Article ID: CJ-23-0174
Background: The PARALLEL-HF study assessed the efficacy and safety of sacubitril/valsartan vs. enalapril in Japanese patients with chronic heart failure with reduced ejection fraction (HFrEF). This open-label extension (OLE) assessed long-term safety with sacubitril/valsartan.
Methods and Results: This study enrolled 150 patients who received sacubitril/valsartan 50 or 100 mg, b.i.d., in addition to optimal background heart failure (HF) therapy. A dose level of sacubitril/valsartan 200 mg, b.i.d., was targeted by Week 8. At OLE baseline, higher concentrations of B-type natriuretic peptide (BNP) and urine cGMP, and lower concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), were observed in the sacubitril/valsartan core group (patients who received sacubitril/valsartan in both the core and extension study) than in the enalapril core group (patients who received enalapril in the core study and were then transitioned to sacubitril/valsartan). The mean exposure to study drug was 98.9%. There was no trend of worsening of HF at Month 12. No obvious changes in cardiac biomarkers were observed, whereas BNP and urine cGMP increased and NT-proBNP decreased in the enalapril core group, which was evident at Weeks 2–4 and sustained to Month 12.
Conclusions: Long-term sacubitril/valsartan at doses up to 200 mg, b.i.d., has a positive risk-benefit profile; it was safe and well tolerated in Japanese patients with chronic HFrEF.
Globally, cardiovascular (CV) diseases are the leading cause of mortality, with approximately 17.9 million deaths (32% of all deaths) reported in 2019.1 In Japan, approximately 1–2 million patients have chronic heart failure (HF).2 In addition, Japan has the highest proportion of elderly people in the world; in 2021, 29.4% of the population was aged ≥65 years.3 Because the incidence of HF increases with age, HF can soon become an epidemic in Japan, with a projected increase of 40% in the proportion of elderly by 2050.4–7 When combined with the trend of rapid Westernization, changing dietary patterns, increasing obesity, and reduced physical activity further add to the gravity of the situation.2 In 2019, >85,000 HF-related deaths were reported in Japan.8 In addition, HF is associated with a high mortality rate and reduced quality of life (QoL).9–11 The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America HF management guidelines12 recommend the first-line angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to reduce morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF). Sacubitril/valsartan has a positive impact on cardiac biomarkers, including B-type natriuretic peptide (BNP), N-terminal pro BNP (NT-proBNP), markers of renal function, and clinical markers; monitoring these biomarkers during sacubitril/valsartan therapy may help assess treatment response, guide medication titration, and provide valuable prognostic information for patients with HFrEF.13 Changes in BNP concentrations with sacubitril/valsartan treatment, particularly when switching patients from angiotensin-converting enzyme inhibitors (ACEIs; e.g., enalapril), could help monitor treatment response. Sacubitril/valsartan also provides high economic value in patients with chronic symptomatic HFrEF compared with ACEIs.12 Based on findings from the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial (conducted in 47 countries, excluding Japan),14 the European Society of Cardiology HF guidelines recommend replacement of ACEIs or angiotensin II receptor blockers with sacubitril/valsartan in ambulatory patients with HFrEF to reduce the risk of HF hospitalization and increase patient survival.15
PARALLEL-HF (Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients), designed to confirm the consistency with PARADIGM-HF findings, showed that sacubitril/valsartan was safe and well tolerated in Japanese patients with HFrEF for a median follow-up of 33.9 months during the core treatment period.16 In 2021, the Japanese Circulation Society/Japanese Heart Failure Society updated their guidelines and now recommend the ARNI sacubitril/valsartan for pharmacological management of HF.17
Here, we present results from the open-label extension (OLE) of the PARALLEL-HF study, which aimed to assess the safety, tolerability, and efficacy of long-term treatment with sacubitril/valsartan.
This was a Phase 3, open-label, approximate 2-year extension of the PARALLEL-HF study that evaluated the efficacy and safety of sacubitril/valsartan 200 mg, b.i.d., compared with enalapril 10 mg, b.i.d., in reducing the risk of CV mortality and morbidity in Japanese patients with HFrEF. Details of the core PARALLEL-HF study (NCT02468232) have been reported previously.16,18 The end-of-study visit of the core PARALLEL-HF was the first visit of the OLE. In this OLE, a single treatment arm of sacubitril/valsartan was included (Figure 1). Slower uptitration of sacubitril/valsartan dosage (target dose 200 mg, b.i.d., by 8 weeks with maintenance for as long as possible) was allowed according to safety and tolerability in individual patients.
