Mohamad H. Yamani, M.D., a heart failure cardiologist, and the director of the Heart Failure Clinic at Mayo Clinic in Florida, presents in the Advanced Heart Failure Grand Rounds series on the pharmacology of heart failure.
I'm going to start with Digital is the oldest medication. As you know the jocks and basically an average the southern part of potassium at PS and by doing so it also direct indirectly. And it was the sodium council exchanges calcium accumulates in the cell. And this is how it increases conductivity. As you know. There is no difference in mortality between the johnson a placebo. However, the johnson did show improvement in heart failure hospitalization by Iran 25% and it's still being used. So it's used in patients with lawyers less than 40%. And basically is class two a Indication one has to be very careful with the Uh dozing as you know, 0.25 mg is the recommended. Uh those what about diabetics, different diaries acting got different levels of the Neff Ron. You have the cap on and hydrate inhibitors acting and approximately to you. Loop diuretics and they're sending them fire size and the continuity table. And you have the eldest Ron antagonists and the collecting. It's very important to remember that when you treat heart failure patients, you will need a higher those of diabetic to be able to achieve the same response, Direct relief congestion but at the same time directed, do activate the Iranian Angela 10cent uh system. And over time you may get some diet. There's some resistance because especially if somebody is taking and said you may get a resistance to the diabetics. This is an old observation showing that here's my is disappeared SRE torso. Mine has Laurie admission of heart failure compared to yours. Mine This was open level study uh done 20 years ago. However, there is an ongoing clinical trial which is called the transform time, which is a random I study comparing torso might versus curiosity might for the management of congestive heart failure. I think the recruitment will be done by the end of this year and we'll have some results next year diuretics till now is class one indication. Uh See because there are not randomized trials except which is the ongoing transform clinical trials. Yeah. What about AIDS initiatives? And they are these takes initiatives, Acts of this level angiotensin one to agent Tencent two by doing so. You are increasing braddock in in which is responsible for the cough and the NGO a demon And the angiotensin receptor blocker. AARP blocks the 80 one over here there has been some clinical trials showing improvement in mortality with the ace inhibitors trials down following congestive heart failure and clinical trials for acute myocardial infarction With a 23 reduction in all cause mortality. This is the initial sort treatment trial when the initial studying done with the use of an electoral and heart failure. Uh the improvement in mortality has been shown efficacious Until 10 years after the clinical trial. You can still see survival benefit with the use of uh uh huh With a P value of 0.01. Also with the prevention clinical trial in patients with asymptomatic LV dysfunction. An Electoral also has shown survival benefits Up to 12 years. And there is a meta analysis calling analysis of all the clinical trials with ace inhibitors showing a reduction in mortality improvement and death related congestive heart failure and improvement in the combined endpoint of death or hospitalization. Remember to start the small those muscular and medication is largely local. 2.5-5 after 40 Remarkable up to 10 mg A day. And this is the last one indication and heart failure. If somebody is uh uh having cough issues with ace innovators, there is alternative you can use the AARP and this has been studied in several patients in our failure as well as following am I. And one of the clinical trial which is called the charm trial showing that there is a in patients who are intolerant, ace inherited Can be something that produce 23% reduction in the primary uh important. So A RVs are class one a indication especially if they are intolerant. But if somebody is already on A. R. V. You can still uh it's already on eighth, inevitably you can use the A. R. B. And this is a class two indications. What about the newest uh medication? The combination of uh certain with secretary which is known as the intestinal uh the secretary of component uh inhabit naturalism. Uh Naturalism by itself is uh 30 days which degrades several practices including athletic baptized by the kind and the villain. So by doing so with this inhibition. These good baptize will go up. So you have an increase and the M P B M P C. M. P. But the anti pro BMP is not affected by the relation. So somebody is an interest of the BMP may go up but the anti pro BMP doesn't uh go up. And the efficacy has been shown in the paradigm clinical trials and patients with our failure and reduced ejection fraction. The showing that there is a 20% reduction in the primary endpoint, 20% reduction in cardiovascular death. Also 20% reduction and hospitalization for heart failure And 16% reduction in all cause mortality. It's very important to allow a wash out period of 36 hours when you are changing from ace inhibitors to antipasto. Always tried to start with a small dose. If the patient is in law those of ace inhibitor or if the patient is on moderate or hide those, you can start with the intermediate those and you need to adjust in patients who have kidney disease and liver disease. So it