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American healthcare is well known for its extreme cost and worst outcomes among industrialized (such as the 38 OECD member) countries, and beyond that to be remarkably opaque. The high cost of prescription drugs contributes, and little has been done to change that except for the government passing the Affordable Insulin Now Act at the end of 2022, enacted in 2023. But in January 2022 Mark Cuban launched Cost Plus Drugs that has transformed how many Americans can get their prescriptions filled at a fraction of the prevailing prices, bypassing pharmacy benefit managers (PBMs) that control 80% of US prescriptions. That was just the beginning of a path of creative destruction (disruptive innovation, after Schumpeter) of many key components American healthcare that Cuban is leading, with Cost Plus Marketplace, Cost Plus Wellness and much more to come. He certainly qualifies as a master disrupter: “someone who is a leader in innovation and is not afraid to challenge the status quo.” Below is a video clip from our conversation dealing with insurance companies. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! The audios are also available on Apple and Spotify.Transcript with External links to Audio (00:07):Hello, it's Eric Topol with Ground Truths, and I have our special phenomenal guest today, Mark Cuban, who I think you know him from his tech world contributions and Dallas Mavericks, and the last few years he's been shaking up healthcare with Cost Plus Drugs. So Mark, welcome.Mark Cuban (00:25):Thanks for having me, Eric.Eric Topol (00:27):Yeah, I mean, what you're doing, you've become a hero to millions of Americans getting them their medications at a fraction of the cost they're used to. And you are really challenging the PBM industry, which I've delved into more than ever, just in prep for our conversation. It's just amazing what this group of companies, namely the three big three CVS Caremark, Optum of UnitedHealth and Express Scripts of Cigna with a market of almost $600 billion this year, what they're doing, how can they get away with all this stuff?Inner Workings of Pharmacy Benefit ManagersMark Cuban (01:03):I mean, they're just doing business. I really don't blame them. I blame the people who contract with them. All the companies, particularly the bigger companies, the self-insured companies, where the CEO really doesn't have an understanding of their healthcare or pharmacy benefits. And so, the big PBMs paid them rebates, which they think is great if you're a CEO, when in reality it's really just a loan against the money spent by your sickest employees, and they just don't understand that. So a big part of my time these days is going to CEOs and sitting with them and explaining to them that you're getting ripped off on both your pharmacy and your healthcare side.Eric Topol (01:47):Yeah, it's amazing to me the many ways that they get away with this. I mean, they make companies sign NDAs. They're addicted to rebates. They have all sorts of ways a channel of funds to themselves. I mean, all the things you could think of whereby they even have these GPOs. Each of these companies has a group purchasing organization (I summarized in the Table below).Mark Cuban (02:12):Yeah, which gives them, it's crazy because with those GPOs. The GPO does the deal with the pharmacy manufacturer. Then the GPO also does the deal with the PBM, and then the PBM goes to the self-insured employer in particular and says, hey, we're going to pass through all the rebates. But what they don't say is they've already skimmed off 5%, 10%, 20% or more off the top through their GPO. But that's not even the worst of it. That's just money, right? I mean, that's important, but I mean, even the biggest companies rarely own their own claims data.Mark Cuban (02:45):Now think about what that means. It means you can't get smarter about the wellness of your employees and their families. You want to figure out the best way to do GLP-1s and figure out how to reduce diabetes, whatever it may be. You don't have that claims data. And then they don't allow the companies to control their own formularies. So we've seen Humira biosimilars come out and the big PBMs have done their own version of the biosimilar where we have a product called Yusimry, which is only $594 a month, which is cheaper than the cheapest biosimilar that the big three are selling. And so, you would think in a normal relationship, they would want to bring on this new product to help the employer. No, they won't do it. If the employer asks, can I just add Cost Plus Drugs to my network? They'll say no, every single time.Mark Cuban (03:45):Their job is not to save the employer money, particularly after they've given a rebate. Because once they give that loan, that rebate to the employer, they need to get that money back. It's not a gift. It's a loan and they need to have the rebates, and we don't do rebates with them at all. And I can go down the list. They don't control the formula. They don't control, you mentioned the NDAs. They can't talk to manufacturers, so they can't go to Novo or to Lilly and say, let's put together a GLP-1 wellness program. All these different things that just are common sense. It's not happening. And so, the good news is when I walk into these companies that self-insured and talk to the CEO or CFO, I'm not asking them to do something that's not in their best interest or not in the best interest of the lives they cover. I'm saying, we can save you money and you can improve the wellness of your employees and their families. Where's the downside?Eric Topol (04:40):Oh, yeah. Yeah. And the reason they can't see the claims is because of the privacy issues?Mark Cuban (04:46):No, no. That's just a business decision in the contract that the PBMs have made. You can go and ask. I mean, you have every right to your own claims. You don't need to have it personally identified. You want to find out how many people have GLP-1s or what are the trends, or God forbid there's another Purdue Pharma thing going on, and someone prescribing lots of opioids. You want to be able to see those things, but they won't do it. And that's only on the sponsor side. It's almost as bad if not worse on the manufacturer side.Eric Topol (05:20):Oh, yeah. Well, some of the work of PBMs that you've been talking about were well chronicled in the New York Times, a couple of major articles by Reed Abelson and Rebecca Robbins: The Opaque Industry Secretly Inflating Prices for Prescription Drugs and The Powerful Companies Driving Local Drugstores Out of Business. We'll link those because I think some people are not aware of all the things that are going on in the background.Mark Cuban (05:39):You see in their study and what they reported on the big PBMs, it's crazy the way it works. And literally if there was transparency, like Cost Plus offers, the cost of medications across the country could come down 20%, 30% or more.Cost Plus DrugsEric Topol (05:55):Oh, I mean, it is amazing, really. And now let's get into Cost Plus. I know that a radiologist, Alex Oshmyansky contacted you with a cold email a little over three years ago, and you formed Cost Plus Drugs on the basis of that, right?Mark Cuban (06:12):Yep, that's exactly what happened.Eric Topol (06:15):I give you credit for responding to cold emails and coming up with a brilliant idea with this and getting behind it and putting your name behind it. And what you've done, so you started out with something like 110 generics and now you're up well over 1,200 or 2,500 or something like that?Mark Cuban (06:30):And adding brands. And so, started with 111. Now we're around 2,500 and trying to grow it every single day. And not only that, just to give people an overview. When you go to www.costplusdrugs.com and you put in the name of your medication, let's just say it's tadalafil, and if it comes up. In this case, it will. It'll show you our actual cost, and then we just mark it up 15%. It's the same markup for everybody, and if you want it, we'll have a pharmacist check it. And so, that's a $5 fee. And then if you want ship to mail order, it's $5 for shipping. And if you want to use our pharmacy network, then we can connect you there and you can just pick it up at a local pharmacy.Eric Topol (07:10):Yeah, no, it's transparency. We don't have a lot of that in healthcare in America, right?Mark Cuban (07:15):No. And literally, Eric, the smartest thing that we did, and we didn't expect this, it's always the law of unintended consequences. The smartest thing we did was publish our entire price list because that allowed any company, any sponsor, CMS, researchers to compare our prices to what others were already paying. And we've seen studies come out saying, for this X number of urology drugs, CMS would save $3.6 billion a year. For this number of heart drugs at this amount per year, for chemotherapy drugs or MS drugs this amount. And so, it's really brought attention to the fact that for what PBMs call specialty drugs, whether there's nothing special about them, we can save people a lot of money.Eric Topol (08:01):It's phenomenal. As a cardiologist, I looked up a couple of the drugs that I'm most frequently prescribed, just like Rosuvastatin what went down from $134 to $5.67 cents or Valsartan it went down from $69 to $7.40 cents. But of course, there's some that are much more dramatic, like as you mentioned, whether it's drugs for multiple sclerosis, the prostate cancer. I mean, some of these are just thousands and thousands of dollars per month that are saved, brought down to levels that you wouldn't think would even be conceivable. And this has been zero marketing, right?Mark Cuban (08:42):Yeah, none. It's all been word of mouth and my big mouth, of course. Going out there and doing interviews like this and going to major media, but it's amazing. We get emails and letters and people coming up to us almost single day saying, you saved my grandma's life. You saved my life. We weren't going to be able to afford our imatinib or our MS medication. And it went from being quoted $2,000 a month to $33 a month. It's just insane things like that that are still happening.Eric Topol (09:11):Well, this is certainly one of the biggest shakeups to occur in US healthcare in years. And what you've done in three years is just extraordinary. This healthcare in this country is with its over 4 trillion, pushing $5 trillion a year of expenditure.[New CMS report this week pegs the number at $4.867 trillion for 2023]Mark Cuban (09:30):It's interesting. I think it's really fixable. This has been the easiest industry to the disrupt I've ever been involved in. And it's not even close because all it took was transparency and not jacking up margins to market. We choose to use a fixed margin markup. Some choose to price to market, the Martin Shkreli approach, if you will. And just by being transparent, we've had an impact. And the other side of it is, it's the same concept on the healthcare side. Transparency helps, but to go a little field of pharmacy if you want. The insane part, and this applies to care and pharmacy, whatever plan we have, whether it's for health or whether it's for pharmaceuticals, there's typically a deductible, typically a copay, and typically a co-insurance.Insurance CompaniesMark Cuban (10:20):The crazy part of all that is that people taking the default risk, the credit risk are the providers. It's you, it's the hospital, it's the clinics that you work for. Which makes no sense whatsoever that the decisions that you or I make for our personal insurance or for the companies we run, or if we work for the government, what we do with Medicare or Medicare Advantage, the decisions we all make impacts the viability of providers starting with the biggest hospital systems. And so, as a result, they become subprime lenders without a car or a house to go after if they can't collect. And so, now you see a bunch of people, particularly those under the ACA with the $9,000, the bronze plans or $18,000 out-of-pocket limits go into debt, significant medical debt. And it's unfortunate. We look at the people who are facing these problems and think, well, it must be the insurance companies.Mark Cuban (11:23):It's actually not even the insurance companies. It's the overall design of the system. But underneath that, it's still whoever picks the insurance companies and sets plans that allow those deductibles, that's the core of the problem. And until we get to a system where the providers aren't responsible for the credit for defaults and dealing with all that credit risk, it's almost going to be impossible to change. Because when you see stories like we've all seen in news of a big healthcare, a BUCA healthcare (Blue Cross Blue Shield (BCBS), UnitedHealth, Cigna, and Aetna/CVS) plan with all the pre-authorizations and denials, typically they're not even taking the insurance risk. They're acting as the TPA (third party administrator) as the claims processor effectively for whoever hired them. And it goes back again, just like I talked about before. And as long as CMS hires or allows or accepts these BUCAs with these plans for Medicare for the ACA (Affordable care Act), whatever it may be, it's not going to work. As long as self-insured employers and the 50 million lives they cover hire these BUCAs to act as the TPAs, not as insurance companies and give them leeway on what to approve and what to authorize and what not to authorize. The system's going to be a mess, and that's where we are today.Academic Health System PartnershipsEric Topol (12:41):Yeah. Well, you've been talking of course to employers and enlightening them, and you're also enlightening the public, of course. That's why you have millions of people that are saving their cost of medications, but recently you struck a partnership with Penn Medicine. That's amazing. So is that your first academic health system that you approached?Cost Plus MarketplaceMark Cuban (13:00):I don't know if it was the first we approached, but it was certainly one of the biggest that we signed. We've got Cost Plus Marketplace (CPM) where we make everything from injectables to you name it, anything a hospital might buy. But again, at a finite markup, we make eight and a half percent I think when it's all said and done. And that saves hospital systems millions of dollars a year.Eric Topol (13:24):Yeah. So that's a big change in the way you're proceeding because what it was just pills that you were buying from the pharma companies, now you're actually going to make injectables and you're going to have a manufacturing capability. Is that already up and going?Mark Cuban (13:39):That's all up and going as of March. We're taking sterile injectables that are on the shortage list, generic and manufacturing them in Dallas using a whole robotics manufacturing plant that really Alex created. He's the rocket scientist behind it. And we're limited in capacity now, we're limited about 2 million vials, but we'll sell those to Cost Plus Marketplace, and we'll also sell those direct. So Cost Plus Marketplace isn't just the things we manufacture. It's a wide variety of products that hospitals buy that we then have a minimal markup, and then for the stuff we manufacture, we'll sell those to direct to like CHS was our first customer.Eric Topol (14:20):Yeah, that's a big expansion from going from the pills to this. Wow.Mark Cuban (14:24):It's a big, big expansion, but it goes to the heart of being transparent and not being greedy, selling on a markup. And ourselves as a company, being able to remain lean and mean. The only way we can sell at such a low markup. We have 20 employees on the Cost Plus side and 40 employees involved with the factories, and that's it.Eric Topol (14:46):Wow. So with respect to, you had this phenomenal article and interview with WIRED Magazine just this past week. I know Lauren Goode interviewed you, and she said, Mark, is this really altruistic and I love your response. You said, “how much f*****g money do I need? I'm not trying to land on Mars.” And then you said, “at this point in my life, it's just like more money, or f**k up the healthcare industry.” This was the greatest, Mark. I mean, I got to tell you, it was really something.Mark Cuban (15:18):Yeah.Eric Topol (15:19):Well, in speaking of that, of course, the allusion to a person we know well, Elon. He posted on X/Twitter in recent days , I think just three or four days ago, shouldn't the American people be getting their money's worth? About this high healthcare administration costs where the US is completely away from any other OECD country. And as you and I know, we have the worst outcomes and the most costs of all the rich countries in the world. There's just nothing new here. Maybe it's new to him, but you had a fabulous response on both X and Bluesky where you went over all these things point by point. And of course, the whole efforts that you've been working on now for three years. You also mentioned something that was really interesting that I didn't know about were these ERISA lawsuits[Employee Retirement Income Security Act (ERISA) of 1974.] Can you tell us about that?ERISA LawsuitsMark Cuban (16:13):Yeah, that's a great question, Eric. So for self-insured companies in particular, we have a fiduciary responsibility on a wellness and on a financial basis to offer the members, your employees and their families the best outcomes at the best price. Now, you can't guarantee best outcomes, but you have to be able to explain the choices you made. You don't have to pick the cheapest, but again, you have to be able to explain why you made the choices that you did. And because a lot of companies have been doing, just like we discussed earlier, doing deals on the pharmacy side with just these big PBMs, without accounting for best practices, best price, best outcomes, a couple companies got sued. Johnson and Johnson and Wells Fargo were the first to get sued. And I think that's just the beginning. That's just the writing on the wall. I think they'll lose because they just dealt with the big pharmacy PBMs. And I think that's one of the reasons why we're so busy at Cost Plus and why I'm so busy because we're having conversation after conversation with companies and plenty of enough lawyers for that matter who want to see a price list and be able to compare what they're paying to what we sell for to see if they're truly living up to that responsibility.Eric Topol (17:28):Yeah, no, that's a really important thing that's going on right now that I think a lot of people don't know about. Now, the government of the US think because it's the only government of any rich country in the world, if not any country that doesn't negotiate prices, i.e., CMS or whatever. And only with the recent work of insulin, which is a single one drug, was there reduction of price. And of course, it's years before we'll see other drugs. How could this country not negotiate drugs all these years where every other place in the world they do negotiate with pharma?Mark Cuban (18:05):Because as we alluded to earlier, the first line in every single pharmaceutical and healthcare contract says, you can't talk about this contract. It's like fight club. The number one rule of fight club is you can't talk about fight club, and it's really difficult to negotiate prices when it's