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CardioNerds co-founders Dr. Daniel Ambinder and Dr. Amit Goyal are joined by Dr. Spencer Weintraub, Chief Resident of Internal Medicine at Northwell Health, Dr. Michael Albosta, third-year Internal Medicine resident at the University of Miami, and Anna Biggins, Registered Dietitian Nutritionist at the Georgia Heart Institute. Expert commentary is provided by Dr. Zahid Ahmad, Associate Professor in the Division of Endocrinology at the University of Texas Southwestern. Together, they discuss a fascinating case involving a patient with a new diagnosis of hypertriglyceridemia. Episode audio was edited by CardioNerds Intern Student Dr. Pacey Wetstein. A woman in her 30s with type 2 diabetes, HIV, and polycystic ovarian syndrome presented with one day of sharp epigastric pain, non-bloody vomiting, and a new lower extremity rash. She was diagnosed with hypertriglyceridemia-induced pancreatitis, necessitating insulin infusion and plasmapheresis. The CardioNerds discuss the pathophysiology of hypertriglyceridemia-induced pancreatitis, potential organic and iatrogenic causes, and the cardiovascular implications of triglyceride disorders. We explore differential diagnoses for cardiac and non-cardiac causes of epigastric pain, review acute and long-term management of hypertriglyceridemia, and discuss strategies for the management of the chylomicronemia syndrome, focusing on lifestyle changes and pharmacotherapy. This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Hypertriglyceridemia Cardiac sarcoidosis can present with a variety of symptoms, including arrhythmias, heart block, heart failure, or sudden cardiac death. The acute management of hypertriglyceridemia-induced pancreatitis involves prompt recognition and initiation of therapy to lower triglyceride levels using either plasmapheresis or intravenous insulin infusion +/- heparin infusion. Insulin infusion is used more commonly, while plasmapheresis is preferred in pregnancy. Medications such as fibrates and omega-3 fatty acids can be used to maintain long-term triglyceride reduction to prevent the recurrence of pancreatitis, especially in patients with persistent triglyceride elevation despite lifestyle modifications. Statins can be used in patients for ASCVD reduction in patients with a 10-year ASCVD risk > 5%, age > 40 years old, and diabetes or diabetes with end-organ damage or known atherosclerosis. Consider preferential use of icosapent ethyl as an omega-3 fatty acid for triglyceride lowering if the patients fit the populations that appeared to benefit in the REDUCE IT trial. Apply targeted dietary interventions within the context of an overall healthy dietary pattern, such as a Mediterranean or DASH diet. Limit full-fat dairy, fatty meats, refined starches, added sugars, and alcohol. Encourage high-fiber vegetables, whole fruits, low-fat or fat-free dairy, plant proteins, lean poultry, and fish. Pay special attention to the cooking oils to ensure the patient is not using palm oil, coconut oil, or butter when cooking. Instead, use liquid non-tropical plant oils. Initiate a very low-fat diet (< 5% of total daily calories from fat) for 1-4 weeks when TG levels are > 750 mg/dL. Recommend and encourage patients to exercise regularly, with a minimum goal of 150 minutes/week of moderate-intensity aerobic activity. If weight loss is required, aim for more than >225 - 250 minutes/week. Develop patient-centered and multidisciplinary stra...
This episode is sponsored by Thuma. Thuma is a modern design company that specializes in timeless home essentials that are mindfully made with premium materials and intentional details. To get $100 towards your first bed purchase, go to http://thuma.co/eyeonai ————————————————————————————————————————— AI deployment is broken—can it be fixed? In this episode, Tuhin Srivatsa, CEO & Co-Founder of Baseten, reveals how his company is DISRUPTING AI infrastructure, making it easier, faster, and more cost-effective to deploy and scale AI models in production. As enterprises increasingly turn to open-source AI models and grapple with the high costs and complexity of scaling, Baseten offers a game-changing solution that eliminates bottlenecks and simplifies the process. Discover how Baseten is taking on AWS SageMaker, OpenAI, and cloud-based AI deployment platforms to reshape the future of AI model deployment. What You'll Learn in This Episode: Why AI deployment & scaling is one of the biggest challenges in 2025 How Baseten enables enterprises to run AI models faster & more efficiently The shift from closed-source to open-source AI models—and why it matters The hidden costs of AI inference & how to optimize for performance Why most AI models fail in production and how to prevent it The future of AI infrastructure: What comes next for scalable AI Whether you're a machine learning engineer, AI researcher, startup founder, or enterprise leader, this episode is packed with actionable insights to help you scale AI models without the headaches. Don't miss this conversation on the next era of AI deployment! #AI #ArtificialIntelligence #MachineLearning #Baseten #AIDeployment #AIScaling #Inference #MLInfrastructure #TechPodcast Stay Updated: Craig Smith Twitter: https://twitter.com/craigss Eye on A.I. Twitter: https://twitter.com/EyeOn_AI ————————————————————————————————————————— (00:00) Tuhin Srivatsa's Journey in AI & Baseten (01:50) What is AI Infrastructure & Why It Matters (03:30) How Baseten Optimizes AI Model Deployment (05:19) Why Most AI Deployments Fail (And How to Fix It) (09:17) The Future of Open-Source AI Models in Enterprise (11:01) How Baseten Automates AI Scaling & Inference (14:12) Why AI Developers Struggle with Cloud-Based AI Tools (18:47) The Real Cost of AI Inference (And How to Reduce It) (20:44) Why AI Scaling is the Biggest Challenge in 2025 (26:55) Can AI Run on Non-NVIDIA Chips? (The Hardware Debate) (31:23) The Future of AI Model Deployment & Inference (37:05) How AI Agents & Reasoning Models Are Changing the Game (40:39) The Truth About AI Hype vs. Reality (45:04) How to Get Started with Baseten (45:48) The Future of AI Infrastructure
Pooling data from the PROMINENT, REDUCE-IT, and STRENGTH trials, Paul Ridker and C. Michael Gibson discuss the residual inflammatory risks for patients treated with statins.
Over the last 30 years, the question over whether omega-3 fatty acids from fish has been the subject of controversy, swinging from exuberance over its potential benefits to skepticism over whether they provide any benefit at all. It seems that one day we hear that fish oil reduces risk for heart attack, while the next day we hear that there is no such benefit, even harm. We've also been subjected to numerous marketing claims for competing products with claims such as “40 times more potent than fish oil” or “You can't buy this in a health food store” that further muddy the waters. So let's review all that we have learned over the past 3 decades to decipher just what role, if any, omega-3 fatty acids from fish oil should play in your program to regain or maintain magnificent health. We dive into the history and outcomes of landmark studies like GISSI-Prevenzione, OMEGA Remodel, and REDUCE-IT, which have left researchers and medical professionals both excited and perplexed. Discover how high-dose EPA might just be the key to reversing coronary atherosclerosis, as outlined in the EVAPORATE trial. Join us as we dissect the data and reveal why omega-3s are more than just a fleeting trend; they could be a cornerstone of heart health backed by decades of research.Learn about different forms of fish oil supplements, and how the absorption rates can vary, cutting through the marketing jargon that often exaggerates their potency. Personalization is key, and we discuss how the RBC omega-3 index can offer tailored dosing advice. With a recommended daily intake of 3,600 milligrams, omega-3s promise noticeable improvements, but patience is needed as it takes about three months to reach a steady state. Subscribe now, and let us guide you through the science-backed journey to achieving optimal health, naturally.________________________________________________________________________________For BiotiQuest probiotics including Sugar Shift, go here.A 15% discount is available for Defiant Health podcast listeners by entering discount code UNDOC15 (case-sensitive) at checkout.*_________________________________________________________________________________Get your 15% Paleovalley discount on fermented grass-fed beef sticks, Bone Broth Collagen, low-carb snack bars and other high-quality organic foods here.* For 12% off every order of grass-fed and pasture-raised meats from Wild Pastures, go here.______________________________________________________________________________OmegaQuant test for RBC Omega-3 Index: https://omegaquant.com/Support the showBooks: Super Gut: The 4-Week Plan to Reprogram Your Microbiome, Restore Health, and Lose Weight Wheat Belly: Lose the Wheat, Lose the Weight and Find Your Path Back to Health; revised & expanded ed
Omega-3 fatty acids are often viewed as beneficial or, at worst, neutral supplements when it comes to supporting cardiovascular health, lowering triglycerides, and offering anti-inflammatory effects. Much of the focus in recent years has centered on understanding how significant these benefits are, particularly for heart health, with many studies highlighting the potential for omega-3s to play a positive role in reducing cardiovascular risk. However, an emerging concern has complicated the conversation around omega-3 supplementation. Several large trials, including the REDUCE-IT and STRENGTH trials, have suggested that omega-3 supplementation might be linked to an increased risk of atrial fibrillation (AF), a common cardiac arrhythmia characterized by an irregular and often rapid heart rate. These findings have sparked debate over whether omega-3s could contribute to this potentially serious heart condition, leaving clinicians and health-conscious individuals uncertain about the safety of these supplements. However, not all the research supports this elevated risk. This discrepancy raises important questions about how we interpret the data from various studies, the design of those trials, and whether other factors might be influencing these results. Understanding this issue in depth is crucial for making informed decisions about omega-3 supplementation and its potential risks and benefits. In this episode we walk through the studies and the key points to consider. Timestamps: 00:30 Updates on Alan's upcoming study 05:06 Atrial Fibrillation and Omega-3 14:52 RCTs and AFib: Key Studies 29:14 Meta-Analyses and Dose-Response 46:46 Practical Implications and Recommendations 53:53 Key Ideas Segment (Premium-only) Links: Join the Sigma email newsletter for free Subscribe to Sigma Nutrition Premium Go to episode page
Judge Thomas G. Moukawsher is a retired Connecticut complex litigation judge and former lawyer, legislator and lobbyist. He is the author of “The Common Flaw: Needless Complexity in the Courts and 50 Ways to Reduce It. It is critical that the US Supreme Court (SCOTUS) have a strong Code of Ethics with enforcement penalties. Recent SCOTUS decisions, especially the absolute immunity, have made it more confusing and difficult to prosecute a corrupt US President. For decades the US has been a beacon for justice and democracy; however, with an attack on our Rule of Law and democratic institutions many nations are alarmed. The US should strongly support the UN's International Court of Justice and the International Criminal Court to maintain our moral authority internationally. The US Constitution and other legal mechanisms played a critical role in developing the United Nations Charter in 1945 and the Universal Declaration for Human Rights in 1948
ESC TV Today brings you concise analysis from the world's leading experts, so you can stay on top of what's happening in your field quickly. This episode covers: Cardiology This Week: A concise summary of recent studies All you need to know about omega-3 fatty acids Lead induced tricuspid regurgitation MythBusters: Pomegranates are heart-healthy Host: Rick Grobbee Guests: Carlos Aguiar, Martin Andreas, Deepak Bhatt Want to watch that episode? Go to: https://esc365.escardio.org/event/1150 Disclaimer This programme is intended for health care professionals only and is to be used for educational purposes. The European Society of Cardiology (ESC) does not aim to promote medicinal products nor devices. Any views or opinions expressed are the presenters' own and do not reflect the views of the ESC. Declarations of interests Stephan Achenbach, Rick Grobbee and Nicolle Kraenkel have declared to have no potential conflicts of interest to report. Carlos Aguiar has declared to have potential conflicts of interest to report: personal fees for consultancy and/or speaker fees from Abbott, AbbVie, Alnylam, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Ferrer, Gilead, Lilly, Novartis, Pfizer, Sanofi, Servier, Tecnimede. Martin Andreas has declared to have potential conflicts of interest to report: proctor/speaker/consultant (Edwards, Abbott, Medtronic, Boston, Braun, Zoll) and institutional Research Grants (Edwards, Abbott, Medtronic, LSI). Deepak Bhatt has declared to have potential conflicts of interest to report: research funding from Amarin paid to Brigham and Women's Hospital and the Icahn School of Medicine at Mount Sinai for my role as Principal Investigator of REDUCE-IT. Davide Capodanno has declared to have potential conflicts of interest to report: Abbott Vascular, Novo Nordisk, Sanofi. Terumo, Medtronic. Emma Svennberg has declared to have potential conflicts of interest to report: institutional research grants from Abbott, Astra Zeneca, Bayer, Bristol-Myers, Squibb-Pfizer, Boehringer-Ingelheim, Johnson & Johnson, Merck Sharp & Dohme.
ACC.24: REDUCE-IT trial - Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl
Vitaminas, Ômega 3, Curcumina, Whey, Creatina... Com tanta informação na internet, a equipe do DozeCast assume o desafio de trazer o que tem de evidência a respeito de suplementação e saúde cardiovascular. Ouvir esse episódio vai te fazer entender quais suplementos realmente podem possuir algum benefício e, principalmente, vai te permitir conversar com entendimento com seu paciente quando o mesmo abordar o assunto. Para discutir esse tema, Diandro Mota e Mateus Prata contam com Dr. Rafael Altoé Chagas (@rafael_altoe_cardio), cardiologista com atuação em medicina do esporte. Minutagem: (00:00) Introdução e apresentação do convidado (06:25) Vitamina D (12:30) Cálcio (14:07) Complexo B (21:44) Vitamina C (24:01) Vitamina A e vitamina E (26:35) Ômega 3 (REDUCE-IT vs STRENGTH) (33:58) Resveratrol e Cúrcuma (43:08) Whey e creatina no cardiopata #cardiologia #suplementos #saúde #mbe #podcast
Qual a importância de toma medicação após um enfarte agudo do miocárdio? Quais os medicamentos mais importantes e que não devemos esquecer? O que é como funciona o eicosapente de etilo? Sendo um novo medicamento, que evidência científica suporta o eicosapente de etilo? Quem pode beneficiar? Existem riscos? Neste episódio, os cardiologistas Hélder Dores e José Ferreira Santos explicam de forma simples os resultados do estudo REDUCE-IT, abordando ainda o funcionamento de um novo medicamento - o eicosapente de etilo -, quem pode beneficiar com ele e se existem riscos associados. Links de interesse: https://cardiodavida.pt/medicacao-apos-um-enfarte-agudo-do-miocardio/ https://cardiodavida.pt/estudo-radical/ Participe no Estudo RADICAL em https://forms.office.com/e/xWCrQA1349
Matt Crawford speaks to Judge Thomas Moukawsher about his book, The Common Flaw: Needless Complexity in the Courts and 50 Ways to Reduce It. Americans are losing faith in our governmental institutions and the courts are at the top of that list. Extreme delays force judges to drop cases or force litigants to settle instead of getting the justice they believe they deserve. This creates a cycle or ineffective and unjust law practices that all parties, including the judges and lawyers fail to understand. The Common Flaw steps into the fray to try and show us what needs to happen and why. With an approach that the layperson can understand Judge Moukawsher lays out a simple blueprint for us to fix and gain trust in our justice system again.
In this thought-provoking episode of "The Rational Egoist," your host Michael Leibowitz engages in a candid conversation with former Connecticut Superior Court Judge, Thomas G. Moukawsher. Together, they delve deep into the intricacies of the U.S. legal system and its tendency to be overly complex. Judge Moukawsher, a seasoned legal expert and author of "Common Flaw: Needless Complexity in the Courts and 50 Ways to Reduce It," brings valuable insights to the table. The discussion revolves around the essence of court cases, which often seem to punish individuals for not aligning with societal expectations. They shed light on how, in the pursuit of justice, a significant amount of time is squandered. These legal proceedings frequently involve maneuvers to avoid responsibility, such as jurisdiction disputes and motions for various technicalities, leading to prolonged court battles. Michael and Judge Moukawsher also tackle the issue of legal jargon and unnecessary complexity within the legal profession, highlighting how these factors contribute to prolonged court cases and billable hours. Tune in to "The Rational Egoist" for a stimulating conversation that unravels the complexities of the legal system and explores the fundamental concept of individual responsibility in contracts and agreements. It's a podcast episode that will leave you questioning the status quo and seeking a more efficient path to justice. Michael Leibowitz is a renowned philosopher, political activist, and the esteemed host of the Rational Egoist podcast. Inspired by the philosophical teachings of Ayn Rand, Leibowitz passionately champions the principles of reason, rational self-interest, and individualism, seeking to empower others through his compelling work.His life's narrative exemplifies the transformative power of Ayn Rand's writings. Having faced challenging circumstances that led to a 25-year prison sentence, Leibowitz emerged from adversity by embracing the tenets of rational self-interest and moral philosophy put forth by Ayn Rand. This profound transformation propelled him to become an influential figure in the libertarian and Objectivist communities, motivating others to adopt reason, individualism, and self-interest in their own lives. Beyond his impactful podcasting endeavors, Leibowitz fearlessly engages in lively political debates, advocating for the protection of individual rights and freedoms through compelling YouTube videos and insightful interviews. His unwavering commitment to these ideals has garnered him a dedicated following of like-minded individuals.Leibowitz is a versatile author, co-authoring the thought-provoking book titled "Down the Rabbit Hole: How the Culture of Correction Encourages Crime." This groundbreaking work delves into societal attitudes surrounding punishment and rehabilitation, shedding light on how misguided approaches have contributed to the rise of crime and recidivism. Additionally, he has authored the book "View from a Cage: From Convict to Crusader for Liberty," offering an intimate portrayal of his personal journey while exploring the philosophies that influenced his transformation.As you embark on your intellectual journey, join Michael Leibowitz as he advocates for reason, individualism, and the pursuit of self-interest, inspiring others to embrace a philosophy that empowers and uplifts the human spirit. For a deeper exploration of his ideas and insights, don't miss the opportunity to read "Down the Rabbit Hole: How the Culture of Correction Encourages Crime," co-authored by Michael Leibowitz. And also, delve into his book "View from a Cage: From Convict to Crusader for Liberty." Both books are available for purchase using the following links:"Down the Rabbit Hole": https://www.amazon.com.au/Down-Rabbit-Hole-Corrections-Encourages/dp/197448064X"View from a Cage": https://books2read.com/u/4jN6xj
As both an attorney and judge, Thomas Moukawsher has spent the majority of his career dealing in complex litigation. And the Connecticut Superior Court judge would like to make the legal system—well, less complex. In this episode of the Modern Law Library, Moukawsher and the ABA Journal's Lee Rawles discuss his ideas and his new book, The Common Flaw: Needless Complexity in the Courts and 50 Ways to Reduce It. Instead of advocating for legislation to simplify the court process, Moukawsher says many of his ideas could be immediately put into practice by judges. Many of Moukawsher's theories were developed in the wake of having to make changes in court proceedings during the COVID-19 pandemic while court buildings were closed. He says being forced to reexamine the habitual ways cases were heard was actually beneficial. Realizing how much could be conducted remotely gave him confidence that broader systemic changes in that direction are worth trying. One such suggestion is to conduct more jury trials remotely to increase juror numbers and diversity. The Common Flaw contains many concrete suggestions for lawyers and attorneys to streamline trials, but it was also written to be enjoyed by the public, Moukawsher tells Rawles. To that end, concepts are liberally illustrated with cartoons, and despite having 51 chapters, the book is not doorstopper-length. Speaking of length, one of Moukawsher's largest concerns is that the length of time many cases drag on decreases public confidence in the legal system as a whole. He says he sees this often in family court, where conflicts that could be handled in weeks stretch out through months or years and can lead to bankruptcy. He and Rawles also discuss his thoughts on the billable hour; how his ADHD helped him prune away unnecessary flummery in court processes; how he would rethink the job duties of law clerks; and his top tips for not fumbling cross-examinations.
As both an attorney and judge, Thomas Moukawsher has spent the majority of his career dealing in complex litigation. And the Connecticut Superior Court judge would like to make the legal system—well, less complex. In this episode of the Modern Law Library, Moukawsher and the ABA Journal's Lee Rawles discuss his ideas and his new book, The Common Flaw: Needless Complexity in the Courts and 50 Ways to Reduce It. Instead of advocating for legislation to simplify the court process, Moukawsher says many of his ideas could be immediately put into practice by judges. Many of Moukawsher's theories were developed in the wake of having to make changes in court proceedings during the COVID-19 pandemic while court buildings were closed. He says being forced to reexamine the habitual ways cases were heard was actually beneficial. Realizing how much could be conducted remotely gave him confidence that broader systemic changes in that direction are worth trying. One such suggestion is to conduct more jury trials remotely to increase juror numbers and diversity. The Common Flaw contains many concrete suggestions for lawyers and attorneys to streamline trials, but it was also written to be enjoyed by the public, Moukawsher tells Rawles. To that end, concepts are liberally illustrated with cartoons, and despite having 51 chapters, the book is not doorstopper-length. Speaking of length, one of Moukawsher's largest concerns is that the length of time many cases drag on decreases public confidence in the legal system as a whole. He says he sees this often in family court, where conflicts that could be handled in weeks stretch out through months or years and can lead to bankruptcy. He and Rawles also discuss his thoughts on the billable hour; how his ADHD helped him prune away unnecessary flummery in court processes; how he would rethink the job duties of law clerks; and his top tips for not fumbling cross-examinations.
As both an attorney and judge, Thomas Moukawsher has spent the majority of his career dealing in complex litigation. And the Connecticut Superior Court judge would like to make the legal system—well, less complex. In this episode of the Modern Law Library, Moukawsher and the ABA Journal's Lee Rawles discuss his ideas and his new book, The Common Flaw: Needless Complexity in the Courts and 50 Ways to Reduce It. Instead of advocating for legislation to simplify the court process, Moukawsher says many of his ideas could be immediately put into practice by judges. Many of Moukawsher's theories were developed in the wake of having to make changes in court proceedings during the COVID-19 pandemic while court buildings were closed. He says being forced to reexamine the habitual ways cases were heard was actually beneficial. Realizing how much could be conducted remotely gave him confidence that broader systemic changes in that direction are worth trying. One such suggestion is to conduct more jury trials remotely to increase juror numbers and diversity. The Common Flaw contains many concrete suggestions for lawyers and attorneys to streamline trials, but it was also written to be enjoyed by the public, Moukawsher tells Rawles. To that end, concepts are liberally illustrated with cartoons, and despite having 51 chapters, the book is not doorstopper-length. Speaking of length, one of Moukawsher's largest concerns is that the length of time many cases drag on decreases public confidence in the legal system as a whole. He says he sees this often in family court, where conflicts that could be handled in weeks stretch out through months or years and can lead to bankruptcy. He and Rawles also discuss his thoughts on the billable hour; how his ADHD helped him prune away unnecessary flummery in court processes; how he would rethink the job duties of law clerks; and his top tips for not fumbling cross-examinations.
