Circulation November 22, 2016 Issue

Carolyn:
Welcome to circulation on the run, your weekly podcast summary
and backstage pass to the journal and its editors. I'm Dr.
[Carolyn Nam 00:00:08], associate editor from the national heart
center and Duke National University of Singapore ...


 
 
In just a moment we will be discussing the exciting new results
of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor
in patients with acute myocardial infarction treated with primary
or cutaneous coronary intervention. But first, here's your
summary of this week's issue ...


 
 
The first study represents the largest published study on the
association between PR interval and cardiac resynchronization
therapy with defibrillator versus implantable cardioverter
defibrillator and real world outcomes. Dr. Friedman and
colleagues from Duke Clinical Research Institute studied 26,451
CRT eligible patients from the National Cardiovascular Data
Registry ICD Registry. They found that a PR interval at or above
230 milliseconds was associated with increased rates of heart
failure, hospitalizations, or death among CRTD but not ICD
patients. The real world comparative effectiveness of CRTD versus
ICD was significantly less among patients with a PR interval
above 230 milliseconds compared to patients with a shorter PR
interval.


 
 
The authors discuss that these findings may be due to the
association between a prolonged PR interval and factors
associated with lower rates of CRT response such as non-left
bundle branch block morphology, ischemic heart disease, or atrial
arrhythmias. It could also be due to the association between
delayed AV conduction, disordered diastolic filling, and
contemporary CRT reprogramming strategies. The take home message
is: in CRT patients with a prolonged PR interval, recognize that
they are at high risk for poor outcomes and merit close follow up
and consideration of AV optimization ...


 
 
The next study is the first adolescent study of serum lipidomics
that identifies a new panel of serum glycerophosphocholines that
are associated with cardiovascular risk. First author Dr. [Sine
00:02:29], corresponding author Dr. [Palsova 00:02:31], and
colleagues from Hospital for Sick Children in University of
Toronto recognize that atherogenic dislipidemia is traditionally
assessed with high abundance lipids, such as cholesterol and
triacylglycerols, which accumulate at millimolar levels in blood.
Current advancements in mass spectrometry now allow the discovery
and study of new low abundance lipids, which circulate at micro-
or nanomolar blood levels. And one such example are the
glycerophosphocholine metabolites.


 
 
They studied a population based sample of 990 adolescents with
age range 12-18 years using liquid chromatography electrospray
ionization mass spectrometry. They identify several novel
glycerophosphocholines that were associated with multiple
cardiovascular disease risk factors. Mediation analysis revealed
that these novel glycerophosphocholines mediated their respective
relationships between visceral fat and cardiovascular disease
risk factors. Furthermore, a particular glycerophosphocholine
shown recently to predict incident coronary heart disease in
older adults was already associated with several cardiovascular
disease risk factors in these adolescents.


 
 
The clinical implication is that the development of a lipidomics
signature that could facilitate early intervention or treatment
of those at high risk of cardiovascular disease or monitor
response interventions could help triage limited healthcare
resources. Furthermore, future research on glycerophosphocholines
might improve biological understanding of disease and identify
potential drug targets to impede cardiovascular disease
development ...


 
 
The next study also describes plasma lipidomic profiles but this
time in patients with type 2 diabetes. This study is from first
author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly
00:04:37], and colleagues from the Baker IDI Heart and Diabetes
Institute in Melbourne, Australia. These authors performed a
targeted lipidomic analysis using liquid chromatography
electrospray ionization tandem mass spectrometry in a case cohort
of 3,779 patients with type 2 diabetes and one or more additional
cardiovascular risk factors from the advance trial.


 
 
They found that sphingolipids, phospholipids, cholesterol esters,
and glycerol lipids were associated with future cardiovascular
events and cardiovascular death. The addition of 7 lipid species
to a base model of 14 traditional risk factors and medications
improved the prediction of cardiovascular events. The prediction
of cardiovascular death was also improved with the incorporation
of 4 lipid species to the base model. These results were further
validated in a subcohort of type 2 diabetes from the lipid trial.
In summary, this important study demonstrates the potential of
plasma lipid species as biomarkers for cardiovascular risk
stratification in diabetes ...


 
 
The last study sheds new light on the optimal ablation method for
atypical atrioventricular nodal reentrant tachycardia or atypical
ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel
Deaconess Medical Center, Harvard Medical School in Boston,
Massachusetts study 2,079 patients with AVNRT subjected to slow
pathway ablation. In 113 patients, atypical AVNRT or coexistent
atypical and typical AVNRT without other concomitant arrhythmias
was diagnosed. Ablation data and outcomes were compared to a
group of age and sex matched control patients with typical AVNRT.
The authors found that in the atypical group slow pathway
ablation was accomplished from the right septum in 110 patients
and from the left septum in 3 patients. There was no need for
additional ablation lesions at other anatomical sites and no
cases of AV block were encountered.


