Podcasts about Ticagrelor

In this episode of the Scope of Things, host Deborah Borfitz delivers the news on an investigation into data reporting problems in major Ticagrelor clinical trial PLATO, the need for more sex-aware cancer research, Alzheimer's studies looking at brain shrinkage associated with immunotherapies (and repurposing drugs as potential new treatments), and a large, decentralized trial that successfully uncovered disease-causing genetic variants in hundreds of participants. Benjamin Vandendriessche, chief delivery officer of Digital Medicine Society, also joins in to talk about a newly completed project with the FDA that is providing guidance and resources on how to validate novel digital clinical measures.  News Roundup PLATO trial investigation Findings published in The BMJ “OncoSexome” project Paper in Nucleic Acids Research Brain shrinkage with Alzheimer's treatment Research in The Lancet Neurology  Repurposing drugs for Alzheimer's Study in Alzheimer's & Dementia  Mayo Clinic Tapestry study Article in Mayo Clinic Proceedings Guest  Benjamin Vandendriessche, chief delivery officer, Digital Medicine Society The Scope of Things podcast explores clinical research and its possibilities, promise, and pitfalls. Clinical Research News senior writer, Deborah Borfitz, welcomes guests who are visionaries closest to the topics, but who can still see past their piece of the puzzle. Focusing on game-changing trends and out-of-the-box operational approaches in the clinical research field, the Scope of Things podcast is your no-nonsense, insider's look at clinical research today.

Our initial review of the PLATO trial, published in April 2024, was based on the data available to us at that time. We have since became aware of new information that reduces our confidence in the PLATO results. This new information has major implications for clinical practice. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Despite representing only 6.9% of the total P2Y12 inhibitor prescriptions among Medicare beneficiaries in 2020, Ticagrelor accounted for nearly two-thirds of total Medicare spending on these drugs in the same year. We summarize important points below but you can refer to this investigation at BMJ for more details.1. Unexplained Regional Variation: In our original review, we highlighted the treatment effect interaction based on region of enrollment, where ticagrelor was less effective compared to clopidogrel for patients enrolled in North America. It appeared to be a strong signal and was associated with a p-value for the interaction of 0.05. However, we were cautious in our interpretation since overall, patients enrolled in North America represented a relatively small fraction of total patients and we could not think of a reasonable explanation.Information in the BMJ investigation now sheds new light on these findings. In our review, we only presented data contained in the supplement accompanying the PLATO trial manuscript, which categorized patients based on region of enrollment but did not provide country specific information. The BMJ report notes that in a separate subgroup analysis, based on country of randomization, the primary outcome was numerically higher with ticagrelor in the United States (12.6% vs 10.1%, HR: 1.27, 95% CI: 0.92 – 1.75). This subgroup represented 7.6% of the total trial participants. Overall, 9.7% of trial participants were enrolled from North America. This means the US data drove the findings from the North American subgroup.The explanation provided by AstraZeneca (the manufacturer of ticagrelor) to explain the observed treatment effect heterogeneity was that aspirin dosing in the United States was higher than in other countries. It even led the FDA to issue a black box warning to avoid an aspirin maintenance dose of >100 mg in patients taking ticagrelor. An extensive statistical analysis of the regional variation in PLATO yielded four interesting points. First what was the prior likelihood of observing a ticagrelor vs clopidogrel HR of > 1.25 in the US, when the overall HR was actually equal to 0.84? That probability is ≤ 0.01. This alone suggests more than chance. Second point: a strong US/nonUS interaction was noted for each of the 3 components of the primary endpoint—CV death, MI, stroke. Third: they found a very strong interaction between treatment and median aspirin dose, and, importantly, the aspirin interaction effect was similar in US and nonUS settings. Fourth, an analysis of contract research organization (CRO) vs sponsor monitoring of the site accounted for 61% of the treatment-by- region interaction. The authors downplayed this finding because of the four countries monitored by a CRO (Israel, US, Georgia and Russia), the US made up the majority and thus is confounded by the aspirin interaction. Noteworthy was a lack of direct analysis of CRO vs sponsor test for interaction. One problem though: the BMJ investigation found that the lead author, Kevin Carroll was the head statistician at AstraZeneca and had worked at the company for 20 years. Carroll presented the PLATO results at the FDA advisory meeting. The paper lists Carroll as having no conflicts. Carroll told the BMJ that he had disposed of all conflicts of interest before submitting that analysis. But, in our opinion, the aspirin explanation does not pass muster because of biologic implausibility. See next section: How would a higher dose of aspirin reduce the efficacy of ticagrelor?The primary composite endpoint was vascular death, MI or stroke. If the higher aspirin dose impacted this, we would hypothesize that it caused more major bleeding in the ticagrelor group with some events resulting in vascular death, type 2 MI and hemorrhagic stroke, driving the treatment effect in favor of clopidogrel. But there is no evidence of this.The figure below is from the original subgroup plots provided in the PLATO supplement. The difference in the treatment effect for the primary endpoint for North American patients is striking but there is no difference for major bleeding.In our opinion and the opinion of others, the role of supervision of the centers could be important. Most centers were monitored by the sponsor. Four countries (Israel, US, Georgia and Russia) were monitored by a contract research organization. All four of these countries had numerically higher rates of the primary outcome in the ticagrelor group. This has major implications and we do not take them lightly. Essentially, it suggests malfeasance on the part of the sponsor. So is there anything else to support such a claim? Well, yes. 2. Concerns about event adjudication. Based on a report from Victor Serebruany, an adjunct faculty member at Johns Hopkins University, and the BMJ investigation, FDA records indicated that site reports documented 504 myocardial infarctions in patients who received ticagrelor compared to 548 in patients who received clopidogrel. However, after adjudication, the count increased only for the clopidogrel group, reaching 593. There was also some imbalance among groups in adjudicating death. These imbalances raise concerns about potential unblinding and result tampering. We read many of the authors' replies and we did not find a clear explanation of why all readjudicated extra MIs were in the clopidogrel group (45 clopidogrel; ticagrelor 0). 3. There were also concerns about the accuracy of death records as sites death records did not always match the FDA records.We cite from the BMJ: The BMJ's analysis also found omissions in PLATO's landmark publication. The paper, published in NEJM and reported as an intent-to-treat analysis, reports 905 total deaths from any cause among all randomized patients. An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths “discovered after withdrawal of consent.” The BMJ obtained some records for patients whose deaths were not reported in NEJM (see table 1) and asked the journal for a response.NEJM editor in chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice,” concluding that “it does not appear that correcting this 15-year-old article is going to have any impact.”It is noteworthy that the United States Department of Justice launched a formal investigation into the PLATO trial in 2013; however, the probe was closed in 2014. The BMJ column cited a spokesperson for the US attorney's office who said…”we determined that the allegations lacked sufficient merit such that it was not in the best interests of the US to intervene in the suit.” 4. Mortality reduction in PLATO defies explanation: Shortly after PLATO was published, Drs. Victor Serebruany and Dan Atar wrote an editorial in the European Heart Journal titled: The PLATO trial: do you believe in magic? They noted that the overall HR for all-cause death ticagrelor vs clopidogrel was 0.78 (95% CI: 0.69 - 0.89; p< 0.001). There were 107 more lives saved with ticagrelor vs clopidogrel. To explain the surprise of this massive effect size, they compared it to the COMMIT trial of clopidogrel vs placebo in patients with acute MI. In COMMIT, 119 lives were saved with clopidogrel (vs placebo), but COMMIT had three-fold more patients than PLATO—and the gain was vs placebo. They tempt the reader to ask: how could ticagrelor fare that well against a drug that crushed placebo? We note two other reasons to be concerned about the outsized mortality reduction in PLATO. One is plausibility. The all-cause mortality benefit exceeded the reduction in MI, CV death or stroke. Given the numerically higher rate of bleeding, how else does ticagrelor reduce death vs clopidogrel? The second reason is the lack of such a signal in Phase 2 studies, such as this one. 5. PLATO results are on outlier: Multiple observational studies have failed to replicate the benefits of ticagrelor observed in the PLATO trial. While observational studies are inherently limited by confounding factors and are inferior to randomized trials, their findings warrant a re-evaluation of ticagrelor's benefits. Furthermore, two randomized trials—one conducted predominantly in Japanese patients and another in South Korea—did not demonstrate the superiority of ticagrelor, instead showing higher bleeding rates and a numerical increase in ischemic events.Ticagrelor also significantly underperformed against another new antiplatelet drug, prasugrel. In the non-industry-funded ISAR-REACT 5 trial, which enrolled patients with acute coronary syndrome, the primary event of death, MI, or stroke was 36% higher in the ticagrelor arm (9.3% vs 6.9%, HR 1.36, 95% CI: 1.09 - 1.70). Major bleeding was also numerically higher in the ticagrelor arm. 6. PLATO authors have responded to these arguments.We provide links to four of the authors responses. * Thrombosis and Hemostasis https://www.wellesu.com/10.1160/TH11-03-0162* Stroke https://www.ahajournals.org/doi/10.1161/strokeaha.111.000514* Inter J of Cardiol https://doi.org/10.1016/j.ijcard.2014.06.029* Circulation https://doi.org/10.1161/CIRCULATIONAHA.111.047498Conclusion These are vitally important revelations regarding PLATO and ticagrelor. The FDA advisory committee recommended that FDA require a confirmatory trial. This was not done. As such, ticagrelor gained serious market share in the non-clopidogrel antiplatelet market for more than a decade. Yet no other compelling evidence for its benefit over clopidogrel has come to light. It clearly underperformed vs prasugrel. These old and new revelations have changed our positive view of ticagrelor. We no longer have confidence in this drug. We strongly agree with the recommendation for another properly controlled trial. We also believe this highlights the benefits of having either two regulatory trials or a single regulatory trial combined with a mandated post-approval trial. These revelations also emphasize the benefits of robust critical appraisal and skeptical but not cynical approaches to surprising evidence. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

TWiM explains how ticagrelor alters the membrane of S. aureus and enhances the activity of vancomycin and daptomycin without eliciting cross-resistance, and the development of a novel continuous disinfectant technology that decreases healthcare-associated infections in ICUs by 70%. Hosts: Vincent Racaniello, Michael Schmidt, and Michele Swanson. Become a patron of TWiM. Links for this episode Ticagrelor and S. aureus (mBio) Novel disinfectant technology (Am J Inf Control) UVC-LED to inactivate foodborne pathogens (Appl Envir Micro) UV disinfection systems (ACS Photonics) High-touch surfaces in specialized patient care area (CDC) Take the TWiM Listener survey! Send your microbiology questions and comments (email or recorded audio) to twim@microbe.tv  

34th ESC 2024: Ticagrelor monotherapy vs. dual antiplatelet therapy

In this episode of Medmastery's Cardiology Digest, we dive into three groundbreaking studies that are set to reshape our understanding and approach to cardiology. STUDY #1: First, we discuss a landmark piece of research that sheds new light on the benefits of percutaneous coronary intervention for patients with significant coronary artery disease who need a transcatheter aortic valve replacement. This study addresses important questions about patient selection for this intervention.   Lønborg, J, Jabbari, R, Sabbah, M, et al. 2024. PCI in patients undergoing transcatheter aortic-valve implantation. N Engl J Med. Published online. (https://doi.org/10.1056/NEJMoa2401513) STUDY #2: Next, we examine an insightful meta-analysis that evaluates patient-level data to inform the future of dual antiplatelet therapy after percutaneous coronary intervention. Discover the factors influencing the transition to ticagrelor monotherapy post-PCI and why this could change current guideline recommendations.  Valgimigli, M, Hong, S, Gragnano, F, et al. 2024. De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: A systematic review and individual patient-level meta-analysis of randomized trials. Lancet. 10456: 937–948. (https://doi.org/10.1016/S0140-6736(24)01616-7) STUDY #3: Lastly, we take a closer look at the EPIC-CAD study, which aligns with previous findings from the AFIRE trial. Learn why anticoagulant monotherapy is now being considered for the majority of patients with atrial fibrillation who require anticoagulation and have stable coronary artery disease, and what this means for your clinical practice. Cho, MS, Kang, D-Y, Ahn, J-M, et al. 2024. Edoxaban antithrombotic therapy for atrial fibrillation and stable coronary artery disease. N Engl J Med. Published online. (https://doi.org/10.1056/NEJMoa2407362) Tune in to this episode for an engaging in-depth discussion of these studies and stay ahead in the ever-evolving field of cardiology!  Learn more with Medmastery's courses: Percutaneous Coronary Intervention Essentials (6 CME) Percutaneous Coronary Intervention Essentials Workshop (6 CME) Get a Basic or Pro account, or, get a Trial account. Show notes: Visit us at  https://www.medmastery.com/podcasts/cardiology-podcast.