opaque and everything's obfuscated where you can't really get into the details. So it's not that we're not capable of it, but it's just when there's no data there, it's really difficult because look, up until we started publishing our prices, how would anybody know?Mark Cuban (18:39):I mean, how was anybody going to compare numbers? And so, when the government or whoever started to negotiate, they tried to protect themselves and they tried to get data, but those big PBMs certainly have not been forthcoming. We've come along and publish our price list and all that starts to change. Now in terms of the bigger picture, there is a solution there, as I said earlier, but it really comes down to talking to the people who make the decisions to hire the big insurance companies and the big PBMs and telling them, no, you're not acting in your own best interest. Here's anybody watching out there. Ask your PBM if they can audit. If you can audit rather your PBM contract. What they'll tell you is, yeah, you can, but you have to use our people. It's insane. And that's from top to bottom. And so, I'm a big believer that if we can get starting with self-insured employers to act in their own best interest, and instead of working with a big PBM work with a pass-through PBM. A pass-through PBM will allow you to keep your own claims, own all your own data, allow you to control your own formulary.Mark Cuban (19:54):You make changes where necessary, no NDA, so you can't talk to manufacturers. All these different abilities that just seem to make perfect sense are available to all self-insured employers. And if the government, same thing. If the government requires pass-through PBMs, the price of medications will drop like a rock.Eric Topol (20:16):Is that possible? You think that could happen?Mark Cuban (20:19):Yes. Somebody's got to understand it and do it. I'm out there screaming, but we will see what happens with the new administration. There's nothing hard about it. And it's the same thing with Medicare and Medicare Advantage healthcare plans. There's nothing that says you have to use the biggest companies. Now, the insurance companies have to apply and get approved, but again, there's a path there to work with companies that can reduce costs and improve outcomes. The biggest challenge in my mind, and I'm still trying to work through this to fully understand it. I think where we really get turned upside down as a country is we try to avoid fraud from the provider perspective and the patient perspective. We're terrified that patients are going to use too much healthcare, and like everybody's got Munchausen disease.Mark Cuban (21:11):And we're terrified that the providers are going to charge too much or turn into Purdue Pharma and over-prescribe or one of these surgery mills that just is having somebody get surgery just so they can make money. So in an effort to avoid those things, we ask the insurance companies and the PBMs to do pre-authorizations, and that's the catch 22. How do we find a better way to deal with fraud at the patient and provider level? Because once we can do that, and maybe it's AI, maybe it's accepting fraud, maybe it's imposing criminal penalties if somebody does those things. But once we can overcome that, then it becomes very transactional. Because the reality is most insurance companies aren't insurance companies. 50 million lives are covered by self-insured employers that use the BUCAs, the big insurance companies, but not as insurance companies.Eric Topol (22:07):Yeah, I was going to ask you about that because if you look at these three big PBMs that control about 80% of the market, not the pass-throughs that you just mentioned, but the big ones, they each are owned by an insurance company. And so, when the employer says, okay, we're going to cover your healthcare stuff here, we're going to cover your prescriptions there.Mark Cuban (22:28):Yeah, it's all vertically integrated.Mark Cuban (22:36):And it gets even worse than that, Eric. So they also own specialty pharmacies, “specialty pharmacies” that will require you to buy from. And as I alluded to earlier, a lot of these medications like Imatinib, they'll list as being a specialty medication, but it's a pill. There's nothing special about it, but it allows them to charge a premium. And that's a big part of how the PBMs make a lot of their money, the GPO stuff we talked about, but also forcing an employer to go through the specialty mail order company that charges an arm and the leg.Impact on Hospitals and ProceduresEric Topol (23:09):Yeah. Well, and the point you made about transparency, we've seen this of course across US healthcare. So for example, as you know, if you were to look at what does it cost to have an operation like let's say a knee replacement at various hospitals, you can find that it could range fivefold. Of course, you actually get the cost, and it could be the hospital cost, and then there's the professional cost. And the same thing occurs for if you're having a scan, if you're having an MRI here or there. So these are also this lack of transparency and it's hard to get to the numbers, of course. There seems to be so many other parallels to the PBM story. Would you go to these other areas you think in the future?Mark Cuban (23:53):Yeah, we're doing it now. I'm doing it. So we have this thing called project dog food, and what it is, it's for my companies and what we've done is say, look, let's understand how the money works in healthcare.Mark Cuban (24:05):And when you think about it, when you go to get that knee done, what happens? Well, they go to your insurance company to get a pre-authorization. Your doctor says you need a knee replacement. I got both my hips replaced. Let's use that. Doctor says, Mark, you need your hips replaced. Great, right? Let's set up an appointment. Well, first the insurance company has to authorize it, okay, they do or they don't, but the doctor eats their time up trying to deal with the pre-authorization. And if it's denied, the doctor's time is eaten up and an assistance's time is eaten up. Some other administrator's time is eaten up, the employer's time is eaten up. So that's one significant cost. And then from there, there's a deductible. Now I can afford my deductible, but if there is an individual getting that hip replacement who can't afford the deductible, now all of a sudden you're still going to be required to do that hip replacement, most likely.Mark Cuban (25:00):Because in most of these contracts that self-insured employers sign, Medicare Advantage has, Medicare has, it says that between the insurance company and the provider, in this case, the hospital, you have to do the operation even if the deductibles not paid. So now the point of all this is you have the hospital in this case potentially accumulating who knows how much bad debt. And it's not just the lost amount of millions and millions and billions across the entire healthcare spectrum that's there. It's all the incremental administrative costs. The lawyers, the benefits for those people, the real estate, the desk, the office space, all that stuff adds up to $10 billion plus just because the hospitals take on that credit default risk. But wait, there's more. So now the surgery happens, you send the bill to the insurance company. The insurance company says, well, we're not going to pay you. Well, we have a contract. This is what it says, hip replacement's $34,000. Well, we don't care first, we're going to wait. So we get the time value of money, and then we're going to short pay you.Mark Cuban (26:11):So the hospital gets short paid. So what do they have to do? They have to sue them or send letters or whatever it is to try to get their money. When we talk to the big hospital systems, they say that's 2%. That's 2% of their revenue. So you have all these associated credit loss dollars, you've got the 2% of, in a lot of cases, billions and billions of dollars. And so, when you add all those things up, what happens? Well, what happens is because the providers are losing all that money and having to spend all those incremental dollars for the administration of all that, they have to jack up prices.Eric Topol (26:51):Yeah. Right.Mark Cuban (26:53):So what we have done, we've said, look for my companies, we're going to pay you cash. We're going to pay you cash day one. When Mark gets that hip replacement, that checks in the bank before the operation starts, if that's the way you want it. Great, they're not going to have pre-authorizations. We're going to trust you until you give us a reason not to trust you. We're not short paying, obviously, because we're paying cash right there then.Mark Cuban (27:19):But in a response for all that, because we're cutting out all those ancillary costs and credit risk, I want Medicare pricing. Now the initial response is, well, Medicare prices, that's awful. We can't do it. Well, when you really think about the cost and operating costs of a hospital, it's not the doctors, it's not the facilities, it's all the administration that cost all the money. It's all the credit risks that cost all the money. And so, if you remove that credit risk and all the administration, all those people, all that real estate, all those benefits and overhead associated with them, now all of a sudden selling at a Medicare price for that hip replacement is really profitable.Eric Topol (28:03):Now, is that a new entity Cost Plus healthcare?Mark Cuban (28:07):Well, it's called Cost Plus Wellness. It's not an entity. What we're going to do, so the part I didn't mention is all the direct contracts that we do that have all these pieces, as part of them that I just mentioned, we're going to publish them.Eric Topol (28:22):Ah, okay.Mark Cuban (28:23):And you can see exactly what we've done. And if you think about the real role of the big insurances companies for hospitals, it's a sales funnel.Getting Rid of Insurance CompaniesEric Topol (28:33):Yeah, yeah. Well, in fact, I really was intrigued because you did a podcast interview with Andrew Beam and the New England Journal of Medicine AI, and in that they talked about getting rid of the insurers, the insurance industry, just getting rid of it and just make it a means test for people. So it's not universal healthcare, it's a different model that you described. Can you go over that? I thought it was fantastic.Mark Cuban (29:00):Two pieces there. Let's talk about universal healthcare first. So for my companies, for our project dog food for the Mark Cuban companies, if for any employee or any of the lives we cover, if they work within network, anybody we have the direct contract with its single-payer. They pay their premiums, but they pay nothing else out of pocket. That's the definition of single-payer.Eric Topol (29:24):Yeah.Mark Cuban (29:25):So if we can get all this done, then the initial single-payers will be self-insured employers because it'll be more cost effective to them to do this approach. We hope, we still have to play it all through. So that's part one. In terms of everybody else, then you can say, why do we need insurance companies if they're not even truly acting as insurance companies? You're not taking full risk because even if it's Medicare Advantage, they're getting a capitated amount per month. And then that's getting risk adjusted because of the population you have, and then there's also an index depending on the location, so there's more or less money that occurs then. So let's just do what we need to do in this particular case, because the government is effectively eliminating the risk for the insurance company for the most part. And if you look at the margins for Medicare Advantage, I was just reading yesterday, it's like $1,700 a year for the average Medicare Advantage plan. So it's not like they're taking a lot of risk. All they're doing is trying to deny as many claims as they can.Eric Topol (30:35):Deny, Deny. Yeah.Mark Cuban (30:37):So instead, let's just get somebody who's a TPA, somebody who does the transaction, the claims processing, and whoever's in charge. It could be CMS, can set the terms for what's accepted and what's denied, and you can have a procedure for people that get denied that want to challenge it. And that's great, there's one in place now, but you make it a little simpler. But you take out the economics for the insurance company to just deny, deny, deny. There's no capitation. There's no nothing.Mark Cuban (31:10):The government just says, okay, we're hiring this TPA to handle the claims processing. It is your job. We're paying you per transaction.Mark Cuban (31:18):You don't get paid more if you deny. You don't get paid less if you deny. There's no bonuses if you keep it under a certain amount, there's no penalties If you go above a certain amount. We want you just to make sure that the patient involved is getting the best care, end of story. And if there's fraud involved as the government, because we have access to all that claims data, we're going to introduce AI that reviews that continuously.Mark Cuban (31:44):So that we can see things that are outliers or things that we question, and there's going to mean mistakes, but the bet was, if you will, where we save more and get better outcomes that way versus the current system and I think we will. Now, what ends up happening on top of that, once you have all that claims data and all that information and everybody's interest is aligned, best care at the best price, no denials unless it's necessary, reduce and eliminate fraud. Once everybody's in alignment, then as long as that's transparent. If the city of Dallas decides for all the lives they cover the 300,000 lives they cover between pharmacy and healthcare, we can usually in actuarial tables and some statistical analysis, we can say, you know what, even with a 15% tolerance, it's cheaper for us just to pay upfront and do this single-pay program, all our employees in the lives we cover, because we know what it's going to take.Mark Cuban (32:45):If the government decides, well, instead of Medicare Advantage the way it was, we know all the costs. Now we can say for all Medicare patients, we'll do Medicare for all, simply because we have definitive and deterministic pricing. Great. Now, there's still going to be outlier issues like all the therapies that cost a million dollars or whatever. But my attitude there is if CMS goes to Lilly, Novo, whoever for their cure for blindness that's $3.4 million. Well, that's great, but what we'll say is, okay, give us access to your books. We want to know what your breakeven point is. What is that breakeven point annually? We'll write you a check for that.Eric Topol (33:26):Yeah.Mark Cuban (33:27):If we have fewer patients than need that, okay, you win. If we have more patients than need that, it's like a Netflix subscription with unlimited subscribers, then we will have whatever it is, because then the manufacturer doesn't lose money, so they can't complain about R&D and not being able to make money. And that's for the CMS covered population. You can do a Netflix type subscription for self-insured employers. Hey, it's 25 cents per month per employee or per life covered for the life of the patent, and we'll commit to that. And so, now all of a sudden you get to a point where healthcare starts becoming not only transparent but deterministic.Eric Topol (34:08):Yeah. What you outline here in these themes are extraordinary. And one of the other issues that you are really advocating is patient empowerment, but one of the problems we have in the US is that people don't own their data. They don't even have all their data. I expect you'd be a champion of that as well.Mark Cuban (34:27):Well, of course. Yeah. I mean, look, I've got into arguments with doctors and public health officials about things like getting your own blood tested. I've been an advocate of getting my own blood tested for 15 years, and it helped me find out that I needed thyroid medication and all of these things. So I'm a big advocate. There's some people that think that too much data gives you a lot of false positives, and people get excited in this day and age to get more care when it should only be done if there are symptoms. I'm not a believer in that at all. I think now, particularly as AI becomes more applicable and available, you'll be able to be smarter about the data you capture. And that was always my final argument. Either you trust doctors, or you don't. Because even if there's an aberrational TSH reading and minus 4.4 and it's a little bit high, well the doctor's going to say, well, let's do another blood test in a month or two. The doctor is still the one that has to write the prescription. There's no downside to trusting your doctor in my mind.Eric Topol (35:32):And what you're bringing up is that we're already seeing how AI can pick up things even in the normal range, the trends long before a clinician physician would pick it up. Now, last thing I want to say is you are re-imagining healthcare like no one. I mean, there's what you're doing here. It started with some pills and it's going in a lot of different directions. You are rocking it here. I didn't even know some of the latest things that you're up to. This seems to be the biggest thing you've ever done.Mark Cuban (36:00):I hope so.Mark Cuban (36:01):I mean, like we said earlier, what could be better than people saying our healthcare system is good. What changed? That Cuban guy.Eric Topol (36:10):Well, did you give up Shark Tank so you could put more energy into this?Mark Cuban (36:16):Not really. It was more for my kids.Eric Topol (36:19):Okay, okay.Mark Cuban (36:20):They go hand in hand, obviously. I can do this stuff at home as opposed to sitting on a set wondering if I should invest in Dude Wipes again.Eric Topol (36:28):Well, look, we're cheering for you. This is, I've not seen a shakeup in my life in American healthcare like this. You are just rocking. It's fantastic.Mark Cuban (36:37):Everybody out there that's watching, check out www.costplusdrugs.com, check out Cost Plus Marketplace, which is business.costplusdrugs.com and just audit everything. What I'm trying to do is say, okay, if it's 1955 and we're starting healthcare all over again, how would we do it? And really just keep it simple. Look to where the risk is and remove the risk where possible. And then it comes down to who do you trust and make sure you trust but verify. Making sure there aren't doctors or systems that are outliers and making sure that there aren't companies that are outliers or patients rather that are outliers. And so, I think there's a path there. It's not nearly as difficult, it's just starting them with corporations, getting those CEOs to get educated and act in their own best interest.Eric Topol (37:32):Well, you're showing us the way. No question. So thanks so much for joining, and we'll be following this with really deep interest because you're moving at high velocity, and thank you.**************************************************Thank you for reading, listening and subscribing to Ground Truths.If you found this fun and informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to each of them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.FootnoteThe PBMS (finally) are under fire—2 articles from the past week Get full access to Ground Truths at erictopol.substack.com/subscribe

