Medical Management of Heart Failure with Reduced Ejection Fraction

Educational Objectives

The goal of this program is to improve management of heart failure with reduced ejection fraction (HFrEF). After hearing and assimilating this program, the clinician will be better able to:

1. Prescribe quadruple therapy to eligible patients with newly diagnosed HFrEF.
2. Identify renin-angiotensin system inhibitors recommended for first-line treatment of HFrEF.

Summary

Guideline-directed medical therapy (GDMT): the 4 class 1-recommended medications to reduce mortality for heart failure with reduced ejection fraction (HFrEF) are β-blockers, renin-angiotensin system (RAS) inhibitors (including angiotensin receptor-neprilysin inhibitors [ARNIs]), mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, eg, empagliflozin, dapagliflozin

HFrEF management: social determinants of health, access to care, access to insurance, access to cost, transportation, and health literacy are profoundly important; intravenous administration of iron makes patients feel better (although it has not been shown to improve mortality); other treatment options include medications (eg, diuretics), devices (eg, pacemakers, cardiac resynchronization therapy, and defibrillators), and cardiac rehabilitation (provides significant mortality and morbidity benefit)

Prognosis of HF: Bozkurt et al (2025) — the Heart Failure Society of America reported that the 5-yr mortality after index hospitalization for heart failure (HF) was ≈75%, independent of ejection fraction (EF); thus, prognosis remains poor, requiring aggressive treatment and risk factor modification; either mortality or hospital readmission was seen in 100% of patients by 5 yr

HF with mildly reduced EF: when EF is mildly reduced (40%-50%), understanding its trajectory (improvement or decline to the range) is crucial; patients with a declining EF from normal to 40% to 50% had a poor prognosis with high rates of hospitalization (Savarese et al [2019])

Undertreatment of HF: patients with stable HF (New York Heart Association class 2) and no recent hospitalizations have a significantly higher risk for hospitalization or death ≤1 yr than patients with high atherosclerotic cardiovascular disease risk; Greene et al (2018) — ≈25%, ≈33%, and ≈67% of eligible patients were not prescribed RAS inhibitors, β-blockers, and MRA therapy, respectively; Greene et al (2024) — the rates of prescriptions of GDMT for HF at the index clinic visit was low; only ≈15% of eligible patients were prescribed quadruple therapy; the most common reason for not initiating medical therapy was clinically stable HF and/or adequate symptom control; stable HF does not imply good long-term prognosis and is a high-risk situation that requires a proactive approach, ie, rapid initiation of quadruple therapy or maximum dose of RAS inhibitors or β-blockers

Significant benefits of quadruple therapy: the benefits of GDMT for HF are rapid, ie, a 25% relative risk reduction ≤30 days with β-blockers, a ≥40% reduction in cardiovascular death or hospitalization with ARNI, a 40% relative risk reduction with MRA, and ≈60% reduction in the composite endpoint of death, hospitalization, or worsening HF; in the SGLT2 trials (the DAPA-HF and EMPEROR-Reduced studies), it took ≈30 days to observe the primary outcome and ≈2 wk for reduction in hospitalization to be evident; initiating quadruple therapy in patients with HF can yield substantial short and long-term benefits, eg, ≈6.5 yr and ≈4.5 yr of additional life expectancy in patients 55 yr of age and 65 yr of age, respectively

Medication-attributable adverse events (AEs) in HF trials (Harrington et al [2023]): in clinical trials of GDMT for HFrEF, AEs were observed in ≈80% of patients in both the treatment and placebo groups; severe AEs were lower in the treatment group

Drug-specific AEs: angiotensin-converting-enzyme (ACE) inhibitors — rate of cough was ≈9% higher; β-blockers — dizziness was observed; MRA — requires follow-up of potassium levels; gynecomastia can occur in men using spironolactone (switching to eplerenone is recommended); SGLT2 inhibitors — are well tolerated in a non-diabetic population; they have lower risk for mycotic infections; good blood glucose control reduces the risk for these AEs

