Circulation December 13, 2016 Issue

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly
podcast summary and backstage pass to the journal and its
editors. I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore. Today we
will be discussing the pooled analysis results of the 10 ODYSSEY
Trials with important implications for the reduction of lipids in
major cardiovascular events. But first, here's your summary of
this week's journal.


The first paper provides experimental data on vascular disease
that brings into focus the critical roles of transcription
factors such as GATA2 in the maintenance of endothelial cell
function, as well as the role of selected microRNAs as a novel
player of vascular regulation. In this study by first author Dr.
Hartman, corresponding author Dr. Thum from Hanover Medical
School, and colleagues, authors used GATA2 gain and loss of
function experiments in human umbilical vein endothelial cells to
identify a key role of GATA2 as a master regulator of multiple
endothelial functions, and this via microRNA-dependent
mechanisms.


Global microRNA screening identified several GATA2-regulated
microRNAs, including miR-126 and miR-221. GATA2 deficiency led to
vascular abnormalities, whereas supplementation with miR-126
normalized vascular function. In a mouse model of carotid injury,
GATA2 was reduced and systemic supplementation of miR-126-coupled
nanoparticles enhanced miR-126 availability in the carotid artery
and improved reendothelialization of injured carotid arteries in
vivo.


In summary, GATA2-mediated regulation of miR-126 and miR-221 has
an important impact on endothelial biology. Thus, modulation of
GATA2 and its targets miR-126 and miR-221 represents a promising
therapeutic strategy for the treatment of vascular diseases.


The next study is the first to show that current smokers from the
general population have lower levels of circulating cardiac
troponin I, a seemingly paradoxical observation given the known
detrimental cardiovascular impact of cigarette smoking.


First author Dr. Lyngbakken, corresponding author Dr. Omland, and
colleagues from the University of Oslo used data from the large
population-based HUNT study, in which cardiac troponin I was
measured in 3,824 never smokers, 2,341 former smokers, and 2,550
current smokers. Current smokers had significantly lower levels
of cardiac troponin I than never smokers and former smokers, an
association that remains significant even after adjustment for
potential confounders.


The authors also found an association between increasing
concentrations of troponin I and clinical endpoints, namely acute
myocardial infarction, heart failure, and cardiovascular death in
the total cohort. However, this association was attenuated in
current smokers and was significantly weaker than in never or
former smokers with a p for interaction of 0.003. The prognostic
accuracy of troponin I as assessed by C-statistics was lower in
current smokers than in never smokers. Troponin I provided no
incremental prognostic information to the Framingham
Cardiovascular Disease risk score in the current smokers.


Together, these results suggest that mechanistic pathways other
than those involving subclinical myocardial injury may be
responsible for the cardiovascular risk associated with current
smoking. Future studies are needed to determine whether a lower
cardiac troponin I threshold should be considered for exclusion
of myocardial infarction in smokers or whether prognostic tools
other than measurement of cardiac troponins should be utilized
when evaluating risk of future events in current smokers.


The next study contributes to our understanding of cardiomyocyte
signaling in response to ischemic injury. In the study by first
author Dr. [Wool 00:05:04], corresponding author Dr. [Ju
00:05:04] from Tongji University School of Medicine in Shanghai,
and colleagues, authors sought to understand the role of
low-density lipoprotein receptor-related proteins 5 and 6 as well
as beta-catenin signaling in the heart. They did this using
conditional cardiomyocyte-specific knockout mice who had
surgically induced myocardial infarction. They found that
deletion of lipoprotein receptor-related proteins 5 and 6
promoted cardiac ischemic insults. Conversely, deficiency of
beta-catenin, a downstream target, was beneficial in ischemic
injury. Interestingly, although both insulin-like growth
factor-binding protein 4 and Dickkopf-related protein 1 are
secreted beta-catenin pathway inhibitors, the former protected
the ischemic heart by inhibiting beta-catenin, whereas the latter
enhanced the injury response mainly through inducing
lipoprotein-related protein 5 and 6 endocytosis and degradation.


