Management Updates in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

This supplement is supported by Bayer.

ABSTRACT

Heart failure (HF) is a clinical syndrome characterized by structural or functional impairments in ventricular filling or the ejection of blood from the heart. In the United States, HF represents a growing public health concern, affecting an estimated 6.7 million adults 20 years or older, with prevalence expected to continue rising. Despite advances in guideline-directed medical therapy (GDMT), rates of hospitalization and mortality remain high. Therapeutic options are particularly limited for the most prevalent HF phenotypes—HF with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF)—resulting in substantial unmet clinical need. This supplement reviews the pathophysiology, epidemiology, and staging of HF with an emphasis on HFmrEF and HFpEF, and summarizes current GDMT recommendations, including the evolving roles of SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs). A main focus is on the safety and efficacy of finerenone, a nonsteroidal MRA, as an adjunct to standard therapy in patients with HFmrEF or HFpEF. Persistent barriers to optimal care—including challenges related to diagnostic nomenclature, coding, and access—contribute to a disproportionate economic burden associated with these HF phenotypes. Together, these considerations highlight the need for managed care strategies that facilitate appropriate initiation of therapy and access to emerging treatments to improve outcomes while addressing health care resource utilization.

Am J Manag Care. 2026;32(suppl 6):S87-S94. https://doi.org/10.37765/ajmc.2026.89948

For author information and disclosures, see end of text.

Introduction

Heart failure (HF) is a clinical syndrome characterized by structural or functional impairments to ventricular filling or the ejection of blood from the heart, resulting in signs and symptoms of disease, including, but not limited to, shortness of breath, fatigue, lightheadedness, and edema. It is commonly classified by left ventricular ejection fraction (LVEF), as this measure guides treatment decisions.¹ Classifications include HF with reduced ejection fraction (HFrEF), formerly systolic HF; HF with preserved ejection fraction (HFpEF), formerly diastolic HF; and a third type, HF with mildly reduced ejection fraction (HFmrEF), formerly considered a borderline subcategorization of HFpEF or a transitory state of improvement from HFrEF.^1,2 Precise EF values that correspond to each of these types of HF are available in Table 1 alongside their former classifications.^1,2

HF is a current and growing public health challenge in the United States. According to the Heart Failure Society of America (HFSA), an estimated 6.7 million Americans over the age of 20 years currently have HF, and this prevalence is projected to rise by more than 70% to 11.4 million patients between now and the year 2050.³ An aging population is the major contributor to the expected increase, since HF is most prevalent among adults 60 years or older.³

Despite advancements to guideline-directed medical therapy (GDMT), hospitalization and mortality rates remain high among those with HF, as evidenced by 1.2 million hospitalizations among 949,075 unique individuals in 2021,³ a postdiagnosis 5-year mortality rate of about 65% among untreated patients with HFrEF or HFpEF,⁴ and a posthospitalization 5-year all-cause mortality rate that approaches 80%, regardless of patient sex or LVEF phenotype.⁵ Whereas the incidence of HFrEF has been decreasing, the incidence of HFpEF has increased in recent years.¹ Moreover, far fewer medication types are recommended to treat HFpEF and HFmrEF compared with HFrEF.¹ By EF phenotype, HFmrEF and HFpEF account for an estimated 55% to 74% of all HF cases in the US, representing a substantial unmet treatment need.^3,6,7

The economic burden of HF is also substantial. Hospitalizations and hospital readmissions are primary cost drivers, and HF overall is associated with high rates of these drivers.^8,9 In the US as a whole, annual medical costs associated with HF care—including direct and indirect costs—are projected to increase from approximately $31 billion in 2012 to approximately $70 billion by 2030, or about $244 for every adult in the US.¹⁰ In the subpopulation of patients with HF on Medicare fee-for-service plans, an analysis over a 3-year period (2016-2018) observed costs totaling $16.5 billion and $27.1 billion, respectively, in the 30- and 90-day periods following an HF hospitalization,¹¹ highlighting the expense of inpatient and postacute care. Although payers bear the brunt of these costs, health systems face reimbursement penalties if they have higher-than-expected readmission rates for chronic conditions like HF.¹² A newly proposed reimbursement structure, the Ambulatory Specialty Model (ASM), similarly ties specialists’ reimbursements to patients’ outcomes. It aims to reduce health care expenditures on HF by competitively incentivizing provider performance on metrics like care quality, cost reduction, clinical improvement activities, and provider interoperability, but implementation of this model would not begin until 2027.¹³

Toward both improving the clinical outlook of patients with HF and managing expenses associated with this condition, the goal of this article is to explore recent updates to GDMT for HF and broad HF managed care considerations. Special focus will be paid to HFmrEF and HFpEF due to historical unmet needs among patients with these types of HF.

