Management of Chronic Heart Failure with Reduced Ejection Fraction
==================================================================

* Brandon Williamson
* Carl Tong

## Abstract

Heart failure with reduced ejection fraction (HFrEF) is a commonly seen clinical entity in the family physician’s practice. This clinical review focuses on the pharmacologic management of chronic HFrEF. Special attention is paid to the classification of heart failure and the newest recommendations from the American Heart Association concerning the use of guideline-directed medical therapy. β blockers, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists are discussed in detail. The new emphasis on sacubitril-valsartan and SGLT2i’s as therapies for HFrEF are reviewed, followed by a brief discussion of more advanced therapies and comorbidity management.

*   Heart Failure with Reduced Ejection Fraction
*   Pharmacotherapy

Heart failure with reduced ejection fraction (HFrEF) is increasing and prevalence and 5-year mortality remains high. Make sure you are including the most recently recommended therapeutics in your treatment plan. This review draws heavily from the American Heart Association (AHA) Guideline for the treatment of heart failure, as well as its evidence with an emphasis on pharmacologic management.1

## Practice Recommendations

In patients with HFrEF patients should be on the following classes of medications based on their strength of recommendation taxonomy (SORT) 

*   An angiotensin receptor-neprilysin inhibitor (ARNi) is preferred (SORT B), otherwise an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin (II) receptor blockers (ARB) (SORT A)

*   A beta blocker (SORT A)

*   A Mineralocorticoid Receptor Antagonist (MRA) (SORT A)

*   A Sodium-Glucose Cotransporter 2 Inhibitor (SGLT2i), regardless of the presence of diabetes (SORT A)

## Background

Heart failure (HF) prevalence is increased in the United States. Prevalence has increased from 2007 to 2010 at 5.1 million2 to 2017 to 2020 approximately 6.7 million.3 HF prevalence is projected to increase by 46% from 2012 to 2030 to affect more than 8 million American adults.4 Outside of prevalence, the lifetime risk of HF at 50 years of age has increased between 2 different epochs in the Framingham Heart Study.3 Incidence seems stable with HFrEF declining and HFpEF increasing.5 Overall, black individuals have the highest incidence of HF.6 Risk factors for HF include obesity, hypertension, diabetes, coronary heart disease (CHD), and smoking, among others.7 Approximately 1 in 3 adults in American have at least 1 risk factor for HF, also known as stage A HF.8 Worse, COVID-19 adds 11.6 new HF cases per 1000 infections above the expected annual incidence.9

## Classification

HF occurs when the heart loses its ability to provide sufficient blood to the body. Thus, “HF is a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood.”1 HF is caused by a number of conditions such as ischemic heart disease, hypertension, valvular heart disease, various causes of nonischemic cardiomyopathy, among numerous others. (Figure 1). HF is defined by 3 major components of stage, left ventricular ejection fraction (LVEF), and patients’ ability to function. Stages (A-D) describe the status of the heart in terms of risk, structure, cardiac function, and HF progression (see Figure 1 and Table 1). The failing heart has different underlying pathophysiology and responds differently to treatment based on initial LVEF at diagnosis; therefore, LVEF groupings is used to direct treatment (reduced: LVEF ≤ 40%; improved: previous LVEF ≤ 40% but now better; mildly reduced: LVEF 41 to 49%; and preserved: LVEF ≥ 50%) (Table 2). The New York Heart Association (NYHA) functional classification (I-IV) describes level of exertion that triggers HF symptoms (see Table 3). Of note, a HF stage-C patient can experience NYHA II-IV levels depending on the success of treatment.

![Figure 1.](http://www.jabfm.org/https://www.jabfm.org/content/jabfp/37/3/364/F1.medium.gif)

[Figure 1.](http://www.jabfm.org/content/37/3/364/F1)

Figure 1. 
**Heart Failure Progression.** Many underlying disease processes cause the heart to fail. Unless a correctable underlying cause is found and successfully treated, the majority of heart failure (HF) patients will progress in an undulating downward fashion toward death. American Heart Association (AHA) Staging describes the status of HF1: A “at risk for HF,” has underlying risk but without detectable dysfunction, such as hypertension; B “pre-HF”: has underlying cause and detectable cardiac dysfunction but without over heart failure symptoms; C “symptomatic HF”: has documented cardiac dysfunction and heart failure symptoms; D “advanced HF”: patient has refractory heart failure without chance of meaningful return to an acceptable plateau. The New York Heart Association (NYHA) classification describes a patient’s overall function (I: normal; II: moderate exertion causes symptoms; III: mild exertion causes symptoms; IV: symptoms at rest or with minimal exertion). Continuous inotropic infusion can provide a bridge to intervention (heart transplant or left ventricular assist device), bridge to medical treatment to achieve a better plateau, or palliative comfort care.

