Circulation June 04, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg
Hundley:            
I'm Greg Hundley, Associate Editor for Circulation and Director
of the Pauley Heart Center in Richmond, Virginia at VCU Health.


Dr Carolyn
Lam:               
So Greg, ever wondered if prophylactic use of ICDs would help
prevent sudden cardiac death in dialysis patients? Well, guess
what? We're going to be discussing it in the feature discussion
of the ICD II trial coming right up. First, I hear you've got a
very interesting probabilistic paper.


Dr Greg
Hundley:            
Yes. It's very sweet. This is from Renata Micha at Tusk
University and it's examining the cost effectiveness of the US
Food and Drug Administration added sugar labeling policy for
improving diet and health. So Carolyn, in this study,
investigators used a validated micro simulation US impact food
policy model to estimate cardiovascular disease and type II
diabetes mellitus cases averted, quality adjusted life years,
policy costs, health care, informal care, and loss productivity
in health related savings and cost effectiveness of two different
policy scenarios.


                                               
First, the implementation of the US Food and Drug Administration
added to your labeling policy or just the sugar label. And
second, further accounting for corresponding industry
reformulation the sugar label plus reformulation. The models used
nationally represented demographic and dietary intake data from
the national health and nutrition examinations survey and
diseased data from the centers for disease control and preventive
wonder data base and policy affects in diet disease effects from
meta-analysis and policy and health related costs from
established sources. Probabilistic sensitivity analysis accounted
for model parameter uncertainties and population heterogeneity.


Dr Carolyn
Lam:               
Sweet indeed, so tell us all about probabilistic analysis Greg.


Dr Greg
Hundley:            
Okay Carolyn, so between 2018 and then forecasting out into the
future, so this is probabilistic, in the year 2037. The sugar
label would prevent 354,400 cardiovascular disease cases, and
599,300 diabetes mellitus cases, gain 727,000 quality adjusted
life years, and save 31 Billion dollars in net health care costs.
Or 61.9 Billion dollars in societal costs incorporating reduce
loss productivity and informal care costs and similar findings
were accomplished for the sugar label plus reformulation
scenario, both scenarios were estimated with greater than 80%
probability to be cost saving by the year 2023.


                                               
Thus, the results of this simulation exercises indicated that
implementing the FDAs added sugar labeling policy could generate
substantial health gains and cost savings for the US population
particularly if the new label stimulates industry reformulation.
The authors point out that the compliance date for updating the
nutrition facts label including the added sugar perversion has
been continuously delayed. And the authors believe, their
findings highlight the need for timely implementation of this
label so as to maximize health and economic gains.


                                               
An excellent editorial was written by Elizabeth Magnuson at Saint
Luke's Mid America Heart Institute revealing the strengths of
this work and explains some of the variants that could occur in
the results based on assumptions that were used in the authors
micro simulation model.


Dr Carolyn
Lam:               
That is so interesting Greg, thanks. So from policy to guidelines
and this time on cardiopulmonary resuscitation or CPR, now we
know that an out of hospital cardiac arrest, chest compression
only CPR has emerged as an alternative to the standard CPR where
we use both chest compressions and rescue breathes. Since 2010,
CPR guidelines recommend chest compression only CPR for both
untrained bystanders and trained bystanders who are unwilling to
preform rescue breaths.


                                               
The current study really aimed to describe the changes in the
rate and type of CPR perform before the arrival of emergency
medical services doing three consecutive guideline periods with
gradual adoption of compression only CPR and this was in Sweden.
Now these were authors led by Dr Hollenberg from The Center of
Resuscitation Science, Karolinska Institute in Stockholm, Sweden
and colleagues and basically, they study all bystander witness
out of hospital cardiac arrest reported in the Swedish register
for CPR from 2000 to 2017. They found that there was a six fold
higher proportion of patients receiving compression only CPR and
a concomitant almost double rate of CPR before emergency medical
services arrival, and these changes occurred over time. Any type
of CPR was associated with doubled survival rates in comparison
with cases not receiving CPR, and this association was observed
in all time periods studied. They also found a small but
significantly higher chance of survival after CPR with
compression and ventilation in comparison with compression only
CPR.


Dr Greg
Hundley:            
So Carolyn, does this mean we should go back to standard CPR?


Dr Carolyn
Lam:               
Well, remember these we observational findings, albeit really
amazingly done and nationwide. But the findings really support
continuous endorsement of the compression only CPR as an option
and that's because its associated with higher CPR rates and
overall survival of the no CPR skill. The authors ended up
calling for randomized controlled trials, which are really needed
to answer the question of whether or not CPR with compression and
ventilation is superior to compression only CPR, especially in
cases where bystanders have had the previous CPR training. Now,
this is discussion in a wonderful editorial by Drs. Hsu and
Neumar from University of Michigan Medical School.


