest death or transplant occurred in
fifty five patients or thirteen percent, an overall transplant free
survival at five, ten and fifteen years after establishing ADHD
care was eighty eight percent, eighty percent, and sixty six percent, respectively.
Many different medications were found in univarid analysis to be
(04:21):
associated with worse outcomes, and using these data, a multivariable
model was developed to evaluate the relationship between medications and
transplant free survival and in this model, loop diuretic prescription
remained significant with the hazard ratio of about fifteen. And
what factors were significantly associated with loop diuretic prescription on
multivariable models, Well, it was heart failure with the hazard
(04:45):
ratio of two point sixty three. On multivariable analysis, there
was a significant inverse relationship between transplant free survival and
the comorbidities of systolic and distolic heart failure and liver cirrhosis,
which were significant. There is a terrific sense illustration looking
at the percentage of patients in the cohort of four
hundred and twenty nine adults with fontanes and specified medication classes,
(05:07):
and it shows the percentage of patients prescribed the different
agents and shows that loop diuretics were associated with a
nine point five hazard ratio of heart transplant or death
and that heart failure was similarly associated with heart transplant
or death with a hazard ratio of two point sixty three.
In their discussion, the author's state and I quote this
retrospective study reports one of the first large scale studies
(05:30):
of prescription patterns within the population of adults living with
Fontanne circulation at a single AHD center. We demonstrate a
significant negative association between loop diuretic prescriptions and transplant free
survival when accounting for patient comorbidities. No other medication class
showed a significant association with transplant free survival. The author's
(05:52):
review how this study shows much more medication usage amongst
these ACHD Fontanne patients than prior studies on child fontane papineas,
and they offer some thoughts as to why they might
be this difference. They bemoaned the low usage of more
novel heart failure therapies such as antiotensin receptor neprilicine inhibitor
agents less than one percent, or SGLT two inhibitors only
(06:17):
two percent, which are commonly used in the adult heart
failure population, but was used so rarely in this group,
despite twenty percent of these patients actually having heart failure.
The authors remind that though older patients and those with
liver cirrhosis and pl were more likely to be prescribed
loop diuretics, these comorbidities did not themselves explain the association
(06:37):
scene between loop diuretics and worse outcome. They did find, however,
that the prescription of loop diuretics and the presence of
congestive symptoms are most strongly associated with the sickest fontine
group when compared with other manifestations of fontine failure. They
review also how the use of doacts seemed to trend
with actual improved transplant free survival and was the only
(07:00):
agent that seems associated with possible improvement in outcomes on
univarible analysis. They review the hypercoaggubal state that we know
of existing in the fontane patient and suggest that more
data are needed in the future to confirm this possible trend.
In regard to limitations, the authors point to the single
center nature of this work that is retrospective and how
(07:20):
this quantinary referral center may not be generalizable to other
practice settings. There is also a bias of it being
an adult center, which by definition means that patients survive
to adulthood, which will obviously introduce bias. There is also
no data on medication adherents, only prescription of medication, and
they speak about other unknown confounders and so they conclude
(07:44):
this is one of the first large scale studies of
medications prescribed in adults living with fontan circulation. The most
common medications prescribed were anti platelet agents, ace ARBs, anticoagulants,
anti rhythmics, and diuretic agents. Loop diuretic agents had the
strongest association with transplant free survival. Patients prescribed loop diuretic
(08:07):
agents had significantly worse transplant free survival with and without
adjustments for patient comorbidities. Well, this is an interesting work
in that it seems to impugne the old fashioned loop
diuretic in bad outcomes with the Fontaine. Of course, the
obvious question is whether the loop diuretic prescription itself is
the cause of the worstening outcomes or simply a strong association.
(08:29):
What might be a primary manner in which these agents
cause problems for the fontine patient. I'm also intrigued by
the author's finding a possible reduction in risk for those
treated with doacts, and this might be worth conversation with
doctor Fredo. In the interest of time, therefore, I think
we should move forward with our conversation with the work's
first author, doctor Andrew Fredo. Joining us now to discuss
(08:51):
this week's work is the work's first author, doctor Andrew Fredo.
Doctor Fredo is presently an adult congenital heart fellow at
Ohio State. He's a graduate from the University of Michigan
for both his MD and PhD degrees, and he proceeded
to perform his Medpete's residency at the University of Pennsylvania,
followed by pediatric Cardiology fellowship at the Children's Hospital Philadelphia.
(09:13):
It is a delight to welcome him to the podcast.
Welcome doctor Fredo to Pdhart.
Speaker 3 (09:18):
I'm here now with doctor Andrew Fredo. Doctor Fredo, thank
you very much for joining me this week on Pdheart
Listen bovies. So much for having me, real great pleasure
to have you. Very much enjoyed your work. Congratulations to
you and all of your co investigators. You know, the
first question that came to mind as I was reading
this is to ask you what your thoughts are on
why it is that loop diuretics were associated with worse outcomes.
(09:42):
And you know, this is sort of a chicken or
the egg question. Do you believe that the medication itself
may be the cause of the worst outcomes reported or
do you think maybe it's just a marker of more
ill patience. And I wondered if there was a way
to ferret this out from your data and if it's
the medication itself might be the presumed mechanism for harm.