The Brainy Business | Understanding the Psychology of Why People Buy | Behavioral Economics
In this episode of the Brainy Business podcast, host Melina Palmer interviews Carlos Hoyos, a behavioral scientist and content creator from Latin America. They discuss the challenges of creating content in a non-English language and the importance of making behavioral science accessible to a wider audience. Hoyos shares his approach to creating content, including his YouTube channel, Behavioral Pills, and his e-learning platform, which offers one-hour sessions on various behavioral science frameworks. The conversation highlights the need for more diverse voices in the behavioral science community and the opportunities for growth and learning in different regions around the world. Show Notes: [00:42] Welcome Carlos Hoyos, Senior Behavioral Designer at BeWay, and Co-Founder at Kestudio. [02:19] Behavioral science is important everywhere. [03:42] Carlos shares about himself, his background, and the work he does in behavioral science. [05:35] In recent years he has dedicated his whole career to developing his knowledge in terms of behavioral science and design and specifically to find ways to apply it in business. [07:15] Carlos was named Content Person of the Year by Habit Weekly. (Merle van den Akker – last week's guest – and I were both finalists as well – congrats Carlos!) [10:15] There are many companies now that are investing in behavioral science in Latin America. [13:12] He sees himself as a content curator because he shares what other good professionals are doing. [14:46] People love to talk about human behavior. It really connects to people. [16:36] He found that there is so much information out there in English. Instead of being just one more, he decided to focus on Spanish because there is so little in Spanish right now. [19:32] Daring to do the thing no one else has done yet is what helps people to stand out. [22:20] Carlos shares some of the work he is doing with BBVA. They have merged behavioral science into day-to-day decision-making. [24:53] One project they worked on at BBVA was with credit cards. People weren't interested in applying for the credit cards because of a lack of trust – they wanted to change that. [27:34] Experimentation and testing are a must in their projects. [29:20] In 2022, they did more than 130 experiments in different areas of the business and that actually represented an extra income of around 45 million euros in the year. [30:46] There are so many little things where behavioral science can make a very big impact in any type of business all around the world. [32:20] There is plenty of opportunity and room for growth in behavioral science – in the US and around the world. [35:16] The stress on the brain when you are trying to hurry and rush leads to problems that have to be fixed down the line. [37:23] Experimenting and testing every decision you want to make will help you make better decisions now and for the future. [38:42] If you torture the data long enough it will confess to anything. [41:34] Carlo's Behavioral Pills are one-hour e-learning sessions where he explains things concepts he considers basic for a behavioral scientist to know. [43:33] Melina's closing thoughts [45:03] Don't be scared of being first. There are lots of people like you who have done this in their own way or their own language. Thanks for listening. Don't forget to subscribe on Apple Podcasts or Android. If you like what you heard, please leave a review on iTunes and share what you liked about the show. I hope you love everything recommended via The Brainy Business! Everything was independently reviewed and selected by me, Melina Palmer. So you know, as an Amazon Associate I earn from qualifying purchases. That means if you decide to shop from the links on this page (via Amazon or others), The Brainy Business may collect a share of sales or other compensation. Let's connect: Melina@TheBrainyBusiness.com The Brainy Business® on Facebook The Brainy Business on Twitter The Brainy Business on Instagram The Brainy Business on LinkedIn Melina on LinkedIn The Brainy Business on Youtube Join the BE Thoughtful Revolution – our free behavioral economics community, and keep the conversation going! Learn and Support The Brainy Business: Check out and get your copies of Melina's Books. Get the Books Mentioned on (or related to) this Episode: Outsmart Your Brain, by Dan Willingham Good Habits, Bad Habits, by Wendy Wood Predictably Irrational, by Dan Ariely Evolutionary Ideas, by Sam Tatam Friction, by Roger Dooley Connect with Carlos: Carlos Website Carlos on LinkedIn Carlos on YouTube Top Recommended Next Episode: How To Set Up Your Own Experiments (ep 63) Already Heard That One? Try These: Saving Peru's Environment One Nudge At A Time with BE OEFA (ep 195) Habit Weekly: A Discussion With Creator Samuel Salzer (ep 284) Dan Ariely Interview: Discussing Shapa, the Numberless Scale (ep 101) Nudges and Choice Architecture (ep 35) How To Change, an interview Dr. Katy Milkman (ep 151) Evolutionary Ideas with Sam Tatam, Ogilvy's Global Head of Behavioural Science (ep 204) Herding (ep 264) Priming (ep 252) Where CX and Behavioral Science Meet, with Jennifer Clinehens (ep 141) The Speed and Economics of Trust, with Stephen M.R. Covey (ep 148) Friction, with Roger Dooley (ep 274) Sludge: What It Is and How to Reduce It (ep 179) Using Behavioral Science to Tackle Addiction with Richard Chataway (ep 134) Reciprocity (ep 238) Framing (ep 16) Other Important Links: Brainy Bites - Melina's LinkedIn Newsletter Behavioral Pills Website
The Brainy Business | Understanding the Psychology of Why People Buy | Behavioral Economics
In today's conversation, I am joined by Richard Shotton. His first book, The Choice Factory, is a best-selling book on how to apply findings from behavioral science to advertising. His new book, The Illusion of Choice: 16 ½ Psychological Biases that Influence Why We Buy, is a phenomenal add to what he has already contributed to the field of behavioral science. This book (and conversation!) are both full of great examples from traditional academic research and from practical application. And, one of my favorite things that Richard does is take research and recreate it. Sometimes it replicates (and does even better than expected) and sometimes it doesn't – whatever the results, they are shared and there are learnings for everyone involved. And, of course, that includes you. Does precision matter? Should you speak in abstract or concrete terms? Tune in and get ready for these amazing lessons and many more… Show Notes: [00:43] In today's conversation, I am joined by Richard Shotton. Richard is the author of The Choice Factory, a best-selling book on how to apply behavioral science to advertising. [02:42] Richard shares himself, his background, and the work he does in behavioral science. [04:06] There are thousands of biases. He covers 25 in The Choice Factory. His new book covers 16 and ½ more. (The half chapter is around the power of precision.) [06:51] Precision is powerful. Generally if someone knows the subject they speak in precision, if not they speak in generalities. [09:30] The precise price tends to be seen as lower than rounded ones. [11:52] If you want to change behavior, remove friction. If you want to boost appreciation of your product, you might want to add some friction. [13:10] The importance of framing the question is key if you are going to use behavioral science practically. [15:42] You have this huge swing in memorability based on whether terms are concrete or abstract. If we can picture a term it becomes very sticky if not it becomes forgettable. [18:02] Increasingly brands talk in abstract terms. It is ineffective to use that language. If you want to communicate one of those abstract objectives you have to translate it into more concrete terminology. [20:43] Academics sometimes make behavioral science more complex than it has to be. Reading modern academic papers is a chore. [22:41] The evidence shows that if you communicate simply you come across as more prestigious and more intelligent. [25:50] People were twice as likely to remember the rhyming than the non rhyming phrases. Alliterating phrases have a boost of believability and memorability. [28:06] We have to make sure that what we do is what our clients want us to do rather than worrying about the kudos that we as individuals get. [30:19] The cafe had a problem that people didn't want to go on a Monday. So if you go on Monday you get to roll the brass dice. If you roll a six everything you have eaten is free. (Love this!) [33:27] If you know that this is the thing on Monday, everyone is going to order a little bit more because they might get it all for free. [36:01] People are not only interested in maximizing the financial benefit of the situation. They also wanted to know that they are being treated well and not being taken advantage of. [38:35] Questions are so important. Questions can give people a pause for thought and influence them more subtly. [41:12] Professionals are just as influenced as consumers with the vast majority of biases. The only difference is they are even more loathe to admit it. [42:43] Podcasts and books are a wonderful way of quickly understanding lots of different experiments. The ones you think are most interesting are worth finding the original paper and exploring further. [44:53] Melina's closing thoughts Thanks for listening. Don't forget to subscribe on Apple Podcasts or Android. If you like what you heard, please leave a review on iTunes and share what you liked about the show. I hope you love everything recommended via The Brainy Business! Everything was independently reviewed and selected by me, Melina Palmer. So you know, as an Amazon Associate I earn from qualifying purchases. That means if you decide to shop from the links on this page (via Amazon or others), The Brainy Business may collect a share of sales or other compensation. Let's connect: Melina@TheBrainyBusiness.com The Brainy Business® on Facebook The Brainy Business on Twitter The Brainy Business on Instagram The Brainy Business on LinkedIn Melina on LinkedIn The Brainy Business on Youtube Join the BE Thoughtful Revolution – our free behavioral economics community, and keep the conversation going! Learn and Support The Brainy Business: Check out and get your copies of Melina's Books. Get the Books Mentioned on (or related to) this Episode: The Choice Factory, by Richard Shotton The illusion of Choice, by Richard Shotton Alchemy, by Rory Sutherland Friction, by Roger Dooley Sludge, by Cass Sunstein Connect with Richard: Richard's Website Richard on Twitter Top Recommended Next Episode: Friction, with Roger Dooley (ep 274) Already Heard That One? Try These: Herding (ep 19) Status Quo Bias (ep 142) The Voltage Effect with John List (ep 190) What Problem are You Solving? (ep 126) Sludge: What It Is and How to Reduce It (ep 179) IKEA Effect & Effort Heuristic (ep 112) Habits (ep 21) Framing (ep 16) The Sense of Sight (ep 24) Get Your D.O.S.E. of Brain Chemicals (ep 123) Inequity Aversion: That's Not Fair! (ep 224) Unlocking the Power of Numbers (ep 17) Relativity (ep 12) Peak-End Rule (ep 97) Social Proof (ep 87) Other Important Links: Brainy Bites - Melina's LinkedIn Newsletter Schindler Precision Dynamic Pricing in a Labor Market: Surge Pricing and Flexible Work on the Uber Platform
Cardiovascular professionals are coming together for ACC.23 in New Orleans, March 4-6, to learn the latest practice-changing breakthrough research and trials results from around the world. In this View episode, guest host Deepak Bhatt MD, MPH, FACC, offers a preview of some of the hottest trials at ACC.23. Kicking us off on Day 1, Saturday, March 4, we will hear the positive outcomes from the CLEAR OUTCOMES trial and the favorable data for structural heart disease coming out of the TRILUMINATE trial. Day 2, Sunday, March 5, can't be missed! Among the many presentations: UK MINI MITRAL weighs the minimally invasive approach versus conventional sternotomy for mitral valve repair surgery and the RENOVATE COMPLEX PCI trial that examines intravascular imaging-guided versus angiography-guided procedural optimization in complex percutaneous coronary intervention – a subject of particular interest to interventionalists. And that's just the beginning: the 5-year final results from the COAPT trial are in; the 3-year outcomes from the EVOLUT low risk trial sound positive and continue to be in favor of TAVR; the BIOVASC trial data will be released, and it's likely the findings will continue to be in favor of complete revascularization strategies in patients presenting with acute coronary syndromes and multivessel coronary disease. On Monday, the last day of the conference, Dr. Valentin Fuster will present the FREEDOM COVID ANTICOAG trial, discussing anticoagulation strategies in non-critically ill hospitalized COVID patients. Next up, the STELLAR trial, a study of sotatercept in combination with background therapy for the treatment of pulmonary arterial hypertension, will be presented. And finally, the findings of the collaborative analysis of participants in the three major trials are also scheduled: the PROMINENT, REDUCE-IT, STRENGTH trials. Be sure to check back on Eagle's Eye View throughout the meeting for further updates. Subscribe to Eagle's Eye View
The Brainy Business | Understanding the Psychology of Why People Buy | Behavioral Economics
I love partitioning! It is such an under-discussed concept, which is why I decided to refresh this episode from 2019 for you here today. Partitioning is closely related to friction or sludge, but it isn't exactly the same. While an experience that has partitions may be creating friction/sludge, it isn't just about that. And, it isn't always about reducing it. Sometimes, adding a partition is really useful when you want someone to stop and think. I'll get into that more as we dig into the episode. As you get ready to listen to the episode today, I encourage you to have some experiences in mind. Try and think of a time when you had a great experience with a company, where things were seamless and streamlined or it felt easy. And another where you were part-way through buying and then stopped or when you changed your mind on a project or whatever else. Try and think through what happened along the way and keep that in mind as you consider the idea of partitioning. Where were the unintended partitions and where did the lack of them make a difference? Of course, look to your own experiences in your company as well. If you have a hard time closing deals or lose people partway through an application form keep that in mind too. It can all tie back to partitions. So let's dive in and learn how you can use partitions in your business to create a seamless experience for your customers. Show Notes: [00:37] Today's episode is all about partitioning. I love partitioning! It is such an under-discussed concept. [02:39] Partitioning has shown us that when you put tiny barriers into place it causes a consumer to consider their options and be presented with a new decision point. This can be good or bad on both sides depending on the situation. [04:33] Melina shares a study with bottomless soup bowls. [06:34] Another study found that adding some sort of measurement reminder can help reduce consumption even if the cups are large. [08:45] One study found that once something became common it no longer acted as a partitioning mechanism. [10:21] It isn't just effort that matters but drawing the attention of the conscious brain really matters too. [12:56] It is so easy to be tricked by our brains. [15:07] Those with a high aversion to gambling were significantly impacted by the partitions. [16:24] Partitioning money has also been found to help people save more and spend less. [17:26] Essential with shopping…once you start the process of spending you are more likely to spend again until you hit a partition. [19:07] Any cognitive intervention (something that makes the user stop and think) can trigger partitioning. This can be done using sounds, rhetorical questions, targets, or progress markers. [21:37] It doesn't have to feel bad or negative for the consumer. [23:41] The cashier in an airport store bringing up the price of the almonds and forcing us to rethink our decision multiple times caused anticipated regret and lowered the total amount spent significantly. [25:18] It is easy to talk people out of a sale, make them feel bad about a purchase, or start to regret it even when you are trying to be helpful. [26:07] Setting up targets or progress markers, on the other hand, can be great partitions for a business to set up to keep on the radar of their current, past or potential customers. [27:21] Removing partitions and obstacles can be great for businesses and customers alike. [29:29] Partitions in the selling process are a recipe for getting ghosted. Always schedule circle-back meetings in the moment. [32:03] Make it easy for people to do business with you. Remove unnecessary partitions in the process and everyone will be happier. [32:13] Melina's closing thoughts [32:42] The concept of partitioning can help you to look for opportunities to make it easier to work with you, especially up front. Partitions are particularly dangerous early on and in the selling process. Thanks for listening. Don't forget to subscribe on Apple Podcasts or Android. If you like what you heard, please leave a review on iTunes and share what you liked about the show. I hope you love everything recommended via The Brainy Business! Everything was independently reviewed and selected by me, Melina Palmer. So you know, as an Amazon Associate I earn from qualifying purchases. That means if you decide to shop from the links on this page (via Amazon or others), The Brainy Business may collect a share of sales or other compensation. Let's connect: Melina@TheBrainyBusiness.com The Brainy Business® on Facebook The Brainy Business on Twitter The Brainy Business on Instagram The Brainy Business on LinkedIn Melina on LinkedIn The Brainy Business on Youtube Join the BE Thoughtful Revolution – our free behavioral economics community, and keep the conversation going! Learn and Support The Brainy Business: Check out and get your copies of Melina's Books. Get the Books Mentioned on (or related to) this Episode: What Your Customer Wants and Can't Tell You, by Melina Palmer Friction, by Roger Dooley Sludge, by Cass Sunstein The Experience Maker, by Dan Gingiss The Selling Staircase, by Nikki Rausch Top Recommended Next Episode: Sludge: What It Is and How to Reduce It (ep 179) Already Heard That One? Try These: Friction - What It Is And How To Reduce It, with Roger Dooley (ep 72) How to Make it Easy to Do Business With You With Nikki Rausch (ep 96) What Your Customer Wants and Can't Tell You: All About Melina's First Book (ep 147) How To Set Up Your Own Experiments (ep 63) Surprise and Delight (ep 60) Pain of Paying (ep 240) Peak-End Rule (ep 97) How to Create Remarkable Experiences with Dan Gingiss (ep 85) Other Important Links: Brainy Bites - Melina's LinkedIn Newsletter Nikki's Website - Your Sales Maven
The Brainy Business | Understanding the Psychology of Why People Buy | Behavioral Economics
Decisions are everywhere — we are making them all day long. Even if you know you are making a lot of decisions, you probably don't grasp the full weight of them. Think about yesterday, how many decisions can you remember making? How many decisions do you make on an average day? Research shows that people make 35,000 decisions every single day! Can you believe it? Clearly, the bulk of those are done subconsciously as we couldn't exist if we had to do all of those on a conscious level. So, how do we make better decisions? What happens when we make too many decisions? Is there a point in the day when we have hit our decision number and it's all downhill from there? Or is there an opportunity to recharge those batteries and have a second wind? When do we reach the point of decision fatigue and what can we do to avoid it? That's what this episode is all about. This refreshed episode originally came out on Christmas day, 2020 (at the end of a year full of decision fatigue). It includes tips for making better decisions around the holidays and is useful all year round. Ready to optimize your decisions? Listen in… Show Notes: [00:39] Today's episode is all about decision fatigue. [03:21] We humans make an incredible number of decisions each day. [04:48] We all make about 35,000 decisions every single day. Some of those are big choices evaluated by our conscious brain but over 90% are made by your subconscious. [05:51] As you begin to get fatigued, you rely on your subconscious rules of thumb to make decisions. You'll be more cautious and make decisions that are risk-averse without even noticing the change in your behavior. [07:48] If you don't bog down your brain with mundane choices you can free it up so it doesn't get fatigued as quickly. [09:34] Doing something today is the best way to make tomorrow easier. [11:14] Decision fatigue is similar to overwhelm but they are not the same thing. Your brain can get overwhelmed by more than just decisions. [14:08] Be thoughtful about the things you will be thoughtful about. There are lots of things that seem important at the moment that simply aren't. [14:33] Dopamine is a chemical that your brain likes. It forms lots of habits around getting more of it and Dopamine goes hand and hand with anticipation. [15:16] Just because it feels bad or painful doesn't mean it is wrong or that it isn't in your best interest to continue down the path. It might just be your subconscious rebelling about not getting the Dopamine it is used to. Take that painful moment as a good sign and celebrate it and keep moving forward. [16:58] It is so important to put extra thought into your customer experience journeys. You want to reduce that friction and make it as easy as possible to do business with you. [19:04] You are making it easier for someone to make a choice. [20:47] Look for ways to reduce decisions and make it easier to work with you. [21:12] Decision fatigue is another reason batching content and tasks is so important. When you set aside some time to plan out content in advance, you condense all those decisions into one. It is a super simple brain hack. [22:17] Another closely related item to batching is delegating. Don't hold onto every little decision and choice on a project. Fight the urge to have everything done perfectly in the way you would do them and free up your brain from making decisions that someone else could do. [24:04] Take breaks. Take a lunch break, weekend off, breaks throughout the day, and even naps. [25:59] It isn't selfish or self-indulgent in a bad way. It's actually beneficial to your overall decision-making to take this time for yourself. It helps keep your brain clear, your decisions stronger, and your work better and more meaningful. Taking care of your brain is important. [27:41] Melina's closing thoughts [27:53] When you can streamline the things you do and reduce the unnecessary decisions in your life by making them habits, it can really help you to do more and better things. [29:45] The more you streamline and plan while you are in a cold state (before the moment of distraction hits) the easier it will be in the long run. Thanks for listening. Don't forget to subscribe on Apple Podcasts or Android. If you like what you heard, please leave a review on iTunes and share what you liked about the show. I hope you love everything recommended via The Brainy Business! Everything was independently reviewed and selected by me, Melina Palmer. So you know, as an Amazon Associate I earn from qualifying purchases. That means if you decide to shop from the links on this page (via Amazon or others), The Brainy Business may collect a share of sales or other compensation. Let's connect: Melina@TheBrainyBusiness.com The Brainy Business® on Facebook The Brainy Business on Twitter The Brainy Business on Instagram The Brainy Business on LinkedIn Melina on LinkedIn The Brainy Business on Youtube Join the BE Thoughtful Revolution – our free behavioral economics community, and keep the conversation going! Learn and Support The Brainy Business: Check out and get your copies of Melina's Books. Get the Books Mentioned on (or related to) this Episode: Essentialism, by Greg McKeown Good Habits, Bad Habits, by Wendy Wood Friction, by Roger Dooley The Selling Staircase, by Nikki Rausch Sludge, by Cass Sunstein Top Recommended Next Episode: Habits: 95% Of Decisions Are Habitual - Which Side Is Your Business On? (episode 21) Already Heard That One? Try These: The Overwhelmed Brain & Its Impact on Decision Making (ep 32) Defaults: The "D" in NUDGES (episode 38) Good Habits, Bad Habits: An Interview with Wendy Wood (ep 127) Bikeshedding (ep 99) Time Discounting (ep 51) Get Your D.O.S.E. of Brain Chemicals (ep 123) Friction - What It Is And How To Reduce It, with Roger Dooley (ep 72) How to Make it Easy to Do Business With You With Nikki Rausch (ep 96) Sludge: What It Is and How to Reduce It (ep 179) Planning Fallacy (ep 114) How to Set, Achieve & Exceed Brainy Goals (episode 70) Other Important Links: Brainy Bites - Melina's LinkedIn Newsletter How Many Daily Decisions Do We Make? Decision Fatigue: What it is and how it's killing your focus, motivation, and willpower How Willpower Works: How to Avoid Bad Decisions When Thinking is Hard: Managing Decision Fatigue You're facing a lot of choices amid the pandemic. Cut yourself slack: It's called decision fatigue. What is Decision Fatigue? The Science of Decision Fatigue How to Identify When You're Experiencing Decision Fatigue
The Brainy Business | Understanding the Psychology of Why People Buy | Behavioral Economics
Today is all about the aversion that humans have to uncertainty and ambiguity, our fear of the unknown, and how it can cause us to choose something we are familiar with even though it may not be in our best interest. While this can often align with risk aversion, they are not the same thing, and while they do often correlate, they don't have to. More on that, and of course, loss aversion and inequity aversion – all the aversions – on the show today, but because this is a concept I'm guessing you'll “get” pretty easily, there is less on the research studies (they are linked in the notes). That leaves the bulk of the episode to focus on how this applies to you in two aspects of business: internal communication and customer experience. Ready? Let's get started. Show Notes: [00:43] Today is about the aversion that humans have to uncertainty and ambiguity, our fear of the unknown, and how it can cause us to choose something we are familiar with even though it may not be in our best interest. [02:38] The most important thing to know is that we don't like the unknown. We don't like uncertainty in our choices and will prefer known risks over unknown risks. And also, because our brains are lazy and rely on rules of thumb, we often will avoid making complex (and not so complex) calculations. [03:39] Consider the stock market. This can have unknown risks and so people can feel hesitant to put their money there even when the probabilities and rates of return are relatively known over time. [05:30] As with everything, when you present information, how you talk about it matters more than what you are saying. Frame the information you present to highlight what IS known to make it easier for someone to see the positive. (Note: don't gloss over important risks or problems. Use good judgment.) [07:47] When you are presenting a change at work, there are so so so many variables at play, and if you leave a lot of uncertainty and ambiguity – say you share too early or in an incomplete way – there is a good chance people will rebel against that unknown future state. [09:17] A real problem that happens a lot (and is unfathomably detrimental to change initiatives at work), is when someone is given ambiguous information and they feel the need to get their own brain relief by reducing their own mental burden (and wanting someone to help fill that void) in a way that they will find any possible way to justify telling someone (or in some cases, many someones) to cover up that uncertainty. [11:26] As George Lowenstein proposed, “Curiosity is like an itch on the brain and we need anything we can find to scratch that itch.” When there is information to be found, we can fill the gap with learning. When there isn't like in these scenarios, it can be gossip, fear, and doomsday-style planning for the worst, which will cause people to rebel against the potential future before it even has a chance to bloom. [12:55] Everyone on your team needs to be trained on how to share the information and when, and make sure the message is properly framed with regard to all the ambiguous pieces that could cause people to revert to the known instead of the unknown. [14:19] Melina shares some questions you can ask yourself to help determine when it is the right time to share information. [15:38] Just forcing yourself to take a step back and a calming breath as you consider what is really happening can be so helpful. You may want to get out and take a walk or sleep on it or whatever else you do to gain perspective. [18:35] Sharing too much information can cause overwhelm as well, which is stressful and creates its own avoidance, so it is about sharing the right information in the right way at the right time to the right people. Remember that “fair” isn't always equal, and different people need to hear different information at different times. [19:50] The early days of Covid are such a perfect case study for what happens when we feel uncertainty and a lack of control. When people feel a lack of control and like they can't do anything to protect themselves or their families, they may strive to find control in other areas – like hoarding toilet paper. It feels like you are doing something, and can reduce some of that stress. [21:59] Time moves differently on the two sides of a decision in ambiguous times. This presents a big communication problem and disconnect that teams need to pay attention to if they want to be effective. [22:51] The “no update update” can be really helpful for companies. I know you want to wait until everything is perfect to share, but that rumor mill is going to be piling up in a way that is working against you and you owe it to your employees to help relieve some of that stress. [25:30] “No update updates” can be really helpful to diffuse some pressure when there is a lot going on and things are scary on the other side of the decision, but you can't do too many “no update updates” in a row without it starting to be a new problem… [28:06] Let's look at the customer experience side. We like to think people want a lot of choices and to be treated as individuals with very unique experiences. While that can be true, there is also a real issue with the ambiguity side of things if we allow ourselves to rest on the easy answer of “it's custom.” [29:56] When people feel uncertain, they are more likely to look to what others like them do in this situation, so testimonials, social proof, and case studies are all your friends in fighting ambiguity aversion. You don't want or need to share all the nuts and bolts, but at least let them know that there is a process. [32:02] You owe it to your clients and customers to take the time to make this as easy and streamlined as possible – and the benefit is it will make it easier for people to choose you and do business with you. [32:29] Melina's closing thoughts [35:02] Adapting your lenses and looking from multiple angles and depths is really important to make that possible, which is why an episode like this is so valuable. Thanks for listening. Don't forget to subscribe on Apple Podcasts or Android. If you like what you heard, please leave a review on iTunes and share what you liked about the show. I hope you love everything recommended via The Brainy Business! Everything was independently reviewed and selected by me, Melina Palmer. So you know, as an Amazon Associate I earn from qualifying purchases. That means if you decide to shop from the links on this page (via Amazon or others), The Brainy Business may collect a share of sales or other compensation. Let's connect: Melina@TheBrainyBusiness.com The Brainy Business® on Facebook The Brainy Business on Twitter The Brainy Business on Instagram The Brainy Business on LinkedIn Melina on LinkedIn The Brainy Business on Youtube Join the BE Thoughtful Revolution – our free behavioral economics community, and keep the conversation going! Learn and Support The Brainy Business: Check out and get your copies of Melina's Books. Get the Books Mentioned on (or related to) this Episode: What Your Employees Need and Can't Tell You, by Melina Palmer The Paradox of Choice, by Barry Schwartz Sludge, by Cass Sunstein Nudge, by Richard Thaler & Cass Sunstein Friction, by Roger Dooley Top Recommended Next Episode: Inequity Aversion: That's Not Fair! (episode 224) Already Heard That One? Try These: Availability Bias (ep 15) Familiarity Bias (ep 149) Status Quo Bias (ep 142) Loss Aversion (ep 9) Framing (ep 16) Bikeshedding (ep 99) Planning Fallacy (ep 114) Paradox of Choice: Why More is Less (ep 171) Sludge: What It Is and How to Reduce It (ep 179) NUDGES & Choice Architecture (ep 35) Other Important Links: Brainy Bites - Melina's LinkedIn Newsletter RISK, AMBIGUITY, AND THE SAVAGE AXIOMS The Itch of Curiosity Ambiguity (uncertainty) aversion Treatment decisions under ambiguity
The landmark REDUCE-IT trial demonstrated that icosapent ethyl (IPE) 4 g daily significantly reduced cardiovascular events in high-risk patients when added to statin therapy, but is a fancy fish oil supplement really worth our coin? Guest Authors: Joseph Nardolillo, PharmD, BCACP and Vivian Cheng, PharmD, BCPS, BCACP Music by Good Talk
Back with the "Happy in 15" -format, Sami and Pasi dive into the topic of how to answer to Cost Saving Pressure as an IT Team and how Experience Management and ITXM™ can help. Key talking points: 1. Reduce IT costs and prioritize 2. Optimize IT outsourcing 3. Automate areas that matter Make sure to check out the The Global IT Experience benchmark, to see the graphs we talk about. https://happysignals.com/report --- HappySignals YouTube Channel: https://www.youtube.com/channel/UCZt8YNTGsNBiVCPEPWYr1nA Take the ITXM™ foundation course here - https://itxm.academy/itxm-foundation/ Read more about ITXM™ framework here - https://www.happysignals.com/itxm-framework-it-experience-management Learn more about HappySignals - https://www.happysignals.com/
In this feature from the 2021 Midyear Clinical Meeting, our content matter experts share updates from the REDUCE-IT and STRENGTH trials and the role current therapies, as well as new and emerging therapies, play in managing dyslipidemia. The information presented during the podcast reflects solely the opinions of the presenter. The information and materials are not, and are not intended as, a comprehensive source of drug information on this topic. The contents of the podcast have not been reviewed by ASHP, and should neither be interpreted as the official policies of ASHP, nor an endorsement of any product(s), nor should they be considered as a substitute for the professional judgment of the pharmacist or physician.
