Heart Failure: Pharmacotherapy

Heart Failure: Pharmacotherapy

Editor's Note: J. Nile Barnes, PharmD, BCPS is a Clinical Assistant Professor of Health Outcomes and Pharmacy Practice at the University of Texas at Austin College of Pharmacy. He's also a clinical pharmacist for an academic medical center. Prior to becoming a pharmacist, he spent several years as a paramedic.

Basically, he's got hands on experience with most levels of medical practice and education. And he's kind enough to share that experience with us all. 

The following is Part 3 of an (excellent) 3 part series on heart failure. Dr. Barnes will tackle background and pathophysiology here; before moving on to signs and symptoms and then pharmacotherapy.

As a quick side note, this is my personal favorite of the series. I've never seen heart failure broken down in such an easy to understand (and remember) way. 


Heart Failure: Pharmacotherapy

Just a reminder where we have been and where we are going today.

Episode 1—Pathophysiology (especially hemodynamics)

Episode 2—Signs and Symptoms (focusing on mechanism)

Episode 3—Return of the JEDI Mechanisms, using the mechanisms as drug targets.

Ok, so now onto pharmacotherapy.

Last time we talked about signs and symptoms and discussed the Frank-Starling curve. We are going to talk about the agents used in HF and how they affect this curve.

You might notice that the labels on the axis have changed since the last installment, but don’t worry, there are just different surrogate markers we can use for the same thing….

Stroke volume related to Cardiac Output which is normalized to Cardiac Index. Ventricular filling pressure is related to Left End Diastolic Pressure. So it does not really matter which ones I pick.

In the figure above, taken from Goodman and Gilman’s... 

  • D=Diuretics
  • I=Inotropes
  • V=Vasodilators

The solid green line represents normal function, the red line represents someone with severe HF. The two dashed lines represent improvement with drugs that we will discuss below.

If the red dot represents where the patient is in severe cold, wet failure, you can see that adding a diuretic alone, simply moves the patient down the curve from cold and wet failure to cold and dry failure. Drying the patient a bit would decrease LVEDP with little effect on stroke volume.

Just adding an inotrope would move that patient’s curve (and spot on the curve) from cold and wet to warm and wet failure. The increase in Cardiac Index (or Stroke Volume) would move that patient from cold and wet to warm and wet HF.

Just adding a vasodilator would decrease afterload, which would allow for a greater stroke volume and would drop vascular pressure....which would move the curve upward (improved stroke volume) and the patient down the curve (relative decrease pressure).

You can also see the effects of adding all three agents. In Acute Heart Failure Syndromes these effects are what we are trying to achieve. In Chronic Heart Failure, we don’t have to be so aggressive, but we follow the same plans.

I want you to look at the palm of your left hand now. You should see something like this:


We are going to use your hand and fingers to remember how to treat HF.

I must begin by saying most of the evidence applies to SYSTOLIC or HFrEF, but we often do the same things in diastolic or HFpEF. This discussion applies primarily to CHRONIC HF not Acute HF.

BTW, thank you to Dr. Mark Granberry for this memory device, he taught this to me over a decade ago and I still use it.

So your Thumb represents A

A stands for ACE-Is, ARBs and ARNI, and IN THAT ORDER.  

The 1992 SOLVD Treatment study established enalapril as first line therapy in preventing HF progression. Additional trials established this was a class effect for ACE-Inhibitors.

ARBs or angiontension II receptor blockers, were evaluated as substitutes for ACE-I in the 2001 Valsartan Heart Failure Trial or Val-HeFT. In this trial Valsartan was established as an alternative to ACE-I in patients who were intolerant of ACE-I.

Note that ACE not only cleaves angiogensin I into angiotensin II, but also works on other substrates, notably, kinins, of which bradykinin is responsible for the cough found in many patients on ACE-Is.

The latest in this group is the ARNI—an ARB and neprilysin inhibitor. The PARADIGM-HF study published in 2014, showed non-inferior outcomes for LCZ696 vs enalapril.

LCZ696 is not a great generic name. This is brand name, Entresto®, which is valsartan-sacubitril. Neprilysin degrades brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). By inhibiting their metabolism, sacubitril blocks neprilysin and therefore raises BNP and ANP levels which helps maintain cardiac function.