Speaker 4 (10:03):
No, that's definitely a question that plagued us throughout the study,
wondering if it's going to be the chicken or the egg,
and I think we really came down on the.
Speaker 5 (10:12):
Side of that.
Speaker 4 (10:12):
It's why the medication was prescribed, why patients were prescribed
to loop diuretic. So there does seem to be some
independent effect of loops diuretics having patients have a worse outcome.
We tried to figure this out with doing a sensitivity analysis,
seeing if we included other comorbidities or reasons that patients
were prescribed loop diuretics, such as heart failure, pl or
(10:34):
chronic kidney disease, if those would mitigate the effect of
loop diuretics on transplant free survival, and we still had
a significant effect. Actually, in Figure one of the paper,
we see that the Kaplan Miro curve still shows that
there's a pretty significant drop off for patients prescribed a
loop diuretic versus those who weren't, even when accounting for
these comorbidities. In spite of this, there probably is some
(10:57):
other factors that we're not accounting for. Other commerbatis that
we didn't measure or that we couldn't measure in other
confounding factors. But it is also important, I think, to
highlight in terms of mechanisms to the kind of the
second part of your question that Luke eiretics definitely have
a risk of decreasing pre load for our patients, and
we know that fontane patients are very pre low dependent.
(11:17):
So I think it maybe just highlights that we should
be thoughtful about using these medications and maybe not trying
to dry out our patients too much because that could,
for other reasons, cause warse outcomes.
Speaker 3 (11:28):
Yeah, well, good points. Thank you very much, very insightful.
I'm wondering if you could share with the audience you
know how you practically came to do this study. Many
of the listeners of the podcast are cardiology fellows or
residents who are interested in our field. How did you
come up with this idea? How difficult was it to
navigate the IRB processes and collect all these data?
Speaker 5 (11:50):
Definitely it was a very much of a journey.
Speaker 4 (11:53):
So I came into Piatric Cardiology fellowship knowing I wanted
to do AHD, so right when I arrived at a
chop By hit the ground running and looked for mentors
and found doctors Bankou than doctor Kim to be great
mentors in the ACHD research space. Initially, we actually were
planning to do a similar study using the OPTIM database,
which if you're not familiar, is like a more of
(12:14):
a medication claims database and would draw from data nationwide,
and we thought this would be a wonderful multi center
study and be awesome to get some of these descriptive data.
But unfortunately, the more we looked into it, the limitation
was that we didn't really know if patients that were
coded as fontan's were truly fontanes. And we had some
other other collaborators find that some patients who were coded
(12:36):
as having a fontane we're like seventy or eighty years old,
and that would seem very unlikely based on that, so
we decided to pivot and work on more of the
Singer single center study that you see here in this
in this manuscript. And fortunately the i RB study or
ib process was not too complicated. We were exempt under
(12:57):
under the i RB and so we were able to
collect data relatively easily or get started.
Speaker 5 (13:01):
On that process relatively easily.
Speaker 4 (13:03):
I think some of the challenges for me was since
I was new to a larger institution, and this definitely
speaks to how other fellows or residents may be moving
from one institution to another.
Speaker 5 (13:12):
You may not know what the resources are available to you.
Speaker 4 (13:16):
And so I think that was one of the challenges
I had was I didn't know what exactly all the
data collection, stats resources were at CHOPS. So I kind
of just started doing it myself and then asked for
help and forgiveness later. And I think just having that
kind of desire to jump in obviously once all the
logistical hurdles are are covered or surpassed, that you can
(13:39):
dive into the project without feeling like you're limited by
other factors that are out of your control. So I'm
really grateful that we were able to actually do this
as a single center study because we got all these
details that we would not have had.
Speaker 5 (13:53):
From a multi center study.
Speaker 4 (13:55):
And now, for the fellows and residents who may be listening,
a little plug for Single Ventuble Outcomes Network sv ONE
unformally the Fontaine Outcomes Network. They're actually a great multi
center learning collaborative that is allowing for multi center studies
to be using to be done using their data as well,
So I think there are some opportunities to use those
(14:16):
data and multi center data going forward that I didn't
have access to just a few years ago.
Speaker 3 (14:20):
Well, great points, Thanks so much for it. Sounds like
it was a challenge, but a lot of good support
that you had and a lot of motivation on your part,
good combination.
Speaker 5 (14:31):
You know.
Speaker 3 (14:32):
I was wondering, do acts seem to trend towards possible
improvement and long term outcomes in patients in this work,
and we're really alone in this regard amongst all the
different medicines you assessed in actually providing benefit. Can you
offer for us some thoughts on why it might possibly
reduce mortality in this patient group? And I also wondered
(14:52):
if you might be able to summarize a little bit
of what we know about the use of do acts
in fontine patients.
Speaker 4 (14:58):
Definitely something that really st out to me when we
were first analyzing this dad these dato is that you know,
everything had had a positive association transplant or death, and
this was the exception to the rule. I would say
that I would hesitate to make large, sweeping conclusions based
on this study that doucs have a true benefit because
(15:19):
A didn't statistical significance, but it was closer to doing so.
