Podcasts about alirocumab

This week, Carolyn, Greg, and Peder welcome podcast hosts Laxmi Mehta and Eva Rocha of The Journal of the American Heart Association's new podast "Aha! With JAHA." Then, please join author Leopoldo Pérez de Isla and Associate Editor Stefan James as they discuss the article "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study.  For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230508.620091  

Editor's Summary by Kristin Walter, MD, Senior Editor of JAMA, the Journal of the American Medical Association, for the May 10, 2022 issue.

Causes of sudden death, inclisiran, DOAC choices, and alcohol and VT/VF are the topics discussed by John Mandrola, MD, in this week's podcast. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I – Causes of Sudden Death - Cardiac Device Interrogation After Death 'Richly Informative' https://www.medscape.com/viewarticle/965730 - Postmortem Interrogation of Cardiac Implantable Electronic Devices: A 15-Year Experience https://www.jacc.org/doi/full/10.1016/j.jacep.2021.10.011 - Sudden Death in Patients With Cardiac Implantable Electronic Devices https://pubmed.ncbi.nlm.nih.gov/26098676/ - Cardiac Implantable Electronic Device Interrogation at Forensic Autopsy https://www.ahajournals.org/doi/full/10.1161/circulationaha.117.032367 II – Inclisiran - FDA Approves First-in-Class Inclisiran to Lower LDL-C https://www.medscape.com/viewarticle/965464 - ORION: Inclisiran Phase 3 Trials Published https://www.medscape.com/viewarticle/927107 - Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia https://pubmed.ncbi.nlm.nih.gov/32892993/ - Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease https://www.nejm.org/doi/full/10.1056/nejmoa1615664 - Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome https://www.nejm.org/doi/10.1056/NEJMoa1801174 III – DOAC Choice - Apixaban: The 'Anticoagulant of Choice' for AF https://www.medscape.com/viewarticle/965390 - Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation https://jamanetwork.com/journals/jama/fullarticle/2787319 IV – Alcohol and VT/VF and SCD - Some Good News on Alcohol and 'Holiday Heart Syndrome' https://www.medscape.com/viewarticle/965498 - Alcohol consumption and risk of ventricular arrhythmias and sudden cardiac death: An observational study of 408,712 individuals https://www.heartrhythmjournal.com/article/S1547-5271(21)02215-3/fulltext 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

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and    backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Poly Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC simultaneous publication issue, isn't it? So the original papers were simultaneous publications at the European Society of Cardiology meeting this year. Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So Carolyn, later we're going to listen to the authors of this feature discuss the association between ICD use and all-cause mortality in a contemporary heart failure reduced ejection fraction cohort and examine relevant subgroups. So Carolyn, I'm going to get started with my first paper and it's a randomized trial of one hour, one-hour deponent T protocol and suspected acute coronary syndromes and it's a rapid assessment in emergency rooms and it's from professor Derek Chew from Flinders Medical Center. High sensitivity troponin assays promise earlier discrimination of MI, yet the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols with respect to subsequent testing and clinical events has not been evaluated in an in-practice, patient level, randomized study. So this multicenter study evaluated the non-inferiority of a zero to one hour, zero to one-hour, high sensitivity troponin T protocol compared with a more traditional zero to three-hour mask, high sensitivity troponin T protocol in those suspected with ACS. Dr Carolyn Lam: Interesting. So what did the study show? Dr Greg Hundley: So participants in the zero to one-hour arm were more likely to be discharged from the ED quicker and that would be expected. So 45% versus the standard arm, which was 32%. Also their median ED length of stay was shorter, and we would expect that. Four and a half versus five and a half hours. Those randomized to the zero to one-hour protocol were less likely to undergo functional cardiac testing. The zero to one-hour high sensitivity troponin T protocol was not inferior to standard of care and among patients discharged from the ED, the zero to one-hour protocol