This week we venture back in time to 2023 to review the results of the update of the Single Ventricle Reconstruction trial, specifically SVR III. How are HLHS patients are faring post Norwood at age 12? What is the overall transplant-free survival rate in this group? Are there differences in survival seen at 12 years between BTTT shunt patients and RV-PA conduit shunt patients? How do they compare in exercise capabilities? What about rates of PLE or arrhythmias seen? Are there interventions that may improve outcomes going forward? These are amongst the questions reviewed this week with the first author, Dr. Caren Goldberg who is Professor of Pediatrics at the University of Michigan.
DOI: https://doi.org/10.1161/circulationaha.123.065192
DOI: https://doi.org/10.1161/circulationaha.123.065192
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:00):
Hello everybody, This is rob Past, the host of the podcast.
This week, we'll be replaying episode two hundred and seventy
five from a year and a half ago on the
SVR Trial three, specifically the twelve year follow up with
doctor Karen Goldberg. I hope everybody enjoys this important episode.
I'll see you next week with a brand new episode.
(00:34):
Welcome to Peeniehart Pediatric Cardiology Today. My name is doctor
Robert Passon. I'm the host of this podcast. I am
Professor of Pediatrics at the Icon School of Medicine at
Mount SINAI thank you for joining me for this two
hundred and seventy fifth episode of the podcast. I hope
all enjoyed last week's extra special episode, in which we
sat down and spoke with New York Times writer James
(00:54):
Robinson about his most recent memoir, More Than We Expected,
chronicling the life of his child, Nadav Robinson, who had
single ventricle heterotaxi syndrome and who tragically died at five
years of age. Mister Robinson provided a lot of wisdom
for all of us caring for children and adults who
have congenital heart disease, and for those of you with
(01:14):
an interest in this topic, I'd certainly recommend you tech
to listen to last week's episode two hundred and seventy four.
As I say every week, 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 single ventricle and hypoplastic left
heart syndrome. The title of the work we'll be reviewing
(01:34):
is Longitudinal follow Up of Children with Hypoplastic left heart
Syndrome and Association between Norwood Shunt type and long term outcomes,
the SVR three study. The first author of this work
is Karen Goldberg and the senior author, Jane Neuberger On
behalf of the Pediatric Heart Network investigators. When we're done
reviewing this paper, I am hopeful that doctor Karen Goldberg
(01:58):
will be kind enough to speak with us. Therefore, let's
move straight onto the article and then a conversation with
its author. This week's work is the latest report of
the single Ventricle Reconstruction or SVR trial that has been
going on now for over a decade. The authors reminded
that the original SVR trial randomized hypoplastic left hard patients
in fifteen centers across North America to receive either an
(02:20):
RV to PA sinoshunt or a modified BTTT shunt in
what was the first ever multi center clinical trial comparing
surgical strategies and congenital heart disease, and the goal initially
was to compare transplant free survival at twelve months. You'll
recall that way back in twenty eighteen, we reviewed the
six year follow up date of this study with one
(02:42):
of the founders of the study group, doctor Richard Oyer
of the University of Michigan. Way back in episode nine,
which is two hundred and sixty one episodes ago, you'll
remember that the first study showed twelve month improved survival
for RV to PA patients, but by six years, children
assigned to the rv TODAS shunt compared to the modified
btt shunt no longer had improved transplant free survival, which
(03:06):
was sixty four percent with the RV to PA group
and fifty nine percent with the modified BTTT shunt, and
that difference was not statistically significant. The only notable difference
at six years was that the RV to PA patients
needed interventions more commonly. This work that we're reviewing this
week is the so called SVR three study, and the
(03:27):
formal name of the study is the Long Term Outcomes
of Children with Hypoplastic Left Heart Syndrome and the impact
of Norwood Shunt Type Study. The goal of this work
was to quote the author's determine whether shunt type was
associated with RV function, transplant free survival, exercise performance, or
morbidity by the preteen years. The goals were to seek
(03:48):
out risk factors that might be associated with lower RVEF
which was the primary outcome, or worse transplant free survival
after the fontine through early adolescence. The investigators remind that
patients were randomly assigned initially to SHUN type, and again
I would refer you back to episode nine to learn
a bit more about this famous study in the event
(04:09):
that you are less familiar. The authors explained that at
this point in time, a one time CMR was performed
between June of twenty fifteen and September twenty twenty for
each study participant with a target age of ten to twelve,
though some had it as late as fourteen due to
scheduling issues. The primary outcome was r v ejection fraction
measured by CMR. The authors reviewed their complex methodology of
(04:32):
statistical analysis, and I would certainly refer you to page
thirteen thirty two for the details and on to the results.
There were initially five hundred and forty nine patients in
this study, and at the time of follow up of
this work, which is about twelve years, three hundred and
thirteen or fifty seven percent were alive and transplant free
at the time of screening. There's a nice float chart
(04:55):
Figure one showing that of the three hundred and thirteen
alive patients at the screening for them SVR three study,
two hundred and thirty seven were actually enrolled in the study,
or about seventy five percent, because thirty seven were lost
to follow up, thirty one declined participation, and eight were
transplanted or died in the time of the study. Of
(05:15):
the two hundred and thirty seven patients, one hundred and
seventy seven or seventy five percent had a CMR, two
hundred and twenty six or ninety five percent had an echocardiogram,
and one hundred and eighty one or seventy six percent
had a ramp cyclogometer stress test, and so let's review
the most important data first, and most important, transplant free survival.
(05:37):
They were similar fifty nine percent transplant free survival for
the RV TOWPA shunt patients fifty four percent for the
BTT shun patients, and these differences were not significant. Additionally,
a competing risk plot is shown in Fig. Four, clearly
demonstrating that ongoing risk for transplant or death was the
same between the two groups. Interestingly, risk factors for worse
(06:01):
survival after transplant in both groups included post fontine length
of stay over fourteen days and a greater number of
serious adverse events in the first year of life. Next,
what about RV function, the primary outcome of this work.
