Dr. J. Thomas Heywood spotlights the latest therapies for treating patients with heart failure.
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Hello. Good morning. Thank you very much for joining us today. Um, my name's Tom Heywood. Uh, this is our annual heart failure meeting, and we very much appreciate you attending in these trying times. We're certainly, uh, in the midst of this pandemic. It looks like it's accelerating, unfortunately, and so, you know, we're going to be virtual for a while beginning into next year. Fortunately, we have good news on the vaccine front, and, uh, hopefully, maybe, in January we could begin vaccinations throughout the country with some safe vaccine. So one of especially thank the sponsors is well for continuing to support this our enterprise here. This allows us to have a very reasonable cost for you to join our program and get see me credit. Very nice. Uh, program today somewhat shortened thio because it's hard to be on zoom for eight hours at a time. I've done that once. I wouldn't recommend it, but so we'll have. We'll have very compact lectures today, full of useful information and some useful cases to discuss. So with that, Scott, if you could bring up the sides will get going. Okay. Thank you. So I'm going thio. Really spotlight. Three therapies Uh, Cooper 12 Al certain SGL T two inhibitors and the use of cardi memes in heart failure in a half an hour. We don't have too much time, but I really want thio. Try to convey some of the excitement that we have for these therapies and how you can use them effectively in your patients. So the paradigm trial came out now six years ago, comparing sick uber till Valse Artan to an al a pro in patients with heart failure. This was a large trial, one of the largest trials we've ever done with heart failure over 8000 patients. C Cooper trioval certain or intrest toe is is true drugs one. It's Val Sartre in the other part is so cooper trill. So Cooper trill is a natural listen inhibitor It blocks, uh, natural ice in which breaks down naturally. Peptides. So when you take C Cooper trove al certain your BMP levels go up. This causes visibility ation that lowers your blood pressure reduces Aldo Astro own levels. So in a way, it's like a natural diuretic. One of the problems that we have with this agent is does significantly lower blood pressure and can cause significant diaries is too. So you often have to adjust diuretic doses as you use this. But it certainly met its combined in point of 20% reduction in the risk of heart failure, hospitalization or cardiovascular mortality. And it really was a clinical trial home run in that it, uh, reduced all cause mortality. Almost no therapy does this. It's never a primary endpoint because it's so difficult to reach. But any agent that reduces all cause mortality is really quite quite important because in general people don't care what they die of. They just don't want to die. So it's very important that if you see this signal, it's really strong. Sit on this Y we saw strongly try to get our patients on sick uber Jovel, certain because of this marked mortality benefit. As with any drugs, there are patients that can't get it. Any rast blocker can't be used in pregnancy, so we don't use aces, Airbnb's or spironolactone in pregnancy. Any history of angio oedema is a contra indication. So swelling of the lips or tongue in the past within a stray ARB. We would not use this agent using an ace concurrently, with So Cooper trioval certain is not recommended because and Joe Dema risk goes up so we typically stop a 36 hours before the first dose. So if you're seeing the patient on Monday and you want to prescribe prescribed the agent, you would tell them, Don't take your ace today or tomorrow and then start the sick uber trove al certain on Wednesday. There, on an ARB they need to stop for 24 hours. Hypertension is an issue. Blood pressures of 95 or so We were admitted into the study. We would certainly try it in those patients, but we would be cautious, often will use half the dose, so the lowest dose is 24 26. Um, that's 24 mg of one agent in 26 of the other. That's how it's marketed. We would use half of that dose, and we might even use half of that dose just a night if the blood pressures marginal, because that lowers the blood pressure and can cause diaries as you can see renal problems. So we always check labs within a week or so of starting at, um, we just to make sure, and like a nace. If the create names really quite bad, we wouldn't use the drug. It's not indicated if they have, uh, if they have, if they're on dialysis or if they have severe cirrhosis. So not just stop reduces heart failure. Hospitalizations. But, er visits were reduced 34%. All caused hospitalizations, reduced 16%. So really quite a significant benefit. So the paragon trialing waas looking at patients in the outpatient setting with reduced the F. What about patients in the hospital in this trial? But drug was started in patients who weren't hypertensive that weren't on nine a tropes. And they were either given analogy, Brill or C Cooper trove, all certain. And at eight weeks, there was a 44% reduction in heart failure hospitalizations for those who are started with the kubatko Val starting in the hospital. So this is really very important news. Uh, you know, readmissions to the hospital or quality indicator. They clog our hospitals Really a marker. You know, you hate it when patients get admitted again. Uh, you know, we try to avoid that at all possible. So this is an