Physician adherence and patient-reported outcomes in heart failure with reduced ejection fraction in the era of angiotensin receptor-neprilysin inhibitor therapy

This Korean nationwide, multicenter, noninterventional, prospective cohort study aimed to analyze physician adherence to guideline-recommended therapy for heart failure (HF) with reduced ejection fraction (HFrEF) and its effect on patient-reported outcomes (PROs). Patients diagnosed with or hospitalized for HFrEF within the previous year were enrolled. Treatment adherence was considered optimal when all 3 categories of guideline-recommended medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor-neprilysin inhibitors; beta-blockers; and mineralocorticoid receptor antagonists) were prescribed and suboptimal when ≤ 2 categories were prescribed. The 36-Item Short Form Survey (SF-36) scores were compared at baseline and 6 months between the 2 groups. Overall, 854 patients from 30 hospitals were included. At baseline, the optimal adherence group comprised 527 patients (61.7%), whereas during follow-up, the optimal and suboptimal adherence groups comprised 462 (54.1%) and 281 (32.9%) patients, respectively. Patients in the suboptimal adherence group were older, with a lower body mass index, and increased comorbidities, including renal dysfunction. SF-36 scores were significantly higher in the optimal adherence group for most domains (P < 0.05). This study showed satisfactory physician adherence to contemporary treatment for HFrEF. Optimal adherence to HF medication significantly correlated with better PROs.

www.nature.com/scientificreports/ Heart failure (HF) is a major threat globally, owing to its association with increased morbidity, mortality, and deterioration in the quality of life of patients. It also imposes a substantial economic burden on the society 1-3 . Recent HF guidelines recommend evidence-based medications to reduce mortality in patients with HF with reduced ejection fraction (HFrEF) 4 . These medications include angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) [1][2][3]5 . Based on the results of landmark randomized controlled trials, angiotensin receptor-neprilysin inhibitors (ARNIs) were included as a class I indication in the recently updated HF guidelines. Subsequently, recent trials have investigated the potential of ARNIs in increasing the survival and quality of life of patients with HF [6][7][8][9] . However, to date, large-scale performance-measure trials in HF have not included patients treated with ARNIs, a drug class that can improve patient outcomes and treatment cost-effectiveness 8,10 . The changing clinical profiles of patients with HFrEF necessitate a reassessment of patient quality of life and physician adherence to the latest HF guidelines, which now include 5 different classes of recommended medications (class I indication). Moreover, a gap exists between the recommended guidelines and the current practice of HF treatment with respect to physician adherence. An observational nationwide study using the Korean National Health Insurance Claims database showed that 28.6% of elderly patients with HF did not receive optimal evidence-based treatment 11 . Furthermore, compelling data from a previous study show that many patients with HF do not take their medications as prescribed by their healthcare providers. According to these data, the overall compliance among patients with HF was 72%, and noncompliance contributed to worsening of HF symptoms, thereby leading to hospitalization 12 . Therefore, further studies on contemporary medical treatment patterns, including use of ARNIs, in patients with HFrEF are necessary to gain insights into improved treatment strategies in these patients.
Poor quality of life resulting from uncontrolled symptoms is a major concern and an important target for treatment in patients with HF. Notably, patients with HF with uncontrolled symptoms had low scores in all domains of the 36-Item Short Form Survey (SF-36), a tool designed to evaluate quality-of-life parameters such as physical health and mental status 13 . Patient-reported outcome (PRO) measures are used to evaluate patientreported information in terms of subjective health, including health-related quality of life, symptoms of anxiety and depression, and symptom burden. Evaluation of PROs in patients with HFrEF is important because HF is a common chronic illness that is accompanied by frequent acute exacerbations, often requiring hospitalization, and a significant symptom burden 14 . PROs enable physicians to deliver more patient-centered care, thereby improving patients' quality of life. A recent study showed that nonadherence to medication also correlated with poor PROs 15 . Real-world nationwide data on adherence to guideline-recommended treatment and PROs in Asian patients with HF are lacking with respect to ARNIs. Therefore, this study aimed to analyze the treatment patterns of patients with HFrEF in the era of ARNIs and to evaluate PROs according to physician adherence to guideline-recommended treatments.