Speaker 3 (15:23):
And B.
Speaker 4 (15:24):
I think there probably are a lot of other factors
that were at work within the study period. We didn't
directly compare the patients who were on war from versus
those who were on DOACs, so I can't necessarily say
one versus the other, which patients were which, but I
can say that, you know, looking at when the DOACs
were prescribed, these tended to be patients prescribed do X
(15:45):
later on in our study period, which encompassed two thousand
and nine to twenty twenty four, so it allowed for
you know, maybe some recency bias, and like we were
using these medications more more in the recent years, potentially
also since have in the last few years become more
in vogue so to speak, a more commonly used in
the ACHD and specifically the fontane population. Probably some hesitancy
(16:08):
from people at our center and probably nationwide to use
these and sicker patients and maybe use these in lower
risk patients. So there may have been some self selecting
for the patients being prescribed DOAX. So I do hesitate
with those caveats to consider do X being a truly
protective effect. That being said, there is a lot of debate,
as I alluded to, about what anti coagulation to use
(16:30):
in our fontan patients. I was just at a meeting
and there was just kind of informal show of hands,
and it was really disparate the difference between patient people
who were always like on the Warfarne side of the coin,
as people were always on the do X side, are
more strongly on the doe Ex side of the coin.
For patients with fontan circulation without a mechanical valve, it's
definitely very split in the field.
Speaker 5 (16:52):
The studies have shown that.
Speaker 4 (16:53):
Do KX are non inferior to war for in anti coagulation,
so I think that definitely speaks to their potential utility
in our population and in adults with reduced dejection.
Speaker 5 (17:07):
Fraction with acquired heart disease.
Speaker 4 (17:08):
DOACs are the first line for needing needs for anti
coagulation if you don't have a mechanical valve. So I
think there's definitely this kind of a pendulum swing towards DOAX,
but we just don't don't know. I would say as
well that in terms of adherence, Warfaring, as we all
know is very challenging to maintain patients on high or
appropriate i in rs, and previous studies have shown that
(17:32):
it's better to be on a more consistent anti coagulation
regimen than to be on warf In with a poorly
controlled in R. So I think if you're concerned about
lab testing or other reasons that a patient may not
be able to maintain an appropriate in R with Warfarin,
even if you normally would reach for from maybe I
would reach for a DOAC instead.
Speaker 5 (17:51):
But it would be really great to see how.
Speaker 4 (17:52):
We kind of compare this comparing contrastics across multiple centers,
because like I said, each person in each center has
their own different way of conceptualizing coagulation.
Speaker 3 (18:01):
Yeah, I guess the coagulation is only as good as
if you use it. So yeah, Well, for those in
the audience, doctor Fredo was nice enough to speak with
us right at the start of a very busy day.
So I'm going to wrap it up here by just asking,
you know, it's often nice to ask the author, and
how should we, as the reader of this work use
these data to inform clinical decisions? Should we be avoiding
(18:25):
the use of luke diuretics? Should we just be thinking
maybe more about our patients who are needing them as
being at a higher risk. How do you think about
this in terms of individual patient of application.
Speaker 4 (18:38):
No, I think that that's an excellent question and something
to try to bring, you know, the words on the
page to the actual clinic and your clinical experience.
Speaker 5 (18:47):
I would say that probably for many who are.
Speaker 4 (18:50):
Been practicing ACHD MPs your curiolity for for years, there's
probably not many surprises from the paper.
Speaker 5 (18:57):
You know, of course, many.
Speaker 4 (18:58):
Of the medications that if your prescribes many pations in
our univariable analysis, you're probably gonna have a higher chance
of transplant or death. So I don't probably don't think
there's any you know, groundmaking things or a piece of
information on that part. What I think I would take away,
especially as someone who's new to AHD, this helps me
to really conceptualize when I meet a patient for the
(19:18):
first time, especially with fontane circulation.
Speaker 5 (19:20):
And they're on a diuretic. Why are they on a diuretic?
Speaker 4 (19:23):
Maybe if they were being followed every six months and
they need to be followed every three months, or are
we should we be talking more about transplant or other
later stages of fontanae circulation or fontane failure earlier on
versus versus later on in these patients. So I think
really it's kind of like a almost like a VPA
and epic if you're familiar with that, kind of like
a little like alert, say like okay, like take an
(19:45):
extra look at this patient and what else could be
going on that we're missing in the in the background.
I think obviously this in terms of markers is much
more of a reactive marker, seeing that someone had already
decided to put them.
Speaker 5 (19:59):
On a diuretic for one reason or another.
Speaker 4 (20:01):
Obviously, it would be wonderful for all of us to
have more proactive markers and look at more you know,
serier markets, which is what I'm hoping to do here
at Ohio State and my fellowship here to determine what
else we may be able to do to proactively determine
which patients are more at risk for fontane failure and
more on the road to transplant or end stage disease
compared with others. And then I think that will just
(20:24):
be really wonderful to move forward with the larger data networks,
like I said, sv one Network and other multi center
collaboratives to investigate outcomes, but recognizing that you lose some
of the granularity that you have with this single center study,
so I think that it should just serve as a
marker that something's not quite right, maybe not full alarm,
(20:44):
but just to be aware of and to make sure
that we're not missing anything.
