Abstract
Aims
The long‐term effect of angiotensin receptor–neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment.
Methods and results
The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow‐up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all‐cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow‐up (median follow‐up, 44 [interquartile range, 34–51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs.
Conclusions
Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF.
Keywords: Angiotensin receptor–neprilysin inhibitor, Heart failure with improved ejection fraction, Heart failure with reduced ejection fraction, Reverse remodelling
Introduction
Heart failure (HF) is a common disease worldwide with increasing prevalence owing to the aging population and advancements in cardiovascular disease treatment. 1 , 2 Angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), 3 , 4 , 5 , 6 beta‐blockers, 7 , 8 , 9 , 10 and mineralocorticoid receptor antagonists (MRAs) 11 , 12 have been recognized as the cornerstones in the pharmacologic treatment of HF. Recent studies have reported that compared with enalapril, angiotensin receptor–neprilysin inhibitors (ARNI) reduce morbidity and mortality by improving the ejection fraction (EF) and inducing left ventricular (LV) reverse remodelling in patients with HF with reduced ejection fraction (HFrEF). 13 , 14 , 15 , 16 , 17 , 18 , 19 Currently, HF guidelines recommend ARNI as the frontline therapy for patients with HFrEF. 20 , 21 , 22 However, whether ARNI remain effective in patients who achieved an improvement in LV systolic function or significant LV reverse remodelling after a certain period of treatment as well as in patients without these improvements is unclear. Thus, this study aimed to investigate the real‐world impact of prolonged use of ARNI versus ACEIs/ARBs in patients with and without significant treatment response based on echocardiographic findings following 1 year of HF treatment.
Methods
Study population
This observational cohort study retrospectively included patients with HFrEF who underwent echocardiography between January 2017 and January 2020 at Kyungpook National University Hospital. The definition and classification of HF were based on the current guidelines and the universal definition and classification of HF. 20 , 22 , 23 The ARNI group included patients who were prescribed ARNI for >6 months during the 1 year follow‐up, and the ACEI/ARB group included those who were taking ACEIs/ARBs and never prescribed ARNI for 1 year from the index echocardiography. Patients who underwent follow‐up echocardiography between 10 and 13 months after the index echocardiography were included in this study. Treatment response was evaluated using the left ventricular ejection fraction (LVEF) and LV reverse remodelling from the follow‐up echocardiography. The ARNI and ACEI/ARB groups were reassessed according to changes in LVEF or the presence of LV reverse remodelling after 1 year of treatment. Accordingly, patients were reclassified into subgroups of (i) HF with improved ejection fraction (HFimpEF) and those with persistent reduced ejection fraction (HFrEF) and (ii) patients with and without LV reverse remodelling. HF with improved EF was defined as LVEF recovered to >40% and at least a ≥10‐point increase compared with index measurements. 22 , 23 LV reverse remodelling was defined as ≥20% reduction of LV end‐systolic volume. 24
The prognosis of patients was assessed using the composite events of all‐cause mortality and rehospitalization for HF. Moreover, mortality was separately analysed in each subgroup. The comparison of the prognosis in the overall population and subgroups was performed in the index analysis, starting from 1 year following the initial echocardiography. Data on patient mortality were gathered from the National Health Insurance Database of the Republic of Korea and medical records. Additionally, data regarding rehospitalization for HF were obtained from medical records. This study was approved by the Institutional Review Board (IRB) of Kyungpook National University Hospital (IRB No: 2021‐08‐044). Informed consent was waived by the IRB. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee.
Statistics
Continuous variables were expressed as means ± standard deviations, and categorical variables were expressed as frequencies and percentages. Comparative statistical analysis was performed using Student's t‐test and Pearson's χ 2 test. Univariate and multivariate analyses were performed using a Cox proportional hazard model to compare the impact of variables on all‐cause mortality and rehospitalization for HF. To analyse the time‐to‐event outcomes and evaluate the impact of each medication on the overall population and subgroups, the Kaplan–Meier method was employed. Hazard ratios (HRs) of using ARNI versus ACEIs/ARBs were estimated using Cox proportional hazard models after adjusting for variables significantly associated with the prognosis in univariate analysis models, and the results were presented with 95% confidence intervals (CIs). 25 A P‐value <0.05 was considered statistically significant. All data were analysed using the R programming version 4.2.1 (The R Foundation for Statistical Computing, Vienna, Austria, http://www.R‐project.org).