 
 
In summary AVNRT, regardless of the type, appears to be
successfully ablated by targeting the anatomic area of the slow
pathway. When a right septal approach is not successful, the
anatopic area of the slow pathway can be ablated from the left
septum and so it seems the slow pathway participates in both
typical and atypical AVNRT. The take home messages are that
catheter ablation at the anatomical area of the slow pathway from
the right or left septum may be the treatment of choice for
atypical AVNRT. The approach is not associated with an increased
risk of inadvertent AV block. The recurrence rate following
ablation of atypical AVNRT may not be significantly higher than
that seen following the ablation of typical AVNRT.


 
 
Those were the highlights from this week's issues. And now for
our feature paper ...


 
 
We're so pleased to have with us today for our podcast interview
first and corresponding author of the Prague 18 study, Dr.
[Zuzana Motovska 00:08:12] from Charles University in Prague.
Welcome Zuzana.


 
Zuzana:
Thank you for having me.


 
Carolyn:
We're also so lucky to have Dr. [Gabriel Stig 00:08:21],
associate editor from Paris, and I understand you're even
traveling at the moment. Thank you, Gabriel for making the time.


 
Gabriel:
Yes, hello Carolyn, hello Zuzana.


 
Carolyn:
So let me start by congratulating you Zuzana on this first
head-to-head comparison study of prasugrel versus ticagrelor in
patients with acute myocardial infarction treated with primary or
cutaneous coronary intervention. And what a lovely study acronym
of course, Prague 18. Could you maybe start by describing, in the
Czech Republic before your study, how were clinical decisions
being made between prasugrel and ticagrelor in these patients?


 
Zuzana:
The current guidelines prefer newer P2Y12 inhibitors over
clopidogrel for patients with acute coronary syndromes. Prasugrel
and ticagrelor are being increasingly used in patients [with just
00:09:15] primary PCI in Czech Republic. Analysis of our registry
documented that doctors did not view these two drugs as
interchangeable and prasugrel is a drug associated with a high
risk of bleeding. Our data show that safety in terms of bleeding
risk was the most important aspect under consideration when
choosing one of new agents for an individual patient. The same
observation has been reported from other contemporaries from
other countries and according to the published subgroup analysis
of [stratum 00:09:54] and other studies we have also perceived
prasugrel to be a more effective agent for primary PCI. We prefer
this drug in patients with a high thrombotic risk.


 
Carolyn:
Could you, maybe now, clearly describe what you did in this study
and what were your findings?


 
Zuzana:
The Prague 18 study truly [inaudible 00:10:19] was designed to
test the hypothesis on whether one of the newer drugs, prasugrel
or ticagrelor, is more effective and safer than the other one in
acute myocardial infarctions, which is the primary [treatment
00:10:36] strategy. We randomized the total 1,230 in 14
participating sites. I highlighted hemodynamic instabilities, was
not an [excluding 00:10:52] criterion for study participation.
The patients were randomized for prasugrel or ticagrelor
immediately on hospital arrival and the recommended dosing
regiments were used for both drugs. The prasugrel dose was
reduced during the maintenance phase in patients over 75 and
[reduced vein 00:11:12] was the [sixth 00:11:14] feature around
presence of both these parameters was an exclusion criterion.


 
 
So, what we find. Fewer [unsourced 00:11:23] primary endpoint
composed of all cause of death or reinfarction show serious
bleeding or urgent vessel revascularization within 7 days after
randomization or discharge if prior to the seventh day. They did
not differ between groups, either for in 4 person prasugrel group
and in 4.1 person in ticagrelor group. The appearance of key
secondary end point composed of cardiovascular death, nonfatal
MI, or nonfatal stroke. Within 30 days did not show any
significant difference between prasugrel and ticagrelor,
furthermore no significant difference was found in any of the
components of the primary and secondary endpoints and also no
significant difference was observed in the appearance of definite
vein thrombosis [inaudible 00:12:17] days after randomization.


 
 
So the study did not show any difference between ticagrelor and
prasugrel in the early phase of a mild [treatable 00:12:26]
primary PCI. Because of small sample size the confidence for the
estimation of the [interval 00:12:35] of either were quite high,
however we identify differences, which are very low in absolute
numbers and [inaudible 00:12:45]


 
Carolyn:
That was very nicely explained Zuzana, thank you. Now could you
share a little bit more about, were you powered for this analysis
and the decision to stop early.


 
Zuzana:
Oh yes, the power analysis was computed for primary endpoint
difference of 2.5 person and the needed sample size was estimated
at 2,500 patients. The interim analysis led to a decision to
terminate the study prematurely because of futility. No
significant difference in primary endpoint was found between the
two study drugs in the course of the entire randomization
process, moreover the difference in appearance of the primary
endpoint between the compare groups was declining with a growing
number of randomized patients and analyzed on the different 0.1%
and this was the decision why we stopped the trial prematurely.


