MALE SPEAKER: I'm going to start with digitalis. The oldest medication, as you know, digoxin basically inhibits the sodium potassium ATPase. And by doing so, it also indirectly inhibits the sodium calcium exchange. Calcium accumulates in the cell, and this is how it increases contractility.

As you know, there is no difference in mortality between digoxin and placebo. However, digoxin did show improvement in heart failure hospitalization by around 25% [INAUDIBLE]. And it's still being used. So it's used in patients with low EF, less than 40%, and basically, it's class IIa indication. One has to be very careful with the dosing. As you know, 0.25 milligrams is the recommended dose.

What about diuretics? Different diuretics [INAUDIBLE] different levels of the nephron. You have the carbonic anhydrase inhibitors acting in the proximal tubule, loop diuretics in the ascending limb, thiazides in the distal convoluted tubule. And you have the aldosterone antagonist in the collecting duct.

It's very important to remember that when you treat heart failure patients, you will need a higher dose of diuretic to be able to achieve the same response. Diuretics relieve congestion, but at the same time, diuretics do activate the renin angiotensin system. And over time, you may get some resistance, because-- Especially if somebody is taking NSAIDs, you may get resistance to the diuretics.

This is an old observation showing that furosemide is superior to-- sorry-- torsemide as lowering admission of heart failure compared to furosemide. This was open label study done 20 years ago. [INAUDIBLE] is an ongoing clinical trial, which is called the TRANSFORM trial, which is a randomized study comparing torsemide versus furosemide 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 I indication C, because there are no randomized trials except which is the ongoing TRANSFORM clinical trial.

What about ACE inhibitors and ARBs? ACE inhibitors [INAUDIBLE] this level angiotensin I to angiotensin II. By doing so, you are increasing bradykinin, end which is responsible for the cough and the angioedema. And the angiotensin receptor blocker, ARB, blocks the AT1 over here. There has been several clinical trials showing improvement in mortality with the ACE inhibitors, trials done following congestive heart failure, and clinical trials for acute myocardial infarction with a 23% reduction in all cause mortality.

This is the initial SOLVD treatment trial when the initial study done with the use of enalapril and heart failure. The improvement in mortality has been shown efficacious until 10 years after the clinical trial. You can still see survival benefits with the use of enalapril with a p value of 0.01. Also, with the prevention clinical trial and patients with asymptomatic LV dysfunction, enalapril also has shown survival benefit up to 12 years.

And there is a meta-analysis pooled analysis of all the clinical trials with the ACE inhibitors showing a reduction in mortality, improvement in death related congestive heart failure, and improvement in the combined endpoint of death or hospitalization. Remember to start a small dose. [INAUDIBLE] medication is lisinopril, 2.5 to 5 up to 40, ramipril up to 10 milligrams a day. And this is a class I indication in heart failure.

If somebody is having cough issues with the ACE inhibitors, there is alternative. You can use the ARB. And this has been studied in several patients in heart failure as well as [INAUDIBLE]. MI in one of the clinical trials, which is called the CHARM trial showing that there is a-- in patients who are intolerant to ACE inhibitor can do something. It produced 23% reduction in the primary endpoint. So ARBs are class Ia indication, especially if they are intolerant. But if somebody is already on ARB or is already on ACE inhibitor, you can use the ARB. And this is a class II indication.

What about the newest medication, the combination of valsartan with sacubitril, which is known as Entresto? The sacubitril component inhibits neprilysin. Neprilysin by itself is endopeptidase which degrades several peptides including natriuretic peptides, bradykinin, and adrenomedullin. So by doing so with this inhibition, these good peptides will go up. So you will have an increase in the ANP, BNP, CNP. But the NT-proBNP is not affected by the neprilysin. So if somebody is on Entresto, the BNP may go up, but the NT-proBNP doesn't go up.

And the efficacy has been shown in the PARADIGM clinical trial in patients with heart failure and reduced ejection fraction. They're showing that there is a 20% reduction in the primary endpoint, 20% reduction in cardiovascular death, also 20% reduction in 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 inhibitor to Entresto, always try to start with a small dose if the patient is in low dose of ACE inhibitor. Or if the patient is on moderate or high dose, you can start with the intermediate dose. 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 wash out period.

