Oct 31, 2016
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.