Podcasts about prasugrel

In this episode, we review the new 2025 ACC/AHA Acute Coronary Syndrome (ACS) guidelines, with a particular focus on guideline recommendations for analgesics, P2Y12 inhibitors, parenteral anticoagulation, and lipid management. Key Concepts Nitrates and opioids are recommended for symptomatic relief of chest pain. Some patients may not be appropriate for nitrates (e.g. recent PDE-5 inhibitor use, hypotension, or right ventricular infarction). Opioids are used for nitrate-refractory angina but have a theoretical risk of delaying the effect of oral antiplatelet medications. Prasugrel and ticagrelor are preferred P2Y12 inhibitors over clopidogrel in most patients. Patient-specific factors, including the use of PCI, play a role in P2Y12 inhibitor selection. Anticoagulation with heparin is recommended in nearly all acute coronary syndrome (ACS) scenarios. Alternative anticoagulants may be used depending on whether PCI/CABG is planned and whether the anticoagulant is used prior to PCI/CABG (“upstream”) or during the PCI procedure itself. LDL goals after ACS have changed again. All ACS patients should have an LDL goal < 70 with a consideration of an LDL goal of 55-69. A variety of non-statin therapies may be added to a high intensity statin regimen if LDL is not at goal. References Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Published online February 27, 2025. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001309

N Engl J Med 2019;381:1524-1534Background Dual antiplatelet therapy after percutaneous coronary intervention had become a standard of care. Both prasugrel and ticagrelor had been shown to provide more rapid and consistent platelet inhibition than clopidogrel. Randomized controlled trials had shown both drugs were superior to clopidogrel in patients with acute coronary syndromes. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The two drugs have different loading strategies in patients who have acute coronary syndromes without ST-segment elevation. In these patients, ticagrelor is usually administered as pretreatment before diagnostic angiography, but prasugrel is administered only after the coronary anatomy has been assessed by means of diagnostic angiography since no advantage has been observed when prasugrel is used as pretreatment.Before ISAR-REACT 5, there had been no direct comparisons of the two antiplatelet drugs. ISAR-REACT 5 was an investigator-initiated multicenter, non-industry funded RCT to compare the efficacy and safety of the two treatments in patients with acute coronary syndrome. Patients The trial enrolled 4013 patients from 23 centers. Patients were eligible with either STEMI, NSTEMI or unstable angina for which intervention was planned. Exclusion criteria included intolerance of either drugs, history of stroke or intracranial bleeding or any condition that increased the risk of bleeding. Patients could not be on concomitant oral or i.v. therapy with drugs affecting CYP3A4 system. Baseline Characteristics There were 2012 patients assigned to ticagrelor and 2006 patients assigned to prasugrel. The suspected diagnosis at admission was STEMI in 41%, NSTEMI in 46%, and unstable angina in 13% of the patients. The average age was 64 years. Female sex was 24%. Average systolic blood pressure and heart rate was 144 mmHg and 77 bpm. All factors were well balanced. Trial Procedures Therapy with ticagrelor was started at a loading dose of 180 mg and continued at a maintenance dose of 90 mg twice daily. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomization. Therapy with prasugrel was started at a loading dose of 60 mg and continued at a maintenance dose of 10 mg once per day. A reduced maintenance dose of 5 mg daily was recommended in patients who were 75 years of age or older and in those who had a body weight of less than 60 kg. Prasugrel therapy turned on presentation. STEMI patients were given prasugrel as soon as possible after randomization. In those without STEMI, the loading dose was delayed until knowledge of the coronary anatomy. Prasugrel loading was given before crossing the lesion. In patients with a coronary angiography–confirmed acute coronary syndrome who were not considered to be candidates for PCI but who were considered to be candidates for conservative therapy, dual antiplatelet therapy (aspirin and the randomly assigned trial medication) was recommended. About 83% of patients received PCI, 2% CABG and 13-14% were managed conservatively. Clinical follow-up was scheduled at 30 days, 6 and 12 months.Endpoints The primary end point was a composite of death, MI, or stroke at 1 year after randomization. Secondary end points included the safety end point, which was the incidence of bleeding at 1 year (type 3, 4, or 5 on the Bleeding Academic Research Consortium [BARC] scale, which ranges from 0 to 5, with higher values indicating more severe bleeding), the incidence of the individual components of the primary end point at 1 year, and the incidence of definite or probable stent thrombosis at 1 year.The sample-size calculation assumed a primary endpoint would occur in 10% in the ticagrelor group vs 12.9% in the prasugrel group. This led to an estimate of 1900 patients in each group and 80% power to detect a relative risk reduction of 22% in the ticagrelor group. All analyses, including the analysis of the primary end point, were performed according to the intention-to-treat principle Only the safety end point was analyzed in a modified intention-to-treat population, which included all patients who received at least one dose of the randomly assigned trial drug and were assessed for bleeding events up to 7 days after discontinuation of the trial drug.Results At discharge, 81% of patients in both groups received the randomly assigned trial drug. Slightly more patients in the ticagrelor group stopped taking the study drug by one year (15.2 vs 12.5%). One-year follow-up was complete in all but 90 patients (41 patients in the ticagrelor group and 49 patients in the prasugrel group).A primary end-point event (death, MI, stroke) occurred in 184 of 2012 patients (9.1%) in the ticagrelor group and 137 of 2006 patients (6.8%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P=0.006). The composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 161 of 2012 patients (8.1%) in the ticagrelor group and 124 of 2006 patients (6.3%) in the prasugrel group (hazard ratio, 1.32; 95% CI, 1.04 to 1.66).The rates of death, stroke and stent thrombosis did not statistically differ in the two groups. But the risk of MI was 63% higher in the ticagrelor group (4.8% vs 3.0%; HR 1.63; 95% CI, 1.18 to 2.25).Major bleeding was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P=0.46).No heterogenous treatment effects were obvious from the subgroup analyses. Discussion For patients with acute coronary syndrome who were considered for intervention, prasugrel was superior to ticagrelor for the reduction of the primary endpoint. The effect size was large (ticagrelor 36% worse compared to prasugrel), and this was statistically robust. The reduction was obtained without an increase in bleeding. The trialists noted that this was not simply a comparison of drugs, but a comparison of treatment strategies. Authors had assumed that pre-treatment of ticagrelor would be superior. But this trial showed that a prasugrel-based strategy with deferred loading (after knowing the coronary anatomy) was superior. The primary endpoint finding was bolstered by the composite of cardiovascular death, MI and stroke also being 32% higher in the ticagrelor arm. This was an investigator-initiated non-industry funded study with an event rate in the ticagrelor arm similar to expected findings. We find this compelling evidence for the superiority of prasugrel in this patient population. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2014;371:1016-1027Background: Prior trials have demonstrated that combining P2Y12 inhibitors with aspirin in patients with acute coronary syndrome reduces cardiovascular events. Prasugrel, in the TRITON-TIMI 38 trial, and ticagrelor, in the PLATO trial, were administered in the hospital.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Older trials had suggested that early administration of glycoprotein IIb/IIIa inhibitors improves outcomes in patients with ST elevation myocardial infarction (STEMI).The ATLANTIC trial sought to test the hypothesis that pre-hospital compared to in-hospital administration of the P2Y12 inhibitor, ticagrelor, improves outcomes in patients with STEMI.Patients: Patients were enrolled if they had STEMI and had experienced symptoms for at least 30 minutes but no longer than 6 hours, and were expected to have EKG to balloon inflation of less than 120 minutes. Patients were excluded if they had prior intracranial bleeding, moderate to severe liver disease, gastrointestinal bleeding within 6 months, planned fibrinolytic therapy or required dialysis.Baseline characteristics: The average age of patients was 61 years with 80% being men. The average weight was 80 kg. About 14% had diabetes, 9% had prior myocardial infarction, 4% had chronic obstructive pulmonary disease and 2% had chronic renal failure. TIMI risk score was 0-2 in 61% of the patients. About 90% had Killip class I. Coronary angiography was performed in 98% of the patients and percutaneous coronary intervention (PCI) with stent placement was performed in 82%. The use of glycoprotein IIb/IIIa inhibitors was high in the study and was administered before percutaneous coronary intervention in 29% of the patients.Procedures: Patients were randomized 1:1 to receive ticagrelor en route to the hospital/ catheterization lab (group 1) or at the catheterization lab (group 2). In group 1, patients received ticagrelor 180mg en route to the hospital and placebo in the catheterization lab. In group 2, patients received placebo en route to the hospital and ticagrelor 180mg in the catheterization lab. Following that, all patients received ticagrelor 90mg twice daily for at least 30 days and the treatment was recommended to continue for 12 months. Clinical endpoints were adjudicated up to 30-days post randomization.Endpoints: There were two coprimary endpoints – proportion of patients who did not have 70% or greater resolution in their ST-segment elevation before PCI and proportion of patients without TIMI grade III flow in the infarcted artery before PCI. Review of EKG and angiographic data was blinded.A secondary prespecified endpoint included the composite of all-cause death, myocardial infarction, stent thrombosis, stroke or urgent revascularization at 30 days.Analysis was performed based on the modified intention-to-treat principle, defined as patients who received at least one loading dose of the study drug. Patients with missing EKG or angiographic data were excluded from the primary endpoint analysis.The sample size estimate was based on an anticipated event rate of 15% in the control group for the EKG endpoint. They estimated that 779 patients would be needed in each group to show a 6% absolute difference with 80% power and an alpha of 2.5%.Results: The trial randomized 1,862 patients, 909 patients to the prehospital group and 953 to the in-hospital group. The median time from randomization to angiography was 48 minutes and the median time between the two loading doses was 31 minutes.There was no significant difference in the proportion of patients who did not have 70% or more ST segment resolution before PCI (86.8% for the pre-hospital group vs 87.6% for the in-hospital group, OR: 0.93, 95% CI: 0.69 – 1.25; p= 0.63) or the proportion of patients who did not have TIMI III flow in the infarcted artery before PCI (82.6% for the pre-hospital group vs 83.1% for the in-hospital group, OR: 0.97, 95% CI: 0.75 – 1.25; p= 0.82).There was also no significant difference for the secondary composite endpoint (4.5% vs 4.4%, OR: 1.03, 95% CI: 0.66 – 1.60; p= 0.91). Stent thrombosis at 30-days was lower in the pre-hospital group (0.2% vs 1.2%, OR: 0.19, 95% CI: 0.04 – 0.86; p= 0.02). Myocardial infarction was not significantly different between both groups (0.8% vs 1.1%; p= 0.53). All-cause death was numerically higher in the pre-hospital group (3.3% vs 2.0%, OR: 1.68, 95% CI: 0.94 – 3.01; p= 0.08).Major bleeding not related to CABG was not significantly different between both treatment groups (1.3% in both groups using the TIMI criteria and 2.9% in the pre-hospital group vs 2.5% in the in-hospital group, using the STEEPLE criteria).Conclusion: In patients with STEMI, pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration. Although pre-hospital administration of ticagrelor reduced stent thrombosis at 30-days, this did not reduce all-cause mortality. In fact, all-cause mortality was numerically higher in the pre-hospital group.A notable finding is that within the in-hospital group, definite stent thrombosis occurred in 1.2% of patients while 1.1% were adjudicated to have myocardial infarction. Stent thrombosis is a serious condition that leads to myocardial infarction. The trial protocol used many definitions for myocardial infarction. This underscores the complexity of counting and adjudicating events in clinical trials and highlights the importance of relying on outcomes less susceptible to bias, such as mortality.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