Disease Background and Clinical Impact

Pathophysiology

Although the different types of HF present with similar, nonspecific signs and symptoms,¹ the heart muscle itself tends to exhibit distinct structural alterations that correspond to a patient’s HF subtype, and the causes of these structural changes may be mediated by different stimuli. HFrEF, for example, is predominantly described as an inability of the left ventricle to contract normally, reducing the volume of blood that can be ejected with each cardiac contraction. (Note that HFrEF also presents with diastolic dysfunction, but the main alteration that leads to reduced EF is impaired contractility).^14,15 HFrEF systolic dysfunction develops out of cardiomyocyte loss, which may result from genetic predisposition, coronary artery disease and myocardial infarction, inflammation induced by myocardial toxins, increased cardiac stress over time (often from hypertension), immune infiltration from other conditions, and other causes.¹⁴ In contrast, classical explanations of HFpEF describe an inability of the left ventricle to normally relax, impairing the low-pressure filling capacity of the ventricle and increasing filling pressure; high filling pressures lead to further thickening of cardiac walls and subsequent stiffening of the heart muscle in a sort of feedback loop.¹⁶ Initial cardiac stiffening may result from stimuli affecting the cardiac extracellular matrix or heart muscle cells; these stimuli include hypertension, systemic inflammation, endothelial dysfunction, altered myocardial energetics, and abnormalities in skeletal muscle.¹⁶

Increasingly, HFmrEF is understood within the context of LVEF as a continuous variable, with many patients falling into this category due to dynamic improvement or deterioration of LVEF.¹ Accordingly, the pathophysiology of HFmrEF may be more closely related to that of HFrEF than HFpEF.¹⁷ Historically, however, patients with HFmrEF were variably included or excluded from clinical trials due to inconsistent definitions of HFpEF.¹⁷ The result has been unclear evidence and correspondingly cautious guidelines regarding pharmaceutical interventions for patients with HFmrEF.¹

Staging and Epidemiology

Corresponding to the progressive nature of the disease, HF may be staged from A to D depending on risk, symptoms, and functional or structural changes to the heart.¹ Stage A indicates substantial risk for HF based on inherited traits and noninherited risk factors like high blood pressure, obesity, diabetes, cardiac inflammation, toxicity from drugs, poor nutrition, stress, metabolic/endocrine abnormalities, and cardiovascular disease, but HF symptoms, structural heart disease, and cardiac biomarkers remain absent at this stage.¹ Stage B, or pre-HF, includes those patients who do not yet exhibit HF symptoms but may have evidence of structural heart disease, increased filling pressures, or increased biomarkers such as B-type natriuretic peptide (BNP) or cardiac troponin.¹ Patients in stage C exhibit current or prior symptoms of HF as well as structural heart disease.¹ Finally, patients in stage D are those with advanced HF who experience symptoms that interfere with daily life, often resulting in recurrent hospitalizations despite attempts to optimize GDMT.¹ The goal of progressive staging is to gradually introduce therapeutic interventions to modify risk and reduce symptoms, morbidity, and mortality.¹

HF affects a heterogeneous population, although several broad trends are evident within patient demographics. In general, prevalence increases with age, and HF is more prevalent among men than among women.³ However, as mentioned, the incidence of HFpEF is increasing while that of HFrEF is decreasing.¹ Therefore, it is noteworthy that, relative to patients younger than 65 years, older patients with HFpEF are more likely to be women according to a study that examined age-related differences in clinical characteristics and outcomes among patients with HFpEF.¹⁸ Results from this study also showed disproportionate mortality among older patients with HFpEF,¹⁸ indicating patient care disparities related to demographic characteristics.

Similar disparities have been observed in other patient populations. A separate study examined cardiovascular outcomes among patients with HFpEF stratified by racial group and found that Black patients with HFpEF had a higher annualized incidence of HF hospitalizations, although racial differences in cardiovascular mortality were not evident.¹⁹ Taken together, these demographic trends and the corresponding disparities in care indicate a diverse population of patients for whom current GDMT are insufficient to improve patient prognoses.

