Circulation June 20/27, 2017 Issue

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Dr. Carolyn Lam: Welcome to Circulation on the Run your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Is it time to end our debates on short versus long duration of dual anti-platelet therapy? Well I will be discussing this with two very special guests in just a moment. But first here is your summary of this week's journal.

The first paper tells us that HDL particle number may serve as a biomarker of residual risk when assessed on statin therapy. First author Dr. Khera, corresponding author Dr. Mora from Brigham and Women's Hospital and colleagues of the JUPITER trial assessed HDL cholesterol levels, apolipoprotein A-1, cholesterol efflux capacity and HDL particle number at baseline and 12 month in a nested case control study of the JUPITER trial. That was a randomized primary prevention trial that compared rosuvastatin to placebo in individuals with normal LDL but increased CRP levels.

In the current study the authors found that cholesterol efflux capacity was moderately correlated with HDL cholesterol, apoA-I, and HDL particle number. Baseline HDL particle number was inversely associated with incident cardiovascular disease, while there was no significant association for baseline cholesterol efflux capacity, HDL or apoA-I levels. On-statin cholesterol efflux capacity was inversely associated with incident cardiovascular disease but HDL particle number again emerged as the strongest predictor.

Thus for both baseline and on-statin analyses, HDL particle number was the strongest of four HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. Whether therapies designed to enhance cholesterol efflux capacity or an increased HDL particle number can also reduce cardiovascular risk however remains uncertain.

The next study sheds light on mechanisms underlying the de-differentiation and lineage conversion of adult human fibroblast into functional endothelial cells. First author Dr. Zhang, corresponding authors Dr. Rehman and Malik from University of Illinois College of Medicine first generated CD34+ progenitors by de-differentiating adult human skin fibroblasts and showed that these intermediate progenitors could give rise to endothelial cells as well as erythrocytes. They then showed that lineage conversion of fibroblasts via partial de-differentiation recapitulated in part the embryonic development of the vasculature as evidenced by up regulation of anti-aging enzyme telomerase and the bi-lineage potential of the generated progenitors.

Importantly they showed that transcription factor SOX17 functioned as a switch which regulated the cell fate of CD34+ progenitors towards an endothelial versus erythroid lineage. Finally implanted fibroblast derived CD34+ progenitors stably engrafted to form functional human blood cells in mice that improved cardiac function after myocardial infarction. Thus the molecular switch SOX17 provides a means to optimize the generation of endothelial cells for vascular tissue regeneration or disease modeling.

What do drones have to do with out of hospital cardiac arrest? Well in this next study by first author Dr. Boutilier corresponding author Dr. Chan and colleagues from University of Toronto, the authors hypothesized that a drone network designed with the aid of a mathematical model combining both optimization and queuing could reduce the time to AED arrival.

Using data from over 50,000 historical out of hospital cardiac arrests covering over 26,000 square kilometers in Ontario, Canada, they found that a drone network designed to reduce the median AED arrival time by three minutes relative to the historical 911 response could also reduce the 90th percentile of the AED arrival time by between 6 minutes and 43 seconds in most urban regions and 10 minutes and 34 seconds in most rural regions.

Thus this study tells us that drone delivered AEDs have the potential to be a transformative innovation in the provision of emergency care to cardiac arrest patients especially those who arrest in a private or rural setting.

The next study provides thresholds for ambulatory blood pressure among African Americans. Dr. Ravenall and colleagues from New York University School of Medicine analyzed data from the Jackson Heart Study, a population-based cohort comprised exclusively of African-American adults and of whom more than 1000 participants completed ambulatory blood pressure monitoring at baseline.

Based on the outcome derived approach for systolic blood pressure and a regression derived approach for diastolic blood pressure, the following definitions corresponded to clinic blood pressure of 140/90 and were proposed as ambulatory blood pressure definitions for African Americans. Daytime blood pressure above 140/85, 24 hour blood pressure above 135/80 and nighttime blood pressure above 130/75 mmHg. Note that these ambulatory blood pressure thresholds identified for African Americans were higher than those from published recommendations mainly derived in European, Asian and South American populations. The use of these ambulatory blood pressure thresholds for African Americans will lead to a lower prevalence of daytime, 24 hour and nighttime hypertension compared with the current published recommendations.

The next paper provides pre-clinical evidence of a novel target in plaque information in atherosclerosis. Dr. Stachon and colleagues from Heart Center Friburg University in Germany hypothesized a functional role of the signal axis ATP binding to purinogenic receptor P2X7 in inflammasone activation and chronic inflammation driving atherosclerosis.

