Circulation January 30, 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.


                                               
In just a moment, we are going to be discussing the diagnostic
conundrum of elevated high sensitivity cardiac troponin levels in
a patient with renal disease, but also suspected of acute
coronary syndrome. Aha! I bet I caught your attention. A very,
very familiar diagnostic dilemma. So stay tuned right after these
summaries.


                                               
Cardiac allograft vasculopathy is the leading cause of death in
patients more than five years post cardiac transplantation. It
has been hypothesized that cardiac allograft vasculopathy results
from interrupted lymphatic drainage post surgery. Since the donor
lymphatic vessels are not inesthimozed to that of the recipient
during transplantation, thus the lymphatic system may play a
crucial role in the alloimmune response.


                                               
Well, these hypothesis are addressed in the first paper in
today's journal from first author Dr. Edwards, corresponding
author Dr. Wong and colleagues from Kings College, London. These
authors use spect CT lymphoscintigraphy in a pre-clinical model.
And therefore provided objective quantification of lymphatic flow
following transplantation and showed that this correlated to
cardiac allograft vasculopathy. They demonstrated that cardiac
lymphatic remodeling and lymphatic transport dysfunction post
transplant was associated with cardiac allograft vasculopathy and
transplant rejection.


                                               
They further showed that lymphatic flow was increased during
chronic rejection. This in turn may have resulted in enhanced
trafficking of antigen presenting cells to the local draining
lymph nodes in an augmented alloimmune response. Now although the
cause and effect of this phenomenon could not be fully
established, these data provided the impetus for the
investigation of lymphangiogenesis inhibition as a means to
dampen chronic rejection.


                                               
The absorb bioresorbable vascular scaffold is known to completely
resolve within three years after coronary artery implantation.
However, what is the safety and effectiveness of these
bioresorbable scaffolds during this critical three year period.
First author Dr. Ali, corresponding author Dr. Stone and
colleagues from Columbia University Medical Center performed an
individual patient level meta analysis of the four randomized
absorb trial and demonstrated that compared with metallic
everolimus eluting stents, the bioresorbable vascular scaffold
had higher rates of target lesion failure and device thrombosis
cumulatively to three years and between one and three years.
Multi-variable analysis identified the number of treated lesions,
current tobacco use and previous cardiac interventions as
independent predictors of three year target lesion failure.
Whereas diabetes was predictive of three year device thrombosis
in bioresorbable vascular scaffold treated patients.


                                               
The next paper reported the three year follow up of the FAME 2
trial, which compared PCI guided bi-fractional flow reserve with
best medical therapy in patients with stable coronary artery
disease to assess clinical outcomes and cost effectiveness. First
and corresponding author Dr. Fearon and colleagues from Stanford
cardiovascular institute showed that major adverse cardiac events
at three years were significantly lower in the PCI group,
compared with the medical treatment group. This difference was
primarily as a result of a lower rate of urgent
revascularization. Mean initial costs were higher in the PCI
group, but by three years, were similar between the two groups.
The incremental cost effectiveness ratio for PCI compared to
medical therapy was more than $17,000 per quality adjusted life
year at two years and $1,600 per quality adjusted life year at
three years. Thus the authors concluded that percutaneous
coronary intervention in patients with stable coronary artery
disease and at normal fractional flow reserve may be advantages
compared to with medical therapy alone, because it results in
improved clinical outcomes and quality of life at no increased
cost by the end of three years follow up.


                                               
The next study shows for the first time, that pioglitazone may
prevent stroke as a single stand-alone outcome. Today's paper by
first author Dr. Yaghi, corresponding author Dr. Kernan from Yale
School of Medicine and colleagues was a secondary analysis of the
iris trial, which showed that pioglitazone reduced the risk for a
composite outcome of stroke on myocardial infarction among
non-diabetic patients with insulin resistant and a recent stroke
or transient ischemic attack. Now, the current planned secondary
analysis used updated American Heart Association 2013 consensus
criteria for ischemic stroke to examine the effect of
pioglitazone on stroke outcomes. The study found that
pioglitazone reduced the risk by 25% by five years, with absolute
rates of 8% with pioglitazone versus 10.7% with placebo.
Pioglitazone reduced the risk for ischemic strokes, but had no
effect on the risk of hemorrhagic events. These findings add to
the evidence that pioglitazone may be a potent therapy for
vascular disease risk reduction and may help inform shared
decision making by providers and patients for the use of
pioglitazone after ischemic stroke or transient ischemic attack.


                                               
Well, that ends it for our summaries. Now for a feature
discussion.


                                               
The cardiac troponins have really revolutionized cardiology. We
use them in of course the diagnosis of myocardial infarction and
in fact the recent European Society of Cardiology recommendations
say that the rapid zero and one hour triage algorithm for rule in
or rule out of non STEMI should use high sensitivity troponins
and interestingly irrespective of renal function. Now this latter
point has caused some confusion, some questions, since we all
know that patients with chronic kidney disease frequently have
higher or increased levels of cardiac troponins, especially since
we now can detect them with the high sensitivity essays. And this
is even in the absence of an acute coronary syndrome.


