Circulation July 30, 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
cohosts. 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 of Circulation, Director of
the Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr Carolyn
Lam:               
Greg, guess what? We are going to be talking later about
non-inferiority trials. Now, you're going to go like, "Huh?
What?," but then we see more and more non-inferiority
cardiovascular trials. And do we really know the advantages and
limitations of this type of trial design? Which is so important
to understand, because we need to understand the factors that may
impact our confidence and interpretation of these results. So,
that's going to be a really important feature discussion, coming
up right after our coffee chat. Greg, what are your papers?


Dr Greg
Hundley:            
Thanks Carolyn. Boy, I can't really wait to get to that feature
discussion. That's something that we deal with all the time, and
I look forward to that explanation and that discussion. I'm going
to talk a little bit of basic science, with two papers right in a
row.


                                               
And the first one involves catecholaminergic polymorphic
ventricular tachycardia through inhibition of
calcium/calmodulin-dependent kinase II. The lead author is Dr
Vassilios Bezzerides from Boston Children's Hospital.


                                               
Carolyn, this paper focuses on treatment of catecholaminergic
polymorphic ventricular tachycardia, an underlying diagnosis in
at least 12% of pediatric patients who present with unheralded
cardiac arrest. ICDs, as you know, are frequently implanted, but
are problematic because of increased complication rates in
pediatric patients, failure to convert ventricular arrhythmias,
and the risk of fatal ICD-induced electrical storm. Modulating
CaM Kinase II within the heart shows promise to treat this, but
CaM Kinase II is essential in other tissues, most notably the
brain.


Dr Carolyn
Lam:               
How interesting. So, what did the study show?


Dr Greg
Hundley:            
Well, the investigator used adeno-associated viral gene therapy,
which is proven to be a safe and efficient vector for sustained
gene transfer into many cell types to selectively inhibit CaM
Kinase II in cardiomyocytes. They were able to express the
specific CaM kinase II inhibitory peptide AIP in cardiomyocytes
without significant extra cardiac expression, and an inhibition
of CaM Kinase II effectively suppressed ventricular arrhythmias
in a murine model of catecholaminergic polymorphic ventricular
tachycardia after a single therapeutic dose. So thus, in animal
models, delivery of a CaM Kinase inhibitory peptide by AAV
represents a novel single dose gene therapy for catecholaminergic
polymorphic ventricular tachycardia. How about that?


Dr Carolyn
Lam:               
Wow. You've got a second paper?


Dr Greg
Hundley:            
I sure do. So now we're going to jump into, again, looking at
polymorphic VT from engineered human heart tissue. And this
article is from Kevin Parker at Harvard University, "Modeling of
Human Arrhythmias Using Induced Pluripotent Stem Cell-Derived
Cardiomyocytes has Focused on Single-Cell Phenotypes."


                                               
With this said, it is important to realize that arrhythmias are
emergent properties of cells assembled into tissues and the
impact of inherited Arrhythmia mutations on tissue level
properties of human heart tissue. And therefore, newer
technologies are needed to develop more satisfactory therapeutic
interventions. Ones that encompass all of the tissue, not just
single cells.


Dr Carolyn
Lam:               
Interesting. So, what did this particular study do?


Dr Greg
Hundley:            
So, Carolyn, in this study, the investigators report on an
optogenetically-based human-engineered tissue model of
catecholaminergic polymorphic VT, which as we have discussed in
the previous article is promoted by mutation of the cardiac
ryanodine channel 2, which is promoted by mutation of cardiac
ryanodine channel and triggered by exercise. They developed a
human IPSC cardiomyocyte-based platform to study the tissue level
properties and investigated pathogenic mechanisms in polymorphic
VT by combining this novel platform with genome editing. The
authors found that engineered heart tissue, fabricated from human
pluripotent stem cell derived cardiomyocytes, effectively modeled
catecholaminergic polymorphic VT caused by dominant mutations in
the cardiac ryanodine receptor, including induction of
arrhythmias by conditions that stimulate exercise. Using
selective pharmacology and genome editing, the authors identified
activation of calcium/calmodulin-dependent kinase II, or CaM
Kinase II, and CaM Kinase II mediated phosphorylation of
ryanodine at Serine 2814 as critical events that are required to
unmask the latent arrhythmic potential of catecholaminergic
polymorphic VT, causing ryanodine mutations, highlighting a
molecular pathway that links beta adrenergic stimulation to
arrhythmogenesis in this disease.