had a negative predictive value of 99.6% for 30-day death or MI. So Carolyn, how about your first study? Dr Carolyn Lam: Well, from MI risk stratification to heart failure risk stratification. I'm going to tell you about a paper describing the TIMI Risk Score for heart failure in diabetes, which is a novel integer base clinical risk score for predicting hospitalization for heart failure in patients with type two diabetes. This is from Dr Mark Sabatine and the TIMI study group who developed a clinical risk score for heart failure hospitalization in more than 8,200 patients with type two diabetes in the placebo arm of saver TIMI 53, as well as externally validated this score in more than 8,500 patients with type two diabetes in the placebo arm of declare TIMI 58. They found that five clinical variables were independent risk predictors of heart failure hospitalization. These were prior heart failure, history of atrial fibrillation, coronary artery disease, estimated GFR, and urine albumin-to- creatinine ratio, a simple integer base score from zero to seven points. Using these predictors identified a more than 20 full gradient of heart failure hospitalization risk in both the derivation and validation cohorts with high SES statistics. Although the relative risk reductions with dapagliflozin were similar for patients across the risk scores, the absolute risk reductions were greater in those with higher baseline risks. Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical implications of this really thorough study? Dr Carolyn Lam: In summary, the risk score had excellent discrimination in two large clinical trial cohorts. It was well calibrated, and it identified a strong gradient of increasing absolute reduction in risk of heart failure hospitalization with the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk Score for heart failure in diabetes, which is a simple validated clinical risk score, clinicians could better educate patients about their risk for heart failure hospitalizations and could perhaps better identify those patients who have a greater absolute risk reduction in heart failure risk with SGLT two inhibitors. Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back to the world of troponins and talk about a paper from Nicholas Mills from University of Edinburgh. And in this study, they evaluated the safety and effectiveness of risk stratification thresholds of high sensitivity troponin in patients with suspected acute coronary syndrome. 48,282 consecutive patients with suspected ACS were enrolled in a multicenter trial from 10 hospitals within Scotland and they're pre-specified secondary and observational analyses. They compared the performance of the limit of a detection of less than two nanograms per liter versus the optimized stratification threshold of less than five nanograms per liter using the Abbott high sensitivity troponin I assay. Patients with myocardial injury at presentation with less than two hours of symptoms or with ST segment elevation myocardial infarction were excluded and the negative predictive value was determined in all patients in subgroups for a primary outcome of MI or cardiac death within 30 days. And they had a secondary outcome that was MI or cardiac death at 12 months. Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was the optimal one? Dr Greg Hundley: So the negative predictive value for the primary outcome was 99.8% and 99.9% in those with cardiac troponin I concentrations of less than five or less than two nanograms per leader respectively. At both thresholds, the negative predictive value was consistent in men and women across all age groups. Although the proportion of patients identified at low risk fell with increasing age. Compared to patients with cardiac troponin I concentrations of greater than five nanograms per liter but less than the 99th percentile, the risk of MI or cardiac death at 12 months was 77% lower in those with less than five nanograms per liter and 80% lower in those with less than two nanograms per liter. So in conclusion, use of risk stratification thresholds for high sensitivity cardiac troponin I identified patients with suspected acute coronary syndrome in at least two hours of symptoms at low risk presentation irrespective of both age and sex. Dr Carolyn Lam: Very nice. Well, more risk stratification in this next paper, which really evaluated the application of the 2018 ACC AHA Cholesterol Management Guideline recommendations for additional lipid