Circulation December 17, 2019 Issue

Dr Carolyn 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 Greg Hundley: And I'm associate editor, Dr Greg Hundley, from
VCU Health, the Pauley Heart Center, in Richmond, Virginia.


Well Carolyn, our feature discussion, are results from the
Odyssey study and they're presented by Professor Wouter Jukema
from Leiden University Medical Center, regarding the relationship
between ultra-low LDL levels in both ischemic and hemorrhagic
stroke. The study really seeks to answer the question related to
concerns that ultra-low LDL levels, less than 15 milligrams per
deciliter, in patients treated for ischemic heart disease could
increase the risk of hemorrhagic stroke, but more to come on that
intriguing question. Carolyn, how about your first paper?


Dr Carolyn Lam: It's from doctors Condorelli and Kallikourdis
from Humanitas Clinical and Research Center and Institute of
Genetic and Biomedical Research respectively in Rozzano Milan in
Italy. Now, these authors used single cell RNA sequencing to map
the cardiac immune composition in the standard Murine non
ischemic pressure overload heart failure model. They then
integrated their findings using multi parameter flow cytometry,
immunohistochemistry and tissue clarification immunofluorescence
in both the mouse and the human. And they found that despite the
absence of infectious agents or an autoimmune trigger, induction
of disease led to immune activation that involved far more cell
types than previously thought. And that included neutrophils, B
cells, natural killer cells, and mast cells. And this really
opens up the field of cardio immunology to further investigation
using toolkits that have already been developed to study these
immune subsets.


Dr Greg Hundley: Ah, so Carolyn, do they have any specific
examples?


Dr Carolyn Lam: Hmm, indeed they did. They found that activation
lead to up regulation of key subset specific molecules such as
pro inflammatory cytokine onco statin M in pro-inflammatory
macrophages, and PD1 in T regulatory cells. Now these are
significant because they may help to explain clinical findings
such as the refractivity of heart failure patients to anti TNF
therapy and cardio toxicity during anti PD1 cancer immunotherapy
respectively, for the more these subset specific molecules may
become useful targets for the diagnosis or therapy of heart
failure.


Dr Greg Hundley: Oh, beautiful. Well Carolyn, my next article is
from Ambarish Pandey from University of Texas Southwestern
Medical Center and it's entitled Incorporation of Biomarkers into
Risk Assessment for Allocation of any Hypertensive Medication,
According to the 2017 ACC, AHA High Blood Pressure Guidelines, a
Pooled Cohort Analysis.


Dr Carolyn Lam: So I suppose asking does consideration of
troponin or BNP inform cardiovascular risk in those with
hypertension?


Dr Greg Hundley: Great question Carolyn. So in this study, the
authors included participant level data from 12,987 participants
across three cohort studies, ERIC, the Dallas Heart Study and
MESA. And they were pooled excluding individuals with prevalent
cardiovascular disease and those taking antihypertension
medications at baseline. Participants were analyzed according to
blood pressure treatment group from the 2017 ACC AHA Blood
Pressure Guideline and those with high blood pressure, 120 to 159
millimeters of mercury, were further stratified by biomarker
status.


Dr Carolyn Lam: Okay. So what did they find Greg?


Dr Greg Hundley: Participants with elevated blood pressure or
hypertension, not recommended for any hypertensive medication
with versus without either elevated high sensitivity, cardiac
troponin T or N terminal pro BNP, had a 10-year cardiovascular
incidence rate of 11% and 4.6%, with a 10-year number needed to
treat to prevent one event for intensive blood pressure lowering
of 36 and 85 individuals respectively.


In addition, among participants with stage one or stage two
hypertension recommended for antihypertensive medication with a
blood pressure less than 160 over a hundred millimeters of
mercury, those with versus without an elevated biomarker had a
10-year cardiovascular incidence rate of 15.1% and 7.9% with a
10-year number needed to treat, to prevent one event of 26
individuals and 49 individuals respectively.


Dr Carolyn Lam: Wow, Greg, those are impressive numbers. So does
this mean we should be checking biomarkers in everyone?


Dr Greg Hundley: Great question again Carolyn. These results
suggest that a biomarker based approach to cardiovascular risk
assessment may help identify high risk individuals with elevated
blood pressure or stage one hypertension who are currently not
recommended for any hypertensive medication, according to the
2017 ACC AHA Blood Pressure Guideline, but who may benefit from
blood pressure lowering therapy. And it seems the more we
research blood pressure measures, the more we learn regarding
individualizing targets for blood pressure lowering.


Dr Carolyn Lam: Very interesting Greg. Thanks. So my next paper
sought to understand to what extent do drug costs, which are
potentially actionable factors, contribute to medication
non-adherence? A very interesting and relevant question, and this
is from Dr Nasir from Yale New Haven Health System and colleagues
who identified more than 14,000 US adults with a reported history
of atherosclerotic cardiovascular disease in the national health
interview survey from 2013 to 2017. Now participants were
considered to have experienced cost related non-adherence if in
the preceding 12 months they reported either skipping doses to
save money or taking less medication to save money or delaying
filling a prescription to save money. And they used survey
analysis to obtain national estimates.