Welcome back Rounds Table Listeners!We are back today with our Classic Rapid Fire Podcast!This week, Drs. Mike and John Fralick discuss two recent papers exploring the role of ticagrelor with aspirin versus ticagrelor alone after percutaneous coronary intervention in acute MI and the efficacy of empagliflozin after acute MI. Two papers, here we go!Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT) (0:00 – 9:22). Empagliflozin after Acute Myocardial Infarction (9:22 – 16:00).And for the Good Stuff:Impact of presentation at conference with timed release of academic publication (16:00 – 17:32).Top spot in the PWHL and attendance record at stake in latest Montreal-Toronto showdown (17:32 – 19:59).Questions? Comments? Feedback? We'd love to hear from you! @roundstable

Commentary by Dr. Valentin Fuster

Ticagrelor Monotherapy in Patients with Acute Coronary Syndrome: An Individual Patient Data Meta-Analysis of Randomized TICO and T-PASS Trials

N Engl J Med 2009;361:1045-57.Background Similar to Prasugrel, Ticagrelor is a direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Unlike clopidogrel that requires transformation of the prodrug to the active metabolite, Ticagrelor provides faster and more consistent P2Y12 inhibition.In the TRITON-TIMI 38 trial, Prasugrel compared to clopidogrel reduced myocardial infarction in patients with ACS but was associated with more major bleeding and subgroup interactions were evident for patients who were older, had a history of stroke or risk factors for bleeding and who were generally at higher risk for recurrent events.The Study of Platelet Inhibition and Patient Outcomes (PLATO) sought to test the hypothesis that Ticagrelor is superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Eligible patients were hospitalized for ACS, with or without ST-segment elevation (STE), whose onset of symptoms occurred within the previous 24 hours. For patients without STE, at least 2 of the following criteria were required: 1) ST-segment changes on ECG indicating ischemia, 2) a positive biomarker indicating myocardial necrosis, or 3) one or more risk factors including age ≥60 years, previous MI or CABG, CAD with stenosis of ≥50% in at least 2 vessels, history of ischemic stroke, TIA, carotid stenosis, cerebral revascularization, diabetes, peripheral arterial disease or CKD based on creatinine clearance

Commentary by Dr. Valentin Fuster

EpicMedia-EP.32 Ticagrelor o prasugrel frente a clopidogrel en la ICP del síndrome coronario crónico. Dr Pablo Baglioni

⁠DozeNews PRIME⁠: as melhores e mais didáticas revisões de cardiologia direto na sua caixa de entrada! Assine agora e tenha acesso à todo material já produzido! - ⁠https://dozeporoito.substack.com/

Commentary by Dr Jack Tan

Dual antiplatelet Tx. with Ticagrelor and graft failure after CABG

Quanto tempo parar o ticagrelor antes de cirurgias? by Cardiopapers

In this week's episode we'll learn more about the negative findings from the phase three trial of ticagrelor for preventing vaso-occlusive crises in children with sickle cell disease, discuss how residual cytoplasmic UBA1 contributes to the pathogenesis of VEXAS syndrome, and learn more about the impact of host T-cell immunity in the response to chemotherapy in pediatric ALL.

On this episode, I discuss ticagrelor pharmacology, adverse effects, and important drug interactions. Ticagrelor has a warning with regards to the use of aspirin. Higher doses of aspirin can impair the effectiveness of ticagrelor and I discuss this further on this episode. Bleeding is the major adverse effect from ticagrelor and naturally, hematocrit and hemoglobin are important monitoring parameters. I discuss CYP3A4 drug interactions on this episode and how it may affect ticagrelor.

Pyrlcasts, brought to you by Pyrls.com! We take a closer look at interesting and relevant clinical topics related to pharmacotherapy. Want to learn more clinical pearls? Boost your clinical confidence? Visit and sign-up for an account at pyrls.com to get over 10 high-quality charts absolutely FREE! Episode References: Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery [published correction appears in Circulation. 2016 Sep 6;134(10):e192-4]. Circulation. Cattaneo M, Faioni EM. Why does ticagrelor induce dyspnea?. Thromb Haemost. 2012;108(6):1031-1036. doi:10.1160/TH12-08-05472016;134(10):e123-e155. doi:10.1161/CIR.0000000000000404 Krakowiak A, Kuleta J, Plech I, et al. Ticagrelor-Related Severe Dyspnoea: Mechanisms, Characteristic Features, Differential Diagnosis and Treatment. Clin Med Insights Case Rep. 2020;13:1179547620956634. Published 2020 Oct 8. doi:10.1177/1179547620956634 Undem BJ, Kollarik M. The role of vagal afferent nerves in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):355-372. doi:10.1513/pats.200504-033SR PLAVIX- clopidogrel tablet, film coated. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Accessed via DailyMed. Updated March 5, 2021. BRILINTA- ticagrelor tablet. AstraZeneca Pharmaceuticals LP. Accessed via DailyMed. Updated May 9, 2022. PRASUGREL tablet, film coated. Accord Healthcare Inc. Accessed via DailyMed. Updated May 21, 2021.

Dear friends, in this episode we summarized recent data on potent antiplatelet therapy. You can also download the slides via this link:http://ecardiocast.com/wp-content/uploads/2022/06/antiplatelet-therapy.pdf

Dear friends, in this episode we summarized recent data on potent antiplatelet therapy and Kimiara company provided us the data on Brelor. You can also download the slides via this link:http://ecardiocast.com/wp-content/uploads/2022/06/antiplatelet-therapy.pdf

TicaHub 2

Ticagrelor and secondary prevention in CCS

CME credits: 1.50 Valid until: 25-04-2023 Claim your CME credit at https://reachmd.com/programs/cme/bentracimab-immediately-and-significantly-reverses-the-antiplatelet-effects-of-ticagrelor-in-older-people/14057/ tbd

Managing dyspnea induced by Ticagrelor

Ticagrelor in preventing post-ACS thrombotic events

The findings of TWILIGHT Trial

The dosage and indications of Ticagrelor

AF triggers, rising BP during the pandemic, long COVID, cardiac arrest care, and social media are the topics John Mandrola, MD discusses in this week's podcast. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I – AF Triggers - Alcoholic Drinks Stand Out in Novel Trial Exploring AF Triggers https://www.medscape.com/viewarticle/962911 - Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation https://jamanetwork.com/journals/jamacardiology/article-abstract/2786196 II – BP Increase During the Pandemic - Blood Pressure Control Worsened During COVID Pandemic https://www.medscape.com/viewarticle/964329 - Rise in Blood Pressure Observed Among US Adults During the COVID-19 Pandemic https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.057075 III – DOAC after VTE - Apixaban Outmatches Rivaroxaban for VTE in Study https://www.medscape.com/viewarticle/964301 - Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data https://www.acpjournals.org/doi/full/10.7326/M21-0717 - Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes https://www.nejm.org/doi/full/10.1056/NEJMoa1908973 IV – Long Covid - In Long COVID, CPET Finds Abnormalities Other Tests Don't https://www.medscape.com/viewarticle/964250 - Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post–Coronavirus Disease https://doi.org/10.1016/j.jchf.2021.10.002 V – Cardiac Arrest Care - Calcium Does Not Benefit Patients in Cardiac Arrest https://www.medscape.com/viewarticle/964059 - Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest https://jamanetwork.com/journals/jama/fullarticle/2786819 VI – Social Media - Online Reviews Most Important Factor in Choosing a Doctor: Survey https://www.medscape.com/viewarticle/964264 Features: - Booze Out, Coffee Okay to Outsmart Atrial Fibrillation? https://www.medscape.com/viewarticle/961993 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

Quanto tempo parar o ticagrelor antes de cirurgias? by Cardiopapers

RAPID CABG Trial was recently presented at the AHA 2021. It tested the strategy of EARLY CABG AFTER TICAGRELOR vs delayed CABG after Ticagrelor administration.

