Introduction

Following publication of the 2021 European Society of Cardiology (ESC) heart failure (HF) guidelines, several major clinical trials have supported the benefits of specific pharmacologic therapies for patients with HF, particularly for those with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF). These findings have prompted major changes in national and international treatment guidelines. In 2022, the Korean Heart Failure Society (KHFS) released updated guidelines that notably expanded recommendations for treating patients with HFmrEF or HFpEF [1,2]. Among the key updates was the recommendation of sodium-glucose cotransporter 2 inhibitors (SGLT2is)—empagliflozin and dapagliflozin—as class I treatments (Level of Evidence B) for HF patients with or without diabetes, to reduce cardiovascular mortality and hospitalization. Angiotensin receptor-neprilysin inhibitors (ARNIs) were also recommended as class IIa treatments. Compared with the 2021 ESC and 2022 American College of Cardiology/American Heart Association guidelines, which either did not include or offered weaker recommendations for SGLT2is and ARNIs, the KHFS guidelines were considered highly progressive at the time. These recommendations were largely based on timely large-scale randomized trials demonstrating that SGLT2is improve outcomes in patients with HFpEF or HFmrEF [3,4]. In the most recent 2023 ESC focused update, SGLT2is (empagliflozin and dapagliflozin) received a class I recommendation for both HFmrEF and HFpEF [5].

Despite these updated recommendations, it remains unclear whether these guidelines have translated to updated real-world prescribing behavior. As seen in other areas of cardiovascular medicine—such as lipid-lowering therapy—there is often a significant gap between guideline recommendations and clinical practice. The DA VINCI study, for example, revealed that real-world statin prescriptions did not match recommended guidelines, despite clear goals for low-density lipoprotein cholesterol lowering [6].

Similar challenges likely affect HF management. Factors such as physician familiarity with guidelines, reimbursement limitations, and concern about adverse effects can all contribute to nonadherence. Understanding these barriers is critical to improving care. However, to date, data on implementation of the 2022 KHFS guidelines in Korea are limited. This study aims to address that gap by evaluating guideline-directed medical therapy (GDMT) prescribing practices for patients with HFmrEF or HFpEF at a single tertiary care center. Additionally, we explore which clinical characteristics—such as diabetes, renal function, and age—influence prescription patterns.

Methods

Ethical statements: The study protocol was approved by the Institutional Review Board (IRB) of Kosin University Gospel Hospital (IRB No. 2025-08-004) and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.

1. Study design and population

This was a cross-sectional, observational, single-center study. In 2022, updated guidelines for the management of HF were published by the KHFS. We analyzed the prescription patterns of GDMT in patients newly diagnosed with HF. We screened patients at Kosin University Gospel Hospital who had a new International Classification of Diseases (ICD) diagnosis code for HF (e.g., HF, congestive HF) between January 2023 and December 2023. To minimize heterogeneity in the diagnostic criteria for HF, we excluded the following patients.

(1) Patients whose demographic data were not available in the electronic medical records (EMR).

(2) Patients diagnosed with HF by a department other than cardiology, since noncardiologists might not consistently apply the standard HF definition.

(3) Patients who did not undergo echocardiography and cardiac biomarker testing (brain natriuretic peptide or N-terminal pro brain natriuretic peptide [NT-pro BNP]) within 3 months of the initial HF diagnosis code.

(4) Patients who had no follow-up visit at the cardiology outpatient clinic after hospital discharge.

(5) Patients with HF with reduced ejection fraction (HFrEF), defined as a left ventricular ejection fraction (LVEF) <40%.

For patients diagnosed with HF during hospitalization, we assessed their medication use based on the prescriptions provided at the first cardiology outpatient visit after discharge. This approach was used to avoid the confounding effects of hemodynamic instability on GDMT administration during hospitalization.

2. Data collection

Demographic and comorbidity data were collected from the EMR. Baseline characteristics were age; sex; and comorbidities of diabetes mellitus (DM), hypertension, ischemic heart disease (IHD), chronic kidney disease (CKD), and atrial fibrillation (AF). Laboratory data were NT-pro BNP, serum creatinine, estimated glomerular filtration rate (eGFR), and hemoglobin A1c (HbA1c) as well as echocardiographic parameters. IHD was defined as the presence of myocardial infarction or angina with significant coronary artery stenosis (luminal narrowing ≥70%), with or without a history of coronary artery bypass graft or percutaneous coronary intervention. DM was defined as a prior diagnosis of DM, current use of oral hypoglycemic agents or insulin, or an HbA1c level ≥6.5%. CKD was defined as a prior diagnosis of CKD or end-stage renal disease or an eGFR <60 mL/min/1.73 m² at the time of study enrollment.