While using both CMR and ECHO, the RV ejection fractions
(06:21):
were again similar, with a CMR ejection fraction of fifty
one percent in the RV to PA group and fifty
two percent in the Blailock Tausig Thomas shunt group. Interestingly,
if you needed anesthesia for the CMR, the chances of
having worse function in the study were greater. What about exercise, Well, again,
no difference in the peak V two between the RV
(06:43):
to PA and BTTT shunt groups basically both at about
twenty nine to twenty nine point seven millileaders per kilogram
per minute. What about the rate of interventional procedures, which
has in prior works on this been shown to be
greater in the RV to PA group. Once again there
was a difference, with the rate of thirteen point seven
per one hundred patient years in the RV to PA
(07:05):
shunt group versus ten point six per one hundred patient
years in the Blailocktousik Thomas shunt group. What about EP
data in this work, Well, it's not designed to really
critically look at many aspects of this, but the bottom
line is that overall rates of pacemaker insertion, atrial tachy
cardias and ventricular attachy cardias were similar in the two
(07:25):
groups and thankfully relatively low. Finally, and importantly, what about
plastic bronchitis rates or ple Well, the rate of plastic
bronchitis was actually quite low in this relatively young fontine
cohort and there were no differences seen, but it's likely
that this study is under power to show a difference.
But the risk for pl was higher, with five percent
(07:47):
of the RV to PA shunt patients having ple versus
two percent in the shunted patients with a Blaeloktousik Thomas shunt,
and this was statistically significant, so again rates of pl
higher in those who had an RV to PA shunt.
In their discussion, the authors give us some information about
the SVR trial being the first such pediatric cardiac surgical trial,
(08:09):
and they stayed in I quote. Longitudinal follow up of
this landmark cohort to the preteen years demonstrated no significant
differences between the RVPA shunt and modified BTT non transplanted
survivors in cardiac function as measured by RVEF by either
CMR or echocardiography post Fontaine transplant free survival up to
(08:32):
twelve years of age, or exercise performance, which was lower
than predicted by age and height in both groups, consistent
with previous findings in patients undergoing Fontanne procedures by twelve
years of age. The only difference between the shunt types
was a higher cumulative incidence of pl and of interventional
cathoterization procedures. In the RV to PA shunt group. The
(08:54):
rate of entricular rhythmius was very low, similar to that
found in other large cohorts of patients under going the
fontine procedure, with no differences seen between the two shunt groups,
consistent with findings at six years of age in the
same cohort. The author's comment on the fact that they
initially imagined that RV function would be worse than those
who had an RV to PA shunt due to the
(09:15):
incision in the right ventricle, and wonder if the reasons
that they have not yet seen a difference is timing,
since we are still looking at a relatively young cohort,
and they reference a prior work showing that many single
ventrical fontane patients demonstrate CMR dysfunction a bit later in life,
and also remind that there may be differences in diastolic
(09:36):
function that is not assessed in this work. They emphasize
what they termed the striking and sobering finding of the
very heavy burden of death and heart transplantation in this
entire cohort, with nearly half being either deceased or having
undergone a heart transplantation, and mention again how a longer
hospital stay after the first stage or more event in
(09:57):
the first year, where independent factors associ sated with death
or transplantation. They speak a bit about the pl complications
seen and again how RV to PA patients had more
of it, and wonder if it is the fact that
RV to PA patients have less pulmonary blood flow and
that may be affecting pulmonary artery growth and presumably pulmonary
(10:18):
vascular resistance and ultimate pressures in the fontane. They also
suggest it may reflect what we just spoke of, namely
the possibility of distolic differences in function. In regards to limitations,
the authors remind that dysfunction in the surviving patients was
uncommon and so demonstrating differences that are statistically significant is challenging.
(10:38):
They speak of the fact that the socioeconomic characteristics were
trending towards more patients with higher Hollingshead scores, meaning representing
underrepresented minorities more and so this may also limit generalizability
and so they conclude, through extensive follow up and evaluation
of the SVR cohort, we found that shun type has
(11:00):
its little effect on cardiac function post fontine transplant, free
survival or exercise performance through early adolescence. Those who received
RV to PA shunts had higher cumulative incidents, rates of
PL and interventional catheterization, but other morbidities are similar in
the shunt groups. Of foremost concern, the risk of overall
(11:22):
long term morbidity and mortality remain high for children with
hypoplastic left heart syndrome undergoing the normal operation. As neonates,
there is a critical need for further investment in innovative
strategies to reduce the risks from morbidity and mortality and
to improve outcomes for these children. While this is certainly
interesting and disturbing all at the same time, once more
(11:45):
we see that there are not very substantial differences between
the two shunt types, but the overall outcomes are pretty worrisome,
with nearly half not making it to age twelve. Remember
also that these are mostly the best hypoplastic left heart
center in North America. These are not bad centers, and
despite this we see fairly bad outcomes. It's intriguing to
(12:07):
see the higher rates of PL in the RV to
PA shunted patients, and for sure we'll need to follow
this trend and this may be the first indirect evidence
of distolic issues in these patients, which would certainly reflect
one of the concerns that many have had in the
past about RV to PA conduits. Arrhythmia was not different
between the groups. But you'll recall that we recently reviewed
(12:29):
a report showing that there was a suggestion that RV
to PA conduits were associated with more arrhythmia. Certainly, this
is something that will lead further follow up over time.
For sure, as the author's note, the most important finding
is the fairly abysmal outcomes overall, and these findings do
not even speak about how many other important factors and
(12:50):
outcomes such as neurove developmental ones are affected by this condition. Thus,
I guess we all have a long way to go
in understanding and helping these paysations. At this time, in
the interest of time, I think we'll move forward to
our conversation with the author joining us now to discuss
this week's work is its first author, Doctor Karen Sue Goldberg.