Open-label extension (OLE) study design.aPatients who received the double-blind sacubitril/valsartan (sac/val) 100 mg, b.i.d., or enalapril (ena) 5 mg, b.i.d., had the option to start with either OLE sac/val 100 mg, b.i.d., or sac/val 50 mg, b.i.d., at the investigators’ discretion. bDosage was up-titrated at Weeks 2–4 if tolerated, and the general protocol guidance regarding maintenance dose was followed. cDose adjustment was permitted if the dose was not tolerated during the OLE period, and the general protocol guidance regarding maintenance dose was followed. dAn attempt was made to uptitrate and maintain the patient at the target sac/val dose of 200 mg, b.i.d., for as long as possible. (▲), short washout period (~36 h) after patients completed the double-blind treatment and prior to starting the first dose of open-label sac/val in the OLE part to avoid overlapping of sac/val with enalapril or the open-label angiotensin-converting enzyme inhibitors, to minimize the potential risk of the occurrence of angioedema. EOS, end of study; M, months; W, weeks.
This OLE was conducted in accordance with the International Council for Harmonisation Good Clinical Practice regulations/guidelines (https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf [accessed August 11, 2023]) and the ethical principles set forth in the Declaration of Helsinki. The protocol was approved by an independent ethics committee or institutional review board for each study site. The Consolidated Standards of Reporting Trials guidelines were followed. Written informed consent was obtained from all participants before the start of the OLE.
Participants and TreatmentPatients with chronic HF who had completed the double-blind core study were assessed for eligibility (by investigators) and were switched to sacubitril/valsartan 50 or 100 mg, b.i.d. The last dose of study medication that the patient was taking during the core study was considered in determining the starting dose in the OLE. Patients who received double-blind sacubitril/valsartan 100 mg, b.i.d., or enalapril 5 mg, b.i.d., had the option to start with sacubitril/valsartan 50 or 100 mg, b.i.d. The investigators aimed to uptitrate sacubitril/valsartan doses to the target dose level of 200 mg, b.i.d., by 8 weeks. The sacubitril/valsartan core group consisted of patients who had received sacubitril/valsartan in the core study and continued sacubitril/valsartan in the OLE. The enalapril core group consisted of patients who received enalapril in the core study and were switched to sacubitril/valsartan in the OLE. Patients were excluded if the study drug was discontinued during the core study because of an event or intercurrent illness. However, eligibility was reconsidered if the event had resolved and no longer represented a risk to the patient. Detailed inclusion and exclusion criteria are provided in Supplementary Appendix 1.
All patients in the OLE received sacubitril/valsartan, b.i.d. (provided by Novartis), in addition to optimal background HF therapy, as considered appropriate by the investigator and in accordance with standard therapeutic guidelines. The use of ACEIs, angiotensin II receptor blockers, or a renin inhibitor was prohibited during the OLE.
Study Endpoints and AssessmentsPhysical examination, vital signs, New York Heart Association (NYHA) classification, laboratory assessments, plasma/urine biomarkers, echocardiography, adverse events (AEs), and serious AEs (SAEs) were used to evaluate the efficacy and safety of treatment with sacubitril/valsartan, b.i.d., at different doses for approximately 2 years. Detailed procedures used to evaluate the endpoints have been published previously.16 This OLE study did not have prespecified primary or secondary clinical outcomes as part of the protocol.
Efficacy Endpoints Changes in NYHA functional class from the OLE baseline were grouped as improved, unchanged, or worsened. During the OLE period, HF signs and symptoms and NYHA classification were assessed at all patient visits. Biomarkers (BNP, urine cGMP, and NT-proBNP) were obtained from plasma and spot urine samples at the OLE baseline and at Weeks 2–4, Week 8, and Months 4 and 12. Echocardiography was performed at a single core laboratory by qualified personnel at both the OLE baseline and before the administration of study medication at Month 12. Cardiac parameters related to left ventricular (LV) and left atrium (LA) structure and LV systolic and diastolic function, including LV end-systolic/diastolic volume indices, LV ejection fraction (LVEF), and LA volume index, were assessed.