I would suggest using them in the following order (and never together): ACE-I before ARB before ARNI. This article discusses the role of ARNIs in therapy.

I would recommend using ACE-I unless they are intolerant, if intolerant of ACE-I , then go to an ARB. If the ACE-I or ARB is maximized and the patient’s functional class does not improve, consider the new ARNI.

Note that patients should be titrated up from low-dose ACE-I/ARB to the target dose. The "target dose" was the dose used in the various trials that provided the outcome benefit (that outcome was living longer!).

There are lots of tables for these and I will include one at the end of this post. I suggest titrating the ACE-I or ARB up by doubling the dose about every three days until reaching the target dose or until the patient can no longer tolerate (SCr rises by > 30%).

BTW, what is the mechanism? Or how does it affect the Frank-Starling curve? Why do we titrate rather than give the target dose at first?

Each time we give an ACE-I or ARB, we decrease the circulating angiotensin II, a vasoconstrictor (which in effect make ACE-Is and ARBs vasodilators). BUT angiotensin II also causes cardiac remodeling. By blocking it we slow, stop and sometimes reverse cardiac remodeling.

Giving too large a dose up front can cause sluggish renal flow...so to avoid this we slowly titrate these up.

Next is the index finger, which stands for B.

B is for Beta-blockers. And not just any ole BB either. Only three have evidence for use (and of those only two have FDA approval).

Clinking the links below will take you to the landmark study that put these three BB in the guidelines.

Again we have the target dose issue. Only it is harder. If you start a full dose BB to a patient with HFrEF, you will cause Acute Decompensated Heart Failure (ADHF).  

That’s right, the BB to treat HF will cause worse HF. In fact, when I began in healthcare, giving a BB in HF was considered malpractice, now it is the standard of care and NOT giving it is malpractice.

BBs are NEGATIVE inotropes. So if you look at that lovely picture from Goodman and Gilman's earlier in this post, you see the inotropes push the curve up. A negative inotrope will push the curve downward.

That is why it was malpractice in HF in the past, and adding it in ACUTE HF would likely be malpractice also.

The BB will block beta-adrenergic effects of catecholamines (see the second post in this series). In ADHF, the beta-adrenergic effects are what is keeping the patient alive (in fact, we give pressors and inotropes to mimic this in ADHF).

But the continued bombardment of catecholamines causes the heart to continue to work hard well beyond its intended flight or fight mechanism and eventually are no longer needed. By SLOWLY titrating tiny doses of BB up (doubling about every two weeks) until reaching the target dose, we eventually remove this adrenergic distress.

Another Clinical Pearl: as we increase the dose, the heart upregulates the B1 receptors, increasing their numbers, so more BB is need to get the same effect. Abruptly stopping BB in a patient that has upregulated Beta receptors can actually precipitate ischemia, injury and infarction.

So don’t stop the BB abruptly, titrate it downward if the patient presents with Acute on Chronic HF—stopping a high-dose could trigger a myocardial infarction.


Next is the long finger, which stands for C, that is Stage C heart failure. (It does not stand for Calcium Channel Blockers; they have NO role in HF).

This means we need to review the four classes of HF.

A At high risk for HF but without structural heart disease or symptoms of HF
B Structural heart disease or symptoms of HF
C Structural heart disease with current or prior symptoms of HF
D Refractory HF

And just a reminder about the NYHA Functional classes, the OTHER classification.

I Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain.
IV Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

For the record, NYHA functional class is for any and all heart disease, not just HF, but in common practice, it is mostly just used for HF.  

Okay, now what? In Stage C HFrEF patients should already have an ACE-I and BB on board, hopefully, they have been titrated up to target doses.

If not, do that first; but now if the patient has NYHA class II, III or IV disease, it is time to add an aldosterone antagonist.

The two choices are spironolactone and eplerenone. From my experience, there is no advantage in HF for one over the other. Spironolactone is easier on the wallet (eplerenone is a bit wallet toxic). But spironolactone is structurally similar to estrogen and may cause gynecomastia.

I would reserve eplerenone for patients who can afford it and have symptoms of gynecomastia on spironolactone (usually starts with breast tenderness).

