Circulation November 1, 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. Our interview today comes
to you live from Rome at the European Society of Cardiology,
where I talk to authors of The STICH Trial, about their ten year
outcomes that help to answer the question, "Is there such a thing
as being too old for coronary artery bypass surgery in heart
failure?" But first, here's your summary of this week's journal:


 
 
The first paper provides experimental evidence that hypertension
may be a bone marrow disease. In this paper, first author Dr.
Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The
First Affiliated Hospital of Dalian Medical University in China,
recognize that recruitment of leukocytes from the bone marrow to
the vascular wall is a key step in the development of
hypertension. Numerous factors stimulate this leukocyte migration
during inflammation, including chemokines, which are low
molecular weight proteins of the cytokine family which activate
g-protein coupled receptors and induce migration of neutrophils,
monocytes, and macrophages to the damaged vascular wall.


 
 
In this study the authors focus on chemokine receptor CXCR2.
Using mouse models with hypertension they found that aortic MRNA
levels of CXCR2 and its ligand CXCL1 are elevated in these mice
with hypertension. They elegantly demonstrated that mice lacking
CXCR2 are protected from blood pressure elevation, vascular
inflammation of inflammatory cells, fibrosis, reactive oxygen
species formation, NADPH activation and vascular dysfunction in
response to either angiotensin 2 or [dolcasalt 00:02:01].


 
 
These results were recapitulated using a novel, allosteric
inhibitor of CXCR2. Importantly, they also showed in 30
hypertensive patients compared to 20 normatensive controls that
hypertensive patients have increased numbers of circulating
CXCR2-positive cells and that there is a correlation between
blood pressure and the number of CXCR2-positive cells in the
circulation.


 
 
In summary, these findings that CXCR2 inhibition prevents and
reverses hypertension and vascular dysfunction in response to
multiple hypertensive stimuli really help us to understand the
mechanisms involved in CXCR2 action, but also point to a
potential clinical use of CXCR2 inhibition for the treatment of
hypertension. This is discussed in a beautiful accompanying
editorial by Drs. [Montenel 00:02:56] and Harrison.


 
 
The next study suggests that the eyes provide a window to
long-term cardiovascular risk. In this paper from first author
Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon
00:03:13] and colleagues from the Brigham and Women's Hospital,
authors investigated whether retinal vessel calibers are
associated with cardiovascular outcomes in long-term follow-up,
and whether they provide incremental value over the 2013 ACCAHA
pooled cohort equations in predicting atherosclerotic
cardiovascular disease events. They studied 10, 470 men and women
from the [Eric 00:03:41] or Atherosclerosis Risk in Community
Study who underwent retinal photography at their third visit,
which occurred in 1993-1995.


 
 
During a mean follow-up of sixteen years, narrower retinal
arterials, but wider retinal venules were associated with
long-term risk of mortality and ischemic stroke in both men and
women. Coronary heart disease in women was also related to
narrower retinal arterials and wider retinal venules independent
of the the pooled cohort equation variables. In fact, retinal
vessel caliber reclassified 21% of low-risk women as
intermediate-risk for atherosclerotic cardiovascular disease
events.


 
 
In discussing the clinical implications of these findings, the
authors noticed that identification of coronary heart disease is
frequently delayed in women and this under-recognition may party
be due to the fact that non-obstructive coronary artery disease
is more prevalent in women and micro-vascular dysfunction may
largely contribute to myocardial ischemia in women. Since the
retinal vessels offer an insight into micro-vasculature, adding
retinal imaging may be of incremental value to current practice
guidelines in risk prediction in low-risk women. This, of course,
deserves further study.


 
 
The next study challenges the traditional focus on macro-vascular
disease in Type 2 diabetes, namely myocardial infarction,
strokes, and peripheral artery disease, and causes us to focus on
micro-vascular disease instead. In this paper from first author
Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer
00:05:36], and colleagues from the Maastricht University Medical
Center in the Netherlands, authors hypothesized that
micro-vascular dysfunction occurs in pre-diabetics, which may
explain the increased risk of complications of micro-vascular
origin in pre-diabetes and early Type 2 diabetes.


 
 
They studied 2,213 individuals in the Maastricht study, which is
population-based cohort study enriched with Type 2 diabetes, and
they determined micro-vascular function, measured as
flicker-light-induced retinal arterial[inaudible 00:06:12]
percentage dilatation, as well as heat-induced skin percentage
hyperemia. They found impaired retinal and skin micro-vascular
function in pre-diabetics with further deterioration in patients
with Type 2 diabetes. Inverse linear associations were found
between micro-vascular function and measures of glycemia such as
HBA1C, fasting and two-hour post-op glucose levels. All
associations were independent of cardiovascular risk factors.