Results
Baseline characteristics
A total of 671 patients with HFrEF (66.4 ± 14.1 years; males, 66.8%) were included in the final analysis (Figure S1 ). During the follow‐up (mean duration, 44 [interquartile range, 34–51] months), 133 (19.8%) composite events of death and rehospitalization for HF were observed. Hypertension (53.1%), diabetes mellitus (39.2%), and ischaemic heart disease (32.8%) were noted to be common co‐morbidities. Notably, beta‐blockers, MRAs, and sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) were prescribed in 96.4%, 69.6%, and 16.2% of patients, respectively (Table 1 ).
Table 1.
Baseline characteristics of the patients
| Total | ACEIs/ARBs | ARNI | P | |
|---|---|---|---|---|
| (n = 671) | (N = 384) | (N = 287) | ||
| Age (years) | 66.4 ± 14.1 | 68.6 ± 14.0 | 63.5 ± 13.7 | <0.001 |
| Male | 448 (66.8%) | 245 (63.8%) | 203 (70.7%) | 0.071 |
| HTN | 356 (53.1%) | 223 (58.1%) | 133 (46.3%) | 0.003 |
| DM | 263 (39.2%) | 150 (39.1%) | 113 (39.4%) | 0.999 |
| IHD | 220 (32.8%) | 122 (31.8%) | 98 (34.2%) | 0.572 |
| Beta‐blockers | 647 (96.4%) | 365 (95.1%) | 282 (98.3%) | 0.045 |
| MRAs | 467 (69.6%) | 224 (58.3%) | 243 (84.7%) | <0.001 |
| SGLT2 inhibitors | 109 (16.2%) | 39 (10.2%) | 70 (24.4%) | <0.001 |
| Loop diuretics | 633 (94.3%) | 351 (91.4%) | 282 (98.3%) | <0.001 |
| LVESV (mL) | 101.3 ± 49.1 | 88.7 ± 39.0 | 118.2 ± 55.8 | <0.001 |
| LVEDV (mL) | 140.9 ± 56.6 | 126.9 ± 47.6 | 159.6 ± 62.1 | <0.001 |
| LVEF (%) | 29.4 ± 7.6 | 31.0 ± 7.1 | 27.2 ± 7.6 | <0.001 |
| NT‐proBNP (pg/mL) | 2167.8 ± 1372.5 | 2271.7 ± 1337.8 | 2018.3 ± 1410.4 | 0.024 |
ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; DM, diabetes mellitus; HTN, hypertension; IHD, ischaemic heart disease; LVEDV, left ventricular end‐diastolic volume; LVESV, left ventricular end‐systolic volume; LVEF, left ventricular ejection fraction; MRAs, mineralocorticoid receptor antagonists; NT‐proBNP, N‐terminal pro‐B type natriuretic peptide; SGLT2, sodium‐glucose cotransporter‐2.
The ARNI and ACEI/ARB groups comprised 287 and 384 patients, respectively (Figure S1 ). The baseline characteristics of the co‐morbidities and pharmacologic treatments of both groups are presented in Table 1 . Patients using ARNI were younger (63.5 ± 13.7 vs. 68.6 ± 14.0 years, P < 0.001) and less frequently hypertensive (46.3% vs. 58.1%, P = 0.003) than those using ACEIs/ARBs. Regarding pharmacologic therapies, patients using ARNI were more frequently taking beta‐blockers (98.3% vs. 95.1%, P = 0.045), MRAs (84.7% vs. 58.3%, P < 0.001), SGLT2i (24.4% vs. 10.2%, P < 0.001), and loop diuretics (98.3% vs. 91.4%, P < 0.001). Echocardiographic data showed that patients using ARNI had lower LVEF (27.2% ± 7.6% vs. 31.0% ± 7.1%, P < 0.001) with larger LV end‐diastolic (159.6 ± 62.1 vs. 126.9 ± 47.6 mL, P < 0.001) and LV end‐systolic volumes (118.2 ± 55.8 vs. 88.7 ± 39.0 mL, P < 0.001). Patients using ARNI had slightly lower N‐terminal pro‐B type natriuretic peptide levels than those using ACEIs/ARBs (2018.3 ± 1410.4 vs. 2271.7 ± 1337.8 pg/mL, P = 0.024).
