Circulation April 3, 2018 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's feature paper is about statins, and it's the first
population-based study to show a dose-dependent benefit on
amputation and survival in peripheral artery disease. Very
important data and a very important discussion coming right up
after these summaries.


                                               
The first original paper this week indicates for the first time
that the natural history of coronary stenosis is better predicted
by physiologic information by FFR, or fractional flow reserve,
than by anatomic information from angiography. First author, Dr.
Ciccarelli, corresponding author, Dr. DeBruyne, from OLV Hospital
in Belgium compared the values of angiographic diameter stenosis
and of fractional flow reserve in predicting the natural history
among 607 patients from the FAME 2 trial who had documented
stable coronary disease and in whom no revascularization was
performed. The primary end point was defined as vessel oriented
clinical end point at two years, and this was a composite of
prospectively adjudicated cardiac death, vessel-related
myocardial infarction, vessel-related urgent and non-urgent
revascularization.


                                               
The overall results showed that FFR predicted the natural history
better than diameter stenosis. In addition, among the stenosis
with mismatch between diameter stenosis and FFR, more than half
had a low FFR in the presence of an angiographically mild
stenosis and the rate of primary outcome was higher in those with
reduced FFR regardless of whether diameter stenosis was
significant or not. The take-home message is, therefore, that
measurements of FFR should be considered not only an
angiographically intermediate stenosis but also perhaps a mild or
severe stenosis by visual evaluation.


                                               
The next study provides population-based data on cardiovascular
outcomes and risks after initiation of a sodium glucose
cotransporter-2 inhibitor, or SGLT2 inhibitor. First and
corresponding author, Dr. Udell, from University of Toronto, and
his colleagues, performed population-based cohort study among
type 2 diabetes patient with established cardiovascular disease
and newly initiated on antihyperglycemic agents within the US
Department of Defense Military Health System between 2013 and
2016. After propensity matching, more than 25,250 patients were
followed for a median of 1.6 years. Initiation of SGLT2
inhibitors was associated with a lower all-cause mortality, lower
hospitalization for heart failure events, lower major adverse
cardiovascular events, but higher below-knee amputation risk.
Findings underscore the potential benefits and risks to be aware
of when initiating SGLT2 inhibitors. Importantly, it remains
unclear whether the risk of below-knee amputation extends across
a class of medications as the study was not powered to make
comparisons among individual treatments.


                                               
The next paper reports results of the redefined trial, which is
the first trial to study the effects of
renin-angiotensin-aldosterone system inhibitors in adults with
tetrology of Fallot and mild right ventricular dysfunction in the
absence of severe valvular lesions. First author, Dr. Bokma, and
corresponding author, Dr. Bouma from Academic Medical Center
Amsterdam, and their colleagues, studied 95 patients in the
redefined trial and found that 150 mg of losartan daily did not
significantly improve the primary outcome of right ventricular
ejection fraction change compared to placebo. There were no
significant treatment effects on secondary outcomes of left
ventricular ejection fraction, peak aerobic exercise capacity or
NT-proBNP. However, in a post hoc analysis, losartan was
associated with improved right ventricular ejection fraction in a
subgroup of 30 patients with nonrestrictive right ventricles and
incomplete remodeling. The conclusion is, therefore, that
losartan had no significant effect on right ventricular
dysfunction or secondary outcome parameters in repaired tetralogy
of Fallot. Future larger studies may determine whether there
might be a role for losartan in specific vulnerable subgroups.


                                               
The final study reinforces that vesicle trafficking plays an
essential role in the signal regulation of pathologic hypertrophy
and identifies a novel potential target in this process. This
novel target is the transmembrane BAX inhibitor motif containing
1, or TMBIM1. First author, Dr. Deng, corresponding author, Dr.
Li, from Wuhan University in China, and their colleagues, found
that TMBIM1 expression levels were substantially decreased in
both clinical and experimental hypertrophic hearts.
Mechanistically, TMBIM1 interacted directly with tumor
susceptibility gene 101 and accelerated the formation of
multivesicular bodies to degrade activated toll-like receptor 4.
Toll-like receptor 4 degradation in turn was essentially for the
progression of cardiac hypertrophy. Importantly, expressing
TMBIM1 in monkeys via lentivirus protected their hearts from
aortic banding induced cardiac hypertrophy. In summary, these
findings shed light on the role of vesicle trafficking in signal
regulation during cardiac hypertrophy and provide a novel
therapeutic target for treating hypertrophy.