Current Treatment Strategies and Unmet Needs

Since HF is a progressive condition, the overall treatment strategy proceeds stepwise depending on a patient’s staging.¹ Early treatment focuses on strategies to prevent HF progression, with care providers giving patients more advanced treatments as HF symptoms emerge or worsen.¹ Effective and recommended management of HF involves a multipronged, multidisciplinary treatment approach that includes (as necessary) changes to diet and exercise routine, maintenance of a healthy weight and blood pressure, smoking cessation, receipt of recommended vaccinations, and pharmacological treatment.¹ As care providers escalate treatment, patients should maintain any noninvasive treatments like lifestyle changes, follow the directions of their care team regarding pharmaceutical interventions, and learn to self-monitor for signs of worsening HF, including how to respond to those symptoms.¹

Care providers should approach HF treatment from a coordinated, multidisciplinary, team-based perspective. Ideally, primary care providers identify HF, initiate GDMT, and recognize when to escalate care to a cardiologist. From there, cardiologists ought to rule out alternative diagnoses, optimize GDMT, and recognize when an HF specialist would be beneficial. HF specialists can assess patients’ candidacy for advanced therapies like heart transplantation or determine clinical trial eligibility while simultaneously solving diagnostic dilemmas and managing unusual cardiac comorbidities. Multidisciplinary specialists may also need consultation to manage other noncardiac comorbidities.²⁰ The most common comorbidities among patients with HF are hypertension, ischemic heart disease, diabetes, anemia, chronic kidney disease, obesity, frailty, and malnutrition.¹

Guideline-Directed Medical Therapy: Recommendations from a Joint Committee

As patients’ HF symptoms escalate to the point of needing pharmaceutical intervention, treatment recommendations differ depending on the subtype of HF with which a patient has been diagnosed. Table 2 provides details on the medication classes recommended for each subtype of HF and the strength of those recommendations as determined by a joint committee representing the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA).¹ As shown in Table 2, there is a lack of strongly recommended treatment options for HFmrEF and HFpEF.

Symptom Treatment With Diuretics

Under current guidelines, diuretics (as needed) are the only medication class with a strong Class I recommendation across all 3 HF subtypes.¹ Diuretics are adjunctive therapies for managing congestion among patients with HFmrEF and HFpEF that should be used in combination with other GDMT to improve outcomes.¹ Treatment goals for diuretics include minimizing fluid retention using the lowest possible dose.¹ Physicians most commonly prescribe loop diuretics like bumetanide, furosemide, and torsemide. However, some patients may exhibit diuretic resistance, an inability to excrete sufficient fluid and sodium to relieve congestive symptoms despite maximal dosing with a loop diuretic.²¹ Thiazide and thiazide-like diuretics (hydrochlorothiazide, chlorthalidone, or metolazone) are often added to a loop diuretic to treat refractory edema or hypertension.¹ Still, these combinations risk electrolyte imbalances requiring close monitoring and careful management.²¹

Treatment Initiation With SGLT2 Inhibitors

The most recently published ACC/AHA/HFSA joint treatment guidelines for HF offer a moderate, Class IIa recommendation for SGLT2 inhibitors (SGLT2is) in patients with HFmrEF and HFpEF.¹ However, given the increased evidence supporting SGLT2i use since that publication, a subsequently published ACC consensus statement offers a stronger endorsement that, absent contraindications, these medications should be initiated in all patients with HFpEF.²⁰ As of 2023, guidelines from the European Society of Cardiology align with the stronger recommendation based on the results of 2 large, multinational clinical trials that examined the safety and efficacy of empagliflozin and dapagliflozin in patients with HFmrEF and HFpEF.^22,23 Thus, current evidence supports initiating an SGLT2i as soon as possible among patients with HFpEF and HFmrEF. ^1,20

Current data are insufficient to support a clear mechanism by which SGLT2is improve HF outcomes and reduce cardiovascular mortality, particularly in patients with HFmrEF or HFpEF. A diuretic effect has been proposed corresponding with these medications’ effects on sodium and glucose excretion,²⁴ but this effect seems to fade over time and cannot explain long-term improvements.²⁵ The conclusions of a 2021 review article considered numerous interrelated mechanistic effects such as anti-inflammation, anti-oxidative stress, improved diastolic function, reduced calcium and sodium overload, reduced fibrosis, and others; further research is necessary to reach a consensus.²⁵

Alternative Treatment Options

Mineralocorticoid receptor overactivation is associated with cardiac remodeling, fibrosis, and contractile dysfunction; limiting this overactivation is the principle behind the use of steroidal mineralocorticoid antagonists (sMRAs), such as spironolactone, which have a Class IIb recommendation for patients with HFmrEF and HFpEF. ^1,26