 
 
The clinical implications are that micro-vascular dysfunction in
pre-diabetes may at least partially explain the increased risk of
complications that are known to be of micro-vascular origin such
as retinopathy and albuminuria but also diseases such as heart
failure and cognitive decline. The take-home message is that both
early hyperglycemia and micro-vascular dysfunction may be
considered potential targets for early preventive intervention.


 
 
Well, those were your summaries! Now, let's on to Rome.


 
 
Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and
I am so delighted to be reporting from Rome this time at the
European Society of Cardiology. We are discussing the 10-year
followup paper on STICH that includes an age analysis that is
being featured as a hotline session of clinical trials update.
I'm here with the distinguished guest, the first author, Dr. Mark
Petchey, from University of Glasgow, the corresponding author Dr.
Eric [Moleskus 00:07:51] from Duke University, and the associate
editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56]
from University of Arizona. Welcome! [crosstalk 00:07:59]


 
 
Right, let's get straight into this. Eric, remind us what it
first showed and why there's a need to look at the effective age.


 
Dr. Eric M. :
Thank you Carolyn. Thanks to Circulation and to both of you for
really helping us work through this paper. We are very excited
that we're being able to feature this work in Circulation. So, a
STICH trial is a reminder. Surgical treatment of ischemic heart
failure trial has been a 15-year effort actually that started
with the first patient enrolled in 2002, enrollment ending in
2007 and at the ACC with the simultaneous fabrication in the
journal, we published the 10-year results of the STICH trial,
combining medical therapy vs. cabbage plus medical therapy in
patients with ischemic cardiomyopathy defined as an EF less than
35%. Coronary disease [inaudible 00:08:51] to cabbage was over
90% having class 2 or greater heart failure systems.


 
 
What we showed in our 10-year results was that cabbage, when
added to guideline-directed medical therapy, led to a substantial
reduction in all-cause mortality, cardiovascular mortality as
well as all-cause plus cardiovascular hospitalization in those
patients who were randomized to the cabbage arm. This translated
to about an 18 months extension in survival for the cabbage
patients over that time period, a 16% relative risk reduction in
mortality and nearly a 10% after the risk reduction is all-cause
mortality, with the number needed to be treated of approximately
14.


 
 
With those findings, the next question that we want to address
rapidly was whether there was an impact by age. This is what
we're here to talk about, mostly because everyone recognizes that
age is, although something we can't control ... As we age, our
risk for everything increases, and clearly heart failure, which
is the field that we work in clinically, patients who are older
in heart failure have more risks, and worse clinical outcomes in
patients who are younger. Whether there would be a benefit that
would persist in terms of the treatment in younger as well as
older patients was really the subject of this analysis.


 
Dr. Carolyn Lam:
That's great. So maybe, Mark, you could tell us the highlights of
the results. Give us an idea, first of all, of the age range that
we're talking about, what you looked at. And then- this is
definitely going to be an issue if we're talking about age- the
relative risks vs. the absolute risk of the different types of
outcomes.


 
Dr. Mark P:
Sure. So, the patients in the STICH trial were similar age to a
normal heart failure trial. The median age was around 61. What we
did to look at the patients we had in the trial, we looked at
quartiles, first of all. So the lowest quartile was aged less
than 54, and the highest quartile aged more than 67. So we had a
fair spread of age. We didn't have many patients, we were very
elderly or very old. So 65% were above age 75 and 1% above the
age of 80. When we looked at the patients we saw a similar
[inaudible 00:11:18] to a usual heart failure trial. The older
patients had more co-morbidities, not surprisingly, and they had
more... they basically died more often as they got older as we
see in every other trial.


 
 
When we started looking at the results, the treatment effects of
cabbage, obviously we were very eager to know if the benefits,
which Eric's talked about already were seen across all age
groups. I think clinicians, when they look at patients for bypass
surgery have anxieties around sending older people for bypass
surgery. We were thrilled is probably the word to say that we say
benefits across all age ranges. So the point has been for us in
terms of all-cause mortality were all [less than one 00:11:58].
We saw consistent benefit, or certain across-the-board benefit in
terms of all-cause mortality.


 
 
What we did see that we were very interested about were the
younger patients got more benefit in terms of all-cause
mortality, [inaudible 00:12:12] quite strikingly more. The risk
reduction was over 40% for the ... We saw upper age groups having
benefits with [hazard issues 00:12:24], risk reductions of,
roundabout, the [teens 00:12:28], as in the major overall trial
results, the younger patients got particular benefit.


 
 
We then looked at cardiovascular mortality and we saw a slightly
different pattern. We saw the benefit was actually quite similar
across all age groups. The older patients were getting the
similar reduction in cardiovascular mortality as the younger
patients. So there's the main take-home findings.