Speaker 5 (20:50):
Kind of an extra thoroughness with those stations.
Speaker 3 (20:53):
Well, I'm very excited to hear about your new biomarker
work in the future. For those who listen to the
podcast than the past, you may recall that we had
Sasha Opatowski on the podcast, another Ohioan who spoke with
us about his groundbreaking work in that area, and so
very exciting that you're also interested in this fascinating world. Well,
(21:15):
doctor Fredo, I want to congratulate you once more and
I want to thank you so much for being so
kind as to speak with us this week on PD Heart.
Speaker 5 (21:22):
Really appreciate the invitation. Thank you again, and I hope
you have a wonderful day.
Speaker 3 (21:26):
Thank you so much.
Speaker 2 (21:27):
Well, once again, we have a wonderful up and coming
superstar on the podcast, and I'm sure you've found many
of doctor Fredo's comments to be insightful and thoughtful. I
thought that his notion of using the presence of a
loop diuretic with a single ventrical Fontanne patient as a
marker or possible alert of problems to be an important one.
As we discussed, there has been a lot of work
(21:48):
on intrinsic biomarkers for the evaluation or monitoring of the
font Hanne adult patient. But maybe this work has given
us a clue or a signal that this secondary marker
of a doctor having chosen to add a diuretic to
a Fontane patient's maintenance is a sign that someone thought
that there's trouble brewing, and this may prove to be
the lasting benefit or take home point of this week's work.
(22:11):
Once more, I'd like to thank doctor Fredo for taking
time to speak with us this week on Pede Heart.
To conclude this week's episode of p ed Heart, I'm
going to play another relevant to the Metropolitan Opera activity star,
this time the great American tenor Lawrence Brownlee. Mister Brownlee,
who has been featured previously on the podcast, had an
extraordinary last six weeks in which he was called at
(22:32):
last minute to sing the very difficult role of Elvino
in La Sonambula which is role. Mister Brownlee had not
sung previously in seven years, and he subbed in with
one day of preparation, and I was lucky enough to
see and enjoy that performance immensely. The reason he was
available was he was rehearsing with his co stars for
the opera Daughter of the Regiment by Donizetti that was
(22:55):
featured at the metch just two weeks later. And today
we hear him sing the show stopping a Mezsa me
highlighted by nine high seas, all sung with total vocal
security and brilliance by mister Brownlee, as you will hear
today in a live performance from over a decade ago.
Thank you very much for joining me for this three
hundred and sixty first episode, and thanks once again to
(23:15):
doctor Freda. I hope you'll have a good week ahead.
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Abdy iver Seen I, Spy Turn and Honey
Welcome to Pdheart Pediatric Cardiology Today. My name is doctor
Robert Pass and I'm the host of this podcast. I
am Professor of Pediatrics at the Icon School of Medicine
at Mount Sinai, where I am the chief of Pediatric Cardiology.
Thank you for joining me for this three hundred and
sixty first episode of Pdheart. I hope everybody enjoyed last
week's episode, in which we discussed the new Renata minimum stent.
(00:38):
For those of you interested in interventional pediatric cardiology, I'd
certainly recommend you tech to listen to last week's episode.
As I say most weeks, if you'd like to get
in touch with me, my email is easy to remember.
It's pdheart at gmail dot com. This week we move
into the world of adult congenital heart disease. The title
of the work we'll be reviewing is Cardiac medication prescription
(01:01):
pattern and Association with Transplant free Survival in the adult
Fontaine population. The first author of this work is Andrew
Fredo and the senior author Sumt Veikunth. And the authors
of this work come to us from the University of Pennsylvania.
When we're done reviewing this paper, doctor Fredo has graciously
agreed to speak with us about it. Therefore, let's move
(01:22):
straight onto this article and then a conversation with its
first author. The work starts with some general comments about
the fontine operation and the large numbers of adults who
now live with fontine circulation, and the authors bemoan the
absence of true guideline directed medical therapy based on high
level evidence, as is the case with acquired heart disease,
and they explain that this means that there's going to
(01:44):
be wide variability regarding how medications are prescribed in this
fontane patient group. They reference the few prospective trials in
fontine patients, specifically the Fontine fuel Trial and Rubato trials,
but these are few and far between. With this as
a background, the authors explained that the goal of this
work was to describe medications prescribed to patients with fontane
(02:06):
circulation at the University of Pennsylvania's ADHD Center to explore
the relationship between medication prescriptions and adverse outcomes. This was
a retrospective cohort analysis that reviewed fontanne patients at their
center between January two thousand and nine and December twenty
twenty three who had at least one patient encounter in
(02:26):
the outpatient ADHD center in that timeframe. If there were
greater than an equal to eighteen years of age at
the time of the visit, the outcome of interest was
transplant free survival and the author's review how all sorts
of data regarding these patients were obtained, including things like
liver assessments and a arrhythmias status for each patient. Medication
history was collected in non cardiac meds. Inpatient medications, and
(02:49):
pulmonary vase of dilators that were used for erectile dysfunction
were all removed from analysis. The authors explained that the
relationship of each cardiac med and transplant FARRE survival from
the first ADHD encounter was assessed, and then a sensitivity
analysis performed to assess the potential influence of several confounders
on the medication effect in a multi variable model and
(03:12):
onto the results. There were four hundred and twenty nine patients,
of which fifty five percent were male and fifty percent
had a single l V morphology, with a median age
of twenty four years at the time of the first
clinic visit. The median follow up time was four years,
with an intercortel range of one and a half to
seven years. The most common diagnosis was tricuspidatrecia in twenty
(03:32):
seven percent, and most common type of fontaine was a
lateral tunnel seen in fifty nine percent. And so what
was the most commonly prescribed medication in this cohort? It
was an antiplatelet agent and seventy five percent or three
hundred and twenty of the patients, followed by ACE inhibitors
in fifty two percent, and then loop diuretics in forty percent,
followed by metopolol and thirty two percent, and minerali corticoid
(03:55):
receptor antagonists or MRAs in thirty two percent. And what
happened to these patients?
