Circulation November 22, 2016 Issue

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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.

Thank you for having me.

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.

Yes, hello Carolyn, hello Zuzana.

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?

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.

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

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]

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.

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.

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?

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?

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.

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 ...

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

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