If somebody has angioedema with ACE or ARB as well is contraindicated to provide this medication. Pregnancy, lactation, severe liver disease are also contraindications. When a patient has severe low eGFR less than 30, always start with the smallest dose, 24/26 milligrams twice a day. Also, it's contraindicated in patients with severe liver disease. But you can use it in mild and moderate disease. And again, you have to adjust the dose.

So ARNI, this is class I indication. You can switch from the ACE inhibitor to the Entresto. But you should not combine with ACE inhibitor within 36 hours, because you will be producing basically harm. And also, you should not administer it with the history of angioedema. Again, this is class III.

This is a very recent clinical trial. If you recall in the PARADIGM trial, it was mainly tested in mild moderate heart failure, but it didn't include class IV heart failure. This is the LIFE clinical trial, which is including class IV symptoms. However, because of COVID, the trial has been halted prematurely because of the COVID pandemic. And I'm hoping recruitment will be started soon, whether the pandemic is over. So this is a very important trial, because then you'll be able to use it in patients with advanced heart failure stage IV.

What about beta blockers? There has been several clinical trials, evaluating the effect of beta blockers in patients with heart failure and following myocardial infarction. This is a summary of all these clinical trials, showing consistent improvement in mortality.

It's important to note some differences in beta blockers. Metoprolol and bisoprolol are both beta-1 selective. Bucindolol is nonselective. It has some vasodilator action. Carvedilol is nonselective. It has vasodilated action. It also has antioxidant properties and anti-endothelin properties. And that's why carvedilol is the most common used beta blocker on the market.

This is a meta-analysis of all the clinical trials, which have shown benefits with the use of these beta blockers except bucindolol. And the reason for this, because when the clinical trial, BEST clinical trial, it didn't show any benefit between bucindolol and placebo. However, further investigation had shown that if you have arginine mutation, then you will be able to show benefit with the use of bucindolol. 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 bucindolol will work only if you have arginine polymorphism.

It's very important to start with the smallest dose-- bisoprolol 1.25 milligrams a day up to 10 milligrams, carvedilol 25 plus a day. If you have weight above 85 kilograms, you can do 50 twice a day. Metoprolol succinate, up to 200 milligrams. The calculation is very slowly and very cautiously.

Do we need to reach the target dose? The answer is absolutely yes, because the ejection fraction will go up as you are uptitrating the medication. And mortality goes down when you uptitrate the medication. So it's very important to try uptitrating the medication to the target doses. So at this class I indication to provide beta blocker in class I to IV heart failure patients.

What about aldosterone blockade? Aldosterone blockade has been tested initially with the RALES clinical trial, showing that spironolactone improves survival compared to placebo by 30% relative risk. And subsequently, eplerenone has being tested in patients with systolic heart failure and mild symptoms, again, showing 37% reduction in combined endpoint of hospitalization and cardiovascular causes, 24% reduction in all cause mortality.

So aldosterone blockade is advisable. This is class Ia indication. You can also use it following acute MI with ejection fraction of 40% or less with heart failure or diabetes. So if somebody has acute MI, ejection fraction 40%, they don't have heart failure, but they do have diabetes, you can use the aldosterone blockade, and this is class Ib indication. Obviously, it is contraindicated to use it when the creatinine is greater than 2.5 in men or greater than 2 in women or the eGFR is less than 30 or potassium above 5. [INAUDIBLE] which means you may produce some harm.

If we look at the reduction in mortality, ACE inhibitors reduce mortality by 28%. Beta blockers in the mid 1990s, there is additional 34%. Aldosterone blockade, there is additional 15% mortality reduction. And with the use of Entresto, there is a further 16% reduction in all cause mortality.

What about in patients with advanced kidney disease? Do we need to adjust the medication? And this was published last year, showing that the among the medications that may not need so much adjustment is fosinopril because of the liver metabolism. It's 50/50 kidney and liver. But you need to adjust ARBs as well if the eGFR on the lower side, less than 15.