Speaker 2 (04:01):
While the outcome of interest death or transplant occurred in
fifty five patients or thirteen percent, an overall transplant free
survival at five, ten and fifteen years after establishing ADHD
care was eighty eight percent, eighty percent, and sixty six percent, respectively.
Many different medications were found in univarid analysis to be
(04:21):
associated with worse outcomes, and using these data, a multivariable
model was developed to evaluate the relationship between medications and
transplant free survival and in this model, loop diuretic prescription
remained significant with the hazard ratio of about fifteen. And
what factors were significantly associated with loop diuretic prescription on
multivariable models, Well, it was heart failure with the hazard
(04:45):
ratio of two point sixty three. On multivariable analysis, there
was a significant inverse relationship between transplant free survival and
the comorbidities of systolic and distolic heart failure and liver cirrhosis,
which were significant. There is a terrific sense illustration looking
at the percentage of patients in the cohort of four
hundred and twenty nine adults with fontanes and specified medication classes,
(05:07):
and it shows the percentage of patients prescribed the different
agents and shows that loop diuretics were associated with a
nine point five hazard ratio of heart transplant or death
and that heart failure was similarly associated with heart transplant
or death with a hazard ratio of two point sixty three.
In their discussion, the author's state and I quote this
retrospective study reports one of the first large scale studies
(05:30):
of prescription patterns within the population of adults living with
Fontanne circulation at a single AHD center. We demonstrate a
significant negative association between loop diuretic prescriptions and transplant free
survival when accounting for patient comorbidities. No other medication class
showed a significant association with transplant free survival. The author's
(05:52):
review how this study shows much more medication usage amongst
these ACHD Fontanne patients than prior studies on child fontane papineas,
and they offer some thoughts as to why they might
be this difference. They bemoaned the low usage of more
novel heart failure therapies such as antiotensin receptor neprilicine inhibitor
agents less than one percent, or SGLT two inhibitors only
(06:17):
two percent, which are commonly used in the adult heart
failure population, but was used so rarely in this group,
despite twenty percent of these patients actually having heart failure.
The authors remind that though older patients and those with
liver cirrhosis and pl were more likely to be prescribed
loop diuretics, these comorbidities did not themselves explain the association
(06:37):
scene between loop diuretics and worse outcome. They did find, however,
that the prescription of loop diuretics and the presence of
congestive symptoms are most strongly associated with the sickest fontine
group when compared with other manifestations of fontine failure. They
review also how the use of doacts seemed to trend
with actual improved transplant free survival and was the only
(07:00):
agent that seems associated with possible improvement in outcomes on
univarible analysis. They review the hypercoaggubal state that we know
of existing in the fontane patient and suggest that more
data are needed in the future to confirm this possible trend.
In regard to limitations, the authors point to the single
center nature of this work that is retrospective and how
(07:20):
this quantinary referral center may not be generalizable to other
practice settings. There is also a bias of it being
an adult center, which by definition means that patients survive
to adulthood, which will obviously introduce bias. There is also
no data on medication adherents, only prescription of medication, and
they speak about other unknown confounders and so they conclude
(07:44):
this is one of the first large scale studies of
medications prescribed in adults living with fontan circulation. The most
common medications prescribed were anti platelet agents, ace ARBs, anticoagulants,
anti rhythmics, and diuretic agents. Loop diuretic agents had the
strongest association with transplant free survival. Patients prescribed loop diuretic
(08:07):
agents had significantly worse transplant free survival with and without
adjustments for patient comorbidities. Well, this is an interesting work
in that it seems to impugne the old fashioned loop
diuretic in bad outcomes with the Fontaine. Of course, the
obvious question is whether the loop diuretic prescription itself is
the cause of the worstening outcomes or simply a strong association.
(08:29):
What might be a primary manner in which these agents
cause problems for the fontine patient. I'm also intrigued by
the author's finding a possible reduction in risk for those
treated with doacts, and this might be worth conversation with
doctor Fredo. In the interest of time, therefore, I think
we should move forward with our conversation with the work's
first author, doctor Andrew Fredo. Joining us now to discuss
(08:51):
this week's work is the work's first author, doctor Andrew Fredo.