Bonnie Ky, MD, and Marcely Gimenes Bonatto, MD, discuss the study design, findings, future research questions and the potential clinical impact of the use of sacubitril/valsartan for the prevention of cardiotoxicity in high-risk patients undergoing anthracycline chemotherapy.

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.

Anju Bhardwaj, MD, social media editor of JACC: Heart Failure, discusses a recently published original research paper assessing the safety and efficacy of continuing sacubitril/valsartan in patients with deterioration of kidney function below an eGFR of 30 mL/min/1.73 m2.

JACC: CardioOncology Editor-in-chief, Bonnie Ky, MD, MSCE, FACC, Yen-Wen Liu, MD, PhD, Professor of Medicine, FESC and Yu-Ling Hsu, MD discuss the study design, findings and potential implications for clinical practice and future research questions for the prevention of cancer-therapy related cardiac dysfunction in breast cancer patients.

Commentary by Dr. Candice Silversides

Manufacturers of Suboxone and generic Valsartan face class action lawsuits because the drugs have been linked to tooth rot and cancer. But how do you know if you might have a claim against them?In this episode of David v. Goliath, hosts Matt Dolman and Stan Gipe are joined by renowned mass tort attorney Brett Vaughn to discuss the latest in litigation against the manufacturers of Suboxone and generic Valsartan. Brett discusses potential claimants, their injuries, and the next phases of litigation.Learn More and Connect☑️ Brett Vaughn | LinkedIn☑️ Nigh Goldenberg Raso & Vaughn on LinkedIn, Facebook, & Instagram☑️ Matt Dolman | LinkedIn☑️ Stan Gipe☑️ Dolman Law Group☑️ Dolman Law Group on LinkedIn, Facebook, Instagram, YouTube☑️ Subscribe: Apple Podcasts | Spotify | YouTubeThe insights and views presented in this podcast are for general information purposes only and should not be taken as legal advice for any individual case or situation. The information presented is not a substitute for consulting with an attorney. Nor does tuning in to this podcast constitute an attorney-client relationship of any kind. Any case result information provided on any portion of this podcast should not be understood as a promise of any particular result in a future case. Dolman Law Group Accident Injury Lawyers: Big firm results, small firm personal attention.

Commentary by Dr. Candice Silversides

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

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Social Media Editor Eiran Gorodeski

Commentary by Dr. Candice Silversides

Impact: Sacubitril/Valsartan and renal function in HF

Does Posttraumatic stress symptom severity predicts cognitive decline beyond the effect of Alzheimer's disease? Find out about this and more in today's PVRoundup podcast.

Commentary by Dr. Valentin Fuster

Last year, at the age of 41, I faced the heart-wrenching loss of three close friends within a mere five-month span. They were all between the ages of 41 and 44. The overwhelming grief I experienced plunged me into a profound depression for the first time in my life.Many of you are my friends, while others have yet to make my acquaintance. So it's probably a good idea if I start with a brief introduction. I'm a tech and marketing professional who helped build a web hosting company, LiquidWeb, alongside my friends Matt, Chris, Jer, and Gregg. Together, we grew the company to employ 480 employees on two continents and achieve $70 million in Annual Recurring Revenue (ARR). In 2015, we successfully sold the company to a private equity firm for a staggering $224 million.I've seldom mentioned this, as it may come across as boastful, but I became a multi-millionaire before reaching the age of 35. The wealth I amassed at such a young age exceeded my wildest expectations. This early financial success led me to believe that I had achieved life's ultimate goal, which I dubbed my "fake retirement." I didn't have a boss, so I indulged in late-night routines, sleeping until 2 pm and staying awake until 4 am. I often wore black t-shirts and sweatpants, projecting a slovenly image and demeanor. I ate whatever I pleased, avoided exercising, and generally shied away from physical activities. I even sported a shirt that mockingly read "SPORTS!" as an ironic statement.Before long, my unhealthy lifestyle began to take its toll. I gained over 60 pounds and developed a myriad of health issues, including high blood pressure, elevated triglycerides, high cholesterol, rosacea, and poor cardiac fitness. Simple tasks like climbing stairs left me sweating profusely, as I found myself in abysmal physical condition.My well-intentioned and caring doctors were quick to prescribe medications to address the various health issues resulting from my lifestyle. They prescribed fish oil for cholesterol management, Prednisone and Colchicine to combat gout, Valsartan to lower high blood pressure, and Fenofibrate to reduce elevated triglycerides.In no time, I found myself taking four pills daily. They appeared to be effective, at least initially, as my levels decreased. However, as I failed to make any lifestyle changes, my levels gradually began to rise again. Consequently, my dosages increased, putting me on an unsustainable and potentially harmful trajectory.Despite my poor health, life had its bright spots. I married an incredible woman who, I felt, was truly out of my league. Together, we had a son. I fulfilled my dreams of owning a lake house and a boat, and even drove a Tesla, allowing me to feel somewhat environmentally conscious amid my luxurious lifestyle. Additionally, I invested in companies that piqued my interest and became an active member of local boards that aligned with my passions.But suddenly, everything changed in February of 2022. My close friend Joe died of a heart attack due in part to alcohol abuse. Remarkably, throughout my 41 years of life, I had been fortunate enough to avoid experiencing the sudden loss of anyone close to me. Joe's passing deeply affected me, and I struggled to cope with the intense grief I encountered for the first time in my life.In July 2022, just a short while later, I faced the devastating loss of my best friend since age 2, Matt Hill, the founder of Liquidweb, who passed away at 41. Tragedy struck again merely 10 days later when my wife's cousin, a friend, and the officiant at our wedding, was fatally injured by a door in a bizarre accident. Despite my life appearing perfect by most standards, the overwhelming grief and confluence of these events plunged me into clinical depression. I would awaken feeling despondent and retire to bed with the same heavy sadness, struggling to find a sense of purpose.Rationally, I understood that my experiences paled in comparison to the hardships faced by others. This realization brought about feelings of guilt, making me question my right to feel depressed when I seemingly had it all. Yet, I found myself unable to break free from the grip of this profound sadness, even though logic told me it was unwarranted.My attempts to cope with the sadness proved unhelpful as well. Discussing my feelings with friends only seemed to dampen their spirits. Similarly, I unfairly burdened my wife with the expectation that she could miraculously heal my emotional pain. My frustration with her inability to do so put a strain on our marriage, and my demeanor became increasingly difficult to tolerate. I was truly insufferable to be around.I knew something had to change…“If every instinct you have is wrong, the opposite would have to be right.” Is a line Jerry Seinfeld says to George Costanza in the Seinfeld episode The Opposite.  I kept thinking of that quote. It was then that I revisited Admiral William H. McRaven's commencement speech, titled "Just Make Your Bed." In his address, he emphasizes the significance of waking up early and making your bed, as it provides an initial sense of accomplishment to start your day, setting off a chain reaction of positive transformations.“If you want to change the world, start by making your bed”. I decided this is where I would start!  Everyday I would wake up before 8am and make my bed.  This might seem like a small task, but for someone that was never a morning person, it was a challenge. This seemingly minor change of waking up early and making my bed had an unexpectedly profound impact on my life. It instilled in me a newfound confidence, nudged me towards an earlier bedtime, allowed me to enjoy breakfast with my 3-year-old, made me think twice about drinking alcohol the night before, and enhanced my productivity at work.It was a small change, but with a massive influence. Waking up early and making the bed was the antithesis of my behavior during depression. This got me thinking, what if I made more changes? Could they have an even greater impact? And so, I decided to embrace a "year of the opposite."My plan was simple: I would do the opposite of what I had done before. It didn't have to be radical, like speaking Spanish instead of English or biking instead of driving. It just had to challenge me and push me out of my comfort zone. For instance, since I never liked mustaches, I decided to grow one. And since I had never played golf, I decided to become a golfer. At the start of my Year of the Opposite, I didn't overwhelm myself with a long list of changes to make. Instead, I took it one challenge at a time. As I conquered each challenge, I gained more confidence and momentum.As my friends and family became aware of my Year of the Opposite, they started to offer their own suggestions for what I should tackle next. Before I knew it, the list of changes had grown longer and longer throughout the year.But because I was making the changes gradually and incrementally, the list didn't intimidate me. Instead, the longer the list grew the more confidence I gained to keep going, to keep pushing myself, and to keep discovering new things about myself along the way.In the following months, I made several significant changes: I quit drinking alcohol, stopped smoking weed, completed a half marathon, ran 7 miles barefooted, held my breath for 2 minutes and 45 seconds, ran a mile backward, briefly piloted an airplane, learned archery, swam about a mile across my lake, practiced shooting a pistol, won the Blazin Wing Challenge, and took a 9-minute cold plunge in a 35-degree lake, among other things.The transformation didn't occur instantaneously, but it certainly felt swift! Within two weeks, I experienced a daily surge of energy, as if I were on Adderall. Within a month, my depression had vanished. And within six months, all of my lifestyle-induced ailments were "cured." My high blood pressure, elevated triglycerides, rosacea, and high cholesterol were all resolved.In this newsletter, "The Year of the Opposite," I'll share the insights I gained and the outcomes I achieved. I'll discuss both the highs and the lows, as well as my blood work, test results, and the research and science behind what worked and what didn't.I want to be absolutely clear from the outset: none of my accomplishments over the past year were extraordinary or record-breaking. But that's precisely what makes them so remarkable! The changes I made are ones that anyone could implement if they desired to transform their life. If you're grappling with weight issues, sadness, anxiety, or depression, perhaps you could also adopt this approach and find it beneficial.Thank you so much for subscribing.  Next week I plan to share the results from my blood work, the changes in my cardiac fitness (VO2 Max), my weight change, and my blood pressure measurements.Uplift Weekly - Humans Are Awesome! Several years ago, I began sharing hard to find uplifting and positive stories on my Facebook page, summarizing them to the best of my ability. People seemed to really enjoy it. It's no secret that news outlets and social media often prioritize negative stories, as outrage tends to generate more clicks than happiness. Consequently, we find ourselves inundated with sensational, distressing stories from around the globe. This phenomenon not only contributes to societal polarization but also takes a toll on our mental well-being, as numerous studies have shown.With this newsletter, I hope to include a portion that I call "Uplift Weekly," I aim to counterbalance negativity by highlighting the remarkable achievements of humanity. I'll be focusing on technological advancements, scientific breakthroughs, and any news that instills a sense of hope and pride in our world and its people. Here's to hoping that the steady stream of human ingenuity provides ample content for our weekly dose of positivity! :)Without further ado, here is your Uplift Weekly* Scientists have made a breakthrough in creating a superconductor that works at room temperature, according to a recent publication in the journal Nature.* About 10-15% of our electricity on the electrical grid is lost just in the transmission of getting the energy to your house. When it comes to batteries, about 10-30% of the energy is lost. What if there were a type of material that electricity could flow through without any resistance and you didn't lose any of the power? That's what a SuperConductor is! Typically, superconductors only work at extremely low temperatures, which limits their practical applications. However, if a superconductor could work at room temperature, it could transform almost any technology that uses electric energy, from smartphones to maglev trains and even fusion power plants. The latest research, which still faces skepticism due to previous controversy around the scientists involved, could represent the first step towards this goal.* The Lives of Girls Around The World Are Getting Better. This article from Unicef highlights 6 amazing changes. * From 2012 to 2020, more girls completed secondary school - lower secondary school completion rose from 69% to 77% and upper secondary school completion rose from 49% to 59%.* The global adolescent birth rate has decreased from 51 to 42 births per 1,000 girls aged 15-19 since 2012.* New HIV infections among adolescent girls is down by 33% in a decade, but girls still account for most new infections among adolescents. * There are fewer child marriages. In the last 10 years the proportion of young women marriages has fallen from 23% to 19%. However, millions of girls still at risk of marrying young. * Female genital mutilation declined in the last decade, in the 31 countries where it is practiced it has decreased from 41% to 34%. Sadly it still affects the lives of millions of girls. Thank you for reading the first issue of The Year Of the Opposite Newsletter. Your support and encouragement mean a lot to me. If you're a paying subscriber, I'd be delighted to hear from you. Feel free to send me an email at travisstoliker@gmail.com or leave a comment below.If you found this newsletter valuable, please consider sharing it with someone who might enjoy it. Your help in spreading the word would be greatly appreciated. Get full access to Year Of The Opposite - Travis Stoliker's Substack at www.yearoftheopposite.com/subscribe