is contraindicated to start it within 36 hours. And that's why it's mandated to allow this washout period if somebody has Andrea medina with Ace or A R. B. Uh as well as contraindicated to provide this medication pregnancy lactation, severe liver disease. Also contra indication When a patient is have severe pathology of are less than 30. All start with the smallest doors 24 26 mg twice a day. Also it's contraindicated in patients with severe liver disease but you can use it and mild and moderate disease and again you have to adjust the dose. So er and i it is a class one indication you can switch from uh the ace inhibited to the presto. But you should not Combined with ace innovator within 36 hours because you will be producing basically yeah harm. And also you should not administer it with the history of Angela de McCain. This is class three. This is a very recent clinical trial. If you recall in the paradigm trial, it was mainly tested and my moderate heart failure but it didn't include class port or failure. This is the light clinical trial which is including class for symptoms. However, because of covid, the trial has been halted prematurely because of the covid pandemic and I'm hoping it will be recruitment when we started soon whether the pandemic is over. So this is very important trial because then you'll be able to use it in patients with advanced are further stage four. Yeah. What about beta blockers? There has been some clinical trials evaluating the effect of debate of walkers in patients with heart failure and following my garden function. Uh This is a summary of all these clinical trials showing consistent improvement and mortality. It's important to know some differences in beta blockers, NATO cologne and the zocalo are both data and selective. Using the law is non selective. It has some basal dilator action. carvedilol is non selected. It has basal dilator action also has anti oxidant properties and anti on the field and properties. And that's why carvedilol is the most common use the beta blocker on the market. This is a meta analysis of all the clinical trials where which have shown benefit with the use of these beta blockers. Except you send them all. And the reason for this because when the clinical trial best clinical trial, it didn't show any benefit between the use of the law and placebo. However, further investigation has shown that if you have arginine your patient, then you will be able to show benefit with the use of this underdog. But obviously this is not practical to do a genetic polymorphism evaluation to provide this medication because you do have other beta blockers. So, remember that the center lol will work only if you have arginine polymorphism. Okay, It's very important to start with the smallest doors. These are probably 1.25 mg. Once a day, Up to 10 Milligan carried along 25 twice a day. If you have weight above 85 kg, You can do 50 twice a day. The chopper to assassinate up to 200 mg. Detective fiction is very slowly and very cautiously. Do we need to reach the target? Those? The answer is absolutely yes. Because the ejection fraction will go up as you are updating the medication and mortality goes down when you after trade the medication. So it's very important to try after trading medication to the entire year. Uh does is So it is class one indication to provide the beta blocker in the class 1-4 heart failure patients. What about at the strong blockade. Other? Some blockade has been tested initially with the clinical trial showing that spironolactone improve survival compared to placebo By 30% relative And subsequently after Iran on has been tested and patients with systolic heart failure and my symptoms again showing 37% reduction and combined the in point of hospitalization and cardiovascular causes 24% reduction in or cause mortality. Yeah, So Alderson on blockade is advisable. This is class one a year Indication. You can also use it following acute M. I if the ejection fraction 40% or less. Well, heart failure or diabetes. So somebody has acute rejection fraction 40%. They don't have heart failure, but they do have diabetes. You can use the uh the other surround block it. And this is plus one. Be indications obviously it is contraindicated to use it when the creatinine is greater than 2.5 and men or greater than two in women or the G. F. R. Is less than 30 or potassium about five. This is glad. Which means you may produce some heart. Yeah. Look at the reduction in mortality. These narratives using mortality about 28% beta blockers. In the mid 1990s there is additional 34 At the Syringe Blockade, there is additional 15% mortality reduction. And with the use of the interest. So there's a further 1316% reduction in all cause mortality. What about impatience with the advanced kidney disease? Do we need to adjust the uh medication? And this one was published last year showing that among the education that may not need so much adjustment is force inoperable because of the liver metabolism. It's 50 50 kidney and level. But you need to adjust a RDS as one The gr far on the lower side, but less than 15 the air and I is always very important to start with a very small does and the other strong blockade, As we said, it is contraindicated them advanced chronic disease Stage five when the G F R four or five when the G f R. Is less than 40 in terms of beta blockers, no need to adjust except for visit problem. And sometimes they ask on the board, you have a patient with advanced kidney disease, the sambisa crawl, they get