lowering therapies in patients with established atherosclerotic cardiovascular disease and residual dyslipidemia despite maximum tolerated Statin who were enrolled in the ODYSSEY OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol Management Guidelines recommend additional lipid lowering therapies for secondary prevention in patients with LDL above 70 or non-HDL above a hundred despite maximum tolerated Statin therapy. Such patients are considered at very high risk based on a history of more than one major atherosclerotic cardiovascular disease event or a single event and multiple high-risk conditions. So in this paper from Dr Matt Roe from Duke Clinical Research Institute and colleagues, they found that in the ODYSSEY OUTCOMES trial, patients classified as very high risk by these 2018 ACC AHA guidelines and either because of a history of multiple atherosclerotic cardiovascular events or a single event, which is a trial qualifying acute coronary syndrome and multiple high risk conditions, these very high risk patients had more than double the risk of recurrent cardiovascular events as compared to patients classified as not very high risk.  They further looked at the association of Alirocumab with outcomes and found that Alirocumab was associated with a consistent relative risk reduction in both risk categories. But the absolute risk reduction for major adverse cardiovascular events was numerically greater, although not statistically different, in the very high-risk group versus those not at very high risk and among patients at very high risks with multiple prior events versus a single prior event. Dr Greg Hundley: Wow, Carolyn. Can you put all this together? This is a lot of information in this study. Dr Carolyn Lam: Yes, so it would appear that the application of the new ACC AHA 2018 guideline recommendations for risk stratification and the use of additional lipid lowering therapies in patients with established cardiovascular disease clearly identifies patients at very high risk of recurrent cardiovascular events after an acute coronary syndrome and these patients may derive substantial benefit from additional lipid lowering therapy, for example, with a PCSK nine inhibitor. Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off with what other articles we have in this ESC featured issue of our journal. So Jonathan Stamler and John Lundberg in separate letters discuss findings related to whether hemoglobin beta 93 cystine is not required for export of nitric oxide bio activity from the red blood cell. And in additional separate letters, Doug Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and attenuation of pathological and metabolic cardiac remodeling through selective lipid trafficking. In a perspective piece, Blake Thomson from the University of Oxford discusses what Medicare for all in the United States can mean for US medical research and provides lessons from the United Kingdom. In a letter from the United States, Gregory Marcus from University of California San Francisco discusses incident atrial fibrillation among American Indians in California and then both Marco Bergonti from University of Milan and Derek Chew from University of Calgary present two separate cases in our ECG challenge feature. Well, Carolyn, what a great issue and how about we turn to our feature discussion? Dr Carolyn Lam: Yes, let's go. Thanks, Greg. Dr Greg Hundley: Welcome, everyone, to our feature discussion today we have Gianluigi Savarese from Karolinska Institute in Stockholm, Sweden and our own associate editor, Sana Al-Khatib from Duke University. We're going to be discussing implantable cardioverter defibrillators in their mortality and looking at a more recent take on this relative to some of the previous published studies. So Gianluigi, I'd like to start with you. Could you tell us a little bit about the hypothesis and why you wanted to perform your study? Dr Gianluigi Savarese: Yes. Basically we design our study based on three main considerations. First one is recent studies show that the advance in heart-failure therapies have impact patients' risk profile leading to roughly 40% reduction risk of sudden cardiac death in HFrEF and RCTs on ICD use for primary prevention of sudden cardiac death and rural patients more than 20 years ago and thus, nowadays the beneficial prognostic effects of ICD may be different due to the improved risk profile in this population. The second consideration was that efficacy of ICD patients with heart