This week, please join author Amil Shah and Associate Editor Ntobeko Ntusi as they discuss the article "Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study." 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 at the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature, very interesting. Many times in older individuals we understand how to manage severe valvular heart disease, for example, severe aortic stenosis. But do we really know how to manage individuals with mild valvular heart disease, for example, mild mitral regurgitation or aortic valve sclerosis? Well, our feature today will address that issue. And so, listeners, grab a cup of coffee. We're going to go through some of the other articles in the issue first, and then we'll get to that really interesting, very practical feature discussion. Well Carolyn, now that I've got my cup of coffee, this paper's from your group. And I'm going to ask you, Carolyn, as if it was a feature discussion, what was the background information that went into this and what was the hypothesis that you wanted to address? Dr. Carolyn Lam: Oh, it's great because it's at least not a Carolyn quiz, so I'm very happy to talk to you about it. Sex differences, as you know, it's a passion of mine. And in response to heart failure pharmacotherapies, in particular, we know that there are sex differences, wherein women appear to benefit from newer hormonal modulators across a wider heart failure ejection fraction range compared to men. And this was particularly evident in the Paragon heart failure trial of Arne versus Valsartan. However, whether these considerations also apply to the sodium-glucose Cotransporter 2 inhibitors or SGLT 2 inhibitors, remains unclear. So along with the groups from the DAPA-HF and DELIVER trial, we therefore examine and assess the impact of sex on the efficacy and safety of dapagliflozin in a pre-specified pooled analysis of these trials. Dr. Greg Hundley: Very interesting, Carolyn. So, differences between men and women and evaluation of efficacy of SGLT 2 inhibitors. So what did you find? Dr. Carolyn Lam: In essence, women and men derived similar benefits from dapagliflozin for both the primary outcome of worsening heart failure or cardiovascular death. And for secondary outcomes, including improvement in health status across the full spectrum of ejection fraction in heart failure. Dapagliflozin was also safe and well tolerated in both sexes. So these findings are consistent with other SGLT 2 inhibitors and suggest a class effect. And in fact, this is very, very nicely discussed in an accompanying editorial by Dr. Ileana Piña. Dr. Greg Hundley: Ah, very nice, Carolyn. Well, my first study here comes from the world of preclinical science. And Carolyn, this study assesses the role of epsins in modulating endothelial to mesenchymal transition in atherosclerosis. So Carolyn, you may ask what are epsins? Well, epsins are ubiquitously expressed adapter proteins involved in the regulation of endocytosis. And then Carolyn, there's a second process addressed in this study. And Carolyn, it is known that chronic vascular inflammation, a hallmark of atherosclerosis, induces a process called endothelial to mesenchymal transition. And during endothelial to mesenchymal transition, the transition of non-smooth muscle cell-derived cells that are capable of maintaining indices of atherosclerotic lesion stability are lost. And this allows atherosclerosis to progress to a more advanced stage. So Carolyn, in this study led by Dr. Hong Chen, from Boston Children's Hospital, these authors wanted to know if impacting epsins could reduce endocytosis and thereby modify endothelial to mesenchymal transition and attenuate atherosclerosis progression. Dr. Carolyn Lam: Sounds like an important concept to address in the progression of atherosclerosis. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. So the authors found that epsins are required for endothelial to mesenchymal transition, and that the loss of these proteins in the endothelium reduces endothelial to mesenchymal transition by permitting sustained fibroblast growth factor receptor-1 protein, FGRF1, signaling by inhibiting the degradation of this receptor complex. They also demonstrate the efficacy of blocking epsin FGRF1 interactions specifically in atheromas using systemic administration of a targeted epsin UIM containing peptide to inhibit endothelial to mesenchymal transition and atherosclerosis progression in APO deficient and PCSK9 mutant viral induced atherosclerotic models. So Carolyn, in summary, these authors show that blocking these epsin FGRF1 interactions could provide a new approach to combat atherosclerosis progression. Dr. Carolyn Lam: Wow, Greg, thanks. Well, this next paper is an important preclinical paper showing that agents that induce senescence in cells of pulmonary vasculature can unexpectedly worsen rather than ameliorate pulmonary hypertension. So this paper is from Professor Serge Adnot and colleagues from Hospital Henri-Mondor in France. And they began by showing that in human lung tissues from pulmonary hypertension patients, about 30% of lung endothelial and smooth muscle cells have elevated P16, an observation recently also reported by others, as further evidence of senescence. Many of the cells with elevated P16 also had an increase in unrepaired DNA damage. They then used multiple senolytic strategies in several animal models to remove senescent cells and then found unexpectedly that eliminating senescent cells aggravated rather than suppressed pulmonary hypertension development. As models of pulmonary hypertension, the authors examined a number of animal models of pulmonary hypertension. That included rats exposed to chronic hypoxia, rats injected with the toxin monocrotaline, and rats injected with a VEGF receptor blocker prior to exposure to chronic hypoxia. As well as mice over-expressing the serotonin transporter in smooth muscle cells. And mice with P16 over-expression that develop pulmonary hypertension with age. So lots of animal models were tested and these animals also received the senolytic ABT 263 or FOX04-DRI, that would be expected to remove senolytic cells with equivalent results. Dr. Greg Hundley: Wow, Carolyn, so multiple animal models highlighting that senescent cells in the pulmonary vasculature can worsen rather than attenuate pulmonary hypertension. So what are the clinical implications of these models? Dr. Carolyn Lam: Well, this is discussed in a beautiful editorial by Dr. Rabinovitch that accompanies this paper. And quoting from that editorial, "The study is therefore extremely important in pointing out the potential overkill of senolytics in promoting rather than reversing pulmonary hypertension. The study also has particularly important translational implications as it indicates that the potential efficacy of an emerging therapy relies on the underlying disease mechanism and animal model use, the cell specificity dose, and root of administration." So lots of translational implications of this paper. Dr. Greg Hundley: Wow, Carolyn, so we've got some other articles in this issue and it looks like you've got a great review of those to describe. Dr. Carolyn Lam: Sure, I'd love to tell you about them. First there's a letter from Dr. Liao regarding the article, "Association Between Device Measured Physical Activity and Incident Heart Failure: A Prospective Cohort Study of the UK Biobank Participants." There's also a Cardiovascular Case Series by Dr. Ostrominski on "Pulling Out All The Stops: A Case of Progressive Dyspnea." In Cardiology News by Tracy Hampton, there's a story of scientists creating spatial map of cardiac remodeling after myocardial infarction, published in Nature. Loss of Y chromosome in myeloid cells promoting cardiac fibrosis, published in Science. And details behind the DNMT3A and TET2 mutations linking atherosclerosis. And that's published in Immunity. There's also a Perspective piece by Dr. Somers on “Whom to Screen and How to Screen for Obstructive Sleep Apnea in The Cardiology Clinic?” And a Research Letter by Dr. Felker on the clinical implications of negatively adjudicated heart failure events, data from the Victoria study. Dr. Greg Hundley: Wow, Carolyn, this issue, it's just packed with information. Well, how about we get on to that feature discussion? Dr. Carolyn Lam: Let's go. Thanks. Dr. Greg Hundley: Welcome listeners, to this feature discussion on this February 21, where we're going to delve into the world of valvular heart disease. And we have with us today Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our own associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa. Welcome gentlemen. Well Amil, we'll start with you. Could you describe for us some of the background information that really went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Amil Shah: Well, thanks very much, Greg, and let me start by thanking you and the circulation team for the interest in this paper and the opportunity to discuss it with you today. So I think in terms of background, we know that the prevalence and incidence of valvular heart disease increases with age, and that severe valvular heart disease is associated with substantial morbidity and mortality. Sub-severe valvular heart disease is, of course, even more common and has also been associated with worse cardiovascular outcomes. So I'm thinking of earlier studies that have associated even aortic sclerosis in the absence of stenosis with worse outcomes. Acknowledging the progressive nature of valvular heart disease, the ACCHA valve guidelines adopted this framework of valvular heart disease stages, where stage A was really defined as at risk for valvular dysfunction based on valve morphology in the absence of hemodynamic perturbation. Stage B is progressive valve dysfunctions. This is commonly what we would clinically consider mild or moderate valvular lesions. And then stage C, severe asymptomatic valve dysfunction. Stage D, severe symptomatic valve dysfunction. And we believe that looking at valvular heart disease in the context of these stages, as opposed to just as the hemodynamic severity of the lesion, can provide important insights into the burden of valvular heart disease. And especially sub-severe valvular heart disease in at-risk individuals, and in particular in older individuals. But the prevalence of these stages in the community and their progression over time really prior to this, to our knowledge, hasn't been described. And so really our aims and our hypotheses in this paper was to understand the prevalence of valvular heart stages amongst older adults. And really what we anticipate is that a large proportion of individuals in late life would have at least stage A, if not stage B, valvular heart disease. To describe the prognostic relevance of these stages, and particularly the sub-severe stages, and we anticipated that even stage A or stage B relative to no stage would be associated with worse outcomes, based on the prior literature. And finally, to characterize the rate of progression in late life. Dr. Greg Hundley: So rather than just the hemodynamic significance, it sounds like we're going to investigate the stages of valvular heart disease in an elderly population and associate that with prognosis. So how did we do that? What was your study design and can you describe for us also your study population? Dr. Amil Shah: Sure, of course. So we ended up using longitudinal data from a large cohort of older adults who are participating in the Atherosclerosis Risk in Communities, or ARIC study. So ARIC is an NHLBI funded longitudinal epidemiologic cohort. It's actually been following participants from four communities in the US since 1986. So Maryland, Mississippi, North Carolina, and Minnesota. Echocardiography was performed in just over 6,000. So 6,118 individuals are participants in 2011 to 2013. And at that time the mean age was 76. Just under 3,000 of those individuals underwent a repeat echocardiogram in 2018 to 2019. So that's a time elapse of about six and a half years, at which time the mean age was 81. So we're really looking at how things are changing between the ages of 76 to 81 years of age. We really focused on the mitral and aortic valves and determined or ascertained the stage of regurgitation or stenosis in those valves using a combination of quantitative and qualitative criteria based on the study echocardiograms, which are all read and interpreted centrally. And of course, each valve gets its own stage. And so for the purposes of this paper, we classified individuals as an overall valvular heart disease stage based on whichever valve had the highest grade lesion. Dr. Greg Hundley: Very nice. So using the ARIC study and then following the stages. So describe for us, Amil, what were your study results? Dr. Amil Shah: So at the first assessment, so amongst these approximately 6,000 individuals who had imaging in 2011 and 2013, the prevalence of stage A valvular heart disease was about 39% of individuals. Stage B, which again would be progressive, was about 17% of individuals. And stage C or D, which is really severe valvular heart disease, which was just over 1% in this community based population. And again, another 1% had previously undergone valve replacement or repair. And not surprisingly, even amongst this older cohort, older age was associated with a higher prevalence of each one of these stages. Then over a median follow up of about six and a half years, we looked at the association of each one of these stages with incident cardiovascular events relative to that group of individuals who were free of valvular heart disease stage in this cohort. And in each one of these stages, including stage A, was associated with a higher risk of incident heart failure, incident atrial fibrillation, coronary heart disease, which is largely MI, and then all-cause mortality. And that was true after accounting for many of common cardiovascular risk factors we usually think about as being related to risk for these outcomes. Interestingly, there was not an association with incident stroke in this study, although I will say our numbers for incident events were modest. Dr. Greg Hundley: Now, did you find similar results for men and for women? Dr. Amil Shah: So these results were fairly consistent for men, for women. And then the other demographic subgroup we looked at is... One of the unique features of ARIC is that it is a biracial cohort. And so when we looked at demographic subgroups based on both gender and race group, these trends were similar. Dr. Greg Hundley: And I know, Amil, right at the beginning you were discussing the importance of the stages versus the hemodynamic consequences. Did you do any comparisons, for many of us that are following patients, for example, with aortic stenosis? Did you find a discrepancy between using the stage as the defining term for a patient as opposed to the hemodynamic significance of one of these valve lesions? Dr. Amil Shah: Yeah, that's an excellent question. And so I think the first point to make is the valvular heart disease stages, of course, that we are assigning are based on the highest stage lesion, and so, of the four lesions we assessed. And part of this is a little nuanced, I guess, based on how the guidelines have defined these stages. So interestingly, if you look at stage A valvular heart disease, the majority of those individuals are getting in due to mild mitral regurgitation, because mild mitral regurgitation is considered stage A. In contrast, if you look at stage B, the majority of those individuals are getting in because of mild aortic regurgitation, because mild AR is considered stage B. And then stage C/D is really driven by aortic stenosis, probably not surprisingly. So what we can do is look not only overall, but also by stage within lesion. And certainly for aortic stenosis and mitral regurgitation, which are the most common valvular lesions we encountered, we saw similar findings. For mitral stenosis we had very few cases. So I don't think we can really comment on that based on this study. And for aortic regurgitation, we largely had individuals with no regurgitation or mild regurgitation, only a few with moderate. So again, we're a little bit limited in commenting on that. Dr. Greg Hundley: Very nice. Well, thank you so much, Amil. And listeners, now we're going to turn to our associate editor, Dr. Ntobeko Ntusi from Cape Town, South Africa. Ntobeko, you have many papers that come across your desk. What intrigued you about this particular paper? Dr. Ntobeko Ntusi: Thanks, Greg. I'd like to start by congratulating Amil and his co-authors on this paper, which as an associate editor was an absolute pleasure to handle. And the reason why we liked it are two-fold. Firstly, it's a large study, simple science of over 6,000 people. Very well characterized cohort clinically. We also liked its prospective design, as well as the protocolized nature of the echocardiograms. We liked that there was a central facility for core reading of all of these echocardiograms. And the use of a well-validated system of categorizing valvular heart disease. And importantly, we also liked the fact that it is a very representative study in terms of ethnicity and sex. And for me, there were three important takeaway messages from this study which advance our concepts of valvular heart disease. The first is that we've known for a long time that most severe valvular heart disease is associated with poor outcomes. But for the first time, this study provides us with data that shows a clear created association between the valve stage and outcomes related to mortality incident at fila and incident AF. So this is a new contribution. The second important novel contribution from the study is the data they provided on disease progression between stages of valvular heart disease. And then thirdly, I really liked the figures, in particular figure three and figure four, which I think are going to be highly cited and used in many presentations. So figure three demonstrates the Kaplan-Meier curves and shows survival rates dependent on the stage of valvular heart disease. And figure four, beautiful alluvial plot showing disease progression. And for these reasons we thought this was a piece that we would like to include in Circulation. Thanks, Greg. Dr. Greg Hundley: Thanks so much, Ntobeko. Well Amil, based on all this work, where are you going next? What do you see as the next study to really be performed in this sphere of research? Dr. Amil Shah: So two major findings I think that may have downstream consequences for future studies, first relate to identifying a subgroup A. That these valvular heart disease stages progress fairly substantially over fairly limited periods of time in late life. And really identify older individuals with certainly stage B, but even stage A valvular heart disease as a group, not only that we should screen with follow up, as recommended by the guidelines when we do detect sub-severe valvular lesions. But also potentially for therapeutics to prevent progression as those become increasingly available. And so I think one place where this data may be very helpful is in thinking about at-risk groups to evaluate therapeutics in. I think the second place is this relationship of even stage A valvular heart disease with adverse outcomes, which I think suggests that when we see valve deformation on imaging, that is likely a marker of risks that we're not fully capturing using our other traditional cardiovascular risk factors. And potentially could begin to become incorporated into how we think about risk stratifying our patients. Dr. Greg Hundley: Very nice. Ntobeko, do you have anything to add? Dr. Ntobeko Ntusi: Indeed. So I think in terms of future directions, there are probably three questions that I think would be important in taking this work forward. The first one is that this is clearly a descriptive epidemiological study. And for me it would be interesting to look at some of the mechanisms that underlie the adverse clinical outcomes associated with different stages of valvular heart disease. Two, the follow-up is relatively short and I think that it will be interesting as these individuals continue to be followed up long term, to see how these observations are either strengthened or evolve over time. And then finally, which is probably not going to be possible with the ARIC cohort. I think it would be useful to also look at rates of disease progression, but also the associations with outcomes in a younger cohort. And so for me, those would be interesting future ways of taking this work forward in the future. Thank you, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we're going to wrap up and we want to thank Dr. Amil Shah from Brigham and Women's Hospital in Boston, Massachusetts, and our associate editor, Dr. Ntobeko Ntusi from Cape Town in South Africa, for bringing us this study highlighting that subclinical valvular heart disease is common in older adults with 39% at risk for stage A, and 17% with progressive valvular heart disease, or stage B. And they are independently associated with the risk of incident cardiovascular events. Well, on behalf of Peder, Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