On this week's podcast, Drs.Feigenbaum and Baraki review fish oil supplementation and health. WheyRx https://www.barbellmedicine.com/shop/supplements/gainzzz-rx-whey-protein-isolate/ Resources: Case Report- https://pubmed.ncbi.nlm.nih.gov/14742793/ Atrial fibrillation- https://pubmed.ncbi.nlm.nih.gov/34612056/ Measuring n-3 levels- https://pubmed.ncbi.nlm.nih.gov/15353491/ Observational data on heart disease and fish oil- https://pubmed.ncbi.nlm.nih.gov/27357102/ ASCEND Trial- https://www.ncbi.nlm.nih.gov/pubmed/30146932?dopt=Abstract VITAL Trial- https://pubmed.ncbi.nlm.nih.gov/30415637/ REDUCE IT- https://pubmed.ncbi.nlm.nih.gov/30415628/ STRENGTH- https://pubmed.ncbi.nlm.nih.gov/33190147/ Cochrane Meta-Analysis- https://pubmed.ncbi.nlm.nih.gov/32114706/ AHA and fish oil- https://pubmed.ncbi.nlm.nih.gov/28289069/ Cancer Risk- https://pubmed.ncbi.nlm.nih.gov/22591896/ Cognitive function- https://pubmed.ncbi.nlm.nih.gov/22696350/ RA= https://pubmed.ncbi.nlm.nih.gov/22591891 Depression- https://pubmed.ncbi.nlm.nih.gov/26537796/ Bleeding- https://pubmed.ncbi.nlm.nih.gov/24472372/ Pre term labor https://pubmed.ncbi.nlm.nih.gov/26773247/ For more of our stuff: App: https://tinyurl.com/muus5pfn Podcasts: goo.gl/X4H4z8 Website: www.barbellmedicine.com Instagram: @austin_barbellmedicine @jordan_barbellmedicine @leah_barbellmedicine @vanessa_barbellmedicine @untamedstrength @derek_barbellmedicine @hassan_barbellmedicine @charlie_barbellmedicine @alex_barbellmedicine @tomcampitelli @joe_barbellmedicine @rheece_barbellmedicine @cam_barbellmedicine @claire_barbellmedicine @ben_barbellmedicine @cassi.niemann @caleb_barbellmedicine Email: info@barbellmedicine.com Supplements/Templates/Seminars: www.barbellmedicine.com/shop/ Forum: forum.barbellmedicine.com/
https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.122.059410?af=RThe Biomarkers say REDUCE-IT was a scamhttps://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2791663NO! Just NO-- stick with the calculator for nowhttps://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059038start the SLGT-2 inhibitors early! maybe an early dischargehttps://pubmed.ncbi.nlm.nih.gov/35849407/If we could get the EMR to do it automatically else you cant expect providers tohttps://pubmed.ncbi.nlm.nih.gov/35727595/the head CT for psych stuff can probably be put on holdhttps://eprints.whiterose.ac.uk/180135/continue the disease modifying agents
In this special ESC Congress episode of Eagle's Eye View, Drs. Deepak Bhatt, Payal Kohli, and Philippe Gabriel Steg discuss highlights from Day 1 of the ESC Congress 2022: late-breaking science and featured clinical research, including SECURE, ENTRIGUE, TIME, and REDUCE-IT.
In this episode, guest host Deepak Bhatt, MD, MPH, FACC, offers a preview of some of the most important and clinically transformative studies being presented at the ESC 2022 Conference, August 26-29. Day One includes: more data from the EMPEROR trial on the mechanisms and clinical benefits of SGLT2i in heart failure, the TAILOR-PCI randomized trial on genotype-guided oral P2Y12 inhibitor therapy, phase 2 data from the ENTRIGUE study on pegozafermin for the treatment of severe hypertriglyceridemia, and the results of the TIME trial on the timing of morning versus evening medication. Also on Day One, Dr. Valentine Fuster will present the results of the SECURE trial, a polypill strategy in secondary prevention. There will also be a presentation of the ASCEND study on the effects of aspirin and omega−3 fatty acid supplements on heart failure. Dr. Bhatt will present data from the REDUCE-IT trial on the significant reduction in ST-Elevation MI with icosapent ethyl. Day One will also cover the EXHAUSTION project, investigating air temperature and cardiovascular disease, as well as the ADDICT-ICCU study on carbon monoxide and acute cardiac events. Day Two will include: a presentation by Davada Perera on REVIVED, investigating percutaneous revascularization for ischemic ventricular dysfunction, ALL-HEART data on allopurinol and cardiovascular outcomes in ischemic heart disease, and a major presentation by Scott Solomon on the DELIVER trial, examining dapagliflozin in heart failure with mildly reduced and preserved ejection fraction. There will also be a number of pooled analyses on Day Two, including one looking at DAPA-HF and DELIVER, and a pre-specified meta-analysis of DELIVER and EMPEROR-Preserved. Together these studies will firmly cement the concept of the SGLT-2 inhibitors class as a heart failure medication. Day Three opens with an important presentation on INVICTUS, exploring rivaroxaban versus VKA for rheumatic atrial fibrillation. There will also be a group of presentations on some modest but significant Phase 2 trials on factor XIa inhibitor asundexian. Additionally, Renalto Lopes will present data on the APOLLO trial exploring apixaban for prophylaxis of thromboembolic outcomes in COVID-19, and the five-year data from the MOMENTUM 3 study on LVAD Therapy will be presented. On the fourth and final day, presentations include the clinical outcomes at 5 years of follow-up in the ISCHEMIA-CKD EXTEND trial, the review of the MASTERDAPT trial data at 15 months, the primary results of FOURIER-OLE, and data from the PANTHER Trial on P2Y12 inhibitor versus aspirin monotherapy in patients with coronary artery disease. ESC 2022 promises to be a rich and rewarding experience for those who can attend in person or participate virtually.
This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical Trials." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to 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. Dr. Carolyn Lam: It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials. The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we? Dr. Greg Hundley: You bet, Carolyn. And how about if I go first? Dr. Carolyn Lam: Please. Dr. Greg Hundley: So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control. Dr. Carolyn Lam: Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease. Dr. Carolyn Lam: Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age. Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart. Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls. Dr. Greg Hundley: Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find? Dr. Carolyn Lam: Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients. Dr. Greg Hundley: Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.” Dr. Carolyn Lam: There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we? Dr. Greg Hundley: You bet. Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all. And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address? Dr. Paul Ridker: Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts. The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there. In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting. Dr. Greg Hundley: Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design? Dr. Paul Ridker: We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like. What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in. And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated. It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it. Dr. Greg Hundley: Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women. Dr. Paul Ridker: No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results. Dr. Greg Hundley: Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article? Dr. Allan Jaffe: Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look. So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on. Dr. Greg Hundley: Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts? Dr. Robert Harrington: So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials? And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results. And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial. Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here. It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know. Dr. Greg Hundley: Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform? Dr. Paul Ridker: Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture? Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with. On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with. Dr. Greg Hundley: Allan, turning to you. What do you think is a next study to perform in this space? Dr. Allan Jaffe: Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial. Dr. Greg Hundley: And Bob, your thoughts. Dr. Robert Harrington: Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial." But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth. Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?" I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this. On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently. Dr. Greg Hundley: Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events. And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures. Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen. And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address? Dr. Eric Van Belle: Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population. And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device. In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease. So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure. Dr. Greg Hundley: Very nice. And Eric, can you describe for us, your study design, and who was your study population? Dr. Eric Van Belle: Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population. And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure. Dr. Greg Hundley: So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find? Dr. Eric Van Belle: So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population. But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population. Dr. Greg Hundley: Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures? Dr. Emmanouil Brilakis: Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation. I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds. Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is. Dr. Greg Hundley: Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research? Dr. Eric Van Belle: Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this. So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome. Dr. Greg Hundley: And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space? Dr. Emmanouil Brilakis: Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient. So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds. 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. Dr. Greg Hundley: 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.
A specially tailored project 'Maternal Health Education for Migrant and Refugee Women' (MHED) is aimed to increase awareness among migrant women on the delicate issue of stillbirth which is still a taboo in many cultures. The experts believe that the risk of stillbirth is higher for Aboriginal and Torres Strait Islander (ATSI), South Asian and African women. - ਮੈਟਰਨਲ ਹੈਲਥ ਐਜੂਕੇਸ਼ਨ ਫੋਰ ਮਾਈਗ੍ਰੈਂਟ ਐਂਡ ਰਿਫਿਊਜੀ ਵੂਮੈਨ ਨਾਮਕ ਇੱਕ ਵਿਸ਼ੇਸ਼ ਉਪਰਾਲਾ ਅਰੰਭਦੇ ਹੋਏ ‘ਸਟਿੱਲਬਰਥ' ਵਾਲੇ ਨਾਜ਼ੁਕ ਮੱਦੇ ਬਾਰੇ ਪ੍ਰਵਾਸੀ ਔਰਤਾਂ ਨੂੰ ਜਾਗਰੂਕ ਕੀਤਾ ਜਾ ਰਿਹਾ ਹੈ। ਅਜੇ ਵੀ ਕਈ ਭਾਈਚਾਰਿਆਂ ਵਿੱਚ ਇਸ ਮੁੱਦੇ ਨੂੰ ਵਿਚਾਰਨਾ ਵਰਜਿਤ ਹੈ।
The landmark Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT®) was a global outcomes study designed to assess the cardioprotective efficacy and safety of VASCEPA® (icosapent ethyl) as an add-on to statin therapy in reducing major cardiovascular (CV) events in a high-risk patient population. Join endocrine experts Eliot A. Brinton, MD, FAHA, FNLA, FACE, President of Utah Lipid Center, and Past President, of the American Board of Clinical Lipidology, and Betul Hatipoglu MD, Professor of Medicine at CWRU School of Medicine, and Medical Director for Diabetes & Obesity Center at University Hospital Cleveland Medical Center, to learn about the results of the REDUCE-IT® trial and new developments in CV prevention.
CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), Rick Ferraro (cardiology fellow at the Johns Hopkins Hospital), and Dr. Xiaoming Jia (Cardiology Fellow at Baylor College Medicine) take a closer look at the mechanism of icosapent ethyl in triglyceride lowering and ASCVD risk reduction with Dr. Michael Shapiro, the Fred M. Parrish professor of cardiology at Wake Forest University and Director of the Center for Preventative Cardiology at Wake Forest Baptist Health. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC). Relevant disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Icosapent Ethyl Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two major Omega-3 fatty acids found in fish oil. While both have been shown to lower triglycerides, only purified EPA formulations have been shown to reduce ASCVD risk.Mechanisms of triglyceride (TG) lowering by icosapent ethyl are multiple and include reduction of hepatic VLDL production, stimulation of lipoprotein lipase activity, increased chylomicron clearance, reduced lipogenesis, increased beta oxidation, and reduced delivery of fatty acids to the liver.There was only modest reduction of triglycerides in REDUCE-IT and JELIS despite association with significant reduction in cardiovascular outcome events, suggesting likely mechanisms outside of triglyceride lowering that may contribute to ASCVD reduction.While there was an increased signal for peripheral edema and atrial fibrillation associated with icosapent ethyl in prior trials, overall side effect rates were very low.Icosapent ethyl is considered to be cost-effective based on cost-effective analysis. Show notes - Icosapent Ethyl EPA and DHA have differing biological properties that may explain differences in ASCVD risk reduction observed in cardiovascular outcome trials 1.The REDUCE-IT trial, which enrolled secondary prevention and high-risk primary prevention patients with elevated triglycerides who were on statin therapy, showed significant reduction of major adverse cardiovascular events in the icosapent ethyl group compared with a mineral oil placebo2. Only modest reductions of TG were seen in the REDUCE-IT and JELIS trials despite association with significant reduction in events 2,3. Potential mechanisms contributing favorable effects of EPA on ASCVD risk reduction include inhibition of cholesterol crystal formation, stabilization of membrane structures, reversal of endothelial dysfunction, inhibition of lipoprotein and membrane lipid oxidation 4.Pleotropic effects of EPA include influence on platelet aggregation, lower thromboxane activity, increased prostaglandin level, and effects on blood pressure, insulin resistance and inflammation.Triglycerides are a surrogate for triglycerides-rich lipoproteins, which are likely causally associated with ASCVD 5.There is increased signal for bleeding, lower extremity edema, and atrial fibrillation with icosapent ethyl but overall side effect rates are very low 2.In order to ensure higher rates of medication access and adherence, clinicians must be cognizant of the cost to the patient. In practice, it is important to have a structured approach to improve insurance approval rate for medications that require prior authorizationsWith icosapent ethyl, cost effectiveness analyses have shown the medication is cost-effect for ASCVD risk reduction in secondary...
Host: William Boden, MD, FACC, FAHA Patients with ASCVD and a history of MI are at especially high risk for repeat adverse cardiac events. Listen in as Dr. Bill Boden summarizes a post hoc analysis of such patients from the REDUCE-IT trial. Can icosapent ethyl plus a statin provide improved carioprotection by reducing recurrent events in this population? Tune in to learn more! REDUCE-IT is a landmark trial that examined the coadministration of icosapent ethyl and statins in patients for secondary and primary prevention of recurrent events and demonstrated a significant reduction in the key primary and secondary endpoints. This discussion relates to a post hoc analysis of a subset of patients who had prior myocardial infarction, as part of the REDUCE-IT study, and comprised about 45% of the patients with established atherosclerotic coronary disease. The results of this post-MI analysis bring into clear focus that treating hypertriglyceridemia is a critical variable in terms of reducing dyslipidemic risk and overall risk.
Host: William Boden, MD, FACC, FAHA Patients with ASCVD and a history of MI are at especially high risk for repeat adverse cardiac events. Listen in as Dr. Bill Boden summarizes a post hoc analysis of such patients from the REDUCE-IT trial. Can icosapent ethyl plus a statin provide improved carioprotection by reducing recurrent events in this population? Tune in to learn more! REDUCE-IT is a landmark trial that examined the coadministration of icosapent ethyl and statins in patients for secondary and primary prevention of recurrent events and demonstrated a significant reduction in the key primary and secondary endpoints. This discussion relates to a post hoc analysis of a subset of patients who had prior myocardial infarction, as part of the REDUCE-IT study, and comprised about 45% of the patients with established atherosclerotic coronary disease. The results of this post-MI analysis bring into clear focus that treating hypertriglyceridemia is a critical variable in terms of reducing dyslipidemic risk and overall risk.
CardioNerds Tommy Das (Program Director of the CardioNerds Academy and cardiology fellow at Cleveland Clinic), Rick Ferraro (cardiology fellow at the Johns Hopkins Hospital), and Dr. Aliza Hussain (cardiology fellow at Baylor College Medicine) take a deep dive on the REDUCE-IT trial with Dr. Peter Toth, director of preventive cardiology at the CGH medical center in Sterling, Illinois, clinical professor in family and community medicine at the University of Illinois School of Medicine, and past president of the National Lipid Association and the American Board of Clinical Lipidology. Special introduction to CardioNerds Clinical Trialist Dr. Jeff Wang (Emory University). Audio editing by CardioNerds academy intern, Shivani Reddy. This episode is part of the CardioNerds Lipids Series which is a comprehensive series lead by co-chairs Dr. Rick Ferraro and Dr. Tommy Das and is developed in collaboration with the American Society For Preventive Cardiology (ASPC). Relevant disclosures: None Pearls • Notes • References • Guest Profiles • Production Team CardioNerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - REDUCE-IT The Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE-IT) trial was a large randomized controlled trial that showed a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events with use of icosapent ethyl ester in secondary prevention patients and high risk primary prevention patients with diabetes and residual elevated triglycerides between 135 to 499 mg/dL on top of maximally tolerated statin therapy1. Despite the use of high intensity statin therapy, considerable residual risk for future atherosclerotic cardiovascular disease exists in patients with ASCVD.Elevated triglycerides (TGs) are an important marker of increased residual ASCVD risk2.There are two primary types of Omega-3 fish oils: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omege-3 fish oils have been shown to lower triglyceride levels.Low-dose combination EPA and DHA has not exhibited incremental cardiovascular benefit in either primary prevention and secondary prevention patients on top of statin therapy3-5.REDUCE-IT showed the use of high dose EPA in patients with either ASCVD or DM and one additional risk factor, and relatively well-controlled LDL-C levels on maximally tolerated statin therapy and residual hypertriglyceridemia (TG 135-499 mg/dL) results in significant reductions in cardiovascular events over a median follow-up period of 4.9 years1. Show notes - REDUCE-IT Multiple epidemiologic and Mendelian randomization studies have established elevated triglyceride (TG) levels as an important risk factor for atherosclerotic cardiovascular events6-8. However previous clinical trials using TG-lowering medication such as niacin, fibrates and low dose omega-3 fish oil have not shown to reduce cardiovascular events when added to statin therapy in patients with or without ASCVD,9,10.The JELIS trial first demonstrated a significant reduction in cardiovascular events when 1.8g daily of eicosapentaenoic acid (EPA) was added to low-intensity statin therapy in patients with ASCVD and hypercholesterolemia, However, the trial was limited due to open label design without placebo, use of low doses of background statin therapy, and geographic/demographic limitations to participants in Japan11.In a large international multicenter randomized controlled trial, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) randomized 8,179 patients with established atherosclerotic heart disease or diabetes and an additional risk factor, on maximally tolerated statin therapy, to 4 gm/day of icosapent ethyl (a highly purified and stable EPA ethyl ester) or miner...
Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to 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 Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start? Dr. Greg Hundley: Very good. Dr. Carolyn Lam: Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG. Dr. Greg Hundley: Ah, Carolyn. So what did they find in this subgroup of patients? Dr. Carolyn Lam: So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery. Dr. Greg Hundley: Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go. Dr. Greg Hundley: All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery. Dr. Greg Hundley: So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection. Dr. Carolyn Lam: Wow, fascinating. So what did today's paper find? Dr. Greg Hundley: Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper? Dr. Carolyn Lam: Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right? Dr. Greg Hundley: Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn. Dr. Carolyn Lam: Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs. Dr. Carolyn Lam: The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation. Dr. Carolyn Lam: But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit. Dr. Greg Hundley: Okay. Carolyn, what a beautiful summary here. So what's the take home message here? Dr. Carolyn Lam: So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases. Dr. Carolyn Lam: Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention. Dr. Greg Hundley: Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study? Dr. Carolyn Lam: Let's go, Greg. Dr. Mercedes Carnethon: Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization. Dr. Mercedes Carnethon: And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you. Professor Gregory Lip: Hello there. Dr. Connie Hess: Thank you for having me. Dr. Mercedes Carnethon: Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study? Dr. Connie Hess: Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about. Dr. Connie Hess: And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI. Dr. Connie Hess: And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. Dr. Connie Hess: And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out. Dr. Connie Hess: And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction. Dr. Connie Hess: Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication. Dr. Mercedes Carnethon: All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind? Professor Gregory Lip: Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes. Professor Gregory Lip: So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding. Professor Gregory Lip: We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well. Dr. Mercedes Carnethon: Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study? Dr. Connie Hess: Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt. Dr. Connie Hess: I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic. Dr. Connie Hess: A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it. Dr. Connie Hess: I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy. Dr. Mercedes Carnethon: I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal. Dr. Mercedes Carnethon: This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. 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.
Please join first author Cecilia Bahit and Associate Editor Graeme Hankey as they discuss the article "Predictors of Development of Atrial Fibrillation in Patients With Embolic Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to 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 and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to analyze the RE-SPECT ESUS trial. What does that pertain to? Well, you're going to have to wait and find out, but it relates to atrial fibrillation and embolic stroke. But before we get to that, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I sure would. Greg, we know that Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease or diabetes. The question is: What are the effects of Icosapent Ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes from the REDUCE-IT trial? Dr. Greg Hundley: Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What did it encompass there? Dr. Carolyn Lam: The REDUCE-IT trial was a multicenter double-blind, placebo-controlled trial that randomized statin treated patients with elevated triglycerides, who had cardiovascular disease or diabetes, and one additional risk factor, two treatment with icosapent ethyl at 4g daily versus placebo. After a median follow up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina. Dr. Greg Hundley: Ah, great summary of the original paper, but now this is sort of a follow-up paper. What did this paper research? Dr. Carolyn Lam: Well first, remember they focused on renal function and the median baseline GFR was 75 ml/min with a range of 17 to 123 mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent reduction in both primary and secondary composite endpoints across the baseline GFR categories. Patients with the GFR >60 treated with Icosapent Ethyl had the largest absolute, but similar relative risk reduction for the primary composite endpoint. And while patients with GFR >60 treated with Icosapent Ethyl had the highest numerical rates of atrial fibrillation of flutter and serious bleeding. The hazard ratios for atrial fibrillation flutter and serious bleeding were similar across GFR categories. In summary Icosapent Ethyl reduced cardiovascular events among patients with elevated triglycerides in a well-controlled LDL on statin therapy across a wide range of baseline renal function. Dr. Greg Hundley: Oh, Carolyn. Beautiful presentation. That presentation was so good that I know you are ready for a quiz. We haven't had Carolyn's quiz in a week, so we've got to get right back to that. Dr. Carolyn Lam: No, we don't (laughs). Dr. Greg Hundley: Can you describe the primary sequelae of Hutchinson-Gilford progeria syndrome? Dr. Carolyn Lam: Oh wow. Okay. So this is the syndrome where there's premature aging, there's a lot of vascular stiffening, calcification. I'm going to guess some sort of atherosclerotic consequence (laughs). Dr. Greg Hundley: Very nicely done Carolyn. Oh my goodness. I need to get you to take my ABIM recertification- Dr. Carolyn Lam: (laughing) Dr. Greg Hundley: Beautifully done. So Carolyn, this paper comes to us from Dr. Vicente Andrés from Centro Nacional De Investigaciones Cardiovasculares Carlos III, and Hutchinson-Gilford progeria syndrome is a rare disorder characterized, just like you said, Carolyn by premature aging and death, mainly due to myocardial infarction, stroke or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Carolyn, these patients look healthy at birth and symptoms typically emerge in the first or second year of life. In assessing the reversibility of progerin induced damage, and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. Dr. Carolyn Lam: Wow, you've really, really piqued my interest. So what did these investigators do and what did they find? Dr. Greg Hundley: Oh Carolyn, very clever design. So the authors use CRISPR-Cas9 technology to generate mice engineers to ubiquitously express progerin while lacking lain A and allowing progestin suppression in lain A restoration in a time and cell type specific manner upon CRE recombinase activation. They characterize the phenotype of these engineered mice and cross them with CRE transgenic lines to assess the effects of suppressing progestin and restoring lain A ubiquitously at different disease stages, as well as specifically in vascular smooth muscle cells and cardiomyocytes. So Carolyn, what did they find? Well, number one, like Hutchinson-Milford progenia syndrome patients, their engineered mice appeared healthy at birth, and progressively developed Hutchinson-Milford progenia syndrome symptoms, including failure to thrive, Lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electric cardiographic anomalies and early death. Their median lifespan was 15 months versus 26 months in the wild types. Dr. Greg Hundley: Second, ubiquitous progestin suppression in lain A restoration significantly extended lifespan, when induced in six month old, mildly symptomatic mice, and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon the early intervention. And then finally, Carolyn remarkably major vascular alterations were prevented and lifespan normalized in engineered Hutchinson-Milford progenia syndrome mice when progestin suppression and lain A restoration were restricted to: just Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Wow, just fascinating, but, okay. What is the clinical take home message? Dr. Greg Hundley: Right, Carolyn. So these authors findings suggest that it is never too late to treat Hutchinson-Milford progenia syndrome, although the benefit is much more pronounced when progestin is targeted early in mice with mild symptoms. Also, restricting its suppression to Vascular smooth muscle cells in Cardiomyocytes is sufficient to prevent Vascular disease and normalize lifespan in mice, and therefore these data suggest that strategies to treat Hutchinson-Milford progenia syndrome through gene therapy or RNA therapy should consider targeting Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Oh wow. Very, very cool. Well, my next paper is a basic science paper that's significant for both its methods and its results. Dr. Greg Hundley: Oh wow, Carolyn, I can't wait. So tell us about this novel methodology. Dr. Carolyn Lam: Well, this paper is from Dr. Chang from Westlake University in Hangzhou, China, and colleagues who use a gene editing approach to efficiently institute Exon Skipping without introducing DNA double-strand breaks. So harnessing a fusion of a nuclease defective Case protein, and a cytidine deaminase, which is, we're going to abbreviate it as Targeted AID-induced mutagenesis (TAM) or base editor three (BE3), their approach precisely edited conserved guanines at splice sites, thus abrogating Exon recognition resulting in a programmable skipping of the targeted Exons. Isn't that neat? Dr. Greg Hundley: Yeah, it really is sophisticated Carolyn, wow. So what did they do using these methods? Dr. Carolyn Lam: A novel mirroring model of Duchenne muscular dystrophy was generated, which recapitulated many cardiac defects observed in the human form of the disease, including dilated cardiomyopathy, reduced left ventricular function and extensive cardiac fibrosis. Using this model, they examined the feasibility of using a cytidine base editor to install Exon Skipping and rescue the dystrophic cardiomyopathy in vivo. A single dose administration of an Adenovirus 9EtAm, instituted over 50% targeted Exon Skipping in the Chengdu muscular dystrophy transcripts and restored up to 90% dystrophin in the heart. And as a result, early ventricular remodeling was prevented and cardiac and skeletal muscle function were improved, leading to an increased lifespan of the mice. Despite gradual decline of the Adenovirus vector and base editor expression, the dystrophin restoration and pathophysiological rescue of muscular dystrophy lasted for at least a year. And so this technique really has the potential to be applied to monogenic human diseases, to modulate Exon Skipping or inclusion. Isn't that cool? Dr. Greg Hundley: Absolutely, Carolyn. Beautifully explained. Dr. Carolyn Lam: Well, let me end by sharing what else is in today's issue. There's a Perspective piece by Dr. Alexander on “Chest Pain Redux: Updated and Patient Centered.” There is an In Depth paper by Dr. Kroemer on NAD plus metabolism in cardiac health, aging and disease. And there's a Research Letter by Dr. Shepherd on sudden death in female athletes, with insights from a large regional registry in the United Kingdom. Dr. Greg Hundley: Very good, Carolyn. What a great issue. Now, how about we get to that feature discussion? Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Welcome listeners to our feature discussion today on this November 30th. And we have with us Dr. Cecilia Bahit from Rosario, Argentina and our own associate editor, Dr. Graeme Hankey from Perth, Australia to talk to us about a paper pertaining to Atrial Fibrillation. Welcome to you both, and Cecilia, we'll start with you. Could you describe for us a little bit of the background information that went into formulating your study, and then what hypothesis did you want to address? Dr. Cecilia Bahit: Thank you for the invitation. So we all know that embolic stroke of undetermined source, which is called ESUS isn't just a subset of cryptogenic stroke, and is associated with stroke recurrence about 3-6% per year. And on the other hand, we know that continuous cardiac monitoring in this patient population shows that atrial fibrillation can be detected between 10% at six months or 30% at three years. So the underlying atrial fibrillation may be a mechanism for the recurrent thromboembolic stroke in this patient population. So we know that prior studies have identified some predictors of atrial fibrillation in these patients. And if we are able to identify which patients could benefit from cardiac monitoring and have a higher yield to detect atrial fibrillation, we could do a better job at treating them. So, that was our idea behind the paper. So using the RE-SPECT ESUS trial, which was a trial that included patient with ESUS stroke and were randomized to the bigger trend versus Aspirin, we look at predictors of atrial fibrillation unassociated regarding stroke. Dr. Greg Hundley: Very nice. And so, now was this a sub-study here and maybe define for us a little bit, your study design and specific study population. Dr. Cecilia Bahit: So this was a secondary analysis of a randomized clinical trial that as mentioned it was not a sub-study, it was a secondary analysis. We thought all along to do it because of the interest of the clinical question. We look at the total patient population was 5,390 patients. And we looked at those patients who developed atrial fibrillation during the 19 months of follow-up. And it was 7.5%, 403 patients developed atrial fibrillation. Dr. Greg Hundley: Very good. And what were your results? Dr. Cecilia Bahit: So, as I mentioned, we saw that 7.5% of our patient population developed atrial fibrillation during the follow-up. And we know those patients were older, were like, have higher morbidities, and we assessed, we did an one variable analysis and then a multi-variable analysis, trying to identify predictors for atrial fibrillation. And for our model, we identified different predictors, older age, hypertension, lack of diabetes, and higher body mass index, were independent predictors of atrial fibrillation. So the patients who have atrial fibrillation have a higher recurrence of stroke, it was 7.2 versus four, compared to those that did not have atrial fibrillation. Dr. Cecilia Bahit: So I think there's an important part, that 20% of the patient population of the overall trial, this is a little more than a thousand patients, had NT-prob measure at baseline. And when we included this biomarker into the model, only older age and NT-prob were independent predictors of atrial fibrillation. In addition, even though this was not the objective of this analysis, we look at the treatment effect of the bigger trend. And even though we saw that there was a statistical benefit of the bigger trend versus Aspirin in the higher group of these in our score, the overall treatment effect was not there. So we couldn't assess the fact that the bigger trend was better compared to Aspirin in patient with atrial fibrillation, but of course the numbers were very small. Dr. Greg Hundley: Very good. Thank you so much for that wonderful description. And Graeae, now we'll turn to you as associate editor for us at Circulation, and also the editorialist on this particular paper. What caught your attention about this particular study and the results from the many papers that really come across your desk. Dr. Graeme Hankey: Thank you, Greg. And congratulations to Cecilia and her RE-SPECT ESUS colleagues. I mean, this is a landmark study, the RE-SPECT ESUS study, and just to go back, embolic stroke of undetermined source is really common. About one in four ischemic strokes, we don't know the cause of, and it's one of the major subtypes of cryptogenic stroke is an embolic ischemic stroke in which the source could have come from the heart or the aortic arch or the carotids. And we're not really sure. And we think that some of these patients have occult atrial fibrillation, but we can't pick it up at the time. So one way is to try and monitor them with prolonged ECG monitoring. And another way is to actually treat them with anticoagulation because we know that, that's more effective in people with cardio embolic stroke. And so RE-SPECT ESUS and NAVIGATE ESUS used the latter strategy and said, let's see if treating people with ESUS with anticoagulation is more effective than antiplatelet therapy. Dr. Graeme Hankey: And both studies were not significant in terms of showing that Dabigatran or Parovarian for NAVIGATE ESUS was more effective than antiplatelet therapy. So we're left now with this default that all patients with ESUS just get Aspirin, but we have a hunch that some of them actually have cardiogenic embolism and are being undertreated with Aspirin and need anticoagulation. So it's a heterogeneous entity, but we're treating it homogeneously with a sort of weak antiplatelet. So we want to try and find out who's going to get AF or who's already got it that is occult. And this study is a really great and prospective study with 5,000 patients as Cecilia said, who of whom 7% did develop AF just through annual ECG reporting and just with symptom reporting. And that's probably an under report. You know, if they'd had monitoring, they probably would've found about 20 or 30% would've developed AF during that time of 19 months follow up. Dr. Graeme Hankey: And it's the first study to really then show that not just the AF people had a higher stroke rate, but in that group who they predicted to be at high risk of AF with older age and the NT-prob, that the high risk group had a significant reduction with Dabigatran versus Aspirin in that high risk group. It's just, when you look for hetero homogeneity or heterogeneity across the risk groups, it wasn't quite significant. And that might be because it's not significant or it might be that study was underpowered to look at those three, across those three risk subgroups. And also it might be a bit confounded because of it, the patients weren't randomized according to their risk status for AF, they were just randomized, whether they had ESUS, so it's further excited us that there might be a subgroup who needs anticoagulation. And that's why the ARCADIA trial is ongoing now, looking at where the people with ESUS who have high risk of AF benefit from a apixaban versus aspirin. Dr. Greg Hundley: Very nice. And so, with these results that we have here, maybe come back to Cecilia, what do you think would be the next series of studies that needs to be performed in this area of research? Dr. Cecilia Bahit: Well, there's one side that's ongoing as Dr. Hankie mentioned, but I think we should be able to identify which patients have a higher risk of atrial fibrillation and those patients who use cardiac monitoring for long term to identify atrial fibrillation and to treat properly. So I think that would be key in this area. Dr. Greg Hundley: Very nice. And Graeae, what are your thoughts? Dr. Graeme Hankey: Yes. Well, one way is to have our ESUS patients have prolonged ECG monitoring by implantable loop recorders, for example, and then those who develop AF randomizing them to anticoagulation versus antiplatelet therapy. Although if they declare themselves with AF they're usually just go straight onto anticoagulation therapy. So the burning question is, in these people with ESUS who haven't declared themselves as AF, but have predictors of AF like those shown in RESPECT ESUS, like older age, high blood pressure, high BMI ,prob, and perhaps echo features, like left atrial size or ECG features like lots of premature atrial contractions or P wave of abnormalities. Dr. Graeme Hankey: Are these, the subgroups or even LV dysfunction, are these subgroups who need to be more specifically targeted in a randomized trial rather than the whole group of ESUS. And also with longer follow up. NAVIGATE ESUS stopped after 11 months. The bigger RESPECT ESUS stopped after a median follow up of 16 months and the curves were diverging. Maybe with five years follow up, a lot of these people would've developed AF and would've benefited from longer term anticoagulation, but the trials were stopped early, because there wasn't a signal of benefit and there was an early risk of bleeding with anticoagulation. Dr. Greg Hundley: Very good. Well listeners, this has been a really interesting study and we want to thank Cecilia and Graeme for sharing results of the RESPECT ESUS study, highlighting that, in patients with embolic stroke of undetermined source, atrial fibrillation occurs and is a possible source of this stroke, and then also older age, and elevation of NT-prob can be associated with development of atrial fibrillation, subsequent to that stroke event. Dr. Greg Hundley: Well listeners, we want to wish you a great week. And on behalf of Carolyn and myself, look forward to catching you next week on The Run. This program is copyright of the American Heart Association, 2021. 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.
CME credits: 0.25 Valid until: 26-07-2022 Claim your CME credit at https://reachmd.com/programs/cme/clinicians-update-omega-3s-ascvd-risk-reduction/12718/ More than 15 professional societies now recommend the use of icosapent ethyl to treat atherosclerotic cardiovascular disease (ASCVD), but clinical questions about the use of omega-3 fatty acids remain. Dr. Leslie Cho and Dr. Erin Michos discuss the role of DHA and EPA and whether all omega-3 fatty acids are the same. But what about EPA plasma levels, incidence of atrial fibrillation, and differences between the STRENGTH and REDUCE-IT trials? Tune in to get these answers and more!
CME credits: 0.25 Valid until: 26-07-2022 Claim your CME credit at https://reachmd.com/programs/cme/clinicians-update-omega-3s-ascvd-risk-reduction/12718/ More than 15 professional societies now recommend the use of icosapent ethyl to treat atherosclerotic cardiovascular disease (ASCVD), but clinical questions about the use of omega-3 fatty acids remain. Dr. Leslie Cho and Dr. Erin Michos discuss the role of DHA and EPA and whether all omega-3 fatty acids are the same. But what about EPA plasma levels, incidence of atrial fibrillation, and differences between the STRENGTH and REDUCE-IT trials? Tune in to get these answers and more!
Join CardioNerds for a great discussion about key ACC 2021 Prevention highlights featuring the ADAPTABLE and STRENGTH trials. This episode is produced in collaboration with the American College of Cardiology Prevention of Cardiovascular Disease Council with mentorship from the Council's Chair Dr. Eugene Yang (University of Washington Medical Center) who provides a message at the end of the episode. First, Dr. Amit Goyal and Council Representative Dr. Mahmoud Al Rifai (FIT, Baylor College of Medicine) discuss the implications of the ADAPTABLE Trial with Dr. Gina Lundberg (Emory University School of Medicine). Then Dr. Tommy Das (FIT, Cleveland Clinic), Dr. Rick Ferraro (FIT, Johns Hopkins) and Council Representative Dr. Anum Saeed (FIT, University of Pittsburgh Medical Center) discuss the results of the STRENGTH trial's secondary analysis with Dr. Steven Nissen (Cleveland Clinic). Disclosures: Dr Nissen reported grants from AstraZeneca during the conduct of the STRENGTH trial Cardionerds Cardiovascular Prevention PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll Subscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes ADAPTABLE Trial The ADAPTABLE trial is a randomized open label pragmatic trial comparing two doses of aspirin (325 mg vs. 81 mg) for the secondary prevention of cardiovascular disease. The trial employed a range of innovative and low-cost methods to simplify the identification, recruitment, and follow-up of patients. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety outcome was hospitalization for major bleeding. A total of 15,076 patients were followed for a median of 26.2 months. The primary effectiveness and safety outcomes were not significantly different between the two groups. Together with Dr. Lundberg we discuss design and methodological issues related to the trial and applicability to clinical practice. ASA 81 mg is as effective as ASA 325 mg for reducing cardiovascular events ASA 325 mg does not cause more bleeding episodes than ASA 81 mg ASA dosing should be based on a clinician-patient risk discussion incorporating patients' risk profile and their values and preferences Future trials should ensure adequate representation of women and race/ethnic minorities The results of the present trial suggest that either dose of ASA (81 mg or 325 mg) would be adequate to lower patients' risk of death or atherosclerotic cardiovascular events with similar risk of bleeding. ASA dosing should be based on patient values and preferences and clinician judgement as the effectiveness and safety profile of these two regiments appears to be equivalent on the basis of the present trial. STRENGTH Trial, Secondary Analysis Whether omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk has been long debated. Data have largely remained inconclusive with several previous trials, particularly the VITAL and ASCEND, showing no significant cardiovascular benefit DHA and EPA supplementation. However, the REDUCE-IT and the JELIS trials showed cardiovascular benefit with higher dose of purified EPA compared to placebo. Meanwhile, the STRENGTH trial did not show any difference in CVD outcomes in treatment groups using a combined EPA/DHA formulation. In this episode, we discuss a secondary anaylsis from the STRENGTH trial entitled “Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk” presented at the ACC 2021 addressing the effects of carboxylic acid formulation of EPA/DHA (omega-3 CA) compared with placebo among patients with dyslipidemia and high cardiovascular risk. This analysis showed that there was no added clinical benefit or harm i...
CME credits: 0.25 Valid until: 28-05-2022 Claim your CME credit at https://reachmd.com/programs/cme/understanding-differences-between-strength-and-reduce-it-omega-3-fatty-acid-clinical-trials-and-epadha/12618/ In 2019, the REDUCE-IT trial studying eicosapentaenoic acid (EPA), a purified form of omega-3 fatty acid, was published and demonstrated a dramatic 25% reduction in major cardiovascular events. In 2020, the STRENGTH trial that used a carboxylic acid formulation of combined EPA and docosahexaenoic acid (DHA), was surprisingly neutral and the study was halted for futility. A recent post hoc analysis of the STRENGTH study failed to show a difference in the primary endpoint in the highest tertile group receiving the EPA/DHA carboxylic acid treatment. Why did these two major omega-3 clinical trials studying patients with elevated triglyceride levels have disparate results? What does this mean for our patients? Join two experts, Drs. Michael Miller and Brian Olshansky, as they assess the different trials and offer their perspective on the clinical and scientific implications of the results.