                                               
Well, this week's journal contains two papers that address this
topic so well. And I am delighted to have with us the
corresponding author of the first paper, Dr. Christian Mueller
from University Hospital Basel in Switzerland and the author of
the second paper, Dr. Nicholas Mills from University of Edinburgh
in Scotland. For the more, we have Dr. Torbjorn Omland, associate
editor from University of Oslo in Norway.


                                               
Lot's to talk about. Christian, could I start with you? Could you
say in your own words the rationale for looking at this
vulnerable population and then perhaps describe what you did in
your study?


Dr. Christian Mueller:     I'm very thankful
that Circulation shed a lot of light on the population of
patients with renal dysfunction, because both as a clinician and
as a researcher, I'm definitely convinced that they merit a lot
of our attention for several reasons.


                                               
So first, it's important to be aware that the incidents of acute
myocardial infarction among patients presenting with acute chest
pain is much higher in patients with renal dysfunction, as
compared to patients with normal renal function. And second,
atypical clinical presentations also are more frequent in
patients with renal dysfunction. Then possibly third, the ECG of
course also a mandatory tool in our assessment is more often
showing unspecific signs that may mimic or obscure the presence
of myocardial infarctions and most of them are related to left
ventricular hypertrophy. And in addition, patients with renal
dysfunction are more prone to adverse events, both related to
cardiovascular medication. For example, anticoagulation as well
as our cardiovascular procedures, including PCI. Now again, as
both papers have a strong focus on troponin, also cardiac
troponin is a bit more difficult to interpret in patients with
renal dysfunction related to exactly as you mentioned chronic
elevations of cardiac troponin, TNI related to chronic
cardiovascular disease.


                                               
And I think that's so important to stress, any troponin signal in
a patient with renal dysfunction is real and should not be
incorrectly attributed to just a problem of impaired secretion by
the kidneys.


Dr. Carolyn
Lam:              
So definitely an even greater need to diagnose myocardial
infarction accurately in this very high risk population. So tell
us what you did.


Dr. Christian Mueller:     We assessed this
challenging sub group within the APACE study. So APACE is a large
international prospective diagnostic study that is run in five
countries with 12 centers. And we actually enroll consecutive
patients presenting with suspected myocardial infarction. And
then all patients get a very detailed workup and then adjudicated
final diagnosis. And the adjudicated file diagnosis is done by
two independent cardiologists and is based on two enormous
extensive sets of data. The clinical data set that has been
obtained at the local site and of course includes cardiac imaging
and standard troponin testing, ECG data.


                                               
In the second set of data that includes the study specific data
sets, including serial measurements with high sensitivity carry
troponin essay and a lot of details characterization of patients
and patient follow up. So this is the reference standard against
which the one hour algorithm the European Society of Cardiology
evaluated. And the one hour algorithm has been derived and
previously validated in overall population. Mainly patients with
normal renal function. And so we tried to evaluate the
performance of this predefined algorithm specifically in patients
with renal dysfunctions.


                                               
So among a bit more than 3,000 patients, the prevalence of
patients with renal dysfunction was 15%. So we had about 500
patients with renal dysfunction. And the interesting finding from
our work is that first the prevalence of N-STEMI was nearly
threefold in patients with renal dysfunction as compared to
patients with normal renal function. And, fortunately the rule
out part of the algorithm regarding sensitivity still works very
well. It is, however, the efficacy of rule out that is lower in
patients with renal dysfunction, simply because fewer patients
really have very low troponin concentration and are therefore
ineligible for rule out.


                                               
However, as a clinician, the main concern with troponin and renal
dysfunction is the rule in part, and specificity. And as you
would think, specificity of the one hour algorithm was in fact
significantly lower in patients with renal dysfunction. It was
still appropriate for therapeutic consequences, but it was lower
as compared to patients with normal renal function, so the
specificity was 89% in patients with renal dysfunction, as
compared to 96.5% in normal renal function.


                                               
So the overall efficacy of the algorithm was lower in patients
with renal dysfunction, however then when trying to create and
derive optimized cut off levels, so all cut off levels optimized
for use in renal dysfunction, we didn't really find alternative
cut offs that would do a much better job than the official cut
off levels recommended in the guidelines. So our conclusion is
that in patients with renal dysfunction, the safety of the one
hour algorithm still is very high, however the specificity of
rule in and overall efficacy are decreased.


Dr. Carolyn
Lam:              
Right. That's beautifully summarized. And also that different cut
offs didn't really help to increase the efficacy of this
algorithm. And just to clarify to our listeners, I believe you
defined renal dysfunction as an estimated GFR of less than 60,
which is so beautiful because it's perfectly consistent with the
second paper.


                                               
Nick, could you please tell us about your study and your take
home messages as well.