3. Sample size calculation and statistical analysis

The primary objective of this study was to evaluate the prescription rate to the updated KHFS guideline-recommended pharmacological therapy among patients diagnosed with HFmrEF or HFpEF and to identify factors associated with adherence. To ensure a normally distributed sample, we referred to previous data from other institutions in 2024, which reported that 42.2% to 59.6% of patients with HF received appropriate pharmacologic therapy (defined as prescription of at least two GDMT agents) [7]. Assuming a similar adherence rate at our institution and setting a margin of error of 0.05, the required sample size was calculated to be approximately 384 patients. However, to enable a more detailed analysis of prescription patterns for individual GDMT components, we aimed to recruit nearly twice the minimum sample size. Additionally, considering that approximately 5% of patients might be deemed ineligible or excluded during data processing, we set the final target sample size at 700 patients.

All statistical analyses were performed using STATA (version 17, StataCorp.). Baseline characteristics were summarized using descriptive statistics. Normality of distribution was assessed using the Kolmogorov-Smirnov test. Continuous variables are presented as mean±standard deviations and were compared using the Student t-test. Categorical variables are presented as counts and percentages and were compared using the chi-square test. A p-value <0.05 was considered statistically significant.

Results

Among 2,343 patients newly diagnosed with HF based on ICD codes, 1,728 were excluded, leaving 615 to be included in the final analysis (Fig. 1). The mean age was 68.9 years, and 52.4% were female. The average LVEF was 62.9%, with 568 patients classified as HFpEF and 47 as HFmrEF. Baseline characteristics are summarized in Table 1. Among the 615 patients included in the study, 129 (21.0%) were first diagnosed with HF in the emergency department or at hospitalization, and 486 in the outpatient clinic. Common comorbidities included HTN (75.5%), DM (50.9%), IHD (43.7%), and CKD (22.6%). Compared to those with HFpEF, patients with HFmrEF had a significantly higher prevalence of IHD (57.5% vs. 42.6%; p=0.049), CKD (44.7% vs. 20.8%; p<0.001), and AF (56.5% vs. 38.0%; p=0.013), as well as significantly higher NT-pro BNP levels (3,450±6,390 vs. 1,142±3,556 pg/mL; p<0.001).

In the overall population, prescription rates for GDMT were as follows: renin-angiotensin system (RAS) blockers in 73.3%, beta-blockers in 83.7%, mineralocorticoid receptor antagonists (MRAs) in 41.1%, and SGLT2is in 42.9% (Fig. 2).

We further analyzed whether the prescription rates of these medications varied according to clinical factors such as LVEF, DM or CKD, office systolic blood pressure (SBP), and serum potassium levels. Use of SGLT2is was significantly more frequent among patients with DM (71.6%) compared to those without DM (13.2%; p<0.001) (Fig. 3A). However, there were no significant differences in SGLT2i use by CKD status (42.7% in non-CKD vs. 43.9% in CKD; p=0.795) (Fig. 3B) nor between HFpEF and HFmrEF groups (43.4% vs. 37.0%; p=0.395) (Fig. 3C).

Among the 451 patients prescribed RAS blockers, the most commonly used agent was an angiotensin receptor blocker (angiotensin receptor blocker [ARB]; 308 patients, 68.3%), followed by angiotensin-converting enzyme inhibitors (ACEIs; 88 patients, 19.5%) and ARNIs (55 patients, 12.2%) (Fig. 4A). The distribution of RAS blocker types varied according to LVEF category (Fig. 4B). There was no significant difference in the overall use of RAS blockers based on outpatient SBP (<100 mmHg vs. ≥100 mmHg; p=0.210) (Fig. 4C). However, there was a significantly higher ARNI prescription rate in the HFmrEF patients compared to the HFpEF group (40.4% vs. 6.3%; p<0.001) (Fig. 4D).

For MRAs, the prescription rate was significantly higher in the HFmrEF group than in the HFpEF group (56.5% vs. 39.9%; p=0.028) (Fig. 5A). However, MRA use was not significantly affected by CKD status (Fig. 5B) or hyperkalemia (Fig. 5C). Beta-blocker use was significantly higher in patients younger than 75 years compared to those aged 75 years or older (86.8% vs. 77.0%; p=0.002) (Fig. 6A). Additionally, patients with AF were more likely to receive beta-blockers than those without AF (90.1% vs. 79.6%; p=0.001) (Fig. 6B).

Discussion

Our study population consisted of older patients with a relatively high prevalence of hypertension, diabetes, AF, and elevated NT-pro BNP levels, reflecting a cohort consistent with typical HFpEF characteristics. Notably, the high prevalence of AF suggests that a significant proportion of patients had developed HFpEF primarily due to left atrial myopathy. Among these patients, that despite the KHFS guidelines strongly recommending aggressive medical management, the actual prescription rates of certain GDMT agents were relatively low in clinical practice. Even among cardiologists at a tertiary care center—who are presumably familiar with the latest guidelines—GDMT implementation remained suboptimal. This discrepancy calls for cautious interpretation and further investigation.

