Circulation November 14, 2017 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation on the Run, your weekly podcast summary
and back-stage 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.


                                               
What is the evidence we have for LDL-lowering therapy in primary
prevention? For individuals with an LDL cholesterol above 190
mg/dL, well, you may think you know the answer, but today's
featured discussion may surprise you like it did for me, and this
is a must-listen in my opinion for those of us taking care of
these patients. More soon right after these summaries.


                                               
How can we enhance the survival and therapeutic potential of
human pluripotent stem cell-derived endothelial cells? Well, the
first paper in today's journal tells us how. The first author Dr.
Lee, corresponding doctor Dr. Yoon, from Emory University School
of Medicine in Atlanta, Georgia, developed a novel,
fully-defined, cell culture system to generate endothelial cells
from human pluripotent stem cells. They not only showed that
these endothelial cells had pro-angiogenic activities and exerted
favorable therapeutic effects in repairing limb ischemia, but
also showed that encapsulation of these cells in a biocompatible
peptide amphiphile nanomatrix gel improved long-term survival of
these endothelial cells in an ischemic environment and improved
vessel-forming properties. This novel cell culture system and
gel-mediated transplantation may serve as a novel platform for
cell-based therapy.


                                               
The next study brings us one step closer to application of
immunomodulatory therapies in pulmonary arterial hypertension. In
the study, first author Dr. Saito, corresponding author Dr.
Rabinovitch, and colleagues from Stanford University School of
Medicine isolated lung immune complexes and pulmonary arterial
hypertension target antigens from lung tissues from 16 patients
with pulmonary arterial hypertension and 12 controls. SAM domain
and HD1 domain-containing protein, which is an innate immune
factor that suppresses HIV replication, was identified and
confirmed as highly expressed in immune complexes from patients
with pulmonary arterial hypertension. These immune complexes
resulted from elevation in products of human endogenous
retrovirus K. The human endogenous retrovirus K deoxyuridine
triphosphate nucleotidohydrolase, or dUTPase, activated B cells,
elevated cytokines and monocytes and pulmonary endothelial cells,
and increased pulmonary arterial vulnerability to apoptosis, thus
contributing to sustained inflammation, immune dysregulation, and
progressive obliterative vascular remodeling. Furthermore, rats
treated with the human endogenous retrovirus K dUTPase developed
pulmonary hypertension. In summary, this study suggests that
harnessing mechanisms that repress human endogenous retrovirus K
expression and its sequelae could prevent and reverse pulmonary
arterial hypertension.


                                               
The next study looked at the association of timing of coronary
angiography with ischemic outcomes of non-STEMI who are at high
risk with a Gray score of more than 140 in the TAO Trial. In this
report from first author Dr. Deharo, corresponding author Dr.
Steg, and colleagues from L'Hopital Bichat from Paris, France
showed that in these high risk, non-STEMI patients, a very early
invasive strategy of coronary angiography within the first 12
hours was associated with a lower risk of death in MI at 180 days
compared to an early strategy of between 12 to 24 hours or a
delayed strategy of between 24 and 72 hours. The bleeding risk
was not different between patients managed with the very early,
early, or delayed strategy. These observations deserve
prospective confirmation in a randomized trial.


                                               
The next study provides contemporary mortality trends for STEMI
and non-STEMI. In this paper from first author Dr. Puymirat,
corresponding author Dr. Danchin, and colleagues from Hopital
europeen Georges-Pompidou in Paris, France, the authors assess
trends in the characteristics, treatments, and outcomes for EMI
from five month-long registries conducted five years apart and
spanning 1995 to 2015, including more than 14,000 patients
admitted to cardiac intensive care units in metropolitan France.
They observed major changes in the characteristics and management
of both patients with STEMI and those with non-STEMI over the
last 20 years. The mean age decreased in patients with STEMI and
remained stable in patients with non-STEMI, whereas diabetes,
obesity, and hypertension increased. At the acute stage, intended
primary PCI increased from 12 to 76 percent in patients with
STEMI. In patients with non-STEMI, PCI within 72 hours from
admission increased from 9 to 60 percent. In parallel with these
changes, six-month mortality consistently declined in patients
with STEMI, whereas in patients with non-STEMI, six-month
mortality reached a plateau after 2010. The authors concluded
that future challenges will be to reduce pre-hospital mortality
and to improve long-term survival after the acute myocardial
infarction event.


                                               
That wraps it up for your summaries. Now for our feature
discussion!


                                               
What evidence do we have from randomized trials supporting the
benefit of LDL cholesterol lowering as primary prevention among
patients with an LDL cholesterol above 190 mg/dL? You may be
surprised to know that until today's journal, we had very little
trial evidence supporting this. But I'm so pleased to have with
us the corresponding author of our featured paper today, Dr.
Kausik Ray from Imperial College, London, who's going tell us a
bit more and discuss this very intriguing paper with our Editor
for Digital Strategies, Dr. Amit Khera from UT Southwestern.
Welcome, both.


