Podcasts about odyssey outcomes

Reader feedback, leadless pacing, ABIM, SGLT2 inhibitors, peri-operative MI after cardiac surgery, and. AHA late-breakers are the topics John Mandrola, MD, covers in this week's podcast. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. Reader Feedback Sep 22, 2023 This Week in Cardiology Podcast https://www.medscape.com/viewarticle/996694 -   ODYSSEY OUTCOMES trial https://www.nejm.org/doi/full/10.1056/nejmoa1801174 -   FOURIER https://www.nejm.org/doi/full/10.1056/nejmoa1615664 II. Leadless Pacing -   Leadless vs Transvenous Pacemaker Study https://doi.org/10.1093/europace/euad269 III. ABIM News Heart Societies Ready to Split From ABIM Over Long-Standing MOC Disputes https://www.medscape.com/viewarticle/996747 IV. SGLT2 inhibitors Empagliflozin Gets FDA Nod for CKD Without T2D or HF https://www.medscape.com/viewarticle/996873 -   EMPA-Kidney https://www.nejm.org/doi/full/10.1056/NEJMoa2204233 V. Peri-Op MI after Cardiac Surgery Cardiac Troponin Predicts Mortality Post Surgery https://www.medscape.com/viewarticle/996877 -   Austrian Perioperative MI study https://doi.org/10.1016/j.jacc.2023.07.011 -   Vision  https://www.nejm.org/doi/10.1056/NEJMoa2000803 VI. AHA Late Breakers -   Link to Late-Breakers https://professional.heart.org/en/meetings/scientific-sessions/programming/late-breaking-science#late-breaking You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

This week, please join author Rod Stables and Associate Editor Nick Mills as they discuss the article "Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass through the journal and its editors. We're your co-hosts! 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, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature... Very interesting. There is a lot of information about using fractional flow reserve during contrast coronary angiography. But how does that compare to just reviewing the angiograms when managing patients with coronary artery disease? Well, we are going to hear some results from the RIPCORD 2 trial, and they may surprise you a little bit. But, before we get to that interesting feature discussion with authors and editors, how about we grab a cup of coffee and dive into some of the other articles in the issue? Dr. Carolyn Lam: Yeah, let's do that, Greg. Do you have a paper to share first? Dr. Greg Hundley: Oh, thanks Carolyn. Sure. So Carolyn, as we know, Apolipoprotein B or apoB, provides an integrated measure of atherogenic risk. But whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndromes, beyond that provided by low density, lipoprotein cholesterol, or LDLC, that's uncertain. So Carolyn this study emanates from the Odyssey Outcomes trial, which compared the Proprotein Convertase Subtilisin/Kexin Type 9 inhibitor, Evolocumab with placebo in 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite optimized statin therapy. Now the primary outcome was major adverse cardiovascular events. So MACE was coronary heart disease, death, nonfatal myocardial infarction, fatal non-fatal ischemic stroke, and hospitalization for unstable angina. And associations between baseline ApoB or ApoB at four months and MACE were assessed in adjusted Cox proportional hazards and propensity score matched models over median of 2.8 years. Dr. Carolyn Lam: Oh, right. So what were the results, Greg? Dr. Greg Hundley: Right, Carolyn so impatience with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline ApoB strata, and now evolocumab reduced MACE across all strata of baseline ApoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved ApoB was associated with lower risk of MACE, even after accounting for achieved LDLC or Non-HDLC indicating that ApoB provides incremental information. And therefore, Carolyn, if it is modified achievement of an ApoB level less than or equal to 35 milligrams per deciliter may reduce lipoprotein attributable residual risk after ACS. Isn't that interesting? Dr. Carolyn Lam: Yes. Very nice, Greg. Thank you. This next paper is a pre-specified analysis of the EMPEROR-Preserved trial, looking at patients with and without diabetes. Dr. Greg Hundley: So remind us, Carolyn, what was the EMPEROR-Preserved trial and what did it show? Dr. Carolyn Lam: Well, in EMPEROR-Preserved Empagliflozin, the SGLT2 inhibitor reduced risk of the composite of cardiovascular death or heart failure hospitalization, as well as first and recurrent heart failure hospitalizations and slowed renal function decline in patients with heart failure and an ejection fraction greater than 40%. So the current paper sought to determine if effects were consistent in patients with, and without diabetes, of the almost 6,000 patients enrolled, 49% had diabetes. The risk of adverse outcomes, first of all, was higher in patients with diabetes. Now the treatment effect of Empagliflozin was however, similar in that Empagliflozin reduced the rate of the primary outcome and total heart failure hospitalization, irrespective of diabetes status. The effect of Empagliflozen falls into attenuate GFR decline, however, was also present in patients with, and without diabetes, although more pronounced in patients with diabetes. Now across all these three endpoints, the effect of Empagliflozen did not differ in patients with prediabetes or normal glycemia. And importantly, there was no increased risk of hypoglycemic events in either subgroup compared with placebo. So a very nice paper there. And that was from Dr. Gerasimos Filippatos from Athens University Hospital Attikon and colleagues. Dr. Greg Hundley: Wow, Carolyn, just really interesting information coming out of the world of SGLT2 innovation. Well, Carolyn, my next paper comes to us from the world of preclinical science and it's from Dr. Kunhua Song from the University of Colorado Anschutz Medical campus. So Carolyn, abnormalities of calcium homeostasis are closely associated with cardiac arrhythmias and heart failure and conditions that cause death of millions of people every year. Now, Carolyn Triadin physically interacts with the Ryanodine receptor 2 and plays an important role in releasing calcium from the sarcoplasmic reticulum to increase the free intracellular calcium concentration in cardiomyocytes. Now alternative splicing of a single Triadin gene produces multiple Triadin isoforms, the predominant cardiac Triadin isoform mouse Mt1 or human Trisk 32 is encoded by Triadin exons from one to eight. In humans, mutations in the Triadin gene that lead to a reduction in Trisk 32 levels in the heart cause cardiac dysfunction, cardiac arrhythmias and sudden death. Decreased levels of Trisk 32, in the heart, are also common in patients with heart failure. However, mechanisms that regulate alternative splicing of the Triadin gene to maintain levels of cardiac Triadin protein in the heart, remains somewhat elusive. Dr. Carolyn Lam: Wow. I am always learning from these cool papers. Thanks Greg. So what were the results? Dr. Greg Hundley: So Carolyn, the investigators found several things. First, the cardio MyoSite specific long non-encoding RNA or link RNA Triadin AS is essential for maintenance of cardiac function, exercise capacity and normal lifespan and Triadin AS knockout mice were found predisposed to cardiac arrhythmias in response to catecholamine challenge. And finally Carolyn, Triadin AS controls, levels, of cardiac Triadin isoforms, by regulating the splicing of the Triadin gene. Dr. Carolyn Lam: Oh, wow. All right. So could you bring it home for us, Greg? What are the clinical take home messages? Dr. Greg Hundley: Right, Carolyn. So cardiac explants from human heart failure patients as well as patients with cardiac arrhythmias, demonstrate reduced expression of Triadin AS and Triadin. And then next the mechanism of the Triadin AS and Triandin AS mediated alternative splicing of the Triadin gene to specifically control levels of cardiac isoforms of Triadin in the heart, provides a potential strategy for the treatment of cardiac arrhythmias and heart failure. Dr. Carolyn Lam: Wow. Thank you, Greg. Well, let's talk about what else is in today's issue. There's a Research Letter by Dr. Agarwal on Chlorthalidone for resistant hypertension and advanced chronic kidney disease. Dr. Greg Hundley: And Carolyn, I've got a perspective piece by Professor Cowie pertaining to atrial fibrillation entitled, “I'm Sorry, Mrs. Jones, but We Cannot Make You Feel Better Today.” Well, Carolyn, how about we get onto that feature discussion and review the utility of fractional flow reserve measurements, in patients undergoing contrast coronary angiography. Dr. Carolyn Lam: Great, let's go. Dr. Greg Hundley: Welcome listeners to this August 30th feature discussion. And we have with us this afternoon, Dr. Rod Staples from Liverpool and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. And gentlemen, welcome, Rod we'll start with you. Can you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Rod Staples: Okay, well thanks very much for hosting today. I'm very grateful to be working circulation on this. I'm working with my co-lead investigator Professor Nick Harrison from Southampton, who's been doing an enormous amount of work on coronary physiology. He actually did the original RIPCORD study, what I suppose we'd now call RIPCORD 1, but it was called RIPCORD in the early days, an observational study that showed that systematic use of fractional flow reserve at the time of diagnostic angiography. Assessing the functional significance measured in each of the major coronary vessels, appeared in an observational study to have a dramatic effect on the subsequent management plans allocated to patients. And we decided to test this in a prospective randomized trial. Dr. Greg Hundley: Very nice. And so the exact hypothesis that you were going to test was what? Dr. Rod Staples: At the time of coronary angiography, a strategy of systematic measurement of fractional flow reserve in each and every coronary vessel, large enough to be considered for revascularization, would improve outcomes compared to a strategy based on angiographic assessments alone. Dr. Greg Hundley: Very nice. And so you mentioned a randomized trial. Can you describe further your study design and then which study population did you include? Dr. Rod Staples: Well, this is a classic multicenter randomized trial performed in the UK. We actually recruited in 17 different UK centers. We asked them to assess patients who were scheduled for invasive, currently angiography for participation against some very minimal inclusion and exclusion criteria, trying to keep the trial generalizable with good external validity. I think one important point to note is that we did allow the inclusion of both patients being assessed with elective angiography for stable symptoms, but in the end half of the population were recruited in the context of a stabilized acute coronary syndrome, a Non-ST-elevation event a day or so down the line. Dr. Greg Hundley: And just a quick breakdown, how many men, how many women? Dr. Rod Staples: Well, it's in that respect, the population is very, very typical for this type of cardiovascular trial. A 70, 30 split an age in the midsixties, a diabetic population in the high teens. So a very typical population we've seen in all this kind of trial environment. Dr. Greg Hundley: Very nice. And so about 1100 patients. And then what were your study results? Dr. Rod Staples: Well, I think there was a very good adherence to the study protocol, very, very few crossovers. And also we were pleased to see that our investigators stayed true to the protocol in that the median number of epicardial vessels assessed by FFR in that randomized arm was four. So there was a good assessment by FFR. The trial was interesting in another respect, in that we assessed an economic outcome based on all NHS hospital costs over the following year and a patient reported outcome based on quality of life using the WHOQOL, and interestingly we found no significant differences either in total subsequent hospital costs from randomization for a year, or indeed in patient reported quality of life by WHOQOL or Angina symptoms by the Canadian Cardiovascular Society classification. Dr. Greg Hundley: Very nice. And then, what about clinical events? Did you examine those as well? Dr. Rod Staples: We did. And again, just a little caveat here, the trial is again interesting in that, what is often in the UK these days called a lean efficient methodology. Whereby, rather than individually contacting individual trial participants or scouring medical records, we interrogated the central national NHS digital repository of all hospital admissions. And we examined electronically a download of every hospitalization event for every patient using algorithms based on diagnostic and procedural codes to define events. And again, we found a very credible representative rate exactly at incidents and events we would've predicted, but again, no difference between the randomized groups. Dr. Greg Hundley: Very nice, well listeners, now we're going to turn to our own Associate Editor, Dr. Nick Mills. And Nick, again, you see many papers come across your desk. What attracted you to this particular manuscript? And it's very interesting study results. Dr. Nick Mills: Thanks, Greg. Firstly, it addresses an important clinical question. Going beyond that, what appealed to me was it was investigator initiated. It was managed by independent trials unit. It recruited a target, it reported the registered outcomes and it was thoughtfully interpreted. And the fact that it didn't prove the hypothesis was irrelevant because it addresses a really important clinical question. And I think it requires some context, and that is that from the previous randomized trials The FAME series, we have been chastised as interventional cardiologists for not using FFR for relatively low use of FFR clinical practice. It's always around one in 20 patients in most series, given the evidence that FFR guided intervention improves outcomes. But actually what FFR is good at is discouraging you from stenting patients with stable Coronary Disease. And so, I think a pragmatic trial that addresses that, the fundamental question, should we be doing more FFR more broadly in both acute and stable disease to guide revascularization with a definitive message that we shouldn't, it doesn't improve quality of life. It doesn't alter costs. Clinical outcomes are similar, but there are more complications associated with routine pressure wire use, gives us a very clear steer for the future. So this is a really important trial addressing a fairly fundamental clinical question. Dr. Greg Hundley: Very interesting. Well, Rod, we're going to turn back to you with Nick's comments and how we're really seeing an evolution in thought processes regarding both diagnostic angiography, and then also the use of functional testing. What do you see is the next study, really in this sphere of research that would be performed? Dr. Rod Staples: Well, I agree with Nick in a way that this raises important philosophical points about the use of intelligence, selective employment of tests or interventions, and that perhaps we need to reflect this in the way we conduct our future studies. I think we're all aware that fractional flow reserve and other measures of functional significance are tremendously valuable in certain clinical settings. And that value's been proven in randomized trials, but in PRECORD 2, for example, if a patient randomized to angiography only was an acute coronary syndrome patient, who had inverted their T waves in their anterior leads, had an associated troponin rise, an echocardiogram had shown some Hypokinesia in the anterior territory. Then I think the potential value of PCI in the LAD does not necessarily require FFR confirmation, and hence that patient will have an equivalent outcome in the angiography group. Similarly, high quality pre-angiography preparation in the elective population with functional testing, stress testing, other forms of imaging mean that we can reserve the use of invasive fractional flow reserve, tight indices to more selective use. Dr. Greg Hundley: And Nick, turning to you, what do you think is the next research study that could be informative in this space? Dr. Nick Mills: I think our whole philosophy by how to manage stable coronary disease is changing. In part because of some other landmark trials that the Ischemia trial and some of the key secondary analyses of the Ischemia trial that tells the Pathoma burden, low attenuation plaque, other aspects of chronic disease are vitally important in predicting major events in the future. And that leaves us with the role for FFR or CT FFR, primarily to manage symptoms. And I think we're getting increasingly good evaluating patients before they get to the Cathflow, optimizing their medical treatment. And so for me, the trial that we really need to help us, is a CT FFR trial to understand the role of Ischemia testing plus anatomical testing and how they dovetail in guiding treatment decisions before they get to the cath lab. I think we need to move this before the lab, always going to be a role for intelligent FFR testing in selected patients once we get to it. But I think that the question probably needs to be addressed before they get to the cath lab. Dr. Greg Hundley: Very nice. Well listeners, we want to thank, Dr. Rod Staples from Liverpool and Dr. Nick Mills from Edinburgh, Scotland for bringing us this very interesting study, highlighting that a strategy of systematic FFR assessment, when compared to angiography alone, did not result in a significant reduction in cost or improvement in quality of life. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