Doctor Fredo is presently an adult congenital heart fellow at
Ohio State. He's a graduate from the University of Michigan
for both his MD and PhD degrees, and he proceeded
to perform his Medpete's residency at the University of Pennsylvania,
followed by pediatric Cardiology fellowship at the Children's Hospital Philadelphia.
(09:13):
It is a delight to welcome him to the podcast.
Welcome doctor Fredo to Pdhart.
Speaker 3 (09:18):
I'm here now with doctor Andrew Fredo. Doctor Fredo, thank
you very much for joining me this week on Pdheart
Listen bovies. So much for having me, real great pleasure
to have you. Very much enjoyed your work. Congratulations to
you and all of your co investigators. You know, the
first question that came to mind as I was reading
this is to ask you what your thoughts are on
why it is that loop diuretics were associated with worse outcomes.
(09:42):
And you know, this is sort of a chicken or
the egg question. Do you believe that the medication itself
may be the cause of the worst outcomes reported or
do you think maybe it's just a marker of more
ill patience. And I wondered if there was a way
to ferret this out from your data and if it's
the medication itself might be the presumed mechanism for harm.
Speaker 4 (10:03):
No, that's definitely a question that plagued us throughout the study,
wondering if it's going to be the chicken or the egg,
and I think we really came down on the.
Speaker 5 (10:12):
Side of that.
Speaker 4 (10:12):
It's why the medication was prescribed, why patients were prescribed
to loop diuretic. So there does seem to be some
independent effect of loops diuretics having patients have a worse outcome.
We tried to figure this out with doing a sensitivity analysis,
seeing if we included other comorbidities or reasons that patients
were prescribed loop diuretics, such as heart failure, pl or
(10:34):
chronic kidney disease, if those would mitigate the effect of
loop diuretics on transplant free survival, and we still had
a significant effect. Actually, in Figure one of the paper,
we see that the Kaplan Miro curve still shows that
there's a pretty significant drop off for patients prescribed a
loop diuretic versus those who weren't, even when accounting for
these comorbidities. In spite of this, there probably is some
(10:57):
other factors that we're not accounting for. Other commerbatis that
we didn't measure or that we couldn't measure in other
confounding factors. But it is also important, I think, to
highlight in terms of mechanisms to the kind of the
second part of your question that Luke eiretics definitely have
a risk of decreasing pre load for our patients, and
we know that fontane patients are very pre low dependent.
(11:17):
So I think it maybe just highlights that we should
be thoughtful about using these medications and maybe not trying
to dry out our patients too much because that could,
for other reasons, cause warse outcomes.
Speaker 3 (11:28):
Yeah, well, good points. Thank you very much, very insightful.
I'm wondering if you could share with the audience you
know how you practically came to do this study. Many
of the listeners of the podcast are cardiology fellows or
residents who are interested in our field. How did you
come up with this idea? How difficult was it to
navigate the IRB processes and collect all these data?
Speaker 5 (11:50):
Definitely it was a very much of a journey.
Speaker 4 (11:53):
So I came into Piatric Cardiology fellowship knowing I wanted
to do AHD, so right when I arrived at a
chop By hit the ground running and looked for mentors
and found doctors Bankou than doctor Kim to be great
mentors in the ACHD research space. Initially, we actually were
planning to do a similar study using the OPTIM database,
which if you're not familiar, is like a more of
(12:14):
a medication claims database and would draw from data nationwide,
and we thought this would be a wonderful multi center
study and be awesome to get some of these descriptive data.
But unfortunately, the more we looked into it, the limitation
was that we didn't really know if patients that were
coded as fontan's were truly fontanes. And we had some
other other collaborators find that some patients who were coded
(12:36):
as having a fontane we're like seventy or eighty years old,
and that would seem very unlikely based on that, so
we decided to pivot and work on more of the
Singer single center study that you see here in this
in this manuscript. And fortunately the i RB study or
ib process was not too complicated. We were exempt under
(12:57):
under the i RB and so we were able to
collect data relatively easily or get started.
Speaker 5 (13:01):
On that process relatively easily.
Speaker 4 (13:03):
I think some of the challenges for me was since
I was new to a larger institution, and this definitely
speaks to how other fellows or residents may be moving
from one institution to another.
Speaker 5 (13:12):
You may not know what the resources are available to you.
Speaker 4 (13:16):
And so I think that was one of the challenges
I had was I didn't know what exactly all the
data collection, stats resources were at CHOPS. So I kind
of just started doing it myself and then asked for
help and forgiveness later. And I think just having that
kind of desire to jump in obviously once all the
logistical hurdles are are covered or surpassed, that you can
(13:39):
dive into the project without feeling like you're limited by
other factors that are out of your control. So I'm
really grateful that we were able to actually do this
as a single center study because we got all these
details that we would not have had.
Speaker 5 (13:53):
From a multi center study.
