Podcasts about paradigm hf

Tirzepatide vs semaglutide in obesity; GLP1a use is complicated; HF outcomes; the misuse of meta-analyses in HF; and a breakthrough in HF care are the topics John Mandrola, MD, covers this week. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. SURMOUNT 5 Clinicaltrials.gov https://clinicaltrials.gov/study/NCT05822830 Press Release   II. Access to GLP-1 Agonist Drugs CMS statement https://www.cms.gov/newsroom/press-releases/biden-harris-administration-announces-medicare-advantage-and-medicare-part-d-prescription-drug III. SUMMIT TRIAL commentary Has Tirzepatide Scaled the HFpEF/Obesity SUMMIT? https://www.medscape.com/viewarticle/has-tirzepatide-scaled-hfpef-obesity-summit-2024a1000m2h IV. Blank Spot in HF Evidence – All cause hospitalizations   Sayed and colleagues What Is Success in HF Trials? https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2827168 EMPEROR-Preserved https://www.nejm.org/doi/full/10.1056/NEJMoa2107038 Mayo Observational Study 10.1016/j.mayocp.2016.11.009 DIG Trial https://jamanetwork.com/journals/jama/fullarticle/195990 V. Misuse of Meta-analysis by HF Community Lu and colleagues PARAGON/PARADIGM Meta-analysis https://jamanetwork.com/journals/jamacardiology/fullarticle/2823259 Desai 2004 https://jamanetwork.com/journals/jama/fullarticle/199995 PARADIGM HF https://www.nejm.org/doi/full/10.1056/NEJMoa1409077 PARAGON HF https://www.nejm.org/doi/full/10.1056/NEJMoa1908655 VI Integration of Palliative Care Into HF Care Chuzi and colleagues Palliative Care in HF 10.1016/j.cardfail.2024.10.435 Kotecha and colleagues Beta-blocker Metaanalysis 10.1016/S0140-6736(14)61373-8 You may also like: The Bob Harrington Show with the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

In this episode, researchers explore how asymptomatic versus symptomatic hypertension affects heart failure patients on sacubitril valsartan, finding that both types are linked to worse outcomes, but the drug's benefits remain strong, suggesting clinicians should avoid stopping treatment based solely on blood pressure.

Suicidal ideation and GLP-1 agonists, a repeat of PARADIGM HF in Chagas CM, CASTLE HTx critical appraisal, and primary prevention of SCD in HF are the topics John Mandrola, MD, covers this week. This podcast is intended for healthcare professionals only. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I. Suicidal ideation with GLP-1 Signal of Suicidality With GLP-1 RA Semaglutide, but Experts Urge Caution https://www.medscape.com/viewarticle/signal-suicidality-glp-1-ra-semaglutide-experts-urge-caution-2024a1000fa7 Disproportionality Analysis from World Health Organization Data on Semaglutide, Liraglutide, and Suicidality   Variability in Disproportionality paper https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.668765/full II. PARACHUTE HF: Repeating the Mistakes in PARADIGM HF PARACHUTE HF https://www.jacc.org/doi/10.1016/j.jchf.2024.05.021 SOLVD https://www.nejm.org/doi/full/10.1056/NEJM199108013250501 CONSENSUS trial https://www.nejm.org/doi/full/10.1056/NEJM198706043162301 Meta-analysis of Low vs High Dose ACE/ARB https://doi.org/10.1161/CIRCHEARTFAILURE.117.003956 Meta-analysis of Sac/Val vs ARB/ACE Inhibitors https://link.springer.com/article/10.1007/s00228-024-03686-6 PARADISE MI https://www.nejm.org/doi/full/10.1056/NEJMoa2104508 III. CASTLE HTx Critical Appraisal Critical Appraisal of CASTLE HTx https://doi.org/10.1016/j.jacc.2024.06.020 CASTLE HTx https://www.nejm.org/doi/10.1056/NEJMoa2306037 CASTLE AF https://www.nejm.org/doi/full/10.1056/NEJMoa1707855 IV. More Data Suggesting Modest Benefits of the Primary Prevention ICD First and Recurrent ICD Shocks: JICE Paper from Denmark https://link.springer.com/article/10.1007/s10840-024-01873-0 HF trialists https://www.nejm.org/doi/full/10.1056/NEJMoa1609758 PROFID Trial https://profid-project.eu/ DANISH  https://www.nejm.org/doi/full/10.1056/NEJMoa1608029 SCD-HeFT https://www.nejm.org/doi/full/10.1056/NEJMoa043399 You may also like: The Bob Harrington Show with the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net

NEJM 2021:385:1845-55.Background Over two decades had passed since the publications of the seminal trials comparing ACE inhibitors with placebo in post-MI patients with LV dysfunction and congestive heart failure (SAVE, AIRE and TRACE). The VALIANT trial, published in 2003, found that the ARB drug Valsartan was as effective as Captopril in improving survival and reducing cardiovascular morbidity in this patient population. Thus, for many years, a cornerstone of managing post-MI patients with LV dysfunction and heart failure involved afterload reduction with ACE inhibitors or ARBs.Then in 2014, the landscape of heart failure management changed with the publication of the PARADIGM-HF trial which found that Entresto, a drug combining the ARB Valsartan and the neprilysin inhibitor Sacubitril, significantly reduced death and heart failure hospitalizations. We will review PARDIGM-HF later since it enrolled patients with chronic, stable heart failure and not post-MI patients. The rationale for the combination drug is that it simultaneously blocks the renin-angiotensin system and inhibits of the breakdown of several vasoactive peptides including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), serving to enhance vasodilation and reduce blood volume.The PARADISE-MI trial sought to test the hypothesis that early initiation of Sacubitril-Valsartan in post-MI patients with LV dysfunction and congestive heart failure would reduce cardiovascular death or incident heart failure compared to the ACE inhibitor Ramipril.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 Adults without a history of heart failure who had a spontaneous MI within 0.5 to 7 days before presentation who had either a LVEF of /= 70 years, diabetes, previous MI, eGFR

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The following question refers to Section 7.3.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by Palisades Medical Center medicine resident & CardioNerds Intern Dr. Maryam Barkhordarian, answered first by MedStar Washington Hospital Center cardiology hospitalist & CardioNerds Academy Graduate Dr. Luis Calderon, and then by expert faculty Dr. Robert Mentz.  Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz is a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very 2022 heart failure Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22. Welcome Dr. Mentz!  The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #7 Ms. Valarie Sartan is a 55-year-old woman with a history of HFrEF (EF 35%) and well controlled, non-insulin dependent diabetes mellitus who presents to heart failure clinic for routine follow up. She is currently being treated with metoprolol succinate 200mg daily, lisinopril 10mg daily, empagliflozin 10mg daily, and spironolactone 50mg daily. She notes stable dyspnea with moderate exertion, making it difficult to do her yardwork. On exam she is well appearing, and blood pressure is 115/70 mmHg with normal jugular venous pulsations and trace bilateral lower extremity edema. On labs, her potassium is 4.0 mmol/L and creatinine is 0.7 mg/dL with an eGFR > 60 mL/min/1.73m2. Which of the following options would be the most appropriate next step in heart failure therapy?  A  Increase lisinopril to 40mg daily  B  Increase spironolactone to 100mg daily  C  Add sacubitril-valsartan to her regimen  D  Discontinue lisinopril and start sacubitril-valsartan in 36 hours  E  No change  Answer #7 Explanation   The correct answer is D – transitioning from an ACEi to an ARNi is the most appropriate next step in management.   The renin-angiotensin aldosterone system (RAAS) is upregulated in patients with chronic heart failure with reduced ejection fraction (HFrEF). Blockade of the RAAS system with ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), or angiotensin receptor neprilysin inhibitors (ARNi) have proven mortality benefit in these patients.   The PARADIGM-HF trial compared sacubitril-valsartan (an ARNi) with enalapril in symptomatic patients with HFrEF. Patients receiving ARNi incurred a 20% relative risk reduction in the composite primary endpoint of cardiovascular death or heart failure hospitalization. Based on these results, the 2022 heart failure guidelines recommend replacing an ACEi or ARB for an ARNi in patients with chronic symptomatic HFrEF with NYHA class II or III symptoms to further reduce morbidity and mortality (Option D). This is a class I recommendation with level of evidence of B-R and is also of high economic value. Making no changes at this time would be inappropriate (Option E).  While it would be reasonable to increase the dose of lisinopril to 40mg (Option A), this should be pursued only if ARNi therapy is not tolerated.   Mineralocorticoid receptor antagonists (MRAs) have a class I (LOE A...