Kaplan–Meier survival estimates showed that patients using ARNI exhibited significantly better prognosis with a composite event rate of 15.5% compared with 37.0% in the ACEI/ARB group (P < 0.001) in the index analysis following 1 year of treatment for HF (Figure 1 ). Additionally, in the index analysis, patients using ARNI (14.9%) had significantly lower all‐cause mortality than those using ACEIs/ARBs (25.4%, P = 0.004) (Figure S2 ).
Figure 1.
Kaplan–Meier curve analysis for composite events of all‐cause mortality and hospitalization for HFrEF after 1 year of treatment in patients using ARNI and those using ACEIs/ARBs (composite event rate: ARNI, 15.5% vs. ACEIs/ARBs, 37.0%, P < 0.001). ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; HFrEF, heart failure with reduced ejection fraction.
After 1 year of treatment, 57 and 201 patients using ARNI and ACEIs/ARBs, respectively, were reclassified as HFimpEF, and 198 and 286 patients using ARNI and ACEIs/ARBs, respectively, exhibited LV reverse remodelling (Figure S1 ).
Angiotensin receptor‐neprilysin inhibitor versus Angiotensin‐converting enzyme inhibitors/Angiotensin receptor blockers in patients with improved and still reduced ejection fraction following 1 year of treatment
After 1 year of treatment, patients were reclassified into those with HFimpEF (n = 258) and those with persistent HFrEF (n = 363); further, the effect of ARNI versus that of ACEIs/ARBs was analysed in both groups. We observed that ARNIs were consistently related to a significantly lower event rate than ACEIs/ARBs in patients with HFimpEF (7.0% vs. 30.4%, P = 0.020) and in those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001, Figure 2 ). Regarding patients with persistent HFrEF after 1 year, compared with the use of ACEIs/ARBs, the use of ARNI was associated with a 73% reduction of relative risk [hazard ratio (HR), 0.272; 95% confidence interval (CI), 0.167–0.442; P < 0.001] after adjustment of relevant factors (age, sex, hypertension, diabetes, use of beta‐blockers, LV end‐systolic volume, and LV end‐diastolic volume). Although the effect of ARNI was not statistically significant in patients with HFimpEF (HR, 0.479; 95% CI, 0.144–1.587; P = 0.228) after adjustment, no significant interaction was observed between the LVEF improvement and the effect of ARNI (p for interaction = 0.608, Figure 4 ). A similar trend was observed when testing the effect of ARNI versus that of ACEIs/ARBs on all‐cause mortality alone in both HFimpEF and persistent HFrEF groups (Figures S3 and S5 ).
Figure 2.
Prolonged use of ARNI can be superior to ACEIs/ARBs in patients with HFrEF for those who did or did not exhibit significant LVEF improvement following 1 year of treatment. (A) Patients with persistent reduced EF following 1 year of treatment (ARNI vs. ACEIs/ARBs, 17.6% vs. 49.7%, P < 0.001) and (B) patients with HFimpEF following 1 year of treatment (ARNI vs. ACEIs/ARBs, 7.0% vs. 30.4%, P = 0.020). ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; EF, ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFimpEF, heart failure with improved ejection fraction; LVEF, left ventricular ejection fraction.
Figure 4.
Subgroup analysis of hazard ratios for composite events after adjusting for age, sex, hypertension, diabetes mellitus, beta‐blocker, left ventricular end‐systolic volume, and left ventricular end‐diastolic volume. EF, ejection fraction.
Angiotensin receptor‐neprilysin inhibitor versus Angiotensin‐converting enzyme inhibitors/Angiotensin receptor blockers in patients with and without Left ventricular reverse remodelling following 1 year of treatment
After 1 year of treatment, patients were also reclassified into those who exhibited LV reverse remodelling (n = 484) and those who did not (n = 185). Patients using ARNI were associated with a significantly lower event rate than those using ACEIs/ARBs, regardless of whether they presented with LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001, Figure 3 ). After adjustment of relevant factors, compared with the use of AECIs/ARBs, the use of ARNI remained associated with a lower risk of composite events in groups with (HR, 0.524; 95% CI, 0.309–0.887; P = 0.016) and without LV reverse remodelling (HR, 0.233; 95% CI, 0.110–0.495; P < 0.001, Figure 4 ). Moreover, the analysis of all‐cause mortality alone in groups with and without LV reverse remodelling showed a similar trend (Figures S4 and S5 ).