REVERSE- IT Trial. Bentracimab for ticagrelor reversal. AHA 2021

On Episode 10 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2021 issue of Stroke: “Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke” and “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.” She also interviews Dr. S. Claiborne Johnston about “Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.” Dr. Negar Asdaghi: 1) What is the net ischemic benefit derived from combination of ticagrelor and aspirin treatment in patients with mild ischemic stroke or transient ischemic attack? 2) Is the ischemic stroke in patients hospitalized with COVID-19 associated with the rise in biomarkers of inflammation and coagulopathy? 3) What are the characteristics associated with periprocedural stroke in patients treated endovascularly for an unruptured AVM? We'll discuss these topics and much more at today's podcast. Stay with us. Dr. Negar Asdaghi:                        Welcome back to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the November 2021 issue of Stroke, we have a large selection of topics, from peanut consumption reducing the risk of ischemic stroke, and the decline in the rate of progression of coronary atherosclerosis in patients on a Mediterranean diet, to how the efficacy of endovascular thrombectomy diminishes in patients with more pervious thrombus composition, which I encourage you to review in addition to our podcast today. Dr. Negar Asdaghi:                        Later in the podcast, I have the distinct honor of interviewing Dr. Claiborne Johnston from Dell Medical School at UT Austin on his latest work with data from the THALES trial to clarify the net ischemic benefits derived from a combination of ticagrelor and aspirin therapy in comparison with the risks of hemorrhage associated with this treatment in patients with mild and moderate stroke and TIA. But first with these two articles. Dr. Negar Asdaghi:                        COVID-19–associated ischemic stroke, or CAIS, is a new term that, unfortunately, stroke physicians need to be familiar with. While acute ischemic stroke can occur in parallel from, say, traditional causes of stroke in patients infected with coronavirus, ischemic stroke and other thrombotic events, such as myocardial infarction, pulmonary embolism, deep vein thrombosis, and acute limb thrombosis, can occur in the setting of overt hyperinflammation and subsequent coagulopathy that is observed in patients hospitalized with severe COVID-19 illness. Dr. Negar Asdaghi:                        Elevated D-dimer, although quite non-specific, has emerged as a marker of COVID-19–associated coagulopathy, but whether an elevated D-dimer in isolation or in combination with various other inflammatory and coagulation markers is associated with development of acute in-hospital ischemic stroke in those hospitalized with COVID is not known. Dr. Negar Asdaghi:                        So, in the current issue of the journal, in the article titled "Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke,” Dr. Charles Esenwa from the Department of Neurology at Montefiore Medical Center and colleagues did an interesting analysis of over 5,000 patients with COVID-19 who were admitted to one of the Montefiore Health System hospitals between March 1, 2020 and May 8, 2020. This was a retrospective analysis, so they had to work with the available biomarkers for each patient and use a machine learning cluster analysis of these biomarkers to divide the patients basically based on five biomarkers to four clusters. Dr. Negar Asdaghi:                        The following five biomarkers were chosen by this machine learning cluster analysis. These included CRP, D-dimer, LDH, white BC, and PTT. So, they had to come up with some arbitrary rules to exclude biomarkers that were either missing in over 30% of their population, and they also excluded those patients that were hospitalized for a long period of time, and they chose a 30-day hospitalization and over. And they also only used the first reading for each biomarker. Again, these were arbitrary rules that were set forth by the authors, and they found some alarming findings. When they clustered patients based on similarities in these biomarkers, they came up with predicted models for combined thrombotic events and acute ischemic stroke. Dr. Negar Asdaghi:                        For example, in the cluster where the patients had the highest mean values for CRP, D-dimer, LDH, and white BC, and a relatively low PTT, these patients had the highest prevalence of acute ischemic stroke. They had the highest prevalence of in-hospital strokes and severe strokes and highest percentage of total thrombotic events. In contrast, the cluster with the lowest mean of all of these five biomarkers had no cases of in-hospital acute ischemic strokes; they had the lowest prevalence of composite, all thrombotic events, and patients had the least severe complications. Dr. Negar Asdaghi:                        So, they also tested the effects of biomarkers individually for prediction of acute ischemic stroke. And it turns out that when they used a lone marker, only D-dimer again was associated with acute ischemic stroke. Very interestingly, D-dimer was specifically elevated in those COVID-19 patients in whom the stroke was ultimately classified as cryptogenic. Dr. Negar Asdaghi:                        So, what does that mean? That means that it's more likely that a stroke had occurred in the setting of severe COVID-19 hyperinflammatory response, and less likely associated with other classical causes of stroke. Dr. Negar Asdaghi:                        So, what did we learn overall from this study? Well, hospitalized COVID-19 patients with a combination of high CRP, D-dimer, LDH, and white BC, and slight reduction in their PTT, had a 4.5-fold increase in the risk of in-hospital mortality and a fivefold increase in the risk of in-hospital stroke as compared to the COVID-19 patients with the lowest mean values for all the five biomarkers mentioned above. So, important information to keep in mind as we treat hospitalized COVID-19 patients, and we await more prospective data on this topic. Dr. Negar Asdaghi:                        Arteriovenous malformations, or AVMs, are congenital vascular lesions that are associated with long-term excess mortality and morbidity, essentially almost all related to their risk of intracerebral hemorrhage. Roughly half the patients with brain AVMs present with intracerebral hemorrhage, resulting in a first-ever hemorrhage rate of about 0.5 per 100,000 person years. Dr. Negar Asdaghi:                        Annual risk of hemorrhage is estimated at 1 to 4% for all comers with AVMs, but varies significantly, and can be as low as 0.9% in patients with unruptured, superficially located brain AVMs with superficial drainage, but may be as high as over 34% in patients with ruptured, deeply seated brain AVMs with deep venous drainage. So, treatment would entirely be dependent on the type of presentations and characteristics of each patient with an AVM. Dr. Negar Asdaghi:                        Whether unruptured AVMs should be managed clinically or treated either endovascularly or surgically is the subject of the ARUBA trial that is a randomized trial of unruptured brain AVMs. The enrollment of ARUBA was halted by the study's DSMB board, but medical management was found to be superior to treatment arm for the primary outcome of symptomatic stroke and death. Dr. Negar Asdaghi:                        Since then, there's been a lot of focus in the literature and comparison of outcomes between treated and untreated patients with unruptured AVMs, but less has been published on characteristics of patients who suffered from periprocedural stroke, an important part of the primary outcome of ARUBA. So, in the current issue of the journal, we have the study titled “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.” Dr. Negar Asdaghi:                        Dr. Joshua Burks and colleagues from the Department of Neurosurgery at the University of Miami and colleagues evaluated 64 patients with unruptured AVMs enrolled in the ARUBA trial who underwent endovascular treatment as part of the trial and looked at the characteristics of those who suffered a perioperative stroke, defined as a stroke recorded at or within 48 hours of intervention, as this would represent a direct procedure-related complication rather than sequelae of, say, treated or partially treated AVM itself. Dr. Negar Asdaghi:                        All patients who initiated endovascular intervention, including attempted interventions in cases where therapy was aborted secondary to technical or anatomical limitations, were included regardless of randomization or subsequent withdrawal from the study beyond 48 hours following the intervention. So, what they found was that 16% of interventions resulted in stroke, 11% hemorrhagic, and 5% ischemic strokes. And they had no perioperative mortality, which is good news. Dr. Negar Asdaghi:                        In univariate analysis, they found many factors that were more commonly seen in patients that suffered from perioperative stroke as compared to those who did not have a stroke perioperatively. Those factors included, for instance, female sex. Over half of these patients were female. Close to half were enrolled in France. And over 40% of those who suffered a stroke in the perioperative timeframe had Spetzler-Martin grade two AVMs. Dr. Negar Asdaghi:                        When they accounted for all confounding variables, they found that endovascularly treated unruptured AVMs that are supplied by the posterior cerebral artery cortical feeders and those with Spetzler-Martin grade two and three had a higher perioperative stroke risk as compared to their counterparts without these characteristics. Interestingly, there are also significant geographical disparities in the risk of stroke in that patients treated in the United States or Germany had a significantly lower stroke risk than patients treated in other countries. Dr. Negar Asdaghi:                        So, what did we learn from this study? There are patients and lesion characteristics that increase the risk of stroke associated with endovascular treatment of unruptured AVMs. The current study suggests that AVMs with cortical arterial feeders from posterior cerebral artery and those with grade two and three Spetzler-Martin were associated with a higher risk of procedural and periprocedural stroke. Dr. Negar Asdaghi:                        And very importantly, as with every surgical intervention, the risk of a procedure is operator-dependent, as well as center-dependent. And these are important factors to keep in mind as technology evolves and more treatments become available to decide whether to keep or to refer patients with unruptured AVMs to a more experienced center. Dr. Negar Asdaghi:                        Patients with mild ischemic stroke and transient ischemic attack are at high risk of having recurrent ischemic events, especially in the immediate aftermath of their symptom onset. Early diagnosis and initiation of secondary preventive measures, such as antiplatelet or anticoagulation therapies, in the appropriate setting considerably reduce this recurrent risk. Dr. Negar Asdaghi:                        Multiple randomized trials have shown that as compared to treatment with a single antiplatelet agent, dual antiplatelet treatment is more effective in reducing the risk of stroke and other major vascular events in the TIA mild stroke population, a benefit that comes with an expected increase in the risk of hemorrhage. Dr. Negar Asdaghi:                        THALES trial is one of the latest trials to determine the efficacy of dual, which is combination of ticagrelor and aspirin, versus mono-antiplatelet therapy, that is aspirin alone, in eligible patients with non-cardioembolic acute ischemic stroke and TIA. Now, it's important to keep in mind that the primary outcome of THALES is a composite of stroke or death, which included both ischemic and hemorrhagic events. Dr. Negar Asdaghi:                        Now, it's important to understand that while in the setting of a clinical trial, combining the risks associated with dual antiplatelet therapy, which is hemorrhage, and the potential treatment benefit, that is reduction of recurrent ischemic events, is appropriate as part of the outcome selection. In routine practice, this type of primary outcome can obscure the actual trade-offs between the benefits of dual antiplatelet treatment and its inherent hemorrhagic risk. Dr. Negar Asdaghi:                        So, in this issue of the journal, in the study titled "Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack," the THALES investigators led by Dr. Claiborne Johnston sought to separate the ischemic benefits of combination of ticagrelor and aspirin therapy from its hemorrhagic risks in patients enrolled in the trial. Dr. Negar Asdaghi:                        I'm joined today by Professor Johnston to discuss the findings of this paper. Dr. Johnston absolutely needs no introduction to the stroke community and our readership. He's a Professor of Neurology at Dell Medical School at the University of Texas at Austin. He's a leader in the field of cerebrovascular disorders, has served as the primary investigator of multiple randomized trials and large prospective studies to evaluate the preventive treatment outcomes in TIA and mild stroke, and has pioneered the development and validation of predictive models for recurrent stroke in this population. He's authored over 700 peer-reviewed manuscripts, has won several awards for research and teaching, and is recognized for his leadership in the field of medicine and healthcare. Dr. Negar Asdaghi:                        Good morning, Clay. We're delighted that you could join us on the podcast. Dr. S. Claiborne Johnston:           Well, thank you. It's wonderful to be here. Thank you for having me. Dr. Negar Asdaghi:                        Thank you. So, THALES is an exciting new addition to the most recent trials of dual antiplatelet therapy that studied mostly the role of clopidogrel and aspirin combination therapy. Can you please start us off by telling us why did we need a new trial in a very similar patient population? Dr. S. Claiborne Johnston:           Well, the primary reason was, yes, clopidogrel works in combination with aspirin in the setting, but clopidogrel is actually a prodrug. It requires conversion in the liver to its active form. And polymorphisms in CYP2C19 and Cyt P450 pathways are really common and associated with an inability or limited ability to convert that prodrug into its active form. So, there are a number of people who may not benefit much, if at all, from clopidogrel. So, it's kind of surprising that it works as well as it does. Dr. S. Claiborne Johnston:           Ticagrelor doesn't have that problem. It's not a prodrug. It acts directly on the P2Y12 inhibitor. And so, the hope was that we would have a more consistent and pronounced effect on risk reduction in patients after TIA and mild to moderate strokes. Dr. Negar Asdaghi:                        Primary efficacy outcome in THALES was different from the primary efficacy outcome chosen for the POINT trial, that was major ischemic events and death from ischemic vascular events, and that of the CHANCE trial, that was a combination of ischemic and hemorrhagic strokes in 90 days. Can you please tell us about the thought process behind choosing this particular primary efficacy outcome in THALES? Dr. S. Claiborne Johnston:           Yeah, so this was encouraged by the regulatory authorities. And so the primary efficacy outcome in THALES is all stroke, hemorrhagic and ischemic, and all death, hemorrhagic and ischemic. And we teased apart just the ischemic etiologies in POINT. Dr. S. Claiborne Johnston:           The rationale was that we were including all the major outcomes that the drug could impact. The problem is that people forget that it includes hemorrhagic events, and then they weigh that efficacy outcome against the safety outcome. And so there's confusion. There's sort of double-counting of safety elements in doing that comparison. Dr. Negar Asdaghi:                        Okay, great. And now, before we hear about how you disentangled the two safety and efficacy outcomes, can you please remind our listeners about the primary results of THALES, which was published obviously a few months ago? Dr. S. Claiborne Johnston:           Yeah, sure. So, it showed that the combination of ticagrelor and aspirin works. It reduced the stroke and death by about 17% over the 30-day period of treatment. So robust effect. There were some increased hemorrhages, and looking at severe hemorrhage as defined by the GUSTO definition, there was almost a fourfold increase, but it was tiny in absolute terms of 0.4% increase. Dr. Negar Asdaghi:                        Okay. So, now it's very important, as you mentioned, this disentangling of recurrent ischemic, again, safety from efficacy outcomes. Your current study that is published in the November issue of Stroke clarified these results. And we're excited to hear about those results. Dr. S. Claiborne Johnston:           That's right. So, there were two problems with the way people have interpreted the results of the THALES trial. One is this entanglement of safety events and both efficacy outcome and the safety outcome. The other was the use of relative risks as opposed to absolute risks, because a high relative risk for a rare event is less important than a small relative risk for a more difference between more common events. And so we wanted to deal with both of those issues. Dr. S. Claiborne Johnston:           So, we defined new outcomes that were not entangled. So, we defined major ischemic events, similar to what we had done in POINT, and then we defined major hemorrhage as being basically irreversible hemorrhage, and compared outcomes in the two groups. And what we found was that when we did it that way, for every 1,000 patients treated, we avoided 12 major ischemic events and produced three major hemorrhages. So, about a four-to-one ratio of ischemic benefit to hemorrhage risk. And that was true at various cutpoints for disability. Dr. S. Claiborne Johnston:           So, if we said, "Okay, yes, you had an event, and are you disabled at last follow-up at 30 days?" Then if we said that, there was also a four-to-one difference in disabling events, ischemic versus hemorrhagic. And if we said a two or greater, so moderate disability or worse, it was the same ratio, four-to-one. Dr. Negar Asdaghi:                        Okay, so four-to-one ratio of benefit. That's an important number to keep in mind. Also reassuring to see that this net clinical benefit or net clinical impact of the combination of therapy was practically the same across all the pre-specified subgroups in the trial. Were you at all surprised by the subgroup analysis? Dr. S. Claiborne Johnston:           Well you know if you do enough subgroup analyses, you're going to find differences, right? And thankfully, we have the looking at interaction terms to keep us honest, but even so, you look at 20 and you're going to have some significant interaction terms, as well. But yeah, it was reassuring that the effects were so consistent across groups. Dr. S. Claiborne Johnston:           I think there's been a tendency to over-interpret results from subgroup analyses. We don't have any evidence to suggest that we should be doing that here. I'm sure we can pick out groups that do better, and we've done that actually. The group with atherosclerosis does particularly well, but is that a chance event or is that real? I think we just have to be super-cautious about subgroup analyses. Dr. Negar Asdaghi:                        So, absolutely. One of the subgroups that I'm personally very interested in is just the time subgroup. So, all of the patients in THALES were enrolled within the first 24 hours, and the subgroup analysis did not show that there were any differences in terms of the net benefit between those that were enrolled earlier, within the first 12 hours, and those that were enrolled later, between 12 and 24 hours. But in routine clinical practice, we often see patients with TIA and mild stroke actually presented to us later than that timeframe entirely. Should we be giving them dual antiplatelet treatment? Dr. S. Claiborne Johnston:           That's a great question. So, we did an analysis in POINT where we modeled out, would we still have an important significant net benefit if we had started the trial later? And we didn't start the trial later, right? So, this was just pretending like anybody who had an event early on was not in the study in starting at a later timepoint and modeling that out. And basically what we found was that for out to three days, there was still a benefit. And, in fact, if you look at that data and look at those tables, you could even say, even out to five days. Dr. S. Claiborne Johnston:           I would say it's not unreasonable to do that given that the risks are so small and they're going to be even later with later treatment. But I would say, too, that even though we're not seeing greater impact within that first 24 hours versus 12 to 24, it just makes sense with event rates being as great as they are early on that if you don't treat with a preventive medication before an event occurs, it doesn't work. So, it just makes sense that as much as possible we ought to treat people as early as possible after their events. Dr. Negar Asdaghi:                        Very important findings and things to keep in mind. I want to ask you about the top two takeaway messages from the study. Dr. S. Claiborne Johnston:           One is that there's a favorable benefit-to-risk ratio for ticagrelor/aspirin in mild to moderate actually ischemic stroke and high-risk TIA from THALES. So that would be number one. Dr. S. Claiborne Johnston:           And then number two is watch your endpoints carefully. Think carefully, too, about whether balancing safety to efficacy events really makes sense and also whether focusing on relative risks really makes sense. I would encourage us, even though our journals tend to push us towards relative risks and we're more familiar with those, I'd encourage us to get more comfortable with using absolute risks in the way we look at data, but also in the way we talk to patients about their impact. Dr. Negar Asdaghi:                        Fair enough. I remember a few years ago, you visited us here at the University of Miami to deliver the annual Cerebrovascular Scheinberg Lecture. And you had mentioned that the idea of dual antiplatelet therapy treatment of patients with TIA mild stroke had come to you many years back when you were still in training, but it took many years for that idea to turn into reality, into randomized trials, and now translated into clinical practice. Dr. Negar Asdaghi:                        At the time, if you recall, this was right before you went to Europe to present the primary results of POINT at the European conference. And the trial results were not publicly available, so you were sworn to secrecy. You couldn't tell us about the results. It's been a few years since then. You've already completed yet another trial on this topic. Can I ask what's next for you and your team as it pertains to acute treatment of patients with TIA and mild stroke? Dr. S. Claiborne Johnston:           Well, there are a few things. So, CHANCE-2 is a really interesting trial. My role in that was peripheral, just really advisory, but it's an exciting trial. So, basically it's looking at people with those CYP2C19 polymorphisms that I mentioned before, people who don't rapidly and readily convert clopidogrel to its active form, and randomizing them to clopidogrel versus ticagrelor. Dr. S. Claiborne Johnston:           So, it's going to give us some head-to-head data on the two drugs and the people who may benefit the most from ticagrelor. And that is complete, and that will be published in the next few months. So, I that's going to be an important trial in people's thinking about how best to approach these patients. Dr. S. Claiborne Johnston:           The second is, you know, we're not done. We still have a 5% risk of events, even in those three dual antiplatelet therapy. And so we need more agents. And we need to think about secondary prevention extending to other groups as well, just as you said, longer periods of time, more severe strokes, people after thrombolysis/thrombectomy. Those are big groups of patients at extreme risk for secondary events, and we have no agents and no data right now. Dr. S. Claiborne Johnston:           I would be concerned about dual antiplatelet therapy in those patients, just given what we've seen about the risks of hemorrhage in the existing groups, which are again manageable and shouldn't change people's decision about treatment. But for the groups I just mentioned, risks of hemorrhage start to get greater. And so one worries about whether dual antiplatelet therapy's the right thing or whether other agents make more sense. So, yeah, we're interested in looking at other agents, some novel, for those other indications as well. Dr. Negar Asdaghi:                        Professor Johnston, thank you for your time, and we look forward to covering more of your research in the future. Dr. S. Claiborne Johnston:           Well, thank you. It's been a pleasure. Dr. Negar Asdaghi:                        Thank you. Dr. Negar Asdaghi:                        And this concludes our podcast for the November 2021 issue of Stroke. Please be sure to check out the November table of contents for a full list of publications, including two important topical review articles, one on thrombus composition after thrombectomy, and one on pearls and pitfalls of perfusion imaging in acute ischemic stroke, as advanced neuroimaging continues to play a critical role in decision-making for acute stroke therapies. Dr. Negar Asdaghi:                        Now, speaking of advanced neuroimaging and the immense role that neuroimaging plays in our day-to-day practice, let's take a moment as we end our November podcast to remember how the concept of medical imaging first began over 120 years ago with the discovery of X-ray by German professor of physics Wilhelm Röntgen. Dr. Negar Asdaghi:                        On Friday, November 8, 1895, while experimenting with electricity, Röntgen accidentally discovered a new kind of rays that he referred to as X-rays. He soon realized that X-rays were capable of passing through most substances, including the soft tissues of the body, but left bones and metals visible. Dr. Negar Asdaghi:                        One of his earliest photographic plates of his experiments was a film of his wife Bertha's hand with her wedding ring clearly visible. This was the first time that the inside of human body was seen without performing surgery. Dr. Negar Asdaghi:                        From Röntgen's first X-ray image to the advanced neuroimaging that we review today on our portable devices, I can't help but wonder, what will your accidental discovery on a Friday fall afternoon in November do to advance the field of science and stroke 100 years from now, as we continue to stay alert with Stroke Alert. Dr. Negar Asdaghi:                        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.