CME credits: 0.25 Valid until: 28-05-2022 Claim your CME credit at https://reachmd.com/programs/cme/understanding-differences-between-strength-and-reduce-it-omega-3-fatty-acid-clinical-trials-and-epadha/12618/ In 2019, the REDUCE-IT trial studying eicosapentaenoic acid (EPA), a purified form of omega-3 fatty acid, was published and demonstrated a dramatic 25% reduction in major cardiovascular events. In 2020, the STRENGTH trial that used a carboxylic acid formulation of combined EPA and docosahexaenoic acid (DHA), was surprisingly neutral and the study was halted for futility. A recent post hoc analysis of the STRENGTH study failed to show a difference in the primary endpoint in the highest tertile group receiving the EPA/DHA carboxylic acid treatment. Why did these two major omega-3 clinical trials studying patients with elevated triglyceride levels have disparate results? What does this mean for our patients? Join two experts, Drs. Michael Miller and Brian Olshansky, as they assess the different trials and offer their perspective on the clinical and scientific implications of the results. Driplids; image courtesy of C. Michael Gibson, who describes this work as representing plaque regression
Drive with Dr. Peter Attia Podcast Notes Key Takeaways The brain is an electrical system that uses lipids to facilitate firing but uses glucose for energyThe brain prefers glucose as the predominant source of energy via GLUT1; the rest of the body uses GLUT4 (insulin-regulated transporter)The brain does its best to regulate glucose content, not dependent on insulin signalingWhen glucose is not available, the brain extracts all ketone bodies from fatty acids outside the brain to maintain itself Historically, ApoE4 was associated with better outcomes prenatally and against parasite and disease – that changed as more movement, interbreeding, and dietary challenges took place“If you have two copies of ApoE4, your chance of getting Alzheimer’s disease increases 12-fold. If you have one copy of ApoE4 your chance of getting Alzheimer’s increase 2-4 fold” – Dr. Hussein YassineUnlike ApoA or ApoB you can’t make an assumption about the function of ApoE based on its concentrationAncestral diets rich with meat supported richness of ApoE4 – moving to a plant-based diet, increase in carbs supported ApoE 2 and ApoE 3 because they support GLUT1 expressionWe rely on diet to get omega-3s: the human body doesn’t have an efficient system to make EPA and DHA“Omega-3 fatty acids are important for the brain, we can’t make them efficiently, and we’re not consuming enough of them.” – Dr. Hussein YassineThere isn’t enough evidence to suggest supplementing with omega-3s but there is enough to suggest eating one serving of fatty fish per weekRead the full notes @ podcastnotes.org Hussein Yassine is a physician and researcher who studies brain lipid utilization in the context of finding preventative measures for cognitive impairment, specifically Alzheimer’s disease (AD). In my conversation with Hussein, we begin with a fundamental coursework in brain biology—including its architecture and energy systems. We go on to discuss what these systems look like when something goes wrong and cognitive decline ensues. We talk about the evolutionary origins of the ApoE genotype, with specific attention to the ApoE4 allele and its association with AD. We spend time discussing ApoE4 implications for the brain’s fuel utilization, notably omega-3 fatty acids: EPA and DHA. We briefly pivot to the implications of recent omega-3 trials for cardiovascular disease and return to what we currently understand about EPA/DHA and brain health; we contemplate potential dietary interventions across the lifespan to preserve and prolong cognitive function. We discuss: Hussein’s Background and introduction to brain composition (3:00); The blood-brain barrier and brain filtration (8:00); Lipids and brain function (13:00); How the brain utilizes energy (18:00); Apolipoprotein E (ApoE) structure and function in the periphery (27:30); ApoE function in the brain (38:15); Evolutionary origins of ApoE isoforms (43:45); ApoE4 variant and Alzheimer’s disease (AD) risk (53:30); Dietary fuel preference with the ApoE4 allele (1:03:00); The role of omega-3 fatty acids in the brain (1:13:30); Comparing findings from the REDUCE-IT and STRENGTH trial (1:21:45): The relationship between dietary omega-3 intake and brain health (1:34:15); Preventing cognitive decline: A critical window for DHA in ApoE4 carriers? (1:42:30); Hussein’s ongoing research and recommendations for E4 carriers (1:54:00); and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/HusseinYassine Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.
Hussein Yassine is a physician and researcher who studies brain lipid utilization in the context of finding preventative measures for cognitive impairment, specifically Alzheimer’s disease (AD). In my conversation with Hussein, we begin with a fundamental coursework in brain biology—including its architecture and energy systems. We go on to discuss what these systems look like when something goes wrong and cognitive decline ensues. We talk about the evolutionary origins of the ApoE genotype, with specific attention to the ApoE4 allele and its association with AD. We spend time discussing ApoE4 implications for the brain’s fuel utilization, notably omega-3 fatty acids: EPA and DHA. We briefly pivot to the implications of recent omega-3 trials for cardiovascular disease and return to what we currently understand about EPA/DHA and brain health; we contemplate potential dietary interventions across the lifespan to preserve and prolong cognitive function. We discuss: Hussein’s Background and introduction to brain composition (3:00); The blood-brain barrier and brain filtration (8:00); Lipids and brain function (13:00); How the brain utilizes energy (18:00); Apolipoprotein E (ApoE) structure and function in the periphery (27:30); ApoE function in the brain (38:15); Evolutionary origins of ApoE isoforms (43:45); ApoE4 variant and Alzheimer’s disease (AD) risk (53:30); Dietary fuel preference with the ApoE4 allele (1:03:00); The role of omega-3 fatty acids in the brain (1:13:30); Comparing findings from the REDUCE-IT and STRENGTH trial (1:21:45): The relationship between dietary omega-3 intake and brain health (1:34:15); Preventing cognitive decline: A critical window for DHA in ApoE4 carriers? (1:42:30); Hussein’s ongoing research and recommendations for E4 carriers (1:54:00); and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/HusseinYassine Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.
In the first Parallax episode of 2021, Ankur welcomed back Sukh Nijjer from Imperial College London to review the most impactful events and advances in cardiology from 2020. In the first part of the episode, Ankur and Sukh focus on the mechanism of the coronavirus and its effects on the heart including clotting abnormality and troponin elevation. They discuss their clinical experiences and observations within the UK and US settings in light of the latest data. Sukh offers practical tips on how to approach patient management during this pandemic. Following this, Ankur and Sukh analyse the controversial STRENGHT study in light of the results from REDUCE-IT. They discuss the different attitudes toward early cryoablation therapy in the context of STOP AF and EARLY-AF studies. Sukh reviews the findings of the RHAPSODY Phase 3 trial and the revolution of SGLT2 inhibitors in the treatment of heart failure. Which COVID19 patients require risk stratification with a stress test? What are the take-home messages for physicians taking care of patients diagnosed with COVID19? What were the key trials of 2020? What can we learn from the negative results of the STRENGHT study? How have studies like STOP-AF influenced clinical practice?
New in 2021, we will feature 2 Feature Discussions every other week. For this week, we start with author Michael Gold and editorialist Sana Al-Khatib as they discuss the article "Primary Results from the Understanding Outcomes with the S-ICD in Primary Prevention Patients with Low Ejection Fraction (UNTOUCHED) Trial." Then, we switch to an important discussion about children and COVID-19 as author Israel Valverde and Associate Editor Gerald Greil discuss "Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated with COVID-19 Infection in Europe." TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to 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. Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we have two features in this issue. Dr. Carolyn Lam: I know. Greg Hundley: Yeah. And I've got the first one. It's going to be evaluating the acute cardiovascular manifestations in 286 children with multi-system inflammatory syndrome. Dr. Carolyn Lam: Wow. That is so important in the current pandemic. Well, the other is also so important. It's really, really critical results from the subcutaneous ICD trial called UNTOUCHED. I think that one might change clinical practice. So, do you want to tell us about other papers first? Greg Hundley: Yes. Carolyn, I'm going to grab my cup of coffee and we'll get started and my first paper comes from China. Professor Junbo Ge. So Carolyn PCSK9, mainly secreted by the liver and released into the blood elevates plasma load density lipoprotein cholesterol by degrading LDL receptors. Pleiotropic effects of PCSK9 beyond lipid metabolism have been shown. However, the direct effects of PCSK9 on platelet activation and thrombosis, as well as the underlying mechanisms still remain unclear. Greg Hundley: So this group detected the direct effects of PCSK9 on agonist-induced platelet aggregation, dense granule ATP release, integrin a2b beta-3 activation, alpha granule release, spreading and clot retraction. They also investigated the underlying mechanisms. Using myocardial infarct models, they explored the effects of PCSK9 on microvascular obstruction and infarct expansion, post myocardial infarction. Dr. Carolyn Lam: Oh, nice. And what did they find? Greg Hundley: Well, Carolyn, PCSK9 in plasma directly enhances platelet activation and in vivo thrombosis, as well as myocardial infarct expansion post MI by binding to platelet CD36 and thus activating the downstream signaling pathways. PCSK9 inhibitors, or aspirin, abolished the enhancing effects of PCSK9 supporting the use of aspirin in patients with high plasma PCSK9 levels in addition to PCSK9 inhibitors to prevent thrombotic complications. Dr. Carolyn Lam: Wow. Very interesting. Indeed, the pleiotropic effects. Well guess what? My paper talks about the first non-LDL lowering treatment that has been shown to reduce CABG in a blinded randomized trial. Greg, can you guess what that treatment was? Well, here's a hint, here's a hint. It's the REDUCE-IT trial. Greg Hundley: Well, Carolyn, thanks for the hint. It must be icosapent ethyl. Dr. Carolyn Lam: Indeed, indeed. As a reminder, REDUCE-IT was a multicenter double-blind placebo controlled trial, which randomized statin treated patients with elevated triglycerides, controlled LDL and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl at four grams daily or placebo. The primary and secondary composite end points were significantly reduced. The current paper examined all coronary revascularizations, recurrent revascularizations and revascularization subtypes. First revascularizations were reduced by icosapent ethyl versus placebo with a hazard ratio of 0.66, which is a number needed to treat of only 24. Similar reductions were observed in total revascularizations and across elective, urgent and emergent revascularizations. Icosapent ethyl significantly reduced PCI and CABG with a hazard ratio of 0.61. So, icosapent ethyl reduce first and total coronary revascularization, including PCI and CABG in patients with elevated triglycerides and high cardiovascular risk despite well controlled LDL. Isn't that cool? Greg Hundley: Very nice Carolyn. Well, my next paper comes from Professor Kari Alitalo, from the University of Helsinki. So Carolyn recent discoveries have indicated that in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. The author set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B or VEGF-B in the heart and the effect of VEGF-B on recovery from myocardial infarction. Dr. Carolyn Lam: So what were their results? Greg Hundley: Well Carolyn, the myocardial VEGF-B trans-gene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in sub-endocardial myocardium in adult mice and structural and functional rescue of cardiac tissue after myocardial infarction. So VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue. Well, Carolyn that's all of the main articles. How about we turn to some of the other articles and letters in the issue? Dr. Carolyn Lam: Yeah. Why not? And Greg, let me start by talking about an exchange of letters between Dr. Wei and Dr. Fox on interpreting the net clinical benefit from rivaroxaban plus aspirin versus aspirin for chronic vascular disease. There's also an ECG challenge by Dr. Patel elusively entitled, A Rainy Day. Here's a hint, it's about hypothermia. In cardiology news by Bridget Kuhn. She talks about how the pandemic throws cardiovascular trials off course, there is an On My Mind paper by Dr. Most entitled, The Striking Similarities of Multi-system Inflammatory Syndrome in Children and a Myocarditis-like Syndrome in Adults: The overlapping manifestations of COVID-19. As a couple of Research Letters, one by Dr. Malhotra on Defining the Normal Spectrum of Electrocardiographic and Left Ventricular Adaptations in Mixed Race, Male, Adolescent Soccer Players, as well as by Dr. Qi on adherence to a healthy sleep pattern and incident heart failure, a prospective study of more than 400,000 UK Biobank participants. Dr. Greg Hundley: Very nice Carolyn. Well, I've got a primmer review of Cardiac Involvement in Multi-system Inflammatory Syndrome in Children with the corresponding author being Dr. Kevin Freedman. Well, how about we get off quickly to those next two feature discussions? Dr. Carolyn Lam: Yay! Let's go, Greg. Dr. Greg Hundley: Well, listeners, we are to the first of our double feature for the new year 2021. And with me is Israel Valverde from King's College in London and our own associate editor, Dr. Gerald Greil from UT Southwestern in Dallas. Welcome gentlemen. And as we get started Israel, could you tell us a little bit about the background that framed this study and the hypothesis that you wanted to address? Dr. Israel Valverde: Thank you. I mean, the main problem we had in Europe around April 2020, was that both the Center for Disease Control and Prevention in the U.S. simulated a clinical ALIT about a newly described immune disease and inflammatory syndrome in children associated with a COVID infection. And there were similarities with all the well-known syndromes, such as viral myocarditis, Kawasaki disease, Kawasaki shock syndrome, and toxic shock syndrome, that we were a bit of confused, because of the overlap in clinical presentation, because it was a true diagnostics challenge. So the hypothesis in this study is we wanted to describe the cardiovascular implications in this newly described sinus syndrome. Dr. Greg Hundley: Very nice. So tell us a little bit about your study design and what study population did you assemble to address this question? Dr. Israel Valverde: I think that was the most difficult thing in the study, because thanks to the Association For European Pediatric Cardiology, the APC, we coordinated a multicenter study involving all they would appear on centers that we were 55 centers from 17 countries all over Europe. And we were able to recruit 286 children with this new newly described syndrome and cardiovascular manifestations. Dr. Greg Hundley: And tell us, what did you find? Dr. Israel Valverde: I think we can summarize that in three main findings. First is that cardiac involvement is very common in children with multi-system inflammatory syndrome associated with coronavirus disease, 2019 infection. Second, that inflammatory markers were significantly raised in most children, particularly their C-reactive protein, ferritin, pro-calcitonin, N-terminal pro BNP natriuretic peptide, interleukin 6, and D-dimer level. And finally, that 65% of patient with MIS-C had evidence of previous infection with severe acute respiratory syndrome coronavirus too, either by PCR, immunoglobulin M or immunoglobulin G. Dr. Greg Hundley: Were there any particular aspects of your results that may have segregated to the boys versus the girls? Dr. Israel Valverde: Not really. We couldn't find any differences between boys and girls, because our study population was quite similar, but we couldn't find any differences between them. What we found is that there is a huge difference between children and adults. Dr. Greg Hundley: And what was the age range of these children? Dr. Israel Valverde: From a couple of weeks, until 18 years old. Dr. Greg Hundley: And no differences in the scope of the syndrome that they experienced in the younger children versus the- Dr. Israel Valverde: Initially we found two peaks. Similarly to the peaks of viral myocarditises, which is affecting more of the children below two years, and also adolescence. Dr. Greg Hundley: Well Gerald, multi-system inflammatory syndrome in children. How to results from this study compare with perhaps other inflammatory disease processes that have been observed in children, such as Kawasaki disease, et cetera. Dr. Gerald Greil: So we and Circulation were very lucky to get a bunch of submissions regarding a MIS-C and also have a radio article regarding this and I would like to point our readers towards that. I think the key issue is it's a new disease entity. The community is pretty clear about it, that other diseases like Kawasaki disease have similarities, but it's not the same thing. And we wanted to be very clear about this. Obviously, more things need to be investigated, but the key findings where Dr. Valverde pointed out in other study groups within the U.S. and within Europe, all point to the same direction, that is a new entity, we need to further investigate. Dr. Greg Hundley: How about the cardiovascular aspects, what differences in cardiovascular disease with this syndrome, again, relative to other perhaps inflammatory diseases that might affect the heart in children? Dr. Gerald Greil: As far as we know. And once again, when we're talking about a very preliminary data, is that the outcome in children having MIS-C usually good. Dr. Valverde pointed out in his study series of more of 286 children, there was only one death and recovery was pretty high rate. We have similar findings from U.S. groups, other findings from a group in Paris and Europe. So, I would like to point our readers to other summaries where it's pretty clear that it's a new disease entity. Overall, it's actually rare in children. So we want to make a pretty clear point that it's a rare disease, which at this point in time seems to have a good outcome. Dr. Greg Hundley: Well Israel, I'm going to come back to you. What do you see is the next study that should be performed perhaps in this general area of cardiovascular disease for children? Dr. Israel Valverde: So I think what we have learned is that the way to move forward is the collaboration between centers. So now that we have a large study multicenter group, our idea is continue describing the long-term outcomes of the study population, because most of them recovered, but a few of them keep, for example, coronary artery dilatation. So do they recovering when you have time until you have time, do they do the ejection fraction, the function of the heart go back to normality soon? Or do we have to wait? So I think that's the next step forward to probably the long-term outcome of the study population. Dr. Greg Hundley: Longitudinal follow-up. And Gerald, do you have anything to add to that? Dr. Gerald Greil: I would just like to reiterate what Israel said, that we need to focus on multicenter studies. I hope Circulation can be a platform to reunite different groups around the world. Because as I mentioned before, I think we have a new disease entity in front of us. We don't know the long-term outcomes. And in the interest of our children confronted with new disease, we need to be very, very careful to learn how we need to follow up these children and how we potentially need to treat them in the long-term. Dr. Greg Hundley: Well, listeners, this has been a fantastic discussion with Dr. Israel Valverde from King's College in London and our own Dr. Gerald Greil from UT Southwestern, revealing some aspects of this multi-system inflammatory syndrome that's associated with COVID-19 in children. And so, on behalf of Carolyn and myself, well, we've got to get to the next feature. So, I'm not going to let you go just yet. Well, listeners, we are in the double feature year 2021. In our second feature discussion today, we have Dr. Michael Gold from Medical University of South Carolina and our own associate editor, Dr. Sana Al-Khatib, who has written an editorial on this paper. And she is from Duke University. Welcome to you both. Michael, we'll start with you. Could you describe for us a little bit about the background related to this paper and what hypothesis did you want to address? Dr. Michael Gold: Well, thank you. And thank you for this opportunity. The implantable defibrillator is a fundamental aspect of the treatment and prevention of sudden cardiac death. It's been around for almost 40 years now and is commonly used in the system has evolved from being a surgical procedure, requiring a thoracotomy to a transvenous procedure in which leads could be placed into the heart. While it's very effective, the major limitation of this in many people's minds were, major limitations were both of complications associated with the transvenous lead. Those include infections and lead failures, as well as unnecessary or inappropriate shock to patients. And based on that, the subcutaneous ICD was developed as the latest iteration of this technology in which a lead is placed under the skin and tunneled up along the sternum, so that one could sense and shock the heart when necessary without being subjected to an intravascular lead. Dr. Michael Gold: And the device has been around for 10 years or so. It's proven to be effective, but primarily used in niche populations of younger patients, patients with poor vascular access and those considered at relatively low risk with few comorbidities, such as patients with Brugada syndrome or long QT syndrome or possibly hypertrophic cardiomyopathy. We felt it was important both to establish the role of the subcutaneous ICD in a more typical group of defibrillator patients, as well as with the multiple evolutions now of programming, as well as technology within the device of seeing if the more modern contemporary devices were as effective in these sicker populations, and also could reduce some of the issues seen earlier in terms of higher rates of inappropriate shock therapy. Dr. Greg Hundley: So Michael we're working with subcutaneous ICDs. What was your study population and how did you design this study to really test the efficacy of the subcutaneous ICDs relative to the more conventional transvenous lead systems in these high-risk patients? Dr. Michael Gold: So what we did was to first identify a population and the most common population price of the implantation in the United States have for sure, in many of the countries is primary prevention patients and low ejection fraction. So we restricted the study to patients with an ejection fraction less than 35% and primary prevention, meaning have never had an episode of sustained ventricular tachycardia or cardiac arrest. So starting with that population, this was a prospective large registry. The bandwidth was out there to do a very large randomized trial, which was just done, although not as in a sicker patient population that study called PRAETORIAN was going on simultaneously. And what we decided was to be aggressive if you will. And we defined our endpoints for the study by looking at identified studies previously with transvenous ICDs that have the most contemporary programming and the lowest risk of inappropriate shock. Dr. Michael Gold: So we used the MADEIT-RIT study, which most people probably would consider it to be the ultimate, if not one of the two contemporary studies for that. And we wanted to essentially compare head-to-head results with that, obviously without those specific patients, but using that as in some ways a historical control or benchmark. So, we set what we wanted to use as our performance goal based on the MADEIT-RNT study for inappropriate shocks, as well as looked at complication rates, using performance goals that have been well-established by the FDA. And we use an 18-month time window, because that's a time when most inappropriate shocks as well as most complications will show up with this device. Dr. Greg Hundley: So what did you find? Dr. Michael Gold: So, what we found was first that we accomplished the goal of having patients who were had much more comorbidities or sicker, if you will. A majority of patients of the over 1,000 patients in the study had ischemic heart disease. I mean, ejection fraction, it was down 26%. In perspective, the early studies of the S-ICD, I mean, ejection fractions are 40% higher, almost 90% of patients have heart failure rather than a third of patients in previous studies and the incidents of diabetes, kidney disease, hypertension and other things with two to three times higher than what would have been done or shown in any early registries of the S-ICD. So we're very pleased about that. Again, there were over 1,100 patients in this study. And what we showed was that at 18 months, the inappropriate shock rate for the whole population was only 4%, hopefully 2.7% annually, which is quite low compared to any other S-ICD study and was very favorably compared with the MADEIT-RIT study easily met the performance goal for that. Dr. Michael Gold: And if we looked at that subgroup of patients who had generation three of the most modern of the S-ICD devices that have a newer discrimination algorithm, that number even became lower than that. So again, very, very reassuring to see what we found there and for the generation three device, it was only 2.9% of patients in 18 months had any inappropriate shock for that. And if we then looked at the other aspects of it, the all shock rate for appropriate and inappropriate shock was only 10% of 18 months, which meant the performance goal for that as well. And what's important about the all shock rate is that it's nice to show that the device can defibrillate a patient in the lab when you're testing them. And this was successful in 98, 99% of the time, which is typical for transvenous or subcutaneous devices. But when we looked at spontaneous arrhythmic events, it was highly effective, 100% of VT storms, and all but one case of a VTVF episode was converted with defibrillator, that one case actually spontaneously converted, but was officially listed as a failure, because it didn't convert right away. Dr. Michael Gold: But no patients had a cardiac due to ventricular fibrillation that could not be successfully treated or ended up requiring external defibrillation. And finally, despite a much sicker population, again, if you will, we showed that at 18 months, the overall complication rate from the device was only about 7% in total, which again is very low compared to what we'd expect to see with other devices. And no patient developed a bloodborne infection or a true lead failure, which is one of the major complications that, and dreaded complications of transvenous devices. Dr. Greg Hundley: Well, Sana as our editorialist, what stood out to you as being really important findings in this study? Dr. Sana Al-Khatib: First of all, I want to start by congratulating Michael and his team on the completion of this important study. And I agree that this has been a really important addition to the armamentarium of studies related to subQ-ICDs. We have had registries in the past. In fact, Michael alluded to the publication of the PRAETORIAN trial, which was really the first trial to compare the S-ICD with the transvenous ICD in a randomized control trial design. However, despite the important contributions of the PRAETORIAN trial, there were several things that remain unaddressed or unanswered in terms of the rate of the end points, especially in appropriate shocks with the newer S-ICD models. So where we had an abundance of those in the UNTOUCHED study, and then really the important question of do the results of that trial, which was largely not done in the United States, apply to the average patient, seen in the United States. Dr. Sana Al-Khatib: And then could those results be extrapolated to sicker patients, because as Michael very nicely highlighted that those patients were not as sick as patients that we see in routine clinical practice. So from my perspective, those are the findings of the UNTOUCHED study are really important, because we now have confirmation that the S-ICD is actually effective and safe in a patient population representative of the average patient seen in clinical practice in the U.S. with a primary prevention indication for the ICD, no really sicker patients, good representation of women, black patients. So overall, I think this trial really gives me a reassurance that the subcutaneous ICD is safe and effective, that the rate of inappropriate shocks with the newer generation of ICDs is really low. That said, I just wanted to highlight a couple of points that I'm hoping to see more data on as we go forward. Dr. Sana Al-Khatib: The study was only 18 months long. It would be good really to have a longer studies. Again, the average age of patients enrolled in the trial was on the younger side in the 50s, and I would love really to see more data on the S-ICD in older patients. And also as Michael said that these results were obtained in patients who had a primary prevention indication for the ICD on the basis of systolic heart failure. Well, we have other patient populations. And especially with, for example, patients with hypertrophic cardiomyopathy, where the rate of inappropriate shocks might be higher, and it would be great to see even more data as we go forward on that patient population and other subgroups of patients that were not included or not well-represented in the trial, but overall a really important trial. Dr. Greg Hundley: Very nice Sana. And Michael, just swinging back to you, what do you think are some of the next studies that might be performed in this space? Dr. Michael Gold: No, I think that Sana made some nice points. I should point out that, in its, I think appropriate vision, the FDA require as long-term evaluation of devices and studies. So the S-ICD post-approval study, which I'm fortunate enough to be involved with as well, is a five-year followup study. We've already published a little bit on two and three-year data, but we will have five-year data on this device in a patient that is closer to the S-ICD than the early registries. It was not restricted to just low EF patients, but it was a U.S.-only study of over 1,500 patients. So, a larger study that has the typical distribution of patients that we see in a U.S. practice who would be eligible for the S-ICD, those without pacing indications and both primary and secondary prevention patients. So I think that will be very important. Dr. Michael Gold: Where the technology is going is largely, there will still be iterations of longer battery life, smaller devices and those things, but there's been a real push to be able to also provide pacing therapy without the need for intravenous leads. So there are several models and systems approaches being used, including adding a lead-less pacemaker that will communicate with a subcutaneous ICD or placing a lead under the sternum, still extra vascular with the capabilities of pacing. So I think the next sort of group of trials will likely be seeing on this device other than simply looking at other populations in a little more depth will be further expansion of the technology to allow for a greater use of a device for those patients who may require a pacing. Dr. Greg Hundley: Well listeners, we want to thank Dr. Michael Gold from Medical University of South Carolina and Dr. Sana Al-Khatib from Duke University, our editorialists for describing this study. And in regards to those, or in regards to subcutaneous ICDs, providing confirmation that these devices are both effective and safe, particularly in a U.S. population for primary prevention of sudden death and really a high-risk patient population with low ejection fraction. 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, 2021.
