Treatment of Chronic Systolic Heart Failure (HFrEF)

*Now ✨updated✨ with the 2022 ACC/AHA/HFSA Guidelines*

Now that we’ve gotten a clearer grasp on what systolic heart failure is in our heart failure talk, let’s talk about how we classify these patients, how these patients present, and then focus on treatments for these patients in the outpatient setting.

How do we classify heart failure patients?

When talking about how we classify heart failure patients, we like to classify them based on two things:

1. Structural disease of their heart and
2. Symptoms

Structure – ACC/AHA Stages

First let’s talk about the ACC/AHA heart failure stages. This classification system focuses on structural disease.

Stage A.	At risk for heart failure but without structural heart disease or symptoms.
Stage B.	Structural heart disease but without symptoms
Stage C.	Structural heart disease and with prior or current heart failure symptoms.
Stage D.	Refractory heart failure requiring specialized interventions.

Note that class A being patients who haven’t yet developed heart failure but are at high risk based on certain factors (have hypertension, CAD, diabetes, etc) and class D being our refractory (resistant to treatments) end stage patients who have structural disease and symptoms even at rest.

Symptoms – NYHA Heart Failure Classes

Next we have to define patients’ symptoms. We have the NYHA (New York Heart Association) functional classification system for that.

Class 1.	No symptoms and no limitation in ordinary physical activity.
Class 2.	Mild symptoms and slight limitation during ordinary activity.
Class 3.	Significant limitation in activity due to symptoms. Comfortable only at rest.
Class 4.	Severe limitation. Symptoms even at rest.

Now…question for you. Check out both classification/staging systems above ⬆️⬆️⬆️⬆️.

When looking at the stages and the classification systems, are any of them reversible?

In other words, can you “go back” and “improve” between classes (e.g. class D->C or Class B->A) or between stages (e.g. class 4->class 3 or class 2->class 1)?

It should make sense that it’s possible to improve in symptoms (aka NYHA classes) but not in structure (ACC/AHA stages). Once a stage C, always a stage C, until your patient may unfortunately upgrade to class D.

Symptoms can improve, and so just because you’re a class 3 doesn’t necessarily mean you will stay in class 3.

Presentation – How do these patients look?

Let’s talk about what signs and symptoms these patients may have on the outpatient setting. As a refresher, a sign is something that can be objectively seen/observed by someone else (e.g. pulmonary edema on a chest Xray (CXR)) whereas a symptom is noticed and experienced only by the person who has the issue (e.g shortness of breath, sore throat, anxiety (hi it’s me)).

When I think of chronic heart failure, my mind immediately thinks of coughing, orthopnea (the need to use multiple pillows to be able to sleep at night), shortness of breath, peripheral edema, fatigue, reduced inability to exercise, nausea and loss of appetite.

But why are these seen? What about heart failure makes this happen?

It all goes back to pathophysiology and understanding what’s physically happening in the body.

In systolic heart failure, your heart (i.e. your left ventricle) has a really crappy squeeze and contraction force. The force behind the majority of all the above s/sxs all boils down to volume overload as a result from that crappy heart.

Volume overload happens for a couple of reasons in heart failure. Think about what is happening.

First, the heart cannot pump blood efficiently or effectively through the body.

The left ventricle (LV) is struggling to get that blood pumped out of the heart. Because the LV is unable to handle the blood volume load, you can see pressure build up in the LV and that congestion/pressure starts slowly backing up further and further.

The pressure will backup from the LV back to the left atrium (LA) and eventually back up into the pulmonary veins and back up into the lungs (check out that diagram below and mentally trace that pressure as it backs up into each structure). As that pressure builds, that extra volume will now start to leak out into the lung’s vasculature and leak out into the lung tissues, causing pulmonary edema, coughing, and shortness of breath.

Occasionally these patients will be OK at baseline but what will happen to the “demand” of the body as they exert themselves (exercise, walk up stairs, etc)?

Increase! More exercise/exertion/etc. means more oxygen needed to the tissues.