In this fast-paced debate style presentation from the 2020 Midyear Clinical Meeting, content matter experts debate the best oral P2Y12 antiplatelet agents for your patients.  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.

Pedro, Guilherme e João se reunem novamente com o dr. José Carlos para falar de infarto sem supradesnivelamento de segmento ST! Um tema com mudanças recentes e cheio de dúvidas! Qual o melhor antiplaquetário depois do AAS? Fazer na sala de emergência ou na hemodinâmica? E o restante da prescrição? Qual a melhor hora pra fazer o cateterismo? Isso e muito mais nesse episódio! REFERÊNCIAS 1. COLLET, Jean-Philippe et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). European heart journal, v. 42, n. 14, p. 1289-1367, 2021. 2. NICOLAU, José Carlos et al. Diretrizes da Sociedade Brasileira de Cardiologia sobre Angina Instável e Infarto Agudo do Miocárdio sem Supradesnível do Segmento ST–2021. Arquivos Brasileiros de Cardiologia, v. 117, p. 181-264, 2021. 3. SCHÜPKE, Stefanie et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. New England Journal of Medicine, v. 381, n. 16, p. 1524-1534, 2019. 4. COMMIT (CLOPIDOGREL AND METOPROLOL IN MYOCARDIAL INFARCTION TRIAL) COLLABORATIVE GROUP et al. Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet, v. 366, n. 9497, p. 1622-1632, 2005. 5. KUBICA, Jacek et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. European heart journal, v. 37, n. 3, p. 245-252, 2016. 6. HOBL, Eva-Luise et al. Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial. Journal of the American College of Cardiology, v. 63, n. 7, p. 630-635, 2014. 7. MEINE, Trip J. et al. Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. American heart journal, v. 149, n. 6, p. 1043-1049, 2005. 8. ANDERSON, H. Vernon et al. One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial: a randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. Journal of the American College of Cardiology, v. 26, n. 7, p. 1643-1650, 1995. 9. ABUZAID, Ahmed et al. Oxygen therapy in patients with acute myocardial infarction: a systemic review and meta-analysis. The American journal of medicine, v. 131, n. 6, p. 693-701, 2018.