A couple of pearls here:

  1. K+ should be less than 5.0 mEq/L and frankly, I would be very cautious if it was greater than 4.5 mEq/L
  2. Serum creatinine should be 2.5 mg/dL or less in men or 2.0 mg/dL or less in women (or eGFR>30 mL/min/1.73m2).
  3. The mineralocorticord receptor is a nuclear receptor, this means when it is given there will be a delay in effect. The previous products of transcription are still present, but no new products will be made. The old products of transcription will be translated and then will have their effect and eventually be degraded. I usually do not see an effect for a few days.
  4. Spironolactone and eplerenone are also potassium sparing diuretics, but in HF, you should think of them as aldosterone antagonists which have a side effect of diuresis.


We have two fingers left, and they are the double DDs. Digoxin and Diuretics.

So up until now, everything we've talked about has had an impact on outcomes (patients live longer with proper therapy). The double DDs do not influence outcomes, but they do impact quality of life.

Digoxin is an inotrope, but the DIG trial did not result in longer life for HF patients, but it did reduce hospitalizations for HF patients.

Diuretics are incredibly important in fluid overload and may result in avoiding a hospitalization or decompensation, but they do not work to reduce mortality.

We typically use furosemide for diuresis—brand name Lasix®. Just remember that it Lasts Six hours à Lasix, so don’t give the last dose of the day within about 6 hours of bed time or your patient will be awakened in the night.

These five things need to be thought about in every HFrEF patient. There are a few other things that you should have in the palm of your hand for selected patients.

Most every pharmacy student will be able to answer the following question:

What is the first drug to have a Race-based indication?


Bi-Dil®: hydralazine and isosorbide dinitrate

The manufacturer will gladly remind you that there is no generic equivalent. But they just picked a dose of each of the drug that is not otherwise available.

You can get the effect of these drugs at other doses. Remember that they are both vasodilators and will push the Frank-Starling curve upward.

I use this when I have maximized the ACE-I or ARB and BB. Or if I can’t use them. I have had the patient with horrible COPD/Asthma Overlap Syndrome that was so sensitive to BB that I swear she began to wheeze if you discussed a BB in the room with her.

Ivabradine  (Corlanor®) is a relatively new drug that affects the HCN channels of the SA node, slowing firing of the SA. It has not demonstrated any inotropic or conduction effects. It may be beneficial in reducing HF readmissionsin patients with HFrEF who are already have maximized therapy and have a resting HR greater than 70


Heart Failure Pharmacotherapy: Summary

Here is the summary...

A for ACE-I, ARB and ARNI. Start low and titrate to Target dose (can go up every couple of days provided SCr does not jump more than 30%.

B for BB, but only our special three that have data, Start low and go SLOW as you titrate to Target dose (double dose about every two weeks).

C for Stage C patients who have HFrEF (less than 35%) NYHA Class II-!V should be placed on an Aldosterone Antagonist if their SCr and K+ will tolerate it.

D for Digoxin if the patient could use a little inotropic help (S/S on exercise), remembering that it may decrease hospitalizations but not improve mortality.

D for Diuretics if the patient has fluid overload

Hold in the palm of your hand for special patients: Hydralazine, Isosorbide dinitrate, and Ivabradine.

Here are the promised tables:


Start Dose

Target Dose

ACE Inhibitor

Captopril 6.25 - 12.5 mg TID 25 - 50 mg TID
Enalapril 1.25 - 2.5 mg BID 10 mg BID
Ramapril 1.25 - 2.5 mg BID 5 mg BID
Lisinopril 2.5 - 5 mg QDaily 20 - 35 mg QDaily


Carvedilol 3.125 mg BID 25 mg BID
Bisoprolol 1.25 mg QDaily 10 mg QDaily
Metoprolol CR/XL 12.5 - 25 mg QDaily 200 mg QDaily


Candesartan 4 mg QDaily 32 mg QDaily
Valsartan 40 mg BID 160 mg BID

Aldosterone Antagonist

Spironolactone 12.5 mg QDaily 50 mg QDaily
Eplerenone 25 mg QDaily 50 mg QDaily


Isosorbide Dinitrate 20 mg TID 40 mg TID
Hydralazine 37.5 mg TID 75 mg TID
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