Introduction

European guidelines recommend the initiation of all 4 classes of guideline‑directed medical therapies: renin–angiotensin system inhibitors (RASIs; including angiotensin receptor–neprilysin inhibitors [ARNIs], angiotensin‑converting enzyme inhibitors [ACEIs], and angiotensin receptor blockers [ARBs]), β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium‑glucose cotransporter 2 inhibitors (SGLT2is), following a diagnosis of heart failure with reduced ejection fraction (HFrEF).^1,2

RAS activation is a defining pathophysiological characteristic of HFrEF, and a key factor in its development and progression. The clinical benefits of pharmacologic RAS inhibition were demonstrated in numerous clinical trials including HFrEF patients treated with ACEIs or ARBs.^3-5

More recently, the PARADIGM‑HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial⁶ showed that patients with chronic HFrEF treated with an ARNI experienced a 20% reduction in the risk of cardiovascular death or HF hospitalization, as compared with those treated with enalapril. Although the management of patients with HFrEF is clearly defined, real‑world data regarding guideline implementation remain scarce. Hence, the aim of this study was to summarize RASI use in patients with HFrEF included in the HEROES (Heart Failure Observational Study of the Polish Cardiac Society) database (https://heroes.umed.pl).

Patients and methods

HEROES is a prospective, multicenter, observational registry coordinated by the Polish Cardiac Society. Enrollment of consecutive patients with HF, including those hospitalized and those receiving outpatient care, took place between April 2022 and January 2024 at 41 participating institutions. Comprehensive details regarding the study design, baseline patient characteristics, and follow‑up protocols have been reported elsewhere.⁷ The study dataset is available online at http://dx.doi.org/10.60941/JVH1‑5190.

In this analysis, we included individuals with HFrEF. Patients with missing data on left ventricular ejection fraction or those who died during their hospital stay were excluded.

Baseline characteristics regarding demographics, medical history, concomitant diseases, diagnostic test results, and pharmacology were collected.

We summarized RASI treatment in the patients with HFrEF based on reports of RASI use at discharge or at the end of outpatient visits. We also analyzed the frequency of use of specific RASI agents and the most common reasons for withholding RASI treatment.

The Bioethical Committee at the Medical University of Lodz approved the implementation of the HEROES study (RNN/316/20/KE, with subsequent update KE/762/23). Informed consent was obtained from all study participants.

Results

Of 1422 patients listed in the HEROES database, 701 individuals with HFrEF were included in this analysis. Most of them were hospitalized (80.4%) and male (71.4%), and the median (IQR) age of the study group was 66.2 (57.3–74) years. An ischemic etiology of HFrEF was reported in 337 patients (48.1%).

In the entire study group, 624 patients (89%) were treated with RASIs. Of those, 342 (48.8%) received ACEIs/ARBs and 282 (40.2%) received ARNIs. Patient characteristics and details regarding RASI treatment are summarized in Table 1.

Among the inpatients, 524 (88.2%) received RASIs, including 280 (47.1%) who received ACEIs/ARBs and 244 (41.1%) who received ARNIs.

Among the outpatients, 100 individuals (93.5%) were treated with RASIs, with 62 (57.9%) receiving ACEIs/ARBs and 38 (35.5%) ARNIs.

In the group treated with ACEIs/ARBs, the most frequently prescribed ACEI was ramipril (n = 218; 71.5% of those treated with ACEIs), and the most frequently prescribed ARB was valsartan (n = 24; 64.9% of those receiving ARBs).

Main reasons for not using RASIs were renal dysfunction (n = 58; 75.3%), symptomatic hypotension (n = 38; 49.4%), and hyperkalemia (n = 12; 15.6%).

Main reasons for not using ARNIs were a lack of reimbursement (n = 135; 32.4%), symptomatic hypotension (n = 46; 11.1%), renal dysfunction (n = 34; 8.2%), and hyperkalemia (n = 4; 1%). Other reasons were reported by 75 patients (18%).

The median (IQR) daily dose of particular medications was as follows: sacubitril / valsartan, 49/51 (24–49/26–51) mg; ramipril, 5 (2.5–5) mg; and valsartan, 80 (80–160) mg.

The target dose was reached in 161 patients (25.8%) treated with RASIs, including 59 (20.9%) treated with ARNIs and 102 (29.8%) treated with ACEIs/ARBs.