It's another session of CardioNerds Rounds! In these rounds, Co-Chairs, Dr. Karan Desai and Dr. Natalie Stokes and Dr. Tiffany Dong (FIT at Cleveland Clinic) joins Dr. Randall Starling (Professor of Medicine and Director of Heart Transplant and Mechanical Circulatory Support at Cleveland Clinic) to discuss the nuances of guideline directed medical therapy (GDMT) through real cases. As a past president of the Heart Failure Society of America (HFSA) and author on several guidelines, Dr. Starling gives us man pearls on GDMT. Come round with us today by listening to the episodes and joining future sessions of #CardsRounds! This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Cases discussed and Show Notes • References • Production Team CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes - CardioNerds Rounds: Challenging Cases - Modern Guideline Directed Therapy in Heart Failure with Dr. Randall Starling Case #1 Synopsis: A man in his 60s with known genetic MYPBC3 cardiomyopathy and heart failure with a reduced ejection fraction of 30% presents with worsening dyspnea on exertion over the past 6 months. His past medical history also included atrial fibrillation with prior ablation and sick sinus syndrome with pacemaker implantation. Medications are listed below. He underwent an elective right heart catheterization prior to defibrillator upgrade for primary prevention. At the time of right heart catheterization, his blood pressure was 153/99 with a heart rate of 60. His RHC demonstrated a RA pressure of 15mmHg, RV 52/16, PA 59/32 (mean 41), and PCWP 28 with Fick CO/CI of 2.8 L/min and index of 1.2 L/min/m2. His SVR  was 1900 dynes/s/cm-5. He was admitted to the cardiac ICU and started on nitroprusside that was transitioned to a regimen of Sacubitril-Valsartan and Eplerenone. His final RHC numbers were RA 7, PA 46/18/29, PCWP 16 and Fick CO/CI 6.1/2.6. His discharge medications are shown below. Takeaways from Case #1 Unless there are contraindications (cardiogenic shock or AV block), continue a patient's home beta blocker to maintain the neurohormonal blockade benefits. A low cardiac index should be interpreted in the full context of the patient, including their symptoms, other markers of perfusion (e.g., urine output, mentation, serum lactate), and mean arterial pressure before holding or stopping beta blockade. Carvedilol, metoprolol succinate and bisoprolol are all evidence-based options for beta blockers in heart failure with reduced ejection fraction.If there is concern of lowering blood pressure too much with Sacubitril/Valsartan, one method is to trial low dose of valsartan first and then transition to Sac/Val. Note, in the PARADIGM-HF trial, the initial exclusion criteria for starting Sac/Val included no symptomatic hypotension and SBP ≥ 100. At subsequent up-titration visits, the blood pressure criteria was decreased to SBP ≥ 95.In multiple studies, protocol-driven titration of GDMT has shown to improve clinical outcomes, yet titration remains poor. The following image from Greene et al. in JACC shows that in contemporary US outpatient practices that GDMT titration is poor with few patients reaching target dosing. Case #2 Synopsis: A 43 year-old male with a past medical history of familial dilated cardiomyopathy requiring HVAD placement two years prior now comes in with low flow alarms.