Figure 3.
Prolonged use of ARNI can be superior to ACEIs/ARBs in patients with HFrEF for those who did or did not exhibit significant improvement of LV reverse remodelling following 1 year of treatment. (A) Patients without LV reverse remodelling following 1 year of treatment (ARNI vs. ACEIs/ARBs; 15.0% vs. 54.9%, P < 0.001) and (B) Patients with LV reverse remodelling after 1 year of treatment (ARNI vs. ACEIs/ARBs, 15.8% vs. 31.1%, P = 0.001). ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; HFrEF, heart failure with reduced ejection fraction; LV, left ventricle.
Discussion
The present study aimed to investigate the real‐world effect of ARNI on patients with HFrEF following 1 year of treatment for HF. We observed that using ARNI remained superior to using ACEIs/ARBs in patients treated with pharmacologic treatment of HF for 1 year. The advantage of ARNI was consistently noted in patients who achieved improvement in LVEF or LV reverse remodelling as well as in those who did not present a significant improvement in LVEF or LV reverse remodelling.
The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM‐HF) trial demonstrated that ARNI was superior to enalapril in reducing the risk of death and hospitalization for HF in patients with HFrEF. 26 Subsequent clinical trials showed that ARNI can induce LV reverse remodelling and improvement in LV systolic function. 27 , 28 However, the use of ARNI, including natriuresis, vasodilation, and arrhythmia suppression, can be effective even in patients who do not present with significant improvement in LVEF or LV remodelling after the pharmacologic treatment of HF for a certain period. In the present study, patients who did not exhibit a significant improvement in LVEF or LV reverse remodelling following 1 year of treatment may still receive benefits from prolonged use of ARNI versus ACEIs/ARBs.
Data regarding which drug is more significant or still effective for patients with HFimpEF among the drugs listed in the guideline‐directed medical therapies of HFrEF are scarce. Only a few small studies have reported that beta‐blocker withdrawal is related to LVEF deterioration and HF symptom recurrence in patients with HFimpEF. 29 , 30 Furthermore, only a few studies have reported whether ACEIs/ARBs remain beneficial or whether their withdrawal leads to HF deterioration in patients with HFimpEF. One study conducted in Korea monitored 42 patients with HFrEF for 41 months following LVEF improvement. Of these patients, 20% redeveloped LV systolic dysfunction, and the discontinuation of pharmacologic therapy, including ACEIs, was related to the deterioration. 31 More recently, observational data from a larger cohort of Korean patients with acute HF reported rather confusing results that beta‐blockers were associated with a better prognosis; however, ACEIs/ARBs or MRAs had neutral effects in patients with HFimpEF. 32 As several studies on patients with HFimpEF still report evidence of neurohormonal activation, structural abnormalities, and HF symptoms, and as these patients frequently present with the clinical event of acute HF deterioration, the pharmacologic treatment of HFrEF should be continued to avoid LV dysfunction relapse in patients with HFimpEF. 22 , 33 More clinical investigations and validations are needed for the pharmacologic treatment of patients with HFimpEF.
Recent guidelines have recommended considering ARNI as first‐line treatment over ACEIs/ARBs in patients with HFrEF. PARADIGM‐HF and Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON‐HF) trials reported that compared with ACEIs/ARBs, ARNI can be effective in patients with HF with LVEF >40%. 26 , 33 However, these clinical trials did not include HFimpEF, and whether the prolonged use of ARNI versus ACEIs/ARBs is beneficial for patients with HFimpEF is uncertain. The results of the present study indicated that ARNI may be better than ACEIs/ARBs even in patients who achieved improvement in LVEF or LV reverse remodelling.