On Episode 13 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2022 issue of Stroke: “Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage” and “Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis.” She also interviews Dr. Pierre Amarenco about his article “Intracranial Hemorrhage in the TST Trial.” Dr. Negar Asdaghi: 1) Can marijuana use increase the risk of ischemic stroke in patients with aneurysmal subarachnoid hemorrhage? 2) Is there an association between infertility or miscarriage and development of stroke later in life? 3) Does lowering the bad cholesterol increase the risk of intracerebral hemorrhage? We will cover these and much more in today's podcast. This is the latest in Stroke. Stay with us. Dr. Negar Asdaghi:         Welcome to another exciting Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. Dr. Negar Asdaghi:         The February 2022 issue is the second installment of Stroke's annual Go Red for Women issue. This is to highlight the journal's continuous effort to bring to attention the research which focuses on reduction of sex disparities and enhancing inclusivity in stroke care. This issue of the journal features a number of articles from sex disparities in enrollment in randomized trials of stroke, to sex-related differences in ischemic stroke presentation, outcome of endovascular therapy, plaque composition of carotid stenosis, and the sex-dependent rupture rate of cerebral aneurysms and the risk of subarachnoid hemorrhage, which I encourage you to review in addition to listening to today's podcast. Dr. Negar Asdaghi:         Later in the podcast, I have the distinct honor of interviewing one the leaders in the field of secondary stroke prevention, Dr. Pierre Amarenco from Bichat University in Paris, to discuss the latest analysis of the association between LDL cholesterol levels and intracerebral hemorrhage risk in a sub-analysis of the Treat Stroke to Target trial, and what is next to come on cholesterol-lowering therapies post-ischemic stroke. But first with these two articles. Dr. Negar Asdaghi:         It should come at no surprise to our listeners that the use of marijuana in its variety of forms is increasing not only in the United States, but also across the globe, both for recreational purposes and also for treatment of a range of medical conditions. There's also a growing body of evidence to link marijuana use to cerebrovascular disorders, including ischemic and hemorrhagic strokes. In fact, national surveys in the United States show that over two million Americans with established cardiovascular disorders currently use or report having used marijuana in the past. Dr. Negar Asdaghi:         Aneurysmal subarachnoid hemorrhage is a hemorrhagic stroke subtype that is frequently complicated by cerebral vasospasm and delayed cerebral ischemia, or DCI. Now, we know that development of DCI can significantly increase the neurological morbidity and mortality related to the disease. So, the question is, can marijuana use increase the risk of DCI in subarachnoid hemorrhage? And what is the difference between cannabis and marijuana? And how are they even related to the brain and vascular disorders? Now, to answer these questions, we first have to do a quick review of three key points. Dr. Negar Asdaghi:         Key point number one: The word "cannabis" refers to all products derived from the plant cannabis sativa. This plant contains about 540 chemical substances. The word "marijuana" refers to parts of or products from the plant with substantial amounts of tetrahydrocannabinol, or THC. THC is the active ingredient of marijuana responsible for mediating its psychoactive effects through activation of G protein-coupled cannabinoid receptors, which are easier to remember as CB1 and CB2 receptors. Dr. Negar Asdaghi:         Key point number two: CB1 and CB2 receptors are diffusely expressed throughout the brain, but interestingly, CB1 receptors are also richly expressed across various vascular beds, including the cardiac and cerebral vessels. So, there we have it, a connection between marijuana and the blood vessels. Dr. Negar Asdaghi:         Key point number three: The differential activation of CB1 receptors in cerebral vessels may lead to vasoconstriction or vasodilation, potentially linking marijuana to vasospasm seen in aneurysmal subarachnoid hemorrhage, which then leads to DCI. But it should be noted that THC can also lead to ischemia through other mechanisms, such as altering the brain's oxidative capacity, impairing mitochondrial respiratory chain complexes, and increasing reactive oxygen species in free radicals. So, causing brain ischemia through mechanisms other than vasospasm. Dr. Negar Asdaghi:         So, with these three points in mind, in the current issue of the journal, in the study titled "Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage," Dr. Joshua Catapano from the Department of Neurosurgery at the Barrow Neurological Institute and colleagues report on the outcomes of 1,014 aneurysmal subarachnoid hemorrhage patients treated over a 12-year period at their institution from August 2007 to July 2019. Dr. Negar Asdaghi:         The primary exposure was cannabis use, which was detected by routine urine toxicology at the time of hospital presentation with subarachnoid hemorrhage. Patients were also screened for the use of other vasoactive substances, including cocaine, amphetamines, and also tobacco use. The primary outcome was DCI defined as cerebral infarction detected either by CT or MRI or proven on autopsy after exclusion of procedure-related infarctions. Dr. Negar Asdaghi:         And here's what they found. Number one: Overall, 36.2% of their patient population with aneurysmal subarachnoid hemorrhage developed DCI. 50.2% of their total population had poor functional outcome defined as modified Rankin Scale of over two by the time of discharge, and 13.5% died. These are important reminders that aneurysmal subarachnoid hemorrhage remains a deadly form of stroke, despite modern neurosurgical and neurocritical care advances in treatments. Dr. Negar Asdaghi:         Number two: 4.5% of their patient population tested positive for cannabis. And here's the alarming finding of their study. The rate of DCI was significantly higher in those who were positive for cannabis, that was 52%, versus only 35% in those negative for cannabis. This association was not seen with other vasoactive agents such as cocaine and methamphetamine. Now, radiographic vasospasm was also significantly more common in cannabis users, the rate of which was 88% in cannabis users than in non-users, which was 70%. Dr. Negar Asdaghi:         Now, number three: When they adjusted for baseline patient characteristics, presenting Hunt and Hess classification, and other vasoactive substances and active smoking, cannabis use was independently associated with an increased likelihood of development of DCI. So, what did we learn from this study? Active cannabis users were 2.7 times more likely to develop ischemic stroke post-aneurysmal subarachnoid hemorrhage as compared to their non-user counterparts. This is one of the largest studies to potentially link marijuana to development of cerebral ischemia in this population. Dr. Negar Asdaghi:         There is now ample scientific evidence to connect some pregnancy-related complications, such as gestational hypertension, gestational diabetes, preeclampsia, and some pregnancy outcomes, such as preterm birth or having small-for-gestational-age infants, to an increased long-term risk of cerebrovascular events in the mother. Infertility, miscarriage and stillbirth are also common abnormalities in the process of conceiving and being pregnant, but whether there is an association between these abnormalities and development of future vascular disorders in women is not clear. Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women," Dr. Chen Liang from the School of Public Health at the University of Queensland in Brisbane and colleagues report on the results of a systematic review and meta-analysis on this topic. So, let's dive into it. Dr. Negar Asdaghi:         First, a brief look at their methodology. After a comprehensive literature search, a total of 18 studies were included in this meta-analysis, including over 7,800,000 women between the ages of 23 to 63 with a mean follow-up of 3.8 to 19 years. So, a big study. Five studies evaluated the association between infertility and stroke. Infertility was defined in broad terms as either a formal diagnosis or receiving fertility treatment or testing through databanks or medical records. And the other 13 studies explored the association between a history of either miscarriage and/or stillbirth and the main outcome of the study, which was stroke. Dr. Negar Asdaghi:         In 11 studies, the outcomes of ischemic and hemorrhagic strokes were specified, four studies only reported on the ischemic stroke, and the rest did not identify the stroke subtype. So, what did they find? Well, their first finding was on the association between infertility and stroke. Overall, the five studies included over 4,600,000 women, and this association was inconsistent due to heterogeneity of the results between the different studies. But, when excluding the one study from Asia, which created most of the heterogeneity in results, infertility was indeed found to be associated with a 17% increase in the risk of stroke in the mother. In terms of possible causes, well, they looked at common infertility etiologies and vascular risk factors, and not surprisingly, they found many connecting points. Dr. Negar Asdaghi:         For example, polycystic ovarian syndrome is a common cause of infertility and is frequently associated with insulin resistance and type 2 diabetes. Endometriosis, another cause of infertility, is commonly associated with hyperlipidemia and hypertension as a result of chronic systemic inflammation. Another example is premature ovarian insufficiency that could increase the risk of stroke through elevated follicle-stimulating hormone, a lower level of estrogen, and a relatively elevated level of androgen. Dr. Negar Asdaghi:         So, their next finding was on the association between miscarriage and stillbirth in stroke. As you know, both of these conditions, so miscarriage and stillbirth, describe pregnancy loss at various stages. A stillbirth is the loss of fetus after the 20th week of development while a miscarriage refers to a loss of pregnancy before the 20th week of gestation. Women with a history of miscarriage had a 7% increased risk, and those with a history of stillbirth had a 38% increase in the risk of stroke later in life. Now, since having a miscarriage is a very common occurrence, it's important to pay attention to their dose response sub-analysis. When data was available on the number of miscarriages or number of stillbirths, increased risk of stroke was apparent among women with three or more miscarriages, but not two or less. For stillbirths, similarly, a history of repeated stillbirths was associated with increased risk of stroke, but evidence on association for a single stillbirth with stroke was insufficient. Dr. Negar Asdaghi:         These are important findings to keep in mind when reviewing these results, and importantly, when counseling patients in routine practice. Now, in terms of causes, the authors discuss a variety of associated mechanisms, such as persistent endothelial dysfunction, a common cause for both pregnancy loss and vascular disease, elevated level of homocystine, autoimmune disorders, including presence of antiphospholipid antibodies and a cause for both pregnancy loss and development of arterial stenosis, noting that especially for the autoimmune conditions, specifically in the case of the APS syndrome, pregnancy loss is likely to be repeated, which is consistent with the findings of their subgroup analysis and dose response analysis in the paper, showing that repeated miscarriages and stillbirths are more likely associated with a higher risk of stroke rather than a single event. Dr. Negar Asdaghi:         So, bottom line, what my takeaway from this study is, that many factors that can cause infertility, miscarriage and stillbirth can also cause vascular disorders, and these associations should be kept in mind when treating women at a younger age for fertility and pregnancy-related complications. Dr. Negar Asdaghi:         Intensive therapy to lower serum lipid levels with the use of statins is recommended after transient ischemic attack or ischemic stroke of atherosclerotic origin. Treatment with statins has been shown to reduce the risk of major vascular events in the stroke population, but there remains a concern regarding an increased risk of development of intracranial hemorrhage with this therapy. Whether this increased risk of ICH is a class effect related to treatment with statins, or is associated with a certain low target levels of LDL cholesterol, is uncertain. Dr. Negar Asdaghi:         The Treat Stroke to Target randomized trial tested the hypothesis that a target level of LDL cholesterol of less than 70 milligram per deciliter would be superior to a target range of 90 milligrams to a hundred milligram per deciliter in reducing the overall cardiovascular events after an ischemic stroke or TIA in patients with evidence of atherosclerosis. The primary results of the trial was published in New England Journal of Medicine in early 2020. Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Intracranial Hemorrhage in the Treat Stroke to Target Trial," the trial investigators report the results of a pre-specified analysis of the TST trial to evaluate the baseline and on-treatment predictors of incident ICH. I'm joined now by Dr. Pierre Amarenco, who's the first author of the study and one of the primary investigators of the TST trial, to discuss this paper. Dr. Amarenco is an internationally renowned neurologist who absolutely needs no introduction to the Stroke readership, but as always, an introduction is nice. Dr. Negar Asdaghi:         He's a Professor of Neurology and the founder of the Department of Neurology and Stroke Center, as well as the SOS-TIA Clinic, at Bichat University Hospital in Paris. He's a leader in the field of secondary prevention of stroke with special interests in treatment of patients with TIA and mild stroke. He has served as the primary investigator of multiple randomized trials of antithrombotic therapies, lipid modifying agents, and acute revascularization treatments. Dr. Amarenco leads the international TIA registry involving centers from 21 countries around the globe. Welcome to our podcast, Pierre. Thank you so much for joining us all the way from Paris. Dr. Pierre Amarenco:     Good afternoon, Negar. Thank you for asking me. Dr. Negar Asdaghi:         Well, thank you for being here. Let's start with the Treat Stroke to Target trial. It addresses an important gap in the secondary prevention of ischemic stroke literature. Can you please start us off with an overview of the trial? Dr. Pierre Amarenco:     Yes. The objective of Treat Stroke to Target trial was to evaluate in 2,860 patients with ischemic stroke of atherosclerotic origin randomized into a target LDL cholesterol less than 70 milligram or a target LDL cholesterol 90 to 110 milligram per deciliter to see the benefit in the lower target group as compared to the higher target group. That was the purpose of the TST trial. Dr. Negar Asdaghi:         And the trial, Pierre, was terminated early. Do you mind commenting for our listeners as to why this happened? Dr. Pierre Amarenco:     Yes. The TST trial had a very long duration. It was an academic trial with low funding, funded by the French government, which is not quite the same as the NIH-funding trials. To give you an example, patient cost was $1,500 for the whole duration of the trial per patient. Around $1,500 per patient. So, it was a very low funding, and because of that, after nine years, we had to stop. But we had recruited all patients, and we had a three-year follow-up, so we could have a meaningful result. Dr. Negar Asdaghi:         So, perfect. So, just to recap for our listeners: Over eight-year period of time, despite the early termination, you had 2,860 patients enrolled, and so the termination of the trial was administrative reasons alone, as you mentioned. And so what were the primary outcomes of the trial? Dr. Pierre Amarenco:     The primary outcome of the trial was a reduction of 22% in this primary outcome, which was the composite of ischemic stroke and non-stroke, microinfarction, vascular death, and urgent revascularization for coronary or carotid ischemic event. Dr. Negar Asdaghi:         Okay, so the primary outcome was reduction of vascular events, truly, whether cardiac or in the brain. But now coming to the issue that is going to be addressed in your current paper, there remains a concern in the secondary prevention literature regarding an increased risk of intracerebral hemorrhage with statin therapy. Before we talk about the paper again, I want to give us a little bit of a background regarding the roots of this concern. Where does this all stem from? Dr. Pierre Amarenco:     In fact, when you do a meta-analysis of all statin trials, there is no increase of hemorrhagic stroke, particularly trials in primary prevention of stroke. However, in trials in secondary prevention, which include mostly HPS trial with simvastatin and SPARCL trial with atorvastatin, there was a 60% increase in hemorrhagic stroke. That did not outweigh the benefit observed in this trial, but there was a concern about statin in secondary prevention, particularly high dose statin. Dr. Pierre Amarenco:     So, in SPARCL, we did a post-stroke analysis looking at predictors of hemorrhagic stroke, and we found that, as usual, age and male sex increase risk of hemorrhagic stroke, but the most important was uncontrolled hypertension and atorvastatin. Atorvastatin stayed into the model. We know that atorvastatin reduce LDL cholesterol, that low LDL cholesterol in SPARCL was not associated with hemorrhagic stroke. So, there was a paradox because atorvastatin stayed into the model and we know that atorvastatin lower LDL cholesterol importantly. It is possible that something goes wrong between statin and vascular disease in the brain. In SPARCL, we looked at stroke subtypes at the baseline, and we found that atherosclerotic stroke, TIA and cryptogenic stroke were not associated with hemorrhagic stroke. But we found also that patients randomized with brain hemorrhage, 2% of the sample, and patient randomized with lacunar stroke were at increased risk of hemorrhagic stroke. Dr. Pierre Amarenco:     So, altogether, we can say that small vessel disease of ischemic type or hemorrhagic type were associated with hemorrhagic stroke, and we know that small vessel disease is associated with high blood pressure. So, the fact that we found uncontrolled hypertension as a predictor of hemorrhagic stroke in SPARCL was logical since also we found that small vessel disease was a predictor. Dr. Negar Asdaghi:         So, very important points that you mentioned, and I, again, want to repeat them for our listeners. And I think it's one of my questions later on to ask about independent predictors of hemorrhage, but based on the cumulative literature for what we knew before the current study, you had mentioned uncontrolled hypertension, small vessel disease, which is sort of a marker of both ischemic and hemorrhagic events in the brain, were all independent predictors of development of ICH. Whether statin therapy or low target level of LDL adds to that fueling, that fire, or not was something that you wanted to really decipher in the TST trial. I think we're ready to hear about the methodology of your current paper, if you could tell us, please. Dr. Pierre Amarenco:     So, in TST, of course, because of this background, we pre-specified an analysis of incident hemorrhagic stroke. So, we looked at patients with incident hemorrhagic stroke versus those without, and we did a multivariable analysis to look at predictors, and that was the methodology of the paper we use for this specific paper. Dr. Negar Asdaghi:         And what were the primary results? Dr. Pierre Amarenco:     So, the primary result was that after a median of three years follow-up, we found 31 hemorrhagic stroke in the lower target group and 28 hemorrhagic stroke in the higher target group, and the difference was not significant. In the paper, we show a graph with a distribution of hemorrhagic stroke according to the level of LDL cholesterol three months before the hemorrhagic stroke, and it is striking to see that half of the events occurred for an LDL cholesterol above 100 milligram per deciliter and half of the events occurred for an LDL cholesterol below 100 milligram per deciliter. So, clearly, in TST trial, like in SPARCL trial, we did not find a relationship between low LDL cholesterol and incident hemorrhagic stroke. Dr. Negar Asdaghi:         So, very important information for all practicing neurologists and stroke neurologists out there. I want to recap, again, very important numbers that you mentioned. Achieving low LDL cholesterol target, even very low numbers, as you mentioned, was not a predictor of development of intracerebral hemorrhage in the trial. And, as you mentioned, half of them, actually it occurred even before achieving the target LDL for the trial. But you did find some other significant predictors of ICH in the study. Can you please elaborate on those? Dr. Pierre Amarenco:     Yes, we found predictors, and the only predictors we found, in fact, were uncontrolled hypertension, exactly what we found in SPARCL. So, uncontrolled hypertension is really something important, and anticoagulant treatment, which was not found in SPARCL. So they were the only predictors, uncontrolled hypertension and anticoagulant treatment with of use therapeutic implications. When you put patients on a low level of LDL cholesterol, when you target the low level, you have to tightly control blood pressure, which is always a case in secondary prevention of stroke, but particularly when you target the low LDL cholesterol, and then anticoagulant treatment, of course, you have to monitor closely blood pressure and also the level of anticoagulation. Dr. Negar Asdaghi:         So, it's, again, I want to repeat what you mentioned, because it seems like we've been blaming the wrong person all along, concentrating on this issue of statins or low LDL levels being associated or the causative reason for development of intracerebral hemorrhage, and forgetting about the obvious, which is uncontrolled hypertension and now the new finding of being on oral anticoagulants, which is not unexpected. Pierre, my next question was on SPARCL trial, but you've already alluded to the SPARCL study. I'm going to repeat and ask the question regarding SPARCL, because for years and years as practicing neurologists, we've referred to the results of SPARCL, and you already alluded to some of the similarities between the two trials, but is there something else as you compared TST with SPARCL that you want to mention in terms of patient population included in both studies or the differences in the results? Dr. Pierre Amarenco:     The most important difference was that in SPARCL, there was a placebo group, which was not the case in TST since we compared two levels of LDL cholesterol. So, literally all patients were on statins in TST trial, which was not the case in SPARCL since half of the patients were on statins. So, that was the main difference, but the concept of TST clearly came from SPARCL sub-analysis. In SPARCL sub-analysis, we found that achieving an LDL cholesterol less than 70 milligram was associated with a benefit compared to patients with an achieved LDL cholesterol of 100 milligram per deciliter. But that was a post-stroke analysis in SPARCL, and so we had to confirm this, which is why we did the TST trial, which was clearly a follow-up of the SPARCL trial. And then we confirmed what we found in SPARCL, that is low LDL cholesterol was not associated with incident hemorrhagic stroke while there was a benefit of achieving a low LDL cholesterol target compared to a higher target. Dr. Negar Asdaghi:         All right, so just the follow-up question on the LDL levels. Statins are, of course, not the only agent to use to achieve a lower level of LDL cholesterol. There's a growing literature with the PCSK9 inhibitors, especially in patients with acute coronary syndrome, to lower the LDL levels. How are the findings from those studies of PCSK9 inhibitors on the risk of ICH compared to your study? Dr. Pierre Amarenco:     The findings of four-year trial with evolocumab and ODYSSEY OUTCOMES trial with alirocumab was that going to less than 40 milligram per deciliter or even 30 milligram in mean per deciliter in four-year trial was not associated with an increased risk of hemorrhagic stroke. For example, in four year, the risk of hemorrhagic stroke was 0.21% in the evolocumab group versus 0.18% in the placebo group. And in ODYSSEY OUTCOMES trial, it was 0.2% in both groups. So, clearly, going to a very, very low level of LDL cholesterol was not associated with an increased risk of hemorrhagic stroke. To give a comparison, in TST, in the lower target group, we had a 1.25% risk of incident hemorrhagic stroke versus 0.9% in the higher target group. There was a slight increase, but that was not reaching statistical significance, and it was not associated with low LDL cholesterol. Dr. Negar Asdaghi:         Perfect. So, quite reassuring, these results from various trials, again, showing and reassuring that the risk of intracerebral hemorrhage seems to not be significantly associated with lower target levels of LDL cholesterol. Now, we do have time, Pierre, I want to digress a little bit from your current study and ask a question that comes up rather frequently in routine practice. And that is the association between statin therapy, lower levels of LDL and incident ICH in the setting of microbleeds that are found typically incidentally on an MRI study. Do you think there is any possible interaction between the two, or are there plans to look at this as part of TST? Dr. Pierre Amarenco:     Yes. I would like first to say that I don't like the term "microbleeds" or "microbleeding" because it is scary for the patients. I have plenty of patients coming to my outpatient clinic because they are afraid of what they have read on the radiologist report, "microbleeds." "Doctor, my brain is full of microbleeds." I prefer to use the term "microdeposit of hemosiderin," which is descriptive, which is associated with small vessel disease. Dr. Pierre Amarenco:     So, regarding the relationship between microdeposit of hemosiderin and incidence of intracranial hemorrhage on statin, in fact, we don't know the relationship, but we can't say that in SPARCL, there was an association between small vessel disease of hemorrhagic or ischemic type with incident hemorrhage on atorvastatin 80 milligram per day. So, these patients with microdeposits of hemosiderin have small vessel disease, and then they may be at risk of more hemorrhagic stroke. So, in these patients, I would be cautious, and on high dosage of statin. I prefer to use low dosage associated with ezetimibe or with PCSK9 inhibitor to go low for LDL cholesterol, but not with statins. So, this is the way I'm used to do when there is a lot of microdeposit of hemosiderin in my patient, but it has not been tested in clinical trials. Dr. Negar Asdaghi:         So, very important, again, to repeat and recap what you mentioned. First of all, love the term "microdeposit of hemosiderin," and I'm going to use that with my patients. I totally agree with you that telling someone, "Oh, there's tons of blood in your brain," is not quite a good start. But definitely, again, as you mentioned, these are markers of small vessel disease, both for ischemic stroke and hemorrhagic. So, it's important to, again, address the causes of small vessel developments and etiologies very aggressively. And, as you mentioned, the jury's still out whether the statin class affect an association with incident ICH or an association between low target levels of LDL cholesterol, and more to come on that in the future. Pierre, just to end our podcast, what would be your top two takeaway messages for our listeners on the topic of target LDL and incident ICH? Dr. Pierre Amarenco:     Well, the message is simple. Targeting an LDL cholesterol of less than 70 milligram per deciliter in atherosclerotic ischemic stroke non-significantly increases the risk of subsequent intracranial hemorrhage. Incident intracranial hemorrhage were not associated with low LDL cholesterol level. And we found two predictors of incident intracranial hemorrhage, which were uncontrolled hypertension and anticoagulant therapy, which has important clinical implication for our patients. Dr. Negar Asdaghi:         Dr. Pierre Amarenco, it's been a pleasure interviewing you on the podcast today, and we look forward to having you back with more on this topic. Dr. Negar Asdaghi:         And this concludes our podcast for the February 2022 issue of Stroke. Please don't forget to check out this month's table of contents for the full list of publications, including a series of Focused Updates on vascular brain health organized by Dr. Steve Greenberg. Dr. Negar Asdaghi:         February is also a special month for our stroke community, with our annual International Stroke Conference, which this year is held as a hybrid event, both face-to-face in New Orleans and simultaneously as a virtual event for those who cannot attend it in person, as the fight against the COVID-19 pandemic continues. Reminding us all that with every challenge, there comes new ways to live, to cope, and to rise above it all. And we're here to do just that with staying alert with Stroke Alert. Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.  