The ARNIs, always very important to start with a very small dose. And the other strong blockade, as we said, it is contraindicated in advanced chronic disease stage IV or V when the eGFR is less than 40. In terms of beta blockers, no need to adjust except for bisoprolol. And sometimes, they ask on the board, you have a patient with advanced kidney disease on bisoprolol. They get bradycardic. What do you need to do? So it's very important to remember if somebody has advanced chronic disease stage IV or stage V, please remember to adjust bisoprolol, because they will have more bradycardia when they have chronic kidney disease because of the renal excretion.

What about vasodilators? This is the initial study showing the addition of hydralazine/nitrate in the African-American population, showing a reduction in 43% in mortality. So it is used in patients in African-American population and in patients who have kidney disease who cannot tolerate the ACE or the ARB. So hydralazine/nitrate is a class I indication for patients in the African-American population. And it's class II indication in patients who cannot tolerate ACE or ARB because of hypotension or kidney issues.

This is the impact of medical therapy in heart failure reduced ejection fraction. It's always important to know how many patients you need to treat to save one life. And this is a slide showing the mortality reduction in all cause mortality here on this with the different agents, the ACE, ARB, ARNI, beta blocker, aldosterone antagonist, and hydralazine/nitrate.

And this will give you a comparison. During the clinical trial, you need to treat 22 patients with ACE or ARB over 42 months to save one life. And this is the number needed adjusted by one year. You need to treat 36 patients with Entresto over 27 months to save one life, 28 patients with a blocker over one year to save one life, 9 patients with aldosterone blocker over 24 months to save one life, and 25 patients with hydralazine/nitrate to save one life during the clinical trial.

If somebody has congestive heart failure and basically you went all this the equation of medication with the ACE, beta blocker, aldosterone blocker, and there is still room for heart rate, you may choose to use a medication which is called ivabradine which blocks the [INAUDIBLE] of the SA node. And this is a trial done in patients with low EF, less than 35%, who are in sinus rhythm and heart rate 70 beats per minute or higher.

And in these patients, there was reduction, 18%, in all the composite endpoint of heart failure admission and cardiovascular death. There was also a 26% reduction in deaths from heart failure. But there was no significant difference in terms of all cause mortality. But very important to remember that you really need to uptitrate the ACE and the beta blocker to the maximum if you can. Then you can add ivabradine. Or if somebody cannot tolerate the ACE or beta blocker because of hypotension, and they are in sinus rhythm, and they have heart rate above 70, you can use the ivabradine.

It's very important to start a small dose, especially if somebody is above the age of 75 or history if conduction defect, 2.5 milligrams twice daily. Otherwise, you can start with 5 milligrams twice daily. Obviously, it is contraindicated in patients who have heart rate less than 60, if you have AFib or you have severe liver disease, acute decompensated heart failure [INAUDIBLE], advanced heart block. Be careful if there is somebody who has prolonged QT. You may need to start with a very small dose. So ivabradine is class II indication in patients with heart failure, ejection fraction less than 35%, provided they are on beta blocker and on guided medical therapy.

What about anticoagulation in heart failure? In the absence of AFib and the absence of prior stroke or in the absence of embolic [INAUDIBLE], there is no difference between aspirin and warfarin. And this was evaluated in the WARCEF clinical trial. And also, it was evaluated with the use of rivaroxaban in patients with heart failure and sinus rhythm, showing that there is no difference between placebo and rivaroxaban.

So antithrombotic therapy is indicated only if you have that AFib or there is cardioembolic stroke. This is class I indication. If you have just AFib, it's class II indication. But it's not advisable in patients without AFib or without any thromboembolic event.

What about statins? Statins are not recommended in patients with heart failure in the absence of indications. For example, if somebody doesn't have hyperlipidemia or coronary artery disease, obviously, there is no need for statins. It didn't show any benefit. What about omega-3 fatty acid? It has been tested in one clinical trial, showing a little bit benefit of around 6%, 7% reduction in mortality and relative risk. And that's why it's considered to be class II indication.

