October 3, 2025 • 34 mins
This week we review a recent multicenter, randomized trial pitting 2 different immunosuppressive therapeutic approaches against each other. How did a novel approach of everolimus + low dose tacrolimus compare to more standard MMF + standard, higher dose tacrolimus in avoidance of major adverse transplant events or complications? How did this first ever prospective trial in the pediatric heart transplantation world start and how difficult was it to perform in the absence of corporate or NIH support? Why can these data help inform FDA labelling for this novel approach and why is this important? Dr. Kevin Daly of Boston Children's Hospital shares his deep insights into this work this week!
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Episode Transcript
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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'm also the Chief of Pediatric Cardiology.
Thank you for joining me for this three hundred and
fifty seventh episode of Pdheart. I hope everybody enjoyed last
week's episode on the topic of alpha blockade following congeneral
(00:38):
heart surgery. For those of you interested in post operative
care of children following congeneral heart surgery, i'd certainly recommend
you take a listen to last week's episode three hundred
and fifty six. 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 on to the world of cardiac transplantation
(00:58):
and we review a very very important paper. The title
of the work will be reviewing is a Vera Limis
and low dose tacra limis after heart transplant in Children,
a randomized clinical trial. The first author of this work
is Christopher Ahmand, as well as Kevin Daley and the
senior author, Lynn Sleeper on behalf of the teammate trial investigators.
(01:20):
The first author comes to us from Stanford University, and
doctor Daly and doctor Sleeper from Boston Children's Hospital, Harvard University.
When we're done reviewing this paper, I am hopeful that
doctor Daly will be able to join us to discuss
this week's work. Therefore, let's move straight onto this article
and then a conversation with one of its authors. This
week's work begins with some general comments about pediatric heart transplantation,
(01:44):
reviewing that the median survival is about fifteen years and
that there are basically six major ways that allographs are lost,
and these include acute cellular rejection, antibody mediated rejection, infection,
cardiac alligraph vasculopathy, post trans plants, lymphoproliferative disorders, and chronic
kidney disease. The authors explain that a combination of tacrilmus,
(02:07):
which is a calcineurine inhibitor that works to prevent T
cell activation, and mycophenolate mophatyl or MMF have been used
to maintain imminosuppression for nearly twenty years, and the authors
explain that this approach has reduced early mortality after a transplant,
but has not affected longer term survival. The authors then
explain that the m TOR inhibitor a via limis in
(02:30):
combination with lower dose tacrilimits has been shown in adults
to reduce the risk of several transplant complications like carnary
artery vasculopathy, worsening of kidney function, and CMB infection in
the adult's heart transplant patient. The authors review how avia
limis earned a black box warning from the FDA about
its use in heart transplant patients because it was associated
(02:53):
with a higher occurrence of early infections after transplant. What
is not known in children is whether avia limis is
safe if and effective with lower dose tacrileimis if introduced
about six months post transplant, after the peak risk for
post surgical infections and wound healing complications of past With
this as a background, the authors explained that the primary
(03:14):
objective of this randomized trial was to determine whether a
viur limis combined with low dose tacrilemis is more effective
than tacrilimis and mycophenolate in preventing acute cellular rejection caronary
artery vasculopathy and chronic kidney disease in six month survivors
after pediatric heart transplant, and to determine if the regiment
(03:35):
is safe in preventing six major transplant events at thirty months.
The authors also mention that because no rejection medicines or
FDA approved for post cart transplant prophylaxis in children, a
secondary goal was to generate sufficient regulatory data to potentially
get FDA approval for the first rejection prophylaxis regimen for
the pediatric heart transplant patient. This was a phase three
(03:58):
multi centre open label RAMIE so called active comparator trial
in which a vera limits with low dose tacrolimits was
compared with standard higher dose tacro plus micofenolate among six
month survivors after pediatric heart transplant. And this was the
so called TEAMMATE trial which stands for Major Adverse Transplant
(04:19):
Events score. Trial participants were randomized one to one to
receive either of the two approaches, which will call the
evera limus group versus the micofenylate group. Again, this was
open label, so both investigators and subjects were aware of
what they were receiving. The dosing of the medications is
listed in the protocol, but suffices to say that the
tacro dosing was basically set to achieve trough levels that
(04:42):
were approximately one half of the levels in the micofenylate group.
For those interested in the details of the dosing, please
do read the paper and it's on page two that
this is described, and the link to the paper will
be in the show notes. For this work, there were
two primary outcomes. The first was the MATE three score
assessing a proch efficacy the cumulative burden, frequency and severity
(05:05):
of acute cellular rejection, coronary ardor evasculopathy, and chronic kidney disease.
The second was a primary safety outcome or the so
called six mates, which is the three MATE three events
of acute cellular rejection, carnary argoryvasculopathy, and chronic kidney disease
plus antibiody mediator rejection, infection and post transplant lymphoproliferative disorders.
(05:27):
The authors also assessed risk for CMV, since the use
of a vera liimis is associated with a lower risk
for CMB infection. The authors review the statistical approaches used
to analyze these data and suffice it to say that
it was quite robust, and I would once more suggest
that the listener take a look at the paper for
the granular details and toughts of the results. There were
(05:48):
two hundred and eleven children from twenty five US centers
who were more than are equal to six month post
transplant who were randomized to receive either a vera limis
plus low dose tacro, of which there were were one
hundred and seven patients, or standard tacro plus MMF, of
which there were one hundred and four patients. Follow Up
was thirty months in this work. The average age was
(06:10):
eight point two years, and nearly one quarter were treated
for rejection prior to enrollment in this study. During the study,
there were six deaths and three retransplants for a total
of nine graft failures, and four were in the evera
limus group and five in the macofenolate one. I've reminded
that there are many details and findings in this work
(06:30):
and would certainly recommend that those interested in these details
read this masterful work. However, here's my summary of what
I believe are probably the most critical findings and what
you're probably dying to know. What was the outcome well
in regards to the primary outcomes the MATE III looking
at efficacy, which I remind again was largely focused on efficacy,
specifically looking at rejection, carnary artery, vasculopathy, and kidney disease.
(06:55):
The study showed no difference between the Evera limus and
micofenylate groups. Set a different way. At thirty months, a
Vera limis and low dose tacro was not superior to
tacro plus MMF for the composite of rejection, carnary vasculopathy
or chronic kidney disease. In regards to the other primary outcome,
(07:16):
the May six assessing safety, in which the model added
antibody mediator, rejection infection, and PTLD, there were no differences
in graph survival, may free survival, or freedom from any
individual MATE, which again stands for major adverse transplant event.