(13:11):
Doctor Goldberg is a graduate of the University of Cincinnati
for Medical School. Completed her residency at the Children's Memorial
Hospital in nineteen ninety three and completed her fellowship at
the University of Michigan cs Mock Children's Hospital Following this
She continued her career as a pediatric cardiologist working at
cs Mott Hospital. Her career is focused on the evaluation
(13:33):
of long term outcomes of children who have con general
heart disease, as well as determination of factors to help
improve long term function of children who have congeneral heart disease.
It is a pleasure and we are honored to have
her join us this week to discuss the SVR trial.
Welcome doctor Goldberg to the podcast. I'm here now with
doctor Karen Goldberg of the University of Michigan. Doctor Goldberg,
thank you very much for joining us this week in
(13:54):
a very busy week for you.
Speaker 2 (13:56):
Thank you so much for inviting me, Reilly.
Speaker 1 (13:59):
Pleasant pleasure. A lot of buzz about this paper, obviously,
everybody's very excited by the SVR trial and the follow up.
You know, at this time in your work, there were
no statistically significant differences observed between the RV to PA
and BTT shunt groups in regards to transplant free survival.
But I was wondering, as someone who has a great
(14:21):
familiarity with this data, do you have any thoughts or
intuitions regarding what these two groups may do with greater
time in other words, do you think that they're going
to split at some point and do we have any
data I was wondering also on any diastolic functional differences
between the two groups.
Speaker 2 (14:39):
Well, thanks so much for this question.
Speaker 3 (14:42):
As you said, there's no statistical difference at twelve years,
but still transplant free survival was five percent better for
the rv tow PA shunt group just bypoint estimate at
fifty nine percent compared to those with a modified Blay
Lack passic tam of shunt our analysis A long the way,
you have demonstrated that.
Speaker 2 (15:01):
Pre stage two there was a lower.
Speaker 3 (15:03):
Hazard for death or transplant among those with an rvt
PA SHANT, but between stage two and fontane there is
actually a higher hazard among those with an RV to
PA SHANT, and ultimately no difference in hazard in the
post fontane group. We don't know what the future will be,
but certainly if we do want to keep looking at
(15:24):
this cohort to build our understanding, because I also wanted
to say, we hypothesize that the ventriculotomy required at the
time of the RVDPA SHANT would have long term implications
for the ventricle, maybe in terms of an increased risk
of ventricular arrhythmias and also in terms of maybe ventricular
dysfunction for the SBR cohort up to early adolescents. Though
(15:49):
it seems that there was enough in terms of early
survival benefit of the RVPA shant to counteract any negative
implications of the ventric eulotomy, So as you suggest with
your question, we may still see some effects over time
due to differences in di style function. Over the course
of this year, our team will start to look more
(16:11):
closely at further details from the cardiac meris and also
from the echoes, and again following this important patient cohort
into adulthood will be really valuable in answering your questions.
Speaker 1 (16:21):
You know, doctor Goldberger, I was wondering, how do you
guys decide, like when it's time to come back and
look at all of these patients. Is it every three years,
every five years? How is that decision made? Is that
built into the original protocol. I'm sure you must be
in new territory at this stage.
Speaker 3 (16:40):
Well, Longitude will follow up over this time for a
multi center study is unusual. This is one of the
first from a prospective trial for sure. So the original
SBR trial concluded at fourteen months actually when the neuro
(17:01):
developmental testing was done, so at the time that we
were working on concluding the.
Speaker 2 (17:08):
First spr A trial.
Speaker 3 (17:11):
Then what we called SVR two started and we followed
patients from ages two to six as part of SBR two.
And there were a couple of time points at three
years and at six years that we had you know,
pre predetermined that we would take those looks.
Speaker 2 (17:34):
And then again while working.
Speaker 3 (17:37):
On SBR two, we came up with the in person
protocol to bring patients back for what does this follow up?
And so the intent was to follow them until age twelve.
And I do think that you know, when our youngest
patients are twelve, our oldest patients are fifteen to sixteen. Right,
(17:59):
So now we're starting to work on figuring out what
the next follow up of this really important cohort should be.
Speaker 1 (18:08):
Well, you know, doctor Goldberg, five years ago, doctor Rick
Oyer was on the podcast discuss in the ninth episode
of this podcast. Today's episode will be the two hundred
and seventy fifth episode, and in episode nine, Rick talk
to us about SVR two report. Actually, so time moves on,
(18:30):
you know, I noticed that pl was seen more commonly
in the r V too PA group of twelve years.
One of the few differences that you observed so far.
Do you have any thoughts regarding why this might be.
Speaker 2 (18:44):
Yeah, great question.
Speaker 3 (18:47):
You know, we don't have a mechanistic answer through the
study so far, so what I'm going to say is
only conjecture. One hypothesis is that fontan pressures are higher
in the r V TWOPA shunk group, higher endise dog pressures,
and maybe also higher resistance from less developed branch pulmonary arteries.
(19:07):
We know from the study that more interventional catheterizations were
needed among those who had received an RV to PA
SHANT at the Norman operation, So possibly those with an
RV to PA shant have higher systemic venus pressures and
thus are more prone to pl Again Joss conjecture and
one of the many areas more and more studies needed.
Speaker 4 (19:30):
Yeah.
Speaker 1 (19:30):
It definitely has always been my impression that patients who've
had sanos have a little bit more pulmonary artery distortion
and issues of that nature. But I guess time will
tell well for those in the audience. Again, I want
to emphasize that doctor Goldberg was extraordinarily kind to speak
with us this week in a very busy week, which
is a shortened week here in the US. So I'm
(19:51):
going to finish up with just one last question. You know,
transplant free survival in general was pretty bad, near fifty
percent after twelve years. And I'll remind everybody this is
from the best centers in the world. These were not
mediocre places doing these, norwoods. You comment in your paper
on the need for newer approaches based on how bad
(20:12):
these long term outcomes are. As someone who's perhaps more
aware of this literature than it just about anybody, I'm
wondering maybe you could what the appetite of those listening,
What are some of the innovations that you think might
be coming down the pipeline for these patients.