Dr Greg
Hundley:            
Very nice, so you're going to tell us a little bit about
troponin?


Dr Carolyn
Lam:               
Well, the question is "Is Plasma Troponin I measured by the high
sensitivity assay associated with incident cardiovascular disease
in the community?" Well, Dr Ballantyne from Baylor College of
Medicine and colleagues decided to answer this question by
looking at the ARIC Study participants age 54 to 74 years without
base line cardiovascular disease and what they found was that
elevated high sensitivity troponin I was strongly associated with
increased global cardiovascular disease incidents in this general
population, and this was independent of traditional risk factors.
They also found differences between black and white individuals
and between men and women.


Dr Greg
Hundley:            
What kind of differences?


Dr Carolyn
Lam:               
Well high sensitivity troponin I had a stronger association with
incident global cardiovascular disease events in white compares
to black individuals and a stronger association with incident
coronary heart disease in women than in men. The authors also did
a comparative association of high sensitivity troponin I vs.
troponin T, they found that the high sensitivity troponins I and
T show only moderate correlation with each other but were
complementary rather than redundant in risk assessment for
incident cardiovascular events in individuals without known
clinical cardiovascular disease at base line. The bottom line is,
adding biomarkers to traditional risk prediction models presents
a potentially effective approach for future risk prediction
algorithms for cardiovascular disease in the general community.


Dr Greg
Hundley:            
You know, think I might read that paper looking at that
complimentary risk assessment. That sounds really interesting
Carolyn. Well, I'm going to go back to the world of basic science
and discuss a paper from Kun Wang discussing the long non
encoding RNA regulation of cardiomyocyte proliferation and
cardiac repair. Carolyn, post mitotic cardiomyocytes in the adult
heart exit from the cell cycle and cease to proliferate, and
that's the basis for their poor regenerative capacity and
defective repair in response to say a myocardial infraction.
Interestingly, the nonmammalian vertebrates such as our friend
the zebra fish, their heart exhibits a robust capacity for
regeneration. And it can efficiently regenerate its lost cardiac
tissue throughout life due to this retain cardiomyocyte
proliferation capability.


Dr Carolyn
Lam:               
Interesting indeed Greg about our friend the zebra fish. So what
did the authors find?


Dr Greg
Hundley:            
Okay, in this study, Wang and associates investigated whether
long non-encoding RNAs had a role in the regulation of
cardiomyocyte proliferation and cardiac repair. Using
bioinformatics and initial analysis, the identified a long coding
RNA named Cardiomyocyte Proliferation Regulator or CPR that was
comparatively higher in the adult heart as opposed to hearts in
the fetal stage. The silencing of the Cardiomyocyte Proliferation
Regulator or CPR significantly increased the cardiomyocyte
proliferation in the postnatal in adult hearts, more over CPR
deletion restored the heart function after myocardial injury
which was evident from increased cardiomyocyte proliferation,
improvement of myocardial function and reduce scar formation.
Also, neonatal cardiomyocyte proliferation in cardiac
regeneration where markedly suppressed in CPR overexpressing
heart cells, therefore CPR acts as a negative regulator of
cardiomyocyte proliferation and regeneration in fetal hearts.


                                               
So, Carolyn the conclusion of this paper is that the inactivation
or silencing of CPR accelerates cardiomyocyte proliferation along
with significant restoration of cardiac structure and function
after myocardial injury in adult hearts. And as such, further
studies may investigate whether the therapeutic inter fashion of
CPR could be a useful strategy to trigger the expansion of
cardiomyocyte populations and myocardial repair.


Dr Carolyn
Lam:               
Nice Greg, so we've talked about CPR as in Cardiopulmonary
Resuscitation to CPR as in Cardiomyocyte Proliferation Regulator,
how about that? Well, that's as much as we go for now, let’s get
to our feature discussion.


                                               
Dialysis patients are known to have a high mortality rate, a
large proportion of which have been attributed to sudden cardiac
death and yet compared to patients with heart failure, these
patients with dialysis have been either excluded or only
nominally enrolled in all previous trials of implantable
defibrillators or ICDs. Now that's why our feature paper this
week is so important, and it is the Cardioverter-Defibrillator in
the prevention of sudden cardiac death in dialysis patients that
prospective randomized controlled ICD to trial. So pleased to
have with us, the corresponding author Dr Wouter Jukema from
Leiden University Medical Center as well as associate editor Dr
Mark Link from UT South Western to discuss this very important
paper. Wouter, congratulations, this is a very difficult, very
important to do the study though, could you tell us a bit about
what you did and what you found?