failure with non-ischemic cardiomyopathy patients receiving a contemporary heart failure therapy as being a question in Danish trial and the third consideration is that efficacy of ICD in elderly is still debated due to findings again from the Danish trial showing a significant reduction in all-cause death associated with ICD use in patients age younger versus older than 70 years old. Based on these considerations, we decided to assess the use of ICD for primary prevention propose in a contemporary and selected FRF population and to assess the association between ICD use and outcomes in such a population. Dr Greg Hundley: So it sounds like we're doing an update on the utility of ICDs. Can you tell us a little more about your study population and your study design and then let's hear a little bit about your results. Dr Gianluigi Savarese: Sure. First of all, I would like to first highlight of course the observational natural of this study. Our analysis is performed using data from the Swedish Heart Failure Registry, which is a large enough select court of heart failure patients, enrolling patients regardless of ejection fraction. So today we have roughly around 70,000 patients. And of course for the current analysis we select the patients with HFrEF. There were around 15,000 patients with the HFrEF who were eligible for ICD use for primary prevention according to the ESC guidelines. A study design, we used propensity score matching design in order to try to address the issue of potential compounders. Of course this is a very important point in observational studies. So basically, we amassed patients receiving the ICD versus those not receiving ICDs. And we assessed the association between ICD use and all-cause death and cardiovascular death and we accessed one year and five-year outcome. Dr Greg Hundley: And so what were some of those results? Dr Gianluigi Savarese: What we observed is that there was a statistically significant 25 relative risk reduction in all-cause mortality in ICD recipients versus those who didn't receive an ICD within one year and there was also a 12% reduction erased within five years. And we also serve a statistically significant 29% reduction in risk of cardiovascular mortality within one year. But we were not able to observe any association for cardiovascular mortality within five years. We thought it was particularly relevant to have subgroup analysis in our studies since there are so many questions regarding ICD use in specific subgroups, which are, for example, older versus younger patients, those with versus without ischemic heart disease, males versus the females and so on. So what we observed was that results in terms of all-cause mortality were consistent in all of the subgroups considered such as patients older versus younger than 70 years old, versus those without history of ischemic heart disease and those with versus without concurrent CRT use. Dr Greg Hundley: What about the frequency of implanting ICDs? Was the frequency expected in your results? Dr Gianluigi Savarese: We add that only 10% of our patients received an ICD at the baseline. This person's age is quite low in particular. If we compare these with other studies in US for example, or also in other European countries and basically, we can only speculate about the underuse of ICD in primary prevention propose. First of all, a certain proportion of ICD underuse may be explained by the fact that we could not assess whether life expectancy was longer than one year, and this is one of the eligibility criteria for ICD according to the guidelines. Then another point is that in Sweden, the majority of heart failure patients are seen by primary care physician and general practitioners who may have less knowledge and acceptance of device therapy and then higher perception of contraindication. In our previous analysis, we showed that patients not seen by cardiologists have lower likelihood of receiving an ICD and use of devices is higher in centers who do implants, CRT, ICD. So this may be some of the explanation that I can anticipate that some more analysis will follow where we will try to assess the predictors for an under use of ICD for primary prevention. Dr Greg Hundley: Well, thank you very much. Sana, now we're going to turn to you and help us put this study in perspective to what we have already found or observed in other prior studies related to implantation of cardio defibrillators. Dr Sana Al-Khatib: As was mentioned earlier, I was