Limitations
First, in this real‐world data‐based retrospective and observational cohort study, we reported differences in the baseline characteristics between patients using ARNI and those using ACEIs/ARBs. Although the multivariate analysis model was applied to minimize biases, unmeasured confounding may still exist. Second, the number of patients with HFimpEF following treatment with ARNI was small. A potential reason could be that guidelines directed medical therapy at the time. During the initial introduction of ARNI, ACEIs/ARBs served as the primary therapy, with ARNI being considered an alternative for patients who did not exhibit an adequate response to ACEIs/ARBs. Furthermore, patients with improved EF following a short‐term treatment of ACEIs/ARBs did not have the chance to use ARNI owing to the lack of evidence of using ARNI in patients with HFimpEF. However, even in patients with HFimpEF in the present study, patients using ARNI had a tendency for better prognosis than those using ACEIs/ARBs. To ensure the effect of ARNI versus that of ACEIs/ARBs in patients with HFimpEF, further research is needed. Third, owing to the retrospective nature of the study, it was not possible to control or standardize the timing of ARNI initiation, thereby leading to variations. In a recent study, the early use of ARNI has been shown to result in a better prognosis and faster recovery of echocardiographic parameters. 34 Fourth, data on the HF duration before the enrolment was not available. Finally, the study was conducted before the validation of SGLT2i, and the study cohorts had a relatively low SGLT2i prescription rate. Therefore, we could not consider the effect of SGLT2i, which is now becoming a first‐line therapy in patients with HFrEF.
Conclusions
The use of ARNI was associated with better prognosis than the use of ACEIs/ARBs in patients with HFrEF even after 1 year of treatment for HF. In patients who presented with persistent decreased LVEF or without remarkable LV reverse remodelling over the treatment period, ARNIs were associated with better prognosis than ACEIs/ARBs. ARNI may be better than ACEIs/ARBs even in patients who presented with significant improvement in LVEF or LV reverse remodelling, which needs validation in further studies.
Conflict of interest
No relationships relevant to the content and authors have nothing to disclose.
Supporting information
Figure S1. Selection of study population.
Figure S2. Kaplan–Meier curve analysis for all‐cause after 1‐year of treatment in patients with ARNI and ACEI/ARB.
Figure S3. All‐cause mortality of patients using ARNI and those using ACEIs/ARBs according to the changes of LVEF after 1 year of treatment.
Figure S4. All‐cause mortality of patients using ARNI and those using ACEIs/ARBs according to the changes of LV reverse remodelling after 1 year of treatment.
Figure S5. Subgroup analysis of hazard ratio for all‐cause mortality after adjusting for age, sex, hypertension, diabetes mellitus, β‐blocker, left ventricular end‐systolic volume, and left ventricular end‐diastolic volume.
Park, H. K. , Park, J. S. , Kim, M. S. , Lee, E. , Choi, H. , Park, Y. J. , Park, B. E. , Kim, H. N. , Kim, N. , Bae, M. H. , Lee, J. H. , Park, H. S. , Cho, Y. , Jang, S. Y. , and Yang, D. H. (2023) Long‐term impact of angiotensin receptor‐neprilysin inhibitor based on short‐term treatment response in heart failure. ESC Heart Failure, 10: 3430–3437. 10.1002/ehf2.14505.
Se Yong Jang takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Se Yong Jang and Dong Heon Yang contributed equally to the manuscript as corresponding authors.
[Correction added on 16 October 2023, after first online publication: Namkyun Kim's name has been corrected in this version.]
Contributor Information
Se Yong Jang, Email: seyongjang@knu.ac.kr.
Dong Heon Yang, Email: ddhyang@knu.ac.kr.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Selection of study population.
Figure S2. Kaplan–Meier curve analysis for all‐cause after 1‐year of treatment in patients with ARNI and ACEI/ARB.
Figure S3. All‐cause mortality of patients using ARNI and those using ACEIs/ARBs according to the changes of LVEF after 1 year of treatment.
Figure S4. All‐cause mortality of patients using ARNI and those using ACEIs/ARBs according to the changes of LV reverse remodelling after 1 year of treatment.
Figure S5. Subgroup analysis of hazard ratio for all‐cause mortality after adjusting for age, sex, hypertension, diabetes mellitus, β‐blocker, left ventricular end‐systolic volume, and left ventricular end‐diastolic volume.