Speaker 4 (20:28):
Yeah?
Speaker 3 (20:28):
Thanks, I just first I want to agree the transplant
free survival rates were really disheartening, and it does make
us think what are the next steps? Before I talk
about newer approaches, though, I do want to mention that
the patients and the SBR family of studies were enrolled
(20:50):
fairly long time ago. Time does marshaon They were enrolled
between two thousand and five and two thousand and eight,
so the highest mortality was pre stage two, including the
interstage period, and at the time interstage mortality was significantly
higher than it is today.
Speaker 2 (21:12):
Very few sites had home monitoring programs, and.
Speaker 3 (21:15):
I think it's valuable to mention that thanks to the
team from Milwaukee, Nancy Canam and Twaddle and others, and
to the NPCQIC efforts, most children in the US with
hypoplastic left art syndrome are now followed with as through
a special interstage home monitoring program and this has been
associated with improved interstage survival and growth and hopefully will.
Speaker 2 (21:38):
Help to improve longer term survival rates as well.
Speaker 3 (21:43):
To your question about future approaches we realize along the way,
I guess one thing is that we should consider survival
and transplant free survival differently. So when we think about
approaches that may be helpful, it maybe that you know,
some of those approaches that will help improve transplant survival
(22:04):
are going to be important. So in the near dure future,
innovations that help single ventrical candidates be better candidates for
transplant are probably going to have an effect on survival
that's important. Maybe that's exercise programs to help reduce frailty
and the development of ventricular assist devices that really work
(22:27):
for children with Fontana physiology. Stem cell studies to improve
RB function may also have our own future.
Speaker 2 (22:34):
But clearly much more study is needed there. We also should.
Speaker 3 (22:42):
Be learning more about some of the newer heart failure
medications for our pediatric patients with single ventrical heart disease.
Maybe we can find some medication combinations. So there's some
optimistic information about including PDE five inhibitors and some of
the reverse remodeling agents that can be used effectively prophilectically
(23:04):
to avoid development of a failing Fontana physiology.
Speaker 2 (23:09):
Clearly more investigation is needed, but it.
Speaker 3 (23:12):
Will be helpful if we can use some of these
agents already available to us to improve outcomes for people
for starts.
Speaker 1 (23:20):
Yes, a lot of interesting things to think about. And
I really didn't even think about the fact that they
didn't have interstage surveillance projects when the project started. So
probably survival today just from that alone will be ten
or fifteen percent greater, I'm guessing, or I'm hoping at
least I hope.
Speaker 2 (23:39):
So I love Yeah.
Speaker 1 (23:40):
Well, doctor Goldberg, I want to thank you for coming
on the podcast this week, and I also want to
thank you for doing this study. I think this is
just such an extraordinary landmark work, and I think everybody
in our community always waits with bated breath for the
next report from this trial, and I thank you. What
you're doing is with the entire group of many, many
(24:03):
centers and many investigators, is really nothing short of extraordinary.
And I just want to thank you for that effort.
Thank all of the investigators, and again, thank you so
much for joining us this week on the podcast.
Speaker 2 (24:15):
Oh, thank you so much.
Speaker 3 (24:17):
And I'd add to that, yes, thank you to all
the centers that have worked on the study, all the
individuals and as a patients and families who participated in
the study and helped us learn so much over this time.
Speaker 4 (24:33):
No doubt.
Speaker 1 (24:33):
Thank you again. Well, I'm sure that you learned a
lot listening to doctor Goldberg's comments on the SVR three trial,
and I do feel that her comments about the absence
of interstage monitoring programs to be an important one, and
I would hope that with the advent of these programs,
perhaps today's hypoplastic left hard patients will have at least
somewhat improved survival at twelve years. There's so much we
(24:55):
do not know about this patient group, and so many
innovations that are needed to help them these patients. I
did find many of the things that she spoke about
to be very interesting, and I would just re emphasize
her comments about exercise in our fontine patients. I think
that this last point cannot be stressed enough. Consistent exercise
for this patient group is almost certainly going to be
(25:17):
demonstrated to be an important factor in preserving health in
these patients, and perhaps even more so than in those
patients who have two ventricles. I'm sure that, like me,
you're going to be waiting with bated breath for the
next report of this large perspective SVR trial. And I
would once again like to thank doctor Goldberg for taking
time out of her very busy schedule to speak with
us this week. To conclude this replay episode of episode
(25:40):
two hundred and seventy five Single Ventrical Reconstruction Trial, we
end with a wonderful pop song that was recorded by
Placido Domingo and John Denver in the nineteen eighties. Today
we hear Domingo in his advanced stage singing with the
great Mexican tenor Rolando Vilason. And so we have two
operatic superstars from Mexico, Placida Domingo and Orlando Belashan singing
(26:05):
this lovely song perhaps love. Thank you for joining me
for this replay of episode two hundred and seventy five.
I look forward to seeing everybody next week with a
brand new episode.
Speaker 5 (26:15):
Per half saloons like a rest you please.
Speaker 4 (26:19):
So from the storm it excass to give you come.
Speaker 5 (26:24):
It is their to give you warm. And in those
times after run all, when you almost.
Speaker 4 (26:32):
All angel, we'll bring you all.
Speaker 5 (26:40):
Perhaps like a windo perhaps.
Speaker 4 (26:45):
Over it invite you to come to it older.
Speaker 5 (26:51):
It wants to show you.
Speaker 4 (26:52):
Are an e many yourself a lot o.
Speaker 5 (27:02):
Memory mother love see you.
Speaker 2 (27:08):
A song songs so.
Speaker 6 (27:22):
Something so sunsing and some say every day son, same
day on hot This like the old shan for.
Speaker 4 (27:43):
A frumpy to pains, like a fire when it's called
side some money.
Speaker 5 (27:54):
Tis for.
Speaker 6 (27:58):
All.
