Nov 21, 2016
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 ...