the handling associate editor for this paper, so I really enjoyed the handling it and writing an editorial on it. The main points that I wanted to touch on are number one, the significantly low or reduced utilization rate of ICDs. So as was mentioned, the 10% of this patient population received a primary prevention ICDs. Even if you account for some of the new ones is that you can't estimate life expectancy. You can't capture granular clinical data on these patients. So of course some of the non-use of ICDs may have been appropriate. I think 10% by anyone's definition is still pretty low and I'm very encouraged to hear that there are plans to look at predictors of non-use, the characteristics of those patients and hopefully the office can build on their findings and try to implement some strategies to improve the utilization of this life saving therapy. The other thing that I wanted to touch on is clearly the results are positive in favor of the implantable cardioverter defibrillator. Showing that it significantly reduces all-cause mortality within one year, within five years, certainly reduces cardiovascular mortality within one year. As was mentioned, the reduction in cardiovascular mortality within five years was not significant and to me that is probably mostly explained by competing causes of death in this patient population, but I also cannot rule out the possibility of some mis-classification of causes of death, which is not uncommon. I do want to commend the authors for the great and robust methods that they applied in their analysis. As was mentioned, this was a comparative effectiveness research using observational data. These kinds of analyses can be pretty challenging, but the authors defined their patient population very clearly. They used propensity score matching. In fact, they took it a step further by doing a negative control analysis, meaning looking at hospitalizations for renal failure, for pneumonia, respiratory infections, things like that that you don't expect to be affected by the ICD and they found no difference in that. And that is amazing to kind of see this level of analysis that I believe really lends their results more credibility. It is important though to keep in mind that when you have 10% of patients getting an ICD, I suspect that this was a highly selected patient population and most likely people who were thought to benefit the most from ICDs were implanted with an ICD. And yet, as I said, that given the robustness of the methods that they use, I actually believe the results. I think the results are credible. The one last point that I want to comment on is the subgroup analyses that were mentioned. Absolutely important subgroups to look at from a clinical perspective. But I point out the fact that when you start looking at subgroup analyses, and especially when you have a smaller sample sizes and lower event rates that it makes you start thinking about, "Well, are these results valid? Are they believable?" I mean, even honestly, in the setting of a randomized clinical trial, I look at subgroup analyses as hypothesis generating. So I liked that they included those just to kind of really emphasize the importance of looking at these subgroups. But I certainly would not put too much weight on the subgroup analysis results, but overall great results and congratulations to the authors. Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on behalf of Carolyn Lam and myself, we wish you a great week and we look forward to speaking with you next week. Dr Carolyn Lam: This program is copyright American Heart Association 2019.  

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valenti Fuster

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

Heute geht es innerhalb einer kleinen Serie zu Ernährung um das Thema Cholesterin. //   Cholesterin? //   Lipoproteine Low densitiy, niedrige Dichte Gut / schlecht Hohe dichte, korreliert nur Nüchtern Die neue Leitlinie fordert nicht nüchtern zu sein für Lipidprofil LDL-C ist ausreichend, sofern die Triglyceride nicht über 400 mg / dl liegen. //   Cholesterin-reduzierte Diät //   Ca. 30.000 Erwachsenen USA mittlere Nachbeobachtungszeit von 17,5 Jahren //    Höherer Konsum von Eiern und anderem Cholesterin (Fleisch) korreliert mit HKL-Erkrankung und Sterblichkeit, Dosis-Wirkungs-Beziehung.  //   Einschränkungen: //   Zusammenhang zwischen Eierkonsum/Cholesterin mit Plasmalipiden und Lipoproteinen nicht untersucht, nur vermutet LDL Es existieren aber Studien bei denen alle Bestandteile der Diät außer Cholesterin kontrolliert wurden, dort steigende LDL-C: Ginsberg et al. Arterioscler Thromb. 