Unfortunately their weak hearts cannot keep up with this demand and their symptoms will start worsening with exercise or exertion.

When adaptive becomes maladaptive….

You know that feeling when your friend or significant other or spouse or whoever is trying to help you with something and you wish they just…..could stop? (because they are really not helping that much but you don’t want to be mean)?

Well, your kidneys are kinda like that in heart failure.

*sigh* those kidneys.

The kidneys of these patients are trying so hard to help.

They really want to help with what they think is happening. In patients with chronic heart failure, receptors in the kidneys will see a decrease of blood flow to them due to a decrease in cardiac output, and in turn they will activate the renin-aldosterone-angiotensin system.

Now, no one really told the kidneys what the issue here really is – aka the heart muscle is weak/has died – the problem is a struggling heart!

The kidneys just know that they saw decreased blood flow/pressure to them and they want to fix that. By activating the RAAS (renin aldosterone angiotensin system), they will cause two main things to happen:

1. vasoconstriction of vessels via angiotensin II
2. retention of sodium and water via aldosterone

This actually kinda makes everything just…..worse.

Not only does your crappy LV now have to push against an even higher afterload, but now it has to fight to push out higher and higher blood volumes. This volume overload leads to congestion and what we call “third spacing” which is when fluid will start leaking out of your vessels and into your tissues and viola! Peripheral edema.

Now even though we tend to see the most edema in the lower extremities in adults, it can happen in other places too – including the gut/GI tract. And as we get edema in these areas, we get less absorption of certain elements (I’m looking at you, iron), and patients tend to get nauseous and lose their appetite.

Keep in mind that these are all some signs and symptoms patients can experience chronically on the outpatient setting but still “compensate” (e.g. get enough blood to their organs). We’ll talk about acute decompensated heart failure (ADHF) – when these patients need to get hospitalized – another day.

Treatments

Now let’s talk about what our backbone therapies are to treat it and how we classify these patients. Luckily the American College of Cardiology (ACC) did a recent 2021 update for the treatment of HFrEF.🎉🎉🎉🎉🎉🎉🎉

I want to stress that this is only for the treatment of HFrEF or systolic heart failure.

Because the pathophysiology of diastolic heart failure (aka HFpEF) is so different, you will also see that treatment of HFpEF is completely different as well.

To really appreciate where we are today, you’ll have to come on the trip with me to see where we came from and how we got started. We’re going to go through history and see how these therapies came to be.

This is also a friendly reminder for those with imposter syndrome (👀👀👀👀) that before the 80s, we really relatively didn’t know anything about how to help out these patients. So, most of this stuff is actually fairly new knowledge. And experienced cardiologists were lucky enough to truly live through each one of these exciting breakthroughs as they came out in real time.

So. You ready? Let’s go back in time….

The year is 1986. The smell of hairspray is in the air. You are surrounded by bright colors and spandex. You hear the sound of Madonna playing in the distance.

This was in the age before good guideline directed medication therapy (GDMT) existed for systolic heart failure. The treatment of HFrEF at this point mostly focused on helping symptoms through the use of diuretics to help with volume overload and a sprinkling in of some digoxin.

It all started with an idea: It was postulated that if patients have symptomatic heart failure, then maybe use vasodilator therapy – dilate out the veins and arteries – could help to decrease afterload (and preload) and help that weakened heart get blood out more effectively. This makes a lot of sense if you think about it …. by dilating out our venous side, we would reduce preload entering the heart and by dilating out our arterial side, we could reduce afterload and try to decrease the amount of work that sad LV has to work against. (if you don’t know what I mean by these terms, you should check out our talk on preload and afterload)

Docs everywhere were already prescribing vasodilators to their HFrEF patients based on this idea.

It wasn’t until 1986 where we actually had some robust data come out about whether or not these vasodilators treatments actually do anything to reduce mortality in these patients.

Cue the V-HeFT trial.