Speaker 4 (13:55):
And now, for the fellows and residents who may be listening,
a little plug for Single Ventuble Outcomes Network sv ONE
unformally the Fontaine Outcomes Network. They're actually a great multi
center learning collaborative that is allowing for multi center studies
to be using to be done using their data as well,
So I think there are some opportunities to use those
(14:16):
data and multi center data going forward that I didn't
have access to just a few years ago.
Speaker 3 (14:20):
Well, great points, Thanks so much for it. Sounds like
it was a challenge, but a lot of good support
that you had and a lot of motivation on your part,
good combination.
Speaker 5 (14:31):
You know.
Speaker 3 (14:32):
I was wondering, do acts seem to trend towards possible
improvement and long term outcomes in patients in this work,
and we're really alone in this regard amongst all the
different medicines you assessed in actually providing benefit. Can you
offer for us some thoughts on why it might possibly
reduce mortality in this patient group? And I also wondered
(14:52):
if you might be able to summarize a little bit
of what we know about the use of do acts
in fontine patients.
Speaker 4 (14:58):
Definitely something that really st out to me when we
were first analyzing this dad these dato is that you know,
everything had had a positive association transplant or death, and
this was the exception to the rule. I would say
that I would hesitate to make large, sweeping conclusions based
on this study that doucs have a true benefit because
(15:19):
A didn't statistical significance, but it was closer to doing so.
Speaker 3 (15:23):
And B.
Speaker 4 (15:24):
I think there probably are a lot of other factors
that were at work within the study period. We didn't
directly compare the patients who were on war from versus
those who were on DOACs, so I can't necessarily say
one versus the other, which patients were which, but I
can say that, you know, looking at when the DOACs
were prescribed, these tended to be patients prescribed do X
(15:45):
later on in our study period, which encompassed two thousand
and nine to twenty twenty four, so it allowed for
you know, maybe some recency bias, and like we were
using these medications more more in the recent years, potentially
also since have in the last few years become more
in vogue so to speak, a more commonly used in
the ACHD and specifically the fontane population. Probably some hesitancy
(16:08):
from people at our center and probably nationwide to use
these and sicker patients and maybe use these in lower
risk patients. So there may have been some self selecting
for the patients being prescribed DOAX. So I do hesitate
with those caveats to consider do X being a truly
protective effect. That being said, there is a lot of debate,
as I alluded to, about what anti coagulation to use
(16:30):
in our fontan patients. I was just at a meeting
and there was just kind of informal show of hands,
and it was really disparate the difference between patient people
who were always like on the Warfarne side of the coin,
as people were always on the do X side, are
more strongly on the doe Ex side of the coin.
For patients with fontan circulation without a mechanical valve, it's
definitely very split in the field.
Speaker 5 (16:52):
The studies have shown that.
Speaker 4 (16:53):
Do KX are non inferior to war for in anti coagulation,
so I think that definitely speaks to their potential utility
in our population and in adults with reduced dejection.
Speaker 5 (17:07):
Fraction with acquired heart disease.
Speaker 4 (17:08):
DOACs are the first line for needing needs for anti
coagulation if you don't have a mechanical valve. So I
think there's definitely this kind of a pendulum swing towards DOAX,
but we just don't don't know. I would say as
well that in terms of adherence, Warfaring, as we all
know is very challenging to maintain patients on high or
appropriate i in rs, and previous studies have shown that
(17:32):
it's better to be on a more consistent anti coagulation
regimen than to be on warf In with a poorly
controlled in R. So I think if you're concerned about
lab testing or other reasons that a patient may not
be able to maintain an appropriate in R with Warfarin,
even if you normally would reach for from maybe I
would reach for a DOAC instead.
Speaker 5 (17:51):
But it would be really great to see how.
Speaker 4 (17:52):
We kind of compare this comparing contrastics across multiple centers,
because like I said, each person in each center has
their own different way of conceptualizing coagulation.
Speaker 3 (18:01):
Yeah, I guess the coagulation is only as good as
if you use it. So yeah, Well, for those in
the audience, doctor Fredo was nice enough to speak with
us right at the start of a very busy day.
So I'm going to wrap it up here by just asking,
you know, it's often nice to ask the author, and
how should we, as the reader of this work use
these data to inform clinical decisions? Should we be avoiding
(18:25):
the use of luke diuretics? Should we just be thinking
maybe more about our patients who are needing them as
being at a higher risk. How do you think about
this in terms of individual patient of application.
Speaker 4 (18:38):
No, I think that that's an excellent question and something
to try to bring, you know, the words on the
page to the actual clinic and your clinical experience.
Speaker 5 (18:47):
I would say that probably for many who are.
Speaker 4 (18:50):
Been practicing ACHD MPs your curiolity for for years, there's
probably not many surprises from the paper.
Speaker 5 (18:57):
You know, of course, many.
Speaker 4 (18:58):
Of the medications that if your prescribes many pations in
our univariable analysis, you're probably gonna have a higher chance
of transplant or death. So I don't probably don't think
there's any you know, groundmaking things or a piece of
information on that part. What I think I would take away,
especially as someone who's new to AHD, this helps me
to really conceptualize when I meet a patient for the
(19:18):
first time, especially with fontane circulation.