Specifically, spironolactone may reduce the risk of HF hospitalizations, benefitting select patients with HFpEF whose kidney function does not raise concerns regarding hyperkalemia.^20,27 A proposed mechanism of action for spironolactone is through potassium sparing diuresis, underlying its role as both a diuretic and as an antihypertensive medication.²⁸ Additionally, by blocking aldosterone at the mineralocorticoid receptor, spironolactone decreases sodium resorption, which lowers blood pressure.²⁸ Antifibrotic properties have also been proposed; an editorial review of spironolactone use in patients with HFpEF hypothesized that myocardial benefits could be explained in part by reduced arterial wall fibrosis and corresponding myocardial remodeling secondary to blood pressure reduction.²⁹ However, the benefits of sMRAs are uncertain in patients with HFpEF. In the TOPCAT trial (NCT00094302), which compared spironolactone to placebo among patients whose LVEF exceeded 45%, spironolactone failed to meet its primary efficacy outcome.³⁰ Subsequent subgroup analyses led to speculation that inclusion criteria and implementation of trial protocols were inadequately applied in some trial regions due to geographically dependent effects; patients in North America benefitted from spironolactone, while those in Russia/Georgia did not.²⁰ Moreover, subpopulations with HFpEF may experience reduced hospitalization risk.²⁰ Other investigations have not demonstrated significant improvement to quality of life between patients on spironolactone vs those on placebo. ^20,31

The sacubitril/valsartan combination is an angiotensin receptor neprilysin inhibitor (ARNi) that may provide benefit to patients with HFpEF.²⁰ Sacubitril inhibits neprilysin to cause vasodilation and increased diuresis.²⁰ In a pooled analysis of multiple trials, the risk of HF hospitalization was lower in patients on sacubitril/valsartan compared to those on valsartan therapy.³² Thus, ARNis have a Class IIb recommendation for HFmrEF and HFpEF according to the ACC/AHA/HFSA joint guideline.¹

In patients with contraindications for ARNis or for whom ARNi affordability is a concern, angiotensin II receptor blockers (ARBs) are an alternative, with a similar Class IIb recommendation for HFmrEF and HFpEF per the ACC/AHA/HFSA joint guideline.^1,20

Of the medications in this class, a clinical trial of candesartan (NCT00634712) produced the most convincing evidence of benefit in patients with LVEF of at least 40%.²⁰ Specifically, covariate-adjusted analyses revealed a moderately reduced risk of HF hospitalization among patients who received candesartan (HR, 0.84; 95% CI, 0.70-1.00; P = .047), and the composite outcome of cardiovascular death of HF hospitalization approached significance in the covariate-adjusted analysis (HR, 0.86; 95% CI, 0.74-1.00; P = .051).^20,33 A clinical trial for the ARB irbesartan (NCT00095238) was unable to demonstrate benefit among patients with an LVEF of at least 45%, although study-drug discontinuation and concomitant use of angiotensin-converting enzyme inhibitors (ACEi) in this trial may have affected treatment responses.²⁰ Thus, current treatment guidelines suggest ARBs may be most beneficial to reduce the risk of HF hospitalization and cardiovascular death among patients on the lower end of the LVEF spectrum.¹

New and Emerging Approaches

Recent clinical trials have investigated the nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone as an addition to standard therapy in patients with HFmrEF or HFpEF.³⁴ Finerenone prevents mineralocorticoid overactivation in both renal and cardiovascular tissues and is thought to block fibrosis and inflammation.³⁵ Unlike sMRAs, finerenone is nonsteroidal and highly selective for the mineralocorticoid receptor, with no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors.³⁵ Whereas sMRAs like spironolactone can cause gynecomastia due to off-target binding at steroid receptors, finerenone lacks this receptor affinity and therefore does not carry this adverse reaction.²⁸

The FINEARTS-HF clinical trial (NCT04435626) was the primary investigation that showed benefit among patients with HFmrEF and HFpEF who took finerenone in addition to usual therapy.³⁴ Trial participants included patients 40 years and older with symptomatic HF, LVEF of at least 40%, evidence of structural heart disease, and elevated levels of natriuretic peptides.³⁴ The primary efficacy outcome was a composite of total worsening HF events and death from cardiovascular causes.³⁴ Secondary outcomes measured total worsening HF events, change in symptom score from baseline on the Kansas City Cardiomyopathy Questionnaire (KCCQ), improvement in HF functional class at month 12, and a composite outcome of renal health.³⁴ At the primary data cutoff, fewer primary efficacy events occurred in the finerenone group compared to the placebo group (rate ratio [RR], 0.84; 95% CI, 0.74-0.95; P = .007).³⁴ In addition, finerenone was associated with fewer number of worsening HF events, a secondary outcome, compared with placebo (RR, 0.82; 95% CI, 0.71-0.94; P = .006).³⁴ The primary composite outcome also favored finerenone across all prespecified subgroups, regardless of baseline LVEF or baseline SGLT2i use.³⁴ From baseline, patients in the finerenone arm exhibited greater improvement to total symptom score relative to patients in the placebo arm (least-squares mean difference in KCCQ total symptom score, 1.6 points; 95% CI, 0.8-2.3 points; P < .001).³⁴ Improvements to HF functional class or kidney composite outcome events were not statistically different between the finerenone and placebo treatment arms.³⁴ Published after the primary results of the trial, a prespecified exploratory analysis revealed that finerenone was associated with a reduced rate of first outpatient oral diuretic intensification events.³⁶