excellent agent to start in the hospital. If the blood pressure is okay, typically 95 or 100 Not on China. Tropes who are diary sing Well, it's better to start sick uber trove al starting when they're wet rather than the last moment before they leave the hospital. So it be nice They're on it a day or so before you send them home. If blood pressure way almost always started the low dose 24 26 twice a day. Obviously, if somebody comes in on an ace, you're gonna have to stop the A's for two days. So many patients now we're stopping the ace when they come in in anticipation of starting. So Cooper 12, all certain when they leave the hospital. It does have an effect on sudden death, even in patients with defibrillators. So this agent has really profoundly beneficial effects in patients with heart failure. Ah doesn't take the place of a defibrillator, but it works very quickly, and you can see that the curves separate very quickly within ah, few weeks of starting the agent. And in fact, in this study's when patient, when patients were started on it, reduced hospitalizations started within a week of starting the drug. I told you that the sick uber TRO blocks never listen and therefore BNP levels go up. So there's a different effect on in terminal B M P. BNP levels go up, but end terminal BNP goes down. The reason it goes down is because the super trove al certain reduces blood pressure and it causes a diary says so wall stress goes down. So B B and P production actually goes down a little bit, although it stays around longer and so n terminal BNP levels go down and you can see that if patients got an internal BNP less than 1000 but they really had ah, markedly better prognosis. So we use that. You know, patients often are a little reluctant to start a new drug, they say. Well, you know, I'm doing okay on my on my life center, Prell and carvedilol and Spring Blacktown. But if there be MPs over 1000 we know that their prognosis is worse. So we will we will use. This is a kind of a push to get them on. Sue Cooper trove al certain to try to get their BNP levels in terminal BNP levels below 1000. It's not really in the guidelines to tryto add therapy four BNP levels. But if it helps you get patients on guideline directed therapy, I think that's a reasonable thing to do. And patients that started off with high levels and got low levels had the same reduction in mortality is if they had started off low. So you can really markedly improve prognosis and patients that have elevated and terminal BMPs. You should still give it in patients with them or with being in terminal BMPs less than 1000. But you should really give it into the patients that have lo e f and terminal BMPs above 1000. So this data was so strong that within two years it made it into the guidelines. And what the guidelines say is that we should, uh, substitute this agent for an A. So so we started on new patients. And if patients are on an ace or a or B, even if they're quote stable, we still use this agent in them because of the benefits. Most of the patients in Paragon were class two, and even though class to patients look pretty good, that's where it had its most beneficial effect. So so So Cooper Travelstart works best in patients that have mild or even no symptoms that meet the criteria. So you have to have any F 40% or less reduced ejection fraction heart failure. So this has really become the preferred agent. And we're not using aces or a R Bs and low. We have heart failure very much anymore. Unless they can't tolerate super trioval certain so tips for using it. The drug lowers blood pressure and for some, patient has a diuretic effect. Started low dose 24 26 or half that dose. Sometimes we just use half dose of night. We may need to lower the diuretic to maintain blood pressure. We see this frequently, you know, if the patient looks, you've Olynyk and they're on a diuretic. When we start this agent, we might cut the diuretic in half. When we start sick uber 12 al certain Certainly when they come back at their blood, pressure is reduced. The first thing we try to do is change other agents like they're on and am load up in Will will reduce or stop that they're on a diuretic will reduce the diuretic and frequently is we're uptight, trading the Super 12 al certain the patient ends up on no diuretic whatsoever anymore. So that's really quite gratifying that patients may need not need diuretics. In fact, if the blood pressure remains marginal, I start to reduce the sodium restriction. I certainly take off their fluid restriction, and if the blood pressure still marginal, I'll start to liberalize their salt, and that often allows their blood pressure to come up. So, um, why the patients think I'm crazy telling them that they can eat a little more salt, but if it helps protect their blood pressure, they're not fluid overloaded, and it keeps them on. So Cooper trove else, Artan, we're really doing a benefit and, you know, think of the improvement of quality of life in the patients. If we could get them off diuretics and if they can be a little more liberal, they could be a bit more liberal in their diet. Ah really improves their quality of life. I think this is Ah, this is really the preferred agents and I can't overemphasize enough. Anybody with low, we have heart failure. You have 40% or lower. They should be on this agent if it all possible and we go to great lengths, half does. And we just published a paper where half dose lowered, um, and terminal BNP quite a bit. So even have some data that it has