The V-HeFT trial was a trial with n=642 that compared isosorbide dinitrate/hydralazine vs. placebo vs. prazosin (a three arm study) with a 2.3ish year follow up. Like mentioned above, the idea was that use both hydralazine and nitrates would lead to both a decreased preload to help with volume overload and decrease afterload to help out that LV.

TLDR: The V-HeFT trial found that using isosorbide dinitrate in combination with hydralazine showed a numerical trend towards improved survival but nothing came out to be statistically significant.

Of note…..it wasn’t impressive enough to get an FDA indication at the time.

But at the time it’s all we had so 🤷🤷🤷🤷.

The V-HeFT trial will come up again later in today’s talk so stay tuned………👀👀👀

ACE Inhibitors and ARBs

Alright, so the use of hydralazine/isosorbide dinitrate (ISDN) didn’t pan out to be THAT great but at least it wasn’t hurting our patients, right? But we still didn’t have anything really robust to help out our HFrEF patients – nothing to help extend their lives.

But another big class of medications gained momentum in the 80s – the angiotensin converting enzyme inhibitors (ACE-Is). Although these agents also decrease preload and afterload, unlike our ⬆️⬆️ vasodilators (e.g. hydal/ISDN), ACE-I do not work by directly working on the vessel wall.

With the advent of angiotensin converting enzyme inhibitors (ACE-Inhibitors aka ACE-Is), the effects of how these ACE-Is would affect HFrEF wasn’t really known.

Cue the CONSENSUS trial, released in 1987, which randomized n=253 to enalapril versus placebo with mortality as a primary outcome. With an average follow up period up period of 188 days, they found that 6-month mortality was 26% in the enalapril group versus 44% in the placebo group, with a NUMBER NEEDED TO TREAT OF 6. That means that for every six patients you treat with enalapril, at 6 months, you are preventing the death of one of your patients.

OK let’s back up. I really need a minute.

First of all, the fact that these above trials were against placebo should be a little mind blowing but it just shows you that we really had diddly squat up our sleeves at the time for treating these patients and we didn’t have anything to decrease death.

Just to help confirm these results, the V-HeFT II trial compared enalapril versus the combination of ISDN/hydralazine and again saw a crazy benefit of enalapril over the combo of ISDN/hydralazine in regards to death at 2 years with a number needed to treat of fourteen.

Because of all ⬆️⬆️⬆️⬆️⬆️⬆️ the above, you probably guessed it – ACE-Is (and multiple trials proving that ARBs had a similar effect) and ARBs became a class 1, level of evidence A, you better have all your patients on these meds unless you have a damn good reason not to, update in our heart failure guidelines because ACE-Is or ARBs decrease death in these patients and decrease hospitalizations and morbidity.

Hopefully the idea behind why these meds are so helpful in this disease state also makes a lot of sense. Remember how those kidneys were trying to help but not doing a good job and just actually making everything worse for our patients? yeah. *shudders*

These meds will stop that maladaptive process from going on by decreasing preload and afterload by preventing angiotensin II from working and relaxing up that vasculature. Less preload, less blood that the heart has to pump out; less afterload, the less pressure that the heart has to pump out against. Other trials also proved this point (e.g. SOLVD, ELITE I and II, CHARM-Alternative, CHARM-Added, and Val-HeFT).

So, I want you to remember. Guideline directed medication #1 for our heart failure patients:

1. ACE-I or an ARB

Ok so ACE-I or ARB ✔️.

Let’s move that time machine forward to the 90s – yay, I exist now!

OK so it’s the 90s. AIM/AOL and hotmail is all the rage (PS if you still use your AIM, AOL, or hotmail email accounts……time to upgrade).

In the world of systolic heart failure, ACE-Is and ARBs are being used as the backbone of therapy for our patients. We’re decreasing that preload and afterload and make it easier for that weakened heart muscle to work. We’re finally helping keep these patients outta the hospital and extending their lives.

But we’re not just going to study one drug class in this common and deadly disease state, are we? We’re going to keep investigating other drug classes and see if they provide any additional benefit in our patients.