Dr Carolyn
Lam:               
Wow Greg! So, two very interesting and important linked genetic
papers. Well, we're going to switch tracks a little bit and talk
about, well, my favorite topic: heart failure with preserved
ejection fraction and the whole complex issue of the diagnosis of
this syndrome. Now we know that the diagnosis is kind of complex
and there is currently no consensus but several proposed
definitions. So how do the clinical and hemodynamic profile of
patients vary across the different definitions of HFpEF?


                                               
So, this question was answered by Dr Jennifer Ho from
Massachusetts General Hospital and her colleagues, who examined
consecutive patients with chronic exertional dyspnea and an
ejection fraction above 50% who are referred for comprehensive
cardiopulmonary exercise testing with invasive hemodynamic
monitoring. They applied societal and clinical trial HFpEF
definitions and compared the clinical profiles, exercise
responses, and cardiovascular outcomes by these different
definitions. So, of 461 patients, 416 met the ACC/AHA definition,
205 met the ESC definition, and 55 met the HFSA criteria for
HFpEF.


                                               
The clinical profiles and exercise capacity varied vastly across
the definitions, with peak oxygen uptake averaging 16.2 for those
with the ACC/AHA definition and down to 12.7 in those satisfying
the HFSA definition.


Dr Greg
Hundley:            
Wow. What a difference from these societies.


Dr Carolyn
Lam:               
Mm-hmm (affirmative).


Dr Greg
Hundley:            
So Caroline, it sounds like they looked at all comers with
exertional dyspnea. Now how about those that had hemodynamic
evidence of heart failure with preserved ejection fraction?


Dr Carolyn
Lam:               
Yeah, good question Greg. So, you caught me telling you that all
these patients had hemodynamic cats as well, and a total of 243
had hemodynamic evidence of HFpEF, which was defined as an
abnormal rest or exercise feeling pressure. Of these, 222 met the
ACC/AHA criteria, 161 met the ESC criteria, and only 41 met the
HFSA criteria. Over a mean follow-up of 3.8 years, the incidents
of cardiovascular outcomes range from 75 for the ACC/AHA criteria
to 298 events per thousand-person years for the HFSA criteria.


                                               
The application of clinical trial definitions of HFpEF similarly
resulted in distinct patient classification and prognostication.
So in summary, the authors demonstrated significant diversity in
the number of patients meeting HFpEF criteria. And using
different HFpEF classifications variably enriched for future
cardiovascular events, but at the expense of not including up to
85% of individuals with physiologic evidence of HFpEF.
Comprehensive phenotyping of patients with suspected heart
failure really highlighted the limitations and heterogeneity of
current HFpEF definitions and may help to refine HFpEF
sub-grouping to test therapeutic interventions. Now, these are
all discussed in an important accompanying editorial by Michele
Senni, Sergio Caravita, and Walter Paulus.


Dr Greg
Hundley:            
Wow Carolyn. It appears, depending upon the definition, we could
really classify patients drastically differently.


Dr Carolyn
Lam:               
Yeah, an important paper indeed. And again, I would strongly
encourage everyone to read that editorial as well. For my second
pick, we're going to switch to CPR in children.


                                               
So these authors, now led by Dr Rohan Khera from UT Southwestern,
examined the prevalence and predictors of survival of children
who progress from bradycardia to pulselessness in in-hospital
cardiac arrest despite cardiopulmonary resuscitation. So they
looked at almost 5,600 pediatric patients age more than 30 days
to under 18 years of age, who received CPR at hospitals
participating in the Get With The Guidelines - Resuscitation
during 2000 to 2016 each CPR event was classified as bradycardia
with pulse, bradycardia with subsequent pulselessness, and
initial pulseless cardiac arrest. And the authors assessed for
risk adjusted rates of survival to hospital discharge.


Dr Greg
Hundley:            
So Carolyn, what did they find? This is really interesting.


Dr Carolyn
Lam:               
Well, among hospitalized children in whom CPR was initiated, half
had bradycardia with poor perfusion at the initiation of chest
compressions and nearly one third of these progressed to
pulseless in-hospital cardiac arrest despite CPR. Survival was
significantly lower for children who progressed to pulselessness
despite CPR compared to those who were initially pulseless. So,
these findings suggest that pediatric patients who lose their
pulse despite CPR are at particularly high risk and require a
renewed focus on post resuscitation care.