credit card what you need to do. So it's very important to remember somebody is as advanced chronic disease stage four or stage fire. Please remember to adjust deserve at all because they will have more bradycardia when they have chronic kidney disease because of the original exhibition. What about these oscillators? This is the initial study showing the addition of hydrazine nitrate in the african american population showing a reduction in 43% and uh mortality. So it is used in patients in african american population and in patients who have killed the disease who cannot tolerate the ace or the So how does the United States is a class one indication for patients and the african american population and its plans to uh indication who and patients who cannot tolerate ace or RB because of hypertension or kidney issues. This is the impact of medical therapy and heart failure. Reviews ejection fraction. It's always important to know how many patients we need to treat to save one life. And this is its light showing the mortality reduction and all cause mortality here on this with the different agents the S. A. R. B Air and I better blocker. Restaurant, darkness and I as the United States. And this will give you a comparison during the clinical trial. You need to treat 22 patients with ace or will be over 42 months To change to save one life. And this is the number needed adjusted by one year. You need to treat 36 patients with interest over 27 months To Save one Life. 28 patients with beta blocker over one year to save a life. My patients with others around blockers Over 24 months to save my life And 25 patients with others United To Save one Life during the clinical trial. If somebody has congestive heart failure and you basically you went all these uh the equation of medication with the ace beta blocker, Alderson blocker, a blocker and there is still room for heart rate. Uh You may choose to use uh education which is called everybody in which blocks the uh the family current of the S. A. Note. And this is a trial done in patients with lawyer f Less than 35%. What in Sinus Rhythm and Heart a 70 beats per minute or high. And then these patients there was reduction 18% in all in the composite endpoint of heart failure, admission and cardiovascular. There was also 26% reduction and death from our failure. But there was no significant difference in terms of all costs mortality. It's very important to remember that you really need to update the ace and the beta blockers to the maximum. If you can't then you can or if somebody cannot tolerate the ace or beta blocker because of hypertension. And they are in Sinus to them and they have heart shaped above 70. You can use the everybody. It's very important to start a small door especially if somebody is above the age of 75 or history of conduction defect 2.5 mg twice Uh daily. Otherwise you can start with five mg twice daily. obviously this country indicated. And patients who have less heart rate less than 60 if you are a third or you have severe liver disease acute the compensated heart failure. Six Signers advanced our block. Be careful if there's somebody has from beauty. You may need to start with a very small dose. So everybody in is class two indication and patient with our failure. Less injection. Fresh fraction less than 35 uh person provided. They are in beta blocker and unguided Medical. Yeah, exactly. What about anti correlation and heart failure? In the absence of a ship and the absence of price stroke or in the absence of uh symbolic issue. There is no difference between aspirin and warfarin and this was evaluated and we washed a clinical trial and also it was evaluated with the use of uh Iraq Sudan and patients with heart failure and sound system showing that there is no difference between placebo and the works. So anti traumatic therapy is indicated only if you have if all the restarting bullet stroke. This is class one indication If you have just a third class to indication but it's not advisable in patients without if or without any trouble, symbolic event. What about status. Status are not recommended in patients with our failure in the absence of indications, For example, if somebody doesn't have Hyperloop Idina or coronary artery disease, obviously there is no money for statins. It didn't show any benefit. What about Omega three fatty acid? It has been tested on only one clinical trial showing a little bit benefit of around like 6 7% reduction in mortality and uh the rest. And that's why it's considered to be class to uh indication. It's very important to avoid flick and I progressing on the satellite or drone. In patients with our failure. You may use a little the fertilized but you have to be very cautious and any drone is also safe. But you have also to be cautious when using patients with regional and global issues. What about diabetes and heart failure? The H. A. Included a scientific statement. Lost Steel and patients with diabetes and part and this is based on several recent clinical trials. This is a summary of the Islamic summary of the different asians that you treat them diabetes. Yeah, the agents like someone uh areas agents that improve insulin signaling signaling agents that stimulate insulin released such as sex like Lippmann, the GLP agonists such as lyrical style and the saw them glucose uh transported inhibition such as empathy 1000 cannot cannot three laws in which cause reduced fluid retention. And this is based on the mechanism where there is a naturalistic effect when you use the