CME credits: 0.75 Valid until: 30-11-2021 Claim your CME credit at https://reachmd.com/programs/cme/the-new-role-of-omega-3-fatty-acids-in-reducing-ascvd-risk-in-women-expert-dialogue/11988/ The latest information and guideline updates that healthcare professionals need to know for their practice are included in the recent AHA/ACC/Multisociety Blood Cholesterol Guidelines. These guidelines also introduce female-specific risk enhancers to help assess cardiovascular risk in women and discuss several new options for lowering LDL-C. Also examined is the new treatment option available for those with elevated triglyceride levels at risk of ASCVD events. The results from the REDUCE-IT trial on icosapent ethyl have led to new FDA indications and updates to many guidelines that now incorporate its use for patients with a high risk of a serious event and an elevated triglyceride level. The key takeaway from this expert dialogue is that lipid management has been redefined.
Host: Eliot Brinton, MD, FAHA, FNLA Guest: Erin D. Michos, MD, MHS, FACC, FAHA, FASE The latest information and guideline updates that healthcare professionals need to know for their practice are included in the recent AHA/ACC/Multisociety Blood Cholesterol Guidelines. These guidelines also introduce female-specific risk enhancers to help assess cardiovascular risk in women and discuss several new options for lowering LDL-C. Also examined is the new treatment option available for those with elevated triglyceride levels at risk of ASCVD events. The results from the REDUCE-IT trial on icosapent ethyl have led to new FDA indications and updates to many guidelines that now incorporate its use for patients with a high risk of a serious event and an elevated triglyceride level. The key takeaway from this expert dialogue is that lipid management has been redefined.
CME credits: 0.75 Valid until: 30-11-2021 Claim your CME credit at https://reachmd.com/programs/cme/the-new-role-of-omega-3-fatty-acids-in-reducing-ascvd-risk-in-women-expert-dialogue/11988/ The latest information and guideline updates that healthcare professionals need to know for their practice are included in the recent AHA/ACC/Multisociety Blood Cholesterol Guidelines. These guidelines also introduce female-specific risk enhancers to help assess cardiovascular risk in women and discuss several new options for lowering LDL-C. Also examined is the new treatment option available for those with elevated triglyceride levels at risk of ASCVD events. The results from the REDUCE-IT trial on icosapent ethyl have led to new FDA indications and updates to many guidelines that now incorporate its use for patients with a high risk of a serious event and an elevated triglyceride level. The key takeaway from this expert dialogue is that lipid management has been redefined.
What mechanism may explain the positive response in the Reduce It trial?
As 2020 continues to unfurl in a fashion beyond surreal, more and more are descending into the anguished abyss of distress. Awakening to acrid tangerine skies that have transformed sunny California into a Blade Runner dystopia, I myself vacillate between melancholia and a commitment to forge a better world.When the darkness descends, I find sanity in focusing only on those things I can control: my actions and reactions. Nonetheless, waves of anxiety -- and sometimes even despair -- continue to break on the shores of my consciousness. It is in these moments that I resort to a battery of simple but generally quite effective contrary actions. I spend time in nature. Double down on meditation and human connection. I eat better and move more. And I extend myself in service to others.To further explore the many practical and unexacting things we can all undertake during this stressful time to course-correct our emotional disposition, reframe our reality and sustainably serve our well-being, I'm joined by my friend Rangan Chatterjee, M.D. -- who today returns for a third spin on the RRP flywheel.One of the most influential doctors in the U.K., Rangan is a pioneer in the field of progressive, functional medicine. He is double board-certified in internal medicine and family medicine, holds an honors degree in immunology, and has appeared on seemingly every prominent media outlet from the BBC to The New York Times. In addition, Rangan prevails over the wildly popular Feel Better, Live More podcast. His TEDx talk, How To Make Diseases Disappear, has been viewed almost 3 million times. And he is the author of three #1 Sunday Times bestselling books. The focus of today's conversation is his latest well-being tome, Feel Better In 5.A close cousin to my podcast with Atomic Habits author James Clear (RRP #401), today's exchange is all about habit change and habit formation. It's about the power of bite-sized actions. And how, when undertaken regularly, short and simple practices can rapidly and completely change your health and life.We discuss the difference between breaking bad habits versus crowding them out with new, better habits.We explore the realities of food addiction. Our epidemic of emotional eating. And Rangan's personal theory on cause and solution.We talk generally about holistic health and lifestyle medicine, and why progressive wellness should be accessible to all -- now more than ever.Interspersed throughout, Rangan shares how he has helped patients relieve stress, find fulfillment, and engender peace in these chaotic times.But most importantly, we explore his very simple, almost effortless, methods for building a new and sustainable lifestyle to serve our long-term health.The visually inclined can watch it all go down on YouTube (courtesy of Zoom). And as always, the conversation streams wild and free on Apple Podcasts and Spotify.I always enjoy time spent with Rangan, even when it's remote. My hope is that you do as well -- and put his advice into action.Peace + Plants,Listen, Watch & SubscribeApple Podcasts | YouTube | Spotify | Stitcher | Google PodcastsThanks to this week’s sponsorsFour Sigmatic: Nutritious and delicious mushroom brews and elixirs made with only the highest quality adaptogens and easy to take on the go. To try ‘em out visit foursigmatic.com/roll and use the discount code ROLL to get 10% off your order.Harrys: A superior shave at an affordable price. Right now, new U.S. customers can redeem a Harry’s Trial Set which includes a 5-blade razor, weighted handle, foaming shave gel with aloe, and a travel cover. Go to harrys.com/ROLL to start saving and shaving today.Squarespace: The easiest way to create a beautiful website, blog, or online store for you and your ideas. Save 10% at checkout when you visit squarespace.com/richroll and use the discount code RICHROLL at checkout.Note: One of the best ways to support the podcast is to support the sponsors. For a complete list of all RRP sponsors and their respective vanity url's and discount codes, visit my Resources page and click "Sponsors".Books by Dr. Chatterjee:Feel Better in 5*The Stress Solution*How To Make Disease Disappear*The Four Pilllar Plan*SHOW NOTESConnect with Dr. Chatterjee: Website | Twitter | Facebook | Instagram | YouTubeDr. Chatterjee’s Podcast: Feel Better, Live MoreTEDxLiverpool: How to make diseases disappear | Rangan ChatterjeeNew York Times: Stress is Making You Sick. Take Time to Reduce It.Forbes: Can This Doctor Make Disease Disappear?CNN: How Stress is Making us SickThe Telegraph: How to change your life in just 5 minutes a dayThe Telegraph: The Five Minute Workout That Really WorksThe Telegraph: Feeling anxious? How to de-stress your mind - and it only takes five minutesThe Telegraph: Dr Rangan Chatterjee: Nourish your relationships, and de-stress your lifeHer: Dr. Rangan Chatterjee on the 'biggest mistake' people make while setting health goalsHappiful: Dr Chatterjee Shares the Secrets to Feeling Better in 5 MinutesIrish Examiner: Time out: Dr Rangan Chatterjee on resetting your body and mindIrish Times: The doctor who treats the problems of modern lifestylesÖtillö Swimrun World Series: otilloswimrun.comBJ Fogg: Stanford behavior scientist, author of New York Times bestseller Tiny Habits*Helen Hall: Perpetual Forward Motion Run CoachingRelated Podcasts You Might Enjoy:RRP #486: Rangan Chatterjee, MD On Quelling Stress, Cultivating Intimacy & Reinventing Health CareRRP #376: Rangan Chatterjee, MD On How To Make Disease DisappearRRP #511: Charles Eisenstein on the CoronationRRP #401: James Clear On Why Habits Are the Compound Interest of Self-ImprovementThanks to Jason Camiolo for production, audio engineering and show notes; Blake Curtis for video editing and graphics; Chris Terry, Johnny Stephens Photography, Justine Stoddart for images & portraits; and theme music by Tyler Piatt. 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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. Dr Greg Hundley: And I'm Dr Greg Hundley associated editor from the Pauly Heart Center at VCU health in Richmond, Virginia. Well Carolyn, this week's feature investigates the compass trial and is going to examine the role of combination antiplatelet and anticoagulation therapy in patients with diabetes and cardiovascular disease. But before we get to that feature discussion, how about we grab a cup of coffee and jump in and discuss some of the other papers in the issue? Dr Carolyn Lam: You bet, Greg. I've got my coffee right here, and I'd like to start by talking about paclitaxel containing devices. You may already know this, but it was nice to revise that these significantly reduce re intervention in patients with symptomatic femoral, popliteal, peripheral artery disease, as we may expect. However, a recent aggregate data meta-analysis reported increase late mortality in pad patients treat it with these paclitaxel containing devices. Thus today's authors, Dr Rocha-Singh from Prairie Heart Institute of Illinois at St. John's hospital and their colleagues performed an individual patient data meta-analysis to evaluate mortality using data from eight randomized controlled trials of FDA approved paclitaxel coated devices using de identified data that was provided by manufacturers. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: So in 2,185 patients and 386 deaths from eight paclitaxel coated device trials with a four year median follow-up, there was a 4.6% absolute risk of increased mortality associated with paclitaxel coated device use compared to balloon angioplasty at a median of four years follow up, significant loss to follow up and withdrawal rates of 24% and 23% in balloon angioplasty and paclitaxel cohorts respectively through five years were observed. Recovery of lost vital status data reduced the observed paclitaxel device associated mortality rate. And there was no paclitaxel drug dose mortality relationship identified. Dr Greg Hundley: Oh, Carolyn, I think this is really an important finding, and we have a nice editorial, don't we? So what was the take home message? Dr Carolyn Lam: Yeah. In fact, this was discussed in an important editorial by doctors Royce, Chakraborty and Dao from the USFDA. Now listen up. So based on the prior aggregate data meta-analysis and subsequent FDA review, FDA had already communicated that clinicians should consider the increased rate of long-term mortality when making treatment recommendations. They had also implemented updated labeling for this device class to communicate the risk. So in this editorial, the FDA commended the authors of the current individual patient data meta-analysis for providing important information towards signal refinement, and also commend at their collaboration with device manufacturers to work together with a shared goal of patient safety. Now, there are still many unanswered questions, including the mechanism for the observed increase in late term mortality associated with these devices and how the benefit risk profile of these devices may shift across various patient populations. Dr Greg Hundley: Well Carolyn, my paper comes from Professor Antje Beling from Charité – Universitätsmedizin Berlin in Berlin. And it investigates heart specific immune responses in an animal model of auto immune related Meyer carditis mitigated by an immuno proteasome inhibitor and a genetic ablation. So Carolyn, this study used mouse models to understand mechanisms involved in immune checkpoint inhibitor related Maya carditis, a phenomenon that we can observe in 5% to 10% of patients that are receiving these checkpoint inhibitors for treatment of their cancer. Dr Carolyn Lam: So what did they find, Greg? Dr Greg Hundley: Several things, Carolyn. All immuno proteasome deficient strains of mice showed mitigated auto-immune related cardiac pathology with less inflammation, lower pro-inflammatory and chemo tactic cytokines, less interleukin 17 production and reduced fibrosis formation. The auto-immune signature during experimental proponent I auto immune carditis with high immuno proteasome expression, immunoglobulin G deposition, interleukin 17 production in heart tissue, and troponin I directed humeral auto immune responses was also present in two cases of immune mediated related my carditis. Thus demonstrating the activation of heart specific autoimmune reactions by this checkpoint inhibitor related myocarditis therapy. So Carolyn, perhaps by reversing heart specific auto immune responses, immuno proteasome inhibitors applied to these mouse models demonstrated their potential to, in the future, aid in the management of auto-immune bio carditis in humans, possibly including cases with immune mediated myocarditis heart-related specific auto-immunity. Dr Carolyn Lam: Oh, that's really nice, Greg. Thanks. How about a quiz? Remember what desmoplakin is Greg? Dr Greg Hundley: I think this is going to do something with right ventricular cardiomyopathy. Dr Carolyn Lam: Very nice. Desmoplakin is the primary force transducer between cardiac desmosomes and intermediate filaments. And mutations in Desmoplakin indeed cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of desmoplakin cardiomyopathy have been limited to small case series. Today's paper, by Dr Helms from University of Michigan and colleagues is the largest series of desmoplakin mutation carriers reported to date. Dr Greg Hundley: So Carolyn, what did they find here? Dr Carolyn Lam: Among 107 patients with pathogenic desmoplakin mutations and 81 patients with pathogenic Plakophilin-2 mutations as a comparison cohort, they found compelling evidence that desmoplakin cardiomyopathy is a distinct form of cardiomyopathy marked by a high proclivity for left ventricular hypertrophy and arrhythmias and associated with intermittent myocardial inflammatory episodes that appear clinically similar to myocarditis or sarcoidosis. Furthermore they found that diagnostic and risk stratification variables that performed well for Plakophilin-2 associated ARVC exhibited poor accuracy for the diagnosis and risk assessment of desmoplakin mutation carriers. So these results strongly indicate that a genotype specific management approach is essential for desmoplakin cardiomyopathy. Dr Greg Hundley: Wow, Carolyn. Lots of great science in this issue. Well, just like last week, we have got a lot of other papers in this issue. So let me tell you about a few that I've had a chance to preview. The first is a research letter by our own Dr Hesham Sadek from UT Southwestern Medical Center involving the homotypic fusion generates multi nucleated cardiomyocytes in the murine heart. Next is an ECG challenge. It's from Dr G. Neil Kay at the University of Alabama at Birmingham, and really reviews an ECG in a patient that presents with pulmonary embolism. Next, there's a case series from Dr Nil Uriel from Columbia University Medical Center regarding the variety of cardiovascular presentations of COVID-19. Next there's an on my mind piece that comes to us from Dr Ersilia DeFilippis from Columbia University College of and Physicians and Surgeons. And it involves cardiopulmonary resuscitation during this COVID-19 pandemic. And it presents a view from trainees on the front lines. Next, Carolyn, one of your faves, Dr Leslie Cooper from the Mayo Clinic provides an informative white paper on the description and proposed management of acute COVID-19 cardiovascular syndromes. Next is a paper from Dr Francine Marquez from Monash University, and it's a perspective piece on the impact, strategies and opportunities for early and mid-career cardiovascular researchers during the COVID-19 pandemic. So many studies have been stopped and this very nice article highlights the new opportunities in this pandemic. Next, Dr Anabel Volgman from Rush University Medical Center has a piece on the seniors on the sidelines, and it's a call to action. And then finally, Dr Andrew Chapman from University of Edinburgh and professor Christian Mueller from the University Hospital of Basel exchange letters to the editor regarding a prior article of high sensitivity cardiac troponin, and the universal definition of myocardial infarction. Dr Carolyn Lam: Nice. There's also a research letter by Dr Sandoval and colleagues who described the transition to using high sensitivity troponin T in a United States regional healthcare system, namely the Mayo Clinic enterprise. And they really showed that a small increase in MI diagnosis in part due to an increase in type two MI diagnosis occurred without an overall increase in hospital admissions or resource utilization using the high sensitivity cardiac troponin T implementation. And if I may mention, there is also a beautiful white paper by Dr Sana Al-Khatib, whom I was very lucky to coauthor with. And it's on the advancing research on the complex interrelations between atrial fibrillation and heart failure. This a report from the National Heart Lung and Blood Institute virtual workshop. Wow. A bonanza of an issue. Thanks so much, Greg. Let's move on to our feature discussion now. Dr Greg Hundley: Look forward to it. Dr Carolyn Lam: Today's feature discussion was in fact a late breaking clinical trial presentation at the American College of Cardiology meeting this year, 2020. And it's all about the compass trial, this time focusing on diabetes. I'm so, so pleased to have with us, the corresponding author Dr Deepak Bhatt from Brigham and Women's Hospital, as well as Dr Gregory Lip from University of Liverpool who was not only the guest editor, but also an editorialist for this paper. So welcome gentlemen. Deepak, could I start with you? This was an incredible presentation that was very well discussed. ACC not virtually, but I'm just so glad that we can have you on this podcast to tell us again, please, the rationale, the key findings and why this paper is just so important. Dr Deepak Bhatt: So the background really is that prior studies and particular registry studies, the reach registry, for example, have shown that patients with concomitant CAD and/or PAD, that is coronary artery disease and/or peripheral artery disease, plus diabetes, are folks that are extremely high risk of future ischemic events. This is true even if they are apparently stable outpatients. At any rate in the compass trial, these sorts of patients with CAD or PAD, stable patients, both with and without diabetes who are enrolled 27,000 plus patients randomized. And there were three arms in this study, aspirin alone, rivaroxaban alone and aspirin plus low dose rivaroxaban 2.5 milligrams twice a day. And that was the winner, that combination sometimes referred to as dual pathway inhibition significantly reduced the schemic events versus aspirin alone, a significant reduction in cardiovascular death MI stroke, as well a lower rate significantly so of cardiovascular death, and even all-cause mortality was lower. So the overall trial was positive, but what we wanted to examine in this analysis was specifically how to patients with diabetes fare, knowing that they're a higher risk group in general across multiple registries and studies? And indeed we found that they were higher risk, those with diabetes versus those without diabetes and compass, and indeed, though their relative risk reductions were similar, those patients with diabetes had numerically larger, absolute risk reductions than those without diabetes with this regimen of low dose rivaroxaban plus aspirin versus aspirin alone. Dr Carolyn Lam: Thanks Deepak. And I just have to refer the listeners to those beautiful figures in your paper. I mean, just one look at it really explains exactly what you were saying and really highlights that patients with diabetes are at higher risk of adverse events and also in one of the graphs of bleeding. Greg, could I bring you in here? You mentioned that in your editorial as well, that there has to be importantly acceptable bleeding risks. Could you expand on that? Dr Gregory Lip: The compass crowd was a game changer and in this high-risk subgroup, as Deepak elegantly has described. These are diabetic patients, and then we also have the subgroups we call with or without PCI. And those would be so of course, being the higher risk group of patients. Nonetheless, the comparison was basically a dual pathway inhibition, but a combination rivaroxaban plus aspirin compared to aspirin alone. But a high cardiovascular risk and high bleeding risk tend to track each other. So it was important that we certainly want to reduce the adverse outcomes of cardiovascular endpoints, we should certainly individualize our assessment of our patients and make sure that a patient is not an excessive high bleeding risk. I think overall, the study is very reassuring because there was no significant access in the overall population of the subgroup, at least in relation to fatal bleeding, critical organ bleeding or intracranial hemorrhage by dual path inhibition. But I think we, as physicians, just need to assess the patient in front of us just to make sure that particular patient is not at high risk particularly of bleeding, given that high risk of bleeding also generally is high cardiovascular risk as well. Dr Carolyn Lam: Thank you, Greg. And Deepak, perhaps maybe some words from you about this sort of risk benefit ratio? How do you see it? How do we apply these results? Dr Deepak Bhatt: I totally agree with everything Dr Lip said. Really, the key message when we're talking about antithrombotic numbers, something Dr Brunwald had said in this context, that is, there's no free lunch. When it comes to antithrombotics, there's always bleeding risks. There's just no way around that. In any trial that is adequately powered long enough, we'll find that, and that can include bad bleeding. Now, fortunately there was no significant excess and failure endocranial bleeding within the trial or within the subgroup of patients with diabetes. But nonetheless one needs to be cautious because these of course are carefully selected patients at low bleeding risk to get into the trial. There was a run in period. So when applying to real life, of course, there's the potential for bleeding. So we need to be really cautious about that. And it's also not a stat. So if we were talking about secondary prevention, either with or without diabetes, CAD, PAD, both of them together, of course, all those patients should be on Statin assuming they don't have a real type of contraindication. So that's kind of a no brainer. That's a matter of implementation science. A lot of patients that should be on Statin aren't, but that's not an issue of science. We already know the answer there. Here, it's not the case of everyone that is like this who has diabetes, or even who doesn't, who has CAD or PAD should be on this regimen. It needs to be carefully selected patients, patients that are a low bleeding risk. And sometimes doctors ask, "Well, how do you tell that?" Well, it's not always easy, but for sure there's some things that predict future bleeding risks such as prior bleeding. So prior bleeding, anemia, those are powerful predictors of future bleeding. And one would want to be really cautious in these largely stable outpatients that we're talking about in the compass trial in intensifying their antithrombotic regimen. But in the right patients, I think it's a really effective way of reducing important future vascular risk, whether that's cardiovascular risk consisting of MI related end points, stroke, peripheral ischemic end points, including amputation, which was significantly reduced in the trial, and within the subgroup of those with diabetes. So it's a matter of balancing those, but I do think with careful decision-making on the part of the physician, with discussion with the patient, with their understanding of the risks and benefits of intensifying the antithrombotic regimen beyond aspirin, there are a substantial number of patients who could benefit. Dr Gregory Lip: I whole fully agree with Deepak's comments. And we do have to bear in mind also that risk is also a fairly dynamic process and we may well be assessing the patient as the one off initially while we are initiating treatment. But of course risk, whether from cardiovascular risk or whether from bleeding risk particularly, also is influenced by increasing age and by incident comorbidities, which really means that risk reassessment should be performed in every patient we contact. With bleeding risks in particular, there are modifiable bleeding risk factors that we can mitigate. So proactive assessment or rather reassessment of risks, whether both from cardiovascular events and/or bleeding, is necessary as we follow up these patients. Dr Carolyn Lam: Thank you, both. Deepak, I'm just going to build a bit on your analogy of no free lunch. And maybe sort of a general question do you both, because it seems like we've got a bonanza of a buffet now when it comes to diabetes, especially with the new anti-diabetic drugs. So how do you think this fits in altogether? You talked about Statins. We now talk about low dose rivaroxaban in addition to aspirin, and you think diabetic patients should be treated with all? Maybe Deepak first, then Greg. Dr Deepak Bhatt: What a terrific question. In fact, that was asked of me by the late-breaking clinical-trial panel clinical trial panel. They said, "Well, how does it fit in? Because these data look terrific, but there's also other new diabetes drugs and approaches." So for sure, I would say again, barring a real contraindication, I would say everyone that we're talking about here should be on a statin and preferably if they can tolerate it, a high intensity statin. And if that doesn't do the trick in terms of LDL goal, I would say zetomyde. And potentially if they're in a region of the world where it's affordable a PCSK9 inhibitor. Then beyond that, I think we've got to pay attention to triglycerides these days, not just LDL cholesterol and if it's some patient that's sort of like REDUCE IT, well then, they should be on eicosapentaenoic. So we can modify LDL related and triglyceride related risks without too much effort or too much in the way of side effects. Then beyond that, I would say, we've got to think about blood pressure, inadequate control, especially in those with diabetes, but even those without that have cardiovascular disease. And then we have to think about glycemic control. And I don't mean the old-fashioned way, but I mean with some of the newer drugs. SGLT2 inhibitors in particular have been found to be useful for both. That's just the glycemia control part of things, more importantly, cardiovascular outcomes. In particular, heart failure and renal related outcomes. And then GLP 1 agonist as well have been shown to be very useful once more modifying cardiovascular outcomes, including atherosclerotic outcomes. So there is, as you say, quite the buffet. And assuming a patient can tolerate that polypharmacy and afford it, I do think the majority of patients with diabetes should be treated that well. And that's of course on top of lifestyle modification, weight loss is particularly important, plant-based diet, et cetera. But on top of that, then, with all those things that are being done and a patient is still at high ischemic risk but is at low bleeding risk, that's where I think, even in the deceptively stable appearing outpatient, it's worthwhile just running a mental checklist and saying, "Okay, are they on an SGLT2 inhibitor? Check. Did In someone measured their triglycerides? Check." And then on that checklist is, "Yeah, could they tolerate being on more than just aspirin alone in terms of bleeding risk? And if the answer to that is yes, might they benefit from adding this on?" And there are a lot of patients these results apply to, and I think a proportion of those patients who are otherwise optimally treated for their risk factors are the ones to target. Dr Carolyn Lam: Beautifully put. And Greg? Dr Gregory Lip: Deepak does raise an increasingly applied concept in how we approach our patients at high risk of cardiovascular events. That's the so called integrated or holistic approach to management. Because we have in the past tended to just focus on one strand of management. For example, we may well just be putting a lot of focus when on the analytic reduction and ignoring the rest. Well, we can't do that these days. We have to manage the whole patient and not just the bit of the patient. And this brings in this holistic approach, this integrated approach. And I think Deepak summarized that very nicely. It may require a number of medical approaches or medication-based approaches, but we have to practically look at the comorbidities like blood pressure reduction and also the lifestyle changes that Deepak's already summarized. So a holistic and integrated approach to our care of these patients. And in fact, some of the more recent studies showed nicely how this results in better outcomes in our patients at high cardiovascular risk. Dr Carolyn Lam: And in fact, those were exactly the last words of your editorial. A holistic and integrated care approach. Beautifully done, thank you both so much for this excellent discussion. 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. Dr Greg Hundley: This program is copyright the American Heart Association 2020.