This week’s episode features author Jaime Layland and Associate Editor Dharam Kumbhani as they discuss the ariticle "Colchicine in Patients with Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial." TRANSCRIPT BELOW: 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, director of the Pauley Heart Center, VCU Health, in Richmond, Virginia. Dr. Carolyn Lam: Greg, for our feature discussion we're talking about a very hot topic these days, the role of colchicine, this time in patients with acute coronary syndrome, with Australian data. I cannot wait to get to that, but I'm going to make you wait because I want to tell you about a whole lot of other really cool papers in today's issue. Dr. Carolyn Lam: First, have you ever wondered what is the association between risk factor control and cardiovascular disease risk in type 2 diabetes? Well, today's paper answers that. It's from Dr. Wright from University of Manchester and her colleagues who looked at a retrospective cohort using data from the English practices from Clinical Practice Research Datalink, or CPRD, and the Scottish Care Information diabetes dataset. They also linked to hospital and mortality data and identified more than 101,000 patients with type 2 diabetes in CPRD matched with almost 379,000 controls without diabetes and almost 331,000 patients with type 2 diabetes in the Scottish Care Information diabetes database between 2006 and 2015. The main exposure was a number of optimized risk factors, and these are: (1) Nonsmoker; (2) total cholesterol less than 4 mmol/L; (3) triglycerides less than or equal to 1.7 mmol/L; (4) HB A1c less than 7%; and (4) systolic blood pressure less than 140 or less than 130 mmHg of high risk. Dr. Greg Hundley: Carolyn, I am very curious. Lots of data here. What did they find? Dr. Carolyn Lam: So the key findings were: Dr. Carolyn Lam: First, even with optimally managed risk factors, people with type 2 diabetes still had a 21% higher risk for all cardiovascular disease events and non-fatal coronary heart disease, and a 31% higher risk of heart failure hospitalization compared to patients without diabetes. Dr. Carolyn Lam: 2. Only 6% of people with type 2 diabetes had optimal risk factor controls, so a very low percent. Dr. Carolyn Lam: 3. The association between the number of elevated risk factors and cardiovascular disease events and mortality was much stronger in patients with type 2 diabetes but without cardiorenal disease compared to those with established cardiorenal disease. People without cardiorenal disease were also younger and more likely to have suboptimal risk factor control and fewer prescriptions for risk-factor-modifying medication. Dr. Carolyn Lam: So take-home message: Greater use of guideline-driven care, clinical decision support, drug intervention, and self-management support should be encouraged for risk factor control, and people with type 2 diabetes and without cardiorenal disease may especially benefit greatly from cardiovascular disease risk factor intervention. Dr. Greg Hundley: Very nice, Carolyn. Dr. Greg Hundley: Well, my first study comes from Dr. Gregory Lewis from Mass General Hospital in Boston, Massachusetts. Carolyn, another quiz: Have you wondered about differences in metabolism in those who exercise versus those that do not? Dr. Carolyn Lam: Greg, I wonder about that all the time when I'm running out there. Dr. Greg Hundley: In this study, cardiopulmonary exercise testing, or CPET, and metabolite profiling was performed on Framingham heart study participants aged about 54 years with 63% of them being women with blood drawn at rest in 471 subjects and then again at peak exercise in 411. Dr. Carolyn Lam: Nice, and kudos for the majority women. So what were the results? Dr. Greg Hundley: The authors observed changes including reductions in metabolites implicated in insulin resistance and increases in metabolites associated with lipolysis, nitric oxide bioavailability, and adipose browning. Exercise-induced metabolite changes were variably related to the amount of exercise performed, peak workload, sex, and body mass index. There was attenuation of favorable exercise excursions in some metabolites in individuals with higher BMI and greater excursions in select cardioprotective metabolites in women despite less exercise being performed. Four metabolite signatures of exercise response patterns were analyzed in a separate cohort. The Framingham offspring study of 2,045 were about age 55 years and 51% were women, two of which were associated with overall mortality over a median follow-up at 23 years. Dr. Greg Hundley: So Carolyn, in conclusion, the authors found acute exercise elicits widespread changes in the circulating metabolome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise that could be useful in future studies. Dr. Carolyn Lam: Beautiful. I'm going to keep exercising and I bet you will, too, Greg. Dr. Carolyn Lam: So this next paper is a mechanistic study that revealed a special population of tissue regulatory T-cells in the heart with a unique phenotype and pro-repair function. So this comes from corresponding author Dr. Cheng from Tongji Medical College of Huazhong University of Science and Wuhan Hubei, China. He and his colleagues studied the dynamic accumulation of regulatory T-cells in the injured myocardium in mouse models of myocardial infarction, myocardial ischemia re-perfusion injury, or cardiac cryo injury, and using state-of-the-art methods such as bulk RNA sequencing, photo conversion, parabiosis, single-cell TCR sequencing, adoptive transfer, and functional assays. Dr. Greg Hundley: Carolyn, interesting. What did they find? Dr. Carolyn Lam: They showed that regulatory T-cells that accumulate in the injured myocardium after myocardial infarction or myocardial ischemia re-perfusion injuries had a distinct transcriptome which differs from lymphoid organ regulatory T-cells and other non-lymphoid tissue, and this represents a novel population of tissue regulatory T-cells in the heart. These heart regulatory T-cells were mainly thymus driven and recruited from the circulation showed active local proliferation with the IL-33/ST2 axis promoting their expansion. With the phenotype of promoting tissue repair, heart regulatory T-cells over-expressing spark contributed to elevated collagen content and enhanced maturation in infarct scars to prevent cardiac rupture and improve survival after myocardial infarction. Dr. Carolyn Lam: So in summary, this paper identified and characterized a phenotypically and functionally unique population of heart regulatory T-cells, which may lay the foundation to harness these cells for cardiac protection in myocardial infarction or other cardiac diseases. Dr. Greg Hundley: Wow, Carolyn. Very interesting. Dr. Greg Hundley: Well, my next paper comes from Dr. Michael Rubart from Indiana University School of Medicine, and as some background it's going to discuss calmodulin. So calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a P.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying this N98S mutation knocked into CALM1 replicate the human arrhythmia phenotype and then to examine some of the arrhythmia mechanisms. Dr. Carolyn Lam: Okay. So what did they find? Dr. Greg Hundley: Carolyn, several techniques were used in this study. Mouse lines heterozygous for the CALM1 N98S allele generated using CRISPR and caspase 9 technology. Also, adult mutant mice and their wild-type litter mates underwent electrocardiographic monitoring. Ventricular D and re-polarization was assessed in isolated hearts using optical voltage mapping, and action potentials in wholesale currents as well as calcium influx were measured in single ventricular myocytes using patch-clamp techniques and fluorescence microscopy, respectively. Microelectrode techniques were employed for in situ membrane voltage monitoring of ventricular conduction fibers. Carolyn, it was really a comprehensive study. Dr. Greg Hundley: So what did the authors find? Heterozygosity for the CALM1 N9S mutation was causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTC interval prolongation, and bidirectional ventricular tachycardia. Second, beta adrenergically induced calcium influx L dysregulation contributed to the long QT phenotype. And finally third, they found that pause dependent early after depolarizations and tachycardia induced delayed after depolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constituted potential sources of arrhythmia in the CALM1 N98S positive hearts. Dr. Carolyn Lam: Wow. Sounds like a really comprehensive study. Thanks, Greg. Dr. Carolyn Lam: Let's talk about some other papers in this issue, shall we? There is a Perspective piece by Dr. Klassen on the COVID-19 pandemic, a massive threat for those living with cardiovascular disease among the poorest billion. There's an ECG challenge by Dr. Littman on a malignant electrocardiogram. Here's a hint: It's a pseudo-infarct pattern with important learnings. They're in an exchange of letters between Drs. Packard and Schwartz regarding the role of lipoprotein A and modification by alirocumab, a pre-specified analysis of ODYSSEY Outcomes randomized clinical trial. Dr. Greg Hundley: Oh thanks, Carolyn. I've got a couple other papers. Dr. Venkateswaran Subramanian has a Research Letter entitled Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice. Professor Jan Cornell has another research letter entitled Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease. The LoDoCo2 proteomic substudy. And then finally, Dr. Sanjay Kaul from Cedars-Sinai Medical Center has a white paper reviewing the benefit/risk trade-offs in assessment of new drugs and devices. Dr. Greg Hundley: Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and acute coronary syndromes. Dr. Carolyn Lam: Yeah. Let's go, Greg. Today's feature discussion is all about colchicine, that commonly used treatment for gout that has recently emerged as a novel therapeutic option in cardiovascular medicine. I am so pleased to have with us the corresponding author of today's paper, Dr. Jamie Layland from Monash University, as well as our associate editor, Dharam Kumbhani, from UT Southwestern to discuss this very important trial data from Australia. Jamie, could you start us off by telling us all about this Australian COPS trial? Dr. Jamie Layland: We performed the Australian COPS trial back in 2015, and it finished recruiting in 2018. Essentially the trial was a trial to look at the safety and efficacy of colchicine being used in acute coronary syndromes, and this was prior to the release of important trial COLCOT. So essentially we randomized patients who presented to the hospital with an acute coronary syndrome to receive colchicine twice daily for one month followed by colchicine once a day for 11 months, and we followed these patients up for a minimum of 12 months. This was performed across 17 sites across Australia, and we looked at a composite endpoint of total death, acute coronary syndromes, unplanned urgent revascularization, and stroke. Dr. Carolyn Lam: Nice. So Jamie, could I first clarify that this was an investigator-led trial, I'll bet, and man, first of all, applause for doing this. I can only imagine how much work this took and maybe then tell us about the results. Dr. Jamie Layland: Yeah. So this was an investigator-initiated trial through a network of academic investigators across Australia on limited research funding, so through philanthropic and institutional support. So it was a huge effort over a number of years, and I'm very thankful to the support of Circulation and Dharam in supporting the paper, which I think was a great success. Dr. Jamie Layland: So the results of this trial were a surprise to us all, but essentially this was a negative trial in the sense that colchicine did not improve the primary outcome, so there was no improvement in the rate of the COLCOT outcome. And interestingly, there was an increase in total mortality, in particular non-cardiovascular deaths were higher at five compared to the placebo at one. That was over a 12-month follow-up period. Dr. Carolyn Lam: Interesting. So Jamie, I'm going to ask the question that's on everyone's mind then: What's the difference between your trial and COLCOT? Dr. Jamie Layland: That's a great question. Obviously, COLCOT was a much larger trial. COLCOT was an international trial of over 4,000 patients. Similar patient demographics, similar patient subgroup of acute coronary syndromes. However, importantly, COPS was a trial of inpatient initiation of colchicine. So patients when they had their STEMI, or non-STEMI most commonly, they were given colchicine usually within 72 hours of their index hospitalization and sometimes sooner, and this was given prior to discharge. With COLCOT, the median time of administration of colchicine was around 14 days, so slightly different groupings there. However, in COLCOT you were allowed to administer colchicine as an inpatient. You can see obviously from the European side of cardiology the impressive data when colchicine was given earlier in COLCOT how this translated to improved outcomes. So clearly, there is a potential benefit there for early administration of colchicine when you look at these two trials. Dr. Jamie Layland: But we administered colchicine acutely when patients presented in their index hospitalization. We also importantly used a different dosing schedule to COLCOT. So COLCOT was 0.5 mg daily and we used 0.5 twice daily. This was for the first 30 days, and this was based on early data from the group from western Australia who showed that when colchicine was given to patients at a BD dosing in those patients who were already on aspirin and high-potency statins, there was a significant reduction in hsCRP, obviously a commonly used marker of inflammation at four weeks, and also based on data showing that there was a heightened inflammatory response in the early days following an acute coronary syndrome. So we felt that using this twice-daily dose would be advantageous and potentially helpful for our patients. So they're the two main differences between the studies. Dr. Carolyn Lam: Thanks for explaining that so clearly. Dharam, could I have your thoughts? This was, of course, discussed heavily, right, by the editors. Could you give us a sneak peek of what else was discussed? Dr. Dharam Kumbhani: The trial is very important, although it is smaller perhaps in sample size and kind of done with less resources than COLCOT. I do think this adds to the body of literature on colchicine for secondary prevention of CAD. And one of the interesting things is that we see we also have the LoDoCo2 trial, which was a slightly different population, Jamie, which was the chronic coronary artery disease patients, but also still looking at secondary prevention. What is really striking to me is that a very similar signal in non-CV death was noted in that trial as well. Again, it was not seen in COLCOT and LoDoCo1, but it was very interesting that a similar finding was there. So I do think this is something that the field will need to investigate more and really try to understand is this just noise and by chance alone, or is this something that that's a real signal for. Dr. Carolyn Lam: Jamie, what are your thoughts about that and in LoDoCo differences with your trial? Dr. Jamie Layland: Good question, and a very important topic that obviously is currently under discussion amongst the colchicine community. As I said, it was a surprising result. We weren't anticipating this non-CV death signal, but as Dharam said when LoDoCo2 came out, a fantastic trial again, but this signal of non-CV death. I don't know whether it's merely just a noise as you say or whether it's a significant finding, but clearly we need to do more research in this field to understand the mechanism and whether this is a real signal or not. It seems a little bit discordant with previously published work. So if you look at the literature in patients with gout from across the world, there's no real signal of increased non-CV death in those patients. However, with patients with acute coronary syndrome as we are administering the colchicine on a daily basis and then commonly this isn't used for gout, so that is a slight difference. But certainly, there was no signal in the non-CV literature to support the findings that we had and the signal in LoDoCo2. Dr. Jamie Layland: The other thing to note is in a cohort of five non-CV deaths, three out of those five patients were actually not taking colchicine at the time of their death. They stopped the drug prematurely. So I think we just need to take a step back and really await the results. Obviously, we've got two-year and five-year data coming out from the COPS trial which will be interesting to look at, but also the Clear Synergy trial from the McMaster team, that would be a very important trial providing more data on this potential signal. But reassuringly, and I feel more reassured knowing the COLCOT data, which is a slightly similar cohort to ours, showing that there was no trend towards increased non-CV deaths. So I think it's something that we have to be aware of and there will be lots of metro-analysis I'm sure being published in the coming months looking at this specifically. But yeah, I think we shouldn't cast any aspersions on colchicine yet. I think that's too early, but I do think we need more data. Dr. Carolyn Lam: Thanks, Jamie. Speaking of looking deeper in your data and looking at those who died and were they taking the medication and so on, you did some other post-hoc analysis, right? And maybe you could just describe briefly, for example, the 400-day followup. Dr. Jamie Layland: Yes. So the interesting thing with our data, and I had mentioned this before, is that we had limited resources, so we really wanted to do this trial, and obviously competitive funding is tricky at the best of times, but we were really committed to doing this trial and we had a group of investigators who were all committed to doing this trial. But for this to work, we had a single research nurse and a fellow performing the follow-up. So at times, there was a little lag between the timing of the follow-up. So we ended up getting follow-up which was slightly prolonged over the 12-month window. On average, it was around 400 days. When we looked at the 400-day data, we saw that there was an increasing separation of the biomarkers after 365 days. Dr. Jamie Layland: The results, this was obviously not the primary outcome, this was a sensitivity analysis, but there was a suggestion or a significance out to 400 days with an improvement with colchicine. However, this is the primary composite outcome, so revascularization, acute coronary syndrome, stroke, and total death notwithstanding this positive outcome, there was still this trend to high rate of mortality, so that has to be taken into consideration. But there was a suggestion that the longer the duration of colchicine was given for, it culminated into these lights affect. And we see from CT data that colchicine actually has some plaque-modulating effects and reduces high-risk or low-attenuation plaque. So you could hypothesize that as the majority of the benefits seen in colchicine in LoDoCo2, in COLCOT, and in COPS was the reductions in urgent revascularization, stroke, and acute coronary syndromes. Dr. Jamie Layland: So perhaps there is this effect that colchicine is having on plaque stabilization so we're seeing less longer-term events, but this is just hypothesis generated and we need more data to support that. But it is a very interesting finding nonetheless. Dr. Carolyn Lam: Thank you. Dharam, could I hand you the last word on where you think this field is going or where you think it should go? Dr. Dharam Kumbhani: I think Jamie put it really nicely. I think he outlined the study nicely with its strengths and its limitations, and I think this is obviously a debate between perhaps the colchicine believers and the ones that are still perhaps trying to understand a little bit more about its true role, because as was mentioned I think there's really a benefit in ischemia-driven revasc. I think we've seen that in almost all the colchicine trials. There is no reduction in mortality, and as we saw in the COPS data maybe it goes the other way. So I think from a pathophysiological standpoint it makes sense. I think there's good translational data to suggest that it would be beneficial in this patient population, but I think that's the beauty of having clinical trials and the ones that are done by different investigators and perhaps in different settings, because they help us answer the truth. And whether colchicine becomes a stable part of our armamentarium for secondary prevention of CAD going forward, I think the jury is still out and as was mentioned I think Clear Synergy would probably be very helpful in hopefully tying all this together. Dr. Dharam Kumbhani: So again, I want to congratulate Jamie and his team for really providing us with a very interesting trial done in a very pragmatic setting, and I think the field is very thankful to them for providing us with this information. Dr. Carolyn Lam: Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to join me and Greg again next week. Dr. Greg Hundley: This program is copyright the American Heart Association 2020.  