sodium glucose transported. In addition, there is very the construction of the different arterials and vessel dilatation of the different art of yours. And it has been shown in animal experiments. There is a reduction in tubular fibrosis as well as a reduction in my garden fibrosis. With the use of these agents. And this is the original clinical trial, which is known as canvas using kannami, the frozen and heart failure. The initial trial involved heart failure, reduced ejection fraction as well as preserved ejection fraction. And it showed a benefit in terms of combined endpoint cardiovascular death or hospitalization for heart failure. There was also benefits and fatal or hospitalist our failure, but it didn't improve all cause mortality. But there is one significant reduction and hospitalization for our failure. Subsequently publicly frozen has been evaluated in patients with our failure and reduced ejection fraction. And this was published last year in the New England Journal of Medicine showing that there is a significant benefit across the board in terms of primary outcome by 26%. reduction in hospitalization of heart failure, body, 30%. Cardiovascular death improved by 18 And all cause uh, mortality also reduction 17%. So this is a big deal in terms of improvement across the bowl. With the use of uh uh basically frozen. Yeah. And very recently this was published uh with the European Society of Cardiology last month showing that in patients in the same clinical trial that are just show you some of these patients were taking in tiesto and they wanted to see uh frozen. Does it does it effect doesn't differ if you are taking interest or not. And this slide showing that whether you are taking interest though or not interested, which means you are maybe taking other like case or are definitely, definitely frozen did affect the primary outcome. And both conditions did improve cardiovascular death did improve heart failure, hospitalization and all caused. Uh, so whether or not you're taking interest with this medication does help in the treatment of our trailer. And one of the uh uh experts in the european Society of Cardiology was commenting that this is a medication more for heart failure rather than for diabetes. So this is something to remember. And this is a very recent uh clinical trial, which I think was discussed a month ago in the heart failure. General clark using empathy frozen and fairer for the emperor reduced clinical trial Showing that the there is a 25% reduction and primary outcome As well as a 30% reduction and hospitalization for heart failure. But they didn't find a significant mortality benefit in the Emperor Clinical. That's right. What's also more interest was also interesting is that they did find that if you are taking this uh medication, the decline in the kidney function was slower. If you are taking in public flows in compared to the placebo, The decline is 0.55 versus 2.2 AM. L per minute, 1.73 m square. So there is improvement in heart failure and there is also the slowing of the decline kidney function with this medication. And this is a very recent clinical trial. And also I think this uh this trial was discussed in the hardware journal uh clock recently the victoria clinical trial uh evaluating the use of the medication which is called face very single, which basically it it has a direct effect on the grand ole cyclist stimulating the one elite cyclists itself and improving site click GMP improving my garden uh dysfunction and improving the vascular dysfunction as well. So basically what has been tested in patients with our failure and ejection fraction less than 45%. And they looked at the primary outcome, composite of death from cardiovascular causes or first hospitalization for our. And this was published in the new England Journal of Medicine very recently. Was interesting with this medication that There was a reduction in the 10% reduction in the primary uh endpoint. And but there was no difference in terms of all cause mortality. And if you look at this slide here, you will notice that it doesn't produce much benefit if you have Chronic kidney disease stage forward when the GF. R. is less than 30 and it doesn't produce much benefit when the anti pro BMP is very high, more than 5000. So it does have some benefit in patients who have mild to moderate heart failure and mild to moderate kidney disease, but not advanced heart failure or not advanced chronic disease. So the there is a 10% relative risk reduction between the two rules, and this means that you need to treat 24 patients for one year to achieve this benefit. But we have to remember that it didn't affect all cause mortality. And I'm not sure if this medication will fly in the market because the benefit was mainly anarchistic hospitalization And the benefit was only 10%. So I'm not sure that this medication will gain popularity and the our sale in the community. Yeah. And this is my last slide showing the this is an ongoing clinical trying which is called the uh galactic heart failure clinical trial with the use of army camped in on the counter basically at acts specifically on the accent Myerson bonding itself. And by doing so it increases uh contra activity. So uh there are a lot of uh the primary objective is to compare it on cardiovascular death and heart failure, hospitalization. And this is an ongoing clinical trial. They started the recruitment in 2019 last year. And hopefully we'll have some. The recruitment will end by next. Yeah, I think I'm going to stop.