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

Note to readers: Since going live with Cardiology Trials Substack in January of 2024 we have been exclusively covering trials that we have categorized as belonging to the major subject heading “Acute Coronary Syndrome” belonging to the subsection “Medicines”. Our indexing scheme was described in one of our original posts and we encourage our audience to read it if you have not already. This is pertinent because the next several trials being presented may seem to come out of the blue but we assure you there is a method.N Engl J Med 2007;357:2011-15.Background Up to now we have presented trials involving major foundational medical therapies for acute coronary syndrome which include aspirin, thrombolytic agents and anticoagulation, but not those involving percutaneous coronary intervention (PCI) as they are reserved for another section. But, by the turn of the 21st century, PCI had become the dominant up-front strategy for revascularization in many countries around the world. Clinical trials demonstrated it improved outcomes, the main one being re-infarction, compared to thrombolysis in patients with STEMIs, and there was an evolving evidence for it in non-ST-segment elevation acute coronary syndrome (STEACS) as well, where thrombolysis had not demonstrated any significant benefits.As PCI became dominant, antithrombotic strategies for optimizing outcomes following PCI evolved along with it. These early trials generally involved a mixture of patient phenotypes (acute vs elective PCI) and were relatively small and of limited quality by comparison to many of the seminal trials presented thus far. Instead of presenting each of these smaller studies, we direct readers to a narrative review that nicely describes the evolution of dual-antiplatelet therapy for PCI and other indications.Briefly: dual-antiplatelet therapy with aspirin and ticlopidine, an antiplatelet agent belonging to the drug class of thienopyridines, which inhibits platelet aggregation induced by ADP, was found superior to aspirin alone or aspirin plus anticoagulation when PCI was performed; however, there were concerns about its safety. Clopidogrel was developed after ticlopidine; it had a similar mechanism of action but less safety concerns and could be given as a loading dose to produce more rapid effects. Despite limited evidence from clinical trials comparing it head-to-head with ticlopidine it became the dominant thienopyridine agent on the market and still has a prominent role in the management of cardiovascular diseases today.Following PCI and dual-antiplatelet therapy with aspirin and clopidogrel, patients continue to have an elevated risk of coronary events, in general, and in-stent related coronary events, in particular. Some of this risk has been attributed to limitations of clopidogrel itself. Clopidogrel has modest antiplatelet effects (compared to other thienopyridines) with substantial interpatient variability due to genetic polymorphisms that impact clopidogrel metabolism and antiplatelet efficacy. Clopidogrel also has a delayed onset of action, which is especially relevant regarding its ability to protect against the dreaded adverse event of early in-stent thrombosis.Prasugrel is a thienopyridine—developed after clopidogrel—that inhibits platelet aggregation more rapidly, consistently and to a greater extent. The Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 trial sought to test the hypothesis that prasugrel would reduce major cardiovascular events compared to clopidogrel in patients with acute coronary syndrome undergoing PCI.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 had either moderate-to-high risk unstable angina (UA) or NSTEMI or STEMI. UA and NSTEMI were defined by ischemic symptoms lasting 10 minutes or more and occurring within 72 hours before randomization, a TIMI risk score of 3 or more, and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis. STEMI was traditionally defined. Key exclusion criteria included an increased risk of bleeding, anemia, thrombocytopenia, a history of pathologic intracranial findings, or the use of any thienopyridine within 5 days before enrollment.Baseline characteristics The median age of patients was 61 years with 13% being ≥75 years and 74% were men; over 90% were white. The index event was UA or NSTEMI in 74% and STEMI in 26%.  PCI was performed in 99% of patients and split evenly between those receiving bare metal or drug eluting stent(s).  18% of patients had a prior MI, 23% had diabetes, 64% had hypertension and 38% were tobacco users. Only 11% of patients had CKD defined as a creatinine clearance ≤60 ml/min.Procedures A loading dose of prasugrel 60 mg or clopidogrel 300 mg was given in a double blind manner anytime between randomization up to 1 hour after leaving the catheterization laboratory. In order to be randomized, the plan for PCI had to be known. This could occur before going to the cath lab for planned PCI, if the anatomy was already known or occur in the cath lab during the case where anatomy was determined and PCI was performed. If PCI was planned, patients were eligible to undergo pretreatment with the study drug for up to 24 hours prior to PCI.Treating physicians determined the vessels treated, devices used, and adjunctive medication administered to support PCI. After PCI, patients received maintenance doses of either prasugrel 10 mg daily or clopidogrel 75 mg daily. Use of aspirin at a dose of 75 to 162 mg daily was recommended. Study visits were conducted at hospital discharge, 30 days, 90 days, and 3-month intervals thereafter, for a total of 6 to 15 months.Endpoints The primary efficacy endpoint was a composite of cardiovascular death, nonfatal MI or stroke during the follow up period. A prespecified “landmark” analysis was undertaken to compare the primary endpoint event rate up to 3 days following randomization and from day 3 to the end of the study. The sample size calculation was event-driven and it was determined that 875 primary endpoint events would provide 90% power to detect a relative risk reduction of 20%. A prespecified analysis performed after 650 events revealed a lower than anticipated event rate and the investigators increased the sample size accordingly.Results A total of 13,608 patients (10,074 with UA or NSTEMI and 3534 with STEMI), from 707 sites in 30 countries were enrolled. There were 6,813 patients assigned to the prasugrel group and 6,795 assigned to clopidogrel. The median duration of therapy was 14.5 months. Prasugrel significantly reduced the primary composite endpoint compared to clopidogrel (9.9% vs 12.1%; HR 0.81; 95% CI 0.73-0.90; P

Commentary by Dr Duk-Woo Park

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 Daniele Giacoppo

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.

