Heart failure affects an estimated 6.5 million adults in the United States, approximately 50% of whom have heart failure with reduced ejection fraction (HFrEF). Despite substantial advances in therapeutic options for HFrEF, significant gaps remain in the use of guideline-directed medical therapy in these patients.1

According to registry data, 27% of patients with HFrEF are not prescribed any of the following medications: angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), angiotensin receptor–neprilysin inhibitor (ARNI), or a β-blocker (33%) or a mineralocorticoid receptor antagonist (67%).2

In an article published in JAMA, Murphy et al provide an updated overview of evidence-based treatments for HFrEF, as highlighted below.1

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ACEIs and ARBs

Treatment with ACEIs or ARBs has been found to reduce all-cause mortality by 20 to 30% in HFrEF across multiple studies. These agents are contraindicated in patients who are or plan to become pregnant, as well as those with bilateral renal artery stenosis or previous occurrence of angioedema in response to these drugs.


The ARNI sacubitril/valsartan compared with the ACEI enalapril was found to be associated with greater reductions in cardiovascular mortality (13.3% vs 16.5%, respectively; HR, 0.80; 95% CI, 0.71-0.89) and heart failure hospitalizations (12.8% vs 15.6%, respectively; HR, 0.79; 95% CI, 0.71-0.89) in patients with chronic HFrEF, as well as greater reductions in NT-proBNP (−46.7% vs −25.3%, respectively; ratio of change, 0.71; 95% CI, 0.63-0.81) and heart failure hospitalizations (8.0% vs 13.8%, respectively; HR, 0.56; 95% CI, 0.37-0.84) in patients with acute HFrEF.3,4

Other findings suggest that the benefits observed with sacubitril/valsartan may also extend to patients with heart failure with preserved ejection fraction (HFpEF) and those with midrange EF. Contraindications are similar to those for ARBs. Hypotensive patients are less likely to tolerate ARNIs.


Beta-blockers have been shown to reduce all-cause and cardiovascular mortality, sudden cardiac death, and heart failure hospitalizations in patients with HFrEF and may be prescribed to all without contraindications. In a meta-analysis of 10 randomized controlled trials (RCTs; N=18,254), patients with HFrEF who had normal sinus rhythm and were taking beta blockers, but not those with atrial fibrillation, had reductions in all-cause mortality (HR, 0.73; 95% CI, 0.67- 0.80).5 In other RCTs in which the effect of beta-blockers was examined in patients with HFrEF and atrial fibrillation, all-cause and cardiovascular mortality were reduced (by 30 and 34%, respectively).1 

Noncardioselective beta-blockers are contraindicated in patients with moderate to severe asthma, as these agents have been linked to exacerbations of asthma symptoms.6


Once foundational therapy with ACEI, ARB, or ARNI plus a beta-blocker is established, an MRA should be added to the treatment regimen of patients with HFrEF and left ventricular ejection fraction ≤35% and persistent New York Heart Association (NYHA) class II to IV symptoms, unless serum creatinine is >2.5 mg/dL, estimated glomerular filtration rate is < 30 mL/min/1.73 m2, or serum potassium is >5.0 mEq/L. These agents have been found to reduce mortality by 15 to 30% and heart failure hospitalizations by 15 to 40% in 3 RCTs with patients with chronic HFrEF.1

Additionally, diuretics are typically indicated for patients with chronic HFrEF. Ivabradine may also be considered for patients in sinus rhythm who have a heart rate ≥70 beats per minute (bpm) despite maximally tolerated doses of a beta-blocker.  Hydralazine/isosorbide dinitrate is indicated for Black patients with persistent NYHA class III to IV symptoms despite established guideline-directed therapies.1

For other specific patient groups, consideration of several medical device therapies may be warranted, including cardiac resynchronization therapy, implantable cardiac defibrillation devices, transcatheter mitral valve repair, and wireless pulmonary artery pressure monitoring devices.

Cardiac rehabilitation may further reduce mortality and hospitalization, as well as improve health-related quality of life and exercise duration.

For additional discussion regarding the current state of treatment for HFrEF, we interviewed the following experts: Gregg Fonarow, MD, interim cardiology chief at the University of California, Los Angeles (UCLA), director of the Ahmanson-UCLA Cardiomyopathy Center, and codirector of UCLA’s Preventative Cardiology Program; and Ayesha Hasan, MD, associate professor of clinical medicine and director of the heart failure and transplant fellowship at the Ohio State University Wexner Medical Center.

What are some of the most notable recent updates in the management of HFrEF?

Dr Fonarow: The most notable recent development in management of HFrEF is the demonstration that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for cardiovascular death and heart failure hospitalizations in patients with HFrEF with or without diabetes. Specifically, dapagliflozin 10 mg once daily and empagliflozin once daily, when added to standard background medication therapy, reduced clinical event risk by 25 to 30%.

The benefits were incremental to sacubitril/valsartan, aldosterone antagonists, and beta blockers. The therapy was generally safe and well-tolerated, with adverse event rates similar to placebo. Clinical benefits were observed across all clinically relevant subgroups and evident even within the first 30 days of initiation.

SGLT2 inhibitors thus represent a breakthrough therapy for HFrEF that should be routinely applied to eligible patients without contraindications. It has been recently reported that optimal implementation of this therapy in the United States for HFrEF could result in more than 34,000 lives a year being saved.7 

A recent analysis based on pivotal RCTs in HFrEF showed that, compared with ACEI or ARB and beta-blocker therapy, treating patients with HFrEF with comprehensive disease-modifying medical therapy consisting of an ARNI, beta blocker, MRA, and a SGLT2 inhibitor, could extend median survival by more than 6 years.8 There are thus substantial patient-centered benefits from the use of this so-called “quadruple medical therapy” for HFrEF.