Besides NSYNC and the Backstreet Boys, people are also brainstorming about what other meds might work to decrease the amount of work that poor LV has to do.

Someone proposes: well, what about beta blockers?

Let’s quickly review.

Beta blockers work by mostly blocking the beta-1 receptor, located in the heart. The beta receptor is key to human survival – when cave-woman version of me (Cait) used to get chased by a wild boar, norepinephrine and epinephrine would bind to these receptors to stimulate increase in heart rate, and thus cardiac output (since CO=HRxSV) and keep me going to run away from said wild boar. 2022 Cait gets too much beta stimulation from way more mundane things, like watching Die Hard for the first time (and for the record, this girl thinks it’s a Christmas movie).

The problem is, in chronic systolic heart failure, your left ventricle (LV) is freaking weak. Muscle might be dead/necrotic and the muscle just can’t generate the same kind of squeeze it used to back in the day.

It was hypothesized that slowing down the rate of systole (contraction) of the heart may prevent that systolic heart failure from getting worse, and may even help that left ventricle recover.

There were some lil trials here and there testing this hypothesis but nothing large and directed at looking at mortality.

Then, at the turn of the century, 1999 – the landmark CIBIS-II trial is released in the Lancet. The CIBIS-II trial looked at beta blockade with bisoprolol with the primary endpoint of all-cause mortality in HFrEF patients. The trial was stopped early, because all cause mortality was significantly lower with bisoprolol versus placebo. If you look at the trial itself and check out baseline characteristics, you will find that 96% of patients were on an ACE-I. Afterall, this was now the new mainstay of HFrEF treatment.

Speaking of, this is a super important consideration when looking at any HFrEF trials. Afterall, let’s hypothesize that in the CIBIS-II trial, less than 50% of patients were on ACE-I therapy. It would really be hard to tell if the addition of bisoprolol would have any additive benefit on top of that great mortality reducing ACE-I, right? And it would be very, very unethical to not have patients on an ACE-I at this point since it showed such important mortality reduction and became the new standard of care.

Other beta blockers, specifically carvedilol (COPERNICUS trial and US Carvedilol HF Study) and metoprolol succinate (MERIT-HF) were all found to reduce death in HFrEF with a number needed to treat of roughly 10-20 @ 1 year….and keep in mind this is on top of ACE-Is. When looking at hospitalization rates, the reduction in hospitalizations were also reduced to a similar degree.

This was another huge win for the treatment of these chronic patients, leading to a Class I, level of evidence A, chef’s kiss recommendation that the “use of bisoprolol, carvedilol, or metoprolol sustained release (succinate) for all patients with current or prior symptomatic HFrEF unless contraindicated”.

Beta-blockers should be used as a backbone of therapy on these stable, chronic heart failure patients – but keep in mind the three found to reduce mortality are:

1. metoprolol succinate (not tartrate)
2. bisoprolol
3. carvedilol

It’s also kinda a good time (I guess) to discuss beta blocker selectivity. Beta blockers are classified as either being “cardioselective” or “nonselective”.

Those that are cardioselective tend to work primarily on the beta receptors, especially at lower doses. The nonselective beta blockers work by also hitting/blocking the alpha receptors, which will lead to vasodilation and reduction in blood pressure.

The important thing to note is that the cardioselective beta blockers are just that – selective – not specific – so at higher doses, you might see some blood pressure lowering activity of even metoprolol and the other cardioselective beta blockers.

It might not be the most politically correct way to remember things in 2021, but it works for me. To remember your cardioselective beta blockers, remember “MANBABE”.

This might mean something different to each person. When I think about my cardioselective beta blockers, I think about…Jon Hamm.

So, in our journey so far, I want you to remember that GDMT for HFrEF includes:

1. ACE-I or ARB plus
2. beta blocker (specifically carvedilol, bisoprolol, or metoprolol succinate).

Target Doses

The other thing I want to mention before we continue on:

We really want to mimic the original data as much as possible.