Please join author Milton Packer and Associate Editor Justin Ezekowitz as they discuss the Perspective "Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, it really is so great to be back with you chatting about the papers here in the Journal. Thank you for going solo and for just being the greatest partner on earth. Thank you for that. For everyone listening in, we are back with some gusto and especially with this feature discussion today. You are not going to want to miss it. We are talking to Dr. Milton Packer as well as Dr. Justin Ezekowitz. We are going to compare PARAGON and EMPEROR-Preserved trials in heart failure with preserved ejection fraction. A really interesting discussion you're not going to want to miss, but now let's start with some papers in today's issue. I'd like to start, please. Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Greg, you know the optimal duration of antiplatelet therapy in patients with high bleeding risk with or without oral anticoagulation after coronary stenting? Well, that still remains a question. Today's paper is a pre-specified subgroup analysis of the MASTER DAPT trial and reports on the outcomes of patients with or without an oral anticoagulation indication in this study. Dr. Greg Hundley: Right, Carolyn. Remind us. What was the MASTER DAPT trial? What did it test? Dr. Carolyn Lam: Ah. MASTER DAPT investigated an abbreviated or one-month versus a non-abbreviated or three to 12-month dual antiplatelet therapy and a stopping of antiplatelet therapy at six months strategy after coronary stenting in an all-comer population at high bleeding risk. Dr. Greg Hundley: Carolyn, what did this subgroup analysis of outcomes in patients with and without oral anticoagulation show? Dr. Carolyn Lam: At 12 months of follow-up, ischemic and net risk did not differ with abbreviated versus non-abbreviated anti-platelet regimens in both subgroups, although significantly fewer clinically relevant bleeding events occurred in the group without an oral anticoagulation indication. Whereas only numerically fewer bleeding events occurred in the group with an oral anticoagulation indication that did not reach statistical significance. This subgroup analysis from the MASTER DAPT trial really adds additional evidence that dual antiplatelet therapy beyond one month in patients with or without an indication for oral anticoagulation really has no benefit and only increases bleeding risk. Dr. Greg Hundley: Oh, very important finding, Carolyn. Great research. Well, Carolyn, how the extracellular matrix microenvironment modulates the contractile phenotype of vascular smooth muscle cells and confers vascular homeostasis really remains elusive. Thus, these investigators led by Professor Wei Kong at Peking University applied protein-protein interaction network analysis to explore novel extracellular matrix proteins associated with the vascular smooth muscle cell phenotype. Dr. Carolyn Lam: Huh. Interesting. What did they find, Greg? Dr. Greg Hundley: Right, Carolyn. By combining an in-vitro and an in-vivo genetic mice vascular injury model, they identified nidogen-2, a basement membrane glycoprotein, as a key extracellular matrix protein for maintenance of vascular smooth muscle cell identity. Nidogen-2 exerted its protective function via direct interaction and modulation of Jagged1-Notch3 signaling. Dr. Carolyn Lam: Wow! Nidogen-2 and Jagged1-Notch3. I always learn so much. What are the clinical implications, Greg? Dr. Greg Hundley: Right, Carolyn. Perhaps targeting nidogen-2 to precisely modulate Jagged1-Notch3 signaling, well, that may provide novel therapeutic strategy for atherosclerosis and post-injury restenosis. Dr. Carolyn Lam: Very nice. Well, in the next paper, we discuss inflammation in heart failure. We know that inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Interesting, huh? Well, these authors, Dr. Wollert and colleagues from Hannover Medical School in Germany, identified an adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against persistent afterload stress-induced heart failure in mice. Monocytes and macrophages produced myeloid-derived growth factor in the pressure overloaded myocardium to augment SERCA2a expression in cardiomyocyte's calcium cycling and contractility. Myeloid-derived growth factor plasma concentrations were also found to be elevated in patients with aortic stenosis and to decline after aortic valve implantation indicating that pressure overload also triggers myeloid-derived growth factor release in humans. Dr. Greg Hundley: Carolyn, really informative preclinical science, but what are the clinical implications? Dr. Carolyn Lam: Ah. These observations molecularly defined a feature of the inflammatory response to hemodynamic overload that protects against heart failure development. Inflammation's beneficial trade therefore need to be considered when developing inflammation as a therapeutic target in heart failure. All of this is really discussed in a lovely editorial entitled Inflammation and Heart Failure: Friend or Foe? That's by Drs. Hajjar and Leopold. Dr. Greg Hundley: Great job, Carolyn. Well, my next paper focuses on resistant hypertension. Carolyn, although lifestyle modifications generally are effective in lowering blood pressure among patients with unmedicated hypertension or those treated with one to two antihypertensive agents, the value of exercise and diet for lowering blood pressure in patients with resistant hypertension is unknown. To address this, Professor James Blumenthal and co-authors at Duke University Medical Center enrolled 140 patients with resistant hypertension with an average age of 63 years, 48% women, 59% black, 31% diabetes, and 21% with chronic kidney disease and randomly assigned them to A, a four-month cardiac rehab center-based program of lifestyle modification. We're going to call that C-LIFE, consisting of dietary counseling, behavior and weight management, and exercise. Or number 2 or the B, a single counseling session providing standardized education and physician advice. We'll call that SEPA. Dr. Greg Hundley: The primary endpoint was clinic measured systolic blood pressure. Secondary endpoints included 24-hour ambulatory blood pressure and selective cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of baroreflex on heart rate; high-frequency heart rate variability to assess vagally-mediated modulation of heart rate; flow-mediated dilation to evaluate endothelial function; and pulse wave velocity to assess arterial stiffness; and then finally left ventricular mass to characterize left ventricular structure and remodeling. Dr. Carolyn Lam: Wow! That is a very, first of all, important clinical question. Then also, just very intricate methodology in assessing this. What did they find? Dr. Greg Hundley: Right, Carolyn. Between-group comparisons revealed that the reduction in clinic systolic blood pressure was greater in C-LIFE compared with SEPA. Next, 24-hour ambulatory systolic blood pressure also was reduced in C-LIFE with no change in SEPA. Then next, compared with SEPA, C-LIFE resulted in greater improvements in baroreflex sensitivity, high-frequency heart rate variability, and flow-mediated dilation. There was no between-group differences in pulse wave velocity or LV mass. Dr. Greg Hundley: Carolyn, diet and exercise can lower blood pressure in patients with resistant hypertension. When delivered in a cardiac rehabilitation setting, a four-month program of diet and exercise as adjunctive therapy, results in a significant reduction in clinic and ambulatory blood pressure, and improvement in selected cardiovascular disease biomarkers. Dr. Carolyn Lam: Wow! Really nice, Greg. Okay. Well, looks like we're all going to round up already with what else there is in today's issue. Let me start. There's an exchange of letters between Drs. Fang and Vinceti regarding the article Blood Pressure Effects on Sodium Reduction: Dose-Response Meta-analysis of Experimental Studies. Dr. Greg Hundley: Right, Carolyn. I've got a few things in the mail bag. First, Professor Anker has a Research Letter regarding the Kidney Function After Initiation and Discontinuation of Empagliflozin in Heart Failure Patients With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Dr. Gerstenfeld has an ECG challenge entitled Atrioventricular Block with Narrow and Wide QRS: The Pause That Refreshes. Then lastly, Dr. Donald Lloyd-Jones has an AHA update regarding the American Heart Association's focus on primordial prevention. Well, Carolyn, I can't wait to hear this fantastic feature discussion with you and Dr. Packer. How about we jump to that? Dr. Carolyn Lam: Great. Let's go, Greg. Dr. Carolyn Lam: Because side-by-side exam of PARAGON and EMPEROR is like side-by-side of... Dr. Justin Ezekowitz: You can compare our new and our old prime minister much like your paper did. Dr. Milton Packer: Yeah, yeah. Dr. Justin Ezekowitz: There are [crosstalk] and it could be viewed until they perform in the broader world how it goes. You don't quite know. Dr. Milton Packer: The only problem is you can't do a head-to-head comparison of the old prime minister and the new prime minister. Dr. Justin Ezekowitz: That is true except that the head-to-head comparison includes excellent care by both the new and the old. I think that comparison's going to be pretty equal. I think we can case-control that one. Dr. Carolyn Lam: I really liked that that was politically correct because we are recording. Everybody, welcome to the feature discussion. I am here with Dr. Milton Packer from Baylor and he really needs no introduction. We're discussing heart failure with preserved ejection fraction. As well as our associate editor, Dr. Justin Ezekowitz from University of Alberta. Hence, in case anybody's wondering, we were talking about the Canadian elections. Let's just launch straight into it, a side-by-side comparison of PARAGON and EMPEROR-Preserved. Dr. Packer... Milton, if I may, what in the world drove you to do this? Dr. Milton Packer: My God. Oh, my God. Yes. Dr. Carolyn Lam: Tell us about what drove you to do this and please, if you could just summarize the results. Dr. Milton Packer: Well, let me just say from the outset that this was a commentary, not an original research article. Dr. Carolyn Lam: Yes. Dr. Milton Packer: The commentary was motivated by two very straightforward observations. We had two large scale outcome trials of two different drugs in heart failure with a preserved ejection fraction. I was privileged to serve as you were, Carolyn, on the leadership committees of both trials. It's not as if we have involvement in only one trial. We have involvement in both trials and we are very proud of that involvement. Dr. Milton Packer: One trial came in with a effect size of about 13% on its primary endpoint with a borderline P-value. A second trial, EMPEROR-Preserved, came in with