These findings really add to our understanding of the
beta-catenin signaling pathway in ischemic injury and suggests
that new therapeutic strategies in ischemic heart disease may
involve fine-tuning these signaling pathways.


The next paper from the International Consortium of Vascular
Registries is the first study allowing an assessment of
variations in repair of abdominal aortic aneurysms in 11
countries over 3 continents represented by the Society of
Vascular Surgery and European Society for Vascular Surgery. Dr.
Beck from University of Alabama-Birmingham School of Medicine,
and colleagues, looked at registry data for open and endovascular
abdominal aortic aneurysm repair during 2010 to 2013, collected
from 11 countries. These were Australia, Denmark, Hungary,
Iceland, New Zealand, Norway, Sweden, Finland, Switzerland,
Germany, and the United States.


Among more than 51,000 patients, utilization of endovascular
aortic repair for intact aneurysms varied from 28% in Hungary to
79% in the United States, and for ruptured aneurysms from 5% in
Denmark to 52% in the United States. In addition to the
between-country variations, significant variations were present
between centers within each country in terms of endovascular
aortic repair use and rate of small aneurysm repair. Countries
that more frequently treated small aneurysms tended to use the
endovascular approach more frequently. Octogenarians made up 23%
of all patients, with a range of 12% in Hungary to 29% in
Australia. In countries with a fee for service reimbursement
systems, such as Australia, Germany, Switzerland, and the United
States, the proportion of small aneurysms and octogenarians
undergoing intact aneurysm repair was higher compared to
countries with a population-based reimbursement model.


In general, center-level variation within countries in the
management of aneurysms was as important as variation between
counties. Hence, this study shows that despite homogeneous
guidelines from professional societies, there is significant
variation in the management of abdominal aortic aneurysms, most
notably for intact aneurysm diameter at repair, utilization of
endovascular approaches, and the treatment of elderly patients.
These findings suggest that there is an opportunity for further
international harmonization of treatment algorithms for abdominal
aortic aneurysms. This is discussed in an accompanying editorial
entitled, Vascular Surgeons Leading the Way in Global Quality
Improvement, by Dr. Fairman.


The final paper from Dr. Gibson at Beth Israel Deaconess Medical
Center and Harvard Medical School and colleagues, presents the
results of the apoAI event reducing in ischemic syndromes I, or
AEGIS-I, trial, which was a multicenter, randomized, doubleblind,
placebo-controlled dose-ranging phase 2b trial of CSL112, which
is an infusible, plasma-derived apoAI that has been studied in
normal subjects and those with stable coronary artery disease,
but now studied in the current study in patients with acute
myocardial infarction.


The trial showed that among patients with acute myocardial
infarction, four weekly infusions of a reconstituted, infusible,
human apoAI, CSL112, was associated with a dose-dependent
elevation of circulating apoAI and cholesterol efflux capacity
without adverse hepatic or renal outcomes. The potential benefit
of CSL112 to reduce major adverse cardiovascular events will need
to be assessed in an adequately powered phase 3 trial.


Now for our future discussion. Today I am delighted to have with
us Dr. Kausik Ray from Imperial College London, who's the first
and corresponding author of a new paper regarding the pooled
analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr.
Carol Watson, associate editor from UCLA. Kausik, just let me
start by congratulating you on this paper. I believe this is the
first data that allows us to look under the 50 mg/dL mark of LDL
and really ask if the LDL MACE relationship extends below this
level.


Dr. Kausik Ray: Yes, the reason for looking at this is that the
IMPROVE-IT trial really looked at people down to an average LDL
cholesterol of about 54, and with the new PCSK9 inhibitors, which
instead of giving you a 20% further reduction LDL, they give you
the opportunity for a further 50 to 60% reduction. We actually
get the chance to get people down to levels like 25 mg/dL, and
the question is, does the benefit continue at that level?