We want to get our patients up to the doses studied in the trials, since that are the doses the data shows reduces mortality/ hospitalizations, etc.

We don’t really know what exact benefit lower doses might have, since the data supports these specific doses we call “target doses”. Now, it’s OK if you can’t get your patient up to the target dose but we do want to push those GDMT doses as close to target as we can unless the patient cannot tolerate it. This often means we push those beta blocker doses up until the patient’s HR is as low as 55bpm – as long as they are tolerating their rates in the 50s without any s/sxs of hypoperfusion or dizziness, etc – this is completely OK and what we really should be aiming for on the outpatient basis.

OK cool, so we got our beta blocker on ✅, our ACE-I or ARB on ✅. Time to investigate other drugs.

Well, 1999 was actually apparently a very big year in the world of systolic heart failure. Guess 7 year old Cait missed the excitement at the time. Too busy playing with my Tamagotchi I guess. 🤷🤷🤷

Anyway, around the same time the CIBIS-II trial came out and put beta blockers on the map forever for HFrEF, another important trial came out called the RALES trial. We already knew at the time that blocking part of the RAAS system with our ACE-I or ARBs significantly reduced mortality. What about working on that same RAAS system from a different angle?

Like…..what about using an aldosterone antagonist to stop that aldosterone from having our body hold on to excess volume and sodium?

In 1999, the RALES study was published that looked at the effect of spironolactone in patients with HFrEF. Patients were randomized to spironolactone versus placebo and the majority of patients were on loop diuretics, ACE-Is, and digoxin.

Note that we didn’t see this huge amount of beta blocker use as foundational therapy since this was the same year the CIBIS-II trial was published. Sure enough, just like its ACE-I/ARB friends, aldosterone antagonist spironolactone was found to significantly reduce mortality (a 30% reduction to be exact) and also hospitalization. This trial specifically studied EF <35% and NYHA III-IV patients but did also find that spironolactone (in addition to baseline ACEI or ARB therapy) increased the SCr and rates of hyperkalemia, although not found to be statistically significant.

Alright so we know that spironolactone rocked it on top of an ACE-I, but we don’t really know its additive effects with beta blocker therapy at baseline. Hold that thought.

We’re going to travel to a new millenium. Heck, we’re really going places here.

The year is now 2003. Low rise pants are in. The planet’s computer systems did not all die at the spark of Y2K. Life is good. We know that ACEIs (or ARBs), beta blockers, and aldosterone antagonists – specifically spironolactone- are our standard of care for HFrEF.

It wouldn’t be until 2011, when the EMPHASIS-HF trial was published, that showed us that the benefit spironolactone had was a class-wide effect in these patients. This trial looked at the other aldosterone antagonist, eplerenone, and its effect on chronic HFrEF. The previous 2003 EPHESUS trial showed us that eplerenone worked to reduce mortality in patients with acute HFrEF post ACS, but we currently had no data in chronic HFrEF patients.

The EMPHASIS-HF showed us, for the first time, that eplerenone significantly reduced both death and hospitalization in chronic HFrEF patients. The other good thing is that this trial included patients on baseline ACE-I (or ARB), and a beta blocker (since enough time had passed for the CIBIS-II trial to be incorporated into standard of care), showing the effects of aldosterone antagonists stayed strong in the midst of beta blocker therapy. Wahoooooooo!

Now on our list of HFrEF GDMT, you better try to get on all these meds at their good doses, include:

1. ACEI/ARB
2. Beta blocker (metop succinate, bisoprolol, or carvedilol)
3. Aldosterone antagonist

Study Break ✨Here✨

Afterall, you just travelled over 20+ years of time of HFrEF. Go outside, take a big breath, eat a taco. People in pharmacy/med/PA whatever school in the 1980s didn’t have to learn any of this stuff because it *~*didn’t exist yet*~*. I’m not kidding. Get up. Stretch.

