Circulation November 5, 2019 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.


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


Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC
simultaneous publication issue, isn't it? So the original papers
were simultaneous publications at the European Society of
Cardiology meeting this year.


Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So
Carolyn, later we're going to listen to the authors of this
feature discuss the association between ICD use and all-cause
mortality in a contemporary heart failure reduced ejection
fraction cohort and examine relevant subgroups. So Carolyn, I'm
going to get started with my first paper and it's a randomized
trial of one hour, one-hour deponent T protocol and suspected
acute coronary syndromes and it's a rapid assessment in emergency
rooms and it's from professor Derek Chew from Flinders Medical
Center. High sensitivity troponin assays promise earlier
discrimination of MI, yet the benefits and harms of this improved
discriminatory performance when incorporated within rapid testing
protocols with respect to subsequent testing and clinical events
has not been evaluated in an in-practice, patient level,
randomized study. So this multicenter study evaluated the
non-inferiority of a zero to one hour, zero to one-hour, high
sensitivity troponin T protocol compared with a more traditional
zero to three-hour mask, high sensitivity troponin T protocol in
those suspected with ACS.


Dr Carolyn Lam: Interesting. So what did the study show?


Dr Greg Hundley: So participants in the zero to one-hour arm were
more likely to be discharged from the ED quicker and that would
be expected. So 45% versus the standard arm, which was 32%. Also
their median ED length of stay was shorter, and we would expect
that. Four and a half versus five and a half hours. Those
randomized to the zero to one-hour protocol were less likely to
undergo functional cardiac testing. The zero to one-hour high
sensitivity troponin T protocol was not inferior to standard of
care and among patients discharged from the ED, the zero to
one-hour protocol had a negative predictive value of 99.6% for
30-day death or MI. So Carolyn, how about your first study?


Dr Carolyn Lam: Well, from MI risk stratification to heart
failure risk stratification. I'm going to tell you about a paper
describing the TIMI Risk Score for heart failure in diabetes,
which is a novel integer base clinical risk score for predicting
hospitalization for heart failure in patients with type two
diabetes. This is from Dr Mark Sabatine and the TIMI study group
who developed a clinical risk score for heart failure
hospitalization in more than 8,200 patients with type two
diabetes in the placebo arm of saver TIMI 53, as well as
externally validated this score in more than 8,500 patients with
type two diabetes in the placebo arm of declare TIMI 58.


They found that five clinical variables were independent risk
predictors of heart failure hospitalization. These were prior
heart failure, history of atrial fibrillation, coronary artery
disease, estimated GFR, and urine albumin-to- creatinine ratio, a
simple integer base score from zero to seven points. Using these
predictors identified a more than 20 full gradient of heart
failure hospitalization risk in both the derivation and
validation cohorts with high SES statistics. Although the
relative risk reductions with dapagliflozin were similar for
patients across the risk scores, the absolute risk reductions
were greater in those with higher baseline risks.


Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical
implications of this really thorough study?


Dr Carolyn Lam: In summary, the risk score had excellent
discrimination in two large clinical trial cohorts. It was well
calibrated, and it identified a strong gradient of increasing
absolute reduction in risk of heart failure hospitalization with
the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk
Score for heart failure in diabetes, which is a simple validated
clinical risk score, clinicians could better educate patients
about their risk for heart failure hospitalizations and could
perhaps better identify those patients who have a greater
absolute risk reduction in heart failure risk with SGLT two
inhibitors.


Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back
to the world of troponins and talk about a paper from Nicholas
Mills from University of Edinburgh. And in this study, they
evaluated the safety and effectiveness of risk stratification
thresholds of high sensitivity troponin in patients with
suspected acute coronary syndrome. 48,282 consecutive patients
with suspected ACS were enrolled in a multicenter trial from 10
hospitals within Scotland and they're pre-specified secondary and
observational analyses. They compared the performance of the
limit of a detection of less than two nanograms per liter versus
the optimized stratification threshold of less than five
nanograms per liter using the Abbott high sensitivity troponin I
assay. Patients with myocardial injury at presentation with less
than two hours of symptoms or with ST segment elevation
myocardial infarction were excluded and the negative predictive
value was determined in all patients in subgroups for a primary
outcome of MI or cardiac death within 30 days. And they had a
secondary outcome that was MI or cardiac death at 12 months.


Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was
the optimal one?


Dr Greg Hundley: So the negative predictive value for the primary
outcome was 99.8% and 99.9% in those with cardiac troponin I
concentrations of less than five or less than two nanograms per
leader respectively. At both thresholds, the negative predictive
value was consistent in men and women across all age groups.
Although the proportion of patients identified at low risk fell
with increasing age. Compared to patients with cardiac troponin I
concentrations of greater than five nanograms per liter but less
than the 99th percentile, the risk of MI or cardiac death at 12
months was 77% lower in those with less than five nanograms per
liter and 80% lower in those with less than two nanograms per
liter. So in conclusion, use of risk stratification thresholds
for high sensitivity cardiac troponin I identified patients with
suspected acute coronary syndrome in at least two hours of
symptoms at low risk presentation irrespective of both age and
sex.