Dr Greg
Hundley:            
Very interesting, Carolyn.


Dr Carolyn
Lam:               
Well, that wraps it up for our discussion. Let's go onto the
featured discussion. Shall we, Greg?


Dr Greg
Hundley:            
You bet.


Dr Carolyn
Lam:               
Non-inferiority cardiovascular trials are increasingly being
published and in the highest impact journals. Yet how much do we
really know about these designs of the trial, of the
non-inferiority trials? Well, I have to admit not much in my
point of view, and I was so pleased to see our feature discussion
paper really published in this week's journal, which really digs
deep into non-inferiority trials and talks about time trends and
perhaps some lessons that we should all bear in mind when we look
at these. I'm so pleased to have the first author, Dr Behnood
Bikdeli, to tell us about the study. And he is from Columbia
University Medical Center, New York Presbyterian Hospital, Yale
Center of Outcomes, Research and Evaluation Core, as well as the
Cardiovascular Research Foundation in New York. We also have Dr
Naveed Sattar, associate editor from the University of Glasgow.
Behnood, could you tell us, so what made you look at this
question and what did you find?


Dr Behnood Bikdeli:        For
a while we've been very interested in profiling the
cardiovascular trials, trying to understand a little better, what
are the specific characteristics of the major child that we rely
upon for research but also for clinical practice? Years ago, we
did some studies for surrogate outcome trials and this, let's
just say subsequent piece, where we tried to look into a
randomized cardiovascular trial that use a non-inferiority
design. We had a series of features in terms of quality metrics
and methodological metrics that we wanted to look into. The over
eight almost 27-year period, we identified 111 of these trials.
Reassuringly, most of these trials inherited several important
quality and methodological metrics that we were looking into.
However, we also saw a significant room for improvement. There
were quite a few quality or methodological metrics that some of
these trials were not adhering to and we think it's important
because ultimately for the design reporting and last reading of
these trials, knowing these pluses and minuses would help inform
people.


Dr Carolyn
Lam:               
That's great, Behnood. Now for those of us listening who don't
think about this every day, could you give us some examples of
the top errors perhaps to look out for?


Dr Behnood Bikdeli:        For
example, in the typical superiority trials, when we want to test
an intervention a versus intervention B, all that matters is we
do a very good and adequately sized trial and rest of it is up to
the study and how it goes to see whether or not something panned
out. There was a significant difference between the new
intervention versus the older ones, but in non-inferiority trials
we have something called the non-inferiority margin and that's
very highly relevant when it comes to the outcome that you're
assessing when it comes to the ultimate results of the trial.


                                               
If the investigators choose a very lenient y non-inferiority
margin, they may end up calling an intervention non-inferior.
They may give it a pass. While in reality the intervention has
quite a lot of a risk or harmful profile compared with standard
of care. But in the other side, as a clinical example, we have
several interventional tools at hand, like transcatheter aortic
valve replacement. Most of the indications where it's currently
used came from large bell designed non-inferiority trials. Where
they showed that it was almost as good as surgery, in some cases
better, but also it had a lot of ancillary advantages.


Dr Carolyn
Lam:               
Thanks, Behnood. And you know here, I just want to call out to
the readers. You have to look at this paper. Look at the tables
and figures which are really so helpful. And Naveed, can I bring
you in on this now? I mean, I just love this paper. It's such an
important topic and I've never seen it addressed like this
before. Could you tell us a little bit about what the editors
discussed when we looked at this?


Dr Naveed
Sattar:           
I've been involved in a few non-inferiority trials and some of
the factors that many of us discuss and some of course
associated, sort of our clinical trials, and I've been involved
normally in superiority trials, but increasingly we have cut our
teeth in non-inferiority trials. So, some of the points that the
paper picks up resonated well with us in terms of, one of the
examples was Behnood and his team found that around about 40% of
trials didn't even justify what their non-inferiority margin was.
And that's something I've actually had detailed discussions
involved in various trials with. And that's a really important
point, but it isn't a, you have to be able to justify why you
choose particular margin and what that margin would mean to the
community. Otherwise you potentially could just pick something
out there which really doesn't allow you to make a really strong
non-inferiority claim. And I think that's one of the factors that
you found, Behnood. Is that correct?