In case anyone is interested in what I’m up to in my personal life, it is now Jan 2022 and I mean, life has been hard for all of us. I’m trying a 30 day *~*yoga*~* challenge for better mindfulness and to ✨decrease✨ anxiety and I love this gal Adriene and (also really) love her dog Benji. She is doing a free 30 day yoga thingy babober and she releases a ~30 min video every day that I’m going to try to do (so far so good). Highly recommend if interested ⬇️⬇️⬇️

(https://www.youtube.com/user/yogawithadriene).

PS – I make no money from her or actually from this blog at all (you freeloaders) so this is an actual real thing I am doing I swear.

Alright hopefully we are all refreshed now. Namaste y’all.

Do you remember how, at the beginning of everything, people used to use vasodilators like ISDN/hydralazine and we really didn’t find too much of a benefit and they were never FDA approved for HFrEF?

I told you we would revisit that and I wasn’t kidding.

That old original trial, the V-HeFT trial, the one that didn’t really show much benefit?

Well, someone did a post-hoc (after the fact) subgroup analysis of the V-HeFT trial (10.1016/s1071-9164(99)90001-5) and compared patients according to race (white patients versus black patients) and found that black patients might have a mortality benefit – or at the very least- there might be a difference in response in our black patients.

This hypothesis-generating trial eventually lead to the A-HeFT trial in 2004 which looked at black patients only and the effect the combination of ISDN/hydralazine had on mortality with these patients already on good GDMT and found a significant decrease in mortality, with a number needed to treat of 25.

We didn’t see widespread use of aldosterone antagonists in the A-HeFT trial (39% use) so when looking at our guidelines recs, we don’t require patients be on aldosterone antagonists prior to starting hydral/ISDN.

THUS the class 1, level of evidence A recommendation WAS BORN.

The combination of hydralazine and isosorbide dinitrate is recommended to reduce morbidity and mortality for patients self-described as African Americans with NYHA class III–IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated.

Newer Agents (!)

There are two more main drug classes that I want to discuss, all that happened fairly recently in the world of HFrEF. After all, this disease state still has a huge mortality rate and is unfortunately very common.

The first medication class was newly introduced in 2015, known as sacubitril/valsartan (aka Entresto). You guys might know what the valsartan part is – an angiotensin receptor blocker – but the sacubitril part is what we call a neprilysin inhibitor. As a class, these meds are known as ARNIs (angiotensin receptor/neprilysin inhibitors).

We already knew that blockade of the RAAS system with ACE-Is and ARBs were great for our HFrEF patients so what’s up with this neprilysin blocker?

What does it add?

First of all, what the heck is neprilysin? Neprilysin is an enzyme that, among other things, is responsible for breaking down ANP, BNP and CNP.

Cait, what? ABC, XYZ? Speak my language please. Will do.

ANP, BNP, and CNP are all natriuretic peptides. In other words, they stimulate and encourage the excretion of sodium and therefore water from the body. ANP stands for atrial natriuretic peptide, and is released the atria of the heart in response to excess stretch, or distension. BNP stands for brain natriuretic peptide (fun fact this is because it was originally identified in pig brain extracts), but in humans, is released by the ventricles of the heart in response to excess stretch, or distension. These occur when heart failure patients are volume overloaded, and are released by the body to help compensate to get rid of some of this excess fluid. Lastly, CNP is released by vascular endothelial cells as a response to inflammation and is involved in the regulation of vascular tone.

By blocking chronically neprilysin on top of giving an ARB, this med helps heart failure patients keep volume overload at bay, and can help reduce afterload by stimulating vasodilation, and promote heart relaxation and even inhibit hypertrophy and fibrosis.

The PARADIGM-HF trial was the landmark trial that got sacubitril/valsartan FDA approved and on market for the treatment of HFrEF. This trial, published in 2014, looked at patients with chronic HFrEF, and compared enalapril versus our ARNI on top of other GDMT in both groups.

Sacubitril/valsartan ended up significantly decreasing the composite endpoint of CV mortality or HF hospitalization with a NNT of 21, and secondary outcomes showed that it maintained its significance when looking specifically at CV mortality, HF hospitalization, and all-cause mortality separately. This trial lead to the guidelines recommending ARNIs as one of the first-line, class I recommendations for the treatment of HFrEF patients.