#728- DICA DE PROVA: Quando não usar prasugrel. by Cardiopapers

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

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.

#505 - Como Eu Uso Prasugrel! by Cardiopapers

Dr. Thomas Mavrakanas summarizes the results of his study, "Prasugrel and Ticagrelor in Patients with Drug-Eluting Stents and Kidney Failure," on behalf of his colleagues.

Theme: Cardiology. Participants: Dr Aaisha Ferkh (cardiology fellow), Dr Samia Kazi (cardiology fellow), Dr Khanh Nguyen, Dr Pramod Chandru, Kit Rowe, Shreyas Iyer, Caroline Tyers and Samoda Wilegoda Mudalige.Discussion 1:Lemkes, J., Janssens, G., van der Hoeven, N., Jewbali, L., Dubois, E., & Meuwissen, M. et al. (2019). Coronary Angiography after Cardiac Arrest without ST-Segment Elevation. New England Journal Of Medicine, 380(15), 1397-1407. https://doi.org/10.1056/nejmoa1816897.  Take-Home Points: This study showed that in patients successfully resuscitated from out-of-hospital cardiac arrest, who did not have STEMI, immediate coronary angiography and revascularisation did not improve survival at 90 days. It may be reasonable to consider early coronary angiography in certain patients after discussion with the interventional cardiologist (e.g. if there is a good history of ischemic symptoms prior to the arrest or if the patient has a significant cardiac background). It is also important to focus on other aspects of post-resuscitation care e.g. targeted temperature management, vital organ support, and treating the underlying aetiology of the cardiac arrest. Discussion 2:Aslanger, E., Yıldırımtürk, Ö., Şimşek, B., Sungur, A., Türer Cabbar, A., & Bozbeyoğlu, E. et al. (2020). A new electrocardiographic pattern indicating inferior myocardial infarction. Journal Of Electrocardiology, 61, 41-46. https://doi.org/10.1016/j.jelectrocard.2020.04.008. Take-Home Points: ECG criteria for this pattern (or "Aslanger's pattern"): ST-segment elevation isolated to lead III, concomitant ST depression in any of V4 to V6 (with a positive/terminally positive T-wave), and ST-segment in V1 > V2. This pattern may indicate inferior MI in patients “with concomitant critical lesion/s in coronary arteries other than the infarct-related artery”. This study shows that patients with this particular ECG pattern have a higher risk of short- and long-term mortality than other NSTEMI patients; however, more research is required to corroborate these findings.  If the patient has ongoing chest pain (without any other obvious cause), it is important to do serial ECGs and escalate concerns to the cardiology team (regardless of what their ECG might show).  ECG example (from Life In The Fast Lane):https://litfl.com/wp-content/uploads/2020/12/Aslanger-pattern-of-ECG-chages-in-inferior-myocardial-infarction-2020.png. Discussion 3:Schüpke, S., Neumann, F., Menichelli, M., Mayer, K., Bernlochner, I., & Wöhrle, J. et al. (2019). Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. New England Journal Of Medicine, 381(16), 1524-1534. https://doi.org/10.1056/nejmoa1908973. Take-Home Points: This study demonstrated that, in patients with ACS (with or without ST-segment elevation), the incidence of death, MI, and stroke was significantly lower among patients who were treated with Prasugrel than among patients who were treated with Ticagrelor.  The incidence of major bleeding was similar between the two treatment groups. Prasugrel is currently unavailable in the Australian market and in this context, the preferred agent is Ticagrelor (unless it is contraindicated). However, prior to choosing an agent, it is worth discussing with the cardiology team due to variations in individual practice, local protocols, and time of administration.  When choosing DAPT, always consider the drug's contraindications and risk of potential complications (e.g. bleeding). If a patient has a higher risk of bleeding and is above the age of 70 years, it might be safer to use Clopidogrel. The main contraindications for use of Ticagrelor are increased risk of bleeding and higher degrees of conduction block. With Prasugrel, watch out for history of stroke as that increases the risk of intracranial bleeding.  Credits:The discussions were mediated by ED consultants,  Dr Khanh Nguyen and Dr Pramod Chandru.This episode was produced by the ­­­­Emergency Medicine Training Network 5 with the assistance of Dr Kavita Varshney, Deepa Dasgupta, Cynthia De Macedo Franco, and Paul Scott.Music/Sound Effects Sound effects from https://www.free-stock-music.com. Good Day by Roa Music | https://soundcloud.com/roa_music1031, Music promoted by https://www.free-stock-music.comCreative Commons Attribution 3.0 Unported License, https://creativecommons.org/licenses/by/3.0/deed.en_US. Happy by Mike Leite | https://soundcloud.com/mikeleite, Music promoted by https://www.free-stock-music.comCreative Commons Attribution 3.0 Unported License, https://creativecommons.org/licenses/by/3.0/deed.en_US. Love Trip by Sarah Jansen Music | https://soundcloud.com/sarahjansenmusic, Music promoted by https://www.free-stock-music.comCreative Commons Attribution 3.0 Unported License, https://creativecommons.org/licenses/by/3.0/deed.en_US. Medical Examination by MaxKoMusic | https://maxkomusic.com/, Music promoted by https://www.free-stock-music.comCreative Commons Attribution-ShareAlike 3.0 Unported, https://creativecommons.org/licenses/by-sa/3.0/deed.en_US. Nothing Better by Vendredi ft. ELLE | https://soundcloud.com/vendrediduo, Music promoted by https://www.free-stock-music.comCreative Commons Attribution 3.0 Unported License, https://creativecommons.org/licenses/by/3.0/deed.en_US. Roadtrip by Scandinavianz | https://soundcloud.com/scandinavianz, Music promoted by https://www.free-stock-music.comCreative Commons Attribution 3.0 Unported License, https://creativecommons.org/licenses/by/3.0/deed.en_US. Sax by MBB | https://soundcloud.com/mbbofficial, Music promoted by https://www.free-stock-music.com, Creative Commons Attribution-ShareAlike 3.0 Unported, https://creativecommons.org/licens.  Waterfall by Scandinavianz | https://soundcloud.com/scandinavianz, Music promoted by https://www.free-stock-music.comCreative Commons Attribution 3.0 Unported License, https://creativecommons.org/licenses/by/3.0/deed.en_US. ~Thank you for listening!Please send us an email to let us know what you thought.You can contact us at westmeadedjournalclub@gmail.comSee you next time,Caroline, Kit, Pramod, Samoda, and Shreyas.