Methods
Study design and patient population. This was a Korean nationwide, multicenter, noninterventional, prospective cohort study. Patients with HFrEF who were diagnosed with HF or hospitalized for HF within the previous year were enrolled on an outpatient basis. Data were collected at enrollment (baseline) and after 6 months by review of medical records and patient paper surveys. Only patients who completed the 6-month follow-up were included in the final analysis. Adult patients aged ≥ 19 years with a documented diagnosis of HF using the International Classification of Diseases 10th Revision (ICD-10) codes I50, I50.0, I50.1, I50.9, I11.0, I13.0, I13.2, I25.5, I42, or I42.x on the main or first subdiagnosis; patients with HFrEF with a left ventricular ejection fraction (LVEF) < 40% and New York Heart Association class II-IV; patients diagnosed with HF or hospitalized for HF within the previous year; and patients with an outpatient status at the enrollment date were included in the analysis. Patients who had participated in an interventional clinical trial 1 year before enrollment and patients with an inpatient status at the enrollment date were excluded. The study design is summarized in Fig. 1 Guideline adherence measures. Adherence to guideline-directed medical therapy for HFrEF (3 categories: ACEis/ARBs/ARNIs, BBs, and MRAs) was evaluated using the prescription information at baseline and after a follow-up of 6 months. Adherence to treatment was considered optimal when all 3 categories of medications were prescribed and suboptimal when ≤ 2 categories of medications were prescribed. www.nature.com/scientificreports/ Outcome analysis. The primary objective of the study was to evaluate the treatment patterns of patients with HFrEF according to physician adherence in the era of ARNIs. Patient characteristics and treatment patterns were obtained from hospital medical records. Quality of life was measured using SF-36 16 , which provides scores for physical health as well as mental status. SF-36 scores were compared between the optimal adherence and suboptimal adherence groups at baseline and at 6 months. In addition, the time to HF hospitalization, defined as the duration from study enrollment to hospitalization for HF during the 6-month follow-up, was compared between the 2 groups. Statistical analysis. All data were analyzed without adjustments for outliers or imputation for missing values. Categorical variables are presented as numbers and frequencies, whereas continuous variables are presented as means ± standard deviations. A paired t-test was used to compare the variables at baseline and at the 6-month follow-up within each group. Comparisons of continuous variables between the optimal adherence group and suboptimal adherence group were made using the Student's independent 2-sample t-test. For categorical variables, the chi-square test was used to compare the data between the 2 adherence groups. The log-rank test was used to compare time to hospitalization due to HF between the 2 groups. A 2-tailed P value of < 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics, version 21 (Armonk, NY, USA).

Patient baseline characteristics.
A total of 975 patients from 30 hospitals were enrolled, of whom 854 completed the 6-month follow-up and were included in the analysis. Patients were enrolled from July 2018 to April 2019, and data were collected from July 2018 to November 2019, with a mean ± standard deviation follow-up duration of 183.4 ± 28.7 days (Supplementary Figure S1). Of the 854 patients, 527 (61.7%) were in the optimal adherence group and 327 (38.3%) were in the suboptimal adherence group based on the prescription data collected at enrollment (30.4% of the patients were prescribed medications from 2 categories and 7.6% from 1 category; 0.2% of the patients were not prescribed any of the HF medications; Table 1). Patients in the optimal adherence group were younger and predominantly male, had a higher body mass index, and had fewer comorbidities with preserved renal function. During follow-up, 462 (54.1%) patients remained in the optimal adherence group, 65 (7.6%) patients moveed from optimal to suboptimal adherence, 46 (5.4%) patients changed from suboptimal to optimal adherence, and 281 (32.9%) patients remained in the suboptimal adherence group. Patients' characteristics evaluated at the 6-month follow-up are summarized in Supplementary Table 1.   A significant increase in scores during the follow-up period was also noted in the optimal adherence group, whereas the increase in scores was less prominent in the suboptimal adherence group. SF-36 scores are presented in Table 2 and Fig. 3.