This episode is also available as a blog post: https://gailraegarwood.wordpress.com/2023/01/30/the-valsartan-hyperkalemia-connection/

Impact: Sacubitril/Valsartan and MR severity in HFrEF

On this podcast episode, I discuss valsartan pharmacology, adverse effects, drug interactions, and much more. Valsartan is a fairly common ARB. I mostly see losartan and valsartan used as the most common ARBs in hypertension management. Valsartan has a longer half-life than losartan which is why we can often get away with once daily dosing compared to losartan which sometimes requires twice daily. Hyperkalemia is a major concern with ARBs like valsartan. Trimethoprim and spironolactone are two medications that can increase this risk.

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Meet the meetingChe si tratti di eventi in presenza o virtuali, purtroppo non è sempre possibile partecipare ai congressi. E anche quando ci si riesce, spesso è difficile selezionare e seguire tutte le sessioni su uno specifico tema.Nasce per questo Meet the meeting: un podcast di approfondimenti verticali sulle evidenze presentate a un dato congresso su un dato argomento, a cura dei maggiori esperti di quel settore specifico.Seguici sui nostri socialInstagram (@drtalk_it)Twitter (@drtalk_it)YouTube (DrTalk_it) 

This week, please join author Philipp Lurz and Editorialist Daniel Burkhoff as they discuss the article "Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction" and the editorial "HF?EF: The Mysterious Relationship Between Heart Failure and Ejection Fraction Continues." 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-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: I just cannot wait to tell you about today's feature discussion, Greg. It's about heart failure with preserved ejection fraction and characteristics in the range of that ejection fraction that's above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow. How much are we going to be talking about this ejection fraction thing?" But I'm telling you, everybody has to listen to this. It's really a big stride forward in our understanding of these patients with heart failure and a higher ejection fraction. Plus it includes one of my mentors from Mayo Clinic days, and I just can't wait for everyone to hear this. But before we go there, we've got really, really cool original papers in today's issue too. Would you like to start first? Dr. Greg Hundley: You bet Carolyn, and I can't wait for that feature discussion, especially this is a real area of your expertise. So listeners, hold on for that feature discussion. Well, my first paper, Carolyn, really pertains to physical activity. And Carolyn, the study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan School of Public Health. And it evaluated a total of 116,000 adults from two large prospective US cohorts, the Nurse's Health Study and the Health Professional's Follow up Study that took place from 1988 to 2018. And they were examining self-reported leisure time physical activity and assessed the association between long term leisure time physical activity intensity and all cause and cause specific mortality. Dr. Greg Hundley: Now Carolyn, two types of physical activity were assessed. First, moderate physical activity and we're going to abbreviate that as MPA and that was 150 to 300 minutes per week, which is really recommended. Or second, vigorous physical activity for which it's really recommended that one performs 75 to 150 minutes per week. Now, Carolyn, as you know, some individuals accomplish both of these in their routine, some neither, some one or the other. And so it really remains unclear whether higher levels of long term vigorous or moderate are independently or perhaps jointly associated with lower mortality. Dr. Carolyn Lam: Oh, that's so interesting, Greg. Quick, quick, quick, tell us the results. Dr. Greg Hundley: Right Carolyn. So the nearly maximum association with lower mortality overall was achieved by performing approximately 150 to 300 minutes per week of long term leisure time vigorous physical activity or 300 to 600 minutes per week of long term leisure time moderate physical activity or an equivalent combination of both, so mixing those minutes. Also Carolyn, very interestingly, higher levels, suppose you go beyond those limits of either long term leisure time vigorous physical activity of more than 300 minutes per week or moderate physical activity of more than 600 minutes per week did not show clearly further lower all cause cardiovascular disease or non-cardiovascular disease mortality and nor did they show harm. So if you went above those thresholds, you really didn't experience greater harm. Dr. Carolyn Lam: Thanks, Greg. You know I'm going to be trying to apply that. That's so cool. All right. Well the next paper refers to the Cabana Trial, which I'll remind you is a trial in which catheter ablation did not significantly reduce the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest compared to drug therapy by intention to treat, but did improve quality of life and freedom from atrial fibrillation recurrence. In Cabana, the heart failure subgroup, ablation appeared to improve both survival and quality of life. The current paper led by Dr. Mark and colleagues from Duke Clinical Research Institute looked at the cost effectiveness of this ablation versus angio-rhythmic drug therapy in atrial fibrillation and which was a pre-specified Cabana secondary endpoint. Dr. Greg Hundley: Ah, Carolyn. So what did they find? Dr. Carolyn Lam: Well in this trial based economic evaluation, catheter ablation was estimated to cost $57,893 per QALY or Quality Adjusted Life Year gained compared to drug therapy in the overall cohort. And this was primarily driven by improvement in quality of life. It also cost $54,135 per QALY gained in the heart failure subgroup, driven by both gains in quality of life and survival. In summary, catheter ablation of atrial fibrillation was found to be economically attractive compared to drug therapy in the Cabana trial overall at present benchmarks of healthcare value in the US and based on projected incremental qualities, but not live years alone. Dr. Greg Hundley: Very nice Carolyn. Well, my next paper comes to us from the world of Preclinical Science and it's corresponding author is Dr. Swapnil Sonkusare from University of Virginia School of Medicine. So Carolyn, calcium signals in smooth muscle cells contribute to vascular resistance and control blood pressure. Now increased vascular resistance in hypertension has been attributed to impaired smooth muscle cell calcium signaling mechanisms. And in this regard, transient receptor potential vanilloid four or TRPV4 smooth muscle cell ion channels are crucial calcium entry pathways for smooth muscle cells. However, their role in blood pressure regulation has not been identified. Dr. Carolyn Lam: Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find? Dr. Greg Hundley: Right, Carolyn. So these authors provide the first evidence that TRPV4 smooth muscle cell channel activity elevates resting blood pressure in normal mice. A1AR stimulation activated TRPV4 smooth muscle cell channels through protein kinase calcium signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Dr. Greg Hundley: Surprisingly, intraluminal pressure induced TRPV4 smooth muscle cell channel activity, opposed vasoconstriction through activation of calcium sensitive potassium channels indicating functionally opposite pools of TRPV4 smooth muscle cell channels. And so Carolyn, this team identified novel smooth muscle cell calcium signaling nano domains that regulate blood pressure and demonstrate impairment in hypertension. Dr. Carolyn Lam: Oh wow, Greg. Thank you so much for that. Well, let's cover the other articles in today's issue. There's a primer by Dr. Jaffe on High Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. There's also Research [Letter] in there by Dr. Fordyce on the eligibility for non-invasive testing based on the 2021 American Heart Association and ACC guideline for the evaluation and diagnosis of chest pain, implications from the Promise trial. Dr. Greg Hundley: Great Carolyn. Well, I've also got an exchange of letters to the editor from Professors Benali and Professor Della Bella regarding a previously published article, “Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients with an Implantable Cardioverter Defibrillator, Results from the Multicenter Randomized Partita Trial.” And also there's a very nice Perspective piece from Dr. Udelson entitled “Glucose Insulin Potassium Therapy for Acute Myocardial Infarction, 50 years on and Time for a Relook.” Well, Carolyn, I can't wait to hear more of the discourse between you, the authors and editors on heart failure and preserved ejection fraction. Dr. Carolyn Lam: Yay. Here we go. I'm so excited about today's feature discussion. It's on my favorite topic, heart failure with preserved ejection fraction. Although thanks to one of the authors, Dr. Daniel Burkhoff of the editorial that accompanies it, I don't even know how to pronounce, it's Heart Failure question mark Ejection Fraction. I love it. How would you pronounce that? Dr. Daniel Burkhoff: Yeah, no, we debated how to pronounce it. HFQRef…a question mark? Dr. Carolyn Lam: HFQRef. Oh my goodness. What are we going to come up with next? Dr. Daniel Burkhoff: And we actually thought the editors would have a problem with that. Whenever we put something cute in the title, we always get knocked down. So we haven't yet got knocked down, so we'll see. Dr. Carolyn Lam: No, I'm not knocking you down. Dr. Daniel Burkhoff: But it just really emphasizes that we're in a very confusing time now as it comes to heart failure and ejection fraction, that we have to move on beyond ejection fraction. And although we have these strict buckets and upper and lower limits for each range, that maybe this is in a little bit of a way, doing us a disservice and doing the patients at disservice in terms of treatment. Dr. Carolyn Lam: That's really great. And everybody that was Dr. Daniel Burkhoff from the Cardiovascular Research Foundation in New York. He's the editorialist of today's feature paper. And I'm so excited that we have the corresponding author of today's feature paper as well, Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first, I mean, or second, heartfelt congratulations on this beautiful paper, Philipp. If you could start with telling us all about what you did and what you looked at and what made Dr. Daniel Burkhoff call it now, Heart Failure, QREF? Dr. Philipp Lurz: Yeah. So thank you so much, first of all, obviously for having me for the kind introduction and your kind words about our work. The whole thing started with the observation that in recent drug trials, the response in HFpEF patients to drugs which were before proven to be quite successful in HFrEF actually showed a quite heterogeneous response in HFpEF patients. And that there were some patterns according to the range of ejection fractions. So it seemed that those HFpEF patients with the lower ejection fractions, they respond a little bit better to HFrEF medication than those with a higher ejection fraction. Dr. Philipp Lurz: And HFpEF studies, they included patients within and ejection fraction or 40 and above who normally would probably would consider HFpEF to start with 50 and above. But even in those truly HFpEF patients, so from 50 and anything above to 70, there was a suggestion that there might be differences. 