View this table:
[Table 1.](http://www.jabfm.org/content/37/3/364/T1)

Table 1. 
Staging

View this table:
[Table 2.](http://www.jabfm.org/content/37/3/364/T2)

Table 2. 
Classification of Heart Failure

View this table:
[Table 3.](http://www.jabfm.org/content/37/3/364/T3)

Table 3. 
New York Heart Association Classification

## Pharmacologic Therapy

Aside from management of comorbidities, the cornerstone of HFrEF treatment is appropriate pharmacologic management, or guideline-directed medical therapy (GDMT) (Table 4). The goals of GDMT are to alleviate symptoms, decrease the structural progression of HF, decrease HF hospitalizations, and decrease cardiovascular (CV) mortality. After treatment with GDMT some patients improve their EF to normal, called HFimpEF, and it is important that medications not be withdrawn because this has been associated with relapse of HF.10

View this table:
[Table 4.](http://www.jabfm.org/content/37/3/364/T4)

Table 4. 
Comorbid Conditions in Heart Failure with Reduced Ejection Fraction

Despite evidence that GDMT attains these goals, and that achieving target doses improves on the results, appropriate prescribing remains suboptimal for HF patients.11⇓–13 The CHAMP-HF study demonstrated that among patients who were eligible for GDMT, a large number of patients were not prescribed appropriate medications and those that were prescribed were frequently at less than target doses.14 With this in mind, the core GDMT pharmacologic therapies are described below and in Table 5.

View this table:
[Table 5.](http://www.jabfm.org/content/37/3/364/T5)

Table 5. 
Therapies for Heart Failure with Reduced Ejection Fraction1

In general, the most recent guideline recommends individualized titration of GDMT to target doses while maximizing the number of classes of medications utilized with careful monitoring of patient vital signs, symptoms, and serial laboratory evaluation.1 Typically, most trials of newer medications study it as an additional medication to preexisting GDMT, which means that patients frequently are started on a ARNi/RAAS inhibitor or β blocker first, followed by an MRA, and subsequently by an SGLT2i (see below). In the HF guidelines the method of initiation, both sequencing and titration, of GDMT is specifically listed as an evidence gap and opportunity for further research. One author (CT) prefers maximizing categories of medications over maximizing individual dosages. It must be noted that no medication is benign, and all medications have a risk for adverse effects.15

In the pivotal trials, the number-needed-to-treat (NNT) for a decrease in all-cause mortality for each of the core HFrEF medications was less than 100 when standardized over 12 months, from a high of 80 for sacubitril-valsartan, to a low of 18 for mineralocorticoid receptor antagonists (Table 6).1 These numbers decrease further when standardized to 36 months. A limitation of many studies, however, is that they are often industry funded and the most recent guidelines have many authors who disclosed relationships with pharmaceutical companies.

In a patient with chronic HFrEF, who is not hospitalized, there are 4 classes of essential medications that must be considered. Diuretics should be utilized for decongestion in patients with volume overload to relieve symptoms but are not included in the discussion below.

## Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors

The medications that act on the RAAS include the ARNi, ACEi, and ARBs. All 3 categories of medications require monitoring of blood pressure, creatinine clearance, and serum potassium.

Sacubitril-valsartan, the only ARNi currently available, is recommended in patients with NYHA class II or III heart failure who do not have hypotension, a history of angioedema, and do not have barriers to taking the medication due to cost.16 Current guidelines prefer an ARNi instead of an ACEi or ARB because ARNI provided better survival than ACEi.1 If an ARNi is not possible, then prescribing an ACEi is reasonable, provided that there is no history of angioedema.17 If the patient is intolerant of an ACEi due to angioedema or chronic cough, an ARB is acceptable as the risk of recurrent angioedema is similar to placebo.18⇓–20 When switching between an ARNi either to or from an ACEi the minimum duration between the 2 types of medication is 36 hours.

It is important to note that none of the above medications should be combined due to risk of life-threatening hyperkalemia and, in the setting of an ACEi + ARNi, risk of angioedema.

## β Blockers

β blockers remain one of the mainstays of treatment of chronic HFrEF. To date, there are only 3 that are shown to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.21⇓–23 β blockers typically should be initiated at low doses and carefully advanced to target doses, as listed in Table 5. Contraindications include bradycardia and second- or third-degree heart block in the absence of a pacemaker. Careful consideration is suggested in patients with NYHA class IV HF, asthma, recent hospitalization, and signs of hypervolemia.