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My address to my remy is along with you all you.
Speaker 6 (28:30):
So sayyding.
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Some say day on.
Speaker 4 (28:41):
Perhaps all this is like the ocean fu of comfy,
full of pain, like a fire when it's pun outside tom.
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F e more all like me somet my maory is
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Speaker 4 (29:12):
Oh you
Hello everybody, This is rob Past, the host of the podcast.
This week, we'll be replaying episode two hundred and seventy
five from a year and a half ago on the
SVR Trial three, specifically the twelve year follow up with
doctor Karen Goldberg. I hope everybody enjoys this important episode.
I'll see you next week with a brand new episode.
(00:34):
Welcome to Peeniehart Pediatric Cardiology Today. My name is doctor
Robert Passon. I'm the host of this podcast. I am
Professor of Pediatrics at the Icon School of Medicine at
Mount SINAI thank you for joining me for this two
hundred and seventy fifth episode of the podcast. I hope
all enjoyed last week's extra special episode, in which we
sat down and spoke with New York Times writer James
(00:54):
Robinson about his most recent memoir, More Than We Expected,
chronicling the life of his child, Nadav Robinson, who had
single ventricle heterotaxi syndrome and who tragically died at five
years of age. Mister Robinson provided a lot of wisdom
for all of us caring for children and adults who
have congenital heart disease, and for those of you with
(01:14):
an interest in this topic, I'd certainly recommend you tech
to listen to last week's episode two hundred and seventy four.
As I say every week, 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 single ventricle and hypoplastic left
heart syndrome. The title of the work we'll be reviewing
(01:34):
is Longitudinal follow Up of Children with Hypoplastic left heart
Syndrome and Association between Norwood Shunt type and long term outcomes,
the SVR three study. The first author of this work
is Karen Goldberg and the senior author, Jane Neuberger On
behalf of the Pediatric Heart Network investigators. When we're done
reviewing this paper, I am hopeful that doctor Karen Goldberg
(01:58):
will be kind enough to speak with us. Therefore, let's
move straight onto the article and then a conversation with
its author. This week's work is the latest report of
the single Ventricle Reconstruction or SVR trial that has been
going on now for over a decade. The authors reminded
that the original SVR trial randomized hypoplastic left hard patients
in fifteen centers across North America to receive either an
(02:20):
RV to PA sinoshunt or a modified BTTT shunt in
what was the first ever multi center clinical trial comparing
surgical strategies and congenital heart disease, and the goal initially
was to compare transplant free survival at twelve months. You'll
recall that way back in twenty eighteen, we reviewed the
six year follow up date of this study with one
(02:42):
of the founders of the study group, doctor Richard Oyer
of the University of Michigan. Way back in episode nine,
which is two hundred and sixty one episodes ago, you'll
remember that the first study showed twelve month improved survival
for RV to PA patients, but by six years, children
assigned to the rv TODAS shunt compared to the modified
btt shunt no longer had improved transplant free survival, which
(03:06):
was sixty four percent with the RV to PA group
and fifty nine percent with the modified BTTT shunt, and
that difference was not statistically significant. The only notable difference
at six years was that the RV to PA patients
needed interventions more commonly. This work that we're reviewing this
week is the so called SVR three study, and the
(03:27):
formal name of the study is the Long Term Outcomes
of Children with Hypoplastic Left Heart Syndrome and the impact
of Norwood Shunt Type Study. The goal of this work
was to quote the author's determine whether shunt type was
associated with RV function, transplant free survival, exercise performance, or
morbidity by the preteen years. The goals were to seek
(03:48):
out risk factors that might be associated with lower RVEF
which was the primary outcome, or worse transplant free survival
after the fontine through early adolescence. The investigators remind that
patients were randomly assigned initially to SHUN type, and again
I would refer you back to episode nine to learn
a bit more about this famous study in the event
(04:09):
that you are less familiar. The authors explained that at
this point in time, a one time CMR was performed
between June of twenty fifteen and September twenty twenty for
each study participant with a target age of ten to twelve,
though some had it as late as fourteen due to
scheduling issues. The primary outcome was r v ejection fraction
measured by CMR. The authors reviewed their complex methodology of
(04:32):
statistical analysis, and I would certainly refer you to page
thirteen thirty two for the details and on to the results.
There were initially five hundred and forty nine patients in
this study, and at the time of follow up of
this work, which is about twelve years, three hundred and
thirteen or fifty seven percent were alive and transplant free
at the time of screening. There's a nice float chart
(04:55):
Figure one showing that of the three hundred and thirteen
alive patients at the screening for them SVR three study,
two hundred and thirty seven were actually enrolled in the study,
or about seventy five percent, because thirty seven were lost
to follow up, thirty one declined participation, and eight were
transplanted or died in the time of the study. Of
(05:15):
the two hundred and thirty seven patients, one hundred and
seventy seven or seventy five percent had a CMR, two
hundred and twenty six or ninety five percent had an echocardiogram,
and one hundred and eighty one or seventy six percent
had a ramp cyclogometer stress test, and so let's review
the most important data first, and most important, transplant free survival.
(05:37):
They were similar fifty nine percent transplant free survival for
the RV TOWPA shunt patients fifty four percent for the
BTT shun patients, and these differences were not significant. Additionally,
a competing risk plot is shown in Fig. Four, clearly
demonstrating that ongoing risk for transplant or death was the
same between the two groups. Interestingly, risk factors for worse
(06:01):
survival after transplant in both groups included post fontine length
of stay over fourteen days and a greater number of
serious adverse events in the first year of life. Next,
what about RV function, the primary outcome of this work.