1994;14(4):576-586; Ginsberg et al. Arterioscler Thromb Vasc Biol. 1995;15(2):169-178. Aber nicht immer: Nicht immer: Blesso & Fernandez Nutrients. 2018; 10(4):E426. Beobachtungstudie, keine gezielte Intervention mit Kontrolle, nur Korrelation, keine Ursachen-Wirkungsbeziehung, Nur für sehr hoher Ei-Verzehr 2-4 Eier pro Tag deutlich (ähnlich Salz-Studien…) //   Demgegenüber //   Gewichtsverlust / Diät //   Ob Fett- oder Kohlehydrat-reduzierte Diät, egal, innerhalb 12 Monaten -> Nochmal separat Diäten... //   doi:10.1001/jama.2018.0245 //   Fett-Ersatz/Austauschstoffe //   ErsatzPhysikalischen Eigenschaften von Fett, chemisch keine Ähnlichkeit mit natürlichen Fetten. Zucker mit anderen Kohlenhydraten und Fettsäuren und Paraffinen (Erdöl / Braunkohle) Olestra seit den 1990er-Jahren zugelassen, nicht EU. kein Brennwert, unverdaulich, unverwertet wieder ausgeschieden: Kartoffelchips und andere Snacks. //   AustauschIn der EU zugelassen. Natürliche Ausgangsprodukte, Kohlenhydraten oder Eiweiß. Vor allem in Light-Produkten, um den Fettgehalt und Brennwert zu reduzieren. Nur begrenzt erhitzen, da Eiweiß nur bis etwa 65°C hitzestabil. In Süßspeisen, Eiscreme oder Mayonnaise. Carrageen, Inulin, Maltrin: Kohlenhydrat bzw. Stärke Simplesse: Eiweiß //   Beides pervers: Ungesunde Fehlernährung wird zum Schein korrigiert Hände weg / Löffel weg von solchen prozessierten Kunstprodukten //   Cholesterin-Senker Statin Ezetimib - HDL - Ionenaustauschharze - Antientzündlich Cantos HKL gesenkt DOI: 10.1056/NEJMoa1707914 => Statin-Therapie //   Durch die pharmakologische Senkung des LDL-C werden die ASCVD-Ereignisse (Myokardinfarkt, Schlaganfall und kardiovaskulärer Tod) reduziert. //   Das Prinzip, dass eine niedrigere LDL-C-Dosis besser ist, wurde durch neue Studien bestätigt Ezetimib oder Proprotein-Convertase-Subtilisin / Kexin Typ 9 (PCSK9)-Hemmer zu einer Statin-Therapie addiert wurden. //   Sekundärprävention= Wenn klinische Symptome,  //   LDL-C um mehr als 50% reduzieren, Statine hoher Intensität Atorvastatin ≥ 40 mg / d oder Rosuvastatin ≥ 20 mg / dl Bei sehr hohem Risiko (Abbildung) LDL-C auf weniger als 70 mg / dl Ezetimib und gegebenenfalls einen PCSK9-Inhibitor, Alirocumab und Evolocumab. //    Primärprävention = Noch keine Symptome, aber LDL-C ≥ 190 mg/dL geringere vaskuläre Ereignisse mit Statinen, nicht jedoch Ezetimib.40-75 JDiabetes + LDL-C von 70 mg / dl Statin-Therapie mit mittlerer Intensität.HKL-Risiko berechnet niedriges Risiko über einen Zeitraum von 10 Jahren weniger als 5% bezeichnet mittel 7,5% bis 19,9% Reduktion um mehr als 30% hoch 20% oder höher ie bei Patienten mit Symptomen: LDL-C-Reduktion von mehr als 50% einleiten;  //   doi:10.1001/jama.2019.0015 //   WissenslückenPersonen im Alter von 20 bis 40 Jahren ≥ 160 mg / dL + Familienanamnese + hohen HKL-Risiko; aber epidemiologische Studien Anza...

shared decision making for lung cancer rarely happens in the community and when it does happen 2/5 said no thanks to cancer screening https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2720126 vit d. - does not work on a bus it doesn't work with white women or black women anyone https://www.ncbi.nlm.nih.gov/pubmed/29905969 achilles tendon rupture- if you go to surgery NNT for rerupture of 1 and 66 but risk of infection 1/33 https://www.bmj.com/content/364/bmj.k5120 Topical pain creams dont work for chronic pain- BUT low risk of side effects and still getting almost 2 point decrease on 10 point scale-- I will take it! https://annals.org/aim/article-abstract/2724041/compounded-topical-pain-creams-treat-localized-chronic-pain-randomized-controlled Alirocumab is still way too expensive https://www.ncbi.nlm.nih.gov/pubmed/30597485 concussion in an athlete-- get them to the sub-symptom heart rate https://jamanetwork.com/journals/jamapediatrics/article-abstract/2723523

This week in clinical cardiology: Alirocumab reduces both type 1 and 2 MIs. Despite failed primary endpoint, MI alert device has predictive value. Look for alcohol septal ablation in the next HOCM guideline. FDA: Forty ARBs free of nitrosamines. You can contact the Cardiocast with ideas, suggestions, stories, or questions for Dr. Dwyer by emailing us at podcasts@mdedge.com and you can follow MDedge Cardiology on Twitter at @MDedgeCardio.

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Commentary by Dr. Valentin Fuster