 
Dr. Carolyn Lam:
OK, so by extrapolation then, the younger patients, a greater
proportion of their deaths were probably cardiovascular, or
there's a bit more of a competing risk, so to speak from
non-cardiovascular deaths in the elderly, is that kind of the
idea?


 
Dr. Mark P:
Carolyn, that's exactly right. Because the cardiovascular
mortality was similar across all age groups, because all people,
as we know, die more commonly of non-cardiovascular events, we
saw that clearly in the trial the benefits in terms of all-cause
mortality weren't quite as much. Just to emphasize, the
cardiovascular reduction was consistent across all age groups.


 
Dr. Carolyn Lam:
With bypass compared to medical, yes.


 
Dr. Mark P:
Exactly.


 
Dr. Eric M. :
I think an important aspect to remember and I think STICH reminds
us is that even in the oldest population- and although we did
these analyses continuously, we described this in quartiles for
the purpose of the paper- we have to remember in heart failure
patients like these who have coronary disease, cardiovascular
death is the most common cause of death, regardless if you're
young or old. What happens is that as we get older, there is an
increasing rate of non-cardiovascular deaths. It's not surprising
to us, that of the findings we found, which is that as the risk
of non-cardiovascular deaths increase in the ages, the impact on
all-cause mortality is mitigated slightly, while the effect on
cardiovascular mortality remains consistent because it's still by
far the most common cause, I think more than double the cause
even in the oldest group.


 
Dr. Carolyn Lam:
That's a great point. Now I've got to ask something though. What
did you do about crossovers? Because this is a 10-year thing. The
original results of STICH came out 5 years. You'd expect that
there's quite a bit of crossover or no?


 
Dr. Eric M. :
I'll just comment on the effect of crossovers in STICH in
general, and then we can focus on the age analyses. What's really
interesting is that in STICH approximately over time, over the
time period, there was approximately an 18% rate of crossovers.
That actually led to, by the intention to treat analysis, a
decrease in the effect [inaudible 00:15:15] intention to treat.
But when you look at crossovers, the medical therapy patients who
were randomized to medical therapy but received cabbage at some
point, and the patients who were randomized to cabbage but never
did receive cabbage. But actually when you look at as-treated
analyses, by the treatment they received, not [inaudible
00:15:36] they were randomized, the effect of cabbage actually
increases. The relative risk reduction is about 25% in that
group. Thankfully, the effect of crossover into different age
quartiles were [inaudible 00:15:51] different. We had the same,
relatively the same effect, so there were no, we were [eventually
knowing 00:15:57] to make sure that there was no increase in
crossover rates in the older vs. the younger and we did not find
that. I started the discussion, maybe you can complete it.


 
Dr. Mark P:
Thank you for hitting the nail on the head, Eric, that there
weren't many crossovers, but if there were crossovers, if the
crossover towards the cabbage, the benefits seemed the be greater
and that was seen across all age groups. There was no
differential between the older patients and the younger patients.


 
Dr. Carolyn Lam:
You know then, I just want to know what's your take-home message
and then I'd really like to hear from Nancy the take-home message
we wanted to convey in our journal.


 
Dr. Mark P:
I think for me the take-home message goes back to the fundamental
approach to assessing a heart failure patient in a clinic. Over
the years there's been a tendency for patients not to investigate
and look for coronary heart disease. People tend to focus on
medical therapy and device therapy but the coronary arteries have
been the poorer cousin. I think we would urge people to think
about revascularization by surgery, coronary artery bypass
drafting's a treatment for  for heart failure, so certainly,
my practice, we look for coronary artery disease more than we
think about the patient and weigh out the pros and cons and
certainly this analysis was done to give us [granularity
00:17:14] from the perspective of the older person and the young
person and the relative benefits. Basically, it's steered me
towards looking for coronary artery disease. Also you can inform
the patient in the clinic and have discussions with the surgeons
about the benefit in terms of the all-cause mortality across the
age group, and the cardiovascular mortality as well.


 
Dr. Carolyn Lam:
Yeah, it's consistent. That's brilliant. Nancy, speak on behalf
of our journal.


 
Dr. Nancy S.:
So at Circulation, we were very excited to get this paper because
as heart failure clinicians, we all struggle with this issue in
older patients in particular. When we look and find coronary
disease, these tend to be patients with higher surgical risks.
Our surgical colleagues are often hesitant to operate. The
benefits are perhaps less apparent, and this data's very helpful
to show us that in a patient in whom the heart disease is the
primary morbidity, surgical revascularization has a clear benefit
for these patients.