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


                                               
Peripheral artery disease, a disease that affects more than 200
million individuals worldwide and associated with a high risk of
cardiovascular events and death and, of course, the much feared
amputations. Yes, statin guidelines for peripheral artery disease
are largely based on coronary artery disease or stroke data.
Well, today's feature paper really addresses an important
knowledge gap between statins, doses, amputation survival in
peripheral artery disease. I'm delighted to have the first and
corresponding author, Dr. Shipra Arya from Stanford University
School of Medicine and, of course, our favorite, Dr. Josh
Beckman, Associated Editor from Vanderbilt University.


                                               
Now, Josh. I understand there's a bit of a back story of how this
paper came to circulation. Want to share?


Dr Josh
Beckman:           
Oh, absolutely. First of all, I have to say that one of the jobs
of an associated editor is someone who kind of goes antiquing in
every single store. Every place I am where people are presenting
really good science, I'm kind of scoping it out. I'm interested.
I want to see what's going on. I like to talk to the people who
are doing the work to see how they're thinking about it, and I
was lucky enough to see Dr. Arya's presentation. I think it was
at an ATVB meeting, wasn't it?


Dr Shipra
Arya:                 
That's right.


Dr Josh
Beckman:           
I thought that this is an incredibly cool piece of work, and I
basically hoped, I prayed, I asked. I said, "You know, maybe you
should send this to us because we would really like to see the
full manuscript," because inside I hoped that it would be just as
impressive when it was written out as a full manuscript as it was
when she was discussing it at the meeting. And, lo and behold, we
were lucky enough that she submitted it to us and you can see the
results online right now.


Dr Carolyn
Lam:               
Indeed! Well put. Shipra, with that kind of lineup, please, tell
us about your study and what you found.


Dr Shipra
Arya:                 
Thank you for that invitation to submit to Circulation because
initially I wasn't sure if Circulation would be interested in my
work, so it was really great to hear when Josh said that this is
something that it would certainly consider. The basic premise was
to try and find out whether high-intensity statins as defined by
the 2013 lipid guidelines, they would also have limb protective
effects for PAD along with reduction mortality. As you said in
the introduction, most of the data comes from either coronary
data or comes from small groups of PAD patients, but never from
such a large population.


                                               
We identified about 150,000 veterans in the National VA database
from 2003 to 2014 and excluded people who didn't have a diagnosis
of PAD before 2003, and why this was such a labor of love was
also to figure out how to identify the certainty that people had
PAD and then getting into their pharmacy files and trying to
parse out whether they were on high-intensity, low, moderate, or
no statin. Initially, I had done the analysis of no statin, but
then after review and discussion, it became clear that we needed
a control group, which was people who were also on some
guideline-directed therapy and not just no statin because they
could be patients who were the noncompliant patients and who
don't show up to the doctor's visits, and that's why they do
poorly.


                                               
That's why we chose a control group which were on antiplatelet
therapy, at least aspirin or Plavix, any other antiplatelet
agent. Even in that comparison, we find that after risk
adjustment, patients who are on high-intensity statin had a more
than 30% risk reduction of amputation as well as about a 24, 25%
risk reduction of mortality compared to people who did not take a
statin but at least took an aspirin. Low to moderate intensity
statins were also effective, about 20%. Risk reduction in both
amputation and mortality, but high-intensity statins when
directly compared to the low to moderate intensity statins
outperformed them.


                                               
Just to be sure of our findings, we did it so many different
ways. We did the Cox modeling. Then we did propensity matching
that which person is more likely to receive the statin versus the
other. Then we did subgroup analyses where we put people in
different subgroups that people who had coronary artery disease
as an indication, maybe that's why they were on these statins.
But, people without coronary artery disease also same association
[stack 00:11:12]. We were pretty confident in our findings, and
that's why we sent it to Circulation.


Dr Carolyn
Lam:               
Wow. You know, Josh, you are the best at putting papers like this
into context and really expounding on the significant. Tell us,
why did this catch your attention so much?