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 Greg Hundley, associate editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: We've got a juicy, juicy feature discussion coming up. It's on a pre-specified analysis of the ODYSSEY OUTCOMES randomized clinical trial, this time to ascertain whether PCSK9 inhibition reduces the risk of peripheral arterial disease events or venous thromboembolism after acute coronary syndrome. And, also to answer, these effects are related to levels of lipoprotein(a) or LDL cholesterol. I'm going to keep everyone guessing, as we get on our coffee chat and talk about the other papers in this issue. And I want to go first, because the first original paper I want to discuss is really quite related to the feature discussion too. And it asks the question, what is the relationship between cholesterol levels and risk of venous thromboembolism? And, what is the effect of PCSK9 inhibition on the risk of venous thromboembolism? So this is from Dr Marston from the TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts, and colleagues who performed a post hoc analysis of the FOURIER trial, testing whether evolocumab reduces the risk of venous thromboembolic events. That is, deep venous thrombosis, a pulmonary embolism. The authors then looked at data from FOURIER and the ODYSSEY OUTCOMES trial and combined them in a meta-analysis to assess whether there was a class effect of PCSK9 inhibition on the risk of venous thromboembolism. As a reminder, the ODYSSEY OUTCOMES trial tested alirocumab as the PCSK9 inhibitor. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: Well, first Greg, remember, this is the first study to demonstrate a significant reduction in venous thromboembolism with PCSK9 inhibition. Interestingly, the reduction in venous thromboembolism was associated with the degree of lipoprotein(a) lowering and not LDL cholesterol lowering, suggesting that lipoprotein(a) may be the mediator of venous thromboembolic risk. More coming up in our feature discussion. Dr Greg Hundley: Wow, Carolyn. Well, I'm going to go into the world of PCSKs, but talk about PCSK6. So this study involves a secretome analysis of cardiomyocytes as novel players in cardiac remodeling after myocardial infarction and the corresponding author is Dr Florian Leuschner from Heidelberg University. So Carolyn, we know that acute occlusion of coronary artery results in swift tissue necrosis and bordering areas of the infarcted myocardium may also experience impaired blood supply and reduced oxygen delivery leading to altered metabolic and mechanical processes. While transcriptional changes in hypoxic cardiomyocytes are well-studied, little is known about the proteins that are actively secreted from these bordering cells. So in this study, the authors established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis. Dr Carolyn Lam: Wow, sounds like very advanced methods and what did they find? Dr Greg Hundley: Okay. Carolyn lots of results here. They found that PCSK6 expression was elevated in hearts of mice, following three days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements and human serum also indicated distinct kinetics for PCSK6 in patients suffering from acute myocardial infarction with a peak on day three post infarction. One of these beautiful studies combining basic science and human subjects in the same paper. In addition, adeno-associated virus nine mediated cardiomyocyte specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis as well as decreased left ventricular function after MI. So Carolyn, this study demonstrates how novel mass spectrometry-based approach allows the investigation of the secretome of primary cardiomyocytes. That's a first for that technique. And then analysis of hypoxia-induced secretion led to the identification of PCSK6 to be crucially involved in cardiac remodeling after MI, demonstrating increased collagen expression and cardiac fibrosis in those border zones. Dr Carolyn Lam: Wow, fascinating, Greg. Well, I want to switch tracks here. Maybe ask, when you're choosing between antithrombotic therapies for patients with atrial fibrillation and a recent acute coronary syndrome, have you ever wondered what is the tradeoff of risk? Risk of bleeding and benefit that would be in terms of prevention of ischemic events over time? Well, guess what, I'm not going to put you on the spot here because our next paper addresses this very question. And it's from corresponding author, Dr Alexander from Duke Clinical Research Institute and colleagues who performed a post hoc analysis of the AUGUSTUS trial. Dr Greg Hundley: Okay, Carolyn. I'm going to digress for just a minute here. We have this wonderful producer, Augie Rivera, and he's just fantastic and we should give him accolades because he really helps put all these together. Now I'm not going to ask him this time, but maybe in one of our future discussions, we may need to bring him into one of these because of his expanded knowledge of all of science, but getting back, Carolyn, can you remind us what is the AUGUSTUS trial? Dr Carolyn Lam: All right, so in the AUGUSTUS trial, patients with AF and a recent ACS and/or PCI taking a P2Y12 inhibitor had less bleeding and rehospitalization with apixaban, than vitamin K antagonists and less bleeding with placebo than aspirin. The composite of death or hospitalization was also reduced with placebo compared to aspirin. However, the risk of several recurrent ischemic events, including stent thrombosis, where numerically higher in patients assigned placebo. Further analysis of the stent thrombosis outcomes suggested that most of the increase in risk was early within 30 days of randomization. And hence the objective of the current paper, which is a post hoc analysis to explore the balance of risk and benefit using a variety of composite outcomes between randomization and 30 days and between 30 days and six months over time comparing apixaban versus vitamin K antagonists and aspirin versus placebo. So, here's what they found. Apixaban caused fewer ischemic and bleeding events than warfarin in the first 30 days after ACS and/or PCI and similar or fewer ischemic and bleeding events from day 30 to six months. Use of aspirin acutely, and for up to 30 days, resulted in an equal tradeoff between an increase in severe bleeding and reduction in severe ischemic events. However, after 30 days aspirin continued to increase bleeding without significantly reducing the ischemic events. So these results really informed shared patient-centric decision making regarding the ideal duration of use of aspirin after an ACS and/or PCI in patients with AF already receiving oral anticoagulation. Dr Greg Hundley: Very nice, Carolyn. You know, lots of data coming out about how we perform anticoagulation, the administration of aspirin, both an atrial fibrillation, ischemic events, those with stents and this is just another piece of important data that we're so fortunate to have published in circulation. Well in the rest of the issue Carolyn, there's a lot of information. I want to talk about a research letter from Dr Armand Killick from the University of Pittsburgh, and he describes the outcomes of the first 1300 adult heart transplants in the United States following a policy change in the U S related to allocation of hearts. In an EKG challenge, Dr Nobuhiro Takasugi from Gifu University and colleagues reviewed the etiology of wide complexes. Are they aberrantly conducted supraventricular beats? Are they premature ventricular complexes or intermittent ventricular prereq citation in an individual 70 years old presenting with symptoms of palpitations? Then Carolyn, in one of our COVID-19 articles, there's an in-depth piece by Dr Kevin Clerkin and associates from Columbia University. And they review coronavirus disease that is caused by severe acute respiratory syndrome, coronavirus 2 or SARS-CoV-2, which invades cells through the angiotensin converting enzyme or ACE-2 receptor. Among those with COVID-19, they note there is a higher prevalence of cardiovascular disease and more than 7% of patients suffer myocardial injury as evidence from elevated cardiac troponin values from the infection and in 22% of those that were critically ill. And despite ACE-2 serving as a portal for infection, the role of ACE inhibitors or angiotensin receptor blockers requires further investigation. And right now, as you know, in your field is a heart failure expert, they are not recommendations to consider discontinuation for those drugs. And then lastly, in a prospective piece, Professor Gianluigi Condorelli from Humanitas University in Milan, presents critical organizational issues for cardiologists in this COVID-19 outbreak, including prioritization of unstable patients with cardiovascular disorders by postponing visits, and in this situation they did so by 80%, reorganizing clinical activities in terms of ward, ICU beds and outpatient visits, using a hub-and-spoke model to prioritize management acute MI, and then finally rapidly acquiring and training physicians and staff in the correct use of PPE. All very valuable lessons from Italy that was so hard hit by this devastating disease. Dr Carolyn Lam: Indeed, and you know what, Greg, I just want to tell everybody about our circulation YouTube channel, where we have frontline interviews with people dealing with this from all over the world. Thank you to Augie and his team for making all of this happen. Let's go on to our future discussion, shall we? Dr Greg Hundley: Absolutely. Dr Carolyn Lam: Patients with acute coronary syndrome are at risk of peripheral artery disease events and venous thromboembolic events. Now we've heard a lot about PCSK9 inhibitors in patients with acute coronary syndrome, but what is the effect of PCSK9 inhibition on the risk of PAD or venous thromboembolic events? Well, we're about to find out. The feature paper is a pre specified analysis of the ODYSSEY OUTCOMES trial. And I'm so pleased to have the first and corresponding author, Dr Greg Schwartz with us from the University of Colorado, School of Medicine, as well as our guest editor, Dr Erin Michos from Johns Hopkins School of Medicine. So welcome. And Greg, could I ask you to start us off. Tell us why you looked at this in ODYSSEY OUTCOMES and what you found. Dr Gregory Schwartz: All of our patients or nearly all of our patients with acute coronary syndrome have had an atherothrombotic event and most of them also have a heightened inflammatory state. These factors are also thought to have a role in the pathogenesis of peripheral artery disease events, and perhaps also venous thromboembolism. We typically think of the risk factors for peripheral artery disease as being diabetes and smoking, and less so dyslipidemia, although dyslipidemia may play a role in PAD events as well. And although the association of LDL cholesterol levels with PAD events has been inconsistent in the literature, there's more consistency actually with levels of lipoprotein(a) and the risk of PAD events. And that kind of makes sense because we think that Lp(a) has both atherogenic and pro-inflammatory and perhaps also prothrombotic properties. So elevated levels of that lipoprotein might promote the risk of PAD events. Now statins, which are obviously the mainstay of our treatment of patients with atherosclerosis, lower levels of LDL cholesterol, but they don't affect the levels of Lp(a). In contrast, inhibitors of PCSK9 lower the levels of both of those key lipoproteins. So we looked at the relationship of baseline and on treatment levels of both LDL cholesterol and lipoprotein(a) on the risk of PAD events and also venous thromboembolism, which has been associated with lipoprotein(a) in some observational studies. Dr Carolyn Lam: Nice. So, could you tell us what were the results? Dr Gregory Schwartz: So first, we used data from the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in nearly 19,000 patients with a recent acute coronary syndrome. And as you mentioned, Carolyn, those patients may be at elevated risk for other types of arterial and venous atherothrombotic or thrombotic events. We had three goals in our analysis. First, we looked at the relationship of PAD and venous thromboembolic events to the baseline levels of lipoprotein(a) and LDL in the trial cohort. Second, we looked at the effects of randomized treatment on both of those types of events, PAD events, and venous thromboembolism. And lastly, we determined the relationship of treatment effects on lipoproteins to the risk of those events in the alirocumab active treatment group. What we found are four principle findings. First, although this was an acute coronary syndrome cohort, and there were only four percent of the trial cohort who had a prior history of PAD, there was nonetheless a substantial risk of PAD events. About two percent of the placebo group suffered a PAD event during the trial and about one percent had a venous thromboembolic event. In the placebo group. We found that there was a very strong association between baseline lipoprotein(a) concentration and the risk of PAD events. So to put that in a quantitative framework, if we compared the highest quartile of baseline lipoprotein(a) with patients in the lowest quartile of baseline lipoprotein(a), there was a more than twofold elevated risk of PAD events. And by that, I mean, critical limb ischemia, revascularization, or amputation for ischemia, more than a twofold elevated risk in the highest quartile of baseline lipoprotein(a). There was a non-significant relationship of venous thromboembolic events to the baseline concentration of lipoprotein(a). The patients who were treated with alirocumab, the PCSK9 inhibitor, achieved the expected approximately 50 percent reduction in LDL cholesterol and a median 23 percent reduction in lipoprotein(a) concentration. And those effects were associated with significant reduction in PAD events, a hazard ratio of point six nine, and a nearly significant peak, well point zero six reduction in the risk of venous thromboembolic events with a hazard ratio of point six seven. And incidentally, in the same issue of circulation, there is a companion paper from the FOURIER study, which looked at the risk of venous thromboembolic events with another PCSK9 inhibitor, evolocumab. They found something very, very similar. And again, the results of that trial individually were kind of on the margins of statistical significance, but putting the two trials together in their analysis, there was a highly significant reduction in the risk of venous thromboembolic events with PCSK9 inhibition, compared with placebo. They also related those effects to lipoprotein(a), but not to LDL cholesterol levels. So we found that the magnitude of the reduction in lipoprotein(a) was related to the reduced risk of PAD and VTE events, but a similar relationship between the magnitude of LDL cholesterol reduction and the risk of those events was not found. So to put it all together, lipoprotein(a) may be the stone that we haven't turned over, but should, when we encounter patients with PAD events or VTE events that we can't otherwise explain. And although these two trials were not purposed primarily to look at PAD events, the findings certainly suggest that treating elevated levels of lipoprotein(a) might be an effective strategy to reduce risk of PAD events and VTE. Dr Carolyn Lam: Wow. Congratulations, Greg, that was beautifully summarized. A novel on at least two levels, right? One is the PCSK9 inhibition effects on these two outcomes that we never thought of before. And second, that role of lipoprotein(a). Erin, could I bring you into this discussion? You were guest editor when this paper came across your desk. Could you tell us what were the considerations and frame how novel these findings are for us? Dr Erin Michos: Oh, Carolyn excited to be the associate editor for this paper. People who know me know; I love all things lipids. So as a preventive cardiologist, I'm very excited to have drugs like PCSK9 inhibitors in my toolbox. They are certainly known for their powerful LDL lowering effects, but also further lipoprotein little a reducing effect who these combined data show the PCSK9 inhibitors, not only reduced incident major adverse cardiovascular events and PAD events, but potentially can reduce VTE events as well in patients prescribed this therapy. So I thought it was really interesting and this new analysis from ODYSSEY, that it was the levels of lipoprotein little a, but not LDL cholesterol that predicted the risk of future PAD event and we saw a similar trend with VTE. And then furthermore, on treatment with alirocumab. It was the magnitude of Lp(a) little a reduction, but not LDL reduction that was associated with reduced PAD and VTE events. And so this suggests that the reduction of PAD events is mediated by the lipoprotein little a lowering and not the LDL lowering. You know, lipoprotein(a) is a particularly risky type of LDL. It's strongly inheritable it's atherogenic similar to LDL, but prothrombotic, so it's this double whammy of badness due to its structural homology with plasminogen competes with berberine binding and inhibits tissue plasminogen activator and ultimately inhibits fibrinolysis. And so that's why lipoprotein(a) may be a mediator of this apparent effect of PCSK9 inhibitors with PAD and VTE incidents. So how do I put this in practice? Prior to PCSK9 inhibitors, we really didn't have any lipid modifying therapies to actually lower lipoprotein little a, except niacin, which we don't really use. This was mentioned by Greg, statins don't really lower lipoprotein(a) and they actually increase lipoprotein little as levels. Although we do know that statins of course reduce ASCBD risk. So, I'm checking lipoprotein little a now in all my secondary prevention patients with established CVD and in high risk primary prevention with those with family history. While we're all anxiously awaiting outcome trials, such as the antisense oligonucleotides that can lower lipoprotein(a) by 80 percent, that therapy is not here now, we don't have that available in practice. But we do have PCSK9 inhibitors now, which can reduce lipoprotein little a by 20 to 25 percent and have meaningful outcome data like the alirocumab data we see here in this ODYSSEY OUTCOMES study. With a 31 percent reduction of PAD, that is really meaningful. So I'm particularly excited about PCSK9 inhibitors and my patients with PAD who often have concomitant CAD, polyvascular disease, and then regarding the VTE effects, I think we should point out that the absolute risk reduction of VTE was pretty modest. We didn't really see significance until we combined it with the FOURIER data. So I think given the cost of the drug, it's not warranted to prescribe PCSK9 inhibitors to the general population, specifically for VTE prevention alone. But in patients with ASCBD, who would be recommended for a PCSK9 inhibitor to reduce incident CBD, you know, there may be this added special benefit of reducing risk of VTE as well. Dr Gregory Schwartz: I just wanted to comment on a few things that Erin said, I think we’re really important. All of these patients were on intensive statin therapy in the background. So although we did not see a relationship between the further reduction in LDL cholesterol with alirocumab and the risk of these events, it doesn't mean that lowering LDL cholesterol has nothing to do with the risk of those events because everybody was on background statin therapy, 90 plus percent. So, I think that's important to point out. And I think the comment that was made about when to check a lipoprotein(a) level is very pertinent. And, in the European guidelines, they direct us to check lipoprotein(a) at least once in a lifetime for everyone, even if there's no other signs or risk factors for cardiovascular disease. So I think as Erin indicated, with some tools in the toolbox now, and more tools, perhaps on the way with both the antisense, and also there are small interfering RNA approaches to lower lipoprotein(a), we should get more accustomed to looking at this, to turning over that stone. Even if we're not a hundred percent certain what to do with what we find underneath it, we should still look because there may be some things we can do in the interim. Dr Carolyn Lam: Thanks, Greg. Erin, can I give you the last word? Any take home messages? Dr Erin Michos: I definitely think that as we move forward with other therapies such as the small interfering RNA and the antisense oligonucleotides, we need really more phase three clinical trials specifically assessing VTE. And then I just want to mention, although I didn't write an editorial for this study, I did have the pleasure of writing an editorial for another ODYSSEY OUTCOMES analysis that was published in December. You know, my editorial was entitled, "Achievement, a Very Low LDL. Is it Time to Unlearn the Concern for Hemorrhagic Stroke?" And I mention this because one of the barriers I get in clinical practices, people get very worried about the very low LDL levels that we see with PCSK9 inhibitors and I think important to point out from ODYSSEY that, with the reduction in ischemic stroke, that there was no signal for increased hemorrhagic stroke and that provides additional reassurance. So I think that's important to mention, I think this PCSK9 therapy is being under-utilized in clinical practice and ASCBD and PAD, these are really high-risk patients who have really high risk of recurrent events and our efforts to ward off these devastating consequences. We need to make sure that we're appropriately utilizing this important therapy. Dr Carolyn Lam: Thank you so much, Erin. Thank you so much, Greg. You've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr Greg Hundley: This program is copyright, The American Heart Association, 2020.  