Now we know from adult works that a Vera limis
(07:36):
plus low dose tacro would be expected to possibly have
less nephrotoxicity than the more traditional tacro dosing approach, and
so was this borne out in this work?
Speaker 2 (07:46):
Why?
Speaker 1 (07:46):
Yes, it was. The Evera limis arm had a greater
improvement in EGFR at twelve months, with a mean difference
of ten and a half millileaters per minute one point
seventy three meters squared. The other concern would be CMB
infection rates differing, since using lower dose tacro might be
thought to be a way of reducing CMB infection and yes, indeed,
(08:07):
in this work, there was a lower incidence of CMV
infection in the Everilimis arm with a hazard ratio of
zero point five zero, and so, to summarize, initiating a
vierilimits plus low dose tacrilymis at greater than equal to
six months post heart transplantation in children appeared to be
safe by the composite safety metric and not inferior with
(08:29):
respect to major transplant events, but it did not show
superiority for the primary efficacy. Composite potential advantages observed were
better short term renal function at twelve months unless CMB infection.
Findings that may make the regimen attractive for patients at
risk for calcinurine nephrotoxicity or CMV, but the regiment is
(08:51):
not demonstrated to reduce rejection, carnary artery vasculopathy or chronic
kidney disease over thirty months. To quote the authors in
their discuss In this study amongst six month survivors after
pediatric heart transplantation, evera limis and low dose tacrilemits did
not differ from tacylimis and mycophenolate in preventing the composite
(09:13):
endpoint of cellular rejection, coronary artery vasculopathy, and chronic kidney disease. However,
the regiment appears to be safe based on the total
burden of six mates at thirty months. In exploratory analyzes,
evera limis appeared to be associated with less CMB infection
and a lower rate of HLA sensitization, but higher rates
(09:35):
of stomatitis and hyperlipidemia. Drug tolerability was similar overall in
the two treatment groups, but differed with regard to specific
adverse events. The authors speak about how this teammate trial
almost never happened, as there was no industry support for
the trial and there was not even donation of medication
from the companies who manufacture the agents, which meant that
(09:56):
there was a built in seven million dollar cost for
this project from medication alone. Thankfully, health insurers paid for
the drugs for the vast majority of the patients. Some
of the limitations of this work art's open label design
and follow up of only thirty months, meaning we don't
know the long term impact on graph survival of this approach. Also,
the trial excluded very early post transplant initiation of evera limmis,
(10:20):
meaning less than six months, due to prior safety concerns
for infection, and so they conclude in summary among six
month survivors after pediatric heart transplant, evera limis and low
dose tacrilemas did not differ from tacrilemits at microphenolate in
preventing the composite endpoint of acute cellular rejection, carnary artery vasculopathy,
(10:40):
and chronic kidney disease. However, the regiment appeared to be
safe based on the total burden of six mates at
thirty months. Although evera limis was not associated with an
improvement in exploratory outcomes such as patient and graph survival,
mate free survival, or individual mates, vera limis may be
associated with kidney function, less CMV infection and a lower
(11:03):
rate of the composite endpoint of acute cellular rejection, carnary
artery vasculopathy, chronic kidney disease and CMB infection. Participants randomized
to a vera limits were more likely to develop apty
stomatitis and hyperlibidemia, complications that the investigators found to be
manageable in children. These findings informed clinical decisions and regulatory
(11:25):
considerations regarding the safe and effective use of vera limis
with low dose tacro in children after heart transplantation. Well,
this is simply an awesome trial, a match and basically
no industry support other than governmental grants to conduct a study,
including twenty five US centers, this is an extraordinary achievement
(11:45):
and when you look at the numbers of heart failure
transplant doctors who were involved in this study, it's amazing.
Basically every pediatric heart transplant doctor in the US worked
on this, but wow, what a testament to cooperation. I
think that this might be the most important lesson of
this work, maybe even as great as the critically important
data that these devoted physicians have determined. This is an
(12:07):
example where if there is a will, there is a way,
And I am sure that you share my admiration for
our heart failure and transplant colleagues who have been so
far ahead of the curve on the notion of multi
center work to advance the science of cardiology. I wonder
if the authors are using these data for FDA approval,
and so that will certainly be amongst the questions will
(12:28):
be interested in asking of doctor Daly in our interview
to follow. In the interests of time, I think we
should move forward to our conversation with one of the
works authors, Doctor Kevin Daly, joining us now to discuss
the work. Is a system professor of pediatrics at Harvard
Medical School. Doctor Kevin Dally, doctor Day, is the medical
director of the Heart Transplant Program and Associate cardiologist in
(12:50):
the Department of Cardiology at Boston Children's Hospital. He is
a graduate of Harvard for undergraduate work followed by medical
school at Columbia University following this. He can plead it
is categorical residency in pediatrics at montsif your medical center,
and then did general cardiology and heart failure transplant fellowships
at Boston Children's Hospital. It is a delight to welcome
(13:11):
him to the podcast. Welcome Kevin to PD Heart.
Speaker 3 (13:14):
I'm here now with doctor Kevin Daily of Boston Children's Hospital. Kevin,
thank you very much. For joining me this week on
pd heart. Thanks so much for having me real pleasure.
Sometimes when I'm starting these interviews, I'll ask the author
of the work if they might be able to summarize
for the audience what you believe, as the author, are
maybe the most important three or four findings of this
really massive undertaking.
Speaker 4 (13:36):
Yeah, thanks very much.
Speaker 5 (13:38):
I think that the most important is that both the
regimens of tackri limas and michael fedalite mofatil or everlynmus
with low dose tackri limas are both safe and effective
immunisuppression regimens that can be used after transplanting children. While
everlymus and low dose tackrilemas was not superior at preventing
the composite endpoint of coronary disease cellular rejection in kidney disease,
(14:02):
it was superior at preventing the secondary endpoint when CMV
infection was included, which does represent a significant important virus
in the care of transplant patients. In terms of adverse events,
drug discontinuation was slightly higher in the tacrilimus and microphenolate group,
with about twenty one percent discontinuing compared to fourteen percent
(14:25):
in the ever alignments group, and the ever alignmis group
was associated with improved kidney function early.
Speaker 6 (14:30):
In the study.
Speaker 5 (14:31):
That difference did narrow toward the end of the study period,
probably because the tacrilimas levels started to come closer together
between the two regiments, and ever alimis did have an
association with a lower prevalence of anti HLA ant bodies
at the end of the study. I would note that
it's important to educate patients and parents that approximately thirty
(14:53):
percent of the patients and the ever alignmis group did
experience mouth ulcers, which is.
Speaker 6 (14:57):
A manageable side effect that we found during this but
it is an important one to consider.