Dr Carolyn Lam: Very nice. Well, more risk stratification in this
next paper, which really evaluated the application of the 2018
ACC AHA Cholesterol Management Guideline recommendations for
additional lipid lowering therapies in patients with established
atherosclerotic cardiovascular disease and residual dyslipidemia
despite maximum tolerated Statin who were enrolled in the ODYSSEY
OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol
Management Guidelines recommend additional lipid lowering
therapies for secondary prevention in patients with LDL above 70
or non-HDL above a hundred despite maximum tolerated Statin
therapy.


Such patients are considered at very high risk based on a history
of more than one major atherosclerotic cardiovascular disease
event or a single event and multiple high-risk conditions. So in
this paper from Dr Matt Roe from Duke Clinical Research Institute
and colleagues, they found that in the ODYSSEY OUTCOMES trial,
patients classified as very high risk by these 2018 ACC AHA
guidelines and either because of a history of multiple
atherosclerotic cardiovascular events or a single event, which is
a trial qualifying acute coronary syndrome and multiple high risk
conditions, these very high risk patients had more than double
the risk of recurrent cardiovascular events as compared to
patients classified as not very high risk.


 They further looked at the association of Alirocumab with
outcomes and found that Alirocumab was associated with a
consistent relative risk reduction in both risk categories. But
the absolute risk reduction for major adverse cardiovascular
events was numerically greater, although not statistically
different, in the very high-risk group versus those not at very
high risk and among patients at very high risks with multiple
prior events versus a single prior event.


Dr Greg Hundley: Wow, Carolyn. Can you put all this together?
This is a lot of information in this study.


Dr Carolyn Lam: Yes, so it would appear that the application of
the new ACC AHA 2018 guideline recommendations for risk
stratification and the use of additional lipid lowering therapies
in patients with established cardiovascular disease clearly
identifies patients at very high risk of recurrent cardiovascular
events after an acute coronary syndrome and these patients may
derive substantial benefit from additional lipid lowering
therapy, for example, with a PCSK nine inhibitor.


Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off
with what other articles we have in this ESC featured issue of
our journal. So Jonathan Stamler and John Lundberg in separate
letters discuss findings related to whether hemoglobin beta 93
cystine is not required for export of nitric oxide bio activity
from the red blood cell. And in additional separate letters, Doug
Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and
attenuation of pathological and metabolic cardiac remodeling
through selective lipid trafficking. In a perspective piece,
Blake Thomson from the University of Oxford discusses what
Medicare for all in the United States can mean for US medical
research and provides lessons from the United Kingdom. In a
letter from the United States, Gregory Marcus from University of
California San Francisco discusses incident atrial fibrillation
among American Indians in California and then both Marco Bergonti
from University of Milan and Derek Chew from University of
Calgary present two separate cases in our ECG challenge feature.
Well, Carolyn, what a great issue and how about we turn to our
feature discussion?


Dr Carolyn Lam: Yes, let's go. Thanks, Greg.


Dr Greg Hundley: Welcome, everyone, to our feature discussion
today we have Gianluigi Savarese from Karolinska Institute in
Stockholm, Sweden and our own associate editor, Sana Al-Khatib
from Duke University. We're going to be discussing implantable
cardioverter defibrillators in their mortality and looking at a
more recent take on this relative to some of the previous
published studies. So Gianluigi, I'd like to start with you.
Could you tell us a little bit about the hypothesis and why you
wanted to perform your study?


Dr Gianluigi Savarese: Yes. Basically we design our study based
on three main considerations. First one is recent studies show
that the advance in heart-failure therapies have impact patients'
risk profile leading to roughly 40% reduction risk of sudden
cardiac death in HFrEF and RCTs on ICD use for primary prevention
of sudden cardiac death and rural patients more than 20 years ago
and thus, nowadays the beneficial prognostic effects of ICD may
be different due to the improved risk profile in this population.


The second consideration was that efficacy of ICD patients with
heart failure with non-ischemic cardiomyopathy patients receiving
a contemporary heart failure therapy as being a question in
Danish trial and the third consideration is that efficacy of ICD
in elderly is still debated due to findings again from the Danish
trial showing a significant reduction in all-cause death
associated with ICD use in patients age younger versus older than
70 years old. Based on these considerations, we decided to assess
the use of ICD for primary prevention propose in a contemporary
and selected FRF population and to assess the association between
ICD use and outcomes in such a population.


Dr Greg Hundley: So it sounds like we're doing an update on the
utility of ICDs. Can you tell us a little more about your study
population and your study design and then let's hear a little bit
about your results.


Dr Gianluigi Savarese: Sure. First of all, I would like to first
highlight of course the observational natural of this study. Our
analysis is performed using data from the Swedish Heart Failure
Registry, which is a large enough select court of heart failure
patients, enrolling patients regardless of ejection fraction. So
today we have roughly around 70,000 patients. And of course for
the current analysis we select the patients with HFrEF. There
were around 15,000 patients with the HFrEF who were eligible for
ICD use for primary prevention according to the ESC guidelines. A
study design, we used propensity score matching design in order
to try to address the issue of potential compounders. Of course
this is a very important point in observational studies. So
basically, we amassed patients receiving the ICD versus those not
receiving ICDs. And we assessed the association between ICD use
and all-cause death and cardiovascular death and we accessed one
year and five-year outcome.