Discussion

The currently recommended treatment for HFrEF is an undeniable success of modern cardiology. There are therapies proven to be effective in patients with HFrEF, including ACEIs/ARNIs, β-blockers, MRAs, and SGLT2is, which are strongly recommended by European and American guidelines due to their mortality and morbidity benefits.^1,2,8 Administering all 4 drug classes in appropriate doses may offer optimal outcomes for patients with HFrEF; however, such an approach is rarely observed in everyday clinical practice, as patients either receive doses lower than recommended or are undertreated with not enough drugs.^9,10 It is widely recognized that ACEIs/ARNIs are one of the pillars of HFrEF treatment, and every patient without contraindications should receive a drug from the RASI group.¹¹ In this study, RASIs were prescribed to 89% of the patients with HFrEF, which is similar to the rate observed in the OPTIMA‑HF (Optimization of Therapy in the Italian Management of Heart Failure) registry (89.1%).¹² Comparable rates, exceeding 90%, were reported in the SwedeHF (Swedish Heart Failure) Registry¹³ and the Danish Heart Failure Registry.¹⁴ In contrast, the CHAMP‑HF (Change the Management of Patients with Heart Failure) study reported a lower prescription rate of 73.4%.¹⁵ RAS‑modifying drugs have a long history of clinical use, and clinicians are familiar with initiation and monitoring practices, making the implementation of related guideline recommendations relatively straightforward. Moreover, ACEIs/ARBs are also indicated for conditions other than HF, such as hypertension and coronary artery disease; management of such comorbidities is a key element of comprehensive HF care.^1,2 In Poland, a high proportion of patients receive ACEIs/ARBs for reasons other than HF, as demonstrated in a registry of patients with stable coronary artery disease.¹⁶ The use of ACEIs/ARBs in Polish patients exceeds that reported in other countries.¹⁶ In this study, most patients treated with RASIs received ACEIs/ARBs (48.8%), while 40.2% were treated with ARNIs. The TRANSITION (Comparison of Pre- and Post‑discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event) and PIONEER‑HF (Comparison of Sacubitril–Valsartan versus Enalapril on Effect on NT‑proBNP in Patients Stabilized from an Acute Heart Failure Episode) studies confirmed the clinical benefits of ARNI therapy in patients with HFrEF, both in de novo cases and in individuals with chronic HF exacerbation.^17,18 It is well established that treatment of HFrEF patients with sacubitril / valsartan is safe and associated with significant clinical and objective improvement.^6,17 Considering the current state of knowledge, and in line with the American guidelines and expert opinion of the Heart Failure Association of the Polish Cardiac Society, an ARNI should be preferred over an ACEI/ARB in patients with HFrEF.^8,19 Implementing the HF guidelines in clinical practice remains difficult and inadequate. However, limited access to the drug resulting from the lack of reimbursement remains the main barrier to initiating ARNI therapy in patients with HFrEF.

This factor appears to influence ARNI use in other countries as well. In the previously cited Italian registry, ARNIs were prescribed to 70.2% of the patients,¹² while the rate observed in the American registry was 17.2%.¹⁵ The proportion of patients treated with ARNIs increased over time since drug registration. In the SwedeHF registry, there was a progressive increase in ARNI use among the patients with HFrEF, rising from 8.3% in 2017 to 26.7% in 2021. This trend was observed in both inpatients, increasing from 6.4% in 2017 to 25.5% in 2021, and outpatients, rising from 9% in 2017 to 27% in 2021. In our study, the proportion of hospitalized patients was 80%, as compared with 24% in the SwedeHF registry. Contrary to that registry, we found a lower rate of ARNI use among the outpatients than the inpatients. As demonstrated in the Swedish study, initiation of ARNI therapy during hospitalization or shortly after discharge is uncommon; only 8% of ARNI‑naive inpatients started ARNI treatment in the hospital or within 14 days postdischarge. However, this initiation rate was still slightly higher than that observed in the outpatients (6%). On the other hand, the authors reported that ARNI treatment was more likely to be initiated later during the disease course.

In addition to financial constraints, ARNIs have medical contraindications that may limit their application, including chronic kidney disease (CKD), hypotension, and hyperkalemia. In this study, the most frequent contraindication to both RASIs and ARNIs was CKD. ARNIs are generally well tolerated: in the international TRANSITION trial, which enrolled patients hospitalized for acute decompensated HFrEF, the rate of permanent discontinuation of sacubitril / valsartan therapy was low in both the Polish (3.9%) and non‑Polish (6.4%) cohorts.¹⁷ Another factor limiting the treatment is discontinuation of the prescribed medication. This scenario occurs when patients with HFrEF are initiated on ARNIs in hospital settings but, for various reasons, the medication is later discontinued in outpatient care. In our study, a majority of patients were hospitalized, which may have had a significant impact on the relatively high proportion of individuals receiving ARNIs.

Current guidelines simplify the foundational treatment approach in HFrEF. They no longer dictate the exact sequence for the initiation or uptitration of first‑line therapies, but instead emphasize the benefit of establishing all HFrEF patients on the 4 pillar medications and optimizing therapeutic doses thereafter. In other words, the guidelines provide a final therapeutic goal (ie, the use of all recommended drug classes at full doses), but allow for an individualized approach to achieve it. In this study, target doses of RASIs were achieved in 23% of the patients with HFrEF, more frequently among those treated with ACEIs/ARBs than those receiving ARNIs. However, a higher proportion of patients receiving ARNIs than those on ACEIs/ARBs were still undergoing uptitration. Since a majority of patients in this study were hospitalized, the proportion of patients in the process of reaching target doses was high. In the TRANSITION study, the primary end point of achieving the target dose of sacubitril / valsartan by week 10 of treatment was met by 45.6% of the Polish patients and 48.4% of the non‑Polish participants.¹⁷ Barriers to achieving the target dose of ARNIs may include CKD, hypotension, or hyperkalemia. A secondary analysis of the PARADIGM‑HF study, showed that among the MRA‑treated patients with symptomatic HFrEF, severe hyperkalemia was more likely to develop during treatment with enalapril than with sacubitril / valsartan. These data suggest that neprilysin inhibition attenuates the risk of hyperkalemia when MRAs are combined with other inhibitors of the RAS.²⁰

This study has several important limitations. The main one is its observational design. First, some patient records contained incomplete information. Second, the study focused mainly on hospitalized patients. It should be emphasized that the HEROES population reflects the wider Polish HF study group, which makes these results especially relevant and distinctive in the national context.