## Mineralocorticoid Receptor Antagonists (MRAs)

In patients with HFrEF and NYHA Class II to IV an MRA should be utilized to reduce both morbidity and mortality.24⇓–26 Both spironolactone and eplerenone can cause life-threatening hyperkalemia. Patients are eligible if their eGFR is > 30 mL/min/1.73 m2 and their serum potassium is <5 mEq/L. Regardless of initiation, careful monitoring of renal function and potassium is required, especially with any other medication that place the patient at risk for hyperkalemia and acute renal failure, such as diuretics and RAAS inhibitors. Spironolactone is associated with an incidence of gynecomastia of approximately 10%,22 whereas eplerenone is noted have an incidence of gynecomastia similar to placebo.23

## Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)

In patients with chronic symptomatic heart failure a newer recommendation is to add an SGLT2i to the pharmacologic regimen to reduce HF hospitalizations and CV mortality regardless of the presence of diabetes.27,28 Patients should be monitored for euglycemic ketoacidosis, genital and soft tissue infections. Care should be taken to avoid hypovolemia when combining an SGLT2i with a diuretic.

## Additional Medications and Therapies

After considering the above medications there remain several additional pharmacologic options. For patients who have refractory symptoms digoxin may be considered but does not offer mortality benefit.29,30 For patients who identify as African American isosorbide mononitrate in combination with hydralazine can be considered to improve symptoms and mortality.31,32 In patients on maximal GDMT and with a HR ≥ 70 and in sinus rhythm ivabradine may be beneficial.33

For patients fitting specific criteria, as detailed in Table 5, automated implanted cardioverter defibrillator (AICD) and cardiac resynchronization therapy (CRT) are options.1

Eventually, many HF patients will progress to the point of needing advanced care. Advanced care is best coordinated with an advanced heart failure and transplant cardiologist (AHFTC). Some thresholds for AHFTC referral include cardiogenic shock (SBP < 90 mmHg with signs of end organ dysfunction), needing inotropic support, needing to decrease GMDT, worsening renal function, LVEF ≤ 25%, persistent NYHA class 3 to 4 symptoms, and ≥ 2 unplanned hospital visits within 12 months (admission or ER visit) (see Table 7).34 Advanced heart failure therapy includes chronic inotropic infusions, mechanical circulatory support (MCS), and heart transplantation. Chronic inotropic infusions can bridge patients to a more permanent solution.1 Early referral is recommended before significant end organ dysfunction, such as end stage renal disease and pulmonary hypertension, which precludes advanced therapies.

## Management of Associated Conditions

Comorbidities in patients with HFrEF should be appropriately managed to prevent worsening of heart failure (Table 3). Hypertension, diabetes, atrial fibrillation, and valvular disease can all contribute to heart failure and therapy should follow published guidelines. Avoidance of excessive salt intake is reasonable to reduce congestive symptoms based on limited data.1 IV iron in the setting of iron deficiency and heart failure is associated with decreased cardiovascular death and hospitalizations according to 2 meta-analyses.35 The distinction between obstructive or central sleep apnea is difficult to make clinically, and treatment is dependent on the type.1 Statins are recommended for patients with HF secondary to ischemic heart disease and can reduce HF hospitalizations.36 Ischemia and atherosclerosis should be considered in all cases of heart failure and appropriate workup performed, which is beyond the scope of this review.

## Conclusion

The most recent evidence makes several changes to the management of chronic HF. An emphasis on ARNi’s and the addition of SGLT2i’s lie at the heart of the changes, with the continuing strong recommendation for β blockers and MRA’s. Ensure that eligible patients are on an appropriate regiment to reduce HF hospitalizations and cardiovascular mortality, and do not withdraw therapy in the setting of HFimpEF.

## Notes

*   This article was externally peer reviewed.

*   *Funding:* None.

*   *Conflict of interest:* None.

*   Bwilliamson{at}tamu.edu, Ctong{at}tamu.edu

*   *Acknowledgments:* Submitted after discussion with Dr. Seehusen; accepted manuscript in original form for the *Journal of Family Practice* before its cessation of publication

*   To see this article online, please go to: [http://jabfm.org/content/37/3/364.full](http://jabfm.org/content/37/3/364.full).

*   Received for publication November 27, 2023.
*   Revision received January 16, 2024.
*   Accepted for publication January 22, 2024.

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