Discussion
This nationwide, multicenter, prospective cohort study demonstrated that (1) physician adherence to guidelinedirected medical therapy was satisfactory (92.1% of patients were prescribed > 2 categories of HFrEF medications, and 61.7% of patients were prescribed all 3 categories); (2) patients in the suboptimal adherence group tended to be older and had a lower body mass index and increased comorbidities, including renal dysfunction; and (3) patients in the optimal adherence group had better PROs at baseline and a more prominent improvement in PROs at the 6-month follow-up compared with those in the suboptimal adherence group.
Treatment patterns in patients with HFrEF. Data regarding treatment patterns obtained from the current Korean nationwide prospective cohort study are more robust compared with the data obtained from previ-  www.nature.com/scientificreports/ ous international or national registries [17][18][19][20][21] . Data on physician adherence from previous HF registries or trials were focused only on the 3 categories of guideline-recommended HF medications-ACEis/ARBs/ARNIs, BBs, and MRAs. Data from these HF registries 17-21 revealed a lower prescription rate for all 3 categories of medications. However, recent prospective HFrEF trials showed a higher prescription rate for these medications 15 . In the present study, the use of renin-angiotensin system blockers was 91.5%, which included ARNIs (32.4%). The use of BBs and MRAs was also high, accounting for 89.8% and 72.3%, respectively. Compared with previous registry data in the country, the current data show a substantial improvement in physician adherence to HF therapy guidelines, particularly with respect to the use of BBs (49.9% in the The Korean Acute Heart Failure (KorAHF); Fig. 4) 17 . Compared with previous studies, this study showed a satisfactory prescription rate, which could be attributed to the effect of indirect intervention that may have enhanced physician awareness, and the fact that most patients in this study were enrolled at tertiary university hospitals with dedicated HF specialists. Moreover, the emergence of ARNI, a new treatment option for HFrEF, and its large diffusion could have also influenced adherence to HF therapy guidelines.
Physician adherence and PROs in HF. Patient adherence to guideline-directed HF medications is crucial to reduce mortality and morbidity [1][2][3]22 . Physician adherence is also important in the management of patients  SF-36 has been validated for measuring health-related quality of life in patients with chronic illnesses in several countries [28][29][30][31] , but data on the Asian population are still lacking. The results of this study showed that optimal adherence was associated with higher SF-36 scores at baseline, and a noticeable improvement was observed at the 6-month follow-up. However, considerable improvements were also observed in several SF-36 domains in the suboptimal adherence group as patients in this group received at least some degree of guideline-directed pharmacological treatment, and nonpharmacological treatment was administered regardless of the medication status during the study period. SF-36 scores observed in this study were higher than those reported in the previous registry data from Western countries 32 ; this may be attributable to the prospective nature of the current study, which might have had an indirect effect on physician adherence, resulting in higher PRO scores.
Patient adherence to medication in HF. Various measures have been developed and applied to increase patient-level adherence or compliance for better outcomes 33 . The interventions implemented in the current study to improve patient adherence, such as training/education sessions, patient reminder systems, self-care support, physician factors, and organizational changes, were effective in decreasing mortality and rehospitalization. In the previous study, patients' noncompliance to therapy was significantly associated with an increase in the number of medicines 34 . This result indicates the difficulty in maintaining optimal compliance with an increase in the number of medications. Physicians need to pay continuous attention during their everyday practice to maintain an optimal level of treatment in patients with HF.
Variables related to suboptimal physician adherence. According to a previous study, the factors associated with underuse of guideline-directed therapy in HF were female sex, older age, renal dysfunction, liver dysfunction, bradycardia, and hypotension 35 . These factors also correlated with poor outcome and further increased the risk of poor physician adherence to optimal management 36 . In this study, we observed that older age, female sex, low body mass index, more diverse comorbidities, elevated NT-proBNP, decreased renal function, and a relatively preserved left ventricular systolic function were consistently associated with suboptimal adherence at baseline and at the 6-month follow-up. Worsening renal function and combined comorbidities associated with polypharmacy may interfere with optimal HFrEF medication in these patients. Significantly higher NT-proBNP level also reflect the high-risk features of suboptimal adherence group. However, patients with comorbidities who are at higher risk of adverse outcomes require more intensive optimal medical therapy. Patients with relatively preserved left ventricular systolic function (LVEF > 35% to < 40%) are not frequently prescribed all 3 categories of medications as the current guidelines do not recommend routine use of MRAs for LVEF > 35% and partly because of physician inertia in patients with a relatively higher LVEF. Improving physician adherence is crucial, particularly in the context of such high-risk patients. As the aging population increases worldwide, particularly in Asia (including Korea), the issue of adherence trend linked to underlying patient factors needs to be addressed.

Strengths and limitations.
To the best of our knowledge, this is the first prospective cohort study to evaluate the effect of physician adherence on PROs in the era of ARNIs. Current HF guidelines recommend the use of ARNIs over ACEis/ARBs to improve outcomes. Considerable use of ARNIs (> 32%) is reflective of the current real-world treatment pattern for HF.
Despite the above-mentioned strengths, this study has several potential limitations. First, adherence to guidelines was evaluated by medication categories without considering the target dose. However, because of the diversity in the up-titration and dose-adjustment process, calculation of the absolute value of the medication dose during a specific period is difficult. Furthermore, a substantial number of patients cannot reach the target doses even in prospective trials, and a lower dose of medication has proven to be effective in those trials. Second, unlike the previous studies on physician adherence, this study showed no difference in clinical events (HF hospitalizations). This could be due to the short follow-up period and the relatively lower incidence of adverse events observed in the present study. The nonblinded nature of the study might have had an impact on physician and patient awareness, resulting in better HF education and self-management in the entire study population, thereby weakening the early effect of optimal physician adherence. Third, the patients included in this study were relatively younger than those in the previous HF registry study. The trend toward a younger study population has also been seen in previous PRO studies that required patients to have preserved cognitive function to answer the survey questions. Extended observation might elucidate the effect of physicians' optimal adherence on clinical outcomes.

Conclusions
Data from the Korean nationwide, prospective registry showed favorable physician adherence to contemporary medical therapy for HFrEF. Optimal physician adherence to HF medications was associated with better PROs. Further studies are required to elucidate the effect of optimal physician adherence on clinical outcomes.

Data availability
The data that support the findings of this study are available from Novartis Korea Ltd. but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Novartis Korea Ltd.