In an elegant series of experiments they showed that P2X7 receptor activation was crucial for inflammasone assembly and interleukin-1-beta secretion. The lack of P2X7 in mice abolished inflammasone activation in atherosclerotic lesions. P2X7 was expressed in murine and human atherosclerotic lesions. LDL receptor deficient mice lacking P2X7 receptor had reduced plaque inflammation and were less prone to develop atherosclerosis.

Thus this study shows that P2X7 inhibition could be a treatment strategy against plaque inflammation in atherosclerosis.

The next paper describes the first prospective clinical study of adenosine use in pediatric and young adult patients after heart transplantation. Now prior to this study adenosine was relatively contraindicated post-transplant due to a presumed risk of prolonged atrioventricular block in denervated hearts.

In the current study first author Dr. Flyer corresponding author Dr. Silver and colleagues from Columbia University performed a single center prospective clinical study testing whether adenosine caused prolonged asystole after transplant and if it was effective in blocking AV nodal conduction in healthy heart transplant recipients aged 6 months to 25 years presenting for routine cardiac catheterization. Following catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose escalation protocol until AV block was achieved.

Eighty patients completed adenosine testing. And no patient required rescue ventricular pacing. AV block was observed in 77 patients with the median longest AV block of 1.9 seconds and the mean duration of adenosine effect of 4.3 seconds.

Thus, this study suggests that adenosine may be safe and effective in patients post transplantation and establishes both a safe and effective starting dose of 25mcg/kg or 1.5mg for patients weighing 60kg and more. It also establishes a stepwise therapy escalation plan to avoid prolonged bradycardia. Although patients after heart transplantation may require less adenosine to achieve AV block it appears to be safe and effective as therapy for evaluation and or treatment of tachycardia in this population.

Well those were your summaries, now for our feature discussion.

Today for our feature discussion we are talking about a very familiar situation, dual anti-platelet therapy following coronary intervention and the decision of long versus short duration of therapy. A debate we've heard many times but according to the perspective piece in today's journal, maybe a debate we should end. And I am so pleased to have the author, Dr. Glenn Levine from Baylor College of Medicine as well Dr. Laura Mauri associate editor from Brigham and Women's Hospital.

Welcome both.

Dr. Laura Mauri: Thank you Carolyn.

Dr. Glenn Levine: Thank you.

Dr. Carolyn Lam: Glenn would you like to start by presenting your case. It's time to end a dualistic short versus long duration of DAPT debate. I really like that title, tell us more.

Dr. Glenn Levine: Thank you Carolyn.

The point we make in our editorial is that over the last five or six years there have been studies comparing what I term standard, which is usually about 12 months DAPT versus shorter duration DAPT and there are other studies comparing standard DAPT versus longer duration DAPT. Those generated important information in different people interpret them in different ways. What though has happened over the last several years is certainly for both educational and entertainment value at meetings as well in editorials, the idea of how long people should be treated with DAPT has been oversimplified to whether all patients should be treated with short duration or long duration. And Laura herself knows that as she has been in many of these debates.

While I think that initially that was educational and entertaining, I think these days people understand those points and a greater issue is in that we should treat some people with short duration, some with what I call standard and some with long duration. And rather than debating whether everyone should treated with short or everyone should be treated with long, I think what we need to focus on now is which patients should be treated with short duration, which are probably best treated with a standard duration and which are best treated with prolonged or extended duration DAPT.

And that in a nutshell is the main point that we make in this perspective editorial.

Dr. Carolyn Lam: Laura, so do you agree?

Dr. Laura Mauri: I couldn't agree more. I think clinicians really are looking for guidance and what happens at these debates is you see these polarizing opinions that debaters are asked to defend when in actuality there's such a wide spectrum of what individual patients need. And the real question I think going forward is how to end these debates and how to provide really more tailored information so clinicians and patients can make better decisions together. And I think that's really where the piece that Glenn has written really helps direct us.

Dr. Carolyn Lam: Yeah, Glenn, I mean are we talking about the usual risk versus benefits and precision metsan or individualized risk assessment here?

Dr. Glenn Levine: Yeah, what we're talking about is looking at the ischemic risks which are primarily leg stent thrombosis or spontaneous MI versus the bleeding risks which is obviously bleeding and balancing them. And there clearly are decision tools available to clinicians. Laura has pioneered the DAPT score which is an incredibly user friendly and easy tool to use to assess which patients should be continued with prolonged DAPT or not. And there are also some other tools out there including the Paris registry score perhaps a little more complex and then there's also now the precise DAPT score which one can at least assess bleeding risk and indirectly assess the ischemic and bleeding risk.