 
Carolyn:
Right. Gabriel could you comment a little bit as the associate
editor managing this paper, how do you think it's going to impact
practice?


 
Gabriel:
First of all, let me start by congratulating Zuzana and the team
of the Prague 18 trial for this academic trial. I think it's
really important that we have a clinically led effort to
investigate optimal treatments in modern cardiology in general
and specifically in acute coronary syndromes. We've known for
several years now, through large randomized trials, that the
novel P2Y12 agents, ticagrelor and prasugrel, are clearly
superior to clopidogrel but we don't know which of the two agents
to choose and we know that comparison across trials are fraught
with major methodological problems. So with evidence that
prasugrel is superior to clopidogrel for PCI treated ACS
patients, there was evidence that ticagrelor was superior to
clopidogrel for ACS patients in general but we didn't have any
rational data on which to base a rational selection process
between the two agents.


 
 
Really, I think it's an important issue and often people state
that these are delicate differences between agents, and we
shouldn't expect that this is going to impact clinical outcomes.
Actually it does impact clinical outcomes because we know that
those novel agents have had a roughly 20% reduction in major
heart outcomes compared to clopidogrel so this is not a moot
point. It's not a minute difference, it's a huge difference and
it's an important clinical issue. That's my first point, I think
it's an important question and I really want to commend the
investigators for launching this trial despite not having the
support of industry.


 
 
The second point I want to make is I think that the results from
the trial are not yet complete because we don't have the one year
follow-up and I know that this is planned and the investigators
are continuing follow-up of their patient cohort, which I think
is going to be important because it's conceivable that
differences may emerge over time as was, in fact, the case in
some of the previous trials. In [plato 00:15:49] there was a
modest difference early on but the curves diverged over time
between clopidogrel and ticagrelor so it's conceivable that
differences that are absent at 30 days might emerge over time.


 
 
In fact, I have a question for Zuzana. One of the interesting
features and important issues that needs to be addressed is ... I
know that in some sites in the Czech Republic, because of the out
of pocket expenses related to the cost of the novel agents, it
was allowed for patients to be switched back to clopidogrel after
hospital discharge. Do you have any sense of what is the
proportion of patients who are scaled back to clopidogrel instead
of prasugrel or ticagrelor after initial index submission?


 
Zuzana:
Thank you Gabriel, it's true the study ... a lot of patients who
are unable to bear the cost associated with long term treatment
with the study medications and switch to clopidogrel. Therefore,
a second goal of the study was to assess the rate, the reason,
and also the consequences of switching from a study drug to
clopidogrel after the acute phase in the course of 12 months
follow-up. We are not focusing on the study completion and
analysis that are related to the second study. There are, of
course, patients who switch from prasugrel or ticagrelor to
clopidogrel also in first 30 days and this proportion was about
one third of patients.


 
Gabriel:
The other point I want to make really relates to the power issues
and Zuzana already pointed out herself this important issue. The
paper is actually accompanied by an excellent and very cogent
editorial by Steve [Webiok 00:17:31], who discusses explicitly
and in great detail the issue of sample size. We know that the
relative difference between the novel agents and clopidogrel is
in the range of 20% so we might expect that the difference
between the two novel agents themselves, when we compare
prasugrel and ticagrelor, might be less. Yet the study was
powered for actually a greater relative risk reduction than what
was seen in the pivotal trials of prasugrel and ticagrelor
compared to clopidogrel. So the study is really on the low end of
the power spectrum and I think, as you pointed out Zuzana, it's
important to keep in mind that the confidence interval for the
relative risk between ticagrelor and clopidogrel both act
together on prasugrel, both for the primary endpoint, which is a
combination of efficacy and safety, as well as for the key
secondary endpoint of efficacy.


 
 
It's really very wide and we can't rule out a major benefit or a
major detrimental effect of one agent versus the other. I think
this is important to keep in mind because many people equate a
neutral result of a trial, a non-significant result, particularly
in the [secondary 00:18:36] trial, with lack of difference or
clinical equivalence or non-inferiority and I think it's
important to remember the readers that this is not a
non-inferiority trial, it's not a clinical equivalence trial,
it's superiority trial that is actually with a neutral result.
It's really and important issue.


 
 
Yet, because it's the first head-to-head comparison, because it's
an academic effort independent, and because it's going to report
one year outcomes, I think this is a critical effort and the
investigators need to be lauded for that. Even if this study
isn't powered, it will be able to be pulled in further
meta-analysis with other upcoming studies that are similar that
also may be underpowered and provide us with a hint of evidence
of what might be the best agent to use, which is an every day
clinical question. This is a very, very common condition and any
unbiased evidence we can get from randomized trials is very
valuable ...


 
Carolyn:
Thank you, everyone, for listening to this episode of circulation
on the run. Tune in next week ...