a 21% reduction and its primary endpoint with a really small and persuasive P-value. The two patient populations in the two trials were really amazingly similar. We wanted to understand why it was 21% in one trial and persuasively so and why it appeared to be smaller in the PARAGON trial with sacubitril/valsartan. We thought, well, maybe that difference was related to how endpoints were defined or maybe that difference was related to the influence of ejection fraction. The reason we got excited about that was that as almost everyone knows, PARAGON found an influence of ejection fraction on the effect of sacubitril/valsartan in patients with HFpEF. We found an influence of ejection fraction on the effect of empagliflozin in HFpEF in EMPEROR-Preserved. We wanted to understand whether that influence was similar in the two trials. Dr. Milton Packer: Just to make life simple, PARAGON had created certain cut points for ejection fraction. They had presented and previously published in Circulation endpoints based on those cut points of ejection fraction. All we did was we used their endpoints and their cut points, and we put the two trials side by side. We did not do a statistical comparison of the effect size. There're actually no P-values in the whole commentary. But what we wanted to see was: Was the shape of the ejection fraction influence relationship similar or different in the two trials? Well, very simple. In PARAGON, as has been reported, there was a linear relationship: as ejection fraction increased, the effect of sacubitril/valsartan got smaller. In EMPEROR-Preserved, there was also an attenuation at a highest ejection fraction, but the relationship wasn't linear. It was like a hockey stick. It was flat and then went up at an ejection fraction over 62.5, which was the cut point that PARAGON used. Dr. Milton Packer: When we compared patients between the low 40s and the low 60s, the effect size in empagliflozin appeared to be larger than the effect size of sacubitril/valsartan in that ejection fraction group using the same endpoints. In fact, for hospitalizations for heart failure, which is really what SGLT2 inhibitors do, it was twice as great with empagliflozin in EMPEROR-Preserved than with sacubitril/valsartan in PARAGON-HF. We thought this was really interesting. We put the pictures up side by side. We wrote a commentary and Circulation was so kind to accept it. Dr. Carolyn Lam: Oh, but Milton, you were very, honestly as always, very clever to have done this analysis. But if I could reiterate a few things for the audience, which is very important. First of all, as you rightly first pointed out, it's a perspective piece. It is not a head-on comparison with P-values. It could not be. Let's just also give the audience a bit of background in that PARAGON included patients with an ejection fraction of 45% and above. EMPEROR-Preserved was above 40. PARAGON looked at total heart failure hospitalizations and cardiovascular death as a primary outcome. EMPEROR looked at first cardiovascular death or heart failure hospitalization. Dr. Carolyn Lam: Let's just remember the designs were different. Of course in the comparison, PARAGON compared sacubitril/valsartan versus valsartan. I like the way you very carefully wrote in your study that it was more a study of neprilysin inhibition since it's sacubitril/valsartan against valsartan and it was empagliflozin versus placebo. We know that it's important to state that as a basis. Then really important to say to everybody out there, pick up our journal. You must look at this bigger. I myself have already cited it at least twice already, Milton, because people will just naturally ask that. "Are the results different because of ejection fraction or different endpoints?" What you did there in that beautiful figure is that you tried as best as you can to match it up in terms of ejection fraction bins and match it up in terms of hospitalizations. There. I just wanted to state those few things, but I'm really- Dr. Milton Packer: Oh, no. No. Carolyn, you're 100% right. That's why there are couple of things. I just want to underscore what you said because I think your points were spot on. First of all, we really lined up the endpoints and the ejection fraction. We tried our best to compare apples and apples. It would not have been a useful exercise for us to compare different endpoints and different ejection fraction subgroups. But I just want to make sure that everyone understands: I'm a big fan of sacubitril/valsartan and I'm a big fan of neprilysin inhibition. As you know, both PARADIGM-HF and PARAGON-HF weren't really tests of sacubitril/valsartan; they were tests of neprilysin inhibition. They were great tests at that. PARAGON in particular was a great test of that. We're comparing neprilysin inhibition and SGLT2 inhibition. Dr. Milton Packer: But here's my most important point: we do not want people to choose one over the other. That was not the intent. We think that there are data in patients with certain ejection fractions, let's say between 40 and 60, I'm just creating a range, where both interventions are appropriate. Now I understand there are cost considerations and I don't want to minimize that, but we are not suggesting that anyone prefer one drug over the other. All we wanted to do was we wanted to ask the question: Since the effect size in one trial seemed to be different than the effect size in the other trial, what were the ejection fraction subgroups that represented that difference? We found that the patients with ejection fractions greater than 60, 65% did not contribute to that difference. It was the patients with lower ejection fractions that contributed to the difference. I hope that's helpful. Dr. Carolyn Lam: Ah. That's wonderful. Justin, have you recovered from the talk about the Canadian elections? Dr. Justin Ezekowitz: Oh. I have indeed. Dr. Carolyn Lam: I'm on swinging. Dr. Justin Ezekowitz: I have indeed. Thanks for recognizing that Canada just had a major election we carried out in six weeks. But, Milton, I really enjoyed reading this. Maybe I can just ask you about two elements within this perspective piece, which is number 1, what's incredibly concordant is a lack of difference across cardiovascular death for both agents in both trials regardless of the trial differences and the potential differences in patient populations recruited; that's number 1. It's incredibly flat for cardiovascular death. Dr. Justin Ezekowitz: But number 2 is there is a danger in comparing trials even non-statistically. That's often a pitfall we get into, but we have to put some frame of reference on that. What is the one or two key things you think differ between PARAGON and EMPEROR-Preserved that you say, "You really need to look at these trials differently"? Those two questions came to mind when looking at this great figure that you produced. Dr. Milton Packer: Okay. The first question is so much easier and that is that these drugs don't reduce cardiovascular deaths. Full stop. It's really interesting because sacubitril/valsartan reduces cardiovascular death in people with ejection fractions of 40% or less, but not in patients with ejection fraction greater than that. The primary effect is heart failure hospitalizations. Empagliflozin didn't reduce cardiovascular death even in patients with the ejection fraction less than 40% or greater than 40%. What we're really, really talking about two drugs where the major effect is a reduction in heart failure hospitalizations. That comes out whether you do the analysis as time-to-first-event or total heart failure hospitalizations. Dr. Milton Packer: Of course, we're looking forward to the DELIVER trial with dapagliflozin. My own personal expectation is they're going to come out with a very striking effect on heart failure hospitalizations and not on cardiovascular deaths. Cardiovascular deaths in patients with HFpEF is really... It's a hard goal because only half of the deaths are cardiovascular. These patients have so many comorbidities that influence prognosis. The other thing, which is really important, is that heart failure hospitalizations only represented 18% of all hospitalizations in these patients; it's really small. I think of empagliflozin as being a treatment of the heart failure of HFpEF, not a treatment for HFpEF. I hope that makes sense. Justin, what was your second question? Dr. Justin Ezekowitz: Absolutely. Dr. Milton Packer: Oh, the differences between- Dr. Justin Ezekowitz: Yeah. Thank you, Milton. Dr. Milton Packer: Okay. There's always differences between two trials. As I said before, Carol and I were involved in both trials. They were done slightly at different times. They didn't overlap. Remember that the cut points in the two trials, one was 40%, one was 45%, really didn't matter to our analysis because we corrected for that in our ejection fraction subgroups. I was actually really much more impressed by the similarities than by the differences, but here's the catch. HFpEF is an incredibly heterogeneous disease. When we look at baseline characteristics, we're looking at means, medians, percentages. We're not picking up on any heterogeneity and there's a lot of heterogeneity. I actually think that HFrEF is a reasonably homogeneous disease. I think HFpEF is an incredibly diverse disease with a whole host of different disorders. What I'm amazed by is that we actually got an effect size that was greater than 20% in an all-comers HFpEF analysis. Dr. Milton Packer: But in all honesty, Justin, it wasn't really all-comers. We excluded people with BMIs over 45. There are a lot of patients who are obese and had BMIs greater than 45 who have HFpEF. By the way, especially in Texas. I didn't say that. We didn't enroll those patients. In all honesty, if I had to do it all over again, I would have. By the way, PARAGON didn't enroll them either. Dr. Carolyn Lam: Well, this is an incredible conversation. I know that we could just do a whole hour of chatting about what this implies for the higher ejection fraction, what this implies for how we should be treating heart failure. I don't even dare to ask for some last words maybe from both Justin and Milton, but recognizing that the time is short, anything else to add? Dr. Milton Packer: I think Justin should do last words. Dr. Justin Ezekowitz: Well, let me summarize by saying there is a hockey stick. We love hockey sticks in Canada. A simple and an excellent comparison. I think people should really look at that figure to understand it, but do not undertreat your patients with HFpEF and look at these with a grain of salt. Thanks for joining us, Milton. Thanks, Carolyn. Dr. Milton Packer: Thank you so much. Dr. Carolyn Lam: On behalf of Greg and I, you've been listening to Circulation on the Run. Thank you so much for joining us today and don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.