While using both CMR and ECHO, the RV ejection fractions
(06:21):
were again similar, with a CMR ejection fraction of fifty
one percent in the RV to PA group and fifty
two percent in the Blailock Tausig Thomas shunt group. Interestingly,
if you needed anesthesia for the CMR, the chances of
having worse function in the study were greater. What about exercise, Well, again,
no difference in the peak V two between the RV
(06:43):
to PA and BTTT shunt groups basically both at about
twenty nine to twenty nine point seven millileaders per kilogram
per minute. What about the rate of interventional procedures, which
has in prior works on this been shown to be
greater in the RV to PA group. Once again there
was a difference, with the rate of thirteen point seven
per one hundred patient years in the RV to PA
(07:05):
shunt group versus ten point six per one hundred patient
years in the Blailocktousik Thomas shunt group. What about EP
data in this work, Well, it's not designed to really
critically look at many aspects of this, but the bottom
line is that overall rates of pacemaker insertion, atrial tachy
cardias and ventricular attachy cardias were similar in the two
(07:25):
groups and thankfully relatively low. Finally, and importantly, what about
plastic bronchitis rates or ple Well, the rate of plastic
bronchitis was actually quite low in this relatively young fontine
cohort and there were no differences seen, but it's likely
that this study is under power to show a difference.
But the risk for pl was higher, with five percent
(07:47):
of the RV to PA shunt patients having ple versus
two percent in the shunted patients with a Blaeloktousik Thomas shunt,
and this was statistically significant, so again rates of pl
higher in those who had an RV to PA shunt.
In their discussion, the authors give us some information about
the SVR trial being the first such pediatric cardiac surgical trial,
(08:09):
and they stayed in I quote. Longitudinal follow up of
this landmark cohort to the preteen years demonstrated no significant
differences between the RVPA shunt and modified BTT non transplanted
survivors in cardiac function as measured by RVEF by either
CMR or echocardiography post Fontaine transplant free survival up to
(08:32):
twelve years of age, or exercise performance, which was lower
than predicted by age and height in both groups, consistent
with previous findings in patients undergoing Fontanne procedures by twelve
years of age. The only difference between the shunt types
was a higher cumulative incidence of pl and of interventional
cathoterization procedures. In the RV to PA shunt group. The
(08:54):
rate of entricular rhythmius was very low, similar to that
found in other large cohorts of patients under going the
fontine procedure, with no differences seen between the two shunt groups,
consistent with findings at six years of age in the
same cohort. The author's comment on the fact that they
initially imagined that RV function would be worse than those
who had an RV to PA shunt due to the
(09:15):
incision in the right ventricle, and wonder if the reasons
that they have not yet seen a difference is timing,
since we are still looking at a relatively young cohort,
and they reference a prior work showing that many single
ventrical fontane patients demonstrate CMR dysfunction a bit later in life,
and also remind that there may be differences in diastolic
(09:36):
function that is not assessed in this work. They emphasize
what they termed the striking and sobering finding of the
very heavy burden of death and heart transplantation in this
entire cohort, with nearly half being either deceased or having
undergone a heart transplantation, and mention again how a longer
hospital stay after the first stage or more event in
(09:57):
the first year, where independent factors associ sated with death
or transplantation. They speak a bit about the pl complications
seen and again how RV to PA patients had more
of it, and wonder if it is the fact that
RV to PA patients have less pulmonary blood flow and
that may be affecting pulmonary artery growth and presumably pulmonary
(10:18):
vascular resistance and ultimate pressures in the fontane. They also
suggest it may reflect what we just spoke of, namely
the possibility of distolic differences in function. In regards to limitations,
the authors remind that dysfunction in the surviving patients was
uncommon and so demonstrating differences that are statistically significant is challenging.
(10:38):
They speak of the fact that the socioeconomic characteristics were
trending towards more patients with higher Hollingshead scores, meaning representing
underrepresented minorities more and so this may also limit generalizability
and so they conclude, through extensive follow up and evaluation
of the SVR cohort, we found that shun type has
(11:00):
its little effect on cardiac function post fontine transplant, free
survival or exercise performance through early adolescence. Those who received
RV to PA shunts had higher cumulative incidents, rates of
PL and interventional catheterization, but other morbidities are similar in
the shunt groups. Of foremost concern, the risk of overall
(11:22):
long term morbidity and mortality remain high for children with
hypoplastic left heart syndrome undergoing the normal operation. As neonates,
there is a critical need for further investment in innovative
strategies to reduce the risks from morbidity and mortality and
to improve outcomes for these children. While this is certainly
interesting and disturbing all at the same time, once more
(11:45):
we see that there are not very substantial differences between
the two shunt types, but the overall outcomes are pretty worrisome,
with nearly half not making it to age twelve. Remember
also that these are mostly the best hypoplastic left heart
center in North America. These are not bad centers, and
despite this we see fairly bad outcomes. It's intriguing to
(12:07):
see the higher rates of PL in the RV to
PA shunted patients, and for sure we'll need to follow
this trend and this may be the first indirect evidence
of distolic issues in these patients, which would certainly reflect
one of the concerns that many have had in the
past about RV to PA conduits. Arrhythmia was not different
between the groups. But you'll recall that we recently reviewed
(12:29):
a report showing that there was a suggestion that RV
to PA conduits were associated with more arrhythmia. Certainly, this
is something that will lead further follow up over time.
For sure, as the author's note, the most important finding
is the fairly abysmal outcomes overall, and these findings do
not even speak about how many other important factors and
(12:50):
outcomes such as neurove developmental ones are affected by this condition. Thus,
I guess we all have a long way to go
in understanding and helping these paysations. At this time, in
the interest of time, I think we'll move forward to
our conversation with the author joining us now to discuss
this week's work is its first author, Doctor Karen Sue Goldberg.
(13:11):
Doctor Goldberg is a graduate of the University of Cincinnati
for Medical School. Completed her residency at the Children's Memorial
Hospital in nineteen ninety three and completed her fellowship at
the University of Michigan cs Mock Children's Hospital Following this
She continued her career as a pediatric cardiologist working at
cs Mott Hospital. Her career is focused on the evaluation
(13:33):
of long term outcomes of children who have con general
heart disease, as well as determination of factors to help
improve long term function of children who have congeneral heart disease.