Adverse reactions that were reported more commonly in patients taking finerenone than in those taking placebo included hyperkalemia (serum potassium > 5.5 mmol/L, 14.3% vs 6.9%, respectively)³⁴ and other adverse events related to worsening renal function (18% vs 12%), including renal impairment (7% vs 4%), decreased estimated glomerular filtration rate (5% vs 4%), acute kidney injury (4% vs 2%), and renal failure (3% vs 2%). The majority of these were reported as mild or moderate.³⁵ Hyperkalemia led to hospitalization in 16 patients taking finerenone (0.5%) and in 6 patients in the placebo group (0.2%), but none of these hyperkalemic episodes led to patient death.³⁴ Considered together, these safety and efficacy data supported finerenone gaining an indication in 2025 to reduce the risk of cardiovascular death, HF hospitalization, and urgent HF visits in adult patients with HF whose LVEF is at least 40%.³⁵ As updated guidelines for HF management are awaited, a recently published consensus statement supports rapid initiation of finerenone either concomitant or in rapid sequence with 2 other medications.³⁷

Barriers to Care Access

Because of changing naming conventions and inconsistent terminologies, practicing physicians may lack familiarity with current HFrEF, HFmrEF, and HFpEF designations, raising the possibility that GDMT treatment decisions based on this nomenclature could be affected. Prior to the 2013 ACC/AHA joint guideline statement for the management of HF, HFrEF was generally referred to as systolic HF, and HFpEF was generally referred to as diastolic HF.² Moreover, before the current HFmrEF naming convention was introduced in the 2022 ACC/AHA/HFSA joint guideline statement on the management of HF, the diagnostic terminology for LVEF in the range of 41% to 49% was problematic; the 2013 ACC/AHA joint guidelines had declared consistent EF measurements of 41% to 49% to be HFpEF, borderline, but had also declared EF measurements greater than 40%—which overlapped with the borderline measurements—to be HFpEF, improved if patients’ LVEF recovered following a prior diagnosis of HFrEF.² The term HF with borderline EF (HFbEF) has also been used.⁸ These inconsistencies and recent changes to HF terminologies risk influencing therapeutic decisions, particularly if providers are unaware of them.

In a similar vein, recent updates to medical coding have yet to fully correspond to this new terminology, which may impact treatment reimbursement and access to care. Whereas the International Statistical Classification of Diseases, Tenth Revision, (ICD-10) includes HFrEF and HFpEF under codes for older terminologies (ie, systolic and diastolic HF), there is still no code for HFmrEF.³⁸ A recent British study on HF coding practices in primary care settings revealed common themes of incorrect HF diagnoses and missed diagnoses due to coding errors.³⁹ Likewise, a study of a large, American, community-based health system revealed that only about 10% of HF hospitalizations were accompanied by an ICD-10 code for systolic HF, diastolic HF, or combined systolic and diastolic HF.⁴⁰ Considering the proposed role of primary care providers to differentially diagnose HF and initiate GDMT,²⁰ the implications of missed or incorrect diagnoses due to absent or incomplete coding may amount to inappropriate treatment selection, clinical confusion, psychological distress among patients, impacts to insurance premiums, and inappropriate insurance denials for medically appropriate therapies.³⁹

Managed Care Considerations

While clinical guidelines provide a framework for optimal HF management, real-world implementation is shaped not only by physician awareness and coding practices but also by the broader economic and administrative environment. These challenges translate into measurable financial consequences for patients, providers, and payers. Indeed, the costs of HF care encompass multiple dimensions, which together contribute to a significant burden on the health care system. Recent analyses provide insight into how these costs vary across HF phenotypes, offering a clearer picture of where the economic impact is most pronounced.

A broad analysis of health care expenditures compared cost burdens between patients with or without HF of any LVEF phenotype using nationally representative payer data from the Medical Expenditure Panel Survey.⁴¹ This comprehensive analysis included an adult sample of more than 250,000 participants (1742 with HF; 249,078 without HF) and measured mean annual health care expenditures from 2009 to 2018 (final costs expressed in inflation-adjusted 2018 US$).⁴¹ Across all years and expenditure categories, mean annual costs were substantially higher among those with HF than those without (Figure 1).⁴¹ Notably, health care expenditures for HF were greater than those for other chronic health conditions, and the cost inflation for HF care between 2009 and 2018 was only outpaced by cost inflation for diabetes care.⁴¹