Speaker 3 (15:03):
Really interesting. Thank you that really crystallized the paper so nicely.
Really appreciate that.
Speaker 4 (15:10):
Kevin.
Speaker 3 (15:10):
Can you speak about the genesis of this problem, of
this project rather and what the major hurdles were to
proceeding with this really impressive perspective trial and maybe comment
on why this was actually and correct me if I'm wrong,
but I believe this is the first such perspective trial
in the pediatric heart transplant literature on immunosuppression for children
after a heart transplant.
Speaker 5 (15:32):
Yeah, absolutely, This was a tremendous effort by the pediatric
heart transplant community. As with any study of this magnitude,
there's always a story, and it started actually with a
conversation that a bunch of us were having at the
International Society of Heart Lung Transplant meeting back in twenty fourteen.
(15:53):
We were sitting at the bar and talking about how
we didn't want to just listen to another retrospective, registry
based study and its implications for clinical care, and we
really wanted to set out to define what the most
important questions we could answer where the prospective study were.
So we really were energized at that meeting and subsequent
(16:16):
discussions after that led to a trial comparing outcomes using
proliferation signal inhibitors as part of rejection prophylaxis. The story
then evolves, right, we in order to fund this kind
of a study, you need an endpoint that can power
a relatively small pedetric card transplant trial. So we worked
(16:38):
with the PHTS to develop the MATE score right, which
combines six major transplant events including infection, coronary disease, kidney
disease PTLD, and the two types of rejection, and we
showed that the higher the mate score, the higher the
risk of allograph loss.
Speaker 4 (16:57):
We then took that to.
Speaker 6 (17:00):
The FDA and had created a study protocol.
Speaker 5 (17:03):
And we asked for their input and they provided us
some feedback on their study design. And then the next step, obviously,
is to get the study funded. And that was a
bunch of unsuccessful attempts. He applied to the FDA, we
were unsuccessful. We applied to the NIH, we were unsuccessful.
And finally we applied to the US Department of Defense
(17:24):
Clinical Trials Grant program, and we were successful and they
wound up studying.
Speaker 6 (17:31):
Or funding the study.
Speaker 3 (17:33):
Wow. Yeah, I was really taken aback by reading that
you did not have any commercial support for this study.
That must have been a very depressing finding when you
were considering doing this trial, that Noah wanted to pay
for it such an important trial. I guess ultimately the
small usage in children relative to adults probably was part
(17:56):
of their thought process.
Speaker 4 (17:57):
I'm guessing, yeah, that was part of it. You know.
Speaker 6 (18:01):
There's a couple of actual really interesting.
Speaker 4 (18:03):
Things in that question.
Speaker 5 (18:05):
One is that the manufacturer of ever alignments actually there's
a black box warning for use in adult heart transplantation
because of an increased incidence of early infection that was
noted in the adult transplant studies, so I think they
were a little bit wary about studying the drug and
kids if there were similar adverse events.
Speaker 6 (18:26):
We mitigated that risk by starting the drug six.
Speaker 5 (18:28):
Months after transplant, and we actually didn't see a significantly
increased risk of serious infection. But the other thing is
that the incentives for the drug companies are not.
Speaker 6 (18:38):
Really there for orphan diseases.
Speaker 5 (18:41):
While the Best Pharmaceuticals for Children's Act does provide six
months of patent exclusivity as sponsors for doing pediatric studies,
oftentimes the FD only requires one pediatric study and they
usually will choose kidney transplant if it's a transplant related drug,
and pediatric hard transplant kind of gets forgotten.
Speaker 4 (19:00):
I see.
Speaker 3 (19:01):
I wondered Kevin as I was reading this that it
seemed that evera Limus treated patients did as well or
maybe in some ways better than the more traditional MMF
patients who can also get tecro. And how do you
think the trial's outcomes will affect management in pediatric transplant patients.
I'm wondering if you might be able to share with
(19:22):
the audience, like what is the present most commonly used approach,
and do you think that the data from this study
are going to justify a change of this approach or
maybe has that already happened.
Speaker 5 (19:32):
Yeah, so I think that's fascinating. Tacrolemis and micopenalley remain
the most commonly used immunu suppression, especially right after transplant,
but I think that this trial really provides strong evidence
that at four to six months after transplant you can
consider a switch and that there are some potential long
term benefits.
Speaker 4 (19:52):
Ever alimmis with.
Speaker 5 (19:54):
Lotos TAC was superior at preventing the composite of a
post transplant cornerary disease, cellular rejection of kidney disease, and
CMV and the lower rate of coronary disease in the
composite endpoint is quite promising because this is a major
complication that contributes to alligraph loss. And the finding was
not unexpected because the adult studies did demonstrate that ever
(20:15):
alenis was associated with lower rates of CAV and they
actually measured that using intravascular ultrasound, something that we were
unable to do in our trial because of the size
of the catheter in most of the patients enroll. So
we think that ever Alenas and lotus tacklelemas is definitely
a regimen that should be considered. One of the things
that we found very interesting in randomizing and consenting patients
(20:39):
is that sometimes at six months after transplant, families and
kids and teenagers in particular were happy with the medicine
they were on. They say, I feel pretty good and
I don't really want to change, and so I think
that'll be a continued barrier, but hopefully this data will
convince some of them that this may be a more
superior regimen for the longer term.
Speaker 3 (20:59):
I see, well, this study only has data to thirty months,
which is still quite impressive, but it's you know, for
a child, maybe not that long. I wondered if there's
a plan to extend the length of this study, continue
to follow this cohort even longer. And I wondered, has
this already been done in adult heart transplant patients, And
(21:21):
do we know if this approach is equivalently excellent for
longer term use for heart transplants in general.
Speaker 5 (21:30):
Yeah, so we definitely do intend to collect five and
seven year follow up data. As you mentioned, we did
follow the cohort for thirty months. There's always some pluses
and minuses to that type of long term follow up.
Speaker 6 (21:44):
One is that there's going to be some crossover.
Speaker 5 (21:47):
Right even within the study, about twenty percent of the
treatment group's crossed over to the other group were to
a different type of treatment. I know that after the
study concluded, there were some centers that were universally switching
or recommending patients switch to ever alimas.
Speaker 4 (22:01):
And lodos tack.
Speaker 5 (22:02):
Others left patients on the regimen that they were current
they were randomized to, and others made more individual treatment decisions.
So anytime you change your treatment, you may dilute your
treatment effect. So I think that there are some limitations
with that, but nonetheless it's certainly an interesting clinical question
and something that we intend to do, hopefully with a
(22:24):
relatively low cost grant that would support such a study.