Today's episode is a compilation of a few short monologues. We provide an oncologist's evidence-based medicine perspective on four papers: CheckMate 274, adjuvant nivolumab in urothelial cancer; PARADIGM-HF/Entresto; the POLO trial, olaparib in pancreas cancer; and the paper "An algorithmic approach to reducing unexplained pain disparities in underserved populations". CheckMate 274: doi.org/10.1056/NEJMoa2034442 PARADIGM-HF: doi.org/10.1056/nejmoa1409077 POLO: doi.org/10.1056/NEJMoa1903387 Knee pain: doi.org/10.1038/s41591-020-01192-7 Back us on Patreon! www.patreon.com/plenarysession Check out our YouTube channel: www.youtube.com/channel/UCUibd0E2kdF9N9e-EmIbUew

This week's episode features author Kieran Docherty and Associate Editor Torbjørn Omland as they discuss the article "The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts: I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate, editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, we've got an exciting feature this week involving Neprilysin license inhibition and left ventricular remodeling in patients with asymptomatic left ventricular systolic function after they've sustained myocardial infarction. But before we get to that feature discussion, how about we grab a cup of coffee and jump in on some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I'd love to, and I want to talk about transcatheter aortic valve replacement, or TAVR, that we all know is really transforming our management of aortic stenosis. Despite rapid improvements, however, serious complications remain relatively common and are not well-described by single outcome measures. So the purpose of this paper was to determine if there was site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. And this is from Dr. Desai and colleagues from Hospital of University of Pennsylvania. So they performed a retrospective cohort study using data from the STS/ACC TVT registry to develop a novel-ranked competent performance measure that incorporates mortality and serious complications. Based on the associations with one-year risk adjusted mortality and health status, they identified for peri-procedural complications to include in the composite risk model, in addition to mortality. And ranked empirically, according to severity, these were: stroke, major life-threatening or disabling bleeding, stage three acute kidney injury, and moderate or severe perivalvular regurgitation. Dr. Carolyn Lam: Now, based on these ranked outcomes, they found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better-than-expected site performance was observed in 8% of sites, whereas performance as-expected was observed in 80%, and worse-than-expected performance was observed in 11% of sites. Dr. Greg Hundley: Carolyn, really interesting comprehensive data. So how do we put this all together? And what's the take-home message for us, clinically? Dr. Carolyn Lam: Well, there are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine the structural, process-related, and technical factors associated with high- and low-performing sites. And all this is discussed in a beautifully, beautiful accompanying editorial by Drs. Dharam Kumbhani and Eric Peterson.   Dr. Greg Hundley: Oh, fantastic. You know, Carolyn, those editorials are so helpful in helping us put these new data in perspective. Well, my next paper comes to us from the world of preclinical science, and it's from Professor Vincent Christoffels from Amsterdam in UMC. So genetic variants of SCN10A, encoding the neural voltage-gated sodium channel NaV1.8 are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. And these investigators studied the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, and coding the major essential cardiac sodium channel NaV1.5. Dr. Carolyn Lam: Wow, great. So what did they find, Greg? Sounds like a first-of-its-kind study. Dr. Greg Hundley: Right, Carolyn. So genetic variants in and around SCN10A modulate enhancer function and expression of the cardiac-specific NCN10A short transcript, and the authors propose that non-encoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV .8 and cardiomyocytes that impacts NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility. Dr. Carolyn Lam: Wow, that was a lot. So what are the implications, Greg? Could you simplify it for us? Dr. Greg Hundley: Yes. Right, Carolyn. So three things. First, the authors uncovered a novel alternative mechanism for how the SCN10A locus regulates cardiac conduction. Second, their data implicate that genetic variation-sensitive regulation of expression of NCN10A short modulates conductivity of the heart, and can predispose to arrhythmia in the human population. And then finally, Carolyn, in deciphering the underlying mechanism of the increased NaV1.5 mediated current density by NaV1.8 short, the authors believe their findings could ultimately lead to the development of novel therapeutic strategies for particular conduction disorder. Dr. Carolyn Lam: Thanks, Greg. Well, this next paper is really interesting. It's the first validation of the enhanced potency of human-induced pluripotent stem cells-derived cardiomyocytes over-expressing Cyclin D2, or CCND2, under the control of myosin heavy chain promoter, and differentiated into cardiomyocytes. Now, that was a mouthful, but so interesting, because Dr. Zhang and colleagues from University of Alabama in Birmingham used infarcted pig hearts, and transplanted these amazing cardiomyocytes, and found that they were associated with proliferation of recipient heart cardiomyocytes, epithelial cells, and smooth muscle cells, all, at least partly, by paracrine activity. Dr. Greg Hundley: Well, Carolyn. Really an involved clinical design. So, what are the clinical implications of all this research?   Dr. Carolyn Lam: Well, first, I think the paper validated a novel therapeutic strategy aimed at upregulating proliferation of recipient cardiac cells using human-induced pluripotent stem cells-derived cell or cell products. Furthermore, targeting the myocyte cell cycle regulators, such as Cyclin D2, holds a strategic potential for re-muscularization of an infarcted region. Dr. Greg Hundley: Very good, Carolyn. Well, how about we see what else is in this issue? So I'll start first. There's a Research Letter by Professor Marston, entitled 'Combining High-Sensitivity Troponin with the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide of Avelumab Therapy'. Next, there's an ECG challenge from Dr. Feliciano, entitled 'An Ominous EKG'. And then finally, there's a very nice exchange of letters from Drs. Lang and Sattar regarding a prior publication: volume status is the key in heart failure. Dr. Carolyn Lam: And finally, a very important perspective piece by Dr. Catapano on omega-3 for cardiovascular disease: where do we stand after reduce it in strength? Wow, that was great, Greg. But let's move on now to our feature discussion. Dr. Greg Hundley: You bet. Dr. Greg Hundley: Well, listeners, we are on to our feature discussion today, on this July 20 issue. And we're very excited to have with us Dr. Kieran Docherty from University of Glasgow in Glasgow, Scotland, and our own associate editor, Dr. Torbjørn Omland from University of Oslo in Oslo, Norway. Welcome, gentlemen. And Kieran, let's start with you. Could you describe some of the background related to your study, and what was the hypothesis that you wanted to address? Dr. Kieran Docherty: Well, firstly, thank you very much for the invitation to discuss our trial today on the podcast. The background of our trial was that we are all aware that the development of left ventricular systolic dysfunction following acute myocardial infarction places patients at a subsequent increased risk of the development of heart failure, and the process of progressive dilatation of the left ventricle and a reduction in stroke volume, known as adverse left ventricular remodeling, is the process which underlies this elevated risk of heart failure. And many of the treatments that have been shown to be beneficial following myocardial infarction, such as [inaudible 00:09:24] , and angiotensin receptor blockers and beta blockers, the benefit of these medications, in part, is due to their ability to attenuate this process of adverse remodeling. Now, our hypothesis was that it would be possible to further attenuate, prevent, or delay the process of adverse remodeling in patients at risk of heart failure following myocardial infarction, by the addition of a Neprilysin inhibitor to current standard of care. Dr. Kieran Docherty: Now, as we all know, a Neprilysin inhibitor in the form of sacubitril valsartan when combined with an angiotensin receptor blocker, has been shown to improve outcomes in patients with symptomatic heart failure, with reduced ejection fraction in the PARADIGM-HF trial, and Neprilysin inhibitors increase endogenous levels of natriuretic peptides, amongst a range of other substrates for Neprilysin, including adrenomedullan, GLP-1, and bradykinin. And our hypothesis was that adding in a Neprilysin inhibitor, thereby increasing endogenous levels of these peptides with potentially beneficial effects, such as reducing fibrosis, reducing hypertrophy, [inaudible 00:10:34] and diuresis, may have an additive beneficial effect on left ventricular remodeling in these high-risk patients with left ventricular systolic dysfunction following myocardial infarction. Dr. Greg Hundley: Very nice hypothesis. So, how did you set up, Kieran, your study design, and what study population, how many patients and whatnot, did you include in your study? Dr. Kieran Docherty: Well, the first consideration when designing the study was broadly, what group of patients should we involve? And the main limitation was the indication for the use of sacubitril valsartan in patients with symptomatic heart failure, so we did not feel that we could include these patients. Therefore, our study population included patients who had asymptomatic left ventricular systolic dysfunction following previous myocardial infarction. And specifically, we wanted patients who were at least three months following my cardiac infarction. And the reason for that was to try and exclude patients who had transient systolic dysfunction or left ventricular stunning. And we performed a screening transthoracic echo at this time point. And if patients had an ejection fraction of 40% or less on echo, and if they were tolerant of a minimum dose of an ACE inhibitor, 2.5 milligrams of ramipril BD or equivalent, and they were taking a beta blocker, unless contraindicated or not tolerated, then they were suitable for randomization. Dr. Greg Hundley: Very good. And what did you find? Dr. Kieran Docherty: So we find that in comparison with the ARB Valsartan, sacubitril valsartan did not have any beneficial effects on cardiac MRI-based measures of left ventricular remodeling. And the primary end point of our study was left ventricular end systolic volume index. There was also no improvements in biomarkers of myocardial stress, i.e. NT-proBNP, or my cardio injury, i.e. high sensitivity to Troponin I. Dr. Greg Hundley: Very nice. And any pertinent issues relevant to, perhaps, some subgroups, regardless of age or perhaps gender? Dr. Kieran Docherty: So in a post-hoc analysis, we performed an analysis of the primary endpoint in patients who were below or at or above the median NT-proBNP level, which is 238 p-grams per mil. And we found, very interestingly, the suggestion of a benefit, in terms of left ventricular remodeling with a reduction and systolic volume index in patients who had higher levels of NT-proBNP compared to those who had lower levels. Dr. Greg Hundley: Very good. Well, listeners, let's turn now to our associate editor, Dr. Torbjørn Omland, who... Torbjørn, you see many papers come across your desk. What attracted you to this manuscript? And then how do you put the results of this study in the context with other studies that have been published, particularly recently, in patients with heart failure that have received sacubitril valsartan? Dr. Torbjørn Omland: So, Greg, there were many aspects of this trial that made it very attractive for circulation. I think the hypothesis was very interesting, and also it is a very well-conducted study using the reference methods for assessing left ventricular function, using that for assessing the primary endpoint. And they also have a broad array of secondary end points that also sort of provide insight in potential pathways or mechanisms that can explain the effect sacubitril Valsartan. So, that's also a very sort of hot topic within the cardiology research currently, and we know that the ACC, actually a much larger study, PARADISE-MI, was presented. And we knew that this study was also very interesting, because we knew when we received this manuscript, that another, bigger trial that's sort of related would be presented at the ACC at the late-breaking clinical trial sessions there the PARADISE-MI study. But this sort of provided insight that nicely complimented the results of that study. Dr. Torbjørn Omland: And I think as Kieran alluded to, we already have the very impressive results from PARADIGM-HF is showing a very substantial benefit in patients with chronic heart failure and reduced ejection fraction. And then we have sort of the borderline results from the Paragon trial, in those with preserved ejection fraction, where it actually was a gradient from those with mildly elevated, where there seemed to be a beneficial effect to those with more normal EF, where there was no effect. So, this study sort of provided new information, very relevant to the whole field, I think. Dr. Greg Hundley: Very nice. Well, gentlemen, I want to turn back to you and ask each of you, first Kieran, and then Torbjørn. Kieran, what do you think is the next study that needs to be performed in, really, this sphere of research? Dr. Kieran Docherty: As Torbjørn has already alluded to, PARADISE-MI kind of... It fills the gap across the spectrum of heart failure. So in patients who are at high risk of heart failure immediately following myocardial infarction, that that group of patients were studied in PARADISE-MI. And there is an echocardiographic sub-study of PARADISE-MI, which we await the results for. And I think that will be very interesting, because our patient population was distinct from the group studied in PARADISE-MI, namely the fact that the median time from MI was 3.6 years. So, these patients were not in the throes of the neural humoral activation at the time of acute myocardial infarction and prior to the development of established my cardio scar and fibrosis. And so, it may be that the addition of a Neprilysin inhibitor to patients immediately following myocardial infarction may have some benefits, in terms of attenuating or preventing ventricular dilatation reduction and injection fraction that is observed. So I think we await the echocardiographic results of PARADISE-MI with great interest. Dr. Greg Hundley: Very good. And Torbjørn , do you have anything to add? Dr. Kieran Docherty: Yes. I found observations that actually, in terminal proBNP measurements, could potentially identify a higher-risk group that actually could benefit from the intervention. It was very interesting. So I think we always speak about precision medicine and cardiology, and I think this is sort of one avenue that we should pursue and see whether we use biomarkers like NT-proBNP to identify those patients who will benefit most from interventions like sacubitril Valsartan Dr. Greg Hundley: Excellent. Well, listeners, we've heard a really interesting discussion today. Another study investigating Neprilysin inhibition in combination with angiotensin receptor blockers, and basically highlighting that in patients with asymptomatic left ventricular dysfunction following several years after myocardial infarction, that treatment with sacubitril Valsartan did not have a significant reverse remodeling effect just compared with valsartan alone. Well, on behalf of Carolyn and myself, we want to thank Dr. Kieran Docherty and his submission here to circulation, and also our own associate editor, Dr. Torbjørn Omland. Dr. Greg Hundley: And for all of you, we wish you a great week, and we hope to catch you next week on The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more visit ahajournals.org.  