Commentary by Dr. Valentin Fuster

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.  

This week in cardiology: PCSK9 inhibition cuts events in very-high-risk groups ODYSSEY OUTCOMES analyses peg prior CABG and polyvascular disease as targets for alirocumab. Cardiovascular cost of smoking may last up to 25 years Past smokers face an elevated cardiovascular risk for up to 25 years after they quit. Impact of climate change on mortality underlined by global study This may be the largest study ever to assess the effects of inhalable particulate matter around the world. HCV coinfection adds to the cardiovascular risk in HIV-infected patients Hepatitis C virus and other injections were independently linked to the risk of having a cardiovascular event in HIV-infected patients. You can contact the MDedge Cardiocast by emailing us at podcasts@mdedge.com or following us on Twitter at @MDedgeTweets. 

Commentary by Dr. Valentin Fuster

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 Greg Hundley, also Associate Editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                I'm so excited about our feature discussion today, Greg, because it is about a familiar but very important problem of hypertension, and we will be looking at trial results of a new drug, a first in its class type of drug. And tackling a problem that is particularly important perhaps in black patients with hypertension. Well, more very soon. First, let's discuss some papers, shall we? Do you have one? Dr Greg Hundley:             My paper is from Joseph Burgoyne from King's College in London and pertains to resveratrol. Now, resveratrol is a non-flavonoid polyphenolic compound that has been found in the skin of several fruits, with the most notable being grapes. The compound exhibits beneficial effects, including the prevention of cardiovascular neurologic diseases, cancer, metabolic syndrome, as well as it promotes bone and eye health. And in this study, the investigative team explains how resveratrol may mediate its numerous beneficial effects including lowering of blood pressure by direct thiol oxidation. Also, they demonstrate that resveratrol can counter-intuitively induce direct protein oxidation, a process that is enhanced under pro-oxidative conditions associated with disease. The oxidation of cyclic GMP dependent protein kinase 1 alpha, or PKG1 alpha, by resveratrol lowers blood pressure in hypertensive mice. Dr Carolyn Lam:                Okay. But what does that mean for us clinically, Greg? Dr Greg Hundley:             Well, the results demonstrate how blood pressure can be lowered by using resveratrol, and targeting cysteine 42, or PKG1 alpha, may provide a new class of anti-hypertensive agents. In addition, identifying additional proteins modified by resveratrol may provide new targets for therapy to treat cardiovascular disease. Carolyn, how about your first paper? Dr Carolyn Lam:                We are going to look at the further results of the ODYSSEY OUTCOMES trial. And as a reminder, ODYSSEY OUTCOMES was a double-blind randomized comparison of the PCSK9 antibody Alirocumab with placebo in almost 19,000 patients who had an acute coronary syndrome 1-12 months previously and elevated at the atherogenic lipoproteins despite intensive statin therapy.                                                 And that trial found that Alirocumab reduced the risk of the primary composite outcome of coronary heart disease, death, ischemic stroke, myocardial infarction, or unstable angina requiring hospital admissions. The current paper looked further at the effects of Alirocumab on death. Dr Greg Hundley:             So Carolyn, what did they find? Dr Carolyn Lam:                Well, there are quite a number of findings here. The first, there were fewer deaths in total that occurred with the PCSK9 inhibitor Alirocumab versus placebo, and this resulted from a non-significantly cardiovascular and non-cardiovascular deaths with Alirocumab. The second finding was that in a pre-specified analysis of more than 8,200 patients eligible for 3 or more years of follow-up, Alirocumab reduced death.                                                 And then, the third finding was that patients with non-fatal cardiovascular events were at increased risk for both cardiovascular and non-cardiovascular deaths, and a post-Hoc analysis found that compared to patients with a lower LDL, those with a baseline LDL above 100 had a greater absolute risk of death, and a larger mortality benefit with Alirocumab. In the Alirocumab group, all cause death declined with a lower achieved LDL achieved at 4 months of treatment to a level of approximately 30.                                                 So in summary, Alirocumab added to intensive statin therapy, has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for 3 or more years, and if baseline LDL is 100 or more, or if achieved LDL is low. Dr Greg Hundley:             That's great, Carolyn. My next paper is going to talk a little bit about endothelial cells. And what I think we're going to learn is that not all endothelial cells are alike. This comes from Dr Rajat Gupta from Brigham and Women's Hospital, and I really thought this was an interesting article that used single-cell RNA sequencing to make it possible to identify and characterize cellular sub-populations. Dr Greg Hundley:             The investigative team performed enzymatic dissociation of 4 whole mouse aortas, followed by single-cell sequencing of over 10,000 cells. Dr Carolyn Lam:                Wow. What did they find? Dr Greg Hundley:             Well using cluster analysis of gene expression from the aortic cells, they identified 10 populations of cells representing each of the main arterial cell types. There were fibroblasts, vascular smooth muscle cells, endothelial cells, immune cells, including monocytes, macrophages, and lymphocytes. And importantly, there were 3 distinct endothelial cell sub-populations with differences in them driven by major functional gene programs including adhesion and lipid handling.                                                 Comparison of aortic single-cell RNA sequence data sets from normal and Western diet-fed mice suggested that these sub-populations exist under both dietary conditions and have some unified responses to diet alteration. Also, immunofluorescence using single marker genes to identify endothelial cell sub-populations showed that the VCAM1 positive population was spatially located in regions of disturbed flow like the lesser curve of the aorta. Dr Carolyn Lam:                Okay. So bring it home for us, Greg. What does this mean clinically? Dr Greg Hundley:             Yeah exactly, Carolyn. So, characterizing functional sub-populations may serve as a novel method for understanding endothelial health in patients with vascular disease. And although aortic endothelial cell sub-populations demonstrate some unified responses to vascular disease relevant stimuli, like a Western diet, functionally different sub-populations may contribute differentially to vascular diseases, enabling sub-population targeted therapies to perhaps be implemented in the future. Dr Carolyn Lam:                Cool. So Greg, cardiomyopathies have often been seen as genetic in origin, but what about potentially modifiable causes? So, this next paper that I picked looked at that, and it's from corresponding author Dr Rosengren from Sahlgrenska University in Gothenburg, Sweden, who with her colleagues, sought to investigate a potential link between obesity in adolescence and being diagnosed with cardiomyopathy in adulthood.                                                 So, this was a nation-wide register-based prospective cohort study of almost 1 million 690,000 adolescent men who were enlisted for compulsory military service from 1969 to 2005. Now at baseline, body mass index, blood pressure, and medical disorders were registered, along with test results for fitness and muscle strength. Cardiomyopathy diagnosis was then identified from the National Hospital Register and Cause of Death Register.                                                 So, they found that during a median follow-up of 27 years, 4,477 cases of cardiomyopathy were identified, of which 59% were dilated, 15% were hypertrophic, and 11% were alcohol or drug-induced. Increasing body mass index, or BMI, was strongly associated with elevated risk of cardiomyopathy, especially dilated cardiomyopathy, starting at levels considered normal, meaning a BMI of 22.5 to less than 25 kilograms per squared meters.                                                 And this was even after adjusting for age, years, center, and baseline comorbidities. There was a more than 8 fold increased risk of cardiomyopathy at a body mass index of 35 and above, compared with a BMI of between 18.5 and less than 20. Dr Greg Hundley:             So, it sounds like BMI elevations and cardiomyopathies don't go together. So, what are the clinical implications? Dr Carolyn Lam:                This really shows that even mildly elevated body weight in late adolescence may contribute to being diagnosed with cardiomyopathy in adulthood. So, the already marked importance of weight control in youth is really further strengthened by these findings, as well as the greater evidence for obesity as a potential important cause of adverse cardiac remodeling that is independent of clinically evident ischemic heart disease. Dr Greg Hundley:             Outstanding. So, BMI, not good. Dr Carolyn Lam:                Nope, Greg. High BMI, not good. That was fun, Greg. So, shall we move on to our feature discussion? Dr Greg Hundley:             Absolutely. Dr Carolyn Lam:                For our feature discussion today, we are talking about a familiar problem, but just so very important, and that is hypertension. And guess what? Our feature paper discusses a new first in class centrally-acting renin-angiotensin system blocker that has such remarkable initial results. I am so pleased to have with us the corresponding author for the paper, Dr Keith Ferdinand from Tulane University School of Medicine, as well as our Guest Editor, Dr David Calhoun from University of Alabama and Birmingham.                                                 Keith, could you start by telling us a little bit about the kinds of patients you see there in New Orleans that struggles with hypertension control perhaps? And then, please tell us about Firibastat. Dr Keith Ferdinand:         I'm in New Orleans. In fact, I'm a native New Orleans. And as you know, most of the south and southeast and part of the United States has a high proportion of African American or US blacks. This population has higher rates of hypertension, increased prevalence, more severe hypertension, and more uncontrolled hypertension.                                                 We also note in the south that there tends to be an increase in obesity, which is a powerful risk factor for all patients with hypertension, regardless of race or ethnicity. And unfortunately, the rates of obesity appear to be increasing. So based on the fact that we have an increase in obesity, we have many patients whose blood pressures are not controlled, and some of the previous data have suggested less response to first step or monotherapy with ACE inhibitors and angiotensin receptor blockers, I initiated a trial with a first in its kind oral active brain aminopeptidase A inhibitor. Dr Carolyn Lam:                Wow. Could you tell us a little bit more about brain aminopeptidase, and this new drug Firibastat? Dr Keith Ferdinand:         Most people don't know anything about this molecule, because this is something that was discovered by some French physiologists. They approached me to design the clinical trial here in the United States. And what it does is, it blocks the conversion of angiotensin II to angiotensin III in the brain. Angiotensin III is actually the active component of the renin-angiotensin system centrally, and if you block angiotensin III production, it has a triple therapy effect.                                                 One is that it causes the diuresis. It decreases sympathetic tone, and it stimulates the carotid artery, such that you have, again, a decrease in sympathetic tone. Now, why choose it for patients who are obese, and why want to include a large proportion of non-Hispanic blacks here in the United States? Well, the reasons are that when you look at some of the bench research using rats, it appears to have a more beneficial effect in DOCA-salt rats, which is a model for salt-resistant hypertension.                                                 Salt-resistant hypertension is more common in blacks, more common in patients with obesity, and may indeed be one of the reasons why monotherapy or first-step with conventional renin-angiotensin system agents, specifically ACE inhibitors and ARBs, have not been as effective in the past. Dr Carolyn Lam:                Gosh. That is so interesting, and it's really making me think about my patients too here in Asia, where we have a lot of salt-sensitive hypertension. Now, could you please tell us about the trial you did, and what you found? Dr Keith Ferdinand:         We looked at a cohort of patients. All of the patients were overweight and obese. They were washed out for 2 weeks, and had a systolic blood pressure of 145-170, and a diastolic of less than 105. We wanted to get at least 50% self-identified blacks or Hispanics, and I suspect that any patient who meets this phenotype, and that would include Asians, or even Whites, may respond similarly.                                                 We then placed them in an open label format, and I can discuss why we used an open label, with monotherapy with Firibastat. After 2 weeks, we then titrated the dose level from 250 twice daily to 500 twice daily if needed, and we had a low dose thiazide and hydrochlorothiazide 25 mg addition, if needed, for escape, if patients had a blood pressure greater than 160/100.                                                 The other thing that was interesting and unique about this particular trial is that we used the automatic office blood pressure, where the blood pressure was taken 6 times. The first time was discarded, and then averaged, without a particular doctor or a nurse being there to do the blood pressure. We felt that this was a valid means of getting blood pressure loaded. It tends to mimic, to a large extent, what you see in 24 hour inventory daytime systolic blood pressure.                                                 So, this was a valid means of measuring blood pressure loads. This was a relatively high risk patients. And these were patients whom, previously, probably would not have responded as well to monotherapy with ACE inhibitors or ARBs. Dr Carolyn Lam:                That's really clear, and clever design. I would love to hear a little bit more about why the open label, and of course, the results. Dr Keith Ferdinand:         Well, that's one of the criticisms of this study, but actually, we presented to the FDA when we were discussing designing this trial, perhaps doing a placebo control trial. And we were told by the FDA that if you use a valid means of measuring blood pressure load, so that would be ambulatory blood pressure, or automated office blood pressure, that a placebo would not be necessary, because those means of checking blood pressure load would be considered a true valid means of finding a blood pressure effect.                                                 The other thing is, dealing with minority patients, and really dealing with patients in general, for blood pressure, if they have substantial hypertension, the message has been out there that this is a killer and cause of cardiovascular disease. It would probably have been very difficult to enroll the patients, you've got 254 patients in a national study. It would have been very difficult to enroll these patients, who would have known easily that they had substantial elevation of blood pressure, and we said, "You know, 50% chance you're going to get a sugar pill that has no effect." Dr Carolyn Lam:                Right. Right. Very nice. The results? Dr Keith Ferdinand:         Well, the results were a robust 9.7 mm reduction in systolic blood pressure. At day 56, the p-value was less than 0.0001. And when you do a sub-group analysis of patients who were in the study, it was effective for persons who are under 65, or over 65, male or female. All patients were overweight, and the patients who were obese, with a BMI of 30 or above, had a trend towards even a better blood pressure effect, which again, is not seen with first step with conventional ACE and ARBs.                                                 We also did an analysis based on black and non-black, and there was no difference, again with the trend towards the black patients actually doing fairly well. So, the take home from the particular study was this is the first in its kind, new approach to central Ras blockage with aminopeptidase A inhibitor, that was effective in a population which was overweight and obese, with over 50% minority, and showed substantial blood pressure reduction using a valid means of checking blood pressure, the automated blood pressure in the clinic. Dr Carolyn Lam                  Keith, congratulations. A very important study. David, could I bring you in here? What were your thoughts as you were managing this paper, and what do you think are the future steps here? Dr David Calhoun:            Looking at the submission, I was obviously excited about the results and the potential implications. I think, like Keith, in treating a lot of resistant or obesity-related hypertension, we're frustrated that control rates are not better, that the initial response to monotherapy is not better, and that's particularly true of Ras blockers. I think many of us are investigating the initial use of Ras blockers for a variety of reasons related to outcome benefit and reduction in incident and diabetes.                                                 So, I know I like to start with such an agent. I'm particularly excited that there may be, firstly, a new opportunity to block the Ras system, and potentially comparable or even better in the most difficult patients to treat. That is, the African American and the Hispanic patients, who often have very severe hypertension. So, my initial reading was I was very excited to see the potential, and that was brought out by the reviews as well. They shared my excitement. So, I'm looking forward to Keith advancing this compound. Dr Carolyn Lam:                Indeed. Keith, I'm sure everyone's thinking now, wow, remarkable results. What's the drawbacks? How well-tolerated was this drug? Dr Keith Ferdinand:         One of the drawbacks is that the structure of Firibastat included a sulfhydryl group. And we saw with early studies with captopril, which also has a sulfhydryl group, some skin rash, and we saw those similar changes with some of the patients in this particular study. At least 2 of them were suggested to potentially have erythema multiforme, although this was not proven. This was an investigator initiated adverse event.                                                 So, I don't know if we're going to be able to structure a similar type of aminopeptidase inhibitor without a sulfhydryl group. The other thing is that in its presence formulation, it's given twice daily. We know optimally you'd like to have a long-acting agent that can be given once daily. And I don't think we need a placebo control trial, but we may need to do a trial where patients are on 2 or more medications, and then, you add the Firibastat versus adding placebo. But, I don't think at this particular point, we need to get some of these more difficult to treat patients, and just place them on placebo, and watch and see what happens.                                                 We know what happens. The blood pressure goes up. Many of them may have acute heart failure, or progression of renal failure. And I just don't think it's necessary. And the FDA doesn't think it's necessary to prove that hypothesis. Dr Carolyn Lam:                David, what do you think about that? Do we need a placebo control trial? And that use of ambulatory blood pressure, that's novel aspects of this trial too. Dr David Calhoun:            I think use of placebo comparison has been for the traditional or conventional approach. I think most investigators, most clinicians, sort of anticipate seeing the placebo corrected effect. So, I think the results would have been, or will be potentially, more compelling if that's done. But, I can also appreciate Keith's contention, and it sounds like the FDA, that in this day and age, with use of automated office blood pressure measurements tend to minimize that white coat effect, and particularly true of ambulatory monitoring, that it may be that not using a placebo comparison maybe is compelling as well. Dr Carolyn Lam:                Indeed. I really enjoy actually just digging deep into the study like this. Keith, if I could just ask for some final words from you, learning lessons, or even what have you got planned next. Dr Keith Ferdinand:         The first lesson is, we need to continue to pay attention to hypertension. It's kind of been placed on the back burner with more interest now in diabetes and sugar, a lot of interest in lipids because of some of the new agents. But if you look across the globe, Asians, blacks, whites, regardless of race or ethnicity or geography, hypertension is the most potent cardiovascular risk factor, and I think we need to continue to address that.                                                 In terms of this particular agent, I believe that we will have to have some sort of placebo arm, but again, I think it's going to be built on a conventional medication, and then randomized with Firibastat versus placebo on top of conventional medications. In a more severe or a more difficult to treat hypertension, I'm just not really convinced that we need to do a purely placebo arm. Dr Carolyn Lam:                Great, Keith. And David, how about yourself? Any take home messages? Dr David Calhoun:            I think when there's a new in-class compound, I think that's always exciting, particularly when it has the initial results, preliminary results, that Keith is reporting. As many agents as there are out there to treat hypertension, we still are not doing as well as we should be. I think it can only help to have additional classes of agents as therapeutic options, and I think that's particularly true with minority patients, who are, as Keith has indicated, are at the biggest need in terms of controlling blood pressure. Keith, these initial results are very exciting, and I look forward to future studies. Dr Carolyn Lam:                Completely sharing your enthusiasm here. Thank you so much, Keith, for publishing this remarkable paper with us at Circulation. Thank you, David, for helping us manage it.                                                 And thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

In this week's View, guest host Dr. Deepak Bhatt offers a preview of some of the hottest trials at ACC.19, taking place March 16-18 in New Orleans, including the Apple Heart study, results of the open-label extension of the PIONEER-HF trial, the HoT-PE study, results of the PARTNER 3 trial, Self-Expanding TAVR or SAVR in Patients at Low Risk of Surgical Mortality, echocardiographic outcomes from the COAPT trial, primary results of the AUGUSTUS trial, MOMENTUM 3, 1-year outcomes from the CardioMEMS post-approval study, the First Randomized Human Experience with a Ticagrelor Reversal Agent, the DEFINE PCI trial, MRUSMI, primary results of the GLOBAL LEADERS adjudication sub-study, the CLEAR Wisdom Trial, the CREOLE Study, DECLARE, REDUCE-IT, the STOPDAPT-2 trial, SMART-CHOICE, ODYSSEY OUTCOMES, and IRAD.