Episode 10 - Fear - Use It, Lose It, or Reduce It
CME credits: 0.25 Valid until: 31-03-2021 Claim your CME credit at https://reachmd.com/programs/cme/evidence-and-value-of-prescription-omega-3-fatty-acids-in-cardiovascular-disease-management/11291/ Despite the success of statin therapy in significantly reducing patients’ LDL-cholesterol and the risk of cardiovascular events, there remains a considerable need for event reduction. Fortunately, we now have findings from the REDUCE-IT landmark trial on icosapent ethyl that could help us find a way to meet that need. This activity will provide practical information on the evidence, clinical utility, and use of icosapent ethyl in patients at risk of ASCVD events.
CME credits: 0.25 Valid until: 31-03-2021 Claim your CME credit at https://reachmd.com/programs/cme/evidence-and-value-of-prescription-omega-3-fatty-acids-in-cardiovascular-disease-management/11291/ Despite the success of statin therapy in significantly reducing patients’ LDL-cholesterol and the risk of cardiovascular events, there remains a considerable need for event reduction. Fortunately, we now have findings from the REDUCE-IT landmark trial on icosapent ethyl that could help us find a way to meet that need. This activity will provide practical information on the evidence, clinical utility, and use of icosapent ethyl in patients at risk of ASCVD events.
In this week's View, guest host Dr. Deepak Bhatt offers a preview of some of the hottest trials at ACC's Scientific Session Together with World Congress of Cardiology (ACC.20/WCC) Virtual, taking place online only March 28-30, including VICTORIA, VOYAGER PAD, COMPASS, TAILOR PCI, SPYRAL HTN-OFF MED PIVOTAL, TWILIGHT, TICO, E3, REDUCE-IT, and ISCHEMIA.
Aujourd’hui à l’émission, Camille Chaï et François Barruel reçoivent le Dr Jean-Claude Tardif, directeur du Centre de recherche de l'Institut de cardiologie de Montréal, membre du Comité exécutif et chercheur principal canadien du projet REDUCE-IT, ainsi que le Dr Jean C. Grégoire, cardiologue à l'Institut de cardiologie de Montréal et investigateur local du projet REDUCE-IT. Et… Cet article Nouveau traitement pour les maladies cardiovasculaires est apparu en premier sur Canal M, la radio de Vues et Voix.
CME credits: 0.50 Valid until: 27-02-2021 Claim your CME credit at https://reachmd.com/programs/cme/reduce-it-trial-studying-icosapent-ethyl-an-in-depth-review-of-usa-dataset-with-commentary/11163/ Join an internationally recognized panel of experts as they provide a comprehensive review and commentary of the results from the REDUCE-IT trial, which studied the effect of icosapent ethyl on cardiovascular outcomes. The expert panel also offers insights and pearls on how these results affect clinical lipid management in patients at risk for ASCVD, especially after the FDA expanded the indication of icosapent ethyl to include the reduction of ASCVD events. Time Topic Format 16 minutes REDUCE-IT USA Subgroup AnalysisDeepak L. Bhatt, MD Audio over slides 7 minutes Panel Discussion 1 and Q&A Audio 8 minutes Panel Discussion 2 Video
CME credits: 0.50 Valid until: 27-02-2021 Claim your CME credit at https://reachmd.com/programs/cme/reduce-it-trial-studying-icosapent-ethyl-an-in-depth-review-of-usa-dataset-with-commentary/11163/ Join an internationally recognized panel of experts as they provide a comprehensive review and commentary of the results from the REDUCE-IT trial, which studied the effect of icosapent ethyl on cardiovascular outcomes. The expert panel also offers insights and pearls on how these results affect clinical lipid management in patients at risk for ASCVD, especially after the FDA expanded the indication of icosapent ethyl to include the reduction of ASCVD events. Time Topic Format 16 minutes REDUCE-IT USA Subgroup AnalysisDeepak L. Bhatt, MD Audio over slides 7 minutes Panel Discussion 1 and Q&A Audio 8 minutes Panel Discussion 2 Video
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 Centre and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial. So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. So, Greg, do you remember what the REDUCE-IT trial was about? Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah! Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer. Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find? Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo. Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy. Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find? Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy. Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers? Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented. Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues. Dr Greg Hundley: Ah, so I'm interested. What was this interaction? Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding. Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women. Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg? Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis. Dr Carolyn Lam: Ah, so are there any possible solutions to this? Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy. Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find? Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions. Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association. There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association. Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response. Well, Carolyn, how about onto that feature? Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well. Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper? Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same. In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction. Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found? Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study. Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum. Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this? Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction. Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction. And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies. Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott. Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women. And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction. Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it. But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper. Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read. Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF. And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women. So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men. Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating. Scott, I'm going to give you the last word. Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients. Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week. Dr Greg Hundley: This program is copyright The American Heart Association 2020.
Dr. Bernie explains how the EVAPORATE trial sheds light on the CV benefits of the REDUCE-IT trial and what it means for US population outcomes.
Check out this episode as Dr. Dave Dixon talks about REDUCE-IT and REDUCE-IT USA. Check out cardioscripts.com for episode show notes and references!
VITAL and REDUCE-IT trials conclude with different results on the impact of Omega-3 on the reduced risk of cardiovascular disease.
Vascepa approved for cardiovascular risk reduction The FDA’s decision on cutting events in high-risk patients was based primarily on the REDUCE-IT trial. ENGAGE AF-TIMI: Insulin linked to greater risk for stroke, CV death, bleeding Novel oral anticoagulants may be preferred over warfarin in patients with diabetes and AFib. HHS drug importation proposals aim to address high costs Trump administration drops key health care proposal on day of impeachment vote. End ‘therapeutic nihilism’ in care of older diabetic patients, says expert ‘It’s not hyperglycemia that’s killing people; it’s heart disease and renal disease.’ * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgeTweets
Icosapent ethyl cost effective in REDUCE-IT analysis Treatment with the fish-derived drug Vascepa for CV event reduction is more effective and less costly than placebo. * * * Help us make this podcast better! Please take our short listener survey: https://www.surveymonkey.com/r/podcastsurveyOct2019 * * * DAPA-HF: Dapagliflozin benefits regardless of age, HF severity The SGLT2 inhibitor had similar efficacy in the elderly and across the spectrum of baseline symptom status. Colchicine cut post-MI CVD events Colchicine fulfilled the promise first seem in CANTOS that anti-inflammatory treatment can reduce cardiovascular disease events. Cardiac arrests peak with pollution in Japan The incidence of out-of-hospital cardiac arrests in Japan increased on days when counts of particulate matter spiked from the day before. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgeTweets
In this interview, Ronald Hoffman, MD, describes the scientific research associated with essential fatty acids, specifically omega-3 fats from fish oil. Hoffman touches on some of the controversial research and then focuses on the practical clinical applications that have been confirmed in the scientific literature. About the Expert Ronald Hoffman, MD, is a physician in private practice of integrative medicine in New York City. He is a graduate of Columbia College and Albert Einstein College of Medicine. Since 1984, he has served as Medical Director of the Hoffman Center in Manhattan. Hoffman is past president of the American College for the Advancement of Medicine. Hoffman is the host of Intelligent Medicine, a nationally syndicated radio program, and he produces the daily Intelligent Medicine podcast. He is a Certified Nutrition Specialist and the author of several books, including How to Talk with Your Doctor (About Complementary and Alternative Medicine). For more information, visit drhoffman.com. About the Sponsor Since 1965, Carlson Labs has produced fresh, pure, award-winning vitamins, minerals, fish oils, and other nutritional supplements. The company began with a single vitamin E product in Founder Susan Carlson’s small Chicago apartment and quickly grew to offer the most complete line of all-natural vitamin E supplements in the world. In the early 1980s, we helped launch the omega-3 market in North America, importing our high-quality, great-tasting, sustainable fish oils from Norway. In 2009, we released a new marine oil sourced form an abundant species of calamari. Today, the next generation of Carlson leads the company—daughters Carilyn Anderson and Kirsten Carlson—and the innovations continue. Carlson recently announced the opening of Carlson Healthy Oils, our new, state-of-the-art bottling facility in Søvik, Norway. Søvik is located near one of the busiest and most important fishing harbors in the north Atlantic, ensuring that only the finest, freshest fish oils are delivered to Carlson Healthy Oils for refining, distillation and bottling. Transcript Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Thank you for joining me today. Our topic is the utilization of essential fatty acids in clinical practice. And my guest is integrative health expert, Dr. Ronald Hoffman. Before we begin, I'd like to thank our sponsor Carlson Labs. And thank you Dr. Hoffman for joining me today. Ronald Hoffman: Well, thanks for inviting me, Karolyn. Gazella: Well, this is a great topic. And I know that you are consistently a food first clinician. So let's start with something very basic. How much fish does a patient have to eat each week to get the benefit of the omega-3 fats? Hoffman: Well first, let me just say, this is a controversial topic. And especially when it comes to supplementation, but it's generally acknowledged that a fish is healthy. It's beneficial for a variety of reasons in particular for cardiovascular prevention. And usually the suggestion is that people consume 2 to 3 small to moderate portions of oily fish per week to obtain the optimal amount of omega-3s. So, for example, a 6-ounce portion of wild salmon contains about 900 milligrams of the EPA, and about 1,000 milligrams of DHA. And 2 to 3 servings a week of salmon, in particular, in a setting where you have a low intake of omega-6, which competes with omega-3, would be adequate for most people. There's also some information that suggests that the omega-3s in fish are more bioavailable than the omega-3s that you get from a capsules where it's in isolated form. And there may be other compounds within fish, even certain fish peptides or proteins, which may have a beneficial effect. So you're getting kind of an all round benefit when you eat fish. Gazella: That makes a lot of sense. Now I want you to remind us, you mentioned heart health, but can you remind us why these omega-3 fats are so important to human health? Hoffman: Well, there there's so many ways. First of all, fish oil seems to have an anti-inflammatory effect. It works on tamping down pro-inflammatory pathways within the body. These so called eicosanoid pathways. And also, it has a lot to do with membrane fluidity. So fluid membranes help our blood vessels expand and contract, helps the ingress and egress of compounds into our cells, helps nerve transmission. And that may be why fish oils have what are called pleiotropic effects, which means that they work in a multiplicity of ways to help the body. Brain, heart, circulatory system, joints. There may be even an anticancer effect because of its ability to reduce inflammation, which is a trigger for cancer. Gazella: Yeah. And I think sometimes when a substance such as fish oil and these essential fatty acids have multiple effects, and can do so much good on so many levels, there's almost a tendency to be a bit suspicious. But it seems— Hoffman: Right. One of the "too good to be true" phenomenon. It sounds like a panacea. So that tends to induce a little bit of doubt. Gazella: Exactly. So I think that that's when integrative doctors like yourself and our listeners look to the science. So I'd like to talk a little bit about the science as it relates to the practical use in clinical practice. So which conditions in clinical practice will positively and confidently be impacted by essential fatty acid consumption? Hoffman: Well, let's start with the controversy, which is about cardiovascular health. And this really dates back to studies of Greenland Eskimos, which showed a near absence of cardiovascular disease. And so then that sort of triggered the gold rush for fish oil supplementation because they thought, well they consume so much of that stuff, this is going to protect the hearts of normal folks in the West. Lately there's been a lot of blow back against that because, for example, the Cochrane Collaborative has ruled that there is no definitive evidence that fish oil supplementation has heart benefits. But I got to say I critique some of those conclusions because a lot of the studies that show no benefit from fish oil are done with very low doses of fish oil supplements, a capsule or 2 of fish oil of unclear quality. Also, often when we test fish oil for cardiovascular disease, we have people really tanked up on medication. They're on aspirin, they're on statins. Maybe that will blunt the benefit of the fish oil. And also it may be that fish oil is very preventative against cardiovascular disease, and we'll see the benefits if we do a 20- or 30-year study. But if we take very sick people who are near end stage when it comes to cardiovascular outcomes, we're not going to see that taking a fish oil capsule to 2 is going to make a difference. But the really exciting development on the fish oil front, and I got to give credit to the company that did this, Amarin, which is the maker of a pharmaceutical fish oil, has a come up with a study, the REDUCE-IT trial, which suggests that their very concentrated version of fish oil can reduce cardiovascular disease risks by 25%. Now they were very quick to say by no means does this suggest that fish oil pills are equivalent to our medication. But Vascepa is really concentrated EPA. And so it remains to be seen if supplementary fish oil has that robust effect. In many studies, it came up short. Gazella: So let's stick with the cardiovascular effects. When you're talking about that Cochrane Collaborative, was that the study that came out late last year that you're talking about that was a bit controversial, and pretty widely publicized? Hoffman: Right. And with kind of lurid headlines like there was an editorial in, I guess, it was Journal of the American Medical Association, which is "The Last Nail in the Coffin of Fish Oil." It's almost gleefully pouncing on the supplement industry saying that it doesn't work. But by the same token, I'm pretty sure that the self same journals are going to run ads for the Amarin product that's been validated by scientific research. Another problem with some of these studies is when some of these studies compare fish oil to an inert placebo, which is olive oil. Well that may be a mistake. Because olive oil actually has cardiovascular benefits. And interestingly in the Amarin study, the REDUCE-IT trial, their placebo was mineral oil. And because you had to give a lot of of these refined fish oil capsules in the active group, you had to have a lot of mineral oil capsules. A lot of people were consuming a lot of mineral oil, which some people would say could actually be deleterious when it comes to a cardiovascular health and reducing the absorption of other critical nutrients. So this is a very fraught area of discussion because some people say, well, fish oil doesn't make a difference. I would say that it may be different strokes for different folks. Some people who are very deficient in omega-3 would obtain a great deal of benefit. Other people are pretty tanked up on dietary fish consumption. So the benefit is not going to be that great. There may be some genetics involved. Also, it may be that if you're consuming a lot of omega-six fatty acids from seed oils, these are pervasive in our western diet. That may blunt the benefits of omega-3s because we look at the ratio of omega-3 to 6 as being an important determinant of health. Gazella: Yeah, that's a good point. So I'd like to stick on the clinical applications here. There are a lot of doctors that I interview that actually think of fish oil or these essential fatty acids as foundational. And if their patients are not eating enough fish, and they're not getting enough of these in the diet, they automatically supplement even if there's no real clinical application. What's your view in your clinical practice? Do you supplement? When do you supplement? And for what conditions other than cardiovascular may you consider fish oil supplements? Hoffman: I do believe in that, what you just stated. Which is I think that that's part of, if one's going to construct a [inaudible 00:09:43] series of 4 or 5 supplements that people should take, I think fish oil is right up there. I personally take fish oil. I have my family members taking fish oil. I have my patients taking fish oil. And it's kind of an insurance policy against lack of the requisite amount of fish oil that prevents a variety of diseases. We see also benefits in pregnancy. A recent study showed that there was a preventive effect against preeclampsia of omega-3 supplementation. That's a bad pregnancy outcome. Also reduces the instance of premature births. There may be some benefits in terms of a kid's ultimate intellectual development, DHA, which is a constituent of fish oil. Docosahexaenoic acid is naturally present in breast milk. So it was only recently that US manufacturers joined the rest of the world in adding DHA to infant formulas. Long overdue. Also in brain conditions. We look at a lot of neurodegenerative conditions where there's an inflammatory component. These include Alzheimer's, also depression. There are actually some very good studies looking at depression and omega-3 fatty acid administration. Certainly that would be an area of application. Autoimmune disorders, inflammatory disorders, dermatological conditions that are inflammatory, on and on it goes. There's so many different applications. Gazella: Yeah. Now you mentioned DHA, and often when we think of omega-3s, we do think specifically of DHA and EPA. Now you mentioned the applications of DHA in terms of pregnancy and childbirth. So from a clinical perspective, is there a time when you look to one of these to be emphasized over the other? Can you expand on that a little bit more? Hoffman: Yeah. And I wish there was a rocket science answer to that. And I've just looked long and hard into the literature over the past few years. And it appears that EPA may be more important as an anti-inflammatory. And many studies suggest it's good for the brain because it reduces inflammation. But also DHA plays a very important role in brain health. It's certainly important in neurodevelopment. Deficiency of DHA is associated with behavioral problems and intellectual problems in kids. And so it really is unclear. And if someone says it's DHA or EPA as a definitive answer, I would say, walk away from that conclusion. They seem to work synergistically to support health. The question is sometimes ratio, sometimes in certain conditions we might go for more DHA, other conditions we might emphasize EPA. But it appears that they both play central roles, and sometimes in the very self same condition. Gazella: Yeah. Now, before I leave the topic of the research, because we talked about the controversial negative research that came out late last year, and sometimes bubbles to the surface every now and then. It seems like, and I know you're in the scientific literature all the time, it seems like the more I look at the scientific literature, gosh, there's not a month that goes by where I don't read a new study on fish oil. So in general, are you pleased with the research that's coming out about these essential fatty acids? Hoffman: Well, the last time I checked, there are at least 20 or 30,000 articles that support the benefits of fish oil for one or another health problem. So when some group like the Cochrane Collaborative comes out and says fish oil is worthless, I think it's a conclusion that ignores the vast amount of evidence that supports the benefits of fish oil. So, it's not binary. I think that we can't overhype or overestimate the universal benefits of fish oil supplementation. And there are appropriate cautions when we look at some of these big studies. But still, I'm generally supportive of especially targeted use of omega-3 for specific conditions. Gazella: So now let's dig into some practical aspects. If a patient can't get the omega-3s that they need from diet alone, what dosage or ratio of these fats are typically recommended as a dietary supplement? Hoffman: Well again, it depends. So for example, for cardiovascular, I'm thinking if people have serious cardiovascular problems, they need higher doses. So that comes to us for the REDUCE-IT study that used 4,000 of EPA, pure EPA to reduce cardiovascular risk. So it kind of depends on what you're dealing with. To lower triglycerides, for example, you need pretty high doses, not just a pill a day, or even 2 pills a day. But for general supplementation, I suggest one of the potent formulations of omega-3 that delivers a high percentage of EPA-DHA per capsule. The 1,000 milligram capsules, not the little teensy tiny capsules, 1 capsule, twice daily for general prevention. Gazella: So that's 1,000 milligrams twice daily for general. And then what's the upper dose for somebody who may be having cardiovascular issues? Did you say 4,000? Hoffman: I would say 4,000 for somebody with cardiovascular issues. Now what we have to be a little careful because some people have bleeding tendencies, or who are on blood thinners. And I notice it's very individual because some people taking high doses of fish oil have no problem whatsoever. Others have more easy bruising, or some signs, nosebleeds, that suggest that that is thinning the blood inordinately. Gazella: Right. And I agree- Hoffman: And that's a good effect. Ultimately, from a cardiovascular disease standpoint, that's actually a good effect. Gazella: Right. And I do agree with you, it's a highly individualized approach that each practitioner