NAMIJENJENO ISKLJUČIVO ZDRAVSTVENIM DJELATNICIMA. PRISTUPOM PODCASTU POTVRĐUJETE DA STE ZDRAVSTVENI DJELATNIK.PREDAVAČ:Prof.dr.sc. ALEN DŽUBUR, dr.med.specijalista interne medicineKlinika za bolesti srca, krvnih žila i reumatizamKCU SarajevoSarajevo, BiHLINK NA TEČAJPristupom na CME aktivnost na Portalu CME.ba imate priliku da na kraju iste uradite završni test, te da dobijete akreditovani CME certifikat.U naše dvije prethodne CME aktivnosti smo govorili o sakubitril/valsartanu i o dvije studije PROVE-HF i PARADIGM-HF koje su evaluirale efikasnost ovog lijeka u terapiji srčane slabosti. U ovoj aktvnosti pak, predavač se osvrće na još jednu studiju, PIONEER-HF, koja je evaluirala nivoe NT-proBNP u kontekstu terapije sa sakubitril/valsartanom, kao i kompozitne ishode definisane kroz neželjene događaje, kao što su smrtnost, hospitalizacije zbog pogoršanja srčane slabosti itd.U drugom dijelu ove jako zanimljive aktivnosti, predavač se osvrće na praktičnu primjenu sakubitril/valsartana kroz prikaz slučaja pacijenta sa pogoršanjem srčane slabosti, te na efekte terapije u kratkoročnom i srednjeročnom periodu.Aktivnost je preporučena za specijaliste i specijalizante interne medicine, kardiologije, anesteziologije, porodične medicine, a primjerena je i za studente medicine. Ova CME aktivnost je besplatna za registrirane članove. Registracija je također, besplatna.----------Ukoliko želite postati partner portala CME.ba ili želite da se Vaš brand ili audio poruke pojave na našim podcastima, mollimo da se javite na email info@cme.ba. Više informacija za potencijalne partnere potražite na OVOM LINKU.

NAMIJENJENO ISKLJUČIVO ZDRAVSTVENIM DJELATNICIMA. PRISTUPOM PODCASTU POTVRĐUJETE DA STE ZDRAVSTVENI DJELATNIK.PREDAVAČ:Prof.dr.sc. MEHMED KULIĆsubspecijalista kardiologijeJU Dom Zdravlja Kantona SarajevoSarajevo, BiHLINK NA TEČAJPristupom na CME aktivnost na Portalu CME.ba imate priliku da na kraju iste uradite završni test, te da dobijete akreditovani CME certifikat.Srčana slabost je patološko stanje koje se vrlo često sreće i u primarnoj i u sekundarnoj praksi. Često zahtjevno za liječenje, povezano sa postupnim propadanjem srčane funkcije, godinama je liječeno kombinacijom manje starih i više starih lijekova sa minucioznim poboljšanjima glede terapijskog efekta.PARADIGM-HF je velika studija koja je prvi puta evaluirala kombinaciju sakubitrila, nove klase angiotenzin receptor neprilizin inhibitora (ANRI) u kombinaciji sa već poznatim valsartanom. Rezultati ove studije su bili toliko značajni da su promijenili smjernice u liječenju srčanog zatajenja, te je od 2016.godine sakubitril/valsartan uključen kao nova terapijska klasa u smjernice Evropskog društva za kardiologiju (ESC).U ovom jako zanimljivom i iscrpnom tečaju nacionalni ekspert iz polja kardiologije daje prikaz glavnih rezultata PARADIGM-HF studije, mehanizma djelovanja sakubitril/valsartana i mjesta ovog lijeka u modernom pristupu liječenju srčanog zatajenja.Tečaj je preporučen za specijaliste i specijalizante kardiologije, interne medicine, porodične medicine, a primjeren je i za studente medicine i magistre farmacije.----------Ukoliko želite postati partner portala CME.ba ili želite da se Vaš brand ili audio poruke pojave na našim podcastima, mollimo da se javite na email info@cme.ba. Više informacija za potencijalne partnere potražite na OVOM LINKU.NOVARTIS Pharma, Predstavništvo Sarajevo At Novartis, we are reimagining medicine.