Safety Endpoints AEs, SAEs, and their severity and relationship with the study drug were assessed at all visits. Angioedema or angioedema-like events were monitored and reported based on their frequency. Liver safety monitoring was performed throughout the OLE to ensure patient safety and enhance reliability in determining the hepatotoxic potential of sacubitril/valsartan. Liver enzyme abnormalities were summarized based on event criteria.
Statistical AnalysisAnalysis Set Patients in the OLE who received ≥1 dose of sacubitril/valsartan were analyzed for both safety and efficacy endpoints.
Data Analysis Demographic variables and baseline characteristics at OLE baseline were summarized by treatment arm in the double-blind treatment period. Descriptive summary statistics for biomarker changes from the OLE baseline to each post-baseline visit are presented for each treatment arm. Graphs of the geometric mean and 95% confidence interval (CI) and by treatment arm in the double-blind treatment period are presented for BNP, NT-proBNP, and urine cGMP. AEs and SAEs were summarized by preferred term with the number and percentage of patients in whom events occurred. Descriptive analyses (mean±SD, median, minimum, and maximum) are presented for continuous variables, and numbers and percentages are presented for categorical variables for patients presented by the core study treatment groups.
Sample Size Calculation Sample size calculation was not performed for the OLE.
The first patient visit for the OLE occurred on January 4, 2019; the last patient visit was on February 18, 2021. In all, 150 patients were enrolled in the OLE and received sacubitril/valsartan. The sacubitril/valsartan core group comprised 79 patients and the enalapril core group comprised 71. Overall, most patients (82.7%; n=124) completed the OLE. Primary reasons for treatment discontinuation included AEs, individual decision, physician decision, or death (Supplementary Figure 1).
Baseline demographic and disease characteristics were well balanced between the groups (Table 1). The mean (±SD) age of patients was 69.9±10.5 years. Most patients (70.7%; n=106) had NYHA Class II disease. Median NT-proBNP concentrations at baseline were lower in the sacubitril/valsartan core group than in the enalapril core group. The proportion of patients with diabetes was higher in the sacubitril/valsartan core group than in the enalapril core group. The proportion of patients with hypertension and cardiac resynchronization therapy/implantable cardioverter-defibrillator was higher in the enalapril core group (Table 1).
| Sac/Val core group (n=79) |
Enalapril core group (n=71) |
Total (n=150) |
|
|---|---|---|---|
| Age (years) | 70.6±10.6 | 69.1±10.5 | 69.9±10.5 |
| Age group (years) | |||
| <65 | 17 (21.5) | 20 (28.2) | 37 (24.7) |
| ≥65 | 62 (78.5) | 51 (71.8) | 113 (75.3) |
| <75 | 52 (65.8) | 46 (64.8) | 98 (65.3) |
| ≥75 | 27 (34.2) | 25 (35.2) | 52 (34.7) |
| Female sex | 11 (13.9) | 12 (16.9) | 23 (15.3) |
| BMI (kg/m2) | 24.3±4.3 | 25.7±4.2 | 25.0±4.3 |
| LVEF (%) | |||
| n | 71 | 57 | 128 |
| Mean (±SD) | 36.0±10.1 | 35.0±10.0 | 35.6±10.1 |
| SBP (mmHg) | 119.6±20.5 | 119.9±15.0 | 119.7±18.1 |
| DBP (mmHg) | 70.0±14.7 | 71.2±12.3 | 70.6±13.6 |
| Heart rate (beats/min) | 75.6±15.2 | 74.3±13.3 | 75.0±14.3 |
| eGFR (mL/min/1.73 m2) | |||
| n | 78 | 69 | 147 |
| Mean (±D) | 53.4±17.3 | 53.8±15.9 | 53.6±16.6 |
| eGFR (mL/min/1.73 m2) | |||
| <60 | 51 (64.6) | 47 (66.2) | 98 (65.3) |
| ≥60 | 27 (34.2) | 22 (31.0) | 49 (32.7) |
| NT-proBNP (pg/mL) | 755.0 [12.5–17,708.0] | 1,050.0 [12.5–7,684.0] | 966.0 [12.5–17,708.0] |
| NYHA class at OLE baseline | |||
| Class I | 20 (25.3) | 17 (23.9) | 37 (24.7) |
| Class II | 56 (70.9) | 50 (70.4) | 106 (70.7) |