But really I think that is the focus now on balancing bleeding and ischemic risks and having pools to allow clinicians to easily do that.

Dr. Carolyn Lam: That's true. Now do you think guidelines have to catch up or have they caught up?

Dr. Glenn Levine: Our DAPT duration guideline was coming out just as Laura's DAPT score was about to be published, several months after it had been presented. And we did mention the DAPT score in our paper, it was too early to formally incorporate it into the guidelines. Nevertheless, the way our guidelines are written, they clearly give practitioners the option for individualizing therapy based on ischemic and bleeding risk and Laura's DAPT score fits perfectly into what we aim to do, namely to encourage practitioners to assess patients on an individual level and assess what duration of DAPT is best.

Dr. Carolyn Lam: I do have a question for Laura here though. I see Asian patients, I'm talking to you here from Singapore. And sometimes you wonder the trial situations and what you derive there. How does it differ from real world and how is it impacting your practice for example Laura?

Dr. Laura Mauri: That's a great question. I think you have a number of points there. One is the generalized ability or results from one trial across the world where you might have many different patient populations. And while the DAPT score was an international trial it would be interesting to see more data coming out from other different countries. And as you know there are trials in Asia that have looked at randomized DAPT duration as well.

I think now that we have better access to information especially in cardiology globally, we can get that information and better tailor therapy. When we look at any one randomized trial the results might seem kind of black and white and to certain extent so do guideline recommendations but we are getting better at using the results from randomized trials to really identify risk factors. I think that with time we'll be able to either validate the DAPT score in other patient populations or develop tailored scores from unique data sets. I think the challenge really is making sure that we still get good randomized evidence for our treatment decisions but then when we have treatments that have both benefit and risk that we identify which sub-populations of patients really do achieve most of the benefit. And then the other populations that might be harmed. And that's really what we try to do with this score.

And I think what you'll see, you asked about precision medicine which usually we think about using genetics but I think there's so much just really basic information that we have about patient lesion characteristics and other specific factors that we record routinely in their medical records that we can use and you'll see this, I think more and more frequently across different areas of investigation and in cardiovascular medicine.

One really interesting example recently was this French trial. Data was used to be able to predict, very similar to what we did, but to predict which patients would benefit from lower blood pressure without the risk of more aggressive treatment.

Dr. Carolyn Lam: Yeah, I love the way you put that. Those are really words of wisdom, I do think that that is the way cardiovascular medicine is gonna move. Glenn, how do you put all this into practice for yourself?

Dr. Glenn Levine: I think whether or not I formally calculate a DAPT score or Paris registry score, I think clearly we integrate the factors in those scores into our everyday practice. And clearly there are patients who are at high bleeding and low ischemic risk and vice versa. I would also encourage listeners to in addition to all the scores, one has to think about the consequences of a recurrent MI or stent thrombosis. Obviously someone who has stent thrombosis of a proximal LED lesion, if they already have a depressed EF or occluded RCA, those consequences are likely much more dire then someone who occludes say at a distal OM3 stent who has the normal ejection fraction. It also encourages them to think about the consequences of stent thrombosis as well as the consequences of a recurring MI.

Dr. Laura Mauri: Just to make it clear, we know that clinicians have always tried to balance these different risks of ischemia and bleeding when faced with this decisions. I think the challenge really has been the limited amount of information that we've had to be able to do that. And so we've really just used kind of our gut until recently when we've had several large randomized data sets to be able to look to. And what that's done is it's given us the ability to construct these new tools to be able to make practice more data driven. Now still individualized but based on data that's tailored to our patients.

And so I think we can use that to be able to improve outcomes. That being said, we don't want to rely on a statistic or a score alone and things like the DAPT score are based on patients like the ones that were enrolled into the randomized trial. Those were patients who could take longer anti-platelet therapy. It helps to identify who can take it for longer. But there are patients who get anti-coagulation or have other serious bleeding risks who really are going to benefit from new technologies to be able to shorten anti-platelet therapy.

Dr. Carolyn Lam: Well thank you Glenn once again for a wonderful perspective piece that has really got us thinking about situations even beyond dual anti-platelet therapy. Thank you Laura for your insights and thank you listeners for joining us today. Join us again next week.

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