It is a pleasure and we are honored to have
her join us this week to discuss the SVR trial.
Welcome doctor Goldberg to the podcast. I'm here now with
doctor Karen Goldberg of the University of Michigan. Doctor Goldberg,
thank you very much for joining us this week in
(13:54):
a very busy week for you.
Speaker 2 (13:56):
Thank you so much for inviting me, Reilly.
Speaker 1 (13:59):
Pleasant pleasure. A lot of buzz about this paper, obviously,
everybody's very excited by the SVR trial and the follow up.
You know, at this time in your work, there were
no statistically significant differences observed between the RV to PA
and BTT shunt groups in regards to transplant free survival.
But I was wondering, as someone who has a great
(14:21):
familiarity with this data, do you have any thoughts or
intuitions regarding what these two groups may do with greater
time in other words, do you think that they're going
to split at some point and do we have any
data I was wondering also on any diastolic functional differences
between the two groups.
Speaker 2 (14:39):
Well, thanks so much for this question.
Speaker 3 (14:42):
As you said, there's no statistical difference at twelve years,
but still transplant free survival was five percent better for
the rv tow PA shunt group just bypoint estimate at
fifty nine percent compared to those with a modified Blay
Lack passic tam of shunt our analysis A long the way,
you have demonstrated that.
Speaker 2 (15:01):
Pre stage two there was a lower.
Speaker 3 (15:03):
Hazard for death or transplant among those with an rvt
PA SHANT, but between stage two and fontane there is
actually a higher hazard among those with an RV to
PA SHANT, and ultimately no difference in hazard in the
post fontane group. We don't know what the future will be,
but certainly if we do want to keep looking at
(15:24):
this cohort to build our understanding, because I also wanted
to say, we hypothesize that the ventriculotomy required at the
time of the RVDPA SHANT would have long term implications
for the ventricle, maybe in terms of an increased risk
of ventricular arrhythmias and also in terms of maybe ventricular
dysfunction for the SBR cohort up to early adolescents. Though
(15:49):
it seems that there was enough in terms of early
survival benefit of the RVPA shant to counteract any negative
implications of the ventric eulotomy, So as you suggest with
your question, we may still see some effects over time
due to differences in di style function. Over the course
of this year, our team will start to look more
(16:11):
closely at further details from the cardiac meris and also
from the echoes, and again following this important patient cohort
into adulthood will be really valuable in answering your questions.
Speaker 1 (16:21):
You know, doctor Goldberger, I was wondering, how do you
guys decide, like when it's time to come back and
look at all of these patients. Is it every three years,
every five years? How is that decision made? Is that
built into the original protocol. I'm sure you must be
in new territory at this stage.
Speaker 3 (16:40):
Well, Longitude will follow up over this time for a
multi center study is unusual. This is one of the
first from a prospective trial for sure. So the original
SBR trial concluded at fourteen months actually when the neuro
(17:01):
developmental testing was done, so at the time that we
were working on concluding the.
Speaker 2 (17:08):
First spr A trial.
Speaker 3 (17:11):
Then what we called SVR two started and we followed
patients from ages two to six as part of SBR two.
And there were a couple of time points at three
years and at six years that we had you know,
pre predetermined that we would take those looks.
Speaker 2 (17:34):
And then again while working.
Speaker 3 (17:37):
On SBR two, we came up with the in person
protocol to bring patients back for what does this follow up?
And so the intent was to follow them until age twelve.
And I do think that you know, when our youngest
patients are twelve, our oldest patients are fifteen to sixteen. Right,
(17:59):
So now we're starting to work on figuring out what
the next follow up of this really important cohort should be.
Speaker 1 (18:08):
Well, you know, doctor Goldberg, five years ago, doctor Rick
Oyer was on the podcast discuss in the ninth episode
of this podcast. Today's episode will be the two hundred
and seventy fifth episode, and in episode nine, Rick talk
to us about SVR two report. Actually, so time moves on,
(18:30):
you know, I noticed that pl was seen more commonly
in the r V too PA group of twelve years.
One of the few differences that you observed so far.
Do you have any thoughts regarding why this might be.
Speaker 2 (18:44):
Yeah, great question.
Speaker 3 (18:47):
You know, we don't have a mechanistic answer through the
study so far, so what I'm going to say is
only conjecture. One hypothesis is that fontan pressures are higher
in the r V TWOPA shunk group, higher endise dog pressures,
and maybe also higher resistance from less developed branch pulmonary arteries.
(19:07):
We know from the study that more interventional catheterizations were
needed among those who had received an RV to PA
SHANT at the Norman operation, So possibly those with an
RV to PA shant have higher systemic venus pressures and
thus are more prone to pl Again Joss conjecture and
one of the many areas more and more studies needed.
Speaker 4 (19:30):
Yeah.
Speaker 1 (19:30):
It definitely has always been my impression that patients who've
had sanos have a little bit more pulmonary artery distortion
and issues of that nature. But I guess time will
tell well for those in the audience. Again, I want
to emphasize that doctor Goldberg was extraordinarily kind to speak
with us this week in a very busy week, which
is a shortened week here in the US. So I'm
(19:51):
going to finish up with just one last question. You know,
transplant free survival in general was pretty bad, near fifty
percent after twelve years. And I'll remind everybody this is
from the best centers in the world. These were not
mediocre places doing these, norwoods. You comment in your paper
on the need for newer approaches based on how bad
(20:12):
these long term outcomes are. As someone who's perhaps more
aware of this literature than it just about anybody, I'm
wondering maybe you could what the appetite of those listening,
What are some of the innovations that you think might
be coming down the pipeline for these patients.
Speaker 4 (20:28):
Yeah?
Speaker 3 (20:28):
Thanks, I just first I want to agree the transplant
free survival rates were really disheartening, and it does make
us think what are the next steps? Before I talk
about newer approaches, though, I do want to mention that
the patients and the SBR family of studies were enrolled
(20:50):
fairly long time ago. Time does marshaon They were enrolled
between two thousand and five and two thousand and eight,
so the highest mortality was pre stage two, including the
interstage period, and at the time interstage mortality was significantly
higher than it is today.