 
 
I do think that it's important to remember though, that STICH
population is a selected population, and probably a little
healthier than the average patient we see in clinic. As Mark
rightly pointed out, the discussions with surgical colleagues I
think can now occur with a greater level of data substantiation
and understanding of the true benefits, and then competing risks
and morbidities in this patients need to be considered with the
reality that surgical revascularization benefits the patients.
We're really excited to have worked with you, this fantastic
group of authors to get this paper to a point where I think it's
really going to have a clinical impact, and that's what we're
trying to do. As you know, Carolyn, editorial board at Circ now
has published really high-quality science that's going to impact
the practice of clinicians seeing patients on a daily basis.


 
Dr. Carolyn Lam:
Thanks so much for that Nancy, and actually I was going to
congratulate you gentlemen. In your paper you so humbly said that
these are exploratory, I think, and I was actually thinking that
we're never going to have a better trial than this and it's
something I am personally taking to be clinically applicable in
my heart failure patients so congratulations. I'm going to switch
tracks a little bit... we're actually going to a simultaneous
publication in Circulation from the European Society of
Cardiology and I think that's really neat for our journal,
Circulation. I want to ask each of you as author perspective and
as associate editor who made this happen, what do you think of
these simultaneous publications? Were there challenges, what was
it like, and what was your experience like?


 
Dr. Mark P:
So I have to confess that usually when we submit papers for
review, there is a mixture of trepidation, fear, generally quite
negative thoughts. We submitted it, and I've got to say that it
was the most interactive, positive experience I've had so far. It
was quite clear that was interested in the data, and wanted to
publish it in a way that informed the clinical community. They
certainly worked with us to make sure the message was honed and
as accurate as possible to reflect the results. We were really
thrilled. It was a "breakneck pace" is also probably the best way
to describe it. We worked day and night actually, but there was
phone calls and emails happening in very rapid sequence and lots
of responsiveness. I could almost describe it as "fun".


 
Dr. Carolyn Lam:
Kudos to you, Nancy! And from your point of view, was it fun?


 
Dr. Nancy S.:
It actually was fun.


 
Dr. Carolyn Lam:
(laughs)


 
Dr. Nancy S.:
You know, we've all had the experience of- on both sides- being
an editor and being an author. Getting a paper, getting reviews,
sending it back, getting the revision, it's not quite what you
want, reviewing it again, sending it back, getting it back, it's
not quite what you want, and then you feel obligated to publish a
paper that's not really what you want. What we've decided to do
is a much more interactive process to say "We're going to work
with you to make this the paper we want to publish. We hope that
as authors that's the paper you want to have written." We're
doing this on a regular basis at Circulation but this was at
hyperspeed, I would say.


 
Dr. Carolyn Lam:
[inaudible 00:21:34] how long?


 
Dr. Nancy S.:
We knew the paper was going to come in. We had been in contact
with Eric. I identified reviewers before we even received the
manuscript. I identified reviewers who would commit to a 72-hour
turnaround. In fact, our reviewers did it in less than 24 hours.
Then I looked at it, added to it, called Eric, and we talked it
over. And then we sent it back with the formal replies. I think
Mark then worked 24/7 to get it back to us very quickly. I worked
with one of the senior associate editors; at that point we didn't
involve the reviewers. We basically track-changed the paper to
make the changes we really thought were necessary at the point.
It wasn't a lot but I think they were critically changes. At that
point, Mark and Eric were kind enough to accept those changes and
the paper was on track for simultaneous publication. I do want to
mention that we have simultaneous publication of five different
presentations here at ESC in Circulation online which is
certainly a record for Circulation and we're really proud of
that.


 
Dr. Eric M. :
First of all, I want to think the journal. Really a remarkable,
wonderful experience. I've been very fortunate in my career to be
in a position to submit simultaneous publications previously, and
this was a wonderful- I think it was a 14-day turnaround, it was
remarkable. And the responses from the reviewers were outstanding
even if they were reviewed in a very short time, and I think the
paper definitely improved.


 
 
A general comment about simultaneous publications as you bring it
up, I think it's an area of controversy. I think my perspective
as a person who does clinical trials, as well as sees a lot of
patients, there's an ethical mandate that exists to... Once you
have information that you're putting out there, to be in a
position, if we think it's clinically impactful, and we feel that
the data is mature, to get that into people's hands, all of it,
as soon as possible. There's a certainly a difference between
what I can speak to in 8-10 minutes on stage with slides that
will get distributed anyway across the world, and what, with
Nancy's help, we are able to put into journal-wide circulation
and really explain the story and give it a full [vetting
00:24:05]. I feel like, from the ethical perspective, being able
to push forward with this simultaneous publication is in the best
interest of our patients, and it's so exciting to see Circulation
now doing this with the European Society, which is a remarkable
achievement for this new editorial board, so thank you again.


 
Dr. Carolyn Lam:
You've been listening to Circulation on the Run. Tune in next
week for more.