Dr Greg Hundley: And so what were some of those results?


Dr Gianluigi Savarese: What we observed is that there was a
statistically significant 25 relative risk reduction in all-cause
mortality in ICD recipients versus those who didn't receive an
ICD within one year and there was also a 12% reduction erased
within five years. And we also serve a statistically significant
29% reduction in risk of cardiovascular mortality within one
year. But we were not able to observe any association for
cardiovascular mortality within five years. We thought it was
particularly relevant to have subgroup analysis in our studies
since there are so many questions regarding ICD use in specific
subgroups, which are, for example, older versus younger patients,
those with versus without ischemic heart disease, males versus
the females and so on. So what we observed was that results in
terms of all-cause mortality were consistent in all of the
subgroups considered such as patients older versus younger than
70 years old, versus those without history of ischemic heart
disease and those with versus without concurrent CRT use.


Dr Greg Hundley: What about the frequency of implanting ICDs? Was
the frequency expected in your results?


Dr Gianluigi Savarese: We add that only 10% of our patients
received an ICD at the baseline. This person's age is quite low
in particular. If we compare these with other studies in US for
example, or also in other European countries and basically, we
can only speculate about the underuse of ICD in primary
prevention propose. First of all, a certain proportion of ICD
underuse may be explained by the fact that we could not assess
whether life expectancy was longer than one year, and this is one
of the eligibility criteria for ICD according to the guidelines.


Then another point is that in Sweden, the majority of heart
failure patients are seen by primary care physician and general
practitioners who may have less knowledge and acceptance of
device therapy and then higher perception of contraindication. In
our previous analysis, we showed that patients not seen by
cardiologists have lower likelihood of receiving an ICD and use
of devices is higher in centers who do implants, CRT, ICD. So
this may be some of the explanation that I can anticipate that
some more analysis will follow where we will try to assess the
predictors for an under use of ICD for primary prevention.


Dr Greg Hundley: Well, thank you very much. Sana, now we're going
to turn to you and help us put this study in perspective to what
we have already found or observed in other prior studies related
to implantation of cardio defibrillators.


Dr Sana Al-Khatib: As was mentioned earlier, I was the handling
associate editor for this paper, so I really enjoyed the handling
it and writing an editorial on it. The main points that I wanted
to touch on are number one, the significantly low or reduced
utilization rate of ICDs. So as was mentioned, the 10% of this
patient population received a primary prevention ICDs. Even if
you account for some of the new ones is that you can't estimate
life expectancy. You can't capture granular clinical data on
these patients. So of course some of the non-use of ICDs may have
been appropriate. I think 10% by anyone's definition is still
pretty low and I'm very encouraged to hear that there are plans
to look at predictors of non-use, the characteristics of those
patients and hopefully the office can build on their findings and
try to implement some strategies to improve the utilization of
this life saving therapy.


The other thing that I wanted to touch on is clearly the results
are positive in favor of the implantable cardioverter
defibrillator. Showing that it significantly reduces all-cause
mortality within one year, within five years, certainly reduces
cardiovascular mortality within one year. As was mentioned, the
reduction in cardiovascular mortality within five years was not
significant and to me that is probably mostly explained by
competing causes of death in this patient population, but I also
cannot rule out the possibility of some mis-classification of
causes of death, which is not uncommon. I do want to commend the
authors for the great and robust methods that they applied in
their analysis. As was mentioned, this was a comparative
effectiveness research using observational data. These kinds of
analyses can be pretty challenging, but the authors defined their
patient population very clearly. They used propensity score
matching. In fact, they took it a step further by doing a
negative control analysis, meaning looking at hospitalizations
for renal failure, for pneumonia, respiratory infections, things
like that that you don't expect to be affected by the ICD and
they found no difference in that.


And that is amazing to kind of see this level of analysis that I
believe really lends their results more credibility. It is
important though to keep in mind that when you have 10% of
patients getting an ICD, I suspect that this was a highly
selected patient population and most likely people who were
thought to benefit the most from ICDs were implanted with an ICD.
And yet, as I said, that given the robustness of the methods that
they use, I actually believe the results. I think the results are
credible.


The one last point that I want to comment on is the subgroup
analyses that were mentioned. Absolutely important subgroups to
look at from a clinical perspective. But I point out the fact
that when you start looking at subgroup analyses, and especially
when you have a smaller sample sizes and lower event rates that
it makes you start thinking about, "Well, are these results
valid? Are they believable?" I mean, even honestly, in the
setting of a randomized clinical trial, I look at subgroup
analyses as hypothesis generating. So I liked that they included
those just to kind of really emphasize the importance of looking
at these subgroups. But I certainly would not put too much weight
on the subgroup analysis results, but overall great results and
congratulations to the authors.


Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on
behalf of Carolyn Lam and myself, we wish you a great week and we
look forward to speaking with you next week.


Dr Carolyn Lam: This program is copyright American Heart
Association 2019.