Behnood
Bikdeli:             
Absolutely. And that's a great point. Thank you. To us, there
were two things about it. One was whether or not they provided
any detailed justification for it exactly as you said, not that
they're just picking up something because that's the sample size
that they could achieve or that's the number that they felt
comfortable with. But also the second piece of it, a respective
of how they calculated or came up to the number, their readers
have a right to know how this was calculated or were this came
from, so it's the reporting part of it. Sometimes they reported
both in the published paper and a study protocol or a design
paper. Sometimes it was only in one of them. Sometimes as you
mentioned, it was not mentioned in either, which puts the reader
in a very difficult situation.


                                               
So we think, and these were the best of the best trials in the
highest impact journals. Probably if we look high and low
elsewhere it's going to be even more challenging. So, we think
there's a lot of room for improvement for the readers to expect
cleaner, more comprehensive papers to come, but also for the
trialist to report them with more clarity.


Dr Naveed
Sattar:           
And going forward, issue a nice figure that shows that the trend
is that we are going to see more of these trials probably because
you've got lots of better treatments now. So, you know it's
getting harder, in the sense, in many areas of cardiovascular
medicine to show superiority. So, there is a need for more trials
which actually show benefits beyond just perhaps the main outcome
in ways that you've explained in the particular paper.


                                               
Do you think the FDA does enough in this particular area in terms
of this helping investigators decide what the non-inferiority
margins are? Or is that something in terms of the quality of the
trials that needs a bit more investigation? I think your papers
partly are pushed to say, "Actually we need to do these better.
We need to justify them better. We need to look at them better."
Because actually they do have a greater influence going forward.


Dr Behnood Bikdeli:       
First, I cannot agree more. We are going to see a lot more of
non-inferiority trials sort of, maybe because we have reached a
ceiling effect when traditional intervention for superiority, but
there's a lot of room to find interventions that are at least as
safe or as good but have a lot of side advantages and ancillary
benefits that's happened with some of the anticoagulants among
other therapies available.


                                               
In terms of the regulatory aspects, one of the things we were
fortunate about was within our team, we had people with expertise
on the trialist side while communicating with the regulatory
bodies and also from people who were consulting to the FDA for
assessment of non-inferiority trials. So, we were fortunate to
look into several of the methodological or quality metrics that
were being thought of and we consulted with the in-source
guidelines and FDA guidelines. That said, I completely agree
that, for example, the suggestions that you provided in one of
the tables could hopefully help shape some of these trials in a
more rigorous way. Or at least a reporting, which is also an
important piece, would be more transparent ultimately for the
readership.


Dr Naveed
Sattar:           
Absolutely. And transparency is really pivotal so that the
readers completely understand what was done, what was predefined,
and what was found so that they can make a proper judgment. And
probably the final question I have in terms of, you make a good
point that actually if the trials are not done well and there's a
bit of slippage either in terms of loss of data or methodological
issues, that then really pushes a trial towards a "no", in a
sense you get a false reassurance of non-inferiority, but partly
because the methodology wasn't robust enough. And it's really
very critical for these trials, perhaps at least as critical as
they are in superiority trials, but perhaps even more so. Is that
a fair judgment?


Dr Behnood Bikdeli:        No,
no, no. You're absolutely right. That's another very important
point in the typical superiority trial, if any bias drives the
results toward no difference. Investigators are naturally
guarding against that because it's going to be very problematic
in non-inferiority trials. Depending on the effect measure that
they choose, it could actually falsely favor the intervention of
interest because it might show a false assessment of
non-inferiority, and there are ways to work around it. There are
ways to correct for it, such as choosing both absolute and
relative effect measures, which practically addresses this
concern. Again, gets back to the importance of appropriate design
and appropriate transparency to report the results in a robust
way, both intentions to treat and has treated or per protocol,
both relative effect measures and absolute effect measures.


Dr Naveed
Sattar:           
My sense of and getting back to you, but I think this will be a
really seminal paper for the community to look at and really help
us as a community to improve our conduct of such trials in the
future because there will be more of these coming forward.


Dr Carolyn
Lam:               
And I couldn't have said that better, Naveed. I think the take
home message is right there. Pick it up, have a look and
especially have a look at those tables and figures. It's really
going to help you read many, many journals.


                                               
Thank you so much, Naveed and Behnood. Thank you audience for
joining us on Circulation on the Run. Talk to you next week.


                                               
This program is copyright American Heart Association 2019.