We did a pooled analysis of 10 of the ODYSSEY Trials, really in
some ways to try and help predict what you might see in ODYSSEY
outcomes, what you might see in the [Fuliay 00:12:00] trial, and
to also manage expectations as well, because there's probably
been a lot of hype around the two New England Journal papers
about 50, 60% reductions of all potential reductions based on
small numbers of events. So the question is, if you reduce LDL by
39 mg/dL, how might that reduce your risk, and is the
relationship continuous? So those were the aims.


Dr. Carolyn Lam: That's great, and maybe could you give us an
idea of the number of patients you are looking at and the number
of events?


Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under
5,000 individuals, and we had just about 6,700 person years'
worth of followup. In total, we had 104 first MACE events. To put
this into context, it's about one third of the number of events
that the first [framing 00:12:53] of analysis had. It's an
observation analysis rather than randomized trial data, so you
got to bear that in mind with the usual caveats that go with
observational data. But the same endpoints that were adjudicated,
this is [inaudible 00:13:10] heart disease death, non-fatal MI,
ischemic stroke, and unstable angina requiring hospitalization.
This is the same endpoint that is in the ODYSSEY Outcomes Trial,
so it's interesting in that regard.


Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line?
What did you find?


Dr. Kausik Ray: What we found was that there was a continuous
relationship all the way down to LDL cholesterol levels of about
25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk
went down by about 24%. If you looked at [apo-like 00:13:48]
approaching be on non-HDL cholesterol, again, you found the same
continuous relationship with a similar point estimate for a
similar standardized difference in LDL cholesterol. We also
looked at many of the guidelines, talk about percentage
reduction. We actually looked at percentage reductions. If you
start with a baseline LDL of X and you achieve a 50% further
reduction in LDL, how much further benefit does that give you? A
50% further reduction gave you a 29% further lower risk of MACE.
So we didn't find any threshold or limit all the way down to LDLs
of about 25.


Dr. Carolyn Lam: That's really a key, novel finding that you
contributed, so congratulations once again. I suppose the
question will always be, you're talking about relative risk
reductions here. At such low levels, can you give us an idea of
the absolute risk reductions?


Dr. Kausik Ray: Yes. You've got to remember that the relative
risk reductions are what you can apply to population differences.
If you pick a high-risk patient population, you would expect to
see a much bigger absolute risk reduction than maybe this study
or another study. Similarly, if you pick a low-risk group, you
are going to see a much smaller absolute benefit. I always try to
advise a little bit of caution that if you basically look at the
range ... If you start with let's say an LDL of 150 and you go
down to let's say an LDL of 25, you are talking about a 1.25%
absolute risk reduction. Remember, these patients are possibly
going to be a slightly lower risk than the ones that are
recruited into the ODYSSEY Outcomes and into the [Fuliay
00:15:46] trial, for example.


Dr. Carolyn Lam: I think you mentioned what I was going to just
ask you about. This is observational. You had 104 events, and I
suppose another limitation might be that your followup was two
years at max, if I'm not wrong? What do you say about that, and
are there plans for future analyses?


Dr. Kausik Ray: Within the context of these studies, I think that
the whole of this data will eventually become dwarfed by what we
see with the big CDOTs, because you've got 18, 27,000 people, 3
years' worth of exposure and followups, so you are going to have
many, many more events. That is a limitation, but I think what is
interesting is that we know that the baseline LDL cholesterol
level is around about 90 mg/dL. We don't actually know what the
actual baseline ... because the baseline [characters 00:16:43]
haven't been published for ODYSSEY Outcomes, but the [Fuliays
00:16:46] around about 89. What it tells you is what the point
estimate is likely to be. It's likely to be in the 24 to 32%
ballpark because that's what your baseline LDL is and that's what
we'd predict in the regression lines that we observed here.