physiologic effect at that dose. The next kid on the block are sodium glucose co transport inhibitors, CSG lt two inhibitors. These agents are we're substances Vly developed for diabetes. But our have a major role now in patients with coronary disease and congestive heart failure. The way they work is in the glamorous Aeolus. The all the glucose because it's such a small molecule is filtered and it gets re absorbed either in the proximal tibial or the descending loop of Henley, where about 10% of it is re absorbed by STL t one, uh, transport mechanism. So most of its re absorb if you've given S t l t two inhibitor, it blocks some of this re absorption. So glucose remains in the collecting system and excreted into the urine. So the qualities that really make thes attractive agents for heart failure and diabetes is that there one tablet once daily, you could take them any time. But AM is recommended. And for diabetes that lowers a one C about as well as any pill. About 10.5 lowers fasting. Blood sugar. There's no there's almost no hypoglycemia because as glucose levels go down than less, glucose is excreted into the urine. A realtor tremendous side effect of these agents is you see weight loss of 3 to 5% of body weight. So patients typically lose about £8 which they love. It lowers blood pressure. It lowers triglycerides. Um, you know, they have minimal side effects. UT eyes are the same, but in women they have more genital yeast infections. So you have to warn them about that so they can be ready to treat that if it happens. But most women don't get these infections, but it can be seen. But U T eyes are not seeing more commonly either in men or women. So the first riel data that came out about the SD lt in two inhibitors in coronary disease was the Emperor wreg trial impact local flows in on this was a safety trial because many diabetic agents actually increased cardiovascular events. The FDA required that all agents, um, be put through a safety test. And so this was a large trial. Or patients either got placebo or impact low flows and at two different doses to make sure that it was safe. We knew that lower blood sugar. We just want to make sure that there weren't cardiovascular increasing cardiovascular events. Well, the surprising thing. And actually, when this data was presented in Copenhagen five years ago, people people actually got up and cheered because they had never seen any data like that and to get endocrinologist up on their feet to cheers. Pretty amazing. So it certainly met its primary outcome, which was cardiovascular death, non fatal in Mayan stroke. But death from cardiovascular causes was really reduced. And that's where this where most of the endpoints were driven and so cardiovascular deaths were reduced by 38%. So not only was it it's safe, but it was much safer than placebo. I mean 30. This was just shocking. And the other thing is, as I mentioned with Sue Cooper travel, certain death from any cause was reduced. So these were patients that had overt coronary disease and diabetes that really high risk group and you'll notice that the end of the trial the placebo group really had an increase in events. So this is a very high risk population, and in particular that flows and really helped to stabilize them. So, uh, this this was amazing data. And then what was really unexpected was hospitalizations for heart failure reduced. And look at this. Notice how quickly these, uh, there's a reduction in heart failure. Hospitalizations. They were reduced by 35%. Now, this was not a primary endpoint. So this can This has to be, um, hypothesis generating. But this really got people's attention about this reduction. And how does this work exactly? By now might be from lowering blood pressure Might be from losing weight. When you When you taken SGL two inhibitor, you excrete about 80 g of glucose a day in your urine. So that's about 300 calories a day that you lose in your urine. So that's why you have weight loss. But the glucose may take along with its sodium in the water is well, so there may be a diuretic effect. So, um, so the next study waas um Emperor reduce. So this was these were cardiovascular outcomes and patients with heart failure, Not necessarily diabetes. Um, So these patients were given, uh, in popular flows in and some of them had diabetes, but many of them didn't. They had reduced, uh, ejection fraction. Heart failure. Scott, can I go backwards? Is that okay? One more. Good. So this was the primary endpoint you can see here. So it met its primary endpoint. Cardiovascular death, heart failure. Hospitalization reduced by 25%. Next slide. And this was this is first and recurrent heart failure. Hospitalization reduced 30%. So this was also shown with another SD lt two inhibitor and definitely flows in. So we now so which has actually been approved for heart failure. Uh, Pegolo frozen is not approved yet for heart failure. So probably by next year we'll have two agents that are approved for heart failure. Certainly in diabetics were using this agent, and we're using it in non diabetics as well. You don't see much blood sugar reduction in non diabetics. That's not what we're using it for, but certainly in our patients that have coronary disease and diabetes are patients with heart failure. We're starting to use these agents, even if they don't have diabetes because of the significant reduction in heart failure. Hospitalization. We don't see the mortality benefit that we saw in people with diabetes and coronary disease, But there are very high