Dr. Kausik
Ray:                 
Hi.


Dr. Amit
Khera:                
Thanks for having us.


Dr. Carolyn
Lam:              
Kaus, you are a familiar voice and so pleased to have you here.
Please tell us, is this the first evidence we have from a
randomized trial for primary prevention in those with LDL above
190? Tell us about it.


Dr. Kausik
Ray:                 
Yeah, it is. It really came about because we were interested in
familial hypercholesterolemia and we used the level of 190 to
talk about either primary hypercholesterolemia, which may have a
genetic basis, or not. I kept hearing that there is no trial
evidence, so you're not going to be able to ethically do a trial
today despite the fact there's not much evidence, because most of
us think that it's a bad thing to leave people on placebo in
patients above 190, so I thought the only way to do this was to
go historically to the WOSCOPS Study, which is, as you remember,
6,500 people, elevated LDL cholesterol. Interestingly, you go to
WOSCOPS, the median LDL in that population is very close to 190.
So, that gives a good starting point, thinking that we'll have at
least half the population.


                                               
Now interestingly in WOSCOPS, although none of the patients had a
history of myocardial infarction, a very small number of the
6,500, about 1,000 actually had evidence of some other vascular
disease, so maybe a TIA, maybe angina, maybe some sort of ECG
non-specific change of coronary disease. Today, you would say,
well, actually, you've got to give these people a statin because
there's evidence of vascular disease, PVD, et cetera. So we had
to take those people out and that left us with 5,529. Once you
break people down by LDLs above and below 190, you have 2,560.
You could actually look at the randomized treatment effect of
pravastatin, which was the statin chosen, over a five year period
both above and below 190.


                                               
But interestingly, this was the first study and what we showed
was that in this population, even with as little as 23% reduction
in LDL cholesterol, over a five year period, you saw a
statistically significant 27% reduction in CHD and if you take
the usual 3 point MACE of current clinical trials, there was a
25% reduction, already statistically significant. We also had the
ability to link data over 20 years. Remember, after the five year
randomized treatment period, it becomes observational in nature,
but what it showed was that when you gave nearly 40% in each arm
statins and you followed people up this legacy effect, over a 20
year period, the people with the LDL above 190, that translated
into this 28% reduction in CHD death. It translated into a 25%
reduction in CV death, and actually an 18% reduction in all-cause
mortality, which you didn't see in the population with slightly
lower LDL cholesterol.


                                               
This is the best evidence we're ever going to get, really, and
answer the question about what should we do in this patient
population. Should we treat with lipid-lowering therapy? The
answer, unequivocally, is yes, and the longer you treat, the more
likely you are to see survival benefits.


Dr. Carolyn
Lam:              
Oh, my goodness! I just love his paper. I have to humbly admit. I
mean, it's in the guidelines already that we should treat these
individuals with LDL above 190, and it really made me think how
I'd taken for granted that there would be a whole body of
evidence behind it from randomized trials, and you are right!
This is the first, and likely going to be the last we're going to
get, because we can't randomize them. So, congratulations. What
you said just now, I can already hear myself playing this podcast
to my patients. May I just ask, are there other remaining
questions to answer, and then what do you also say to those that
say, well what are the harms? How do you balance that with any
potential harms?


Dr. Kausik
Ray:                 
In this particular study, given there was overall safety data
observed in the WOSCOPS Trial population and in their extended
follow-up in the overall 6,500 person cohort, we didn't go on and
look at that. There was no evidence of harm in the extended
follow-up of 6.500 people, so we didn't see the potential added
gain in specifically looking for that. The main question we
wanted to answer, because people had always pulled primary and
secondary prevention patients together, and in fact, your best
evidence is actually from CTT, pooling of primary and secondary
prevention patients where they break the data down by an upper
limit of about 175. With patients above 175, they don't
specifically answer that question. So, to answer your question,
we didn't look at that in the overall WOSCOPS Trial population.
There was no signal for harm that was noticed. Even things like
glucose elevation, if you remember in WOSCOPS, tended to be a
little bit lower.


Dr. Amit
Khera:                
Let me comment on a few things about this paper. First, I want to
congratulate Dr. Ray and his colleagues. I was a history major
and I think this is a great use of a historical tool. At this
point, I think we can talk about WOSCOPS. It's 22 years old. It
is part of the medical history and a very seminal article. I
think they got creative because, as he mentioned. We have
guidelines that support this treatment, but this is almost an
unanswerable question, whether you say it's from ethics, or from
equipoise, it was essentially unanswerable. So, they had to go
back and take this historical study where practice patterns were
different, to be able to look at this question. It was pointed
out, there's pretty clear evidence in here and I think if you
look at that during the five-year study period of the randomized
period, pretty clear evidence that treating participants with
LDLs above 190 without vascular disease certainly lowers
cardiovascular disease events.