Commentary by Dr. Valentin Fuster

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.                                                 In today's feature discussion, we will be doing a deep dive into the LEADER trial results, looking at new results of liraglutide and its effects in patients with type two diabetes, with or without a history of myocardial infarction or stroke. All of that coming right up after these summaries.                                                 In today's issue, five groups of investigators in two original basic research articles and three research letters tackled the same biological question, and all reached the same conclusion that cells in the heart expressing the SCA-1 cell surface antigen do not become cardiomyocytes to any meaningful degree, and instead become endothelial cells. Among the original basic papers, first author Dr Vagnozzi, corresponding author Dr Molkentin from Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, and their colleagues use the inducible recombinase method and generated a constitutive recombinase at the SCA-1 locus. They found that cardiac resident SCA-1 positive cells were not significant contributors to cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells generated cardiac vasculature throughout development, during aging, and following injury with trivial contribution to the cardiomyocyte population.                                                 In the second paper from co-first authors, Drs Zhang and Sultana, with corresponding author Dr Cai from Indiana University School of Medicine and colleagues, these authors engineered a series of genetically altered mice to identify and track SCA-1 positive cells in the heart, and found that SCA-1 positive cells were purely of the endothelial lineage. Together with three research letters, these five papers add to the growing body of evidence that in adult mammals, our new cardiomyocytes arise from preexisting cardiomyocytes and rarely, if at all, from adult cardiac stem cells.                                                 Could metformin be cardioprotective in patients with type one diabetes? Co-first authors Drs Bjornstad and Schafer, corresponding author Dr Nadeau from University of Colorado School of Medicine, and their colleagues hypothesized that adolescents with type one diabetes have impaired vascular function, and that metformin may improve insulin resistance and vascular dysfunction.                                                 To test this hypothesis, they studied 48 adolescents with type one diabetes and 24 non-diabetic controls using MRI of the ascending and descending aorta, as well as assessment of carotid intima-medial thickness by ultrasound, brachial distance ability by DynaPulse, fat and lean mass by DXA, fasting labs following overnight glycemic control, and insulin sensitivity by hyperinsulinemic euglycemic clamp. The adolescents with type one diabetes were randomized one as to one to three months of 2000 milligrams metformin or placebo daily, after which the baseline measures were repeated.                                                 The authors detected early signs of cardiovascular disease with MRI in these adolescents with type one diabetes compared to controls. They further found that three months of metformin therapy improved insulin sensitivity as assessed by gold standard hyperinsulinemic euglycemic clamp, both in normal weight and obese adolescents with type one diabetes. Moreover, metformin improved carotid intima-medial thickness and aortic wall shear stress and stiffness. Thus, metformin may hold promise as a cardioprotective intervention in type one diabetes.                                                 What are the clinical genetic and environmental determinants of varicose vein formation? Co-first authors Drs Fukaya and Flores, corresponding author Dr Leeper from Stanford University, and colleagues applied machine learning to agnostically search for risk factors of varicose veins in nearly half a million individuals in the UK bio bank. They found that greater height appeared as a novel predictor of varicose vein disease in machine learning analyses, and was independently associated in multi-variable adjusted Cox regression. Using Mendelian randomization, they demonstrated that greater height had a causal role in varicose vein development. A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development, and skeletal/limb biology, and discovering a strong genetic correlation between varicose veins and deep vein thrombosis. The knowledge greatly expands our understanding of disease pathophysiology, and may help future improvements in the management of varicose veins and their associated complications.                                                 The final original paper describes the effect of glucagon-like peptide-1 receptor agonist liraglutide on cardiovascular events, and all-cause mortality in patients with type two diabetes and chronic kidney disease. First and corresponding author Dr Mann from Friedrich Alexander University of Erlangen in Germany and their colleagues performed a post hoc analysis of the LEADER trial comparing the liraglutide's treatment effects in patients with and without kidney disease.                                                 As a reminder, LEADER was designed to recruit a subgroup of at least 660 patients with an estimated glomerular filtration rate, or eGFR, less than 60, approximately 220 patients with severe renal impairment, eGFR less than 30, and at least 440 patients with moderate renal impairment with an eGFR of 30 to 60. The authors found that the liraglutide reduced the risk of major adverse cardiovascular events, and all-cause mortality compared with placebo in patients with chronic kidney disease defined as an eGFR less than 60, and also in patients with albuminuria defined as a urinary albumin to creatinine ratio above 30.                                                 The overall risk of adverse events did not differ between the liraglutide and placebo treated patients either with or without chronic kidney disease in the LEADER trial. In summary, these results show that liraglutide added to standard of care reduced the risk of major cardiovascular events and all-cause mortality in patients with type two diabetes and chronic kidney disease. Furthermore, these results appear to apply across the chronic kidney disease spectrum that was enrolled.                                                 And that brings us to the end of our summaries. Now for this week's feature discussion.                                                 Cardiovascular outcome trials have transformed the world of treating patients with diabetes. And for our feature discussion today, we're going to be talking about a new analysis from a very important trial, the LEADER trial of GLP-1 receptor agonists, and that's the liraglutide. I'm very proud to have the corresponding author of this paper with us, Dr Subodh Verma, and he's from St Michael's Hospital and University of Toronto, and our senior associate editor, Dr Gabriel Steg, from University of Paris. Actually, Gabriel, I'm actually going to start with you for once because I recall perhaps something you may have written about cardiovascular outcome trials. Dr Gabriel Steg:                Yeah, it's really funny. I'll try to take it graciously. You know, I wrote a frame of reference in Circulation a few years ago, wondering whether we were doing good by doing all these large outcome trials for safety with new anti-diabetic drugs, because there had been not one but two, three, four, five, six trials that were essentially neutral, enrolling more than 107 patients and participants at the expense of millions of dollars, and not much came out of it. And this was published in circulation. I was very happy until the next trial comes up, and this is EMPA-REG. And the next one is LEADER. And we have two trials that literally transform our vision of anti-diabetic agents as major agents for cardiovascular prevention. The trial we're going to discuss today, which you wrote about, is one of these trials. And I think I have to revisit my own writings and probably eat my hat. Dr Carolyn Lam:                So indeed, that's a great segue. Thank you, Gabriel. And Subodh, tell us then, what did you look at this time in LEADER? And maybe start by saying a little bit about LEADER, and the rationale for doing this particular sub analysis. Dr Subodh Verma:           Right. So, as Dr Steg mentioned, these were FDA-mandated studies to look at safety and potential efficacy of newer antihyperglycemic agents. The entire premise was that cardiologists and cardiovascular specialists were not really getting that excited about antihyperglycemic therapies in people with diabetes, because there was no data that they did much. And as Dr Steg mentioned, even the data leading up to some of these trials were disappointing, suggesting that they're safe, but they neither reduce nor increase events.                                                 So, I think EMPA-REG and LEADER really changed the calculus in many ways of how we look at cardiovascular risk reduction with antihyperglycemic agents. LEADER was a trial that was 9,340 patients. These are patients that were at high cardiovascular risk, but unlike EMPA-REG that only enrolled people with prior to ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a position of enriching the population with this spectrum of patients with cardiovascular disease and risk factors.                                                 So, some were in so-called high risk primary prevention who had not had established ASCVD, but had multiple risk factors such as uncontrolled hypertension or chronic kidney disease. Some had evidence of ASCVD, but had not had a prior myocardial infarction. And some, in fact, had had a prior MI stroke or PAD. So, it was a broad population of patients that was enrolled. And the primary result, again, for the primary outcome of MACE, demonstrated a significant reduction in favor of liraglutide versus placebo. And then for the individual components of that primary outcome, they were all statistically significant, or at least went in the right direction. Importantly, CV death was reduced by 22% with liraglutide versus placebo.                                                 I would like to emphasize that in this day and age, and Dr Steg has nicely set the stage, we have started thinking about how do we think about cardiovascular phenotypes of patients. You know, is a drug more likely to reduce heart failure? More likely to reduce ischemic events? And with LEADER, we found that in fact the trial actually reduced mostly ischemic events, and was really not that beneficial on heart failure related outcomes.                                                 So, that was the broad positive outcome from LEADER. They've led to guideline changes worldwide that patients with diabetes should be prioritized to receive an agent that has shown benefit, particularly if they have cardiovascular disease. And one of those agents was empagliflozin. The other was liraglutide. But, secondary prevention is a pretty crowded space, and not everybody can get everything, and not everybody should get everything, and not everybody can afford everything. So, I think leaders like the two of you here are often thinking about, how do you risk-stratify these populations, and how do we start thinking about people who are at greater risk, people who can actually derive benefit? And I think that's the smart and thoughtful way of doing this. And is there a certain threshold at which point the therapy loses its ability to reduce cardiovascular events, at least in the short term?                                                 So, in that theme, in that vein, what we looked at here was an analysis of people in LEADER who truly had a prior ischemic event. And the work that Dr Steg and others have done in REACH registries, etc. clearly establish that that's a population of patients, type two diabetes and a prior ischemic event. You don't really need many more calculators beyond that. That's the highest risk population. And then, the next level is really type two diabetes with a ASCVD. And we know that from REACH as well, that that's the next level of risk. And then, what about people who have type two diabetes just by itself? Which certainly are much higher risk than people who don't have diabetes, but we didn't have a non-diabetic group to compare to.                                                 And what we find is that the higher the baseline risk defined by this, the greater is the absolute risk reduction. The P value is consistent for ... You know, this is non-significant for heterogeneity. but specifically, people with a prior ischemic event derive benefit. People without a prior ischemic event who've had ASCVD derive significant benefit. But, in fact, we found that the curves were almost superimposable for people who did not have prior ASCVD. And that's not to say the GLP-1 receptor agonists should not be used in diabetes in the absence of cardiovascular disease, because they're great glucose lowering agents. They cause hypoglycemia, they cause weight loss. And potentially, within longer exposure times, cardiovascular benefit may actually emerge. And we've heard data from Dr Gerstein's study called Rewind that is positive, that will be presented next year. Harmony Outcomes was a study that was presented recently that also showed a benefit. So, whether in the primary prevention group we see a benefit in the future remains to be seen. Dr Carolyn Lam:                Oh, that's a great, great summary. But Subodh, you know, it's become a bit of what do we define as a primary and secondary prevention anymore, you know? And the patient that already got type two diabetes. Now, in this paper, it's very nice. As you said, has a history of myocardial infarction and stroke. And maybe I could just clarify to the audience, you couldn't just pick up the primary paper and see that because the way the inclusion exclusion criteria were designed in LEADER, you can't just pick up the sub-groups. So, this specific analysis, so carefully and wonderfully done, was absolutely needed. But then you know, what do you think? What's primary and what's secondary prevention anymore? Dr Gabriel Steg:                Well, I want to commend the authors for doing the careful stratification of diabetic patients they've done in the paper, and particularly for pointing out that it's one thing to have had an event where you actually ruptured a plaque and had a traumatic event. And it's very different from merely having plaque in one of your carotids or your arteries, and which is, of course, in turn very different from the majority of diabetic patients who have neither an event, nor diagnosed plaque or established plaque. And when we think about preventing cardiovascular and diabetes, we have to remember that the outer circle, the broader circle of diabetic patients who haven't had disease is the largest component. Dr Subodh Verma:           True. Dr Gabriel Steg:                And these are the patients whom we treat every day with the hope of eventually keeping them from harm, safe from harm, or with therapies that are new and potentially beneficial. And I think your research very clearly shows that there's a gradient of benefit. The sicker the patient, the greater the benefit in preventing MACE. And as long as you get to more healthier phenotypes of diabetes, then there is less of a benefit. Which doesn't mean that we shouldn't use these agents. As you point out, they're very convenient and effective agents for glucose control. But then, their cardiovascular benefits are more uncertain. And I think this is the key message from this analysis, and it's a great analysis. Dr Subodh Verma:           Thank you. I appreciate that. I totally agree that for the doctor in the trenches, particularly the cardiologist who's just trying to get their feet wet with antihyperglycemic therapy, you know? Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at low dose, and maybe a new way of doing surgery or putting an LVAD. But it's very hard to get their attention when it comes to antihyperglycemic therapy. So, defining for them the population that matters the most, where the greatest risk and risk reduction can be achieved, I think is quite important from a clinical standpoint. And I think most cardiologists will agree that type two diabetes and a prior ischemic event is a high-risk population. Type two diabetes in a prior ASCVD is a high-risk population, and the magnitude of CV death reduction here is something meaningful for them to pay attention to. Dr Carolyn Lam:                Yeah, indeed. That's what I love best about this paper. It's actually asking the question the way a cardiologist would, exactly like you had both put. So, what do you think is the next step now? Do you think we need to look at this primary prevention type two diabetics with no established cardiovascular disease? Do we really need to? Is it that we need a method analysis, which you can talk about? Or, is it that we need longer follow up? Or, what next? Dr Subodh Verma:           I think that first of all, we have to get rid of the terminology, and maybe as a heart surgeon, I can be a little bit provocative and just say it. I wrote an editorial to the Declare Study that was just published yesterday in The Lancet called "Pumps, Pipes, and Filter: Do SGLT2 inhibitors cover it all?" Then I made a strong statement there that this nomenclature of primary and secondary really is artificial because it only captures ischemic risk, and does not capture risk of heart failure or renal disease. So, in a patient, as you've asked, Carolyn, who has type two diabetes, whose renal function is 54 or GFR is 55, who's not had a prior MI ... Is that patient primary prevention? Maybe from an ischemic standpoint, but he's clearly secondary prevention from a renal standpoint. Dr Subodh Verma:           So, I think we need to just think about all disease as a spectrum, and not as an artificial cutoff that, if you've had an ischemic event, suddenly the world changes for you there. Because, that gradient I think is probably what we need to somehow appreciate as to where that risk lies. The patient who's 40 who's had no risk factors, you know? The Rashami paper from the New England Journal that looks at risk factor control and diabetes make a very compelling story that if you control your five risk factors, you actually don't have an excess risk of cardiovascular events in diabetes, at least from MACE. The story is whether anybody can have those five risk factors controlled. But, early on in diabetes, with diabetes duration not being that significant, with risk factors not being that significant, I think maybe that's not the population to go after. But certainly, waiting for ASCVD to develop and then start therapy is also not the right way of doing it, so ... Dr Carolyn Lam:                Interesting. I really wonder what new guidelines are gonna show. Gabriel, any other perspective? Dr Gabriel Steg:                Well, first of all, I love the editorial. I thought the title was fantastic, and you summarize here what we need to think about when we think about diabetes; not solely the pipes. As an interventional cardiologist, I'm very interested in the pipes. Dr Subodh Verma:           Me, too. Dr Gabriel Steg:                Not solely the pump, but also the filter. And there's more than the heart and vessels in the complications of diabetes. So I thought it was a great, great title. My view is that we still need to remember that if we take the lifetime perspective, a healthy youngster with type one diabetes, a relatively healthy patient in his fifties with type two diabetes, their probability of dying from cardiovascular disease is enormous. Even though risk calculators will give them a relatively low probability over the 5 year or 10 year term, eventually that's what's gonna get them. And therefore, we still have progress to make. We are fortunate to have lived an incredible period in the past few years where we've had emergence of new risk preventive therapies in diabetes. That's incredible. It's an epiphany. But, it's not over. We need more information, more trials in other populations. We need to look at renal function and heart failure. So, it's a great time to be doing clinical trials in diabetes. Dr Subodh Verma:           Right. Dr Carolyn Lam:                And indeed, a great time to be publishing in circulation. We've been really doing a lot of publications in the cardiovascular outcome trials in diabetes here. Dr Subodh Verma:           And it's being noticed. There's no doubt about it. Dr Carolyn Lam:                I hope so. And, maybe a time for a new frame of reference, because what you just said was diametrically sort of in contrast. Dr Subodh Verma:           I would emphasize one more point, and that is, you know in atherosclerosis, the dominant mechanism has been LDL, right? And Dr Steg here is changing the landscape of that with Odyssey Outcomes and many other strategies. But again, in Circulation, Dr Bhatt, and I, along with the LEADER investigators, recently presented and published a paper showing that liraglutide's benefit is seen independent of LDL cholesterol, and all the way down to people with LDLs of below .5. So, the point is that this mechanism of benefit of GLP-1 seems to be complimentary to LDL lowering. And therefore, I think it offers great hope that you can actually reduce the ischemic burden in diabetes, not just by ultra-low LDL, but by potentially additional mechanisms as well. Dr Carolyn Lam:                Absolutely. And then now, because I have to have the last word here on this show, let's not forget heart failure outcomes in diabetes. I think it's underestimated. I think it's really important. Okay, and with that, thank you gentlemen for joining me today.                                                 You've been listening to Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association, 2018.  