First join author Marc Dweck and Associate Editor Victoria Delgado as they discuss the article "Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial." Then, join authors Torbjørn Omland and Geeta Gulati as they discuss the article "Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol." 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: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Hooray, it's another double feature week! And guess what, these two papers are two randomized control trials. One looking at progression of aortic stenosis and the other, looking at a prevention of cardiac dysfunction following adjuvant breast cancer therapies. Dr. Carolyn Lam: So, very interesting two papers coming right up. But Greg, why don't you start by highlighting some of your favorite papers from today's issue. Dr. Greg Hundley: You bet Carolyn. Dr. Greg Hundley: So my first study was conducted by Dr. Gabriela Trifan and colleagues from University of Illinois who performed a meta analysis of major studies that compare the efficacy and safety of dual anti-platelet therapy versus monotherapy for secondary prevention of recurrent stroke or transient ischemic attack in those previously experiencing minor non cardioembolic stroke. And their primary outcomes were stroke and the composite of stroke, TIA, acute coronary syndrome and death of all cause. And the safety outcome was major hemorrhage. Dr. Carolyn Lam: Oh, okay. Very important study. What did they find? Dr. Greg Hundley: Right Carolyn. So the analysis included 27,358 patients. And compared with monotherapy, dual anti-platelet therapy reduced the risk of recurrent stroke and the composite outcome, but increased the risk of major bleeding. And in subgroup analysis at less than or equal to 30 days, dual anti-platelet therapy increased the risk of hemorrhage relative to monotherapy. In sensitivity analyses, the risk for hemorrhage with less than or equal to 30 days of dual anti-platelet therapy, after excluding the combination of aspirin plus Ticagrelor, was comparable to monotherapy. However, the risk of stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remained decreased compared to monotherapy. Dr. Greg Hundley: And so Carolyn, the take-home message from this paper is that dual anti-platelet therapy decreases the risk of recurrent stroke and composite events compared with monotherapy. But, dual anti-platelet therapy increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus Ticagrelor. Dr. Carolyn Lam: Ah, thanks for that last take home message. Thank you. Dr. Carolyn Lam: Well, the paper I'm going to tell you about is the first to examine the role of epicardial fat derived extracellular vesicles in the pathogenesis of atrial fibrillation. And this comes from Dr. Leor from Sheba Medical Center, Tel Aviv University in Israel and his colleagues who collected epicardial fat specimens from patients with and without atrial fibrillation during elective heart surgery. Dr. Carolyn Lam: Epicardial fat samples were grown as organ cultures and the culture medium was collected every two days. And the authors then isolated and purify these epicardial fat extracellular vesicles from the culture medium. Dr. Carolyn Lam: They found that epicardial fat extracellular vesicles of patients with atrial fibrillation had unique pro-inflammatory, profibrotic and proarrhythmic properties. Epicardial fat extracellular vesicles could in fact induce cellular, molecular and electrophysiological remodeling that could result in atrial fibrosis, myopathy and the development of atrial fibrillation. Dr. Greg Hundley: Wow Carolyn, so what are the clinical implications of epicardial fat extracellular vesicles? Dr. Carolyn Lam: Hmm, good question. Well, understanding their role in the pathogenesis of atrial fibrillation may for one lead to the discovery of new diagnostic markers or new targets for the prevention and treatment of atrial fibrillation. And that combined pro-inflammatory profibrotic and proarrhythmic effects of these epicardial fat and extracellular vesicles may in fact be relevant to the pathogenesis of other cardiovascular diseases associated with obesity and abnormal adipose tissue deposition. Dr. Greg Hundley: Very nice Carolyn. Dr. Greg Hundley: My next paper comes again to us from the world of preclinical science and these authors led by Dr. Masanori Aikawa from Harvard Medical School applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. They use global proteomics and high dimensional clustering on multiple vein graft tissues to identify potential pathogenic mechanisms. And experiments were conducted in both in vivo mouse models and in vitro human macrophages. Dr. Carolyn Lam: Oh wow. So what did they find? Dr. Greg Hundley: So Carolyn, peroxisomes proliferator activated receptors or PPAR alpha agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Dr. Greg Hundley: Now, metabolomics, lipidomics, functional metabolic assays and single cell analysis of cultured human macrophages revealed that PPAR alpha modulates macrophage glycolosis, citrate metabolism, mitochondrial membrane sphingolipid metabolism and heterogeneity. Dr. Carolyn Lam: Okay. So what is the take home message Greg? Dr. Greg Hundley: Right Carolyn, thought you would ask me that. Dr. Greg Hundley: So PPAR alpha activation suppresses the development of vein graft and arterial venous fistula lesions. And PPAR alpha reduces macrophage activation by influencing macrophage heterogeneity, mitochondrial integrity, and the metabolome. So Carolyn, given that peripheral arterial disease and chronic kidney disease prevalences are increasing, warranting needs for more vein grafts and arterial venous fistulas, this target discovery platform is applicable to investigating therapies for these diseases. Dr. Greg Hundley: And a really nice accompanying editorial is provided by doctors Reilly and Bornfeldt. Dr. Greg Hundley: Well Carolyn, how about we turn to look at what is in the mailbag this week? Dr. Carolyn Lam: Well let me tell you about it Greg. We've got a cardiovascular case series by Dr. Borlaug on things are not always as they seem, multimodality exercise assessment and evaluation of dyspnea. In cardiology news by Kuhn there's a discussion of Evinecumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag. A perspective piece by Dr. Watkins on time to think differently about sarcomere negative hypertrophic cardiomyopathy. And finally a research letter by Dr. Ahn on reduction in Kawasaki disease after non-pharmaceutical interventions in the COVID-19 era, a nationwide observational study in Korea. Dr. Carolyn Lam: Wow. That wraps it up for the summaries. Let's go on to the feature discussions shall we, Greg? Dr. Greg Hundley: You bet. Dr. Carolyn Lam: We are about to talk about the extended follow-up results of the PRADA trial. Oh, so interesting. So happy to have with us today, doctors Geeta Gulati and Dr. Torbjørn Omland, both from the Akershus University hospital in Norway, and you would probably recognize that Dr. Torbjørn Omland is also one of our associate editors, but both here are the co-corresponding authors of this beautiful paper. Dr. Carolyn Lam: Thank you so much for coming here today. Torbjørn, maybe you could start with what is the PRADA trial? Why did you decide to do an extended follow-up? Dr. Torbjørn Omland: Yeah so PRADA was a two times two factorial randomized double blind clinical trial that sought to evaluate the effects of intervention with receptor blocker Candesartan. And a beta blocker Metoprolol in patients with early breast cancer who received anthracycline therapy as part of their chemotherapy. And then we wanted to assess the effect of this sort of preventative therapy, left ventricular function and injury. Dr. Torbjørn Omland: So we reported the primary results of the trial a few years ago and showed that intervention with Candesartan most associated with a significant elevation of the reduction in left ventricular ejection fraction that these patients may experience, and also that treatment with the beta blocker Metoprolol was associated with an intimation of the increase in cardio proponents suggesting a beneficial effect on myocardial injury. However, whether these results were or these effects were sustained after termination of the study drugs was unknown. And that was what we really wanted to address with extended follow-up study. Dr. Carolyn Lam: Yeah, makes a lot of sense, especially because these injuries I suppose could still continue. And just to be very clear, the medications though were only taken during the adjuvant chemotherapy and therefore could be a variable duration from what I understand. Right? Great. Dr. Carolyn Lam: So Geeta then, could you tell us what did the extended analysis show? Dr. Geeta Gulati: The extended follow-up was interesting and it was something we really wanted to figure out because there are not many studies who have been done on the extended follow-up and you're not giving these study medications afterwards. Dr. Geeta Gulati: So very interestingly we saw that the decline in the ejection fraction was still there in the whole group. But this time there was no difference in the group who received Candesartan do those who didn't. And we show that there was a different in the primary results, but now in the extended follow-up there was no difference. And then also in the Metoprolol group that had previously shown that there was lesser rise in the troponins. Again, there was no difference in the groups now on the extended follow-up. Dr. Geeta Gulati: So this is very interesting because this shows that there is a small, modest decline in a left ventricular ejection fraction during and after the breast cancer therapy. But what does this really mean? It's a small decline and it's within the normal range and the cardioprotection is not working. So, are we perhaps looking at the wrong group? Perhaps we should look at patients who have the higher cardiovascular risk factors. Perhaps even we should look at more novel heart failure or cardiac drugs that may have a stronger effect on the ejection fraction. Dr. Carolyn Lam: Right. So Geeta though, can we unpack that a little bit? You see, the patients were not on the medication anymore at the time of follow-up. So you're saying that even though they were given adjuvant chemotherapy and covered with the drug, that even not having any more chemotherapy, their ejection fraction still fell. And if I'm not wrong, this was an MRI analysis. And so it was only by an ejection fraction of two percent on mean fall, right? How do we think about that clinically? Dr. Geeta Gulati: And that's the important question, isn't it? Because a decline in the ejection fraction of less than two percent within the normal range, what does it really mean? Well initially we thought that if there was a different in those who had cardioprotective medication compared to those that didn't, it may prevent development of further decline in the cardiac function and then heart failure in the future. But now, there is really no difference between the groups. So perhaps the clinical implication of giving cardio protection to all cancer patients is not really that useful. Perhaps they should look at those who are at higher risk because they would have a greater fall in ejection fraction and then more cardioprotective effect of these drugs. Dr. Carolyn Lam: Yeah, totally. And perhaps the metrics that we're used to seeing in the past with greater falls of ejection fraction, maybe it just doesn't apply currently or perhaps with the specific chemotherapeutic regimens perhaps that you're using now. Because with a very small fall, and I believe you only had one heart failure event, right? If I'm not wrong in this extended follow-up. So, just to let the audience know, it was very small fall, little number of events. It's hard to really tease apart what that clinically means. Now, could I ask though, does it mean we need actually a more sensitive marker? Because there was some interesting stuff about global longitudinal strain. Could you- Dr. Geeta Gulati: I would throw that question back to Torbjørn I think. Dr. Torbjørn Omland: Yes. So that's a very interesting question Carolyn. So we did observe what seemed to be a beneficial, but a sort of minor effect on global longitudinal strain. So we know that that is the more sensitive index of systolic function than left ventricular ejection fraction, that was the pre defined primary outcome. So that's raises of course questions whether a future trial should more focus on these more sensitive indices of cardiac function. Dr. Carolyn Lam: Yeah. Geeta, could I then really put it back to you? And the tough question I always get, how do we apply these results clinically then? I mean, you see these patients right? Now what? Do you give or do you don't give? And which one do you give? And how do you identify high risk patients? I don't know. Dr. Geeta Gulati: Again, I think all the patients are unique aren't they? So that's where we have to start. So in my clinic, if I have a high risk patient with hypertension, diabetes, hypercholesterolemia, yeah perhaps they even have had a cardiovascular disease before something like this. Then I will take more care of these patients and be more careful with the echo measurements I'm doing and if I find that they have a decline in their cardiac function, I may be more eager to start them on cardioprotective medication. Dr. Geeta Gulati: But then in R-Regen we follow all the HER two positive breast cancers with echo. If I don't have echoparamaties that clearly tells me that they have a decline in the cardiac function, then I may wait to start cardio protection because none of the studies has really so far show that all patients should have these cardioprotective medication or prevention. Dr. Carolyn Lam: Nice. Thank you. That was a tough one to get at. And I suppose Torbjørn I have to give you another tough one then. Because how to address the remaining unanswered questions, right? Because one of them on my mind too, is how to identify the high risk, do biomarkers play a role? And then the other is if we then start the preventive therapies like ERBs and beta blockers, should we actually continue it forever? And so on. But anyway Torbjørn please, please, what does the future hold? Dr. Torbjørn Omland: I think it's worthy of a recap or underscoring that these are really good news for many breast cancer patients that actually the risk of an important decline in ventricular function is lower than we thought. So that may be because of several things. I think in general, those whose used these cardiotoxic drugs are lower. And we also, I think that there's increased collaboration between oncologists and cardiologists. Also meaning that we are better to pick up the high-risk patients at an early stage. Dr. Torbjørn Omland: But of course, it's very important questions that you asked regarding how to identify the high risk patients. And I think that's where really future research should focus. So there we know that traditional risk factors are important. We are looking into whether biomarkers can be used, if there's more sensitive imaging in this can be used. But so far we haven't really succeeded in getting the risk model that really identifies it on the patient level. So that's work that remains to be done. Dr. Torbjørn Omland: And then we are also looking for new types of intervention, good exercise, good other drugs. We are doing now a PRADA two study where we look at the effects of Sacubitril Valsartan in this setting. And those are also very exciting, I think, and we look very much forward to present that in the future. Dr. Carolyn Lam: Oh wow thank you so much Torbjørn and Geeta. The PRADA two trial. I've got to ask you, why do you then call it the Chanel trial? But I think I'll save that for another day. So thank you. Thank you once again, this is fabulous and congratulations to you both. Dr. Torbjørn Omland: Thank you. Dr. Geeta Gulati: Thank you. Dr. Greg Hundley: Well listeners, welcome to our second feature discussion today. And we have with us Dr. Marc Dweck from University of Edinburgh in Scotland and our own associate editor, Victoria Delgado from Leiden in the Netherlands. Welcome to both of you. Dr. Greg Hundley: Marc, we're going to get started with you. Could you tell us a little bit about the background for your study and what was the hypothesis that you wanted to test? Dr. Marc Dweck: Thanks very much Greg for the invitation. So I guess aortic stenosis is perhaps the last major cardiovascular condition where we don't have a medical therapy. We're unable to treat these patients. We're unable to prevent progression. We're only left with a valve replacement. And so we, like a lot of groups around the world, want to develop a treatment for aortic stenosis. Our group did the first SALTIRE trial, where we looked at statins seeing if we could slow aortic stenosis progression. And that, like similar trials, was neutral. No effect on the valve progression. Dr. Marc Dweck: And so actually I've spent the last 10 years looking at some of the factors associated with aortic stenosis progression in particular. The answers that we've had from those trials have kind of come back telling us that really it's a process of calcification. If you look at what triggers progressive valve narrowness is this calcific process, that seems to be a self perpetuating disease. Dr. Marc Dweck: So the question is, how do you target this calcification process? How can you interrupt it? And how can you do that without compromising bone health in these elderly patients? So in trying to come up with a solution to that we thought about using osteopetrosis agents, which we hypothesized would maintain both bone health and reduce vascular calcification on the basis of observational data and also animal data suggesting that. And that was really where we came from in the design of the SALTIRE two trial. Dr. Marc Dweck: And doing a big trial with clinical endpoints wasn't felt to be feasible and instead we decided to look at imaging end points and see whether we could slow disease progression using these agents. Dr. Greg Hundley: Very nice Marc. And so you're really leading us into, tell us a little bit more about your study population and your study design. Dr. Marc Dweck: Yeah so we wanted to take patients from our outpatient clinic with mild, moderate and even early severe disease, asymptomatic patients crucially, patients that aren't scheduled for aortic valve replacement and see the effects of these drugs on disease progression. Dr. Marc Dweck: So we did a randomized control trial. There was three arms. Patients were randomized to Alendronate, Denosumab, these are the two osteopetrosis agents, or placebo. We then did a series of baseline imaging tests. So the primary end point was based on CT calcium scoring. So they had a baseline CT calcium score. They also had a baseline echocardiogram and they had a baseline fluoride PET scan. So this measures calcification activity in the valve. And then we essentially repeated those tests after a period of time on the drugs, or on placebo. We repeated the calcium score and the echo after two years and repeated the PET scan after one year. Dr. Greg Hundley: Very nice, and so before you tell us your results, a little bit, how many patients? And maybe their average age and the rough distribution of men versus women. Dr. Marc Dweck: Yeah so study recruited roughly 50 patients in each arm. The average age was 72 and there was 21% females in the study. So, like a lot of studies in aortic stenosis, a low female prevalence. Despite our best efforts, that's something we need to attend to in the future, but otherwise, a representative age group and patients with this disease. Dr. Greg Hundley: And what did you find? Dr. Marc Dweck: Well we found that the drugs didn't have an effect on any of these imaging assessments. So, there was no effect on the progression for CT calcium score at two years, no effects on any of the echocardiographic assessments of hemodynamic severity, and no effect on calcification activity as measured with the fluoride. Dr. Marc Dweck: So a very consistent result using multiple different imaging modalities, which I think gives us confidence that there isn't at least a dramatic effect of these drugs on disease activity or disease progression, in aortic stenosis. Dr. Greg Hundley: Very good. Well listeners, we're now going to turn to one of our associate editors, Dr. Victoria Delgado, and she is really a valvular heart disease expert member of our team. Dr. Greg Hundley: Victoria, I know you see a lot of papers that kind of come across your desk. What attracted you to this manuscript? And then how do you put the results in the context of other research that's going on to halt the progression of aortic stenosis. Dr. Victoria Delgado: Thank you Greg. So first the first thing that attracted my attention for this article is the question. We know that we don't have any medical therapy for halting the progression of aortic stenosis. And even if the previous studies have been negative or neutral, still there is the interest of trying to find a less invasive therapy for these patients, or even prevent that they arrive to surgical or transcatheter aortic valve replacement. Dr. Victoria Delgado: And the second is that these are very strong analysis because it's a randomized clinical trial and using as end points imaging. So that trial also in a way answers the question of which imaging technique we need to use in order to see the effects of specific therapies. Previous studies have used mainly echocardiography, but that only gave us information on the modynamic effects of the aortic stenosis. While in this study, we have the combination of CT and a combination of a PET that he give us also information on how the calcification is happening. So that makes the study very comprehensive and give us more insights into this pathophysiology, to this pathology particularly. Dr. Greg Hundley: Very nice. So it sounds like looking at aortic stenosis from multiple different angles, whether it be echocardiography or perhaps imaging processes that look at the progression of calcification. Dr. Greg Hundley: Well, Marc, I want to come back to you. What do you think is the next, sounds like you've been working in this area for an extended period of time. What do you see as the next research study that you and your group may undertake in this area? Dr. Marc Dweck: I Think we've got the study design about right. I think if in the future studies we want to do, I think we would adopt a similar design using these imaging end points. Dr. Marc Dweck: I have to say I'm very influenced by the recovery trial that has been conducted in the UK with COVID. I mean, here's a disease where we wanted to get a treatment as quickly as we can. And in doing that, developing a platform type trial where you potentially test multiple different promising agents simultaneously across multiple centers across the world or the UK, I think that would be the quickest way to developing a treatment. And so I'm encouraged that there are five or six very good targets where we could, for a new therapy in aortic stenosis. And I think a platform type design where we engage multiple groups using imaging as that initial end point. And then, the drugs that appear to have an effect on these imaging end points we can start to recruit more patients at those sites, into those centers, looking for clinical end points. Dr. Marc Dweck: I think that kind of discussion is happening around the world now between groups that are interested because we want to crack this problem quickly. We don't want to wait and do these different studies sequentially. We want to try and do them simultaneously. And I'm excited about that. I think if we do that, we've got a real shot at developing a treatment over the next five to 10 years say. Dr. Greg Hundley: Fantastic. Dr. Greg Hundley: And Victoria, I know you have interest in this particular area. Do you have anything you'd like to add? Dr. Victoria Delgado: Yeah. I think that those studies that Mark said are really welcome and I hope that they are positive. And give us a little bit of more to treat these patients. My main fear is that these patients are not as frequent, for example, as heart failure patients. Where we have several therapies where we have possibility to enroll patients in trials for new drugs, that we know that probably are going to be effective. But for valvular heart disease it has been always the end point to reach surgery or to reach an aortic valve replacement or indication of the mitral valve and mitral valve repair. So in early phase of the disease, my main concern is that maybe the patient is not going to be well-trained to understand what are the consequences. I want to always wait until maybe when is needed for the surgical or transcatheter procedure. Dr. Victoria Delgado: But I think that increasing the awareness of the prevalence of valvular heart disease and the consequences may help people to understand, to put more attention for an early diagnosis and develop new drugs that can help, like in this case, aortic stenosis one of the most frequent valvular heart disease, to prevent the proliferation and to prevent the replacement of the valve. Dr. Greg Hundley: Very nice. Well listeners, this has been a wonderful discussion and we greatly appreciate the input that we've been able to gather today from Dr. Marc Dweck from Edinburgh in Scotland and our own associate editor, Dr. Victoria Delgado. Bringing this information from a randomized trial, evaluating osteoporosis drugs, and really indicating they did not disrupt the progression of calcification in patients with aortic stenosis. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great rest of your week and we will catch you next week on The Run. 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.  