Speaker 3 (22:29):
As the head of the heart transplant program at Boston
Children's Hospital, are you switching many of your patients to
the evera limis lower dose tack approach?
Speaker 5 (22:40):
We have actually gotten a lot more comfortable with switching
patients to ever alimas and lo dose tack relimas, the
everlimas used in the study.
Speaker 6 (22:51):
The liquid formulation is a little bit tricky.
Speaker 5 (22:54):
The parents have to extemporaneously prepare it right before they
administer the dose. And so for some of our patients
we're choosing serrolamus, which is very similar molecule to everolamus.
But in general, yes, we are switching more of our patients,
but not all of our.
Speaker 3 (23:11):
Patients I see. Well, for those in the audience, Starctor
Daily was really nice to give us time right in
the middle of his busy day, and I'm really appreciat
of it. So I'm going to finish up. You know,
at the beginning of this paper, I was reading it.
One of the goals that you and your co investigators
mention is that maybe this work would help towards the
(23:31):
idea of getting FDA labeling of this particular approach for
maintenance immunis suppression and pediatric heart transplant patients. Can you
speak to us about why this might be important? And
I wondered, where's that effort now that this wonderful study
is now published.
Speaker 4 (23:47):
Yeah, that's a great question.
Speaker 5 (23:50):
First of all, I think that it's really important that
we get FDA labeling for the medications we use in
children wherever possible. You know, our patients deserve to have
medications that are rigorously studied, that patients and parents deserve
to know the safety and efficacy of those medications. In addition,
there are advantages as clinicians to having medication regiments have
(24:11):
a clear indication. Our transplant coordinator spend a lot of
time dealing with denials from insurance companies or doing prior authorizations,
and when there's a pediatric indication, it makes our lives
much easier, and it makes our patients' lives much easier.
It makes sure that the drugs are covered by their
insurance plans. And then I think the last thing is
that it's important that there's a sort of stake in
(24:33):
the ground to which other things can be compared, and
so that is something that an FT indication also does.
We are continuing to pursue the steps required for an
FDA submission.
Speaker 6 (24:44):
Obviously this is a little bit more complicated.
Speaker 5 (24:46):
And not something that we're used to doing, but the
data has to be formatted as a clinical study report
according to ICCH guidelines.
Speaker 6 (24:54):
There is help provided by the National.
Speaker 5 (24:57):
Institute of Child Health and Human Development, which has something
called four to nine eye process that could help us.
Speaker 6 (25:03):
With the submission.
Speaker 5 (25:04):
In addition, because we use that liquid formulation of EVER
alignments that was prepared by the parents right before they
administered it to some of the kids, you actually need
to submit some stability data and some sort of benchtop
data about that formulation.
Speaker 3 (25:20):
And that's something else that the NIH would be able
to help us with.
Speaker 4 (25:24):
So we would love to do that.
Speaker 5 (25:27):
We are continuing to pursue it. The FDA did note
that this would be unique in many ways. Oftentimes, what
we're trying to do is extend a patent or an
indication rather for adults to children.
Speaker 4 (25:39):
Here, there's actually no.
Speaker 5 (25:40):
Indication for adult transplant because of that safety concern of
early infection.
Speaker 6 (25:45):
You studied a slightly different study period.
Speaker 5 (25:47):
Nonetheless, this would actually be the first indication for use
of EVER alignments after heart transplant.
Speaker 3 (25:52):
Wow, that would be so unusual that the first indication
approved by the FDA is a children and not in adults. Again,
another demonstration of how truly extraordinary this effort was by
you and your many many co investigators. Kevin, you don't
have the ability to hear what I said prior to
this interview because I recorded over the weekend but I
(26:12):
made the observation that if you look at the co
investigators at the end of this paper, virtually every single
person I'm aware of who does hard transplants in the
United States was a participant in this work. And so
I can only imagine the extraordinarily high level of effort
that was required to get this data collected and get
so many people on board. But it's obviously a very
important effort, and that's why I'm sure so many people
(26:35):
were motivated to participate. I really want to congratulate you
and your many, many co investigators throughout the United States,
and I want to thank you so much for joining
us this week on pd HART.
Speaker 4 (26:44):
It's my pleasure.
Speaker 7 (26:45):
Thank you.
Speaker 1 (26:46):
I'm sure you found many of doctor Daley's comments of
great interest, and I particularly enjoyed his description of how
this project first got started eleven years ago at an
ISHLT meeting. In this era of virtual everything, I still
think there may be no replacing the just sitting down
together over a drink or perhaps a nice meal to
help foster collegiality amongst ourselves and in brainstorming new ideas.
(27:12):
What an incredible degree of bull doggedness the group had
to push so hard for so long, despite the multiple
roadblocks they encountered, to provide a very important work for
us all to enjoy and to help improve the lives
of our pediatric patients with heart transplants. I think there's
likely an important lesson or two in there somewhere. Once again,
(27:32):
I'd like to thank doctor Day for taking time from
his very busy schedule to speak with us this week
on pd Heart. To conclude this three hundred and fifty
seventh episode of ped Heart Pediatric Cardiology, Today we hear
the wonderful up and coming British tenor Adam Smith singing
the Prince's Aria from the Czech opera Ruzalka by de Vorjak.
In this aria, the Prince sings of his enchantment after
(27:54):
first seeing the water nymph Rusalka. This aria is notable
for its expressive romance system, and certainly you can see
why the opera world is increasingly excited by the emergence
of this wonderful singer.
Speaker 2 (28:06):
Adam Smith.
Speaker 1 (28:07):
Thank you very much for joining me this week, and
thanks once again to our guest. I hope we'll have
a good week ahead.
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Not even not Sir snut fa Ce teaching nor can
you ever for ze snicy for.
Speaker 7 (28:28):
A not nazyusey than a sensor and nuzi sprang.
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Sasag for me.
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For the.
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Ons sa j.
Speaker 9 (28:57):
Hou she see that sola.
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Sash h swe dot you s.
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Be g of the aska the ball stay.
Speaker 7 (29:40):
Yeah, moneyl start forble Tommy my loness what forget so
hond on yes, mess and loy yushless and born hoy East.
Speaker 2 (30:09):
Hobby store call next year's laws any.
Speaker 7 (30:12):
Mesty indeed had import him not thy loom.
Speaker 9 (30:21):
So sit it's a slim krell a mos chat.
Speaker 2 (30:48):
Before suss such a sus.
Speaker 7 (31:23):
Shirt shorty shirt, shorty ho a lassie.
Speaker 4 (31:32):
School such he said.
Speaker 2 (31:38):
They said it such as suss s s sec fer he.