A separate analysis provided similar insight into HF cost burden by LVEF phenotype.⁹ This study, which included more than 16,000 patients with HF serviced by Kaiser Permanente Northwest, provided detailed cost estimations (2020 US$) by LVEF phenotype.⁹ Annualized mean costs per person for inpatient hospitalization were lowest among patients with HFrEF ($15,008; 95% CI, $13,440-$16,576) and highest among patients with HFpEF ($16,750; 95% CI, $16,142-$17,369); those for patients with HFmrEF fell in between ($15,877; 95% CI, $14,077-$17,675]).⁹ Similar trends were evident for outpatient costs (HFpEF, $10,544 [95% CI, $10,307-$10,782]; HFrEF, $7978 [95% CI, $7375-$8581]; HFmrEF, $8861 [95% CI, $8169-$9552])⁹ along with pharmacy costs based on retail pharmaceutical prices plus procedures and devices (HFpEF, $4844 [95% CI, $4591-$5098]; HFrEF, $3345 [95% CI, $2702-$3988]; HFmrEF, $3327 [95% CI, $2589-$4085]).⁹ Together, these data indicate not only the substantial cost burden of HF, but also that the LVEF phenotypes with limited GDMT options are associated with the highest overall cost burden.

The frequency of HF hospitalizations magnifies this overall cost burden, because gaps in available treatment options during or soon after discharge contribute to both patient morbidity and payer penalties. The Centers for Medicare & Medicaid Services Hospital Readmissions Reduction Program (HRRP) is a provision of the Affordable Care Act that reduces hospitals’ overall reimbursement across all admissions if the facilities show a higher-than-expected rate of unplanned readmissions for targeted conditions like HF.¹² Between 2016 and 2023, 1.4% of emergency department encounters were due to HF visits (n = 2,626,011), and most of these patients (72.3%) were subsequently admitted to the hospital (n = 1,897,369).⁴² Coupled with the knowledge that approximately 21% of patients with HFpEF may be readmitted within 30 days⁴³ and that annualized per-person inpatient costs exceed $16,750 (2020 US$) in persons with HFpEF,⁹ it follows that the potential financial impact of the HRRP on health systems is substantial. Recent studies have investigated the potential of emerging HF treatments to lessen this impact. Some have demonstrated rapid clinical benefit of emerging treatment,⁴⁴ while others have investigated how the timing of treatment use (early vs late following a worsening HF event or hospitalization) impacts safety and efficacy⁴⁵ or hospital readmissions.⁴⁶ The most recent guideline for the management of HF was published before any of these investigations and, thus, does not make recommendations regarding timing to initiate emerging therapies.¹

Conclusions

In HF, structural or functional impairments to the heart impair the muscle’s high-pressure filling capacity or its ability to eject blood to the rest of the body, resulting in signs and symptoms of the ailment.¹ New terminology differentiates HF phenotypes according to the LVEF, and these include HFpEF, HFmrEF, or HFrEF.¹ Whereas guidelines recommend an abundance of medication classes to treat HFrEF, there is a paucity of treatment options for patients with HFmrEF and HFpEF,¹ resulting in substantial unmet needs among patients due to divergent trends in incidence.¹ Only diuretics are strongly recommended across all LVEF phenotypes,¹ and these medications offer neither morbidity nor mortality benefit, nor are they recommended for use without additional medications¹; diuretic resistance is a further concern that may limit the utility of these medications.²¹

Emerging treatment options like finerenone offer benefit to patients with HFmrEF and HFpEF in terms of reduced risk of cardiovascular death and worsening of the HF event, including HF hospitalization or urgent visit.³⁴ SGLT2is are also recommended for treatment initiation across all LVEF phenotypes, with a recently published consensus statement offering stronger endorsement of these medications for HFmrEF and HFpEF than was provided in the 2022 joint guideline from ACC, AHA, and HFSA.²⁰ A similar consensus statement recently recommended rapid initiation of finerenone concomitant or in rapid sequence with other therapies for patients with HFmrEF and HFpEF.³⁷

Barriers to adequate HF involve providers’ familiarity with newly introduced EF terminology and their ability to accurately code HF diagnoses.² Taken together, these considerations highlight that unmet therapeutic needs in HF not only affect patient outcomes but also contribute to substantial economic burden,^9,41 which underscores the importance of managed care strategies that optimize both access to effective therapies and the efficient use of health care resources.

Authorship Affiliation: Health Economics and Outcomes Research (HEOR), Bayer (JG, BH, BK), Whippany, NJ.

Source of Funding: This supplement was supported by Bayer.

Author Disclosures: Drs Grossman, Hocum, and Kalayeh are employed by Bayer.

Authorship Information: Concept and design (JG, BH, BK); critical revision of the manuscript for important intellectual content (JG, BH, BK); supervision (JG, BH, BK).

Acknowledgments: Alexander Tarlochan Singh Sandhu, MD, MS, of the Stanford University School of Medicine; and Dennis Bruemmer, MD, PhD, of the Cleveland Clinic and Case Western Reserve University School of Medicine; provided edits and corrections. Bayer was given the opportunity to review the content for medical accuracy.