SGLT-2 Inhibitors

The last major class I want to discuss is our newer SGLT-2 inhibitors. These are the newest with their FDA approval for the treatment of HFrEF – specifically only the two SGLT-2 inhibitors dapagliflozin and empagliflozin.

The history of the SGLT-2 inhibitors is actually pretty interesting and something we might get into another day. Basically this class of drugs was originally studied/approved to treat patients with type 2 diabetes.

But they saw something interesting in their trials with their diabetic patients – a reduction of major adverse cardiovascular outcomes.

This led to a lot of interesting data and led them down a rabbit hole to finally look at the effects of these agents specifically to treat systolic heart failure (aka irregardless if these HFrEF patients had diabetes or not).

The DAPA-HF and EMPEROR REDUCED trials demonstrated that these SGLT2 inhibitors reduced cardiovascular mortality and hospitalization for progression of HF on top of our standard GDMT.

What about Diuretics?

Diuretics, and more specifically loop diuretics (I’m lookin’ at you bumetanide, torsemide, and furosemide), are used to prevent the patient from getting too volume overloaded and decompensated based on the pathophys we discussed earlier. Unlike all the other meds we will be talking about today, loop diuretics haven’t been shown to reduce hospitalizations or decrease mortality, but simply to help symptoms. That kind of makes sense when you think about it, because these meds aren’t doing anything to treat/help the root cause of the issue but just helping with the result of the issue (the extra volume).

Putting it all together – The 2022 Guideline Update

Phew that was a lot. Thanks for hanging with me as we went through about 40 years of systolic heart failure research. The road was long, but along the way we came up with some pretty incredible agents to help out these patients.

Take a second to review the recommendations taken right out of the 2022 ACC/AHA/HFSA Guidelines. Hopefully every one of these agents make sense to you now.

To reiterate, the HFrEF GDMT classes (as below) are: ARNis OR ACE-I OR ARBS; plus a beta blocker (carvedilol, bisoprolol, metoprolol succinate); plus an MRA plus an SGLT-2 inhibitor.

HFrEF Potpourri – Digoxin and Ivabradine

Digoxin and ivabradine are both not used as frequently as the other GDMT listed above, and for good reason.

Digoxin: The history of MOA of action of digoxin is actually super interesting and I plan on doing a future post about it, and the use of foxglove (which contains digitalis) for heart failure can be traced back even to the Roman empire. The main data with digoxin stems from the 1997 DIG trial, where patients with HF in NSR (normal sinus rhythm) were studied over 3-5 years to see the effects of digoxin. Digoxin was found to have no decrease in mortality but we did see a decrease in hospitalizations and worsening of HF versus placebo. However, smaller studies (for example, the ancillary DIG trial published in 2006) with ambulatory care patients found no difference in CV hospitalizations. The data is pretty mixed and not super clear. Its role is still present in HFrEF patients but is typically reserved for HFrEF patients that also have atrial fibrillation and its use limited to patients who can’t tolerate beta blockers for rate control due to low blood pressure. Note that you don’t see it highlighted in the diagram from the guidelines above.

Ivabradine: Ivabradine is an agent that helps with rate control and slowing SA activity without lowering blood pressure. Its data comes primarily from the SHIFT trial, where they took >6,000 patients with stable, chronic HFrEF and found that, when added to GDMT, ivabradine significantly reduced hospitalizations. They noted that benefits were especially seen in patients that could not tolerate beta blockers (or were only on <50% of beta blocker target doses), and with a resting HR of >76 bpm. Because of this, the use of ivabradine is extremely niche and its not a commonly used agent in practice for the treatment of HFrEF. As the above guideline suggests, based on the data, ivabradine can be considered in NYHA class II-III patients who have a resting heart rate >70 bpm, and already on maximally tolerated beta blockers, and are in NSR.

And that’s chronic HFrEF in a nutshell.