Speaker 9 (32:53):
Don'st mesnmers the veto joy not real.
Speaker 7 (33:11):
Mob who is gon and not mesting more discrib an.
Speaker 2 (33:36):
This diplow.
Speaker 3 (34:00):
To me the the
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'm also the Chief of Pediatric Cardiology.
Thank you for joining me for this three hundred and
fifty seventh episode of Pdheart. I hope everybody enjoyed last
week's episode on the topic of alpha blockade following congeneral
(00:38):
heart surgery. For those of you interested in post operative
care of children following congeneral heart surgery, i'd certainly recommend
you take a listen to last week's episode three hundred
and fifty six. 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 on to the world of cardiac transplantation
(00:58):
and we review a very very important paper. The title
of the work will be reviewing is a Vera Limis
and low dose tacra limis after heart transplant in Children,
a randomized clinical trial. The first author of this work
is Christopher Ahmand, as well as Kevin Daley and the
senior author, Lynn Sleeper on behalf of the teammate trial investigators.
(01:20):
The first author comes to us from Stanford University, and
doctor Daly and doctor Sleeper from Boston Children's Hospital, Harvard University.
When we're done reviewing this paper, I am hopeful that
doctor Daly will be able to join us to discuss
this week's work. Therefore, let's move straight onto this article
and then a conversation with one of its authors. This
week's work begins with some general comments about pediatric heart transplantation,
(01:44):
reviewing that the median survival is about fifteen years and
that there are basically six major ways that allographs are lost,
and these include acute cellular rejection, antibody mediated rejection, infection,
cardiac alligraph vasculopathy, post trans plants, lymphoproliferative disorders, and chronic
kidney disease. The authors explain that a combination of tacrilmus,
(02:07):
which is a calcineurine inhibitor that works to prevent T
cell activation, and mycophenolate mophatyl or MMF have been used
to maintain imminosuppression for nearly twenty years, and the authors
explain that this approach has reduced early mortality after a transplant,
but has not affected longer term survival. The authors then
explain that the m TOR inhibitor a via limis in
(02:30):
combination with lower dose tacrilimits has been shown in adults
to reduce the risk of several transplant complications like carnary
artery vasculopathy, worsening of kidney function, and CMB infection in
the adult's heart transplant patient. The authors review how avia
limis earned a black box warning from the FDA about
its use in heart transplant patients because it was associated
(02:53):
with a higher occurrence of early infections after transplant. What
is not known in children is whether avia limis is
safe if and effective with lower dose tacrileimis if introduced
about six months post transplant, after the peak risk for
post surgical infections and wound healing complications of past With
this as a background, the authors explained that the primary
(03:14):
objective of this randomized trial was to determine whether a
viur limis combined with low dose tacrilemis is more effective
than tacrilimis and mycophenolate in preventing acute cellular rejection caronary
artery vasculopathy and chronic kidney disease in six month survivors
after pediatric heart transplant, and to determine if the regiment
(03:35):
is safe in preventing six major transplant events at thirty months.
The authors also mention that because no rejection medicines or
FDA approved for post cart transplant prophylaxis in children, a
secondary goal was to generate sufficient regulatory data to potentially
get FDA approval for the first rejection prophylaxis regimen for
the pediatric heart transplant patient. This was a phase three
(03:58):
multi centre open label RAMIE so called active comparator trial
in which a vera limits with low dose tacrolimits was
compared with standard higher dose tacro plus micofenolate among six
month survivors after pediatric heart transplant. And this was the
so called TEAMMATE trial which stands for Major Adverse Transplant
(04:19):
Events score. Trial participants were randomized one to one to
receive either of the two approaches, which will call the
evera limus group versus the micofenylate group. Again, this was
open label, so both investigators and subjects were aware of
what they were receiving. The dosing of the medications is
listed in the protocol, but suffices to say that the
tacro dosing was basically set to achieve trough levels that
(04:42):
were approximately one half of the levels in the micofenylate group.
For those interested in the details of the dosing, please
do read the paper and it's on page two that
this is described, and the link to the paper will
be in the show notes. For this work, there were
two primary outcomes. The first was the MATE three score
assessing a proch efficacy the cumulative burden, frequency and severity
(05:05):
of acute cellular rejection, coronary ardor evasculopathy, and chronic kidney disease.
The second was a primary safety outcome or the so
called six mates, which is the three MATE three events
of acute cellular rejection, carnary argoryvasculopathy, and chronic kidney disease
plus antibiody mediator rejection, infection and post transplant lymphoproliferative disorders.
(05:27):
The authors also assessed risk for CMV, since the use
of a vera liimis is associated with a lower risk
for CMB infection. The authors review the statistical approaches used
to analyze these data and suffice it to say that
it was quite robust, and I would once more suggest
that the listener take a look at the paper for
the granular details and toughts of the results. There were
(05:48):
two hundred and eleven children from twenty five US centers
who were more than are equal to six month post
transplant who were randomized to receive either a vera limis
plus low dose tacro, of which there were were one
hundred and seven patients, or standard tacro plus MMF, of
which there were one hundred and four patients. Follow Up
was thirty months in this work. The average age was
(06:10):
eight point two years, and nearly one quarter were treated
for rejection prior to enrollment in this study. During the study,
there were six deaths and three retransplants for a total
of nine graft failures, and four were in the evera
limus group and five in the macofenolate one. I've reminded
that there are many details and findings in this work
(06:30):
and would certainly recommend that those interested in these details
read this masterful work. However, here's my summary of what
I believe are probably the most critical findings and what
you're probably dying to know. What was the outcome well
in regards to the primary outcomes the MATE III looking
at efficacy, which I remind again was largely focused on efficacy,
specifically looking at rejection, carnary artery, vasculopathy, and kidney disease.
(06:55):
The study showed no difference between the Evera limus and
micofenylate groups. Set a different way. At thirty months, a
Vera limis and low dose tacro was not superior to
tacro plus MMF for the composite of rejection, carnary vasculopathy
or chronic kidney disease. In regards to the other primary outcome,
(07:16):
the May six assessing safety, in which the model added
antibody mediator, rejection infection, and PTLD, there were no differences
in graph survival, may free survival, or freedom from any
individual MATE, which again stands for major adverse transplant event.
Now we know from adult works that a Vera limis
(07:36):
plus low dose tacro would be expected to possibly have
less nephrotoxicity than the more traditional tacro dosing approach, and
so was this borne out in this work?
Speaker 2 (07:46):
Why?