Dr Hasan: Improvements in medical therapy with expansion of drug therapy represent significant developments, including the sacubitril-valsartan combination that was shown to improve survival and hospitalizations for patients with HF. Side effects include low blood pressure, high potassium, cough, and dizziness, and renal function should be monitored.

There is also the risk for angioedema with ACEI. It replaces ACEI/ARB in the heart failure drug regimen but can be taken with aldosterone antagonism. Patients should be optimized on their medications otherwise. There are 3 different doses, and we start the lowest dose in most patients, unless they were on high doses of ACE/ARB (due to the blood pressure effect).

Ivabradine is beneficial in patients with NYHA Class II-III and stable chronic HFrEF (EF <35%) who are otherwise optimized on their heart failure medications, including maximally tolerated beta-blocker dose, and heart rate ≥70 bpm at rest. This cannot be used in those with atrial fibrillation related to valvular heart disease. Ivabradine is was found to be associated with symptomatic and hospitalization improvements in trials. Since this drug affects heart rate, it cannot be used in those with bradycardia or heart block.

The SGLT2 inhibitors dapagliflozin and empagliflozin are indicated in patients with HF and diabetes mellitus, with improvement in cardiovascular outcomes (CV death and hospitalization). These are currently being studied in patients with HF without diabetes to examine the possible expansion of this therapy.

Dr Fonarow, in a 2018 study, you and your colleagues found significant gaps in guideline-directed medical therapy for HFrEF.2 What are these gaps?

Dr Fonarow: There remain substantial gaps in the use and dosing of guideline-directed medical therapy for HFrEF. There are gaps in clinician knowledge regarding the evidence and guidelines, misperceptions on optimal strategies for sequencing and titration of guideline-directed medical therapy, and slow and variable uptake of newer therapies. Clinical inertia is also a driver – clinicians misperceive the patient as being stable despite the patient remaining at risk for underlying disease progression. There is a misaligned “one day” concept – as in, “We will get around to that therapy or uptitrating that dose one day,” but visit after visit, it does not occur. Additional factors are lack of clinical decision support and multidisciplinary care teams in most settings.

What are recommendations to clinicians on how to assess the benefits of drug therapies vs device therapies in some patients?

Dr Fonarow: The ACC/AHA/HFSA Heart Failure guidelines provide valuable guidance regarding the assessment of risk and benefits of medical therapies and device therapies in HFrEF.9 In most circumstances, it is not a consideration of drug therapy vs device therapy, but optimal drug therapy, and then assessment of whether additional device therapy is indicated to be added to optimal HFrEF drug therapy. With optimal medical management, many patients improve to the point that device therapy is not necessary.

Dr Hasan: Treatment decisions should be based on the clinical status of patients – assessing their symptoms (energy level, exercise tolerance, what makes them short of breath), objective measures such as heart rate and blood pressure (if improving), echocardiographic findings such as ejection fraction, and biomarkers such as brain natriuretic peptide. We also look at hospitalizations and emergency room visits for HF symptoms or intravenous diuretics. Another objective measure is the cardiopulmonary exercise test to measure a patient’s exercise tolerance and compare it to previous tests.

What further improvements or developments are needed in this area?

Dr Fonarow: The greatest need is identification and application of strategies for optimal implementation of existing evidence-based therapies for HFrEF. There is an urgent need to discover therapies that can improve outcomes in HFpEF, where currently not a single therapy has been shown to improve survival despite the fact that half of patients with HF have HFpEF and are at substantial risk.

Dr Hasan: We should continue to study medical therapy (such as expanding SGLT2 inhibitor indications to heart failure only, not just patients with HF and diabetes), continue to optimize device therapy such as biventricular pacing and lead placement to help patients respond to such therapy, and optimize treatment of comorbidities such as diabetes, chronic kidney disease, sleep apnea, hypertension, and obesity. Other novel therapeutic agents are being studied and are currently in early phases. We are continuing to make strides in the diagnosis of HF and our understanding of its etiology, including transthyretin amyloid cardiomyopathy (which we now know has been underdiagnosed), with now a treatment approved by the Food and Drug Administration.10


1.         Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart failure with reduced ejection fraction: a review. JAMA. 2020;324(5):488-504. doi:10.1001/jama.2020.10262

2.         Greene SJ, Butler J, Albert NM, et al. Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF registry. J Am Coll Cardiol. 2018;72(4):351-366. doi:10.1016/j.jacc.2018.04.070

3.         McMurray JJV, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077

4.         Velazquez EJ, Morrow DA, DeVore AD, et al; PIONEER-HF Investigators. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548. doi:10.1056/NEJMoa1812851

5.         Kotecha D, Holmes J, Krum H, et al. Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet. 2014;384(9961):2235-2243. doi:10.1016/S0140-6736(14)61373-8

6.         Morales DR, Lipworth BJ, Donnan PT, Jackson C, Guthrie B. Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study. BMC Med. 2017;15(1):18. doi:10.1186/s12916-017-0781-0

7.         Bassi NS, Ziaeian B, Yancy CW, Fonarow GC. Association of optimal implementation of sodium-glucose cotransporter 2 inhibitor therapy with outcome for patients with heart failure. JAMA Cardiol. 2020;5(8):1–5. doi:10.1001/jamacardio.2020.0898

8.         Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396(10244):121-128. doi:10.1016/S0140-6736(20)30748-0

9.         Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. doi:10.1161/CIR.0000000000000509

10.       Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(22):2872-2891. doi:10.1016/j.jacc.2019.04.003

This article originally appeared on The Cardiology Advisor