Address Correspondence to: Brian Hocum, PharmD, MS; 100 Bayer Blvd, Whippany, NJ 07981. Email: brian.hocum@bayer.com

REFERENCES

1. Heidenreich P, Bozkurt B, Aguilar D. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. JACC. 2022;79(17):1757-1780. doi:10.1016/j.jacc.2021.12.011
2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810-1852. doi:10.1161/CIR.0b013e31829e8807
3. 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
4. Tsao CW, Lyass A, Enserro D, et al. Temporal trends in the incidence of and mortality associated with heart failure with preserved and reduced ejection fraction. JACC Heart Fail. 2018;6(8):678-685. doi:10.1016/j.jchf.2018.03.006
5. Writing Committee Members. HF STATS 2025: heart failure epidemiology and outcomes statistics: an updated 2025 report from the Heart Failure Society of America. J Card Fail. Published online August 29, 2025. doi:10.1016/j.cardfail.2025.07.007
6. Golla MSG, Shams P. Heart failure with preserved ejection fraction (HFpEF). In: StatPearls. StatPearls Publishing; 2025. Accessed April 23, 2026. https://www.ncbi.nlm.nih.gov/books/NBK599960/
7. Ibrahim NE, Song Y, Cannon CP, et al. Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry. ESC Heart Failure. 2019;6:784-792. doi:10.1002/ehf2.12455
8. Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70(20):2476-2486. doi:10.1016/j.jacc.2017.08.074
9. Nichols GA, Qiao Q, Linden S, Kraus BJ. Medical costs of chronic kidney disease and type 2 diabetes among newly diagnosed heart failure patients with reduced, mildly reduced, and preserved ejection fraction. Am J Cardiol. 2023;198:72-78. doi:10.1016/j.amjcard.2023.04.035
10. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6(3):606-619. doi:10.1161/HHF.0b013e318291329a
11. Reinhardt SW, Clark KAA, Xin X, et al. Thirty-day and 90-day episode of care spending following heart failure hospitalization among Medicare beneficiaries. Circ Cardiovasc Qual Outcomes. 2022;15(7):e008069. doi:10.1161/CIRCOUTCOMES.121.008069
12. Hospital Readmissions Reduction Program (HRRP). CMS. Updated March 16, 2026. Accessed April 23, 2026. https://www.cms.gov/medicare/payment/prospective-payment-systems/acute-inpatient-pps/hospital-readmissions-reduction-program-hrrp
13. Ambulatory Specialty Model (ASM). CMS. Updated April 22, 2026. Accessed April 23, 2026.
    https://www.cms.gov/priorities/innovation/innovation-models/asm
14. Schwinger RHG. Pathophysiology of heart failure. Cardiovasc Diagn Ther. 2021;11(1):263-276. doi:10.21037/cdt-20-302
15. LeWinter MM, Meyer M. Mechanisms of diastolic dysfunction in heart failure with a preserved ejection fraction: if it’s not one thing it’s another. Circ Heart Fail. 2013;6(6):1112-1115. doi:10.1161/CIRCHEARTFAILURE.113.000825
16. Borlaug BA, Sharma K, Shah SJ, Ho JE. Heart failure with preserved ejection fraction: JACC scientific statement. J Am Coll Cardiol. 2023;81(18):1810-1834. doi:10.1016/j.jacc.20 23.01.049
17. Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol. 2022;19(2):100-116. doi:10.1038/s41569-021-00605-5
18. Tromp J, Shen L, Jhund PS, et al. Age-related characteristics and outcomes of patients with heart failure with preserved ejection fraction. J Am Coll Cardiol. 2019;74(5):601-612. doi:10.1016/j.jacc.2019.05.052
19. Lewis EF, Claggett B, Shah AM, et al. Racial differences in characteristics and outcomes of patients with heart failure and preserved ejection fraction in the Treatment of Preserved Cardiac Function Heart Failure Trial. Circ Heart Fail. 2018;11(3):e004457. doi:10.1161/CIRCHEARTFAILURE.117.004457
20. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023;81(18):1835-1878. doi:10.1016/j.jacc.2023.03.393
21. Wilcox CS, Testani JM, Pitt B. Pathophysiology of diuretic resistance and its implications for the management of chronic heart failure. Hypertension. 2020;76(4):1045-1054. doi:10.1161/HYPERTENSIONAHA.120.15205
22. Rashed A, Wasef M, Kalra PR. The 2023 ESC heart failure guideline update and its implications for clinical practice. Br J Cardiol. 2024;31(2):023. doi:10.5837/bjc.2024.023
23. McDonagh TA, Metra M, Adamo M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195