| Class III | 3 (3.8) | 4 (5.6) | 7 (4.7) |
| Class IV | 0 | 0 | 0 |
| Primary HF | |||
| Ischemic | 39 (49.3) | 32 (45.07) | 71 (47.33) |
| Non-ischemic | 40 (50.6) | 39 (54.9) | 79 (52.7) |
| Medical history | |||
| Hypertension | 54 (68.4) | 52 (73.2) | 106 (70.7) |
| Diabetes | 41 (51.9) | 27 (38.0) | 68 (45.3) |
| Myocardial infarction | 34 (43.0) | 29 (40.9) | 63 (42.0) |
| Atrial fibrillation | 23 (29.1) | 25 (35.2) | 48 (32.0) |
| CRT/ICD | 10 (12.7) | 16 (22.5) | 26 (17.3) |
Data are at the open-label extension baseline and are presented as the mean±SD, median [interquartile range], or n (%). The sacubitril/valsartan (sac/val) core group consisted of patients who received sac/val in the core study and continued to receive sac/val in the OLE part. The enalapril core group consisted of patients who received enalapril in the core study and then switched to sac/val in the OLE part. BMI, body mass index; CRT/ICD, cardiac resynchronization therapy/implantable cardioverter-defibrillator; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; OLE, open-label extension; SBP, systolic blood pressure.
Most patients (88.7%) were treated with sacubitril/valsartan for ≥12 months. The mean patient-years on treatment was 1.6 years. The median treatment duration was 21.2 months (interquartile range [IQR] 20.0–22.5 months), with a median of 21.2 months (IQR 19.9–22.3 months) for the sacubitril/valsartan core group and 21.4 months (IQR 20.0–22.7 months) for the enalapril core group. The mean percentage exposure to study drug was 98.9%.
Treatment Dose and Dose LevelMost patients (89.3%) entered the OLE with a starting dose of sacubitril/valsartan 100 mg, b.i.d. (83.5% of patients in the sacubitril/valsartan core group and 95.8% of those in the enalapril core group). Overall, most patients reached the target dose of sacubitril/valsartan 200 mg, b.i.d., by the end of the OLE. At Week 8, 71.3% of patients (n=107) had reached the target dose of sacubitril/valsartan 200 mg, b.i.d. (at the last visit, 68.8% of patients [n=99] received sacubitril/valsartan 200 mg, b.i.d.). The proportion of patients who reached the target dose at Week 8 was higher in the enalapril core group than in the sacubitril/valsartan core group (76.1% vs. 67.1%, respectively). At Month 4, 103 of 107 patients were maintained at the target dose (sacubitril/valsartan core group: 64.6% [n=51]; enalapril core group: 73.2% [n=52]). The duration of treatment exposure was comparable between groups, with the mean (±SD) duration being 19.7±5.1 and 19.8±5.4 months for the sacubitril/valsartan core group and enalapril core group, respectively. During the OLE, the mean (±SD) daily dose per patient was 319.1±108.2 mg for the overall population, 308.6±116.1 mg for the sacubitril/valsartan core group, and 330.7±98.2 mg for the enalapril core group.
Change in NYHA Class From BaselineThe NYHA class remained unchanged in most patients (Figure 2). There was no clear trend of improvement or worsening of NYHA classification in either of the core groups, with >90% of patients without any change. At Month 12, in the sacubitril/valsartan core group (n=71), NYHA class improved for 4.2% (n=3), remained unchanged for 90.1% (n=64), and worsened for 5.6% (n=4) of patients; in the enalapril core group (n=66), NYHA class improved for 6.1% (n=4), remained unchanged for 90.9% (n=60), and worsened for 3.0% (n=2) of patients.
Changes in New York Heart Association (NYHA) class from open-label extension (OLE) baseline. The sacubitril/valsartan (sac/val) core group consisted of patients who received sac/val in the core study and continued to receive sac/val in the OLE part. The enalapril core group consisted of patients who received enalapril in the core study and then switched to sac/val in the OLE part.