Dr. Nicholas
Mills:           
So high stakes is our clinical trial that we're conducting across
hospitals in Scotland to evaluate the best way to use high levels
of cardiac troponin in clinical practice. One of the areas of
uncertainty is whether these assets really add any additional
value for patients with chronic kidney disease, where troponin
concentrations tend to be higher. And the premise of a high
sensitive test is that we can measure lower concentrations and
improve the sensitivity. But is this just going to create
uncertainty for clinicians?


                                               
So we evaluated 5,000 consecutive patients for performance of
high sensitivity cardiac to put in testing. And those with and
without renal impairment. And based upon what Christian, we
identified that patients with renal impairment are less likely to
have very low concentrations, but that you can rule out
myocardial infarction safely in patients with renal impairment.
And similarly that those with renal impairment are more likely to
have an abnormal troponin concentration at presentation. Around
about 40% of all patients have troponins above the upper
reference limit. And whilst the specificity for myocardial
infarction is lower, type one myocardial infarction or myocardial
infarction due to plaque rupture or cardiac thrombosis remains
the most common diagnosis in this group.


                                               
Finally we looked at one year outcomes. And this is really
critical. Because we found that patients with renal impairment
were two to threefold more likely to die from cardiovascular
disease one year following their presentation than those without
renal impairment. And I think that my general experience during
these tests in clinical practice is that troponin elevations in
patients with kidney disease are often ignored and there's a
concern about what they mean, and therefore these patients don't
get access to the fantastic treatments we have for coronary heart
disease. So our take home message is that high sets of troponin
testing in patients with renal disease does have value, it's
useful for identifying low risk patients although there are fewer
of them, and it performs well as a diagnostic test, highlighting
in particular a group of patients that really have poor clinical
outcomes.


                                               
As a cardiological community, we need to do better.


Dr. Carolyn
Lam:              
What I really love about both or your papers is the consistency
in the messages. Torbjorn, I want to bring you in on this. You
managed both papers. Such a lovely pair of papers that we're so
proud to be publishing and you had also invited an editorial by
Dr. deFilippi and Seliger. Would you like to comment on your
perspective and perhaps the clinical take home message to our
audience?


Dr. Torbjørn Omland:     Yes, I think this
has been pointed very well out by both Christian and Nick. And I
think it's worth recapitulating that renal dysfunction is a major
problem that clinicians often try to explain by just lack of
renal filtration. But that the closest probably are increased
production and underlying cardiac disease. So in the editorial
Dr. deFilippi Filippi and Dr. Seliger points also out in these
things. Moreover they try to look forward and have made comments
to recent studies that showed that in patients with renal
dysfunction have different troponin fragments than patients with
acute myocardial infarctions.


Dr. Carolyn
Lam:              
I find that so fascinating. And it really, really relates to the
field of heart failure and what we are also talking and thinking
about with natriuretic peptides and their different fragments and
the possible different meanings. And how different essays maybe
non specific for different fragments.


                                               
Christian, you think a lot about these things. I'm curious, what
are your thoughts on this and areas of future work that are very
urgent?


Dr. Christian Mueller:     I think Torbjorn
very nicely addressed this. So the current high sensitivity
essays for T and I that we use in clinical practice, they are
designed kind of to detect everything in blood that looks like
troponin, either T or I, including various fragments. And I think
it's a fantastic new avenue of research, trying to find out that
the biochemical signatures can be further differentiated and
exactly that perhaps different troponin fragments or tricordinate
products more prominent in patients having ischemic injuries like
treat myocardial infarction, as compared to for example other
modes of injuries. So I think that's very nice hypothesis and
some early data. But at least from my perspectives and to the
best of my knowledge until now, the diagnostic algorithms that we
have other ways to approach this in clinical practice. And so
it's the higher the blood concentration in patients with acute
chest pain, the more likely it's acute myocardial infarction.
It's not any chronic disease and again the higher the change from
presentation to one hour or two hours, the more likely it's acute
as a dynamic disorder resulting in an acute increase in cardiac
troponin, as compared to the chronic release patterns typically
seen in patients with renal dysfunction.


Dr. Carolyn
Lam:              
Yeah. That's just so fascinating. Nick, we sadly are running out
of time, but I do want to give you the last word. The clinical
take home message, once again. What do you think listeners should
take home that may change their practice, after listening to this
podcast?


Dr. Nicholas
Mills:           
I think the key message for clinicians, is that in a patient with
suspected acute coronary syndrome and has renal impairment and
elevated troponin concentration, serial testing is mandatory to
differentiate between those that have chronic myocardial injury
due to subclinical heart disease and those that are having acute
myocardial injury as a consequence of a presumed acute coronary
syndrome. Field testing is critical to inform which treatment
path and what investigations we recommend for our patients.


Dr. Carolyn
Lam:              
Wonderful. And to take any elevations seriously, because this is
a high risk population.


                                               
Well, audience you heard it right here on Circulation On The Run.
I'm sure you've enjoyed this. I certainly have. Don't forget to
tune in again next week.