In this special episode of the View, Kim Eagle, Peter Block, and Deepak Bhatt discuss the highlights from Day 2 of the 2018 American Heart Association Scientific Sessions, including the Cardiac Remodeling Following Ligation of Arteriovenous Fistula in Stable Renal Transplant Recipients, DTU, ODYSSEY OUTCOMES, and ODYSSEY OUTCOMES Economics trials.

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.                                                 Can we get better at predicting clinical benefit of PCSK9 inhibition based on the severity and extent of coronary artery disease? Well coming right up after these summaries we have an important discussion of an analysis from the FOURIER trial, so stay tuned.                                                 The first original paper this week suggests that targeting visceral adiposity may be the crucial step to limit age-related cardiac remodeling and to promote healthy cardiac aging. Co-first authors Drs Sawaki and Czibik, corresponding author Dr Derumeaux, from INSERM France, and their colleagues, hypothesize that since aging induces cardiac structural and functional changes, linked to increase deposition of extracellular matrix proteins including osteopontin, well osteopontin may play a role in myocardial aging.                                                 To test this hypothesis, they studied osteopontin-deficient mice and their wild-type litter mates at two and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. They found that during aging, visceral adipose tissue represented the main source of ostepontin and altered heart structure and function via its profibrotic secretome. Furthermore, interventions targeting osteopontin, such as visceral adipose tissue removal and osteopontin deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. This work uncovers ostepontin's role in the context of myocardial aging and suggests that osteopontin may be a potential new therapeutic target for a healthy cardiac aging.                                                 The next study shows that higher triglyceride rich lipoprotein cholesterol may be a risk factor for cardiovascular disease and potential therapeutic target. First author Dr Vallejo-Vaz, corresponding author Dr Ray from Imperial College London, and their colleagues assess the relationship between triglyceride-rich lipoprotein cholesterol and cardiovascular risk and whether this risk was modifiable among patients receiving statins in the TNT trial. They found that higher levels of triglyceride rich lipoprotein cholesterol were associated with a significantly higher rate of cardiovascular events among coronary patients treated with statins. Statin therapy reduced triglyceride-rich lipoprotein cholesterol and to a greater extent among those treated with a higher statin dose.                                                 Based on their post hoc analysis of the TNT trial, they found that more intensive statin therapy with atorvastatin 80 milligrams, compared to atorvastatin 10 milligrams, resulted in a significantly greater cardiovascular risk reduction among patients with higher triglyceride-rich lipoprotein cholesterol. These results were consistent for higher triglycerides and directionally concordant for non-HDL cholesterol. A higher percentage reduction in triglyceride-rich lipoprotein cholesterol was associated with lower cardiovascular risk independent of LDL cholesterol reduction. Thus, these findings suggest that triglyceride-rich lipoprotein cholesterol is not only a cardiovascular risk marker, but also potentially a therapeutic target.                                                 Late gadolinium enhancement on cardiac magnetic resonance imaging represents fibrosis and is seen in 60% of adult patients with hypertrophic cardiomyopathy. However, what about in children and adolescents with hypertrophic cardiomyopathy? First author Dr Raja from University of Copenhagen in Denmark, corresponding author Dr Ho from Brigham and Women's Hospital in Boston, and their colleagues looked at cardiac magnetic imaging data from 195 children and adolescents with hypertrophic cardiomyopathy. Late gadolinium enhancement was present in 46% of patients with overt hypertrophy as opposed to 60% typically represented in an adult population of hypertrophic cardiomyopathy. On the other hand, late gadolinium enhancement was not seen in mutation carriers without left ventricular hypertrophy.                                                 In patients who underwent serial imaging, increases in late gadolinium enhancement, left ventricular mass, and left atrial size were detected over two and a half years. Thus these findings in children provide additional insights into the biology and natural history of hypertrophic cardiomyopathy and confirmed that fibrosis is a significant part of the disease process in both children and adults.                                                 Whether the adult mammalian heart harbors cardiac stem cells for the regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. This week's paper adds to the growing knowledge in this area. First author Dr Li, corresponding author Dr Zhou from Chinese Academy of Sciences and their colleagues developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, they assessed if non-myocytes generated any new myocytes during embryonic development, adult homeostasis and after myocardial infarction. Skeletal muscles were also examined after injury and acted as internal controls.                                                 By using this stem cell marker free and dual recombinases mediated cell tracking approach, the author showed that new myocytes arose from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive controls, the same lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. Thus, this study provides in vivo genetic evidence for non-myocyte to myocyte conversion in the embryonic but not the adult heart. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.                                                 Well, that wraps it up for our summaries this week, now for our feature discussion.                                                 Are there subsets of patients that derive greater clinical risk reduction with the PCSK9 inhibitors? Well we're gonna find out about that right now with a discussion of our feature paper entitled the “Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease.” So pleased to have with us Dr Marc Sabatine from the TIMI Study Group, who is the first and corresponding author of today's feature paper, as well as our editorialist, Dr Roger Blumenthal from Johns Hopkins University. And of course, we have a familiar voice, a very important editor of our digital strategies and that's Dr Amit Khera from UT Southwestern.                                                 Welcome everyone, I think I'd really like to start with maybe asking Roger to paint the background of the importance of this paper. Simply because I just love the title of your editorial, which is “Realizing the Value of PCSK9 Inhibitors: Are We Closer to Finding the Sweet Spot?” I think that really encapsulates it. So Roger, your thoughts? Dr Roger Blumenthal:     As Amit Khera knows, I'm a golfer, so when you think about the sweet spot on the club, and we know that PCSK9 inhibitors are a great story of translation from bench to bedside, and we also know that the high cost of the therapy presents a challenge. So what Dr Sabatine and colleagues did was to try to identify the sweet spot for its most effective use and that was a pleasure to comment on Dr Sabatine's excellent study. Dr Marc Sabatine:            I think taking a step back I would say from pure biologic perspective, we know that lowering LDL cholesterol will reduce events and that's true and primary and secondary prevention and so if you have therapies that were safe and inexpensive, then I think you wouldn't need to really look for that sweet spot cause it would be all sweet if you will to extend the analogy. But Roger's absolutely right that when you have therapies that are then expensive, then you have to decide, okay in which patients will I get the biggest bang for my buck? And that's a very legitimate question to ask.                                                 And so in FOURIER, overall the trial was positive but as we look for subgroups we say, "Can we find individuals who enjoy a greater absolute risk reduction?" Because therefore the benefit cost ratio is gonna be particularly favorable. And so we approach that in a couple different ways. First you can look for just predictors of baseline risk, so if someone has twice the baseline risk and the same relative risk reduction, you should get about twice the absolute risk reduction and therefore the number needed to treat would be cut in half. And so based on our experience from other TIMI trials and other datasets, we looked at three features that have identified patients with higher baseline risks.                                                 Amongst those with a history of MI which is in and of itself a heterogeneous group. And so those features were patients with a more recent MI, those with multiple prior MIs and those with known residual multivessel coronary disease. And all three features in the FOURIER dataset, not surprisingly, were predictors of risk with patients having an average about a 50% higher baseline risk. But what was particularly nice was that the subgroups also identified patients who had greater relative risk reduction. And so when you couple the two, the higher baseline risk with the greater relative risk reduction, that translated into greater absolute risk reduction then in each of these high-risk groups, the absolute risk reductions over three years or for CV death, MI, and stroke was around 3% versus around 1% for the low-risk groups.                                                 And so that changes the number needed to treat by a factor of three. Dr Carolyn Lam:                Wow, that's so cool. Amit, do you think you could just give us a sneak peek into the editors’ discussions when you saw this paper? Dr Amit Khera:                  This was an easy one, it's clearly a very important paper and if you step back 10,000-foot view, these drugs were initially approved based on LDL lowering and people were using them without knowledge of whether or not they actually lowered events. Marc's group and others have now shown us that certainly they do lower events, but really the next most important thing is application. Who should we use them in and when should they be used and where might they be most effective and I think it was said out in the introduction of this paper, this idea of personalized medicine. And I think this really is an important step forward, not just for PCSK9 field but in general, how we should be thinking about drugs, about balancing cost and benefits and who would benefit most.                                                 So maybe one analogy, I think PCSK9 was not prescribed as much as they had been predicted given costs and other considerations and maybe with analysis like this they've hit it out of the rough back on the fairway, I threw that in for you, Roger. And I do have one question for Marc, which is this is clearly important to better define who would benefit the most and I guess in terms of action abilities, the goal here to provide guidance for clinicians where, you know, if I'm seeing a patient this morning I would take this into account or is this something larger where we recently saw with alirocumab, they changed pricing based on sub-group analysis of a higher risk group. How do you think we should move forward with this type of information? Dr Marc Sabatine:            I’ll get back to the point I raised earlier, I do want to underscore that I think that the true biologic notion is that all these patients, sub-types of secondary prevention or primary prevention all benefit from LDL lowering. So I wouldn't want people to walk out with the notion that it's the only subset that would benefit and really from a population level, obviously Roger's in a better position to speak about this, but sort of shifting the population LDL lower in general would have a huge impact on the risk for cardiovascular disease. But to your question Amit, looking in for a patient in front of you, I think it's quite fair to say right now there's this kind of tug of war back and forth between payers and clinicians.                                                 Clinicians saying, "I have a patient in front of me, they have known atherosclerotic cardiovascular disease, I wanna lower their risk, I wanna manage their risk factors and I wanna get their LDL cholesterol lower and I have a bunch of great tools in front of me." Statin for sure is the foundation, maybe acetamide and PCSK9 inhibitors. And then payers saying, "Well wait a minute, these are expensive drugs and so we're gonna try to restrict that and create a lot of hoops for clinicians to jump through." And so I would rather than wasting all that time back and forth, I think it is logical to say, "What are the high-risk groups?" Where we can agree there's the large enough absolute risk reduction that for a given cost, that makes sense.                                                 Allow there to be alignment for that and have clinicians just be able to write a script and have it filled rather than wasting a lot of time with preauthorization and letters back and forth. Dr Amit Khera:                  That's a great point, maybe I'll just take one follow-up, which is now trying to sift through all the high-risk groups and they end up maybe becoming a bit of a Venn diagram. I know in Roger's editorial he talked about the other FOURIER analysis with PAD and there's more groups to come or do we have enough of a starting place where we think we have enough for decision making? Dr Marc Sabatine:            I would say there are a variety of groups, there is some overlapping even in the paper then we looked at the union of those three high-risk features, which identified about two thirds of the patients who were enrolled in the trial with a history of MI. But you're right, the other slices of the data that will also identify high risk groups, PAD is a particularly good one because most of the therapy for those patients has focused on antithrombotic therapy, which always will have some downside for increased bleeding, whereas risk factor modification in this case has no downside. So that's a very high-risk group, it certainly is important to focus on. But I think within the MI subset, this is a great place to start the other analyses we're doing.                                                 And probably after we've sort of finished the series of, if you will, these kind of univariant slices, then we'll try to put that together into a more comprehensive picture. Dr Roger Blumenthal:     We tried to say that we still need the formal cost-effective analyses in these specific high-risk groups, but it seems most reasonable to focus on engaging in shared decision making now with our patients about PCSK9 inhibitor use and those with a recent ACS and the basis of Odyssey Outcomes and we're awaiting the final publication of that. Symptomatic peripheral arterial disease, which Marc previously published in Circulation, and then looking at these high-risk features that was the subject of this article, those with a more recent MI within the past two years, multiple prior MIs and residual multivessel coronary disease.                                                 And one of the things that we especially found interesting was among the more than 8,000 individuals without a high-risk feature, the event rates were nearly unchanged in the evolocumab versus placebo groups. So I think that's very important, but one other point that we have to keep in mind is that the focus of the last set of guidelines and probably the next cholesterol guidelines that likely will be out in November, will have a large component of the shared decision making and we need to see where the cost comes down, whether these companies that make these medications will be able to significantly lower the cost in a reproduceable manner and patients and clinicians will have to jointly decide what to do, do we add acetamide? Do we add a PCSK9 inhibitor?                                                 But we finished our editorial saying that all clinicians and patients should currently pursue a comprehensive lifestyle and medical regimen for secondary prevention. We all have to remember that and if a person's LDL, a high-risk individual is at least 70 with high-risk features and certainly above 100 on maximum tolerated statin therapy, it's important to strongly consider a PCSK9 inhibition and it'll be very interesting to see what the final wording is when the ACC/AHA cholesterol guidelines come out in November. Dr Carolyn Lam:                Amit, would you like to add any further take-home for the clinicians listening in? Dr Amit Khera:                  I just first want to congratulate both of these discussions today, I think the paper was so incredibly important and I think Roger's group really helped frame it well in the field. The one thing I'd say is this is a moving target, we have some early guidance now that I do think is actionable, so I actually have clinic in about an hour and I'm sure I'll be thinking about this as I think about how to apply PCSK9. Which groups might benefit most, so I do think this is actionable now, I think the points that were made about cost effective analysis, how do we bundle all these concepts or high risk patients into maybe an algorithm and how do the guidelines interpret this as a moving target. We'll wait to see, but I do think there's some important actionable information even now for our clinical patients. Dr Carolyn Lam:                I just love that, and you know that is just so much in line with the ethos of what Circulation is about now. We really, really love the papers that you have to pick up because they're of immediate applicability to your clinical practice.                                                 Well audience, you heard it right here. Thank you so much for joining us this week and of course don't forget to tune in again next week.  

Left atrial appendage closure slashes stroke risk in high-risk atrial fibrillation patients with Amplatzer Amulet; how diabetes patients fared with alirocumab in ODYSSEY Outcomes; the new word in stents is "abluminal"; and cheerful news about midlife fitness. Listen to Cardiocast for the week's top news.

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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. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal. The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms. Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo. In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases. The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking. First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders. The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers. Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers. The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation. These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways. The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States. Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model. In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman. The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction. The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial. Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level. Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level? We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims. Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events? Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard. Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find? Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25. Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions? Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example. Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses? Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here. I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50? One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you. We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies. Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred. Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall. As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs? That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial. Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help. Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.