β-blockers: include metoprolol succinate, carvedilol, and bisoprolol titrated once every 2 wk; increasing the dose too fast can lead to oversuppression of heart rate or intrinsic inotropy; 12.5 mg of metoprolol succinate is preferred over metoprolol tartrate because it eliminates the peak effect; getting to the highest tolerated dose is important for β-blockers

RAS inhibition: ARNI is the recommended first line treatment option; guidelines recommend that ACE inhibitors and angiotensin receptor blockers (ARBs) should only be considered in patients with contraindications, intolerance, or inaccessibility to ARNI; the sooner ARNI is initiated (vs ACE inhibitors or ARBs), the sooner reductions in death, improvements in EF, and reduction in readmission risk can be observed; sacubitril-valsartan (Entresto) — sacubitril causes vasodilation, less fibrosis, and potent natriuresis (hold loop diuretics for 1 to 2 days); volume status is crucial

Spironolactone (MRA): it offers significant benefits and reduces the risk for death; it does not affect blood pressure; it increases the potassium levels initially (requires monitoring); it should not be withheld for a random high potassium level that may be caused by other factors

SGLT2 inhibitors: 10 mg of dapagliflozin or empagliflozin can be used once a day; both are effective; they have negligible blood pressure effects; the diuretic effects are driven by hyperglycemia; these cannot be used in type 1 diabetes mellitus; these can be used in patients with low glomerular filtration rate; in the EMPA-REG OUTCOME trial (Zinman et al [2015]), empagliflozin was found to be protective against urinary tract infections in patients with diabetic mellitus

Conclusion: timing is important; initiating GDMT as soon as possible and titrating to a maximum tolerable dose ≤3 mo reduces the risk for death or hospitalization and improves patient-reported health status; one should be proactive and initiate GDMT, mobilize a multidisciplinary team, be mindful of the barriers to care, communicate with the outpatient or primary care team, and initiate GDMT in the hospital before discharge

Readings

Bozkurt B, Ahmad T, Alexander K, et al. HF STATS 2024: Heart failure epidemiology and outcomes statistics an updated 2024 report from the heart failure society of America. J Card Fail. 2025;31(1):66-116. doi:10.1016/j.cardfail.2024.07.001; Greene SJ, Ayodele I, Pierce JB, et al. Eligibility and projected benefits of rapid initiation of quadruple therapy for newly diagnosed heart failure. JACC Heart Fail. 2024;12(8):1365-1377. doi:10.1016/j.jchf.2024.03.001; 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; Harrington J, Fonarow GC, Khan MS, et al. Medication-attributable adverse events in heart failure trials [published correction appears in JACC heart fail. 2023 Jun;11(6):733. doi: 10.1016/j.jchf.2023.05.001.]. JACC Heart Fail. 2023;11(4):425-436. doi:10.1016/j.jchf.2022.11.026; Maddox TM, Januzzi JL Jr, Allen LA, et al. 2024 ACC expert consensus decision pathway for treatment of heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution set oversight committee. J Am Coll Cardiol. 2024;83(15):1444-1488. doi:10.1016/j.jacc.2023.12.024; Savarese G, Vedin O, D'Amario D, et al. Prevalence and prognostic implications of longitudinal ejection fraction change in heart failure [published correction appears in JACC heart fail. 2019 Aug;7(8):735-736. doi: 10.1016/j.jchf.2019.06.008. Abstract corrected]. JACC Heart Fail. 2019;7(4):306-317. doi:10.1016/j.jchf.2018.11.019; Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Davis was recorded at the Hearts in Sonoma: UCSF Update on Heart Failure Therapies, held September 19-21, 2024, in Sonoma, CA, and presented by University of California, San Francisco, School of Medicine. For information on upcoming CME activities from this presenter, please visit meded.ucsf.edu/continuing-education. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

FP731902

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.