Circulation July 12, 2016 Issue

 


 


Dr. Lam: Welcome to Circulation on the Run. Your weekly podcast
summary and backstage pass to the Journal and it's editors. I'm
Dr. Carolyn Lam, Associate Editor from the National Heart Center,
and Duke National University of Singapore.
Dr. Sanjay Kaul and Darren McGuire will be joining me in just a
moment to share their perspectives on the EMPA-REG OUTCOME
trials. Are the results with empagliflozin in diabetic patients
at high risk, are they too good to be true. First, here are the
highlights from five original papers in this week's issue.



The first paper is from Dr. Gilboa, from the National Center on
Birth Defects and Developmental Disabilities, Centers for Disease
Control and Prevention in Atlanta, Georgia, and Dr. Marelli from
the McGill Adult Unit for congenital heart diseases in Montreal,
Quebec, and colleagues. These authors recognize that because of
advancements in care there has been a decline in mortality from
congenital heart defects over the last several decades. However,
there are still no current empirical data documenting the number
of people living with congenital heart defects in the United
States.



These authors address this gap in knowledge by using prevalence
data from Quebec, Canada, in the year 2010, as a foundation for a
mathematical model, and estimated that in the United States in
the year 2010, approximately 2.4 million people, including 1.4
million adults, and 1 million children were living with
congenital heart defects. This estimate is significant, because
it corresponds to a 63% increase in the estimated size of the
adult population with congenital heart defects in the United
States since the year 2000. This has significant implications for
resource allocation for health services delivery that will need
to account for this growing population of adults with congenital
heart defects.



The second paper is from first author Dr. Tabot, and
corresponding author Dr. Liao, from the University of Chicago,
and colleagues who aim to understand better the common
complication of angiodysplasia leading to nonsurgical bleeding in
patients with left ventricular assist devices. The authors
studied 101 patients with heart failure, left ventricular assist
devices, or orthotopic heart transplants. They found that
compared to patients with heart failure, or transplant patients,
patients with left ventricular assist devices had elevated serum
levels, and endothelial expression of angiopoietin-2, which is a
potent angiogenic mediator.



Elevated levels of angiopoietin-2 in these patients increase
angiogenesis in vitro, and were associated with bleeding events.
Furthermore, they found that increased thrombin levels in left
ventricular assist device patients were associated with elevated
angiopoietin-2 levels. In aggregate, therefore, the results
indicate that high levels of thrombin induced endothelial
angiopoietin-2 expression, which may then contribute to
angiodysplasia and non-surgical bleeding in patients with left
ventricular assist devices. The clinical implications are that
clinical studies angiopoietin-2, and factor 12 inhibitors may
therefore be indicated to prevent nonsurgical bleeding in
patients with left ventricular assist devices.



The third paper is Dr. Gordon from Hasbro Children's Hospital in
Rhode Island, and Dr. Kieran from the Dana Farber Cancer
Institute in Boston, Massachusetts, and colleagues who addressed
the Hutchinson Gilford Progeria Syndrome. An extremely rare,
fatal segmental premature aging syndrome, where without specific
treatment, death usually occurs at an average age of 14 1/2 years
from an accelerated atherosclerosis.



A PRIA single arm clinical trial has demonstrated that the
protein farnesyltransferase inhibitor, Lonafarnib, ameliorates
some aspects of cardiovascular and bone disease in this syndrome.
The current trial sought to further disease outcomes by
additionally inhibiting progerin prenylation using pravastatin
and zoledronic acid on top of Lonafarnib in 37 participants with
the Progeria syndrome. Results showed that the composite primary
study outcome of increased rate weight gain and decreased carotid
artery echodensity was achieved. Overall, participants
experienced increased bone density, size, and structural
properties. However, unlike the PRIA single arm Lonafarnib
monotherapy trial, mean carotid-femoral pulse wave velocity and
mean carotid artery adventitial echodensity were not improved. In
addition, rates of carotid and femoral artery plaques and
extraskeletal calcifications all increased.