24. Talha KM, Anker SD, Butler J. SGLT-2 inhibitors in heart failure: a review of current evidence. Int J Heart Fail. 2023;5(2):82-90.doi:10.36628/ijhf.2022.0030
25. Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 inhibitors and their mode of action in heart failure-has the mystery been unravelled? Curr Heart Fail Rep. 2021;18(5):315-328. doi:10.1007/s11897-021-00529-8
26. El Mouhayyar C, Chhikara M, Tang M, Nigwekar SU. Clinical implications of mineralocorticoid receptor overactivation. Clin Kidney J. 2024;18(1):sfae346. doi:10.1093/ckj/sfae346
27. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34-42. doi:10.1161/CIRCULATIONAHA.114.013255
28. Aldactone. Prescribing information. Pfizer; 2025. Accessed April 23, 2026. https://www.pfizermedical.com/aldactone/highlights
29. Reddy YNV, Sundaram V. Spironolactone, fibrosis and heart failure with preserved ejection fraction. Eur J Heart Fail. 2022;24(9):1569-1572. doi:10.1002/ejhf.2626
30. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392. doi:10.1056/NEJMoa1313731
31. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781-791. doi:10.1001/jama.2013.905
32. Vaduganathan M, Mentz RJ, Claggett BL, et al. Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF. Eur Heart J. 2023;44(31):2982-2993. doi:10.1093/eurheartj/ehad344
33. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet. 2003;362(9386):777-781. doi:10.1016/S0140-6736(03)14285-7
34. Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024;391(16):1475-1485. doi:10.1056/NEJMoa2407107
35. Kerendia. Prescribing information. Bayer HealthCare Pharmaceuticals; 2025. Accessed April 23, 2026. https://labeling.bayerhealthcare.com/html/products/pi/Kerendia_PI.pdf
36. Cunningham JW, Chatur S, Claggett BL, et al. Finerenone and outpatient worsening heart failure with mildly reduced or preserved ejection fraction: a secondary analysis of the FINEARTS-HF randomized clinical trial. JAMA Cardiol. 2025;10(4):370-378. doi:10.1001/jamacardio.2025.0016
37. Greene SJ, Butler J, Fonarow GC. Simultaneous or rapid initiation of combination therapy for heart failure with preserved ejection fraction. JAMA Cardiol. 2025;10(5):407-408. doi:10.1001/jamacardio.2025.0038
38. ICD-10-CM tabular list of diseases and injuries. CDC. Updated April 1, 2022. Accessed April 23, 2026. https://ftp.cdc.gov/pub/health_statistics/nchs/publications/ICD10CM/2022/icd10cm-tabular-2022-April-1.pdf
39. Crundall A, Crawshaw-Ralli M, Fuat A, et al. Lessons learnt from HF coding in primary care. What might best practice look like? Br J Cardiol. 2024;31(3):037. doi:10.5837/bjc.2024.037
40. Gluckman TJ, Chiu ST, Rider D, et al. Relationship between left ventricular ejection fraction and ICD-10 codes among patients hospitalized with heart failure. Clin Cardiol. 2024;47(12):e70055. doi:10.1002/clc.70055
41. Bhatnagar R, Fonarow GC, Heidenreich PA, Ziaeian B. Expenditure on heart failure in the United States: the Medical Expenditure Panel Survey 2009-2018. JACC Heart Fail. 2022;10(8):571-580. doi:10.1016/j.jchf.2022.05.006
42. Gottlieb M, Moyer E, Bernard K. Epidemiology of heart failure presentations to United States emergency departments from 2016 to 2023. Am J Emerg Med. 2024;86:70-73. doi:10.1016/j.ajem.2024.09.059
43. Jha AK, Ojha CP, Krishnan AM, Paul TK. Thirty-day readmission in patients with heart failure with preserved ejection fraction: insights from the nationwide readmission database. World J Cardiol. 2022;14(9):473-482. doi:10.4330/wjc.v14.i9.473
44. Vaduganathan M, Claggett BL, Desai AS, et al. Time to significant benefit of finerenone in patients with heart failure. J Am Coll Cardiol. 2025;85(2):199-202. doi:10.1016/j.jacc.2024.09.018
45. Desai AS, Vaduganathan M, Claggett BL, et al. Finerenone in patients with a recent worsening heart failure event: the FINEARTS-HF trial. J Am Coll Cardiol. 2025;85(2):106-116. doi:10.1016/j.jacc.2024.09.004
46. Bhatt AS, Vaduganathan M, Claggett BL, et al. Effects of finerenone on readmissions for heart failure: insights from the FINEARTS-HF trial. J Card Fail. 2026;32:134-139. doi:10.1016/j.cardfail.2025.05.006