Speaker 1 (07:46):
Yes, it was. The Evera limis arm had a greater
improvement in EGFR at twelve months, with a mean difference
of ten and a half millileaters per minute one point
seventy three meters squared. The other concern would be CMB
infection rates differing, since using lower dose tacro might be
thought to be a way of reducing CMB infection and yes, indeed,
(08:07):
in this work, there was a lower incidence of CMV
infection in the Everilimis arm with a hazard ratio of
zero point five zero, and so, to summarize, initiating a
vierilimits plus low dose tacrilymis at greater than equal to
six months post heart transplantation in children appeared to be
safe by the composite safety metric and not inferior with
(08:29):
respect to major transplant events, but it did not show
superiority for the primary efficacy. Composite potential advantages observed were
better short term renal function at twelve months unless CMB infection.
Findings that may make the regimen attractive for patients at
risk for calcinurine nephrotoxicity or CMV, but the regiment is
(08:51):
not demonstrated to reduce rejection, carnary artery vasculopathy or chronic
kidney disease over thirty months. To quote the authors in
their discuss In this study amongst six month survivors after
pediatric heart transplantation, evera limis and low dose tacrilemits did
not differ from tacylimis and mycophenolate in preventing the composite
(09:13):
endpoint of cellular rejection, coronary artery vasculopathy, and chronic kidney disease. However,
the regiment appears to be safe based on the total
burden of six mates at thirty months. In exploratory analyzes,
evera limis appeared to be associated with less CMB infection
and a lower rate of HLA sensitization, but higher rates
(09:35):
of stomatitis and hyperlipidemia. Drug tolerability was similar overall in
the two treatment groups, but differed with regard to specific
adverse events. The authors speak about how this teammate trial
almost never happened, as there was no industry support for
the trial and there was not even donation of medication
from the companies who manufacture the agents, which meant that
(09:56):
there was a built in seven million dollar cost for
this project from medication alone. Thankfully, health insurers paid for
the drugs for the vast majority of the patients. Some
of the limitations of this work art's open label design
and follow up of only thirty months, meaning we don't
know the long term impact on graph survival of this approach. Also,
the trial excluded very early post transplant initiation of evera limmis,
(10:20):
meaning less than six months, due to prior safety concerns
for infection, and so they conclude in summary among six
month survivors after pediatric heart transplant, evera limis and low
dose tacrilemas did not differ from tacrilemits at microphenolate in
preventing the composite endpoint of acute cellular rejection, carnary artery vasculopathy,
(10:40):
and chronic kidney disease. However, the regiment appeared to be
safe based on the total burden of six mates at
thirty months. Although evera limis was not associated with an
improvement in exploratory outcomes such as patient and graph survival,
mate free survival, or individual mates, vera limis may be
associated with kidney function, less CMV infection and a lower
(11:03):
rate of the composite endpoint of acute cellular rejection, carnary
artery vasculopathy, chronic kidney disease and CMB infection. Participants randomized
to a vera limits were more likely to develop apty
stomatitis and hyperlibidemia, complications that the investigators found to be
manageable in children. These findings informed clinical decisions and regulatory
(11:25):
considerations regarding the safe and effective use of vera limis
with low dose tacro in children after heart transplantation. Well,
this is simply an awesome trial, a match and basically
no industry support other than governmental grants to conduct a study,
including twenty five US centers, this is an extraordinary achievement
(11:45):
and when you look at the numbers of heart failure
transplant doctors who were involved in this study, it's amazing.
Basically every pediatric heart transplant doctor in the US worked
on this, but wow, what a testament to cooperation. I
think that this might be the most important lesson of
this work, maybe even as great as the critically important
data that these devoted physicians have determined. This is an
(12:07):
example where if there is a will, there is a way,
And I am sure that you share my admiration for
our heart failure and transplant colleagues who have been so
far ahead of the curve on the notion of multi
center work to advance the science of cardiology. I wonder
if the authors are using these data for FDA approval,
and so that will certainly be amongst the questions will
(12:28):
be interested in asking of doctor Daly in our interview
to follow. In the interests of time, I think we
should move forward to our conversation with one of the
works authors, Doctor Kevin Daly, joining us now to discuss
the work. Is a system professor of pediatrics at Harvard
Medical School. Doctor Kevin Dally, doctor Day, is the medical
director of the Heart Transplant Program and Associate cardiologist in
(12:50):
the Department of Cardiology at Boston Children's Hospital. He is
a graduate of Harvard for undergraduate work followed by medical
school at Columbia University following this. He can plead it
is categorical residency in pediatrics at montsif your medical center,
and then did general cardiology and heart failure transplant fellowships
at Boston Children's Hospital. It is a delight to welcome
(13:11):
him to the podcast. Welcome Kevin to PD Heart.
Speaker 3 (13:14):
I'm here now with doctor Kevin Daily of Boston Children's Hospital. Kevin,
thank you very much. For joining me this week on
pd heart. Thanks so much for having me real pleasure.
Sometimes when I'm starting these interviews, I'll ask the author
of the work if they might be able to summarize
for the audience what you believe, as the author, are
maybe the most important three or four findings of this
really massive undertaking.
Speaker 4 (13:36):
Yeah, thanks very much.
Speaker 5 (13:38):
I think that the most important is that both the
regimens of tackri limas and michael fedalite mofatil or everlynmus
with low dose tackri limas are both safe and effective
immunisuppression regimens that can be used after transplanting children. While
everlymus and low dose tackrilemas was not superior at preventing
the composite endpoint of coronary disease cellular rejection in kidney disease,
(14:02):
it was superior at preventing the secondary endpoint when CMV
infection was included, which does represent a significant important virus
in the care of transplant patients. In terms of adverse events,
drug discontinuation was slightly higher in the tacrilimus and microphenolate group,
with about twenty one percent discontinuing compared to fourteen percent
(14:25):
in the ever alignments group, and the ever alignmis group
was associated with improved kidney function early.
Speaker 6 (14:30):
In the study.
Speaker 5 (14:31):
That difference did narrow toward the end of the study period,
probably because the tacrilimas levels started to come closer together
between the two regiments, and ever alimis did have an
association with a lower prevalence of anti HLA ant bodies
at the end of the study. I would note that
it's important to educate patients and parents that approximately thirty
(14:53):
percent of the patients and the ever alignmis group did
experience mouth ulcers, which is.
Speaker 6 (14:57):
A manageable side effect that we found during this but
it is an important one to consider.
Speaker 3 (15:03):
Really interesting. Thank you that really crystallized the paper so nicely.
Really appreciate that.
Speaker 4 (15:10):
Kevin.
Speaker 3 (15:10):
Can you speak about the genesis of this problem, of
this project rather and what the major hurdles were to
proceeding with this really impressive perspective trial and maybe comment
on why this was actually and correct me if I'm wrong,
but I believe this is the first such perspective trial
in the pediatric heart transplant literature on immunosuppression for children
after a heart transplant.