In summary, compared PRIA Lonafarnib monotherapy treatment,
additional bone mineral density benefit, but likely no additional
additional cardiovascular benefit was obtained with the addition
of pravastatin and zoledronic acid. The authors concluded that
since increased bone fracture is not a disease feature, the
addition of a combination of statin and biphosphonate to
Lonafarnib therapy is not recommended for clinical treatment of
Progeria syndrome. However, it is reasonable to consider statins
if concurrent lipid abnormalities need to be treated.



This paper is accompanied by an excellent editorial by Dr.
Francis Collins, who describes our journey in seeking a cure for
this rare disease of Progeria.
The fourth paper is by first author, Dr. Grisenti and
corresponding author Dr. Tilley from Lewis Katz School of
Medicine, Temple University in Philadelphia, and colleagues who
aimed to better understand the role of leukocyte expressed beta-2
adrenergic receptors in regulating immune cell responses to acute
cardiac injury. The authors achieved this aim by studying wild
type mice who were irradiated, and then transplanted either with
isoform specific beta adrenergic receptor knock out bone marrow,
or wild type bone marrow. These chimeric mice, after full
reconstitution then underwent myocardial infarction surgery.



Results showed that immune cell specific beta-2 adrenergic
receptor expression was essential to the repair process following
myocardial infarction. In the absence of beta-2 adrenergic
receptors, vascular cell adhesion molecule-1 expression was
increased in leukocytes, inducing their splenic retention
following injury, and leading to impaired scar formation,
followed by rupture and death. Splenectomy partially restored the
beta-2 adrenergic receptor deficient leukocyte infiltration into
the heart, but gene therapy to rescue the leukocyte beta-2
adrenergic receptor expression completely restored all injury
responses back to normality.



This study is clinically important because it highlights a bit of
a tension that we're facing. On the one had, beta adrenergic
receptors are known to regulate cardiac function and remodeling
following myocardial injury, by their effects through
cardiomyocytes. That's why we use beta blockers to prevent, at
first, cardiac remodeling. However, the current studies now
indicate that inhibition or deletion of the immune cell expressed
beta-2 adrenergic receptor causes leukocyte dysfunction, and
impaired immunomodulatory responses to myocardial injury.
These results may, therefore, have implications on the use of
beta blockers around the time of acute myocardial injury, such as
myocardial infarction, or perioperatively. This is really an area
that needs further research and understanding.



The fifth paper is by Dr. Herman, from the hospital of the
University of Pennsylvania, and colleagues who report on the one
year clinical outcomes of SAPIEN 3 transcatheter aortic valve
replacement in high risk and inoperable patients with severe
aortic stenosis. Now, as a refresher, in the initial partner
trial of transcatheter aortic valve replacement for high risk and
inoperable patients with severe symptomatic aortic stenosis,
there was a demonstration of marked survival advantage compared
to medical management ... But a high one year mortality of 24% in
the high risk, and 31% in inoperable patients.



More recently, the lower profile SAPIEN 3 prosthesis system has
become available. Which has a balloon expandable cobalt chromium
frame, with bovine pericardial leaflets, and an external fabric
seal. The early 30 day outcomes of this system have been
reported, and show a very low rate of adverse events.



The current study now reports the one year survival, and showed
that all cause survival was more than 85% for all patients, above
87% in the high risk, and above 82% in the inoperable subgroups.
Furthermore, there was a high rate of transfemoral access at 84%,
and a high all cause and cardiovascular one year survival in the
high risk transfemoral subgroup of 89% and 93%, respectively.
Between 30 and 365 days, the incidence of moderate perivalvular
aortic regurgitation did not increase. There was no association
between mild perivalvular leak and one year mortality. Although,
a small increase in disabling stroke occurred.



These results, which likely reflect device iteration and
procedural evolution, support the use of Taver as a therapy to
consider in high risk and inoperable patients with aortic
stenosis.



Those were the highlights from this week's issues, and now for
our feature paper. We will be discussing the perspective paper
entitled "Is the Mortality Benefit With Empagliflozin in Type 2
Diabetes Too Good to be True?". To discuss this, we have two very
special guests. First, Dr. Sanjay Kaul, writer of this paper, and
from Cedars-Sinai Medical Center. Second, Dr. Darren McGuire,
deputy editor of circulation from UT Southwestern. Welcome,
Sanjay and Darren.



Dr. McGuire: Thanks, Carolyn.