I think that we're not going to get many more events in these
studies because largely the randomized period of followup is now
over. Many of these people are now into open labels, extensions
for safety, so we won't get many more events from this. In terms
of, I think, the way people should maybe look at this is possibly
as a taster for what's to come in the next 18 months or so. I
think for the time being it answers two questions. Is lower
likely to be better? And it is. I think the other question it
tells is how might you get people down to LDLs below 50?


One of the important things was that if you were just on statins,
in this population, if you were recruited on the basis of a high
baseline LDL, you got no additional people down to LDLs below 50.
You got under 10% with add-on [inaudible 00:18:05], but you got
around about 50% when you used the PCSK9 inhibitor as an add-on
to existing therapy. It tells you about how to get to such low
levels as well. I think that's the other key thing that it
actually gives you.


We did an analysis of safety [inaudible 00:18:23], and I think
that's really important. Once you see the efficacy, or if you see
the MACE events continue to go down ... If you looked at
treatment-emergent adverse events ... and I completely take the
fact that it's every side effect reported altogether, which may
or may not be linked to LDL levels specifically, but when we did
that, the relationship actually was just a horizontal line, so
there was no relationship with percentage reduction or on
treatment LDL, so it gave us a nice idea of both safety and
efficacy that we might experience in the big outcome studies.


Dr. Carolyn Lam: All right. Obviously the big outcome studies are
going to be game changers, and I'd really love to invite [Carol
Scotts 00:19:09] here, because there's a whole lot of other
things that need to be considered if this becomes the case, isn't
it? Carol, I really appreciated that you invited an editorial,
and the editorial is by Neil Stone who entitles it, Looking
Beyond Statins: Will the Dollars Make Cents? Please tell us about
the discussions about this paper that occurred.


Dr. Carol Lam: I would again like to congratulate Dr. Ray on a
fantastic paper, and I would like to reiterate exactly what he
said. I think it really does give us some comfort about this
class of medication and its relative safety. I think that's very
important, because I can't tell you how many patients I get and
how many referring physicians I get who worry when their patients
come back with LDLs of 20 or below. I think that gave us some
comfort, and I do also think it was very important to show that
this would fall along the same regression line that statins
perhaps would fall.


As with all the caveats that Dr. Ray said, I agree with all of
them, but I do say this is a tasty little taster, and I
appreciate and congratulate you for publishing this. The
editorial by Dr. Neil Stone was quite interesting. As you said,
he subtitled it, Will the Dollars Make Cents? C E N T S or S E N
S E, sort of a play on words there. Will the relative benefits
that we can achieve with this class of medications make sense for
the cost of these drugs?


That's obviously a very separate issue from what was discussed in
the manuscript, but it's something to think about. We understand
that there are additional patients that will be helped if they
can get their LDL down, and we hope that that will translate into
the outcomes. Again, just as Dr. Ray mentioned, we will have to
wait for the cardiovascular outcomes trials to be completed. When
they are, if they do show the benefits that we hope, will their
price point make them accessible to enough patients for this to
be a widely applied, utilized therapy? Or will they not? That's
part of what was discussed in Dr. Stone's editorial.


Dr. Kausik Ray: When we were writing the manuscript and stuff
like that, and we were doing this and everybody's like, "Oh, wow,
look at the graphs." I said, "Look, we need to balance all of
these bits and reassure ... We've got an opportunity." So I
suggested them giving those additional analyses, and you saw how
big the online supplement was. There was a ton of work that we
put into this, and to format it into a concise ... I really want
to just thank the editorial board for giving us the chance and
actually being able to help us and work with us on this, because
it's really important. I hope people look at all of those things
because it will help people also that question the LDL. They all
talk about the hypothesis and the safety of really low LDLs, and
people come off statins as a result. I think this will help.


Dr. Carolyn Lam: You're listening to Circulation on the Run.
Thank you so much for being with us, and don't forget to tune in
next week.