Dr. Ebell and Dr. Wilkes discuss the POEM titled ' Ticagrelor plus aspirin is superior to aspirin alone in preventing stroke after TIA or minor stroke (THALES) '

FDA 批准颈动脉窦压力反射刺激疗法治疗心衰Lancet 血ACE2水平与心血管疾病及死亡的关系Science子刊 一种具有几何适应性的人工心脏瓣膜BAROSTIM NEO系统BAROSTIM NEO系统包括一个植入式脉冲发生器（IPG）、一个颈动脉窦含铅套件和一个程序。医生将BAROSTIM NEO脉冲发生器植入晚期心力衰竭患者的左或右锁骨下方，并在患者的左或右颈动脉窦处放置颈动脉窦导线，然后将脉冲发生器连接到颈动脉窦导线上。医生根据病人的个人需求制定脉冲发生器程序，然后向颈动脉的压力感受器传递电脉冲。压力反射激活（BAT）疗法的目的是激活颈动脉壁的压力感受器，刺激自主神经系统的传入和传出神经，大脑接收到神经信号作出相应反应：松弛血管、降低心率、并通过改善肾功能来减少液体储留。2019年8月，FDA批准BAROSTIM NEO系统用于药物治疗无效的、不符合心脏再同步化治疗适应症的、难治性心力衰竭患者。《BeAT-HF研究：这项研究证明了压力反射刺激疗法（BAT）对射血分数降低的心力衰竭患者的安全性和有效性》Journal of American College of Cardiology，2020年7月 (1) BeAT-HF研究是一项多中心、前瞻性、随机对照研究，纳入408名射血分数降低的心力衰竭（HFrEF）患者中，入组要求：纽约心功能分级II-III级、射血分数≤35%、药物治疗方案稳定≥4周、不符合心脏再同步化治疗的I类指征。这篇报告重点汇报了D队列中、NT-proBNP

Date: October 2nd, 2020 Guest Skeptic: Dr.Barbra Backus is an emergency physician at the Emergency Department of the Erasmus University Medical Center in Rotterdam, the Netherlands. She is the creator of the HEART Score and an enthusiastic researcher. Reference: Claiborne Johnston S et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. NEJM […]

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:                                                 Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.                                                 The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.                                                 Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.                                                 The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.                                                 In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.                                                 On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.                                                 In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.                                                 Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.                                                 To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.                                                 They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.                                                 The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.                                                 They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.                                                 These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.                                                 Well, that wraps it up for our summaries. Now for our feature discussion.                                                 For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.                                                 Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.                                                 Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found? Dr. Jason Weatherald:   This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.                                                 We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective. Dr. Carolyn Lam:               Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them? Dr. Kelly Chin:                    I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.                                                 The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.                                                 Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.                                                 I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing. Dr. Carolyn Lam:               Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.                                                 The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason? Dr. Jason Weatherald:   Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.                                 What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.                                                   I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration. Dr. Carolyn Lam:               Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.                                                 Kelly, what do you think are the real take home messages from this? Dr. Kelly Chin:                    I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment. Dr. Carolyn Lam:               Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason? Dr. Jason Weatherald:   I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.                                                 At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.                                                 I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic. Dr. Kelly Chin:                    I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.                                                 But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization. Dr. Carolyn Lam:               Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment? Dr. Jason Weatherald:   Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening. Dr. Carolyn Lam:               And Kelly, what do you think should be next steps? Dr. Kelly Chin:                    I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.                                                 But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies. Dr. Carolyn Lam:               You've been listening to Circulation on the Run. Tune in again next week.  

  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. Our feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.     The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.     Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.     The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.     However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.     In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.     The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.     A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.     The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.     Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.     Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.   Speaker 2: Thank you very much.   Carolyn Lam: We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.   Speaker 3: Hi Carolyn, thanks for having me.   Carolyn Lam: So Jonas, could you start off by telling us why you did this study and what you found?   Speaker 2: We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.   Carolyn Lam: Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.   Speaker 2: It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.   Carolyn Lam: Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?   Speaker 2: We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.   Carolyn Lam: Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?   Speaker 3: I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.     But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.   Carolyn Lam: Actually, Jonas could you let us know is there any sex differences in the performance of the score?   [00:14:46] Speaker 2:   There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.   Carolyn Lam: That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.   Speaker 3: We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.   Speaker 2: We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.   Carolyn Lam: It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.   Speaker 3: Yeah, no absolutely. And I think that's great.   Carolyn Lam: Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?   Speaker 2: We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.   Carolyn Lam: That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.     Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.  

We’re back and better than ever with a NEW host! This season, Kieran Quinn takes the reigns and is excited to bring you the latest and greatest in the world of emerging clinical evidence. Along outgoing host Amol Verma, the two hosts discuss two studies: Just how dangerous are opioids in the treatment of chronic pain ... The post REPLAY – Drugs on the Brain: Opining on Opioid-Induced Death and Ticagrelor for TIA or Stroke appeared first on Healthy Debate.

We're back and better than ever with a NEW host! This season, Kieran Quinn takes the reigns and is excited to bring you the latest and greatest in the world of emerging clinical evidence. Along outgoing host Amol Verma, the two hosts discuss two studies: Just how dangerous are opioids in the treatment of chronic pain ...The post REPLAY – Drugs on the Brain: Opining on Opioid-Induced Death and Ticagrelor for TIA or Stroke appeared first on Healthy Debate.