This week's episode features author Adnan Kastrati and Associate Editor Dharam Kumbhani as they discuss ticagrelor or prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your cohosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature Ticagrelor Prasmul in patients with ST segment elevation myocardial infarction undergoing primary PCI. More on that story later, though. How about we grab a cup of coffee and look at some of the other papers in the issue. Would you like to go first? Dr. Carolyn Lam: I would. And actually, I'm going to talk about two papers and they're all about BET, BET or promo domain, an extra terminal epigenetic reta proteins. And in particular, this one called BRD4. Now these proteins have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecular BET protein inhibitors, such as JQ1 have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet genetic studies elucidating the biology of BET proteins in the heart have not been conducted. Well, at least until this week's issue where we have not one, but two papers, both elegantly using mouse genetic studies. Dr. Carolyn Lam: In the first from Dr. Srivastava from Gladstone Institute of Cardiovascular Disease in San Francisco and Dr. Jain from Perlman School of Medicine in Philadelphia and their colleagues, they found that BRD4, that particular BET epigenetic reader protein, forms a transcriptional regulatory module with GATA4, a lineage determining transcription factor in cardiomyocytes. This BRD4 GATA4 module was a critical orchestrator of mitochondrial bioenergetics in the adult heart. Dr. Greg Hundley: Well Carolyn, that is a wonderful summary. What are the clinical implications? Dr. Carolyn Lam: Identification of this new BRD4 interaction partner, such as GATA4 could provide new insights into developing epigenetic based therapies for heart failure. And the second paper is from Dr. Joseph Hill and Thomas Gillette from University of Texas Southwestern Medical Center and their colleagues. And what they found was that BRD4 was essential to the maintenance of mitochondrial electron transport chain function via transcriptional regulation of a nuclear mitochondrial gene network. BRD4 heterozygous deletion resulted in delayed heart failure, whereas pharmacological BRD4 inhibition using JQ1 induced modest changes in mitochondrial genes suggesting potential cardiac toxicity in targeting BRD4 at baseline. Dr. Greg Hundley: So what does this mean for us clinically, Carolyn? Dr. Carolyn Lam: As more potent and specific inhibitors are developed targeting BRD4 for clinical settings in oncology and other diseases, we must carefully monitor bezel cardiac performance for functional and mitochondrial deterioration. Important clinical message there. Dr. Greg Hundley: Great job, Carolyn. Well, my first paper is entitled "An Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaques" And it comes to us from Dr. Tomas Neilan and his colleagues at the Mass General Hospital. The study was situated in a single academic medical center. And Carolyn in this paper, there are actually three studies described. First, there's a primary analysis that evaluated whether exposure to an immune checkpoint inhibitor during treatment for cancer was associated with atherosclerotic cardiovascular events among 2,842 patients versus 2,842 controls that were matched by age, a history of cardiovascular events and cancer type. Dr. Greg Hundley: In the second study, a case crossover analysis was performed with an at risk period defined as the two year period after, and the control period as the two year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events including myocardial infarction, coronary revascularization, and ischemic stroke. And secondary outcomes included the individual components of that primary outcome. Dr. Greg Hundley: Finally, in the third study in this paper, there's an imaging stub study of 40 individuals, and it looked at the rate of atherosclerotic plaque progression compared from before and after starting the immune checkpoint inhibitor. All study measures and outcomes were blindly adjudicated in this third study. Dr. Carolyn Lam: Wow, a three in one. That really sounds novel. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. In the matched cohort study, there was a three-fold higher risk for cardiovascular events after starting an immune checkpoint inhibitor. There was a similar increase in each of the individual components of the primary outcome. In the case crossover study, there was also an increase in cardiovascular events from 1.37 to 6.55 per hundred person years at the two year time point. Dr. Greg Hundley: And then lastly, Carolyn, in the imaging study, the rate of progression of total aortic plaque volume was three fold higher after immune checkpoint inhibitors from 2.1% per year to 6.7% per year after receiving these agents. The association between immune checkpoint inhibitor use and increased atherosclerotic plaque progression was attenuated with the concomitant use of statins or corticosteroids. Dr. Carolyn Lam: Wow, Greg. So I suppose what all this shows is that we need to be aware of the cardiovascular risk prior to, during and after treatment with immune checkpoint inhibitors and perhaps, you know, optimize these cardiovascular risk factors. Thank you, Greg. Dr. Greg Hundley: You bet. Well, Carolyn, my next paper is from Dr. George Vlachojannis from University Medical Center at Utrecht. These authors conducted a randomized control multi-center trial in the Netherlands enrolling STEMI patients planned to undergo primary PCI. Now patients were randomly allocated to receive in the ambulance before transfer a 60 milligram loading dose of Prasugrel, either being crushed or as integral tablets. The independent primary end points were thrombolysis in myocardial infarction, TIMI three flow in the infarct related artery at initial coronary angiography, and complete greater than they go to 70% ST segment resolution one hour post primary PCI. The safety end points were TIMI major and bleeding academic research consortium, or BARC, greater than three bleedings and secondary end points included platelet reactivity and ischemic outcomes. Dr. Carolyn Lam: Nice trial design. So what did they find? Dr. Greg Hundley: Well, Carolyn, a total of 727 patients were assigned to either crushed or integral tablets of Prasugrel. The median time from study treatment to wire crossing during primary PCI was 57 minutes, and the primary end point of TIMI three flow in the infarct related pre primary PCI artery occurred in 31% in the crushed group versus 32.7% in the integral group. No difference, P .064. Complete ST segment resolution one hour post primary PCI was present in 59.9% in the crush group and 57.3% in the integral group. Again, no difference, P equals .055. Platelet reactivity at the beginning of primary PCI measured as the P2Y12 reactivity unit, differed significantly between the groups. Crushed was 192 versus integral was 227 and the P value was less than 0.01. TIMI major and BARC greater than three bleeding occurred in 0% in the crushed group and 0.8% in the integral group and in 0.3% in the crushed group versus 1.1% in the integral group respectively. So there were no differences observed between groups regarding ischemic events at 30 days. Dr. Greg Hundley: So Carolyn, in conclusion, prehospital administration of crushed Prasugrel tablets does not improve TIMI three flow in the infarct related artery, pre primary PCI or complete SD segment resolution one hour post primary PCI in patients presenting with STEMI planned for primary PCI. Dr. Carolyn Lam: Interesting and interesting stuff with platelet reactivity and bleeding. Thank you, Greg. Well, there are other papers in today's issue. There's an in-depth paper by Dr. Katsanos on stroke prevention in atrial fibrillation, looking forward. There's a research letter by Dr. Berger on myocardial injury in adults hospitalized with COVID-19 and another by Dr. Hacker on again, immune checkpoint inhibitor therapy and how that induces inflammatory activity in large arteries. Dr. Greg Hundley: Well, Carolyn, I've got a couple other papers to talk about in this issue. There's a On My Mind piece from Dr. deFilippi entitled "Navigating Testing for COVID-19." There's a Perspective from Dr. Ridker entitled "Equipoise Trust and the Need for Cardiologists to Randomize Patients into Anticoagulation Trials in the Time of COVID." There's an ECG challenge from Dr. Arias entitled, "A Paced Tachycardia." And then finally, there's an exchange of letters from Drs. Liu regarding a prior publication entitled "Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets." Well, Carolyn, how about we get to the world of anti-platelet therapy, ticagrelor prasugrel in patients with ST segment elevation myocardial infarction, shall we? Dr. Carolyn Lam: Yes, let's go Greg. Dr. Greg Hundley: Well welcome, listeners, to our featured discussion today on this December 15, and we are going to learn and discuss a little more, a paper pertaining to ticagrelor versus prasugrel in patients with ST segment elevation myocardial infarction. And our lead author today is Adnan Kastrati from Deutsches Heart center in Munich. And we also have our own Associate Editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas. Welcome, gentlemen. Adnan, maybe I'll start with you. Could you tell us a little bit about the background related to this article and what was the hypothesis that you wanted to address? Dr. Adnan Kastrati: First of all, thank you very much for having me here to share with you some thoughts. Thank you, Dharam, for handling our paper in Circulation. We are very honored to have it published there. About these are the ISAR REACT-5 series of studies dedicated to optimizing the antiplatelet therapy in patients and anticoagulant therapy in patients with acute and chronic coronary syndromes, mostly who are undergoing a PCI procedure. We started to think about that study immediately after the publication of the platelet trial. We showed the superiority of prasugrel in patients with acute coronary syndromes. These were the two new ADP receptor antagonists at the time. And so as a physician, we are interested to know which of them was better because there was no direct comparison. And so that's why we decided to have an open-label trial randomized. Most of the centers were situated in Germany. Two centers were situated in Italy. The private end point was adopted to the private end point of the trials in this skill. Only one difference was there, instead of cardiovascular death, we put all cause death in the primary end point. Why? Because all cause death may also reflect the gradient end bleeding between the two drugs. We wanted to have a more integrative endpoint in this sense. So it was a combination of all cause death, myocardial infarction, and stroke. Dr. Adnan Kastrati: It was a one year followup study. The study had two groups of steady patients, which was about 40% of the patients, included in the multicentral trial. And what we found in this trial, it was the same results as it was found in the whole trial. The advantages seen for prasugrel was present here also. Although we lost the significance in the evaluation of the primary endpoint. It was a 31% increase or 24% decrease with prasugrel in that sense. But otherwise everything was in the same direction as in the whole trial. And if you look also in the components of the primary end point…, you have the chance to see that numerically, it was the same trend for all components. Although the trial was not powered for going to evaluate the component of the prime end point. This was the main result. Dr. Greg Hundley: It sounds like you had 1,653 patients with STEMI randomized to receive ticagrelor or prasugrel and 10% experienced the primary end point in the ticagrelor group, but only 7.9% in the prasugrel group. But the P value was only .10. We saw trends toward favoring prasugrel rather than sort of a definitive difference. Is that a correct summary? Dr. Adnan Kastrati: Yes, it is a correct summary. I would say this group of patients is the most interesting subgroup of patients in ISAR 5 trial. Why? Because the pretreatment strategy is the same. Because there have been a lot of discussions about non-S-segment segment elevation acute myocardial infarction due to the difference in pretreatment. Although it was intentional, some people felt it's different and they said you have two different strategies there. In the STEMI subgroup, the pretreatment strategy was the same, so it was a head to head comparison of two drugs, even according to the same strategy. This is one. Dr. Adnan Kastrati: Second, you have to look back at the trials in the same field…Both these trials, if you look closely to the results of for STEMI patients, both of these trials haven't shown a significant result for the STEMI subgroup. For plateau it was a P value of 007 and for tritan it was a P value of 0014 only. Why? Because in the tritan it was very specific. They included also patients after fever analyzes and the significance came only from the comparison of tritan in this group, not in the primary PCI group. In the plateau and ISAR-5 we excluded these patients. Dr. Greg Hundley: Dharam, we're going to turn to you now. Adnan's really framed this study nicely, but can you help us from your perspective, put this study in perspective with others that have been published in this space? Dr. Dharam Kumbhani: Yeah, thanks, Greg. And I want to congratulate Adnan and his group for providing the field with another really well conducted study in a very important field. The center has done some very, very landmark trials, and I think this is another one of those. It sort of helps us understand potentially the best treatment mechanism or protocol for patients undergoing primary PCI for STEMI in this case. As you nicely outlined sort of the background for this, the only other trial that I'm aware of in this space is directly comparing pasugrel and ticagrelor head to head was the Prague 18 trial, which was smaller. I think it was about under 1100 patients. So even the STEMI cohort here was larger than that trial. But that trial ended up being terribly underpowered and unfortunately, also discontinued prematurely. So there wasn't really any significant difference that was noted in that trial and there was also a high crossover to clopidogrel in that other trials. Dr. Dharam Kumbhani: So I think that trial, in fact, we had published a trial in circulation as well. And I think this study sort of helps to advance the field a little bit by providing a head to head comparison between the two drugs. If I may extend some of the discussion points that were brought up earlier, I think, again, there is a couple of things that jumped out to me. One is, as you mentioned, the semi cohort is very interesting and very important. The p-value for interaction between the STEMI and the non-STEMI population was not significant for the primary end point. So that is certainly important when considering these results. Dr. Dharam Kumbhani: And the second thing is the differences that were noted in the rates of reinfarction, both spontaneous as well as PCI related. And although that is very interesting, we certainly have to keep that first point in mind when considering that. I think it becomes more hypothesis generating that MI rates ended up being higher with ticagrelor compared with prasugrel, and then sort of trying to tease that out in terms of, was that just a play of chance? Do we end up seeing that, is there a real biological reason for that? All of the trials was extremely well done. There were about 29 patients that did not have one-year follow-up and there were about 67 or so MI events. I think it's very interesting, and I think for at least for me, when I review this trial, I think it brings up some very interesting hypotheses that I think we would need to test further. Those anyway, my sort of high-level thoughts on this excellent trial. Dr. Greg Hundley: Very good. Well, I'd like to ask you just in 20 seconds, each of you, what's the next study that needs to be performed in this field? Adnan, start with you. Dr. Adnan Kastrati: I don't expect trials doing the same thing that we have done in ISAR-X5. We are planning now that ISAR-X6 trial. They are finalizing the protocol, and it will be a large trial of 9,000 patients with acute coronary syndromes in which will test the need for aspirin after discharge. That means all the spaces will be with the potent P2I12 inhibitors. And one group, it will be a placebo controlled trial. One group will have aspirin after discharge, the other placebo. And this is now, for us, the most important thing in this area. Dr. Adnan Kastrati: If I have the chance to respond to Dharam about the mechanistic insights of this effect, I would say that we have shown aggressive cardiology, our data about platelet function. It is the biggest platelet function studies in this area, 600 patients. We have tested in patients after PCI. We tested ADP in used aggregation after ticagrelor and prasugrel. And prasugrel was associated with a 30% reduction in platelet aggregation in these patients. And I think that this offers the mechanistic basis also for our results. And the results will be published shortly. Dr. Greg Hundley: Very nice, and Dharam. Dr. Dharam: Thank you for that response, Adnan. And Greg, to your question, I agree. I think it would be hard, although the field would really benefit from having a head to head comparison between these two drugs again in a larger study. I do think a lot of the interest and excitement in the ACS field is on de-escalation strategies as the outline. And so I suppose that that's sort of where we'll see a lot more in terms of clinical trials. Dr. Greg Hundley: Very good. Well listeners, this has been a wonderful discussion and we appreciate the input from the primary author, Dr. Adnan Kastrati, from the Deutsches Heart Center in Munich and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern. Really reviewing prasugrel versus ticagrelor for primary PCI in patients with STEMI only, and showing really no difference in their primary endpoint of death, myocardial infarction, and stroke, with however an increased risk of reinfection in the patients receiving ticagrelor only. Dr. Greg Hundley: So on behalf of Carolyn and myself, we wish you a great week and look forward to catching you next week On the Run. This program is copyright the American Heart Association, 2020.  