Dr J. Wouter Jukema:     Actually, you just
referred to it as a very difficult study to perform and indeed it
was. Many years ago, actually, twelve years ago, we noticed that
now a lot of death in dialysis patients was attributed to sudden
cardiac death, before we tried to make these type of patients
better with all types of medications, but did not really work and
suddenly the idea was, that came also from death certificates and
death records that they have sudden cardiac death and we said we
should monitor it and we should treat it in a prospective
randomized study. We initiated the study after careful thoughts
and we thought we would do it in 4-6 years but it took us 12. So
it was quite an effort to set up this rightly and spread it
around the Netherlands and activate a Nephrologist and a
Cardiologist to take part in this prospective randomized
controlled study in dialysis patients.


                                               
Of course, you can easily imagine that you could have great
benefit from this ICD devise, but you could also easily imagine
that you would have complications of the implication of the
device. So explaining that we should show it out, I think was the
most important job we had to do and think that was a great
effort, and it was not easy to do.


Dr Carolyn
Lam:               
And that in it of itself is very important observation.


Dr Mark
Link:                    
So you picked patients without doubts, which is great I mean this
is a difficult study, but you also picked with an LDF greater
than 35% and traditionally, ICDs are indicated for under 35%, can
you give us a little explanation on why you chose the greater
than 35% population?


Dr J. Wouter Jukema:     Yeah, I think this
is perhaps the most important remark on the study, because when
we designed the study we had to choose at that time we had
guidelines in general that under 35% of injection fraction you
were entitled to receive an ICD, however of course almost never
dialysis patients were included so there was no formal
recommendation on that not to include them or not to exclude
them, but dialysis patients have a death rate at that time to
sudden cardiac death, anyway regardless of the injection fraction
and we thought okay, the patient population that is first at high
risk of sudden cardiac deaths so any dialysis patients but also
they are entitled to have a meaningful extension of the lives
because the prognosis of patients that are on dialysis with an
injection fraction under 35% is in general so poor that it would
be unfair to start there and most of the Nephrologists also would
not allow it anyway, these patients are at the end of life and if
you extended for two or three months its useless.


                                               
Anyway, so we thought we'd pick the high-risk population and we
prove that there were still on high risk but when we could do
something meaningful to extend their lives, so we thought we do
not pick the worst patients we pick the patients that we think we
can really help. We screened them well, we treated them well and
we see if an ICD on the patient will benefit them. And that's why
we picked the over 35% rage. You need another study to do below
35%, but I don't think that our results are substantiating such
an effort.


Dr Mark
Link:                    
The population with EFs was 6-50%, which also has a high risk of
sudden death in patients with dialysis but it’s still not looking
with the population of less than 35%.


Dr J. Wouter Jukema:     No, I completely
agree, and we acknowledge that in the manuscript, it was always
in the manuscript within the revision that was also pointed out
to us that it should be more clearly acknowledged, why we choose
this patient population and finally, we can of course not make a
formal recommendation on dialysis patients with an injection
fraction of less than 35%. You can extrapolate data but we have
no formal prof of course for this type of population. I fully
agree.


Dr Carolyn
Lam:               
Before we go further, could you first describe, what did you
find?


Dr J. Wouter Jukema:     Basically, the
conclusions are the prophylactic ICD therapy in patients on
chronic dialysis with an injection fraction of 35% or higher was
not associated with a reduced rate of sudden cardiac death nor of
all cause of mortality and besides that the preference of sudden
cardiac death in this type of patients on dialysis was actually
significantly lower compared to its reports from literature, so
that's what we very often see of course if you fill out a death
certificate, you have to fill out a cause of death and of course
in many patients the heart stops, and you say it's a sudden
cardiac death. But that's not what this study actually showed and
finally it's also no authority that this population was not too
healthy to see any benefit, if you look at the results over the
years, then you'll see that after five or six years more than
half of the patients are dead anyway, but due to all kind of
causes and not to a sudden cardiac death.


                                               
So, I think that this is from a pathophysiological background,
this is also a very interesting study because we now have finally
data, real data on sudden cardiac deaths in these types of
patients.


Dr Carolyn
Lam:               
Indeed, and Mark, I know that you invited the editorial from Rod
Passman, just discussing why did we see the results that we did.
Not quite what we expected I suppose, what do you think Mark?


Dr Mark
Link:                    
First, I want to congratulate Dr Jukema for finishing this study,
this was a massive task and a difficult and long one. I think I
was surprised, there has been reported to be a very high rate of
sudden death in dialysis patients regardless of their LDF. The
ICD is very good at preventing sudden deaths, but not good at
preventing other types of deaths, so I would extrapolate to say,
well you can prevent sudden death in dialysis patients, you
should prolong their life and this study did not show that at
all. And I was surprised, and it just goes to what Dr Jukema was
telling us, that what's reported on a death certificate as sudden
death is not necessarily sudden death and could be other types of
death and at the end all death is sudden.