uses. What about contraindications and safety? Anything else that needs to be discussed regarding that? Hoffman: There are some studies that suggest that because omega-3 fatty acids sort of tamp down the immune system, as in autoimmune diseases, I love using them in conditions like Lupus and rheumatoid arthritis, that very high doses might suppress the immune system to the point where people are more vulnerable to infections. But I've seen a couple of suggestions in studies that that can be a problem. But I haven't seen it as a practical situation. Just as a potential caution. I would look to that possibly. Gastrointestinal symptoms limits its use because some people are prone to diarrhea. It's great for all sorts of ulcerative colitis, but that being a GI condition, it's sometimes hard to administer sufficient amounts to get a good effect. Gazella: Yeah. And the autoimmune conditions kind of caught my attention. So did you say that you use higher doses in cases of autoimmunity? Hoffman: I do. There are some studies that suggest that as much as 9,000 per day can be beneficial in ulcerative colitis, which is an autoimmune condition. But again, that too has been subject to question. Some study suggests that it's not as helpful as was once thought for UC. But I think it's just reducing the inflammatory cascade is very important in these diseases. So you can really sort of turn around. It's like using this powerful immune modulators that really target parts of the immune system and knock them out. Well, they knocked the immune system out to the point, the pharmaceutical drugs, where people are vulnerable to infections. And fish oil may be sort of a more gentle immune modulator that kind of turns down the volume on an autoimmune reaction. Gazella: Yeah. That's good information. So a big issue when it comes to fish oil supplementation is quality. I mean obviously quality is always a big issue. But it seems like it's even more important when it comes to fish oil in particular. Why is that? Hoffman: Well, there're a lot of issues with the quality and storage of fish oil. Fish oil, as a polyunsaturated fat, is subject to rancidity. So freshness is a big issue. I would look to a big reputable brand that's been around for a long time. I would also look at third-party certification. There are various places that do that. One of them is called IFOS, which is the International Fish Oil Standard program. There's also the USP and the NSF, the national standards, which give companies a validation that their product is pure and of good quality. You want to make sure there's no flavorings or colorings to bad artificial ingredients. Another issue is sustainability. There's this issue of overfishing the oceans. And one certification is offered by something called the Marine Stewardship Council. Which awards a certificate to companies that farm fish responsibly rather than devastating the environment. Fish oil should have maybe a faintly fishy smell, but if it has sort of a bigger acrid taste or smell, that's likely that it's rancid. And the other thing is just the potency. You want to look at products that deliver the requisite amount of EPA DHA per capsule. And that has to do with the degree of concentration and molecular distillation that they undergo to deliver active ingredient rather than just fishy extract in a capsule. You want to look at the presence of PCBs, or mercury. And there should be a purity guarantee. And especially when companies undertake a responsible self-testing, where they test batches of their material, and you can actually request their specs. You just email the company, or call a 800 number, and they can actually give you the specs on the product that you're taking, just to verify that you're not getting harmful amounts of mercury, or PCBs. So those are among the concerns. If you go to a place, and you find a bottle of fish oil, it's like $9.99 for 500 capsules, I mean, it's not very plausible that they're doing adequate quality control. Gazella: Right. I think that that's a really good point. Now when you're talking about... I want to touch on some of these. Because you brought up a lot for practitioners to think about when it comes to them choosing a high-quality fish oil supplement. So when you're talking about that third-party certification, is that third party company the one that tests for mercury and purity, and things like that? Or is that something that's done in-house by the manufacturer? Hoffman: I think it's actually responsible companies will test the material on receiving the material. First of all, they receive a big batch of fish oil before they encapsulate it. So they want to make sure that their supply chain is reliable. So they'll undertake pre-testing. They'll also sometimes do an audit. They'll say, "Let's take a bottle of this stuff at random, and let's do random testing and see if what comes out of the assembly line is fresh." I think they might do tests for lipid peroxides, but also free of contaminants. So it's more expensive to do that. There's no question. But responsible companies that want to maintain a good reputation and deliver quality products undertake that. And that's actually a selling point for them because the consumer can feel they're reliable. Gazella: Oh, I would agree. And I think for our listeners, they can get the specs of those random testing batches and the third party certification information, that all helps to know that they can— Hoffman: There's a lot number. There's actually a lot number on the products so that people could say, "Well I have lot number 56328. Can you show me the spec sheet?" And your eyes glaze over when you see these spec sheets. But you can actually see the contamination is like 0.0000000... way below what the EPA, for example, Environmental Protection Agency, would consider a toxic exposure. Gazella: Here's a random question. I was told once that if you have a fishy burp that that means the product is rancid. Hoffman: No. I think that's a kind of a misconception. You can minimize the fishy burp in a couple of ways. One is to take what are called enteric capsules, but there's a trade off. A, they're more expensive, and B, they don't contain as much fish oil. Enteric means that they're coated so that they break down lower in your GI track. The fishy burp can be camouflaged also by lemon flavoring, or orange flavoring, or sometimes cherry flavoring. And also to some extent the fishiness is associated with purity of the capsule. So products that are not highly distilled will have some... it's basically you're smelling the proteins, or the various residues that are not the active ingredient. But you can't really use that as an ironclad way of determining if the product you've taken is fresh or rancid. Gazella: Yeah. That's what I was thinking as well. Hoffman: I would not stand by that. And some people are highly sensitive to the smell or taste of fish oil. Some people have GERD or reflux. And they have an aftertaste of many things that they take in. Gazella: Right. Yeah. Okay. So what's your view on krill oil versus fish oil? Do you have a preference one over the other? And if you do, why? Hoffman: Well, okay. There's a lot of promotion of krill oil. And it's based on a couple of basic ideas. One is that while krill oil, the actual capsules may contain less fish oil, and some of the capsules are smaller. Those are usually easier to swallow, that's a selling point. That it's more bioavailable. I've looked at the studies that purport to show that and they're very few and far between. They're based on a small number of individuals. They don't really meet the threshold for demonstrating that the claims are really true, that you're going to get more into your system. The other benefit is said to be that they contain astaxanthin, which is a good thing supposedly. It's an antioxidant. It's got benefits. If you want to take astaxanthin, take it in a separate pill, or just eat farmed salmon. Because farmed salmon is loaded with astaxanthin. It's what they use to make the flesh look red. So I'm not the biggest fan of krill oil. Plus there's also a sustainability issue. It's very aggressively farmed. It's a form of crustacean that supports the whale population. And it's a little worrisome that there a scooping up all the krill to feed a very, very hungry marketplace in Europe and the United States. Gazella: Yeah, I would agree. I think that sustainability issue is really an important one. I also agree. I don't read nearly as many studies on krill oil as I do on fish oil. The issue of astaxanthin, is there even enough in krill oil to have a therapeutic effect? Hoffman: Yeah. First of all, astaxanthin is one of those things that has purported benefits, and I think it's on my radar screen amongst beneficial supplements. But it doesn't have as much robust information to support it as some of the more tried and true things like curcumin, and omega-3 fatty acids, and vitamin D, and coenzyme Q10. I think those are real stayer players. And astaxanthin is a little bit in an intermediate stage of credibility. Gazella: So what do you recommend for your vegetarian and vegan patients when it comes to essential fatty acid supplementation? Hoffman: Well, they can, I mean there's a couple of ways to go. One is to take flaxseed oil, or to eat a lot of nuts like walnuts and flaxseeds that are rich in omega-3 precursors. But the problem is the human body, and it's variable in its genetic capability. Some people convert very readily, and other people don't convert very well at all. So the solution then is to get vegan capsules. They're made from algae, and virtually every company that markets fish oils markets products for vegan users. The concentration of EPA and DHA is going to be a little less these. Most of these products skew more towards DHA than EPA because DHA predominates in algae as opposed to fish that you usually deliver more EPA than DHA. But you can go that that route. I think it's particularly important for vegans to supplement. if you're going to go vegan, you got watch for B12, you got to watch for zinc, you have to watch for your omega-3s, and certainly iron. And then you can frequently be a vegan. Gazella: Yeah, that makes a lot of sense. Now, we covered a lot today, but I want to make sure that we have covered everything associated with the utilization of essential fatty acids in clinical practice. What further advice can you give our listeners who are either using fish oil in their clinical practice, or want to use it differently, or want to use fish oil more in their clinical practice? What your bottom line advice to them? Hoffman: Well, I got to say keep your eye on the specific studies that clearly demonstrate the benefits of fish oil. Look at the therapeutic uses of fish oil. I think kind of ignore some of the bold headlines like "The Final Nail in the Coffin of Fish Oil." That's a little overdramatic. That was a JAMA headline last year that gleefully pounced on a study that showed that fish oil didn't make much difference. And also look to specific conditions. So for example, we're looking at concussions now. A very high dose fish oil in a protocol for concussions has been shown to be efficacious. So, there's 2 aspects. One is the general use. Yeah. Everybody should get some omega-3s. We should certainly eat fish, and perhaps supplement with some omega-3. But also look at the targeted application of fish oil as a therapeutic agent, not just as a dietary constituent for prevention. But as a molecularly targeted therapeutic agent that deserves a place alongside with our commonly used drugs, medications. It's no coincidence that a companies are now making concentrated fish oil, and selling them as prescription drugs on the pharmaceutical marketplace. Gazella: Yeah, I think that's great advice. Taking a look at this from a therapeutic targeted perspective in clinical practice I think is really important. I have to say following the research on fish oil, and EPA, and DHA is pretty exciting. Hoffman: It's a little bit like a watching Djokovic play in the finals at Wimbledon, going back and forth. Gazella: Exactly. I watched that match. It was incredible. Hoffman: It's like, well, let's see. Who's on top? Yeah. Gazella: Yeah. Well, as per usual Dr. Hoffman, this has been great. You've provided us with a lot of information that our listeners can use in their clinical practice. So I want to thank you for joining me. And I also want to, once again, thank our sponsor who is Carlson Labs. So thanks for joining me, Dr. Hoffman. Hoffman: Thank you very much, Karolyn. Really enjoyed talking to you. Gazella: Great. Have a wonderful day. Hoffman: You take care.
Last November we discussed the updated lipid guidelines. We wanted to revisit the treatment options for dyslipidemia and discuss some of the updated data that has been recently released. We review pathophysiology, as well as statin and non-statin therapy options. We walk through the algorithms for secondary prevention for patients with ASCVD, treatment for hypercholesterolemia, primary prevention, and statin use in patients with diabetes. We also review the recently published REDUCE IT trial from the New England Journal of Medicine. Below is the link for the ASCVD Risk Plus calculator: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/ Below is the link to the summary written by Wiki Journal Club for the REDUCE IT trial: https://www.wikijournalclub.org/wiki/REDUCE-IT If you have any questions, reach out to us on any of the following: Mike - mcorvino@corconsultrx.com Cole - cswanson@corconsultrx.com Instagram and other social media platforms - @corconsultrx This podcast reviews current evidence-based medicine and pharmacy treatment options. This podcast is intended to be used for educational purposes only and is intended for healthcare professionals and students. This podcast is not for patients and not intended as advice or treatment.
Recap of random pearls and highlights from SGIM19 Day 1 including: Kidney stone treatment (roller coasters, sex and tamsulosin), aspirin, SGLT2 inhibitors to reduce kidney events, oral antibiotics for endocarditis, preferred physician attire, sexual harassment, writing letters of recommendation, triple therapy for COPD, DAPT for stroke, and more! Special thanks to the Society for General Internal Medicine for their hospitality. Full show notes available at https://thecurbsiders.com/episode-list. Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Credits Written, produced, and cohosted by: Paul Williams MD, Matthew Watto MD, Justin Berk MD, Carolyn Chan MD, Shreya Trivedi MD, Abby Spencer MD, MS, Nora Taranto MS4 (soon to be MD!) Edited by: Matthew Watto MD Special Guest: Abby Spencer MD, MS Time Stamps and Links are included below 00:00 Intro and Disclaimer 02:33 Abby explains what it means to attend SGIM 04:35 Tips for writing letters of recommendation 08:54 How to handle lapses of professionalism in a trainee 10:30 How to address sexual harassment 12:42 Oral antibiotics after 10 days of IV antibiotics are noninferior for left sided endocarditis in non-IVDU (NEJM 2019) 14:22 Patients prefer physicians to dress in more formal attire. (BMJ Open 2018) 16:29 Kidney stone passage occurs more frequently when sitting in the back car of a roller coaster (J Am Osteopath Assoc 2018) 18:00 Sexual intercourse three times weekly improves rate of kidney stone passage (Urology 2015) 18:58 Vancomycin coverage for hospital acquired pneumonia can safely be stopped after four days if cultures remain negative for MRSA (Chest 2019) 20:00 Notes that contain stigmatizing language are associated with negative provider feelings and less aggressive pain management (JGIM 2018) 21:10 Medication errors are less frequent if the medication reconciliation is performed at time of ICU discharge (Ann Intensive Care 2018) 21:56 Five of six pediatricians found Lego heads in their stool after intentional ingestion (J Paediatric Child Health 2018). 24:40 Canagliflozin (SGLT2 inhibitor) improved renal outcomes and cardiovascular events (Credence trial, NEJM 2019; Check out the Freely Filtered (NephJC podcast coverage)) Triple therapy for COPD with LAMA/LABA/ICS is superior to dual therapy (IMPACT trial NEJM 2018) 27:20 The ASCEND trial of aspirin for primary prevention in patients with diabetes contained 97 percent white patients and showed similar NNT to NNH for cardioprotection and bleeding respectively (ASCEND trial NEJM 2018) 28:45 Consider a short course of dual antiplatelet therapy for minor stroke or high risk TIA (BMJ 2018) 30:07 Omega-3 fatty acids decreased cardiovascular events in patients whose triglycerides remained elevated despite statin therapy (REDUCE-IT trial NEJM 2019) 30:24 Tamsulosin did not help pass stones under 5 mm, but might be effective for stones >5 mm (J Fam Pract 2018) 31:06 Trainees who are stressed during residency tend to stay stressed (I was unable to quickly locate this citation. Sorry. -Dr. Watto) 32:02 How does our team choose their pearls for the recap show 35:21 A needs assessment at University of Michigan found that female residents want to learn skills on leadership, negotiation and giving pitches to prepare them for careers in medicine (Poster by Dr Jennifer Lukela). 36:57 Abby Spencer received an AAIM Innovations grant: “Key steps to rise for women trainees in leadership development”. 38:42 Outro
William E. Boden, MD, discusses his research in which he and his colleagues tried to replicate the results seen in the REDUCE-IT trial. His research was also presented at ACC.19 Scientific Session. More at: www.consultant360.com/cardiology.
In this week’s episode, John reviews some pharma breakthroughs—along with one major setback—and discusses the bold statement by the Department of Justice (DOJ) regarding the Affordable Care Act (ACA). Highlights include: The Department of Justice issued a letter stating that it agrees with a federal judge who struck down the entire ACA as unconstitutional. The FDA approved the first drug to treat postpartum depression: Sage Therapeutics’ Zulresso (brexanolone). Amarin Corp. presented updated results for its ongoing Vascepa (icosapent ethyl) clinical trial, REDUCE-IT, at the American College of Cardiology Annual Meeting. Biogen is scrapping its investigational treatment for Alzheimer’s disease, and is canceling its Phase III ENGAGE and EMERGE clinical trials. About Darwin Research Group Darwin Research Group Inc. provides advanced market intelligence and in-depth customer insights to health care executives, with a strategic focus on health care delivery systems and the global shift toward value-based care. Darwin’s client list includes forward-thinking biopharmaceutical and medical device companies, as well as health care providers, private equity, and venture capital firms. The company was founded in 2010 as Darwin Advisory Partners, LLC and is headquartered in Scottsdale, Ariz. with a satellite office in Princeton, N.J.
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.
Dans cette 21e baladodiffusion, le Dr Luc Lanthier discute du traitement des patients avec hypertriglycéridémie à haut risque cardiovasculaire avec des oméga-3 (étude REDUCE-IT), en plus de réviser la littérature médicale de novembre 2018. Quiz clinique (1min10), étude principale (1min40), critique (17min05), autres articles (25min10), réponse au quiz clinique (32min22) Référence principale Bhatt DL, Steg … Continuer la lecture de « BC 021 – Oméga-3 chez les patients à risque cardiovasculaire (étude REDUCE-IT) »
Tony Breu MD joins us for some hotcakes, and “cold cakes” including: how aspirin and zodiac sign affect the treatment of acute MI, a recent study on how exercise is probably still good for you, the recently announced REDUCE-IT trial, and the evidence (or lack thereof) for the treatment of hypertensive urgency. Welcome to another edition of Hotcakes and Hot Takes, where we discuss the most interesting articles and news that we have been reading. Special guest is the prolific Dr. Tony Breu (@tony_breu) who is an Assistant Professor of Medicine at Harvard Medical School and a Hospitalist and Director of Internal Medicine Resident Education at the VA Boston Healthcare System. He is known for his series on "Things We Do For No Reason” as well as his thought-provoking “Tweetorials” online. ACP members can visit https://acponline.org/curbsiders to claim free CME-MOC credit for this episode and show notes (goes live 0900 EST on day of release). Full show notes available at http://thecurbsiders.com/podcast. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Credits Written and Produced by: Sarah Phoebe Roberts MPH, Christopher Chiu MD CME Questions: Christopher Chiu MD Hosts: Matthew Watto MD, Stuart Brigham MD, Paul Williams MD, and Christopher Chiu MD Guest Presenter and Content Planning: Anthony Breu MD Editor: Christopher Chiu MD Cover-Art: Christopher Chiu MD Time stamps 00:00 Disclaimer, intro, guest bio 05:53 Discussion on Tweetorials 08:00 Cold Cake: ISIS-2 and the treatment of acute MI with aspirin 14:04 ISIS-2 and zodiac subgroup analysis 16:19 What is the relationship between cardiorespiratory fitness on mortality? 24:40 Discussion of the REDUCE-IT study 33:00 Cold Cake: VA Cooperative study and the evidence for treating essential hypertension 36:42 TWDFNR and the treatment of hypertensive urgency 46:36 Wrap-up and outro
So many overeat over the Thanksgiving Day weekend but can you eat too much and still be deficient in some vital nutrients? Can you be low in vitamin D and omega-3, not found in turkey or stuffing? Will you be healthier if you supplement routinely with vitamins like D3 and omega-3? There are a number of huge studies on this topic just published that we will review and translate as to what that means for you. We review REDUCE-It, VITAL and Seafood studies on this edition of Heart Doc VIP on Empower Radio.
Cardiac Consult: A Cleveland Clinic Podcast for Healthcare Professionals
Steven Nissen, MD, Chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic discusses several highlights from the 2018 AHA meeting: a summary of the newly released 2018 Management of Blood Cholesterol Guidelines; the outcomes of the VITAL trial which studied vitamin D and Omega 3’s impact on primary prevention of CV or cancer events; REDUCE-IT, a trial looking at the use of EPAs in the prevention of heart disease; and last, the results of a phase II, placebo-controlled study directed at patients with high levels of Lp(a), treated with a new drug.
In this special episode of the View, Kim Eagle and Peter Block discuss the highlights from Day 1 of the 2018 American Heart Association Scientific Sessions, including the VITAL, CIRT, and REDUCE-IT trials.
Amarin recently published data from their REDUCE-IT cardiovascular outcomes trial. Their EPA medicine, Vascepa, showed a 25% relative risk reduction compared to placebo. EPA is an omega-3 fatty acid that previously showed a 19% relative risk reduction in cardiovascular outcomes in a Japanese study (JELIS, 2007). Amarin saw a hazard ratio of 0.75 in their primary endpoint, which evaluated cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina. In this video, I go through two critiques of the study: 1) Lack of mechanistic insight 2) Mineral oil use in the placebo group I believe Vascepa is likely to get FDA approval for the indication of reducing cardiovascular disease in patients with over 150mg/dl Triglycerides on statin therapy. This is not investment advice, do your own due diligence.Relevant links: https://investor.amarincorp.com/ https://www.nejm.org/doi/full/10.1056/NEJMoa1812792 https://www.nejm.org/doi/full/10.1056/NEJMe1814004
-Amarin's EPA medicine, Vascepa, recently showed a 25% relative risk reduction in newly announced data from the cardiovascular outcomes trial, REDUCE-IT. -Today I breakdown the results and talk about how it compares to other CVOT data and whether Amarin is likely to rival companies with a LDL-c lowering drug pipelines.this is not investment/trading advice Follow me @matthewlepoire www.breakingbiotech.comRelevant links: http://investor.amarincorp.com/node/15741/pdf http://investor.amarincorp.com/system/files-encrypted/nasdaq_kms/assets/2018/09/27/10-23-58/AMRN%20Investor%20Deck%20Sept%20Post%20R-IT%20v3.pdf https://www.ncbi.nlm.nih.gov/pubmed/29935936
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