risk group. We certainly see ah, heart failure, hospitalization reduction Now not only that, but there's a benefit in kidney issues, and this is so initially you see a drop in G fr compared to placebo. But over time the GF are stabilizes and actually becomes fairly flat line compared to placebo. We know in heart failure patients there, um, renal function declines over time and that becomes an issue with treating them. They retain more sodium. If we can maintain renal function, that's gigantic in our patients. So in the tri ALS, we actually saw a 50% reduction in the need for dialysis, renal transplant or profound drop in G F. R. 50% drop. So these agents can help preserve renal function. Aziz well as helping to keep patients out of the hospital. In fact, one of the reasons they may help keep patients out of the hospital is that they do preserve renal function. Now you might see a drop or rise and creating it first. But don't be. You know, if it's a mild trump, don't be concerned about that. You might need to drop, uh, hieratic just like we do in sick uber trove Al Certain. But over time GF, I will will be benefited by being on these agents. We typically don't use them. If the GFC is less than 30 you need some GF are so they don't work in dialysis patients. But that may be that they work even with Jafar is less than 30 that's being studied. But right now, about 30 is when we stop using them. So deaf aglow flows in in heart failure reduced the f, uh benefit as well. And this has actually been approved from heart failure, and death from any cause was reduced by 17%. So benefit here. This is a larger trial, so really too strong signals to different of these agents MPA and dapa of the STL to two inhibitors we can use in heart failure. And we're starting to use them in hospitalized patients as well so that they go home on this therapy a swell as Sue Cooper trove all certain so heart failure therapy really consists of four major evidence based drugs. Now the so cooper 12 al certain the beta blockers, specifically carvedilol or long acting beta, long acting beta block metro pre law, uh, the old Austrian antagonists and now the S T l T two inhibitors. So tips for using these agents and heart failure they're not for type one. Diabetics. Not for GF are less than 30. They do increase general or yeast infections and women, but most women don't get them. Hypoglycemia is extremely rare to non existent. May need to decrease diuretics with them as they lose weight. So the last thing I wanted to talk about was, um, the cardi Memes device. This is a device that we put in the pulmonary artery to measure the P A pressure. It's a passive device and meaning that doesn't have an electrical system. As a capacitor here, who's capacitance is affected by the blood pressure. So when we put this in the pulmonary artery, we get papa pressures from the patient. This is what it looks like. We could see the P a systolic pressure, the diastolic pressure and the mean pressure, and our nurses look at thes once a week and we can adjust therapy to lower. The pressure is now. Ordinarily, it's diuretics, but now we can use SGL T two inhibitors or are Super 12 al certain to lower the PPA pressures in the patients? Um, it reduces hospitalizations by about 35% and 38% at 15 months. In the randomized controlled trial, we're doing a large trial now called Guide HF. This is 3600 patients. Very large. Trial doesn't have any F criteria, requires either our prior heart failure, hospitalization or an elevated BMP. There's a randomized arm of 1000 patients for 12 months. Half we see the pressures immediately. Half we don't see them for a year. This We've enrolled completely in this study now, and we're waiting December January to get results to see if there's a mortality benefit with doing this. We know there's a hospitalization benefit. We want to see if there's a mortality benefit. There's a 26 100 non randomized group. Um, where we, um we're trying to answer the question is B and P. Ah, useful marker for need for cardio memes. In other words, we have right Now you have to wait for hospitalization. But could we if they haven't elevated BNP, Is that enough of a signal to put into cardi memes? So we're going to get that. That part of the study is still enrolling. So, um, end of the slide deck. I wanted to just summarize briefly. You know, these I can't overemphasize how important these agents are currently sick. Uber 12 Al Sartain has really been a game changer for us. We have hundreds of our patients now on this agent and we see patients with EFS improving quality of life improving more functional, less diuretics, really beneficial. The G l t two inhibitors or the new kid on the block There quite beneficial is well, they're really benefit is maintaining renal function over time, but also reducing heart failure. Hospitalizations. Your patients have coronary disease, and, uh, and diabetes. It really reduces all cause mortality as well. So quite benefit. And then the cardio memes that we use in patients, no matter what their efs. I'm just saying So Cooper Jovel starting the one negative trial it didn't work in heart failure would preserve DF unfortunately, or trying to see if there's a subgroup or that might work. So I think my time is up this point. Try to give you a brief overview. Lots of exciting things going on in heart failure. Thes days. And, uh, I really hope that you'll embrace the use of super trioval certain and the SCG lt two inhibitors in your patients with heart failure. So thank you very much.