Dr Josh
Beckman:           
Every time I think that statins have become just a standard part
of therapy for patients with atherosclerosis, the first thing I
noticed in this paper was that there were so many people who were
still not on any statins or people who were on homeopathic doses
of statins, and I can't understand how that happens. I think the
mortality data was nice and consistent, but the amputation data
is what really made a big difference. I'll ask Dr. Arya, but in
my impression, the literature has been sort of back and forth as
to whether or not statins really reduced limb outcomes. Your
paper, I think, was clearly the largest sample that had taken a
look at that question. Can you sort of separate out your papers
from some of the previous work in that area?


Dr Shipra
Arya:                 
Sure. I would add that a lot of work about amputations has been
coming out from vascular surgery data, and a lot of that work
just focuses on short term outcome for limb loss. They look at 30
days. Maybe they'll go look up to six months to a year, but
actually patency of bypasses, patency of vessels is a long-term
phenomenon. Much like mortality that can happen years later, your
amputation risk can happen years later, too. I think what
separates us is the lifetime followup for these patients, and we
are looking in a cohort of patients who are in this veterans'
healthcare system so the data is automatically getting captured
even if they get their care outside. Records do make it back and
diagnoses do make it back. It's the VA [inaudible 00:13:03], and
we did some sensitivity analysis to show that, yes, most of the
veterans we have in [inaudible 00:13:09] actually get their care
and have data being added continuously into the corporate data
warehouse.


                                               
That was something I think that lent to the power of making the
[sure 00:13:20] conclusion and that's where previous studies have
not been able to show a significant association with amputation.
The studies, if they are single center or they are focused from
electronic medical records or perspective followup, either the
patients get lost to followup or go see other doctors or other
healthcare systems, and that information doesn't get back to the
researchers, while mortality data you can get from Social
Security Death Index or other sources. I think that's what makes
the study different than other studies in this similar field in
terms of followup.


Dr Josh
Beckman:           
I don't think you're giving yourself enough credit. There's a
whole bunch of things that make the study unique. One of the
things that I was most taken with right upfront was the way that
you defined peripheral artery disease for this population. There
has been, as far as I know, at least seven or eight different
definitions that people have used with administrative data to try
and ferret out who has PAD, and in contrast to coronary disease
and stroke, it's a much more complicated endeavor to do that. So,
when I saw the way that you did it ... I'm going to say this in a
way that I know is going to sound funny, but you made the
complicated look really simple. Your definition is not something
that required 3,000 lines of ICD-9 codes within inclusion and
exclusion criteria and speaks, in my opinion, to the power of the
large sample because, basically, they needed one ICD-9 code and
either two ABIs, a visit to a vascular surgeon or procedural
code. Now, I know that this definition comes from some of your
work, so can you tell us how you derive this and then let's talk
about what that means.


Dr Shipra
Arya:                 
Absolutely. We looked at practice patterns for patients with
vascular disease across the VA, and most patients who undergo
procedures for PAD, we can confidently say that they do have PAD.
When we look at the specificity of just that occurrence, it's
pretty high, like [90% 00:15:23]. Then what we did was we did
some random sampling in the VA data, about 300 patients, and used
different codes to see if patients came back to the vascular
surgeon within ... We used 14 months because it's usually one
year followup that most people prescribe, so whether they went
two months before or after because the appointment hours. We
found that that was again a high specificity of about 80%. Then,
when you look at patients who come back with ABI followup. So, we
looked at CPT codes for ABI. We found out it's like a 99%
specificity. If you have ABI followup within a year, and we
relaxed it to 14 months, you could be 99% confident that this
patient does have PAD.


                                               
We just combined all those three together, and this is ... If
Circulation is interested, I can send you this, too. We are
working on this manuscript where we are giving researchers
different algorithms that they could use to identify PAD because
I wanted a more specific sample because I was looking at PAD
outcomes. I wanted the PAD definition to be tight. Our
specificity is greater than 80% combining all these three
together, about 84%. We are fairly confident in this that, yes,
these patients truly have PAD, so when we follow them up for
outcomes, we can be confident in our results. If researchers
wanted a more relaxed definition of PAD, they could use other
algorithms that we are putting in that paper where they could
say, "We will only use one ABI measurement, or we would use a
combination of these."