When comparing our findings with recent international trials involving HFpEF patients, the STEP-HFpEF trial reported the use of ACEI/ARB/ARNI at 80.2%—the highest among drug classes—followed by beta-blockers at 79%, MRA at 34.8%, and SGLT2is at only 3.6% (noting the exclusion of patients with diabetes) [8]. In the STEP-HFpEF DM trial, which included diabetic patients, beta-blockers and RAS blockers were prescribed in 83% and 82%, respectively, while MRA and SGLT2i usage rates were 32% and 33% [9]. In the FINEARTS-HF trial, beta-blocker usage was highest at 85%, followed by RAS blockers (including ARNI) at 79%, while SGLT2i usage was low at 14% [10]. These multicenter international studies consistently demonstrate the underutilization of MRA and SGLT2i in HFpEF populations, prompting further exploration into the contributing factors.

In our study, the prescription rate of SGLT2is—which carry a class I recommendation for HFmrEF and HFpEF—was 42.9%, with a significant difference based on diabetes status. Renal function did not appear to significantly influence SGLT2i prescription rates, nor did HFmrEF versus HFpEF. The marked difference based on diabetic status suggests that, in HF patients with diabetes, SGLT2i is often the first-line antidiabetic choice, which aligns with recent clinical practice. Updated Korean diabetes guidelines also recommend SGLT2i as the first choice in patients with HF, providing a strong rationale for clinicians [11]. However, insurance reimbursement policies remain a key issue in Korea. Since SGLT2i is not reimbursed for HFpEF patients without diabetes, this likely contributes to clinicians' reluctance to prescribe it in such cases. Another notable finding is the lack of significant difference in SGLT2i use between patients with and without impaired renal function. While it is well established that SGLT2i has long-term renoprotective effects [12,13], the frequent initial dip in eGFR can hinder clinicians from prescribing it to CKD patients. However, our data suggest that this concern does not significantly impact real-world prescribing behavior.

The overall prescription rate of RAS blockers (including ACEIs, ARBs, and ARNIs) was 73.3%, indicating that clinicians generally recognize the value of RAS blockade in patients with HFpEF. However, ARNI usage showed a striking disparity: it was prescribed in 40.4% of patients with HFmrEF, but in only 6.3% of those with HFpEF. Despite the KHFS guidelines granting ARNI a class IIa recommendation—preferably over ACEIs or ARBs—its real-world application remains limited. Although ARNI has demonstrated prognostic benefits in patients with LVEF lower than normal, evidence supporting its efficacy in patients at the higher end of the LVEF spectrum remains limited [14]. In addition, practical barriers such as high medication costs and lack of insurance reimbursement can substantially influence prescribing behavior. In our analysis, the presence of CKD or diabetes, as well as outpatient SBP, did not affect the prescription rate of ARNI. This suggests that, rather than these clinical factors, physicians' confidence in the clinical efficacy of ARNI and systemic policy-related barriers play a greater role in influencing its use. To improve ARNI prescription rates in HFpEF, further robust clinical evidence and practical changes in healthcare policy are necessary.

Despite KHFS guidelines recommending MRA as a class IIa drug for HFmrEF and class IIb for HFpEF, the prescription rate in our cohort was only around 40%. MRA use was significantly higher in HFmrEF than in HFpEF but did not vary significantly by CKD status or hyperkalemia. This low usage rate is consistent with other studies, where MRA prescription rates in hospitalized HFmrEF and HFpEF patients at tertiary centers ranged from 29.8% to 39.7% [7]. Similarly, MRA use in the STEP-HFpEF trial was only 34.8% [8]. Even in HFrEF, where MRA carries a class I recommendation, usage has been reported at less than 50% in some studies. The lack of strong outcome data to support MRA use in HFmrEF and HFpEF [15] might explain some of the limited clinical implementation. Furthermore, potential adverse effects—such as renal dysfunction and hyperkalemia—might contribute to physicians’ reluctance to prescribe MRAs [16]. These adverse effects likely stem from the low selectivity of steroidal MRAs, which also act on nonmineralocorticoid receptors [17]. Recently, however, the role of MRA in HFmrEF and HFpEF has been reconsidered. Finerenone, a novel nonsteroidal and selective MRA, has shown benefits in reducing clinically significant cardiovascular and renal outcomes in patients with type 2 diabetes or CKD [18]. The FINEARTS-HF trial also showed that finerenone significantly reduced the composite endpoint of total worsening HF events and cardiovascular death in patients with HFmrEF or HFpEF [10]. Numerous ongoing studies continue to provide supporting evidence. Additionally, emerging agents such as balcinrenone are under investigation for their potential to overcome traditional MRA limitations [19]. These developments suggest a future increase in recommendation of MRAs in HFpEF.