  Carolyn: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Have you wondered which anti-platelet agent you should use in your patients with diabetes and coronary artery disease? Well, our feature paper deals with just this topic, so stay tuned, I'll be write back with it's author and associate editor. First, here's your summary of this week's journal: The first paper unravels novel peptides involved in atrial extracellular matrix remodelling in atrial fibrillation. This is work from first author Dr. Barallobre-Barreiro, corresponding author Dr Mayr from King's College London, and colleagues. They used novel mass spectrometry methods to analyze extracellular matrix in human atrial appendages from patients undergoing coronary artery bypass surgery.     Now, previous proteomic studies have examined the cellular proteome, but this is the first study to comprehensively characterize extracellular matrix proteins in human cardiac tissues, including the identification of glycosylation sites. They found extensive cleavage in the protein core of decorin which is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis and a variety of other extracellular matrix cell signalling molecules. Decorin processing differed between human ventricles and atria and was altered in disease. It's C-terminus which is important for the interaction with connective tissue growth factor was predominantly detected in ventricles compared to atria. In contrast, atrial tissues from patients in persistent atrial fibrillation had higher levels of full length decorin, but also harbored a unique cleavage site that was not found in atrial appendages from patients in sinus rhythm. This unique cleavage site preceded the M-terminal domain of decorin and altered the binding capacity for myostatin, this altering muscle growth.     The cleaved decorin peptide antagonized myostatin, such that myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and in hearts of decorin-null mice. Furthermore, a synthetic peptide corresponding to this decorin region, those dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. This is clinically important because mystatin inhibition has been implicated as a substrate for atrial fibrillation. This study therefore provides first evidence that peptides generated from the cleavage of extracellular matric proteins such as decorin, constitutes a local regulatory mechanism for growth factors in human cardiac tissue.     The next study looked at therapeutic hypothermia in patients with out of hospital cardiac arrest, and questioned if it may be most effective when induced early during cardiopulmonary resuscitation or CPR, in contrast to prior trials that looked at therapeutic hypothermia induced only after return of spontaneous circulation and hospital admission. This is the RINSE trial from Professor Bernard and colleagues from Ambulance Victoria Australia, which was a multi center randomized controlled trial which assigned adults with out of hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to two liters of cold saline, or standard care. The primary outcome measure was survival at hospital discharge. Secondary end points included return of spontaneous circulation.     The trial was unfortunately closed early at forty-eight percent of the recruitment target, due to changes in temperature management protocols at the major receiving hospitals. Still, a total of one thousand, one hundred and ninety-eight patients were randomized. Six hundred and eighteen to therapeutic hypothermia during CPR, and five hundred and eighty to standard pre-hospital care. Overall there was no difference in outcomes at discharge. In patients with an initial shockable cardiac rhythm there was lower rate of return of spontaneous circulation in patients who received cold saline compared with standard care. Thus, although this trial was stopped early, the data suggests that induction of mild therapeutic hypothermia using a rapid infusion of large volume intravenous cold saline during CPR did not affect outcomes at hospital discharge and may in fact cause harm in the subset of out of hospital cardiac arrest patients who present with shockable rhythm.     The last study provides the first generalizable risk score for sudden cardiac death among American adults from the general population without a history of cardiovascular disease. This large study from Dr. Deo of University of Pennsylvania, and colleagues, derived a sudden cardiac death prediction model using the Atherosclerosis Risk in Communities or ARIC cohort, and validated it in the Cardiovascular Health Study or CHS cohort. They found that the twelve independent risk factors in the ARIC study included age, male sex, African American race, current smoking, systolic blood pressure, use of [anti-hypotensive 00:06:00] medication, diabetes, serum potassium, serum albumin, HDO, estimated GFR, and QTC interval. Over a ten year follow up period this model combining these risk factors showed good to excellent discrimination for sudden cardiac death risk. In fact the model slightly outperformed that of the 2013 ACC AHA pooled cohort risk equations.     Finally, they also showed in the echocardiographic sub-cohort that a left ventricular ejection fraction less than fifty percent was present in only 1.1 percent of these participants and did not enhance sudden cardiac death prediction. This study importantly contributes to the distinguishing of sudden cardiac death risk across the general population, and the results can help target future strategies aimed at sudden cardiac death prevention for the highest risk subgroups in the American general population. That does it for the summaries. Now for our feature paper.     For our feature paper today we are discussing the super important issue of anti-platelet therapy in type 2 diabetes with coronary artery disease. Joining me today are the corresponding author, Dr. Dominick Angiolillo from the University of Florida College of Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate Editor from Paris, France. Welcome gentlemen.   Dominick: Thanks for having us.   Gabriel: Hello.   Carolyn: Dominick, I'd really like to start with you. Your paper entitled the OPTIMUS-4 Study, is really a study of the pharmacodynamic comparison of Prasugrel versus Ticagrelor in these patients with type 2 diabetes and coronary artery disease. The whole question is, what was the rationale to look at the pharmacodynamics?   Dominick: As the title of the study says, OPTIMUS-4, it means that there was an OPTIMUS-1, 2 and 3 in the past, which means that there's a lot of thought that went into this and a lot of background information. The rationale for this specific study was that we're all well aware of the fact that patients with diabetes have high platelet reactivity, which may be one of the reasons why they have a higher risk of recurrent atherothrombotic events. Therefore, the need to define ways to optimize their anti-platelet effects, their levels of platelet inhibition. In this specific study we took an approach of looking at the novel, although we cannot call them novel nowadays, but the newer P2Y12 receptor inhibitors Prasugrel and Ticagrelor. Looking at them in a head to head comparison from a pharmacodynamic standpoint to see if one drug would be superior than the other, again, in terms of a platelet inhibitory effect.     This is the rationale, and just to expand a little bit on this, there's been a perception, again I want to underscore a 'perception' that based on subgroup analysis of the larger clinical trials, that Prasugrel is a superior drug for patients with diabetes. We do know that there's a benefit also with Ticagrelor compared with Clopidogrel, although the absolute risk reductions in the studies led to a perception that Prasugrel would be a better drug. We said to ourselves, "Well, we're never going to have a large scale head to head clinical comparison, why don't we do a head to head pharmacodynamic comparison to see if there are any differences?" This was the overall rationale for conducting this specific study.   Carolyn: That really sets a background perfectly. Tell us about the main findings.   Dominick: The main finding was as follows, we conducted a very detailed pharmacodynamic study, this was a prospective randomized double-blind double-dummy crossover study, with all patients on the background of aspirin therapy. We looked at platelet reactivity, using a variety of assays, I like to say it in every possible salsa that you can imagine. The primary end point which is platelet reactivity at one week into two drugs, using an [ADP 00:10:00] specific assay, actually showed that Ticagrelor was superior to Prasugrel in terms of platelet inhibitory effects. That was the only time point where it was shown, but the study was actually designed to show the opposite, so it was a very interesting finding, while with all the other time points there were no differences between the platelet inhibitory effects between the two drugs.     The other thing that we did look at, which gives a little bit of a novelty to this study is, we went beyond just looking at ADP induced effects, which is the target for these two drugs, we looked at other signalling pathways which one would not believe to be necessarily affected by P2Y12 inhibitors, and we found these also to be reduced by both drugs to a similar extent.   Carolyn: Fascinating. I'm going to get to your second point a bit later. First, that first finding that surprisingly Ticagrelor appeared to perform better using one of the specific assays and so on, I'd really like Gabriel's opinion there. What do you think is the overall clinical implications or what was the message that the editorial board was hoping to get across to the audience? Because I noticed you invited an editorial as well, a beautiful one written by Dr. [Star-ee-an 11:36] Parker. What was the thinking behind that?   Gabriel: I think this is really a very important paper and I'm delighted that Dominick Angiolillo and his team submitted it to Circulation, in fact to be frank, we invited that paper after seeing his presentation at the ACC earlier this year. The reason that paper caught everybody's attention in the editorial board was that it's addressing a frequent and deadly disease, diabetes, that kills really patients with cardiovascular disease. There's a critical issue in the treatment because of the limitations of Clopidogrel because of the increased platelet reactivity in diabetics, and there's tremendous interest in the novel P2Y12 inhibitors Prasugrel and Ticagrelor, and of course any hint of differences between these agents has major clinical implications. In addition, I think I can state that Dominick's team is really one of the premiere international teams looking at this exact issue, platelet reactivity in diabetics. What they did was really state of the art rigorous clinical investigation by a highly skilled team, looking rigorously at a double blind crossover designed four different assays looking at platelet function and platelet response, looking both at the effect of a loading dose and the maintenance dose.     To me, the message is not a minute difference between the treatments, in fact I think that even though it's the primary outcome and it does show a slightly greater response with Ticagrelor than with Prasugrel, the overall most of the other assays at the other time points show a consistent good response with both agents. To us, and to me, the message is that the novel agents are clearly superior to Clopidogrel as we've seen in the clinical trials, but they are fairly consistent in their benefit, and it's reassuring to see this not in healthy volunteers but in actual patients with stable coronary artery disease. I think it was really important to show that. Certainly platelet reactivity doesn't summarize entirely the effects of any drug, and there might be platelet independent effects of Ticagrelor mostly and possibly Prasugrel, but I think on the platelet side, I think that this paper really nails it.   Carolyn: I read that editorial and really agree that that puts everything in perspective really well. I particularly like the figure that accompanied the editorial. In case any of our listeners out there don't really remember all the different pathways and how Prasugrel and Ticagrelor and Clopidogrel are metabolized differently, I'd really refer everyone to that figure as well. Just want to pick up on one of the points that both of you mentioned, and that is the non ADP induced platelet reactivity that Prasugrel and Ticagrelor both seem to have an affect on and so on, and if they're so effective, Dominick, is there still a role for aspirin co-administration with these new anti-platelet agents?   Dominick: The study clearly puts a little bit more beef, let's put it this way, to some of the ongoing clinical studies looking at whether we need aspirin in the patients treated with one of these newer P2Y12 receptor inhibitors. There are a series of ongoing studies out there. There's a laundry list, so I'm not going to go into the details. It does highlight that maybe when you have ultimate P2Y12 blockade, which is a key signalling pathway and blocks other responses by virtue of the fact that there's an interplay between this pathway and others, maybe you do not need this additional anti-platelet agent such as aspirin, which we know there's associated with potential bleeding particularly gastrointestinal side effects.     Having said that, this is not something that I'm advocating at time, but what I am saying is that we'll need to look into the results of the clinical trials. I believe that this study is an additional piece of evidence from an ex vivo standpoint to prior in vitro studies showing that aspirin is not associated with additional platelet inhibitory effects, at least not substantial platelet inhibitory effects. One can say that you may get away with just one of these newer agents. Again, this is based on pharmacodynamic findings, let's just wait for the clinical trial results.   Carolyn: I think that's so fairly put, and I learnt so much just listening to this conversation. Thank you so much for joining me today. Any last words from Gabriel?   Gabriel: Yeah, I'd like to make a couple of points as an Associate editor for Circulation. The first one is, this paper was picked up when we saw Dominick's team's presentation at the ACC, and I think it exemplifies that we really want to pick up the best science from the meetings, either before the meetings and publish it simultaneously as much as possible, but sometimes also at the meetings, so expect to see Circulation Editors at your presentations and maybe you'll seduce them enough with your science that we'll get good science submitted to the journal. The other aspect to it is also that I think with the new editorial board there's really a focus on trying to make the journal very international in it's approach, and I think it's fitting that I am Associate Editor from Europe and I think there's no more international a scientist than Dominick Angiolillo who's not only a good friend but also has been trained in Italy, has practiced in Spain, and now works in the US. I think he embodies how science transcends boundaries and borders. I think there's a definite international outlook to Circulation, and we're looking for great science from anywhere in the world, not solely the US.   Carolyn: Thank you so much Gabriel. Thank you so much Dominick. Thank you listeners for listening today, you've been listening to Circulation on the Run. Don't forget to join us next week for more summaries and highlights.    