It's very important to avoid flecainide, propafenone, d-sotalol, or dronedarone in patients with heart failure. You may use sotalol, dofetilide, but you have to be very cautious. And amiodarone is also safe, but you have also to be cautious when you use it in patients with renal and liver issues.

What about diabetes and heart failure? The AHA included a scientific statement last year in patients with diabetes and heart failure. And this is based on several recent clinical trials. This is a slide summary of the different agents that treat diabetes. You have the agents like sulfonylureas agents that improve insulin signaling, agents that stimulate insulin release such as saxagliptin, the GLP agonists such as liraglutide and the sodium glucose transporter inhibition such as empagliflozin, canagliflozin, which cause reduced fluid retention.

And this is based on the mechanism where there is a natriuretic effect when you use the sodium glucose transporter inhibition. There is vasoconstriction of the afferent arterioles and vasodilatation of the efferent arterioles. And it has been shown in animal experiments there is reduction in tubular fibrosis as well as reduction in myocardial fibrosis with the use of these agents.

And this is the original clinical trial, which is known as CANVAS, using canagliflozin in 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 benefit in fatal or hospitalized heart failure. But it didn't improve all cause mortality. But there is significant reduction in hospitalization for heart failure.

Subsequently, dapagliflozin has been evaluated in patients with heart 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, reduction in hospitalization of heart failure by 30%, cardiovascular death improved by 18%, and all cause mortality also reduction, 17%. So this is a big deal in terms of improvement across the board with the use of dapagliflozin.

And very recently this was published with the European Society of Cardiology last month, showing that in patients in the same clinical trial that I just showed you some of these patients who were taking Entresto-- And they wanted to see if dapagliflozin, does it differ if you are taking Entresto or not?

And this slide is showing that whether you are taking Entresto or not Entresto, which means you are maybe taking other like ACE or ARB, dapagliflozin did affect the primary outcome in both conditions, did improve cardiovascular death, did improve heart failure hospitalization and all cause death. So whether or not you are taking Entresto, this medication does help in the treatment of heart failure. And one of the 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 clinical trial which I think it was discussed a month ago in the heart failure journal club using empagliflozin in heart failure called the EMPEROR-Reduced clinical trial, showing that there is a 25% reduction in primary outcome as well as a 50% reduction in hospitalization for heart failure. But they didn't find a significant mortality benefit in the EMPEROR clinical trial.

What's also interesting is that they did find that if you are taking this medication, the decline in the kidney function was slower if you are taking empagliflozin compared to the placebo. The decline is 0.55 versus 2.28 mL per minute per 1.73 meters squared. So there is improvement in heart failure, and there is also the slowing of the decline in kidney function with this medication.

And this is a very recent clinical trial. And also, I think this trial was discussed in the heart failure journal club recently, the VICTORIA clinical trial, evaluating the use of the medication, which is called vericiguat, which basically has a direct effect on the guanylate cyclase, stimulating the guanylate cyclase itself, and improving cyclic GMP, improving myocardial dysfunction, and improving the vascular function as well.

So vericiguat has been tested in patients with heart failure and ejection fraction less than 45%. And they looked at the primary outcome, composite of death from cardiovascular causes or first hospitalization for heart failure. And this was published in The New England Journal of Medicine very recently. What's interesting with this medication that there was a reduction, 10% reduction, in the primary endpoint. 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 IV when the eGFR is less than 30. And it doesn't produce much benefit when the NT-proBNP is very high, more than 5,000. 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 there is a 10% relative risk reduction between the two groups. 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 in heart failure hospitalization. And the benefit was only 10%. So I'm not sure if this medication will gain popularity in the heart failure community.

And this is my last slide showing this is an ongoing clinical trial, which is called the GALACTIC heart failure clinical trial, with the use of Omecamtiv. Omecamtiv, basically, it acts specifically on the actin-myosin bonding itself. And by doing so, it increases contractility. 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 year. I think I'm going to stop the--