Beta-blocker use in our study was relatively high, possibly due to the high proportion of AF patients in our cohort. Subgroup analyses showed that beta-blockers were used more frequently in patients with AF and less commonly in elderly patients. The prognostic benefit of beta-blockers in HFpEF remains controversial, and current guidelines assign a low (class IIb) level of recommendation. However, a recent meta-analysis based on observational studies showed that beta-blocker therapy can reduce all-cause mortality in HFpEF patients, although it did not significantly affect HF rehospitalization or composite outcomes [20]. Despite these uncertainties, beta-blockers offer diverse benefits in HFpEF, especially considering the heterogeneity of underlying etiologies and comorbidities. In particular, their anti-anginal effects in IHD, blood pressure-lowering effects in hypertension, and rate-control benefits in AF highlight their multifaceted utility. These findings underscore the need for randomized controlled trials to better define the role of beta-blockers in HFmrEF and HFpEF.

Our study has several limitations. First, HF diagnoses were based on ICD codes from the EMR, and we could not assess symptoms and signs directly. To address this, we included only patients who underwent echocardiography and biomarker testing around the time of diagnosis, assuming that these tests were ordered to objectively confirm HF. Second, the single-center, retrospective design limits generalizability and introduces potential selection bias. Additionally, the smaller number of HFmrEF patients compared to HFpEF limits our ability to directly compare prescription rates between groups. Finally, we were unable to account for any changes in patient medication use during follow-up. Nevertheless, despite these limitations, our findings provide valuable real-world insights into GDMT use among Korean HFmrEF and HFpEF patients, which could help guide future efforts to improve care.

In conclusion, our study showed that the rate of use of RAS blockers, beta-blockers, MRA, and SGLT2is among HFmrEF/HFpEF patients was 73.3%, 83.7%, 41.1%, and 42.9%, respectively, with significant variation depending on specific clinical factors. Notably, SGLT2is—despite their class I indication—were prescribed for fewer than half of eligible patients. Large-scale, multicenter studies are warranted to further explore and address this treatment gap.

Article information

Conflicts of interest

Sung-Il Im is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Funding

None.

Author contributions

Conceptualization: BJK. Data curation: BJK, SB. Formal analysis: BJK. Investigation: BJK. Methodology: BJK. Resources: BJK, SB, SJK, SII, JHH. Software: BJK. Supervision: SJK, SII, JHH. Visualization: BJK, SB, SJK, SII, JHH. Writing–original draft: BJK. Writing–review & editing: BJK, SB, SJK, SII, JHH. All authors read and approved the final manuscript.

Fig. 1.

Study population. HF, heart failure; ICD, International Classification of Diseases; EMR, electronic medical records; BNP, brain natriuretic peptide; NT-pro BNP, N-terminal pro brain natriuretic peptide; LVEF, left ventricular ejection fraction; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate.

Fig. 2.

Prescription rate of guideline-directed medical therapy in the overall population. RAS, renin-angiotensin system; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

Fig. 3.

Comparison of SGLT2i prescription rates. (A) SGLT2i by diabetes status. (B) SGLT2i by CKD. (C) SGLT2i by HFpEF vs. HFmrEF. SGLT2i, sodium-glucose cotransporter 2 inhibitor; DM, diabetes mellitus; CKD, chronic kidney disease; HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction.

Fig. 4.

Detailed analysis of RAS blockers. (A) Distribution of RAS blocker components among overall patients. (B) Proportion of individual RAS blocker agents in HFpEF (left) and HFmrEF (right). (C) RAS blockers prescription patterns by in-office SBP. (D) ARNI prescription patterns in HFmrEF vs. HFpEF. RAS, renin-angiotensin system; ARNI, angiotensin receptor-neprilysin inhibitor; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction, SBP, systolic blood pressure.

Fig. 5.

Comparison of MRA prescription rates. (A) MRAs in HFpEF and HFmrEF. (B) MRAs by CKD. (C) MRAs by hyperkalemia. MRA, mineralocorticoid receptor antagonist; HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; CKD, chronic kidney disease.

Fig. 6.

Comparison of beta-blocker prescription rates. (A) Beta-blockers by age. (B) Beta-blockers by atrial fibrillation (AF).

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Figure & Data

References

Citations

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• Bridging the gap between guidelines and real-world practice for heart failure with mildly reduced or preserved ejection fraction
  Hidenori Yaku
  Kosin Medical Journal.2025; 40(4): 239.     CrossRef