Dr. Kaul: Thank you, Carolyn.



Dr. Lam: To start us off, I'd really love if Darren could please
introduce this new content category of circulation. Frame of
reference section, of which this is one of the papers, a
perspective article.



Dr. McGuire: Sure, so we envisioned, as we're evolving
circulation to our new editorship, an opportunity for authors,
luminaries in the field, to give us in a very encapsulated form,
a laser focus perspective on a specific topic. These come in two
flavors, the perspectives piece, which this is, is a little more
evidence and scientific quantitatively based. Then we'll also
have a section called on my mind, which is more of a free-flowing
opinion editorial targeting possibly a contentious or
controversial issue. These are going to be very short, and
hopefully very entertaining, and kind of teasers for the
readership of the Journal.



Dr. Lam: Sanjay, you made it very personal, and I like that, too.
Share with us how this idea came about.



Dr. Kaul: Well, I was very impressed at the reception that the
results of the EMPA-REG outcome trial received at the EAST
meeting at Starcom last year. While I was witnessing the
applause, I had polar reactions. On one hand, I thought that
after nearly five decades of trials with checkered history, with
regards to cardiovascular outcomes, here we have for the first
time a trial demonstrating not only cardiovascular benefit, but a
mortality benefit. I thought maybe it's time to take the trumpets
out and sort of herald this holy grail, which we had failed to
achieve. On the other hand, realizing that we had been fooled
before many times by trials, yielding implausibly large
treatments actually, that were never replicated at subsequent
trials.



I had a skeptical response to it, and sort of asked this question
rather tongue-in-cheek, or maybe used as a rhetorical tool to
address whether this mortality benefit was too good to be true.



Dr. Lam: You know, you didn't just question it. You examined the
data, and provided even more evidence. That's what I was
impressed with in your paper. That table where you provided base
factor, as well as a Bayesian analysis. Could you break that down
for us, and explain what you found?



Dr. Kaul: Yes, I was trying to sort of examine the strength of
the evidence, in terms of the quantitative aspect. Yes, the
effect size for the cardiovascular benefit was quite impressive.
For the primary endpoint, which was a compositive cardiovascular,
death, non-fatal MI, and non-fatal stroke, the p-value was not
very robust. It was .04. The p-value tends to overestimate the
strength of evidence. I utilized base factor, which basically is
a metric that allows the two competing hypotheses to predict the
data. Using the base factor, I was able to demonstrate that the
alternative hypothesis was stronger than the null hypothesis by
eight-fold. The p-value of .04 translated into a base factor of
.13. Which is not strong evidence against the null hypothesis. It
requires independent confirmation and subsequent trials.



A p-value of .04, while meeting the superiority criteria, would
not be sufficient enough to meet the FDA's requirement of
substantial effectiveness. Substantial effectiveness just
basically means that the FDA requires two trials, each with a
p-value less than .05. In 1998, they modified their regulatory
requirement, and accepted that one single trial would be
sufficient, provided that there would be a persuasive p-value.
Persuasive basically is defined as a p-value less than
.001.
The base factor allows us to sort of interpret the strength of
the evidence, with respect to the primary composite endpoint was
not strong enough to meet this requirement. With respect to
cardiovascular mortality, as well as all cause mortality, which
trumps all other endpoints, it was persuasive enough.



Dr. Lam: What's your conclusion on that?



Dr. Kaul: What is controversial about that was that in the three
specified statistical plan, the so-called hierarchical testing
strategy, the non-inferiority for three point MACE, followed by
non-inferiority for four point MACE, and followed by superiority
of three point MACE, and lastly, superiority of four point MACE.
Because the p-value of four point MACE superiority was .08, one
can argue purely from a statistical perspective that you stop
your testing strategy, and any analysis beyond that would be
deemed exploratory. Even though cardiovascular mortality and all
cause mortality was prespecified, the purist would argue that
since you failed superiority for four point MACE, you really
can't proceed further. You can analyze, but it will be considered
an exploratory analysis.