Speaker 5 (19:20):
And they're on a diuretic. Why are they on a diuretic?
Speaker 4 (19:23):
Maybe if they were being followed every six months and
they need to be followed every three months, or are
we should we be talking more about transplant or other
later stages of fontanae circulation or fontane failure earlier on
versus versus later on in these patients. So I think
really it's kind of like a almost like a VPA
and epic if you're familiar with that, kind of like
a little like alert, say like okay, like take an
(19:45):
extra look at this patient and what else could be
going on that we're missing in the in the background.
I think obviously this in terms of markers is much
more of a reactive marker, seeing that someone had already
decided to put them.
Speaker 5 (19:59):
On a diuretic for one reason or another.
Speaker 4 (20:01):
Obviously, it would be wonderful for all of us to
have more proactive markers and look at more you know,
serier markets, which is what I'm hoping to do here
at Ohio State and my fellowship here to determine what
else we may be able to do to proactively determine
which patients are more at risk for fontane failure and
more on the road to transplant or end stage disease
compared with others. And then I think that will just
(20:24):
be really wonderful to move forward with the larger data networks,
like I said, sv one Network and other multi center
collaboratives to investigate outcomes, but recognizing that you lose some
of the granularity that you have with this single center study,
so I think that it should just serve as a
marker that something's not quite right, maybe not full alarm,
(20:44):
but just to be aware of and to make sure
that we're not missing anything.
Speaker 5 (20:50):
Kind of an extra thoroughness with those stations.
Speaker 3 (20:53):
Well, I'm very excited to hear about your new biomarker
work in the future. For those who listen to the
podcast than the past, you may recall that we had
Sasha Opatowski on the podcast, another Ohioan who spoke with
us about his groundbreaking work in that area, and so
very exciting that you're also interested in this fascinating world. Well,
(21:15):
doctor Fredo, I want to congratulate you once more and
I want to thank you so much for being so
kind as to speak with us this week on PD Heart.
Speaker 5 (21:22):
Really appreciate the invitation. Thank you again, and I hope
you have a wonderful day.
Speaker 3 (21:26):
Thank you so much.
Speaker 2 (21:27):
Well, once again, we have a wonderful up and coming
superstar on the podcast, and I'm sure you've found many
of doctor Fredo's comments to be insightful and thoughtful. I
thought that his notion of using the presence of a
loop diuretic with a single ventrical Fontanne patient as a
marker or possible alert of problems to be an important one.
As we discussed, there has been a lot of work
(21:48):
on intrinsic biomarkers for the evaluation or monitoring of the
font Hanne adult patient. But maybe this work has given
us a clue or a signal that this secondary marker
of a doctor having chosen to add a diuretic to
a Fontane patient's maintenance is a sign that someone thought
that there's trouble brewing, and this may prove to be
the lasting benefit or take home point of this week's work.
(22:11):
Once more, I'd like to thank doctor Fredo for taking
time to speak with us this week on Pede Heart.
To conclude this week's episode of p ed Heart, I'm
going to play another relevant to the Metropolitan Opera activity star,
this time the great American tenor Lawrence Brownlee. Mister Brownlee,
who has been featured previously on the podcast, had an
extraordinary last six weeks in which he was called at
(22:32):
last minute to sing the very difficult role of Elvino
in La Sonambula which is role. Mister Brownlee had not
sung previously in seven years, and he subbed in with
one day of preparation, and I was lucky enough to
see and enjoy that performance immensely. The reason he was
available was he was rehearsing with his co stars for
the opera Daughter of the Regiment by Donizetti that was
(22:55):
featured at the metch just two weeks later. And today
we hear him sing the show stopping a Mezsa me
highlighted by nine high seas, all sung with total vocal
security and brilliance by mister Brownlee, as you will hear
today in a live performance from over a decade ago.
Thank you very much for joining me for this three
hundred and sixty first episode, and thanks once again to
(23:15):
doctor Freda. I hope you'll have a good week ahead.
Speaker 6 (23:19):
Cos okay, heard you want to love honestee, Hon Haiding.
Speaker 3 (24:00):
He's Essa is one that I'm aware to go.
Speaker 7 (24:08):
We know that is fallible.
Speaker 6 (24:19):
I mess, I need casual and not hatter should be.
Speaker 4 (24:22):
But she's a.
Speaker 7 (24:25):
Mess.
Speaker 6 (24:25):
I need counsel and not hatter should be. When she's
warm and Jenny, she's any hoss, honey should be.
Speaker 7 (24:41):
She war.
Speaker 6 (24:45):
Drove, Oh say so no, it's any song.
Speaker 7 (25:14):
Sort spell.
Speaker 3 (25:18):
My c.
Speaker 7 (25:24):
Mey change.
Speaker 3 (25:40):
It's so.
Speaker 7 (25:47):
So said.
Speaker 3 (25:55):
For this.
Speaker 7 (26:00):
Mister s Su, I'm not so sure grows.
Speaker 3 (26:14):
It was.
Speaker 7 (26:16):
MEI ebody end can mister.
Speaker 6 (26:30):
S Sad song, I was seen iver Se Beauty Turn
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