FDA 批准MitraClip治疗心力衰竭继发的二尖瓣返流 NEJM 达格列净在射血分数下降的心功能不全的患者中的作用Circulation 恩格列净治疗心力衰竭过程中心脏和肾脏的获益Lancet 支持联合使用ARNI、β受体阻滞剂、盐皮质激素拮抗剂和SGLT2抑制剂作为心衰的新标准治疗Nature PCSK9抑制剂可增强肿瘤的免疫治疗的疗效MitraClip 2019年3月，FDA为MitraClip经导管二尖瓣修复装置增加了新的适应症，用于治疗症状性心力衰竭症状合并继发性或功能性二尖瓣返流（SMR或FMR）。《COAPT研究：经导管二尖瓣修复术治疗心力衰竭患者》New England Journal of Medicine，2018年12月 (1) 左心室功能不全伴有二尖瓣返流的心力衰竭患者预后较差。研究的目的是评价经导管二尖瓣修复术是否能改善预后。研究纳入了心衰、合并中重度二尖瓣返流患者614人，这些患者在使用指南指导下的、最大剂量药物治疗后仍有症状，随机分为经导管二尖瓣修复术加药物治疗（器械组）和单纯药物治疗组（对照组）。器械组24个月内因心力衰竭住院的比例为35.8/100人年，对照组为67.9/100人年（风险比 0.53，P < 0.001）；器械组24个月全因死亡率为29.1%，对照组为46.1%（风险比 0.62，P10mm2或返流量>30ml）的患者，EF介于15%-40%，随机分入器械组（经皮二尖瓣修复加药物治疗）和对照组（单纯药物治疗）。这篇文章汇报了24个月的随访结果24个月时，器械组全因死亡和心衰住院的患者占63.8%，对照组为67.1%（风险比 1.01，无统计学意义）。器械组的全因死亡率为34.9%，对照组为34.2%（风险比 1.02，无统计学意义）。器械组心衰住院比例为55.9%，对照组61.8%（风险比 0.97，无统计学意义）。结论：在心力衰竭合并严重二尖瓣返流的患者中，经皮二尖瓣修复加药物治疗与单纯药物治疗相比，在2年内心衰死亡或住院的风险没有显著降低。小羽点评：MitraClip治疗心力衰竭合并继发性或功能性二尖瓣返流患者的两项大型临床研究COAPT研究和MITRA-Fr研究的结果并不一致，但是FDA根据COAPT研究的结果还是批准了MitraClip治疗心衰的适应症。现在也有文献讨论这种治疗心衰策略的机制，但似乎仍不足以解释我心中的疑惑——这种治疗策略究竟有没有大规模推广的理论基础和确凿的证据。慢性心功能不全治疗 —— SGLT2抑制剂钠-葡萄糖协同转运蛋白2（SGLT2）表达于肾近端小管，介导约90%的滤过葡萄糖的重吸收。SGLT2抑制剂促进肾脏对葡萄糖的排泄，因此可降低血糖、降低血压和体重，通常不会导致低血糖。2020年5月，FDA批准达格列净用于治疗射血分数降低的心衰患者，用以降低心血管死亡和因心力衰竭再住院的风险。这是SGLT2抑制剂中首个获批，用于治疗射血分数降低、纽约心功能分级II-IV级的患者。《DAPA-HF研究：达格列净在射血分数下降的心功能不全的患者中的作用》New England Journal of Medicine，2019年11月 (3)在这个III期、安慰剂对照研究中，纳入了选取了4744名患者纽约心功能分级II-IV级的、射血分数低于40%的患者接受达格列净10mg qd或安慰剂治疗。随访18.2个月，达格列净治疗组主要心血管事件的风险比0.74；心衰恶化的风险比为0.70；心血管死亡风险比0.82；全因死亡危险比为0.83。糖尿病与非糖尿病患者相似；与容量不足、肾功能不全和低血糖相关的不良事件发生频率在治疗组之间没有差异。结论：达格列净可减少心衰恶化或心血管死亡的风险。《DAPA-HF研究亚组分析：达格列净对有或没有糖尿病的射血分数下降的心功能不全的患者的治疗作用》JAMA，2020年3月 (4)DAPA-HF研究中有54%的参与者并未患糖尿病。其中糖尿病患病情况分三种：（1）患糖尿病（有糖尿病史或糖化血红蛋白≥6.5%，n=2,139），（2）前驱糖尿病（糖化血红蛋白5.7%～6.5%；n=1,748），（3）没有糖尿病（糖化血红蛋白＜5.7%；n=839）。患糖尿病的参与者中有更多黑人，心功能更差，更可能有缺血性改变。试验结束时（中位随访时间为，16.6～18.0个月），糖尿病、前驱糖尿病和无糖尿病亚组的风险均出现了相似且与达格列净相关的显著降低（风险比分别为0.75、0.74和0.67；无交互作用）。最常见的不良反应是容量不足和肾损伤，其发生率与治疗或糖尿病状况不相关。结论：射血分数降低的心衰患者中，即使没有糖尿病，使用达格列净仍可以显著降低了心衰恶化或心血管死亡的风险。《DAPA-HF研究亚组分析：达格列净和利尿剂联用治疗射血分数下降的心功能不全的研究》Circulation，2020年7月 (5)DAPA-HF研究中，根据患者是否在服用利尿剂，将患者分为无利尿剂组、利尿剂40mg/d组。这四组患者中，达格列净降低了这些亚组的主要终点时间的风险，风险比分别为0.57、0.83、0.77和0.78。达格列净疗效和治疗的耐受性在各个亚组是一致的。在随访期间，大多数患者的利尿剂剂量没有变化。结论：达格列净在各个利尿剂亚组中的安全性和有效性是一致的。《DAPA-HF研究亚组分析：达格列净和沙库巴曲缬沙坦联用治疗射血分数下降的心功能不全的研究》JACC Heart Failure，2020年7月 (6)DAPA-HF研究中，根据患者是否在随机服用沙库巴曲缬沙坦进行分析。其中10.7%的参与者在基线时接受了沙库巴曲缬沙坦治疗， 这些患者通常来自北美和欧洲，心功能通常更差、血压更低。心血管死亡或心衰恶化的风险比，在服用沙库巴曲缬沙坦人群中为0.75；在未服用沙库巴曲缬沙坦人群中为0.74。次要终点和安全终点，包括与低血容量有关的事件，两组都是相似的。结论：两种药物联合使用可进一步降低射血分数下降的心功能不全患者的发病率和死亡率。《DAPA-HF研究亚组分析：达格列净对门诊射血分数降低心衰的恶化的影响》Circulation，2020年10月 (7)DAPA-HF研究中，根据心衰住院、心衰恶化或心血管死亡为终点事件进行亚组分析，达格列净组22.2%的患者出现终点事件、安慰剂组为28.8%，风险比0.73，P