50 to 60 might be something else and then 60 and above. And this is where we started to look into our cohort and to group them according to ejection fraction and see whether we can see some important and clinically meaningful differences in morphology, obviously in function, but then even also in terms of our biopsy results. Dr. Philipp Lurz: And that also implies that we did quite a deep phenotyping of our patients. So we use imaging, echo obviously. We use magnetic resonance imaging. We were able to acquire in a larger percentage of that cohort, by the way, it was 56 patients in total, we were able to get some left ventricular biopsies. And most importantly, when it comes to the functional properties of the left ventricle, we also acquired pressure volume loops. And that has the great advantage that we obviously we can look at low dependent parameters, but more important, also low independent in disease of both systolic and diastolic function. And that's pretty much what we did. Dr. Carolyn Lam: Oh my goodness. I mean, as an editor at Circulation, can I just first tell you that's what really, really stood out? It's the comprehensive, careful, in-depth characterization. It may be 56 patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it was a lot, a lot that you did. Could you boil it down to what you found and maybe just to first clarify to the audience, how did you bend the ejection fraction? And then what you found? Dr. Philipp Lurz: We divided the cohort in two groups. One with an ejection fraction 50 to 60, and the other groups higher than 60% left ventricular ejection fraction. We ended up in lower group, 21 patients, in the higher group with 35 patients. And they were quite different. They had distinct features in terms of morphology, means that the lower injection fraction group, they had larger ventricles. That's probably what you would expect when you group them according to eject fractions. So not that surprising. Dr. Philipp Lurz: And at that point, and they had the same stroke volume. The low ejection fraction group, you could say that they had a certain degree of eccentric modeling, whereas those were the high ejection fraction group, that concentric modeling. When we then looked at the biopsies, the group with the low ejection fraction group, so 50 to 60, they had higher percentage of myocardial fibrosis at 15%. Dr. Philipp Lurz: And then on left ventricular biopsy, we saw that patients with a high ejection fraction group, they had less myocardial fibrosis, so more fibrosis in those with the lower ejection fraction group. And this is really interesting because when we then look at the real size of the pressure volume loop analysis, despite the fact that the high ejection fraction group had less fibrosis, they had the most stiff ventricles on pressure volume loop analysis. So that's already a very important point because it illustrates once again that we should not mistake fibrosis with stiffness, and also not the other way around. There are other parameters which can cause stiffness such as cellular stiffness, and it's not just the extracellular matrix. Dr. Philipp Lurz: So that's an important point. Those patients with high ejection fraction, they had the most stiff ventricles. They had the most relevant limitations in left ventricular filling, so the most marked diastolic dysfunction. We also looked at systolic parameters and there we found that they had a very high contractility. So this is the end systolic pressure volume relationship or also called elastics and that's a marker for contractility. So these ventricles with high ejection fraction, they can contract very well. They have high contractivity. But this is also a marker of systolic stiffness. So they stiff, both in terms of diastolic properties, but also systolic properties. And there, their most important limitation is the limitation in filling. Dr. Philipp Lurz: The other group, injection fraction 50 to 60, they do have some stiffness. Obviously we are talking about HFpEF. This is a disease of a diastolic dysfunction. So they have increased stiffness, but to a lesser extent. They can feel a little bit better, but what we see there is a reduction in contractility, so systolic properties. So you could argue that in some extent, that group 50 to 60, they behave a little bit more like HFrEF. Whereas those with high ejection fraction, they're completely different. Very stiff, both doing diastolically and sistolly. Dr. Carolyn Lam: Thank you so much. Now I really have to get the gurus insight into this. And of course by guru, I mean, Dr. Daniel Burkhoff. First, I'm going to take this opportunity to share a little private personal story that it's very hard for me to call Dr. Burkhoff, "Dan", although if you will allow me it's because I was a fellow when I first met Dr. Burkhoff. And one of my first papers was actually communicating with Dr. Burkhoff trying to draw these PV loops based on the noninvasive measurements that I was obtaining at the Mayo Clinic in the Olmsted County Cohort. And so this is just really making me smile. So Dan, if I may, what do you make of all this? And if you could give us what you think may be the clinical take home message. Dr. Daniel Burkhoff: Thank you so much, Carolyn. And also again, Philipp, congratulations on really a really important paper. I think as Carolyn was saying, one of the many things that impressed me was the multifaceted aspects of the thorough evaluation using multi modality characterization, which is in my mind, unprecedented, especially for this particular group of patients. And you summarized the main results very well. But to me, the thing that really struck me and that we really tried to emphasize in our editorial was the differential response to exercise, to hand grip exercise in this point. Dr. Daniel Burkhoff: As you already said, and I don't think this could be understated, that in the lower range, the 50 to 60, these patients were able to fill, the ventricle was able to fill more, the end diastolic pressure still went up significantly into an abnormal range, which is of course is one of the requirements for the diagnosis of HFpEF. But those patients, the end diastolic volume was able to increase and that helped them to increase their cardiac output. Dr. Daniel Burkhoff: In the higher EF group, the greater than 60, the end diastolic pressure went up, but the volume did not increase. So the end diastolic pressure volume relationship became higher elevated. And this of course, was reminiscent of what was identified in the early nineties by Dalane Kitzman. And really, he didn't make this distinction between the lower half and the higher half. And we had also in a paper that we did with David K and others, seen a similar finding a couple years ago. And I think this is really, to me, was the along with the apparently disparate findings on myocardial biopsies with fibrosis going the wrong way, if you will, as you already commented on. So this is at least for the higher EF group, is identifying what I would refer to as really true diastolic dysfunction. Dr. Daniel Burkhoff: That means that the patients can't fill, there really is some problem why the EDP can go up, but the volume does not increase. And this is obviously for future research, we have to understand what is the difference between these two groups. There are several speculations about why it might. For example, one thing that has been proposed in the literature is the pericardial restraints. If the heart is constrained in a tight pericardium, the volume is recruited from the venous system, which is another what I think is a very important part of this HFpEF phenotype, but the heart is already constrained. That would elevate both the CVP and the wedge pressure without concomitant increases in RV or LV volumes, and therefore limit the ability to increase the cardiac output. Dr. Daniel Burkhoff: Another alternative is delayed relaxation. That means a true abnormality of active relaxation. The tau if you will, but I believe in your study, if I remember correctly, the tau was not that abnormal and did not really change very much in either group. So it was harder to really pin it on an abnormality of active relaxation. So that was one really, I think, really important finding. Dr. Daniel Burkhoff: The second is now in the group 50 to 60 where they could fill, one of the limitations of the study that you pointed out was that there's no control group. So why this population, this HFpEF population, the EDP increased, but the EDV the end diastolic volume also increased, so what's different between those patients and normals? That we don't really have an answer for yet. So that would be one thing is to compliment these findings with results in a true control group that does not have HFpEF. Dr. Daniel Burkhoff: So we still have this mystery of why does EDP go up in this group? My perspective is not an abnormality of diastolly. It's not a diastolic dysfunction, even though it's a HFpEF. I've been trying to promote this idea for more than 20 years, that all HFpEF is not an abnormality of diastolic ventricular properties. There may be extra cardiac factors even beyond the pericardium in this group. So I think these results are just further telling us how complicated and individualized our approach to the pathophysiology of these patients should be. Dr. Daniel Burkhoff: And also just one final comment, making a strict cutoff at 60% or 57% as we saw from Valsartan Cuba trial, Valsartan study, is clearly also not going to do us justice. Let's say that we're dealing with anyway, patients with two different pathophysiologies. There's going to be a distribution of these different mechanisms and there's going to be an overlap of these distributions. So we need to start thinking about how we individualize and characterize the pathophysiology in individual patients. So maybe patients with EF of 55, certain patients with EF 55 will not respond to Sacubitril- Valsartan and maybe some patients with an EF of 62 will. So we need to go more deep into the clinical characterization. Dr. Daniel Burkhoff: And methods that you use in particular, the pressure volume loop, seem to separate, very nicely, these two different, at least two different subtypes. So I think it's very exciting, and I think people should really take notice of what you found and build on this as a foundation and understand that we need to go deeper on the clinical side to phenotype these patients. Dr. Carolyn Lam: Philip, what are your thoughts? Dr. Philipp Lurz: No, I think that the concept about stress and unstressed volume is extremely important and fascinating, but that's where it gets really complex because you could make the conclusion from our results that especially the high ejection fraction group, they are have a very high preload sensibility, which means that when we reduce pre-load too much in them, they drop the stroke volume very suddenly. So that's probably also the clinical question for the future. There are many patients, HFpEF patients in whom we should reduce stress volume and they can benefit from that. Dr. Philipp Lurz: But I also believe that there is a cord of patients, and those are probably more those with high ejection fraction. They actually, they could experience some harm if you reduce preload too much because of the severe filling restrictions, because of the inability to increase end diastolic volumes, especially as an adaptation to exercise. And I think if we find out ways to differentiate who will benefit from preload reduction and from decongestion and who actually might experience even harm from these interventions, then we are certainly one step further. Dr. Carolyn Lam: If I may, I just, I could go on forever, but I know that there's going to be this question that the audience is immediately thinking. Here we are going into the weeds, hemodynamics, we all love it. In fact, I think we're all kind of a little bit geeky about it, but then you've got, Emperor preserved, the Deliver Trial sort of being positive in heart failure with ejection fraction above 40. So, do we really need to understand the different hemodynamic? What do you think is happening that this sort of blanket benefit can occur? Dr. Philipp Lurz: I don't think that everyone will benefit. And I think that a better understanding of the underlying pathophysiology will help to even increase the rate of responders and dissect of those who will not respond or we need a different therapy. Obviously here we group patients according to ejection fraction. We just discussed that this is a very rough way to characterize patients. So the next step certainly would be to understand or to see distinct patterns in left ventricular functional behavior irrespective of ejection fraction. Because you might can skip ejection fraction at one day, but the conclusion is not, at least not in my opinion, that all heart failure is the same. Dr. Carolyn Lam: Nice. And Dan, what do you think? Dr. Daniel Burkhoff: Well, I think with STLT2 inhibitors, first of all, we're looking forward to actually seeing the results from Deliver what the details of it in terms of mortality versus hospitalizations and quality of life. But with regard to HSGL2 inhibitors, I don't think we know the mechanism. I mean, I've read about six papers that definitively talk about different mechanisms of action. I think we don't know. And even despite, let's say positive studies, there's still a significant residual risk that these patients have. So these are not the end of the story by any means. I think this is the beginning of the story and there's still going to be a lot to learn. Dr. Daniel Burkhoff: I think with SGLT2 inhibitors, I think it's difficult to identify who is or how do you define a responder on an individual patient basis? When we look at groups and you look at mortality and hospitalizations, yes, you can identify them. But that group does not overlap exactly with those who have an improvement in quality of life. So I think that we're just at the beginning, Dr. Daniel Burkhoff: I do think that a deeper phenotyping is going to be the way to go ultimately and I think we're going to need more therapies. Thanks again, Carolyn for inviting me to do the editorial and to participate in this. And I would really be remiss if I did not mention the extraordinary contributions for Mickey Brener and also Barry Borlaug who were equal contributors to this editorial and the evaluation of this paper. So I'm really indebted to both of them for this interpretations. And thank you again, Philipp, for just a wonderful paper. Dr. Carolyn Lam: Couldn't have said it better and I just want to thank you once again for providing that deeper phenotyping for opening the door. Many of us said it again and again, this is the beginning and we need more studies, frankly, in yours. I mean, I think Dr. Burkhoff wants you to send normal, healthy people for MRI biopsies, exercise, echo. I'm kidding, on PV loops, but it's true. We need that data. We need the same and the HFrEF and really just to understand the whole thing. I'm so excited about what this paper opens up. Dr. Carolyn Lam: I am thrilled to see your editorial, Dan. I'm sure it's going to be well received. Everyone who's listening to this, Pick up the paper, pick up the editorial. Thank you so much for joining us today. You've been listening to Circulation on the Run and from Greg and I, don't forget to tune in again next week, Dr. Greg Hundley: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit hajournals.org.