Dr J. Wouter Jukema:     I fully agree with
that remark because that makes is cumbersome to have the right
interpretation of the data, so you have to feel like something
and then finally your heart stops.


Dr Carolyn
Lam:               
What seems that most of the reasoning seems to be maybe a lower
rate of sudden cardiac death than we expected, but there were
also other factors that were considered, for example, if you
could clarify by dialysis did you mean both hemodialysis as well
as peritoneal dialysis, do you think that made a difference? For
example, do you think ICDs work differently in presence of uremic
precipitant of arrhythmias vs. not and so on, what do you have to
say about those factors?


Dr J. Wouter Jukema:     We include on
purpose both types of patients, the peritoneal dialysis and the
hemodialysis patients because you could easily in-visit that
there could be a difference, for instance to fluid or electrolyte
sheaths that are more sudden in the hemodialysis patients than in
peritoneal dialysis and we did a sub-analysis where we looked at
both types, but the results are essentially the same, it doesn't
seem to matter a great deal of what type of dialysis you have,
the amount of sudden cardiac is lowered and expected. By the way
occasionally, of course the ICD did work in sudden cardiac death,
was aborted. So, it’s not that the apparatus doesn't function it
does, it takes it properly and if functions properly. But
finally, it doesn't prolong the life and you will die of
something else, mostly infections in general well-being when
finally, the nephrologist will say this is end of life you have
to stop the dialysis procedures anyway.


Dr Carolyn
Lam:               
Right, great points, now in the last few minutes, I'm dying to
ask, what do you think of the next steps from here. Mark, what do
you think first? And then perhaps I'll give the last word to
Wouter?


Dr Mark
Link:                    
I'll start with a question to Wouter myself, the question is what
are we going to do now with the individuals on dialysis that are
under 35%? I think this study has pretty clearly said that were
not going to extend our CDs to people on dialysis with greater
than 35%. But we still have a population that currently fits
indication for a ICD if their expected longevity is greater than
a year. And currently those people are included in the guidelines
for ICDs, I think this study gives us some pause about what to do
with our population. And many of that population are getting our
CDs and I'd be curious to what Dr Jukema thinks about that
population and whether that population warrants some randomized
trial or whether we should continue with our current guidelines
that recommend implantation of an ICD in any individual less than
35%, as long as their expected life span is greater than a year.


Dr J. Wouter Jukema:     I think these are
excellent questions with excellent remarks, of course, finally,
we do not know because we didn't investigate it, I can only
imagine the difficulties we would have if we were to do a new
additional trial with injection fractions patients less than 35%.
I could tell you we had great great difficulty in persuading
Nephrologists to take part in the study, because many of them
were very reluctant, this is their principal, these are very ill
patients, and a lot of them are more or less going towards the
end of their lives so you cannot do this when we have
Nephrologists telling us that they considered it an unethical
study. A lot of them did not want to participate they said, "You
shouldn't do this to this patient, they have troubles enough,
they suffer from infections and all kinds of things."


                                               
Having said this, I do not advocate that you should never implant
an ICD in a dialysis patient, I think in our study we also
clearly show that in dialysis patients, implantation of an ICD is
feasible within acceptable although better complication risk and
infection risk, so if you have a patient on dialysis where you
feel this patient has a good life expectancy, for instance, he
already suffers an episode of arrhythmia, I think you are
entitled to discuss this with the patient and have it a try, it
might work and prolong their life. So I would not say never do
it, I think our studies show that you can do it, yes, it
sometimes works but do not expect too much of it. You will never
hear me say that in general you should not do it, if you have a
clear indication for it you may do it, secondary effect may
require a good reason, but primary prophylactic indication,
that's a difficult one I think and to do this study in patients
that are even more ill, with injection fraction of less than 35%,
I feel will be exceeding the difficult.


Dr Mark
Link:                    
One other comment I have is the issue of the SUBCU ICD I think
changes the equation in a bit because the risk of infection is
much lower with a SUBCU IDC in patients on dialysis, did you have
any SUBCU ICDs in your study or was it all transvenous?


Dr J. Wouter Jukema:     We don't have any
data, when we designed and the developed study, the such a device
was not even there so we couldn't do that, and during the study
we did not adapt that but of course there is also no formal proof
yet that it's a lot safer, a lot better, and once again this time
of subcutaneous ICD I think you can do it at an acceptable
complication rate. But it’s not effective enough, it's not that
the patients were dying from infections of their ICD, they were
dying of all kinds of infections and malignancies. Infections due
to the ICD were facing procedures, real complications were rare.


Dr Carolyn
Lam:               
Great! Thank you Wouter, thank you Mark, what an important study
and what a lot of lessons that we learned here.


                                               
Thank you very much audience for listening as well, you've been
listening to Circulation on the Run, don't forget to tune in
again next week.


                                               
This program is copyright American Heart Association 2019