FDA 批准MitraClip治疗心力衰竭继发的二尖瓣返流 NEJM 达格列净在射血分数下降的心功能不全的患者中的作用Circulation 恩格列净治疗心力衰竭过程中心脏和肾脏的获益Lancet 支持联合使用ARNI、β受体阻滞剂、盐皮质激素拮抗剂和SGLT2抑制剂作为心衰的新标准治疗Nature PCSK9抑制剂可增强肿瘤的免疫治疗的疗效MitraClip 2019年3月，FDA为MitraClip经导管二尖瓣修复装置增加了新的适应症，用于治疗症状性心力衰竭症状合并继发性或功能性二尖瓣返流（SMR或FMR）。《COAPT研究：经导管二尖瓣修复术治疗心力衰竭患者》New England Journal of Medicine，2018年12月 (1) 左心室功能不全伴有二尖瓣返流的心力衰竭患者预后较差。研究的目的是评价经导管二尖瓣修复术是否能改善预后。研究纳入了心衰、合并中重度二尖瓣返流患者614人，这些患者在使用指南指导下的、最大剂量药物治疗后仍有症状，随机分为经导管二尖瓣修复术加药物治疗（器械组）和单纯药物治疗组（对照组）。器械组24个月内因心力衰竭住院的比例为35.8/100人年，对照组为67.9/100人年（风险比 0.53，P < 0.001）；器械组24个月全因死亡率为29.1%，对照组为46.1%（风险比 0.62，P10mm2或返流量>30ml）的患者，EF介于15%-40%，随机分入器械组（经皮二尖瓣修复加药物治疗）和对照组（单纯药物治疗）。这篇文章汇报了24个月的随访结果24个月时，器械组全因死亡和心衰住院的患者占63.8%，对照组为67.1%（风险比 1.01，无统计学意义）。器械组的全因死亡率为34.9%，对照组为34.2%（风险比 1.02，无统计学意义）。器械组心衰住院比例为55.9%，对照组61.8%（风险比 0.97，无统计学意义）。结论：在心力衰竭合并严重二尖瓣返流的患者中，经皮二尖瓣修复加药物治疗与单纯药物治疗相比，在2年内心衰死亡或住院的风险没有显著降低。小羽点评：MitraClip治疗心力衰竭合并继发性或功能性二尖瓣返流患者的两项大型临床研究COAPT研究和MITRA-Fr研究的结果并不一致，但是FDA根据COAPT研究的结果还是批准了MitraClip治疗心衰的适应症。现在也有文献讨论这种治疗心衰策略的机制，但似乎仍不足以解释我心中的疑惑——这种治疗策略究竟有没有大规模推广的理论基础和确凿的证据。慢性心功能不全治疗 —— SGLT2抑制剂钠-葡萄糖协同转运蛋白2（SGLT2）表达于肾近端小管，介导约90%的滤过葡萄糖的重吸收。SGLT2抑制剂促进肾脏对葡萄糖的排泄，因此可降低血糖、降低血压和体重，通常不会导致低血糖。2020年5月，FDA批准达格列净用于治疗射血分数降低的心衰患者，用以降低心血管死亡和因心力衰竭再住院的风险。这是SGLT2抑制剂中首个获批，用于治疗射血分数降低、纽约心功能分级II-IV级的患者。《DAPA-HF研究：达格列净在射血分数下降的心功能不全的患者中的作用》New England Journal of Medicine，2019年11月 (3)在这个III期、安慰剂对照研究中，纳入了选取了4744名患者纽约心功能分级II-IV级的、射血分数低于40%的患者接受达格列净10mg qd或安慰剂治疗。随访18.2个月，达格列净治疗组主要心血管事件的风险比0.74；心衰恶化的风险比为0.70；心血管死亡风险比0.82；全因死亡危险比为0.83。糖尿病与非糖尿病患者相似；与容量不足、肾功能不全和低血糖相关的不良事件发生频率在治疗组之间没有差异。结论：达格列净可减少心衰恶化或心血管死亡的风险。《DAPA-HF研究亚组分析：达格列净对有或没有糖尿病的射血分数下降的心功能不全的患者的治疗作用》JAMA，2020年3月 (4)DAPA-HF研究中有54%的参与者并未患糖尿病。其中糖尿病患病情况分三种：（1）患糖尿病（有糖尿病史或糖化血红蛋白≥6.5%，n=2,139），（2）前驱糖尿病（糖化血红蛋白5.7%～6.5%；n=1,748），（3）没有糖尿病（糖化血红蛋白＜5.7%；n=839）。患糖尿病的参与者中有更多黑人，心功能更差，更可能有缺血性改变。试验结束时（中位随访时间为，16.6～18.0个月），糖尿病、前驱糖尿病和无糖尿病亚组的风险均出现了相似且与达格列净相关的显著降低（风险比分别为0.75、0.74和0.67；无交互作用）。最常见的不良反应是容量不足和肾损伤，其发生率与治疗或糖尿病状况不相关。结论：射血分数降低的心衰患者中，即使没有糖尿病，使用达格列净仍可以显著降低了心衰恶化或心血管死亡的风险。《DAPA-HF研究亚组分析：达格列净和利尿剂联用治疗射血分数下降的心功能不全的研究》Circulation，2020年7月 (5)DAPA-HF研究中，根据患者是否在服用利尿剂，将患者分为无利尿剂组、利尿剂40mg/d组。这四组患者中，达格列净降低了这些亚组的主要终点时间的风险，风险比分别为0.57、0.83、0.77和0.78。达格列净疗效和治疗的耐受性在各个亚组是一致的。在随访期间，大多数患者的利尿剂剂量没有变化。结论：达格列净在各个利尿剂亚组中的安全性和有效性是一致的。《DAPA-HF研究亚组分析：达格列净和沙库巴曲缬沙坦联用治疗射血分数下降的心功能不全的研究》JACC Heart Failure，2020年7月 (6)DAPA-HF研究中，根据患者是否在随机服用沙库巴曲缬沙坦进行分析。其中10.7%的参与者在基线时接受了沙库巴曲缬沙坦治疗， 这些患者通常来自北美和欧洲，心功能通常更差、血压更低。心血管死亡或心衰恶化的风险比，在服用沙库巴曲缬沙坦人群中为0.75；在未服用沙库巴曲缬沙坦人群中为0.74。次要终点和安全终点，包括与低血容量有关的事件，两组都是相似的。结论：两种药物联合使用可进一步降低射血分数下降的心功能不全患者的发病率和死亡率。《DAPA-HF研究亚组分析：达格列净对门诊射血分数降低心衰的恶化的影响》Circulation，2020年10月 (7)DAPA-HF研究中，根据心衰住院、心衰恶化或心血管死亡为终点事件进行亚组分析，达格列净组22.2%的患者出现终点事件、安慰剂组为28.8%，风险比0.73，P

In this week's View, guest host Dr. Deepak Bhatt offers a preview of some of the hottest trials at the American Heart Association Scientific Sessions 2019, taking place November 16-18 in Philadelphia, PA, including ISCHEMIA, ISCHEMIA QoL, ISCHEMIA-CKD, DAPA-HF, COLCOT, Treat Stroke To Target, REDUCE-IT Cost-Effectiveness, REDUCE-IT USA, EVAPORATE, PARADIGM-HF, and PARAGON-HF.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article? Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm. Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first? Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm. Dr Greg Hundley:             Interesting. What did they find, Carolyn? Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery. Dr Greg Hundley:             Fantastic, Carolyn.                                                 Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension. Dr Carolyn Lam:                Huh. What did they find Greg? Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients. Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.                                                 Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry. Dr Greg Hundley:             Carolyn, what did they find? Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag? Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.                                                 First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal. Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion. Dr Greg Hundley:             You bet.                                                 Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods. Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.                                                 I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation. Dr Greg Hundley:             What was your overall study design and your study population? Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important. Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms? Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan. Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF? Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.                                                 The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.                                                 We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes. Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct? Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well. Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works? Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?                                                 And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion. Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy. Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients. Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that? Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses. Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Commentary by Dr. Valentin Fuster

Update your management of heart failure (HF) with expert tips from Cardiologist Dr. Eric Adler, Associate Professor of Medicine and Director of Cardiac Transplant and Mechanical Circulatory Support at UC San Diego. We cover how to use BNP, a simple way to examine jugular venous distention, medical therapy for heart failure, the PARADIGM-HF trial, and how to use sacubitril/valsartan (Entresto). Full show notes available at http://thecurbsiders.com/podcast Join our newsletter mailing list. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Time Stamps 00:00 Intro 04:25 Rapid fire questions 06:00 Palliative care and heart failure 08:40 Book recommendation 10:20 Advice for teachers and learners 12:27 Clinical case of HF 13:38 Classification and staging of HF 17:07 Discussion of BNP 19:35 How to perform neck vein exam for JVD 21:20 BNP for prognosis 23:00 BNP at hospital discharge 26:36 Factors that affect BNP 27:25 Initial patient counseling 32:35 Exercise in HF 34:00 Additional testing at time of diagnosis 36:28 Initial medical therapy 38:30 Discussion of diuretics and dosing 42:50 Aldosterone antagonists 44:30 PARADIGM-HF and entresto 51:27 Medications to avoid in HF 54:14 Digoxin 57:30 Dr. Adler’s take home points 59:11 Stuart questions dosing conventions 60:48 Outro Tags: arni, assistant, care, diuretics, doctor, education, failure, family, foam, foamed, health, heart, hospitalist, hospital, internal, internist, neprilysin, nurse, management, medicine, medical, physician, practitioner, primary, resident, sacubitril, student

BNP use as a lab and therapeutic are discussed. The episode also explores the PARADIGM-HF trial and Neprilysin inhibition. The novel combination medication sacubitril/valsartan (Entresto) for systolic CHF is evaluated in depth. Clinical tips for avoiding angioedema and other clinical pearls are provided.

In this episode, we discuss the new drug class, ARNI, recently approved for heart failure with a focus on sacubatril/valsartan (Entresto) and the PARADIGM-HF trial.

This week: Changes in incidence and mortality associated with bilateral mastectomy for breast cancer and Neprilysin-inhibition for heart failure Nathan and Amol want you to: 1. Recognize that bilateral mastectomies for breast cancer are increasing in incidence, perhaps because of increased use of MRI, and they are not associated with a reduction in mortality. 2. Understand that ... The post Heart Success! Bilateral mastectomies in breast cancer, the PARADIGM-HF Heart Failure Trial appeared first on Healthy Debate.