In this episode, Dr. Christopher Tookey and Dr. Rose Wolbrink discuss a relatively new goal for blood pressure shown to reduce risk of heart disease and stroke.    We're providing general guidance but everyone is different and you should always discuss with your health care professional management of any disease and therapy before trying anything you discover from a source on the internet (including this podcast). This podcast does not reflect the opinion of our employer. 

Sacubitril/valsartan is considered part of the backbone of guideline-recommended therapies for the management of patients with heart failure. In 2021, sacubitril/valsartan became the preferred treatment over an ACEi or ARB in patients with heart failure with reduced ejection fraction (HFrEF) because it reduces the risk of cardiovascular death and hospitalization for heart failure in nearly all adult patients with chronic heart failure. All clinicians should be familiar with the indications, dosing, safety, and monitoring of sacubitril/valsartan.  Affordability, access, and inappropriate dose titration remain major barriers to achieving optimal outcomes. Guest Authors:  Jessica Wooster, PharmD, BCACP and Elizabeth Yett, PharmD, BCACP Special Guest:  Dustin (DJ) Clark, PharmD, BCACP Music by: Good Talk

Dr. Ebell and Dr. Wilkes discuss the POEM titled ' No improved patient-oriented outcomes with sacubitril/valsartan in adults with heart failure and preserved EF (PARALLAX) '

Robert J. Schroeder, Pharm.D., explains the pharmacological principles of sacubitril/valsartan, recognizes the evidence favoring sacubitril/valsartan in heart failure and describes how to initiate sacubitril/valsartan.  For more pharmacy content, follow Mayo Clinic Pharmacy Residency Programs @MayoPharmRes or the host, Garrett E. Schramm, Pharm.D., @garrett_schramm on Twitter! You can also connect with the Mayo Clinic's School of Continuous Professional Development online at https://ce.mayo.edu/ or on Twitter @MayoMedEd. 

When new drugs are approved by the FDA, they can take time to diffuse across the population as clinicians begin to prescribe them. Uptake is not always quick or uniform, due to reasons that can include clinical inertia, provider familiarity, and the cost to patients. On this episode of Managed Care Cast, we're talking with the lead author of a study published in our December 2021 issue. The article, “Variation in Early Diffusion of Sacubitril/Valsartan and Implications for Understanding Novel Drug Diffusion,” describes how prescribing of the newly approved heart failure drug spread across the nation. Joining us today is Lauren Gilstrap, MD, MPH, of Dartmouth-Hitchcock Medical Center and The Dartmouth Institute for Health Policy and Clinical Practice.

Biden's pick to run the FDA shows a revolving door between Big Pharma and federal regulators. Michigan residents receive a paltry settlement for the Flint water crisis. Litigation continues over cancer-causing Xeljanz and Valsartan pills.

Editor's Summary by Gregory Curfman, MD, Deputy Editor of JAMA, the Journal of the American Medical Association, for the November 16, 2021 issue.

Interview with Douglas L. Mann, MD, and Eugene Braunwald, MD, authors of Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. Hosted by Clyde Yancy, MD.

Interview with Douglas L. Mann, MD, and Eugene Braunwald, MD, authors of Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. Hosted by Clyde Yancy, MD.

Patrick has a problem, but he doesn't know how to address it. Fitting in was something Patrick sought after. Whether it be smoking cigarettes or drinking alcohol excessively at parties, Patrick found a way to make it happen. Years of smoking, drinking, and eating excessively lead to health issues. Patrick had amassed a weight of 302 pounds and was suffering from high blood pressure, migraines, sleep apnea, as well as anxiety and depression. Patrick's physician instructed he take 5 medications (Alprazolam, Sertraline, Valsartan, Furosemide, and Provigil) to address his health issues. But Patrick thought otherwise.  Against the doctor's instructions, Patrick sought after a more natural solution. First he began a vegetarian lifestyle and removed alcohol completely from his diet. He also began minding the composition of his foods to avoid artificial ingredients. After doing his own research about health, food, and wellness, Patrick concluded that veganism was the next logical step.  Three months later, Patrick is excited to share the news of his improved mood and weight loss with his physician. On this visit, Patrick was revealed to have lost 122 pounds and lowered his blood pressure from 150/110 to 110/74. Patrick realized these changes were only possible through the support of his family and friends. Knowing how critical a strong support system is to health and wellness, he now strives to BE that support for others. One of his efforts is a weekly podcast show where he opens up about his life to provide transparency to others who may be going through life issues or need to hear positivity for a change. #WeAllCanWin Instagram  www.Instagram.com/thepodotshow  https://instagram.com/clearmind_fitnesspodcast?utm_medium=copy_link Facebook  https://www.facebook.com/ClearMindPat www.Instagram.com/ELT.thepodcast  Dee    Facebook:  www.Facebook.com/deemariehair    Instagram:  www.Instagram.com/deemariehair    YouTube:  www.YouTube.com/deemariehair    Crystal    Instagram  www.Instagram.com/crystalbaldazo    Abby    Instagram:  www.Instagram.com/theabigailmarie    Facebook:  www.facebook.com/abigailmarieartistry                   

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.  

On this episode, I breakdown the sacubitril valsartan pharmacology.

Is There a Recall on Losartan, Ibersartan, or Valsartan? How to Find Out and What to Consider. Thanks for listening!Small-sized validated blood pressure cuff 9-17 inches here. Regular-sized validated blood pressure cuff 13-17 inches here; Large-sized validated blood pressure cuff up to 16.5 to 21.25 inches here. Extra-large validated large cuff up to 16.5-23.6 inches click here.Need a list of validated blood pressure monitors? click here.Click this link if you need a telehealth appointment with a certified medical doctor: https://text2md.com/******Vitamin D HOME TESTING KIT here (Deficiency is less than 30 ng/ml and Optimal=50-60 ng/ml for the general public, ask your doctor what's good for you.) ******COVID-19 HOME TESTING KIT here How to use the COVID-19 HOME TESTING KIT here****Ask your doctor if you would benefit from any of the following vitamins or supplements that could potentially reduce severe COVID symptoms:Vitamin C with rose hips, Zinc, D3 & K2, Magnesium or this one, B complex, Elderberry, Probiotic or this one, Melatonin, *Quercetin, Braggs Nutritional Yeast, Apple Cider Vinegar, and NAC.*Quercetin may be contraindicated in people with thyroid disease. Ask your doctor and get a TSH, FREE  T3  & T4 , and aTPO before use.****Best thermometer2nd best thermometerAn accurate Pulse oximeter (If you have COVID-19, seek medical help if less than 95% at rest after 1 minute, which could mean you have pneumonia)****Hi, I'm Dr. Tonya Breaux-Shropshire, a clinical research scientist.  I spent the past decade studying hypertension management. I am the author of six first-authored publications in scientific journals. You can read my work HERE.****Would love to hear from you! Send me a comment or question at this link (click here).****Copyright Disclaimer under section 107 of the Copyright Act 1976, allowance is made for “fair use” for purposes such as criticism, comment, news reporting, teaching, scholarship, education, and research.****Royalty-free music: Turn on My Swag 2 Intro by Mr. Willie Breaux****Disclaimer: This podcast is for educational purposes only and not intended to replace medical advice. Affiliate links support the podcast at no cost to you. Thanks for your support!

Valsartan, also known as Diovan, is an angiotensin II receptor blocker (ARB). It is used for treating NYHA class II to IV heart failure along with both treating and managing hypertension. Another common indication is for both STEMI and NSTEMI patients. Typical initiation dosing for heart failure, STEMI and NSTEMI is 20 mg twice daily with titrations up to 160 mg twice daily. When initiating treatment for hypertension the range begins at 80-160 mg po every day up to a max dose of 320 mg per day. Valsartan works by blocking AT2 from the AT1 receptor and is considered to be more efficient than ACEs along with having less side effects such a cough. Some common side effects are orthostatic hypotension, dizziness, and lightheadedness. Common monitoring parameters for valsartan are blood pressure, blood pressure urea, pregnancy, and electrolytes. Patients should avoid salt substitutes containing potassium. There is a black box warning for fetal toxicity because drugs that affect the renin-angiotensin system can cause injury/death to the fetus. Go to DrugCardsDaily.com for my episode show notes which will contain a drug summary, quiz, and a link to FREE drug card sheets. SUBSCRIBE on Spotify or Apple Podcasts or search for us on your favorite place to listen to podcasts. I will go over the Top 100-200 Drugs as well as throwing in some recently released drugs that peak my interest. Also, if you'd like to say hello, suggest a drug, or leave any constructive feedback on the show I'd really appreciate it! Leave a voice message at anchor.fm/drugcardsdaily or message us through twitter @drugcardsdaily --- Send in a voice message: https://anchor.fm/drugcardsdaily/message