I sort of wept and said that because Christopher Columbus had
prespecified that he will be discovering the route to India, the
fact that he stumbled upon America does not mean it doesn't exist
because he had not prespecified it. I think all cause mortality
is the most meaningful endpoint, and the least subjective
measurement error. It meets the key attributes of regulatory
decision making. Which it's prespecified, it's highly persuasive,
therefore, it meets the replication criteria, and the p-value is
so robust that even if you adjust for nearly 100 multiple
comparisons, the p-value would still hold. It meets all the
regulatory criteria for approval.



Dr. McGuire: Sanjay, let me just chime in here. I think it's also
important, not only were these prespecified, but it's important,
I think, for readers of these diabetes programs to realize that
hospitalization for heart failure ... Although it's not part of
the primary outcome ... In virtually every one of these trials,
it is prospectively collected, chartered to find, and essentially
adjudicated by blind endpoint adjudicators. You know, death is
death. Cardiovascular death in these programs are all
adjudicated, as well. I think the prospective collection and
central adjudication also adds legitimacy to the hospitalization
for heart failure are above and beyond the analytic issues.



Dr. Lam: Darren and Sanjay, I hear both of you kind of saying it
does look like, even looking at it from different angles, the
data do look strong. At the end of the day, Sanjay, you concluded
that it does need another trial. Results do need to be
replicated. That was your conclusion. I'd love to hear Darren's
take on this.



Dr. McGuire: I think what Sanjay is saying there, and I think
what we all believe, was we would really love to see this
observation with another member or members of the class. We're
learning a lot in hindsight based on these observations, and
people are exploring potential mechanistic underpinnings. We're
learning a lot about the mechanisms of these medications, above
and beyond their glucose uric effects. There's a lot of
implication about renal physiology and hemodynamics, and altered
myocardial metabolism. I think as Sanjay points out in the paper,
some of this looks like a possible arrhythmic effect. We have a
lot to learn about this mechanism of action, and whether or not
this will be unique to impact gliflozin.
It has been publicly announced, Boehringer Ingelheim is planning,
they're in the planning phases for heart failure trials with
empagliflozin to further explore this signal. I think they will
address Sanjay's desire to have some replication in a different
patient population. Still, we would love to see these extended
into other patient populations. To both extend the use of the
medications if they're found, but also provide further
confirmation of the observations from EMPA-REG outcome.



Dr. Kaul: Carolyn, let me also add, I used the title as a
rhetorical tool, as I stated earlier. I do conclude that the
mortality data is not likely to be spurious. In the back of my
mind, I still have that 1% skepticism that I would like to
eliminate, because the findings were totally unexpected, and
unprecedented, as we discussed earlier. If all the pathways,
including the mechanistic pathways are aligned, I would have
substantial reassurance, beyond any reasonable doubt that the
findings are true. That's why I'm asking for replication. Not
necessarily by empagliflozin in other trials, but by another
molecule within the same class. I think that would be sufficient.



Dr. McGuire: Yeah, and I think it's really interesting to note
there, is that I was involved in the early days of some of these
drugs as they're being developed. When the other two members of
this class went to the FDA, dapagliflozin and canagliflozin, they
provided FDA's requirement and meta analysis from all of the
phase 2B and 3 trials that had been completed to date. The meta
analysis of the cardiovascular outcomes. Both dapagliflozin and
canagliflozin had point estimates of cardiovascular death
reduction of 30%, and 35%, respectively. When we saw those data,
they were based on 25 to 40 total events. We chuckled, thinking
this is spurious, from small events being analyzed. That there's
no way they would prevent cardiovascular death. Sure enough, you
know, you could almost superimpose those point estimate plots
from the phase 2B-3 meta analysis, with the ultimate outcomes
from EMPA-REG. There's some promising, although again, very
statistically imprecise estimates that this may well be a class
effect. As many of the listeners will know, there are ongoing
cardiovascular outcomes trials for all of these medications. That
will come some time in the next year or two.



Dr. Lam: That's fantastic. Thank you both for sharing those
perspectives. I mean, I learned so much. I really think, Sanjay,
your paper achieved exactly what you had meant for it to achieve,
and exactly what circulation was hoping to create the discussion,
as well.



Dr. McGuire: Thank you, Carolyn.



Dr. Kaul: Thank you very much.



Dr. Lam: You've been listening to Circulation on the Run. Thank
you for listening. Don't forget to join us next week for more
highlights and discussions.