Commentary by Dr. Valentin Fuster

In this episode, we discuss the pros and cons of the main antiplatelet agents used in the setting of ACS. Who comes out on top?References:Norgard NB, DiNicolantonio JJ. Clopidogrel, prasugrel, or ticagrelor? A practical guide to use of antiplatelet agents in patients with acute coronary syndromes. Postgrad Med. 2013; 125(4): 91-102Thachil J. Antiplatelet therapy- a summary for the general physicians. Clin Med. 2016; 16(2): 152-160

#274 - SCA sem supra e vai pra angioplastia? Uso prasugrel ou ticagrelor? by Cardiopapers

Akut koroner sendromlar (AKS) acil servislerde sık karşılaştığımız hasta gruplarından. Hepimizin bildiği üzere bu hastaların standart medikal tedavisi: Dual Antiplatelet Tedavisi Adenozin Difosfat Reseptör Antagonisti + Aspirin 3. kuşak tienopiridin (Prasugrel) ve siklopentiltri-azoloprimidin (Tikagrelor), Klopidogrel ile karşılaştırıldığında, daha iyi, daha hızlı ve daha kalıcı platelet inhibisyonu yapıyor​1,2​. Yapılmış olan randomize kontrollü çalışmalar (RKÇ) Prasugrel’in ve Tikagrelor’un AKS’li hastalarda daha başarılı olduğunu göstermekte​3,4​ ve her iki ilaç da ST segment elevasyonlu veya elevasyonsuz AKS’lerde sınıf 1 öneri almış bulunmakta​5,6​. Tikagrelor yükleme dozu koroner anjiografi öncesinde uygulanırken, Prasugrel koroner anatomi görüldükten sonra uygulanmaktadır (Prasugrel anjio öncesinde uygulandığında faydası gösterilmemiştir)​3,4​. Her ne kadar Tikagrelor'ün ve Prasugrel’in AKS’de Klopidogrel'e üstünlüğü gösterilmiş olsa da birçok acil tıp hekimi ve kardiolog hala uzun yıllardır kullandığı Klopidogrel'i tercih edebilmektedir. Bunun sebebini sorduğunuzda alacağınız cevap hep aynı: 'Tikagrelor ve Prasugrel daha çok yeni. Uzun dönem yan etkilerini bilmiyoruz' Peki bu doğru mu? Maalesef kısmen doğru. Literatürde, Prasugrel’in ve Tikagrelor’un invaziv strateji planlanan AKS’li hastalardaki 1 yıllık yan etkilerinin karşılaştırıldığı RKÇ datası maalesef yeterli değil. İşte tam da bu noktada bu eksiği gidermeyi hedefleyerek planlanmış bir çalışmadan​7​ bahsederek tartışmayı derinleştirmeyi hedefliyorum… ISAR-REACT 5 Çalışması Schupke ve arkadaşlarının geçen yıl NEJM’de yayınlanan faz 4, multi-klinik (23 klinik), randomize çalışmasının klinik sorusu: Tikagrelor veya Prasugrel, AKS’li hastalarda 1 yıllık ölüm, AMI veya inme sıklığına katkıda bulunuyor mu? Çalışamaya 18 yaş ve üzeri, AKS tanısı (STEMİ, NSTEMİ veya USAP) almış ve invaziv tedavi planlanan hastalar dahil edilmiş. Tikagrelor veya Prasugrel alerjisi olan hastalar, TİA, iskemik/hemorajik inme öyküsü olan hastalar, intrakranial kitle/AVM/anevrizması olan hastalar, aktif kanama bulguları olan hastalar, 24 saat içinde fibrinolitik tedavi almış hastalar, trombosit