Dr Greg Hundley: Okay, Carolyn. So what did they find?


Dr Carolyn Lam: Listen to this. So they found that one in eight
patients with atherosclerotic cardiovascular disease reported
non-adherence with medications due to cost, representing nearly
1.5 million estimated patients missing doses, 1.6 million taking
lower than prescribed doses and 1.9 million intentionally
delaying a medication fill to save costs, all in the United
States. Patients less than 65 years of age, had a three fold
higher rate of medication noncompliance due to cost, with
significantly higher rates in women and among patients from low
income families and those without health insurance. Now the take
home message I think is that the removal of financial barriers to
accessing medications, particularly among vulnerable patient
groups, may help improve adherence to essential therapies to
reduce atherosclerotic cardiovascular disease, morbidity and
mortality.


Dr Greg Hundley: Great paper, Carolyn. We've got a couple other
articles in this issue. Let's just run through so our listeners
get a synopsis. So Dr Javed Butler from University of Mississippi
Medical Center has a nice white paper regarding heart failure
endpoints in cardiovascular outcome trials of SGLT2 inhibitors in
patients with type two diabetes. Dr Brahmajee Nallamothu in a
perspective piece, discusses issues related to the legal
prosecution of stent cases and the 70/30 rule. Remember Carolyn,
the 70/30 rule, the operator may say a stenosis is 70% of an
intracoronary luminal narrowing, but in review, others seem to
think it's less than 30% and often these cases are prosecuted for
performing coronary artery interventions on these lesions, but
what Dr Nallamothu argues is perhaps, these definitions are
really related to how that stenosis was measured. Are you taking
approximately dilated segment or a distantly dilating segment as
your reference point? Really interesting perspective piece.


The next article is from Dr Prateeti Khazanie at the University
of Colorado in Denver and provides an on my mind piece with Dr
Mark Drazner regarding ethical issues that arise during cardiac
transplant allocation process. They review some of the pitfalls
associated with current physician subjective assessments used for
heart transplants in the United States. Dr Neil Kay presents
another EKG challenge related to T, a new wave alternans and
consumption of alcohol in association with combinations of
antiarrhythmic drugs. Dr Dipan Shah from Houston Methodist
provides new data in a letter, a research letter, regarding the
association of extracellular volume fraction and MRI measure of
interstitial fibrosis in the setting of chronic mitral
regurgitation.


And finally, Carolyn, Dr Nirvik Pal and colleagues write a letter
referring to an earlier publication related to LVAD adverse
outcomes and cardiac transplantation. Well, shall we move on to
that feature discussion?


Dr Carolyn Lam: Yeah, let's do that, Greg.


Dr Greg Hundley: Welcome everyone to our feature discussion and
we're very excited today to have Dr Wouter Jukema from Leiden
University Medical Center who's going to tell us about the
utility of PCSK9 inhibitors on the impact of both ischemic and
hemorrhagic stroke. A large study that comes from the Odyssey
study. Welter, we are so glad that you're with us this morning,
afternoon, evening, wherever you may be in the world. Could you
tell us, what were the thoughts behind putting this study
together?


Dr Wouter Jukema: As we all know that patients with acute
coronary syndromes, ACS, are at an increased risk for a
subsequent stroke. And we also do know that lowering of
atherogenic lipoproteins, including LDL cholesterol of course,
reduces the risk of ischemic stroke in chronic atherosclerotic
cardiovascular disease or recent ACS.


However, concerns have been raised about very low LDL cholesterol
levels and the potential risk and increased risk of hemorrhagic
stroke.


So the effect of lipid lowering by PCSK9 inhibition, both
ischemic and hemorrhagic stroke is actually not fully determined.
So what we therefore did to better investigate this is that in
the obviously outcomes trial, the main publication was of course
in New England Journal of Medicine already, we did a
pre-specified analysis. We was designed to assess the effect of
LRO come up on the ischemic as well as on the hemorrhagic stroke
in patients with a recent ACS in obviously outcomes, all patients
had a recent ACS and we have hypothesized that for patients
treated with LRO come up that would be one, A, a reduction in
risk of ischemic stroke, B, without an increase in hemorrhagic
stroke. And we also hypothesize that the results would be
irrespective of baseline LDL cholesterol and the history of
cerebral vascular disease.


So that was our background and objectives and we investigated
this in urology outcomes trial a huge, huge trial. If you may all
recall post ACS patients one to 12 months post ACS, they all had
a run in period two to 16 weeks of high intensity or maximum
tolerated dose of atorvastatin or rosuvastatin, and then you had
to meet certain lipids criteria and then you were randomized to
LRO come up circuitously every two weeks or placebo. And of
course all the patients and investigators were blinded to lipid
levels and treatment location. So this was a design.


Dr Greg Hundley: Wouter that was a fantastic description of why
we're studying this particular series of issues as both ischemic
and hemorrhagic strokes.


Tell us a little bit about your study results?