Dr Josh
Beckman:           
That brings up two points. You talk about this brings up the
power of large data and the ability to tone down on people who
really, truly, absolutely have PAD without any question. So,
number one, are you worried that you're missing people that
probably do have PAD and would benefit from therapy, and number
two, do you worry that you're basically concentrating on the
sickest right end of the curve of the group of PAD patients?


Dr Shipra
Arya:                 
Right. That's a great point, and I discussed that with my
coauthors and mentors and we wanted to be sure about our outcomes
and not want to include people who did not have PAD, and then we
are kind of including the effect size of what we may find, but
yes, these are truly what we are calling a symptomatic PAD, and I
think I mentioned that in the manuscript somewhere, that we
probably would be missing people who are asymptomatic and not
really being followed up. If we extended this analysis to people
who are not regularly being followed or being under surveillance
for their PAD, the results could be different. So, yes, it does
not generalize the whole of that population. If we had gone that
route and relaxed our inclusion, my worry was that we would get
... Because of large data setting up, as you say, if we include a
bunch of people who are truly not PAD, we would be a [threading
00:18:17] risk in non-PAD patients.


Dr Carolyn
Lam:               
Josh and Shipra, I loved the paper, but after this discussion I'm
even more in love with the paper and impressed, so I think I just
have a question for both of you. Is there any excuse not to give
statins now? Do we actually think a trial is going to come on
this topic? Is this the best data that we have? Is it going to
enter guidelines? What do you think?


Dr Josh
Beckman:           
I can give you my opinion first, if you want, because you're the
person who actually has control of all the data. I would say
this. I think it's been well known that statins should be used in
all the patients with PAD for their cardiac outcome. My guess is
that there are two things that are going to happen that are going
to make people consider statins for limb outcomes.


                                               
One, data like this and there's never going to be a trial, a
prospective randomized trial at this point, I mean unless you
disagree, but there's no way people will randomize to not statin.
I think the second reason is the recent data on the PCSK9
inhibitor, evolocumab, which showed that on top of statins in PAD
patients, there was a further reduction in limb events. I think
we're heading towards getting the LDL to zero. It may take a
couple more steps, but that's basically what's going to happen.


Dr Shipra
Arya:                 
I agree. I think there has been time and time again data that
shows, especially those already data supporting the mortality
benefit for larger cohorts of patients with cardiovascular
disease including PAD. I think this study really nails down the
limb protector effects of statins, and doing a trial of this
magnitude would be very difficult to do because to get that would
be effect size that you have. You would need a huge cohort of
patients, and you probably won't find statin-naïve patients
because you have already half the patients with PAD have coronary
artery disease, as well. So, not every study needs a trial. Not
every question needs a trial, in my opinion. I think that's the
power of large data sets. I think the evidence is overwhelming,
and I would agree with Josh.


Dr Josh
Beckman:           
I have always had a hard time explaining to people who came to
see me for legs problems that they have to take a drug for their
heart. It's sort of a weird two-step that people have a hard time
accommodating. Do you think by telling them that this drug will
also save their leg that they're going to be more likely to take
the medicine by the end of the year?


Dr Shipra
Arya:                 
Yes, absolutely. That's what I tell my patients who come and see
me, that this medication works on arterial plaques, and it
stabilizes them. It's not just the same plaque that you have in
your heart is the one you have in your leg. Maybe a little
different, but to oversimplify, yes. This is not just a heart
medication, and this is not just a cholesterol medication. This
is a medication for your plaques, for your blockages. That's how
I explain it to them, and I think the uptake would be more if we
explain to them that, yes, this will help you keep your leg, stay
ambulatory and stay at home and not end up in assisted living or
nursing home.


Dr Josh
Beckman:           
Carolyn, this is so much fun, especially when we get to talk to
the people that do so much hard work to put stuff in circulation,
so I just want to say thanks again to Shipra and her coauthors.


Dr Shipra
Arya:                 
Thank you so much, and thank you for giving us the opportunity. I
think the comments from Circulation really made our paper better,
so thank you for doing that.


Dr Carolyn
Lam:               
I wish that we could just keep going on and on because I just
know that Josh has even more great questions up his sleeve. See,
Shipra, I told you, he's amazing. But, there you go. You're
amazing, too. Your paper is amazing. Thank you so much for
joining us today.