  Carolyn: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Today we will be diving deep into issues of resistant hypertension, adherence to anti-hypertensive medication, and renal denervation. All this by looking closely at new data from the Renal Denervation for Hypertension trial. First, here are your summaries of this week's journal.     The first paper sought to answer these questions: How can we better re-stratify patients with long QT syndrome type 3? You will remember that as the type caused by a gain of function mutation in the SCN5A sodium channel, and the type that has a more lethal course than types 1 and 2. Another question is, are we sure that beta blockers are effective in type 3 long QT syndrome? Well the current study is by co-first-authors, Dr. Wilde of Academic Medical Center, Amsterdam, and Dr. Moss from University of Rochester School of Medicine and Dentistry, which is the largest multi-center long QT type 3 syndrome cohort described to date.     This study was designed to identify the risk and therapeutic factors associated with cardiac events in patients. The risk factors evaluated included clinical features such as age, gender, ECG measurements, the mutation type, and the therapeutic effects of beta blockers, other medications, and ICD. In almost four hundred patients with type 3 long QT syndrome, 30% experienced at least one cardiac event; that is syncope, aborted cardiac arrest, or sudden death. The risk of a first cardiac event was directly related to the degree of QT prolongation. Each 10 millisecond increase in QTC up to 500 milliseconds was associated with a 19% increase in cardiac events. Prior syncope doubled the risk of life threatening events. Beta blocker therapy was associated with an 83% percent reduction in cardiac events in females, however the efficacy in males could not be conclusively determined due to low number of events. The take-home message is, in your patients with long QT syndrome type 3, recognize the very high risk sub-population with prolonged QTC and a history of syncope.     The next paper is a basic science paper that reveals a novel way in which mitochondrial dysfunction may be targeted in heart failure. This paper is from first author Dr. Li, corresponding author Dr. Tian, and colleagues from the Mitochondria and Metabolism Center at University of Washington. These authors previously found that elevation in the NADH to NAD ratio induces mitochondrial protein hyperacetylation, and renders hearts highly susceptible to stresses, and they showed this in a mouse model of primary mitochondrial dysfunction caused by genetic defects. In the current study they defined the molecular intermediaries linking specific NAD sensitive hyperacetylation targets to the development of heart failure, and further demonstrated the relevance of these mechanisms in human heart failure. Specifically, they identified that hyperacetylation of the regulators of mitochondrial permeability transition poor and malate-aspartate shuttle, mediates the increased susceptibility to cardiac stresses. Further, expanding the cardiac NAD pool via pharmacological or genetic approaches normalized the NADH to NAD ratio, and thereby normalized protein acetylation in hypertrophied and failing hearts. Importantly, these measures improved cardiac function and reduced pathological hypertrophy in mice. Thus, the clinical implication is that restoring the NADH to NAD ratio may be an effective and translatable strategy to treat mitochondrial dysfunction in heart failure.     The next study broadens our considerations of the benefits versus risks of intensive anti-platelet therapy in patients with a prior myocardial infarction, and really suggests that more intensive anti-platelet therapy should be considered, not only to reduce the risks of coronary events, but also to reduce the risk of stroke. This is a paper from Dr. Bonaca and colleagues of the TIMI study group from Brigham and Women's Hospital in Boston, Massachusetts, who investigated the efficacy of ticagrelor, 60 milligrams twice a day, for reducing stroke in patients with a prior myocardial infarction from the Pegasus-TIMI 54 trial.     You will remember that in the Pegasus-TIMI 54 trial, ticagrelor was already shown to reduce the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior MI. Of more than 14,000 patients randomized to placebo or Ticagrelor, 213 experienced a stroke, 85% of which were ischemic. 18% of strokes were fatal, and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke, with a hazards ratio of 0.75, and this was driven by a reduction in ischemic stroke. Hemorrhagic stroke occurred in nine patients on placebo and eight patients on ticagrelor. Furthermore, a meta-analysis of four placebo-controlled trials of more intensive antiplatelet therapy in more than 44,800 patients with coronary disease confirmed a marked reduction in ischemic stroke, with a combined hazards ratio of 0.66. Thus this study really broadens our considerations of benefits versus risks of intensive antiplatelet regimens for the long-term secondary prevention in patients with patients with prior myocardial infarction. It really highlights the broader benefits in reducing ischemic stroke, and not just coronary events. In summary, overall, for 1,000 patients initiated on ticagrelor 60 milligrams twice daily for three years, 13 primary endpoint events would be prevented, including approximately five ischemic strokes. This benefit would come at a cost of nine TIMI major bleeds, but no hemorrhagic strokes or fatal bleeds.     That wraps it up for our summaries! Now for our feature paper. Our feature paper today discusses a really important issue that we face everywhere around the world, and that is the management of resistant hypertension. We're taking a very interesting look at the Renal Denervation for Hypertension trial, because we're actually looking at the adherence to anti-hypertensive therapy, and what we've learned in this trial. I'm so excited because I am sitting right here with first and corresponding author Dr. Michel Azizi, from Georges Pompidou hospital in Paris, France. Hello Michel, thank you!   Michel: Hello, Carolyn. Thank you also for the invitation to discuss about the paper.   Carolyn: We're also so lucky to have the associate editor who handled the paper, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome, Wanpen.   Wanpen: Hi, Carolyn.   Michel: Hi, Wanpen.   Carolyn: This whole issue of resistant hypertension, I'll tell you, to me that means someone who's adequately treated, and despite all the treatment that we can throw at them, they still have a blood pressure that is above a certain level, right?   Michel: Yes.   Carolyn: But your study seems to tell us that that assumption, that everyone's receiving treatment and still having high blood pressure, may need to be questioned, so please tell us a little bit more about what you found.   Michel: This is a clinical trial where we compared the effect of renal denervation to medical treatment, optimal medical treatment. We standardized the anti-hypertensive treatment in the cohort of patients with resistant hypertension, and then we followed them on a monthly basis with home blood pressure monitoring. We also increased the intensity of the treatment every month after randomization between renal denervation against nothing, because this is a probe trial, it is not a double blind trial. We gave them the same treatment in both arms. At the end of the many study we demonstrated that there was 6 millimeter of difference, in terms of ABPM, in favor of renal denervation, against the same medical treatment alone.     However, because this trial was an open trial, it was open to a Hawthorne effect, and the possibility that patients or doctors behave differently in each arm of the study. Those having renal denervation may be more adherent to the treatment, and those not being given the new therapy, not being really adherent to treatment. This was an issue, so we specified analysis. We also measured drug levels in urine after six months of followup, and also assessed the exposure to each individual using a peptide in urine, which is N-acetyl-serylaspartyl-lysyl-proline (AcSDKP)/creatinine.     What we found after six months of followup in patients who really participated to this trial, they were willing to participate to the study, they signed an informed consent where it was written that, indeed, we will monitor drug levels. They knew that we would do this. They also knew that we will follow them very carefully every month, et cetera, that we'll provide them home blood pressure monitor for free. They had access to the same doctor, same nurse, same everything. They could arrive at the time they wanted in the morning for being investigated. After six months of followup we found that more than half of these patients did not take correctly their treatment, and even 15% of them, in reality, took zero medication over seven medications. This was a major, major surprise for us in this trial.   Carolyn: I think that's one of the most significant findings, even in a trial setting, that is such a lot of non-adherents, anti-habitants, of therapy. It really makes us question when we say someone has resistant hypertension, is it really that, or do we have just a very non-compliant patient?   Michel: Yes.   Carolyn: Because it can only be worse in the real-world setting, isn't it? Congratulations, that was a very striking message to me as well. What was the other main finding that you wanted to ... ?   Michel: The other finding was that the rate of non-adherence was similar in both arms. That there was absolutely no influence of being randomized to the renal denervation group or the medical treatment group only. This means that the patients were not influenced, and other physicians behaved similarly in both arms. Because at the end you have exactly the same rate of non-adherence to treatment. This is also very important.   Carolyn: Yes, indeed. Wanpen, I was wondering what your thoughts were, and take-home messages from this paper. We definitely thought it was significant in the editorial board because you even commissioned a wonderful editorial by Dr. David Calhoun on this. What are your thoughts?   Wanpen: In the United States, using the same technique, we found as much non-adherence. I think there is a lot that we need to do and to understand what caused non-adherence. The patient should not be the only party that's to blame. I think that the doctor's as much of a culprit here to try to tease out what's the barrier to the treatment. Also, as pointed out by Dr. Calhoun, is that although the trials show improvement in blood pressure in both groups, at the end number of medications of patients in resistant hypertension, they require to take four to five drugs to get the blood pressure under control. I think this is going to be a lifelong continuing medication treatment that the physicians have to face, and to deal with the adherence problem as well. Just lastly, I think that although people believe that doing drug levels is only for research purpose, but many people don't realize that actually many drug levels for anti-hypertensive drugs actually is clinical available and can be ordered. It takes a little bit more effort to order it, but it can be done, and actually our center has been doing that already anyway.   Carolyn: Wow. I cannot say that my center has been doing that in Asia, but I really have to admit that this paper made me think about it. Especially the editorial when he highlights it, the very unique information that is provided by actually measuring the blood levels. Michel, you were nodding your head vigorously when Wanpen was saying that we should not just blame the patient. Tell me, what are your thoughts, and how does this affect your clinical practice?   Michel: I fully agree with Wanpen. We have to now integrate the fact that it's accessible, you can measure drug levels through technology, with mass spectrometry, et cetera. This is very important to integrate and to change our paradigm that we have to put in our brain. We have to monitor drug levels. Using this technology we have to establish a partnership with the patient.     I think the truth, also, is somewhere, as Wanpen said, we are also culprits. If patients do not take their treatment, okay, there may be some benefit and e have to look why they are not taking pill treatment, but also we are culprits because we don't listen to them, we don't take enough time, et cetera, et cetera. But I think patients should not be only blamed, so it opens a new possibility to discuss with the patient about the fact that we didn't find the drug in levels in their urine, et cetera.     However, taking into account that there will be this toothbrush effect, that is, "Patient, brush your teeth when you go to see the dentist," you'll take the pills when you go to see the doctor so you can be treated. This is one of the difficulties. However I think it's a new possibility to discuss with the patient of his or her difficulties in taking the pills. It gives us the opportunity to discuss, to take time with our patients.   Carolyn: It's really fascinating, you're talking from a system based in Europe. You're based in Paris.   Michel: Yes.   Carolyn: Wanpen just said that she's doing it, and she's based in the US. Do you now routinely, maybe, monitor these medication levels?   Michel: Yes, yes, yes.   Carolyn: Wow.   Michel: In the hospital we have these mass spectrometer platforms, so we have access to this, and we are working with the house authority to have the reimbursement. Because I think it's important, because if it's not reimbursed there is also a problem.   Carolyn: Of course.   Michel: We are working to see how it could be reimbursed for labs doing these measurements.   Carolyn: But this is for maybe selected resistant hypertensive patients that are difficult to ... ?   Michel: Yes, absolutely. Those very difficult to manage. I think, as a rule of thumb, that after four or five drugs given to the patient, if the patient-   Carolyn: Yeah, we should start questioning, are they taking it.   Michel: If the patients do not have secondary hypertension, we should really start questioning ourself whether they are taking or not the treatment, even if they are looking right in your eyes and telling you, "Yes, doctor, I'm taking all the pills."   Carolyn: Wanpen, how about the reimbursement issues and things like that in the United States? How are you getting it done in your institution?   Wanpen: Actually the coding for doing drug levels, it's actually generic. It's the same coding for Digoxin or Cyclosporine. They actually don't care about what the name of the drug. Strangely, they're coded by the technique, so that's how we go with it, but we have to put in miscellaneous "other" for, we wanted to test for this. That's how we get around it.   Carolyn: Do you do that again routinely, or in selected patients that are difficult to manage hypertensive?   Wanpen: Obviously we have to be selective, so we select from people who we would suspect are non-adherent, but they say they're taking it. But if they already came in and made that they're not taking the drug, there's no point doing that for the clinical purpose. We're doing it for people who we suspect it, and we use it the way ... Actually we shall describe very well, not only just to find what drug they're not taking, because when they're not taking, only about 30% are not taking everything, about 20% not taking one or two drugs. When we drill down to that drug they say, "I have side effects to beta blocker and I don't want to tell my physician that I have problems taking it, but I just not take it." I think that's what led us to pinpoint the problem a little bit better with this technique.   Carolyn: What a lot of practical advice, and congratulations once again for very, very meaningful findings. I learned a lot this time. I don't do this, and so I'm definitely going to think about this much more because of your work. Thank you very much Wanpen, Michel.     And thank you, listeners, for tuning in this time. Remember, you're listening to circulation on the run. Listen in again next week. Thanks.    

We’re back and better than ever with a NEW host! This season, Kieran Quinn takes the reigns and is excited to bring you the latest and greatest in the world of emerging clinical evidence. Along outgoing host Amol Verma, the two hosts discuss two studies: Just how dangerous are opioids in the treatment of chronic pain ... The post Drugs on the Brain: Opining on Opioid-Induced Death and Ticagrelor for TIA or Stroke appeared first on Healthy Debate.

We're back and better than ever with a NEW host! This season, Kieran Quinn takes the reigns and is excited to bring you the latest and greatest in the world of emerging clinical evidence. Along outgoing host Amol Verma, the two hosts discuss two studies: Just how dangerous are opioids in the treatment of chronic pain ...The post Drugs on the Brain: Opining on Opioid-Induced Death and Ticagrelor for TIA or Stroke appeared first on Healthy Debate.

FDA Drug Safety Podcast: FDA approves brand name change for antidepressant drug Brintellix (vortioxetine) to avoid confusion with antiplatelet drug Brilinta (ticagrelor)