Akut koroner sendromlar (AKS) acil servislerde sık karşılaştığımız hasta gruplarından. Hepimizin bildiği üzere bu hastaların standart medikal tedavisi: Dual Antiplatelet Tedavisi Adenozin Difosfat Reseptör Antagonisti + Aspirin 3. kuşak tienopiridin (Prasugrel) ve siklopentiltri-azoloprimidin (Tikagrelor), Klopidogrel ile karşılaştırıldığında, daha iyi, daha hızlı ve daha kalıcı platelet inhibisyonu yapıyor​1,2​. Yapılmış olan randomize kontrollü çalışmalar (RKÇ) Prasugrel’in ve …

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains? Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe? Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress. Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find? Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease. Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same? Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different. Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart. Dr Carolyn Lam: Wow. What did they find? Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases. Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common? Dr Greg Hundley: I definitely need phone a friend. Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms. Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI. Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg? Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate. Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find? Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points. Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19. Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR. Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we? Dr Greg Hundley: You bet. Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found. Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock. So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation. Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too. Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies? Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease. We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function. Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not? Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome. But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease. Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts. Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution. And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It’s just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them. Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community? Dr Damien Bonnet: And that there are clinical issues. So the first one is to see or to look at potential cardiac residual anomalies, mitochondrial or coronary arteries aneurism, because today we have not precise information of that. The second is probably observational because it will be difficult to randomize young children, is what is the optimal treatment at baseline or what is the optimal strategy? And is it possible to stratify the strategy as I just said, but I don't have evidence for that. And for the long term, I think that trying to identify why only some children have this disease and why the other don't have, if there is any genetic susceptibility, it will be something interesting. And potentially as we discussed already together, it might give us some keys to better understand Kawasaki disease as well. Dr Gerald Greil: Thank you so much for summarizing that. I mean, we are all very much looking forward to working together with you and other groups around the world to get a little bit more and better insight in this kind of type of disease and how to treat them best and how to follow them up best. Dr Carolyn Lam: Thank you so much, Damien and Gerald. I mean, I'm sure I speak behalf of the entire audience that I learned a lot just listening to your very open and honest conversation of what we've seen, what we've experienced, what we don't yet know. Listeners, you have to refer to a beautiful accompanying editorial that Gerald invited, and it is by Dr John Simpson and Dr Jane Newburger from Evalina London Children's Hospital and Harvard Medical School, respectively. Thank you so much for joining us today. And please remember, you've been listening to Circulation on the Run. Tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore. Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Greg, today's speaker paper is really special on a number of levels. First, it's a research letter and secondly, it's actually basic science. Now, this tells you it's got to be really special. Well, I'll just give you a hint. It talks about a new therapy for stroke. I'm going to leave it at that, leave you guessing because you've got to hang on as we tell you about the rest of the issue and then listen to the feature discussion. Now, the first original paper here, I want to describe as a basic paper focusing on PDE4B in heart failure. Dr Greg Hundley: All right, Carolyn, I'm not even going to let you start to quiz me on this. Can you tell me what in the world is PDE4B? Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really represent a highly diverse super family of enzymes among which PDE3 and PDE4 are the main phosphodiesterases that degrading cyclic AMP with a high affinity in the heart. The cyclic AMP hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key negative regulator of cardiac beta-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal calcium handling and PDE4B is decreased in pressure overload hypertrophy suggesting that increasing PDE4B in the heart may be beneficial in heart failure. These authors led by Dr Vandecasteele from Inserm tested this hypothesis in elegant experiments involving both human cardiac tissues and transgenic mouse lines. Dr Greg Hundley: Carolyn, that was just a wonderful explanation and I really learned about these phosphodiesterases. Now, tell me what did they find in their study? Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was decreased in human failing hearts. Cardiac over expression of PDE4B in mice, resulting in a 15-fold increase in cyclic AMP hydrolysis decreased cardiac contraction and protected against the cardiotoxic effects of chronic beta-adrenergic stimulation. Whereas transgenic mice with a 50-fold increase in cardiac cyclic AMP hydrolysis underwent maladaptive remodeling. Furthermore, cardiac PDE4B gene transfer with serotype nine adeno associated viruses resulted in a significantly lower increase in cardiac PDE4B and protected against chronic catecholamine stimulation and transaortic constriction without depressing basal cardiac function. These results overall suggest that a moderate increase in cardiac PDE4B is beneficial to counteract the detrimental effects of excessive sympathetic system activation in heart failure and increase in PDE4B in the human heart could be achieved by gene therapy with adeno associated viruses or by using recently developed small molecules with PDE4 activating properties. Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps this'll work its way into heart failure management. Well, my study, our first study to describe involves the comparative efficacy and safety of oral P2Y12 inhibitors and acute coronary syndromes. It's a meta-analysis of 52,816 patients from 12 randomized trials. It comes to us from Professor Eliano Navarese from Nicholas Copernicus University. All right, Carolyn, here's your quiz. Have you wondered which PGY inhibitor is optimal for reducing risk of adverse cardiovascular events? Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered, but you're going to tell us the results. Dr Greg Hundley: It's getting harder and harder to trip you up Carolyn. Very clever, okay. This study aims to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in acute coronary syndrome by meta-analysis of 12 randomized clinical trials. Again, involving those 52,816 patients with ACS.  Dr Carolyn Lam: Wow. What did they find Greg? Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly reduced cardiovascular mortality and all-cause mortality. Whereas there was no statistically significant mortality reduction with prasugrel. Dr Greg Hundley: Next, compared with each other there were no significant differences in mortality with prasugrel versus ticagrelor. In addition, compared with clopidogrel, prasugrel reduced myocardial infarction, whereas ticagrelor showed no risk reduction. Dr Greg Hundley: Now stint thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel. Compared with clopidogrel, both prasugrel and ticagrelor significantly increased major bleeding. There was no significant difference between prasugrel and ticagrelor for all outcomes explored.  Dr Carolyn Lam: Summarize that for us. Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced ischemic events, but increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. So a really nice summary evaluating these P2Y12 inhibitors, Dr Carolyn Lam: Indeed. Question for you, Greg, what is the prevalence of deep venous thrombosis, a DVT and its risk factors, prognosis and potential prophylaxis strategies for hospitalized patients with COVID-19? That's what the next paper is about. It is a single center observational study of 143 hospitalized patients confirmed of COVID-19. And this is from co-corresponding authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher Hospital for Children in Philadelphia, United States, they found that DVT was found in a high percentage of these patients. Forty-six percent of the 143 patients and was associated with adverse outcomes with CURB-65 score three to five. Padua prediction score four a more and D-dimer greater than one microgram per mil, which in combination predicted DVT with a sensitivity of more than 88.5%. Thrombo prophylaxis was associated with lower DVT in a subgroup of patients with high Padua prediction score. Dr Greg Hundley: Now, what does this mean for all of us in this era of COVID-19? Dr Carolyn Lam: So this suggests that DVT is more common in hospitalized patients with COVID-19. So ultrasound screening of high-risk patients, as I mentioned before, may be indicated for the more prevention of DVT with low molecular weight heparins in high risk patients, such as those with a high Padua prediction scores may reduce DVT in hospitalized patients with COVID-19. Of course more work needs to be done, but a very interesting paper. Dr Greg Hundley: What a fantastic description. Well, my next paper is more from the world of basic science and involves phosphodiesterase 3A in arterial hypertension and comes to us from Dr Enno Klussmann from the Max Delbruck Center for Molecular Medicine. So Carolyn, autosomal dominant hypertension with brachydactyly clinically resembles salt resistant, essential hypertension and causes death by stroke before the age of 50 years. So in this study, the authors use genetic mapping, sequencing, transgenic technology, CRISPR-CAS based nine gene editing, immunoblotting, and fluorescence resonance energy transfer to identify new patients perform extensive animal phenotyping and explore new signaling pathways related to hypertension with brachydactyly.  Dr Carolyn Lam: Wow. So what did they find, Greg? Dr Greg Hundley: Well, Carolyn, the authors described a novel mutation within a 15 BP region of the PDE3A gene, and define this segment as a mutational hotspot in hypertension with brachydactyly, the mutations cause an increase in enzyme activity, a CRISPR-Cas9 generated rat model with a nine BP deletion within the hotspot analogous to human deletion recapitulated the hypertension with brachydactyly in mice, mutant, transgenic PDE3A over expression and smooth muscle cells confirmed that mutant PDE3A caused hypertension. The afferent signaling found in these models was associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.  Dr Carolyn Lam: Gosh, so what are the clinical implications? Greg? Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that increase peripheral vascular resistance and cause hypertension. These authors presented two new animal models that serve to elucidate these underlying mechanisms further, and their findings could facilitate the search for new anti-hypertensive treatments. Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually one we've already discussed in our special COVID-19 edition and that was aired on 22nd, May, 2020. That's the paper from Dr Poissy and Susen from University Lille in Inserm, and they reported a case-series of COVID-19 patients with pulmonary embolism in their institution of Lille University Hospital. So, please everybody remembers to tune in to that as a refresher. Also in today's journal, the issue of COVID-19 coagulopathy in venous thromboembolism is further discussed in an editorial by Dr Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more about other papers in this week's issue. There are letters to the editor from Dr Mueller and from Dr Gulati all about the paper incidents, trends and outcomes of type two myocardial infarction in the community cohort. There's a letter from Dr Siontis on the blood pressure myocardial infarction paradox. Dr Carolyn Lam: Does hypertension exert a protective effect in type two MI? In the ECG challenge Dr Di Cosola talks about the high, the low end, the narrow QRS in a peripartum cardiomyopathy. There's an online mind piece by Dr Kohli entitled surfing the waves of the COVID-19 pandemic as a cardiovascular clinician, a perspective piece by Dr Albert titled "The Heart of the Matter Unmasking and Addressing COVID-19's Toll on Diverse Populations". In Paths the Discovery series, Dr Rutherford talks about serial innovation to bring transformative precision medicines to people with serious diseases. And this is a conversation with Dr Jeffrey Leiden. Dr Greg Hundley: Very nice. Carolyn, I've got a couple other papers to discuss similar to your paper on DVT, Professor Lin Cai has a research letter involving the extremely high incidents of lower extremity, deep venous thrombosis in 48 patients with severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum Saeed from University of Pittsburgh discusses reinforcing cardiology training during a pandemic. It's an open letter to our leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads to major changes for cardiologists in training. And then finally, Dr Stephen Archer from Queens University provides a nice perspective on differentiating COVID-19 pneumonia from ARDS and high-altitude pulmonary edema, and what are the therapeutic implications. And now Carolyn, how about we get onto that feature discussion, one of the unusual times where we emphasize an important point in a research letter? Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I think one of the most impactful, basic science papers we have, and that is why we're discussing it. I am so pleased to have the first author Dr Luca Liberale from University of Zurich, as well as Dr Peipei Ping associate editor from UCLA. So welcome both. Luca, I really need your help here. Can you please explain what your experiment was and your main findings? Dr Luca Liberale: We really happy that we could set up an experiment design, which has some kind of translation of value. So, differently from any other set up involving the tandem middle cerebral artery occlusion, which is among the most used model for ischemic stroke in basic science. In this case, the treatment is done post-ishchemically. So the mice received the neutralizing antibody against IL-1α only after they scan making salts. And we specifically thought to duties to keep the translational relevant side. As I said before, and trying to mirror the case of a patient, we think come have a stroke that goes to the emergency department, and he is eligible for revascularization therapy. And together with this revascularization therapy being at EPA or whatever for it, it received is also the kind of anti-IL-1α treatment. And another good translation of relevancy we thought this may have is that identifying of IL-1α antibody is already available in the market and being in many phase three trial. So we thought this is a ready to go, ready for the translation from the bench to the bedside, as we used to say. Dr Carolyn Lam: It's just so interesting because when we think about ischemic stroke, you know, we think about thrombolysis as practically the only thing we can do, and forgive me I'm not in neurologist here, but this is so unique to go with an anti-inflammatory mechanism. Now, when you see that this neutralizing antibody is currently in use, do you mean in cancer in other diseases? Dr Luca Liberale: Mainly it's cancer, but it's also other dermatological diseases. It's not only cancer, but oh yes, definitely. Cancer is one of the major fields of its application. Dr Carolyn Lam: Wow. So with that very interesting background, could you tell us about the experiment and what you found? Dr Luca Liberale: What we found is that after inducing ischemia in the animal for 45 minutes, we let them reperfuse for 48 hours during which the animal are under the treatment. So they received a bolus of anti-IL-1α immediately at the time of reperfusion. So when we take out from the carotid artery, the filament, and they received these volumes and they are let survive for 48 hours. So they are free to go in the cage, to seek drinks. After 48 hours, we assessed the neurological deficit and we sacrifice the animal to assess the stroke size by using the quite common PTC staining. And what we could find is that indeed the treatment with the higher dose, because we use two doses, and we could see a dose response, could that reduce the stroke size by 36% as compared to the treatment with the isotype control. And this went together with a significant reduction in that neurological impairment. So it's not only an experimental reduction, but it's also physiologically relevant for the animals. Dr Carolyn Lam: That really is incredible, and the way you manage to convey such a lot of data in a research letters is also remarkable. So, to the audience, you have to pick this up. It's a succinct read, just this one central figure that tells the whole story, and you're about to hear from Dr Ping. Dear Peipei, if you could tell us what the significance of this paper is, maybe some of the discussions that occurred behind the doors, so to speak among the editors.   Dr Peipei Ping: We were super impressed with the fundamental message of the submitted report. Carolyn, as you are fully aware, most ischemic studies speed that in the heart or in a brain model, often select mechanisms that must be activated pre the event you bent of ischemia to induce a protective effect, a neurological protective effect in stroke or cardioprotective effect in the heart. So, as an associate editor who spent her entire 30 years career in this area of study, we often fascinated about the sentencing or the naiveness of the basic scientists in this area. Because you would have to plan an ischemia in the patient knowing when that to happen. And then before that happens, activate all these beautiful signaling and mechanisms, everything you have generated to prevent that ischemia. So the search for the possible mechanistic understanding of a post-ischemic event rescue mechanism has been going on for decades. And it's very, very challenging, Carolyn. Dr Peipei Ping: The beauty of the study is it utilized already in clinical trial, existing human antibody inhibitor, interleukin alpha-one antibody. You said antibody. So the reagent is already bile approved. Then examine very carefully in a post-ischemic fashion to see how relevant that agent in a time window reasonable to rescue ischemic injury. You can already tell from Lucas introduction; the results are profound, and it has stimulated many discussions in the field. It's very relevant to clinical center piece, even though it's still at that translational stage. So we saw this as a beautiful representation of how clinicians and scientists capable of not only bring something from the bench to the clinic or the clinic or to the bench. This is something comes to a full circle. It went from clinic where the reagent was used and created for something to the bench, understanding mechanistic insight, have a beautiful animal of human disease stroke model to test them and then take it to the clinic again. Dr Carolyn Lam: Goodness, Peipei. I love the way you put that. I actually didn't see that Luc[a], till you put it that way. I do have a couple of questions for Luca though. I understand you made it very clear in your paper that the human monoclonal antibody is in clinical use, but in this experiment, you had to use the rodent equivalent because the human antibody doesn't block the rodent IL-1α, which is very reasonable. But then it brings the question, how closely does this rodent model recapitulate thrombotic ischemic, or a stroke in humans? I mean, what do you think? Dr Luca Liberale: Well, what we see when we use our usual approach, this is a model that we're using in our center for molecular cardiology here in Zurich, and this been used in that specific group of Professor Ameche for many years. And this is usually quite well accepted as a model. So that, that the timeframe is 45 minutes of ischemia and 48 hours of reperfusion. I'll got to quite mirror the acute phase of an acute ischemic stroke, which is actually where we think that the inflammatory pathways can play the major roles. Also. I mean, everybody of us know that the recent anti-inflammatory trials confirmed this, that reducing the inflammation and the inflammatory pathways is good but can also be harmful. Dr Luca Liberale: So in the case, we can use an approach, which is limited in the time, maybe really close to that acute phase, really during the acute rates goes to the acute event. Well, maybe this can be quite useful and quite a translationally relevant that prolongs inactivation of such pathways as result. They can ask some for, so the balance in between the benefits and the harms cannot be that clear, can, I mean, needs to be quite well addressed. Dr Carolyn Lam: And that actually brings me to the next question. You know, the word translational has been mentioned quite a number of times here. So can you give us a sneak-peak on what the translational plans that your team may have? What's the next steps? Dr Luca Liberale: The next steps now is back to the company. So our basic findings are here. They will be published soon, and now it's all about the clinical scientist, and how they want to implement these basic findings into the clinic. Dr Carolyn Lam: So target engagement and mechanistic information as well. Peipei, could I just give you the last word, if you don't mind, maybe a bit of a cheeky question. What would you have loved to see in this paper or in a subsequent paper that offers a step closer to translation? Dr Peipei Ping: I think this study has shown most necessary components as a basic science research paper. I think the next level closer to the translation as Luca has already alluded to, has to do with both efficacy studies, as well as safety studies, and those actually would need to be done in the clinic because the mouse model. I think it's a fantastic model to offer these lines of information. Ischemic-wise I think it's very strong and translational value is very high and that was the predominant reason we voted to accept the paper. As you know, the accept and raise of circulation is very, very low as our bar is very high. Dr Carolyn Lam:  Very nice. So target engagement and mechanistic information as well. Congratulations, Luca. Thank you so much Peipei for your great comments. Now, listeners, you heard it first time here on Circulation on the Run. Thank you for joining us today.  Dr Greg Hundley: This program is copyright at the American Heart Association, 2020.  