Dr Wouter Jukema: We looked at the entire population of the
Odyssey outcomes trial. This is almost 19000 patients and then we
looked if they had a history of prior cerebral vascular disease
or we have no history of cerebral vascular disease. The majority,
almost 18000 did not have a history of cerebral vascular disease
and over 900 did have a history of cerebral vascular disease. And
we've also looked at our baseline LDL cholesterol levels. Well,
if you can of course, be sure we appreciate people with history
of cerebral vascular disease or way out, there are a different
study population. So that's of course what you may expect anyway.
And that's what we saw.


But regardless if you have the history of a vascular disease or
you didn't have that, we saw a reduction of any stroke and
actually it was 28% reduction of any stroke, which is quite
impressive, in my opinion, as highly significant with a P value
of point 0.05 and then afterwards of course, we tried to split it
in ischemic stroke and hemorrhagic strokes.


So as I told you, any stroke was reduced with 28% and if you then
look at ischemic stroke, it was 27%. Also significant at the P
value of 0.01. And then of course, the big question, what would
happen with hemorrhagic stroke. And actually this was numerically
less also in the LRO come up group. So there was not only a
reduction in any stroke, but also in ischemic stroke. But also in
hemorrhagic stroke, but this was 17% and then of course you are
in the low numbers. So the ischemic ratio for hemorrhagic stroke
was 0.83 in favor of LRO come up. And of course that by itself is
not significant to the low numbers, but numerically there were
less hemorrhagic strokes on top of that, there were less ischemic
strokes and that was, I think a very reassuring finding. And the
interesting part is that these results were more or less
independent.


If you have a history of cerebral vascular disease are not, so
people without a price were benefiting and with a price were
benefiting. And it was also statistically independent of your
baseline LDL cholesterol level. So the results were basically the
same. If you had a baseline LDL starting below 80 between 80 and
100 and over 100 the results were the same. LRO come up was
always better than placebo. If you look at the data, you could
see that it was perhaps doing slightly even better if you had a
slightly higher cholesterol from the start, which is conceivable.
But the formal test returned 80 did not say show any difference.
So you could say the beneficial effect of other LRO come up on
stroke in post ACA patients is independent of your history of
cerebral vascular disease, is independent of your baseline LDL.
LRO come up is just better for ischemic strokes as well as for
hemorrhagic strokes at least there was no sign.


Never mind add to that, we did even go one step further and we
looked at the risk of hemorrhagic stroke in relation to the HG
LDL cholesterol level. So not your baseline LDL cholesterol
level, but the achieved LDL cholesterol level in the LRO come up
group because there you find the, of course very low numbers and
we divided them and below 25 milligrams per deciliter, which we
could continue really low between 25 to 15, 15 to 17 over 17 and
the numbers of hemorrhagic strokes were exactly the same, always
0.1, 0.2, 0.3%. So very low. And it was certainly not the case
that they do very low numbers. We saw more hemorrhagic strokes.
So this is again very reassuring data. So even at very low levels
of LDL during the trial. Of course we should realize that this
trial is of course only a medium duration of two per date, but we
didn't see more erratic strokes.


So in my opinion, this is very reassuring data.


Dr Greg Hundley: Very good. I loved all that analysis of
subgroups. I want to ask you one quick subgroup question. Was
there any difference in outcomes related to gender or age?


Dr Wouter Jukema: As far as we could see there was no
differential effect in gender nor in age. Of course you should
realize that in very advanced age, of course the numbers get
small and if you then start dividing them again in the history of
stroke or not, then of course the numbers will get low. But in
general there is no age or gender difference.


Dr Greg Hundley: Fantastic. So where do you think, does this
field progress from here and what do you think will be the next
study that we need related to PCSK9 inhibitors and adverse
effects?


Dr Wouter Jukema: I think we have shown now that patients with a
recent ACS and dyslipidemia, despite incentive therapy, they do
benefit from the PCSK9 LRO Come up, which is reflected by a
decrease in the risk of stroke. You should of course realize that
this is a post ACS population, so it was not targeted in a post
stroke population. This is a atherosclerotic disease population,
so the results are applying for an atherosclerotic population of
course, many people that have a stroke in the past may have and
also from embolic processes from a FIP or whatsoever, and those
results may be the same but may of course they may also be
different. So that situation was not tested here. This is a
atherosclerotic post ACS population. Of course you may be
interested in what would happen with strokes in an embolic
population with a FIP and that would of course be a very nice
trial to do as well. But then you have to do an entirely new
trial. And some of these trials are of course underway, but I
cannot, with my publication circulation, I cannot provide you
with the answer.


Dr Greg Hundley: Well listeners, we've had a great discussion on
our feature article today from Dr Wouter Jukema from Leiden
university medical center and really some important insights
related to PCSK9 inhibitors and the fact in this study, a large
study, a sub study from Odyssey that indicates really no increase
incidents of both hemorrhagic or ischemic stroke in patients that
receive these agents and had previously sustained acute coronary
syndromes.


I want to wish you all a great week and on the half of Carolyn
and myself. Hope to see you next week. Take care now.


This program is copyright American heart association 2019.