Speaker 2 (21:12):
Very few sites had home monitoring programs, and.
Speaker 3 (21:15):
I think it's valuable to mention that thanks to the
team from Milwaukee, Nancy Canam and Twaddle and others, and
to the NPCQIC efforts, most children in the US with
hypoplastic left art syndrome are now followed with as through
a special interstage home monitoring program and this has been
associated with improved interstage survival and growth and hopefully will.
Speaker 2 (21:38):
Help to improve longer term survival rates as well.
Speaker 3 (21:43):
To your question about future approaches we realize along the way,
I guess one thing is that we should consider survival
and transplant free survival differently. So when we think about
approaches that may be helpful, it maybe that you know,
some of those approaches that will help improve transplant survival
(22:04):
are going to be important. So in the near dure future,
innovations that help single ventrical candidates be better candidates for
transplant are probably going to have an effect on survival
that's important. Maybe that's exercise programs to help reduce frailty
and the development of ventricular assist devices that really work
(22:27):
for children with Fontana physiology. Stem cell studies to improve
RB function may also have our own future.
Speaker 2 (22:34):
But clearly much more study is needed there. We also should.
Speaker 3 (22:42):
Be learning more about some of the newer heart failure
medications for our pediatric patients with single ventrical heart disease.
Maybe we can find some medication combinations. So there's some
optimistic information about including PDE five inhibitors and some of
the reverse remodeling agents that can be used effectively prophilectically
(23:04):
to avoid development of a failing Fontana physiology.
Speaker 2 (23:09):
Clearly more investigation is needed, but it.
Speaker 3 (23:12):
Will be helpful if we can use some of these
agents already available to us to improve outcomes for people
for starts.
Speaker 1 (23:20):
Yes, a lot of interesting things to think about. And
I really didn't even think about the fact that they
didn't have interstage surveillance projects when the project started. So
probably survival today just from that alone will be ten
or fifteen percent greater, I'm guessing, or I'm hoping at
least I hope.
Speaker 2 (23:39):
So I love Yeah.
Speaker 1 (23:40):
Well, doctor Goldberg, I want to thank you for coming
on the podcast this week, and I also want to
thank you for doing this study. I think this is
just such an extraordinary landmark work, and I think everybody
in our community always waits with bated breath for the
next report from this trial, and I thank you. What
you're doing is with the entire group of many, many
(24:03):
centers and many investigators, is really nothing short of extraordinary.
And I just want to thank you for that effort.
Thank all of the investigators, and again, thank you so
much for joining us this week on the podcast.
Speaker 2 (24:15):
Oh, thank you so much.
Speaker 3 (24:17):
And I'd add to that, yes, thank you to all
the centers that have worked on the study, all the
individuals and as a patients and families who participated in
the study and helped us learn so much over this time.
Speaker 4 (24:33):
No doubt.
Speaker 1 (24:33):
Thank you again. Well, I'm sure that you learned a
lot listening to doctor Goldberg's comments on the SVR three trial,
and I do feel that her comments about the absence
of interstage monitoring programs to be an important one, and
I would hope that with the advent of these programs,
perhaps today's hypoplastic left hard patients will have at least
somewhat improved survival at twelve years. There's so much we
(24:55):
do not know about this patient group, and so many
innovations that are needed to help them these patients. I
did find many of the things that she spoke about
to be very interesting, and I would just re emphasize
her comments about exercise in our fontine patients. I think
that this last point cannot be stressed enough. Consistent exercise
for this patient group is almost certainly going to be
(25:17):
demonstrated to be an important factor in preserving health in
these patients, and perhaps even more so than in those
patients who have two ventricles. I'm sure that, like me,
you're going to be waiting with bated breath for the
next report of this large perspective SVR trial. And I
would once again like to thank doctor Goldberg for taking
time out of her very busy schedule to speak with
us this week. To conclude this replay episode of episode
(25:40):
two hundred and seventy five Single Ventrical Reconstruction Trial, we
end with a wonderful pop song that was recorded by
Placido Domingo and John Denver in the nineteen eighties. Today
we hear Domingo in his advanced stage singing with the
great Mexican tenor Rolando Vilason. And so we have two
operatic superstars from Mexico, Placida Domingo and Orlando Belashan singing
(26:05):
this lovely song perhaps love. Thank you for joining me
for this replay of episode two hundred and seventy five.
I look forward to seeing everybody next week with a
brand new episode.
Speaker 5 (26:15):
Per half saloons like a rest you please.
Speaker 4 (26:19):
So from the storm it excass to give you come.
Speaker 5 (26:24):
It is their to give you warm. And in those
times after run all, when you almost.
Speaker 4 (26:32):
All angel, we'll bring you all.
Speaker 5 (26:40):
Perhaps like a windo perhaps.
Speaker 4 (26:45):
Over it invite you to come to it older.
Speaker 5 (26:51):
It wants to show you.
Speaker 4 (26:52):
Are an e many yourself a lot o.
Speaker 5 (27:02):
Memory mother love see you.
Speaker 2 (27:08):
A song songs so.
Speaker 6 (27:22):
Something so sunsing and some say every day son, same
day on hot This like the old shan for.
Speaker 4 (27:43):
A frumpy to pains, like a fire when it's called
side some money.
Speaker 5 (27:54):
Tis for.
Speaker 6 (27:58):
All.
Speaker 5 (27:58):
My address to my remy is along with you all you.
Speaker 6 (28:30):
So sayyding.
Speaker 5 (28:34):
Some say day on.
Speaker 4 (28:41):
Perhaps all this is like the ocean fu of comfy,
full of pain, like a fire when it's pun outside tom.
Speaker 5 (28:58):
F e more all like me somet my maory is
a will be
Speaker 4 (29:12):
Oh you
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