                                               
One of the best things about working on the editorial board is
being able to work closely with authors, and I have to also thank
Dr. Ray and his colleagues for being so gracious in working with
us closely in some modifications as this went along. We hope, and
I hope he feels this way, too, that at the end of the day, the
product ends up being even better than where we started. That's
our goal is to really help and work with authors in that way and
they were incredibly responsive. The two things I thought they
did really well that were insightful to the US guidelines and
beyond. One is they also restricted to the group without
diabetes, without ASCVD less than 7.5%, and some other parameters
to really hone down on what we have in the current US guidelines
and still the finding was consistent that the statin therapy
benefited that group.


                                               
The other part was just acknowledging that the legacy part, the
long-term effect, is really valuable. They published heavily in
this area, but at that point, it becomes an observational
component. It's not part of the randomized period. The reason
that adds value, if you look at our guidelines above the age of
21, an LDL above 190 can be treated with a statin, there would be
less controversy if your LDL was 200 and you're 55, but if you're
22 or 23, I think there may be more angst. That's where the
long-term data is important, because we're not looking
necessarily always at 10 years, but we're looking at 20 or 30 or
40 or 50 years. I think this does at least shed some light. I
appreciate the study population was older, but a least it helps
us look at maybe some of the long-term benefits.


                                               
If I may, Carolyn, I would love to ask Dr. Ray a question. Kaus,
when you guys did this, the group with the LDL less than 190 had
essentially similar benefit. The p-interaction was no. I think we
have to acknowledge that the LDLs were higher in that group than
what would seem because the lowest level was 155. Is it above
190, or should it be above 160 where we treat patients with
statins?


Dr. Kausik
Ray:                 
Yes, and I really want to thank the editors, because there were
certain things that you pushed us with analyses and I think that
you could make the case that if you have a LDL cholesterol above
155, over a five-year randomized treatment period, there was a
significant reduction in CHD and MACE as well. So, you could make
that point that actually the cutoff should perhaps be pulled down
even further to about 155. What's interesting is, these groups,
when you broke them down, age was identical, BMI was identical,
blood pressure, and everything else. The only thing that was
different, really, was the LDL cholesterol, which impacted on
total cholesterol. TGs, HDLs were absolutely identical. I think
you could probably make the case.


                                               
I think the one thing that we didn't see, although it's
observational in those with slightly lower LDL cholesterols, is
that over the 25 year period, they seem to get slightly less
mortality benefits. Now, that could be a chance finding, because
it's observational. We don't really know the implications of
that, but I think over a five-year period, this is the best
evidence you're going to get for primary prevention, right?


Dr. Amit
Khera:                
Agreed. The US guidelines do say above 160, it's a point of
consideration. It can be a factor to consider as we think about
treatment, so perhaps this helps bolster that point as well.


Dr. Kausik
Ray:                 
It's not just the American guidelines. In the European
guidelines, when they use score, if you look at LDL cholesterol
levels, the European case fatality 10 year risk is 2.5%, which is
equivalent roughly to 7.5% fatal and non-fatal MI in the pooled
cohort equation. There they still have diet and lifestyle, but it
says, "Consider pharmacological," and one of the things I thought
was really interesting is if you did a 10 year risk calculation
in this group, 67% of the population with an LDL above 190, you
would have said the predicted 10-year risk was below 7.5%, but
the 10-year observed risk was double that. It was 15%. If you did
the same thing for the group between 155 and 190, your ten-year
risk predicted would be in most of these people, you would have
said about 90% actually are less than 7.5%, so you wouldn't have
given them a statin. But, their observed event rates in the
placebo group was about 11%.


                                               
So, I think that it tells you if you have an isolated elevated
cholesterol above 155, you're probably going to be
underestimating risk if you're using global risk score, and
perhaps a discussion with the patient about risks and benefits in
the way that most of us try to do and citing data like this might
encourage patients to actually start that therapy earlier, which
most of us probably believe from genetic and legacy effect is
probably beneficial. That's one of the other implications of
this.


Dr. Amit
Khera:                
This is why one has to read not just the abstract, but all the
details, because there are so many kernels of interesting
findings in this paper beyond just the highlights that we hit
upon.


Dr. Carolyn
Lam:              
Thank you both for just a marvelous discussion of an incredible
paper that is really, really going to be extremely clinically
relevant. We're so proud to be publishing this in Circulation
this week.


                                               
Audience, you heard it right here. Don't forget to tune in again
next week as well to Circulation on the Run for even more hot
news.