Speaker 5 (15:32):
Yeah, absolutely, This was a tremendous effort by the pediatric
heart transplant community. As with any study of this magnitude,
there's always a story, and it started actually with a
conversation that a bunch of us were having at the
International Society of Heart Lung Transplant meeting back in twenty fourteen.
(15:53):
We were sitting at the bar and talking about how
we didn't want to just listen to another retrospective, registry
based study and its implications for clinical care, and we
really wanted to set out to define what the most
important questions we could answer where the prospective study were.
So we really were energized at that meeting and subsequent
(16:16):
discussions after that led to a trial comparing outcomes using
proliferation signal inhibitors as part of rejection prophylaxis. The story
then evolves, right, we in order to fund this kind
of a study, you need an endpoint that can power
a relatively small pedetric card transplant trial. So we worked
(16:38):
with the PHTS to develop the MATE score right, which
combines six major transplant events including infection, coronary disease, kidney
disease PTLD, and the two types of rejection, and we
showed that the higher the mate score, the higher the
risk of allograph loss.
Speaker 4 (16:57):
We then took that to.
Speaker 6 (17:00):
The FDA and had created a study protocol.
Speaker 5 (17:03):
And we asked for their input and they provided us
some feedback on their study design. And then the next step, obviously,
is to get the study funded. And that was a
bunch of unsuccessful attempts. He applied to the FDA, we
were unsuccessful. We applied to the NIH, we were unsuccessful.
And finally we applied to the US Department of Defense
(17:24):
Clinical Trials Grant program, and we were successful and they
wound up studying.
Speaker 6 (17:31):
Or funding the study.
Speaker 3 (17:33):
Wow. Yeah, I was really taken aback by reading that
you did not have any commercial support for this study.
That must have been a very depressing finding when you
were considering doing this trial, that Noah wanted to pay
for it such an important trial. I guess ultimately the
small usage in children relative to adults probably was part
(17:56):
of their thought process.
Speaker 4 (17:57):
I'm guessing, yeah, that was part of it. You know.
Speaker 6 (18:01):
There's a couple of actual really interesting.
Speaker 4 (18:03):
Things in that question.
Speaker 5 (18:05):
One is that the manufacturer of ever alignments actually there's
a black box warning for use in adult heart transplantation
because of an increased incidence of early infection that was
noted in the adult transplant studies, so I think they
were a little bit wary about studying the drug and
kids if there were similar adverse events.
Speaker 6 (18:26):
We mitigated that risk by starting the drug six.
Speaker 5 (18:28):
Months after transplant, and we actually didn't see a significantly
increased risk of serious infection. But the other thing is
that the incentives for the drug companies are not.
Speaker 6 (18:38):
Really there for orphan diseases.
Speaker 5 (18:41):
While the Best Pharmaceuticals for Children's Act does provide six
months of patent exclusivity as sponsors for doing pediatric studies,
oftentimes the FD only requires one pediatric study and they
usually will choose kidney transplant if it's a transplant related drug,
and pediatric hard transplant kind of gets forgotten.
Speaker 4 (19:00):
I see.
Speaker 3 (19:01):
I wondered Kevin as I was reading this that it
seemed that evera Limus treated patients did as well or
maybe in some ways better than the more traditional MMF
patients who can also get tecro. And how do you
think the trial's outcomes will affect management in pediatric transplant patients.
I'm wondering if you might be able to share with
(19:22):
the audience, like what is the present most commonly used approach,
and do you think that the data from this study
are going to justify a change of this approach or
maybe has that already happened.
Speaker 5 (19:32):
Yeah, so I think that's fascinating. Tacrolemis and micopenalley remain
the most commonly used immunu suppression, especially right after transplant,
but I think that this trial really provides strong evidence
that at four to six months after transplant you can
consider a switch and that there are some potential long
term benefits.
Speaker 4 (19:52):
Ever alimmis with.
Speaker 5 (19:54):
Lotos TAC was superior at preventing the composite of a
post transplant cornerary disease, cellular rejection of kidney disease, and
CMV and the lower rate of coronary disease in the
composite endpoint is quite promising because this is a major
complication that contributes to alligraph loss. And the finding was
not unexpected because the adult studies did demonstrate that ever
(20:15):
alenis was associated with lower rates of CAV and they
actually measured that using intravascular ultrasound, something that we were
unable to do in our trial because of the size
of the catheter in most of the patients enroll. So
we think that ever Alenas and lotus tacklelemas is definitely
a regimen that should be considered. One of the things
that we found very interesting in randomizing and consenting patients
(20:39):
is that sometimes at six months after transplant, families and
kids and teenagers in particular were happy with the medicine
they were on. They say, I feel pretty good and
I don't really want to change, and so I think
that'll be a continued barrier, but hopefully this data will
convince some of them that this may be a more
superior regimen for the longer term.
Speaker 3 (20:59):
I see, well, this study only has data to thirty months,
which is still quite impressive, but it's you know, for
a child, maybe not that long. I wondered if there's
a plan to extend the length of this study, continue
to follow this cohort even longer. And I wondered, has
this already been done in adult heart transplant patients, And
(21:21):
do we know if this approach is equivalently excellent for
longer term use for heart transplants in general.
Speaker 5 (21:30):
Yeah, so we definitely do intend to collect five and
seven year follow up data. As you mentioned, we did
follow the cohort for thirty months. There's always some pluses
and minuses to that type of long term follow up.
Speaker 6 (21:44):
One is that there's going to be some crossover.
Speaker 5 (21:47):
Right even within the study, about twenty percent of the
treatment group's crossed over to the other group were to
a different type of treatment. I know that after the
study concluded, there were some centers that were universally switching
or recommending patients switch to ever alimas.
Speaker 4 (22:01):
And lodos tack.
Speaker 5 (22:02):
Others left patients on the regimen that they were current
they were randomized to, and others made more individual treatment decisions.
So anytime you change your treatment, you may dilute your
treatment effect. So I think that there are some limitations
with that, but nonetheless it's certainly an interesting clinical question
and something that we intend to do, hopefully with a
(22:24):
relatively low cost grant that would support such a study.
Speaker 3 (22:29):
As the head of the heart transplant program at Boston
Children's Hospital, are you switching many of your patients to
the evera limis lower dose tack approach?
Speaker 5 (22:40):
We have actually gotten a lot more comfortable with switching
patients to ever alimas and lo dose tack relimas, the
everlimas used in the study.
Speaker 6 (22:51):
The liquid formulation is a little bit tricky.