Folge 26: Masken für Kinder, MDR und NDMA in Valsartan

Leo's channel: https://www.youtube.com/c/LeoandLongevity Derek's channel: https://www.youtube.com/channel/UCoR7CHkMETs3ByOv74OAbFw Steve's channel: https://www.youtube.com/user/VigorousSteve TIMESTAMPS: 0:00 intro 0:29 Connor Murphy/ Ayahuasca and DMT 1:36 Kenny KO and Connor 2:10 Leo on psychedelics/ his friend 3:38 Steve on psychedelics 5:29 Marijuana and schizophrenia/ More on Connor 7:45 Man cutting his genitals off on drugs 9:30 Screen sharing on Zoom 9:58 Leo's manic Canadian friend 10:47 Derek will avoid psychedelics 12:13 Derek on being ambitious 13:29 Losing your ego 14:12 How Leo hurt his finger 16:42 Antoine's Vaillant bicep and Olympia placing 19:06 Derek's bodybuilding genetics 20:13 Why Derek stopped doing steroids/ Making money as a bodybuilder 23:16 GH15, Antoine, and Frank Mcgrath 24:44 Bodybuilding, dieting, and tren 26:25 Recovery from injury Beta-blockers either before or after a surgery Nebivolol, collagen and gelatin protein, Propranolol, 29:03 Angiogenesis BPC 157, TB500, erythropoietin 31:06 Growth factors and hair loss/ Icing and cooling injuries 32:06 MK677, ghrelin  and surgeries/ MK677, GH, and IGF1 34:05 MK677, Ghrelin, PTSD, and Insulin 39:22 Jujimufu and Greg Ducette/Canadian accents 43:34 People being hyper-critical of people in the fitness industry. 44:49 Jujimufu, arm wrestling, and stomach distension 47:53 Leo's GH experience 49:31 Jujimufu's genetics 51:06 Looking like you work out while wearing a shirt 52:25 Anabolic pathways 53:30 Dallas McCarver autopsy/ Anthony Roberts ban 58:20 Dallas McCarver organs 1:00:21 Leo's friend taking large sums of steroids/ Derek on the autopsy 1:07:00 Derek and Steve on blood and urine drug tests/ Tren cough 1:11:10 What steroids do to your heart Dislipidemia, HDL goes down, HDLC decreases by approx 50%, APO A1 decreases by 33-41%, increases LDLC by approx 36% Reduce lipoprotein [a] 1:12:41 Homocysteine blood tests/ Chris Masterjohn  Creatine, Choline, B vitamins 1:13:50 More on Lipoprotein [a] Niacin, Repatha, and steroids 1:15:01 Derek's client with strange test results 1:15:54 Hypercholesterolemia  Homozygous APOCIII, CETP, and APOE4 1:17:33 Steroids, left ventricular systolic function, left ventricular diastolic function, and heart hypertrophy. 1:19:15 Heart FMRI 1:20:28 Impaired tonic cardiac autonomic regulation, and Clenbuterol 1:22:32 Leo's list of tests and genetics 1:23:25 Statins, Ezetimibe, and cholesterol 1:25:00 Automated gene searches 1:26:09 Statins and natural status 1:27:24 Lowering LDL and extending life PCSK9 inhibitors, Bempedoic acid, Ezetimibe, and Statins 1:28:41 Steve on Ezetimibe 1:29:32 Leo on Statins (the good and the bad) Pitavastatin, Rosuvastatin crestor ,livalo, lipitor 1:33:56 Telmisartan, Valsartan, Azilsartan and Irbesartan 1:39:17 Diuretics, bloating, and Estrogen 1:41:28 Hyperkalemia, Potassium and drug interactions 1:43:20 Minoxidil as a potassium channel opener and microneedling 1:45:49 Steve doesn't like hair 1:47:40 Leo's hypothesis on hair loss/ Derek on hair loss 1:54:25 Topical dutasteride 1:55:35 70-year-old women and balding 1:56:45 Steve on being secure with hair loss 2:00:40 Men and size 2:02:04 Pre-workout androgens Anadrol, Dianabol, Superdrol and Anadrol 2:08:26 Taking short-acting compounds around your workout 2:10:00 How steroids cause liver cancer and why Anavar doesn't cause it 2:11:56 Dianabol back pumps 2:13:19 Egyptian bodybuilders 2:14:52 Steve's fasting protocols 2:18:15 Reasons to fast 2:20:44 Leo's reasons to fast/ Satchin Panda's book/Valter Longo's fasting-mimicking diet and Prolon 2:23:47 Proper fasts on PEDs Allopurinol 2:27:36 How Steve and Leo prepare salads 2:30:35 The discord group 2:34:19 Unhealthy relations to Youtubers 2:39:58 Epigenetics and children 2:43:14 IVF and metabolic profiles 2:45:35 Coming off of testosterone and getting back to baseline 2:46:37 Having kids at an older age (epigenetic damage over time to sperm) 2:49:42 Steve and Leo on TV 2:50:15 Past downloading services 2:54:06 Unusual pre workout supplements for more strength or a better pump 2:56:40 Why the hell are people taking Phenibut and Kratom pre workout 2:58:00 Low dose Naltrexone therapy 3:00:16 Getting over addiction 3:02:34 Gynecomastia 3:05:43 Removing your glands before you take steroids/ Problems with Nolvadex 3:08:02 Derek and Steve on their gyno experiences 3:10:45 How to deal with gyno if you don't want the surgery 3:11:56 Steve on growing your gyno, to get the surgery JOIN OUR COMMUNITY: Reddit ▶ https://www.reddit.com/r/TheLongLived/ FOR GENETIC ANALYSIS & COACHING: Website ▶ https://www.leoandlongevity.com TO READ MY ARTICLES: Blog ▶ https://www.leoandlongevity.com/blog TO FOLLOW ME ON SOCIAL MEDIA:  Instagram ▶ https://www.instagram.com/leoandlongevity Twitter ▶ https://www.twitter.com/leoandlongevity

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.

Commentary by Dr. Virginia Hahn

In this week's LIVE Q&A Show, Dr. Rogers answers YOUR questions! This week's questions: 1. I have read that taking the high blood pressure medicine, Valsartan, helps with Covid. What is your opinion on this? Also, what do you think about taking Metoprolol? 2. Would Phentermine be okay to take if you have restless leg syndrome? 3. Is Botox safe? I feel weird about injecting something foreign in my face. 4. How do you treat Adrenal Fatigue? How do you know you have adrenal fatigue? 5. When is the best time to start BHRT for a woman? What did you think of this episode of the podcast? Let us know by leaving a review! Connect with Performance Medicine! Sign up for our weekly newsletter: https://performancemedicine.net/doctors-note-sign-up/ Facebook: @PMedicine Instagram: @PerformancemedicineTN YouTube: Performance Medicine Audio

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

In this special meeting edition of the Cardiocast, MDedge Cardiology editor Catherine Hackett is joined by MDedge reporters Mitchel L. Zoler, Bruce Jancin, and Richard Mark Kirkner.  The MDedge cardiology team reviews three big stories from the 2019 annual scientific sessions of the American Heart Association in Philadelphia.  * * *  Help us make this podcast better! Please take this short listener survey: https://www.surveymonkey.com/r/podcastsurveyOct2019 * * * ISCHEMIA trial hailed as practice changing The results of the ISCHEMIA trial were emphatically declared practice changing by interventional cardiologists and noninterventionalists alike at the AHA meeting.  Bruce Jancin discusses the story. DAPA-HF: Dapagliflozin's HFrRF efficacy confirmed in nondiabetes The results in nondiabetics from the practice-changing DAPA-HF trial gives clinicians strong evidence that the diabetes drug dapagliflozin is equally effective at reducing cardiovascular death and acute exacerbations in heart failure patients regardless of diabetes status.  Mitchel L. Zoler discusses this report.  Weakness exposed in valsartan recall ED visits for hypertension in the month after the 2018 recall spiked 55%. The 2018 recall of generic forms of the antihypertensive drug valsartan exposed weaknesses in the recall systems for generics in both the U.S. and Canada that caused many patients who were on the drug to fall through the cracks.  Richard Mark Kirkner goes deeper into this story.  *  *  *   For full coverage of AHA 2019 visit MDedge Cardiology For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgeCardio

Valsartan is a popular blood pressure medication that the FDA has discovered significant contamination involving the industrial chemical NDMA, also classified as a probable carcinogen. If you know someone who has been diagnosed with stomach, colorectal or liver cancern while taking (or previously taking) Valsarten, then you will want to listen to this podcast.

Sacubitril/Valsartan, known as Entresto, is a new dual drug therapy that includes an angiotensin receptor inhibitor and is indicated to reduce the risk of cardiovascular death and hospitalization in patients with chronic heart failure.  Since its approval for the treatment of chronic heart failure with reduced injection fraction, a commonly raised question is whether treatment with this drug challenges the use of B-type natriuretic peptide, or BNP, testing compared to the N terminal proBNP assay because Sacubitril may interfere with BNP clearance. The clinical and analytical studies addressing this issue are limited, along with the fact the diversity of both BNP and NT-proBNP assays used in clinical laboratory practice have not been adequately evaluated in clinical trials or studies to provide an evidenced-based on final decision as to what assay or assays should be used or eliminated from use when a patient is on Entresto. In the September 2019 issue of Clinical Chemistry, a Q&A feature titled, “Role of BNP vs NT-proBNP Testing in the Age of New Drug Therapies” asked five experts with different roles in this field to discuss this issue. 

Lala Madness Fierce Review - All these RECALLS. Valsartan HBP medication, Childrens Ibuprofen, Kansas License Plates Follow me on social media @LalaMadness Email LMFierceReview@gmail.com Watch my videos on Youtube at https://www.youtube.com/channel/UCP--id6nvHQiAq2xckPPF4A --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/lala-madness/message Support this podcast: https://anchor.fm/lala-madness/support

In our second episode, we examine a method lifecycle management approach in monitoring method performance and applying MLCM to address real world issues like nitrosamines (ni-tros-a-mine) in Valsartan.

In den letzten Monaten hatten Apotheken mit diversen Lieferengpässen zu kämpfen. Unsere PTA Theresa und Michael schauen noch einmal zurück und fragen: Wie kommt es zu Lieferengpässen? Wie kommen Apotheken und Kunden an die wichtigsten Infos? Und was könnte besser laufen?

We're taking a week off. Well, Laura is. Robin couldn't resist sharing JUST ONE STORY.Here's the FDA's latest press release about valsartan:https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628189.htm

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. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.                                                 The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.                                                 The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.                                                 In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"                                                 Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.                                                 In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.                                                 Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.                                                 They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.                                                 That wraps it up for our summaries, now for our feature discussion.                                                 Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?                                                 Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.                                                 Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings? Dr Richard Haynes:          So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.                                                 It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan. Dr Carolyn Lam:                Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan? Dr Richard Haynes:          That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way. Dr Carolyn Lam:                Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that? Matthew James:              Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease. Dr Carolyn Lam:                Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right? Dr Richard Haynes:          Eligibility was actually determined by the EGFR, the estimated GFR.                                                 Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm. Dr Carolyn Lam:                Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm? Dr Richard Haynes:          I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial. Dr Carolyn Lam:                Justin, I mean you come from the heart failure world too just like me. What was your take? Dr Justin Ezekowitz:        I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.                                                 Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well. Matthew James:              Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.                                                 I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction. Dr Richard Haynes:          I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients. Dr Justin Ezekowitz         I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.                                                 I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.                                                 The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.                                                 The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published. Dr Carolyn Lam:                You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages? Braden Manns:                 Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes. Matthew James:              I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population. Dr Justin Ezekowitz:        So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely. Dr Richard Haynes:          I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has. Dr Carolyn Lam:                Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.                                                 Thank you very much to audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Valsartan und kein Ende - Auch andere Blutdrucksenker gepanscht? / Gegen Malaria - Soll man Moskitos gezielt ausrotten? / Geparden im Iran - Artenschutz unter schwierigen Bedingungen.

Der Blutdrucksenker Valsartan ist in die Kritik geraten: Krebserregende Zusatzstoffe beunruhigen die Patienten. Nun sind ähnliche Stoffe auch in anderen Präparaten entdeckt worden. Hergestellt wurden die Medikamente in China und Indien. Warum die Produktion dort so schwer zu kontrollieren ist, erklärt der Pharmakologe und frühere Bfarm-Chef Prof. Harald Schweim.

Attorney Mason Boling discusses the recent recall on Valsartan, a high blood pressure medication that is contaminated with carcinogenic substances.

The FDA says that cancer risk associated with NDMA contained in impure valsartan is definitely real, but it is very low. Also today, drinking during pregnancy could impact cognition, sexual function counseling should start early, and those with HIV a develop more frailty.

The South African Heath Products Regulatory Authority (SAHPRA) has issued a recall on blood pressure and heart condition drug, Dynaval Co, due to cancer fears. This follows findings that one of Dynaval Co's ingredients has been contaminated with chemicals that can possibly cause the disease. The contamination was found in Valsartan, which is imported from China. Similar recalls were recently made in Europe and the United States. akina Kmwendo spoke to SAHPRA's representative, Florah Matlala

Medikasie wat gebruik word om bloeddruk mee te behandel, is in twee en twintig lande van die rakke afgehaal. Die farmaseutiese maatskappy, Novartis, het sy produk Valsartan, herroep.

A review of the ARNI approved for the treatment of HFrEF.