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

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.

This article originally appeared on The Cardiology Advisor