Speaker 5 (22:54):
The parents have to extemporaneously prepare it right before they
administer the dose. And so for some of our patients
we're choosing serrolamus, which is very similar molecule to everolamus.
But in general, yes, we are switching more of our patients,
but not all of our.
Speaker 3 (23:11):
Patients I see. Well, for those in the audience, Starctor
Daily was really nice to give us time right in
the middle of his busy day, and I'm really appreciat
of it. So I'm going to finish up. You know,
at the beginning of this paper, I was reading it.
One of the goals that you and your co investigators
mention is that maybe this work would help towards the
(23:31):
idea of getting FDA labeling of this particular approach for
maintenance immunis suppression and pediatric heart transplant patients. Can you
speak to us about why this might be important? And
I wondered, where's that effort now that this wonderful study
is now published.
Speaker 4 (23:47):
Yeah, that's a great question.
Speaker 5 (23:50):
First of all, I think that it's really important that
we get FDA labeling for the medications we use in
children wherever possible. You know, our patients deserve to have
medications that are rigorously studied, that patients and parents deserve
to know the safety and efficacy of those medications. In addition,
there are advantages as clinicians to having medication regiments have
(24:11):
a clear indication. Our transplant coordinator spend a lot of
time dealing with denials from insurance companies or doing prior authorizations,
and when there's a pediatric indication, it makes our lives
much easier, and it makes our patients' lives much easier.
It makes sure that the drugs are covered by their
insurance plans. And then I think the last thing is
that it's important that there's a sort of stake in
(24:33):
the ground to which other things can be compared, and
so that is something that an FT indication also does.
We are continuing to pursue the steps required for an
FDA submission.
Speaker 6 (24:44):
Obviously this is a little bit more complicated.
Speaker 5 (24:46):
And not something that we're used to doing, but the
data has to be formatted as a clinical study report
according to ICCH guidelines.
Speaker 6 (24:54):
There is help provided by the National.
Speaker 5 (24:57):
Institute of Child Health and Human Development, which has something
called four to nine eye process that could help us.
Speaker 6 (25:03):
With the submission.
Speaker 5 (25:04):
In addition, because we use that liquid formulation of EVER
alignments that was prepared by the parents right before they
administered it to some of the kids, you actually need
to submit some stability data and some sort of benchtop
data about that formulation.
Speaker 3 (25:20):
And that's something else that the NIH would be able
to help us with.
Speaker 4 (25:24):
So we would love to do that.
Speaker 5 (25:27):
We are continuing to pursue it. The FDA did note
that this would be unique in many ways. Oftentimes, what
we're trying to do is extend a patent or an
indication rather for adults to children.
Speaker 4 (25:39):
Here, there's actually no.
Speaker 5 (25:40):
Indication for adult transplant because of that safety concern of
early infection.
Speaker 6 (25:45):
You studied a slightly different study period.
Speaker 5 (25:47):
Nonetheless, this would actually be the first indication for use
of EVER alignments after heart transplant.
Speaker 3 (25:52):
Wow, that would be so unusual that the first indication
approved by the FDA is a children and not in adults. Again,
another demonstration of how truly extraordinary this effort was by
you and your many many co investigators. Kevin, you don't
have the ability to hear what I said prior to
this interview because I recorded over the weekend but I
(26:12):
made the observation that if you look at the co
investigators at the end of this paper, virtually every single
person I'm aware of who does hard transplants in the
United States was a participant in this work. And so
I can only imagine the extraordinarily high level of effort
that was required to get this data collected and get
so many people on board. But it's obviously a very
important effort, and that's why I'm sure so many people
(26:35):
were motivated to participate. I really want to congratulate you
and your many, many co investigators throughout the United States,
and I want to thank you so much for joining
us this week on pd HART.
Speaker 4 (26:44):
It's my pleasure.
Speaker 7 (26:45):
Thank you.
Speaker 1 (26:46):
I'm sure you found many of doctor Daley's comments of
great interest, and I particularly enjoyed his description of how
this project first got started eleven years ago at an
ISHLT meeting. In this era of virtual everything, I still
think there may be no replacing the just sitting down
together over a drink or perhaps a nice meal to
help foster collegiality amongst ourselves and in brainstorming new ideas.
(27:12):
What an incredible degree of bull doggedness the group had
to push so hard for so long, despite the multiple
roadblocks they encountered, to provide a very important work for
us all to enjoy and to help improve the lives
of our pediatric patients with heart transplants. I think there's
likely an important lesson or two in there somewhere. Once again,
(27:32):
I'd like to thank doctor Day for taking time from
his very busy schedule to speak with us this week
on pd Heart. To conclude this three hundred and fifty
seventh episode of ped Heart Pediatric Cardiology, Today we hear
the wonderful up and coming British tenor Adam Smith singing
the Prince's Aria from the Czech opera Ruzalka by de Vorjak.
In this aria, the Prince sings of his enchantment after
(27:54):
first seeing the water nymph Rusalka. This aria is notable
for its expressive romance system, and certainly you can see
why the opera world is increasingly excited by the emergence
of this wonderful singer.
Speaker 2 (28:06):
Adam Smith.
Speaker 1 (28:07):
Thank you very much for joining me this week, and
thanks once again to our guest. I hope we'll have
a good week ahead.
Speaker 8 (28:15):
Not even not Sir snut fa Ce teaching nor can
you ever for ze snicy for.
Speaker 7 (28:28):
A not nazyusey than a sensor and nuzi sprang.
Speaker 2 (28:45):
Sasag for me.
Speaker 7 (28:48):
For the.
Speaker 2 (28:51):
Ons sa j.
Speaker 9 (28:57):
Hou she see that sola.
Speaker 7 (29:03):
Sash h swe dot you s.
Speaker 2 (29:33):
Be g of the aska the ball stay.
Speaker 7 (29:40):
Yeah, moneyl start forble Tommy my loness what forget so
hond on yes, mess and loy yushless and born hoy East.
Speaker 2 (30:09):
Hobby store call next year's laws any.
Speaker 7 (30:12):
Mesty indeed had import him not thy loom.
Speaker 9 (30:21):
So sit it's a slim krell a mos chat.
Speaker 2 (30:48):
Before suss such a sus.
Speaker 7 (31:23):
Shirt shorty shirt, shorty ho a lassie.
Speaker 4 (31:32):
School such he said.
Speaker 2 (31:38):
They said it such as suss s s sec fer he.
Speaker 9 (32:53):
Don'st mesnmers the veto joy not real.
Speaker 7 (33:11):
Mob who is gon and not mesting more discrib an.
Speaker 2 (33:36):
This diplow.
Speaker 3 (34:00):
To me the the
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