Prasugrel is a P2Y12 inhibitor that is used in the setting of ACS. Be aware of patients who may be taking over the counter medications that can increase their bleed risk while taking prasugrel. Prasugrel is on the Beers list and in general, should be avoided in most situations for patients who are 75 years of age or older. Morphine has the potential to impact antiplatelet agents like prasugrel and make them less effective. Be sure this is clinically considered prior to using morphine with prasugrel.

Prasugrel bests ticagrelor in ACS in surprise findings ISAR-REACT 5 was the first-ever direct head-to-head look at two potent P2Y12 inhibitors in this setting. European cholesterol guidelines push LDL targets below 55 mg/dL PCSK-9 inhibitors are elevated to a top-tier recommendation in very-high-risk patients. Drug doses for heart failure could possibly be halved for women Women reached the highest level of drug efficacy at half the doses of ACE inhibitors or ARBs and beta-blockers. Post-MI angina in stable patients flags high risk The angina finding should immediately influence practice, expert says.   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgeCardio

#21 - ticagrelor x prasugrel: qual o melhor? by Cardiopapers

In this episode our favourite Pharmacist Kunal Gohil joined us in DREEAM once again this time to cover antithrombotics. In part one we discuss antiplatetets. Whilst the focus is on Aspirin and Clopidogrel we also cover Prasugrel and Ticagrelor with plenty of pharmacology along the way. Visit TakeAurally.com for more information including the Take Visually for this episode. Remember both DREEAM and Take Aurally are on Facebook and Twitter. Part 2 covering anticoagulants will be coming soon!

Commentary by Dr. Valentin Fuster

Dr. C. Michael Gibson discusses the trial findings with Dr. Zuzana Motovska and Dr. Ota Hlinomaz at AHA 2017

Carolyn: Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...     In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...     The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.     The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...     The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.     They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.     The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...     The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.     They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...     The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.     In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.     Those were the highlights from this week's issues. And now for our feature paper ...     We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.   Zuzana: Thank you for having me.   Carolyn: We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.   Gabriel: Yes, hello Carolyn, hello Zuzana.   Carolyn: So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?   Zuzana: The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.   Carolyn: Could you, maybe now, clearly describe what you did in this study and what were your findings?   Zuzana: The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.     So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.     So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]   Carolyn: That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.   Zuzana: Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.   Carolyn: Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?   Gabriel: First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.     Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.     The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.     In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?   Zuzana: Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.   Gabriel: The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.     It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.     Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...   Carolyn: Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...  

  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.    

Commentary by Dr. Valentin Fuster

Une rencontre, une question. Des spécialistes des maladies cardiovasculaires répondent aux questions de Catherine Desmoulins, directrice de la rédaction.

Host: Alfred Bove, MD Guest: Gregg Stone, MD Results of a recent study may change the standard of care for patients with acute coronary syndromes. Although clopidogrel is generally the antiplatelet therapy of choice for patients for whom an invasive strategy is planned for treating their acute coronary syndromes, bleeding can be of concern. Prasugrel often presents the same dilemma. Enter, ticagrelor. The PLATelet inhibition and patient Outcomes, or PLATO, trial compared ticagrelor and clopidogrel, which demonstrated promising results for ticagrelor. Dr. Gregg Stone, professor of medicine and director of research and education at the Center for Interventional Vascular Therapy at the Columbia University Medical Center, and director of medical research and education at the Cardiovascular Research Foundation in New York City, hails the PLATO findings as transformative to the standard of care for acute coronary syndromes. He joins host Dr. Alfred Bove to discuss the new place of ticagrelor among the antiplatelet therapy options.

Host: Alfred Bove, MD Guest: Gregg Stone, MD Results of a recent study may change the standard of care for patients with acute coronary syndromes. Although clopidogrel is generally the antiplatelet therapy of choice for patients for whom an invasive strategy is planned for treating their acute coronary syndromes, bleeding can be of concern. Prasugrel often presents the same dilemma. Enter, ticagrelor. The PLATelet inhibition and patient Outcomes, or PLATO, trial compared ticagrelor and clopidogrel, which demonstrated promising results for ticagrelor. Dr. Gregg Stone, professor of medicine and director of research and education at the Center for Interventional Vascular Therapy at the Columbia University Medical Center, and director of medical research and education at the Cardiovascular Research Foundation in New York City, hails the PLATO findings as transformative to the standard of care for acute coronary syndromes. He joins host Dr. Alfred Bove to discuss the new place of ticagrelor among the antiplatelet therapy options.

Audio Journal of Cardiovascular Medicine, November 5th, 2007 Reporting from: American Heart Association Scientific Sessions, 4-7 November, 2007, Orlando, Florida TRITON-TIMI 38 Prasugrel Or Clopidogrel In Percutaneous Intevention? GORDON TOMASELLI, Johns Hopkins University, Baltimore COMMENT: DANIEL JONES, President, American Heart Association, University of Mississippi, Jackson REFERENCE: Late Breaking Clinical Trials 1, AHA 2007 A potential new option for patients with acute coronary syndromes receiving coronary intervention has emerged following a report on the comparison of prasugrel, a new anti-platelet agent, with clopidogrel. Elliott Antman from Brigham and Women’s Hospital in Boston gave the American Heart Association his findings and recommendations about when and in which patients prasugrel might be favored. Gordon Tomaselli discussed the findings with Sarah Maxwell.