The absolute mean (±SD) values for NT-proBNP at baseline in the sacubitril/valsartan and enalapril core groups were 1,055.2±1,088.2 and 1,416.2±1,417.1 pg/mL, respectively. At Month 12, the absolute mean (±SD) NT-proBNP concentration in the sacubitril/valsartan core group was 1,321.7±1,807.6 pg/mL; there were no significant changes in NT-proBNP concentrations from baseline (Figure 3; Supplementary Table 1). However, a reduction in NT-proBNP concentrations from the OLE baseline to Weeks 2–4 was observed in the enalapril core group, which was sustained to Month 12 (Month 12 absolute mean NT-proBNP 1,057.2±1,096.3 pg/mL; Figure 3). At Weeks 2–4 and Week 8, the geometric mean (95% CI) change (ratio to baseline) in NT-proBNP concentrations was 0.96 (0.88–1.06) and 0.94 (0.85–1.05), respectively, in the sacubitril/valsartan core group and 0.78 (0.71–0.86) and 0.76 (0.68–0.85), respectively, in the enalapril core group. At Months 4 and 12, the geometric mean (95% CI) change (ratio to baseline) in NT-proBNP concentrations was 0.92 (0.81–1.04) and 1.08 (0.94–1.24), respectively, in the sacubitril/valsartan core group and 0.76 (0.67–0.87) and 0.75 (0.65–0.87), respectively, in the enalapril core group. The geometric mean for NT-proBNP change is shown in Supplementary Figure 2. The absolute NT-proBNP concentrations decreased over time for both treatment groups and the decrease was similar in both the enalapril core group and the sacubitril/valsartan core group after Weeks 2–4.
Changes in B-type natriuretic peptide (BNP), N-terminal pro BNP (NT-proBNP), and cGMP concentrations from baseline. The sacubitril/valsartan (sac/val) core group consisted of patients who received sac/val in the core study and continued to receive sac/val in the open-label extension (OLE) part. The enalapril core group consisted of patients who received enalapril in the core study and then switched to sac/val in the OLE part. The geometric mean for BNP, NT-proBNP, and cGMP (urine) is based on repeated measures analysis of covariance (ANCOVA). Data show the geometric mean with 95% confidence intervals in parentheses.
There were no significant changes in BNP concentrations from the OLE baseline up to Month 12 in the sacubitril/valsartan core group; however, BNP concentrations increased in the enalapril core group, which was evident as early as Weeks 2–4 and sustained to Month 12 (Figure 3; Supplementary Table 1). At Weeks 2–4 and Week 8, the geometric mean (95% CI) change (ratio to baseline) in BNP levels was 0.95 (0.85–1.07) and 1.00 (0.88–1.14), respectively, in the sacubitril/valsartan core group and 1.18 (1.05–1.33) and 1.29 (1.12–1.47), respectively, in the enalapril core group. At Months 4 and 12, the geometric mean (95% CI) change (ratio to baseline) in BNP concentrations was 1.02 (0.89–1.18) and 1.17 (0.01–1.36), respectively, in the sacubitril/valsartan core group and 1.31 (1.13–1.52) and 1.32 (1.13–1.55), respectively, in the enalapril core group. Comparison of the ratio of geometric mean for NT-proBNP for Month 4 vs. Month 12 in the sacubitril/valsartan core group was found to be statistically significant (P=0.02). However, the same comparison for BNP did not reach statistical significance (P=0.10).
There were no significant changes in urine cGMP concentrations from OLE baseline up to Month 12 in the sacubitril/valsartan core group (Figure 3; Supplementary Table 1). cGMP concentrations increased in the enalapril core group, which was evident as early as Weeks 2–4 and sustained to Month 12. At Weeks 2–4 and Week 8, the geometric mean (95% CI) change (ratio to baseline) in cGMP concentrations was 1.21 (0.99–1.49) and 1.23 (1.03–1.48), respectively, in the sacubitril/valsartan core group and 1.49 (1.20–1.85) and 1.47 (1.21–1.79), respectively, in the enalapril core group. At Months 4 and 12, the geometric mean (95% CI) change (ratio to baseline) in cGMP levels was 1.27 (1.06–1.52) and 1.07 (0.89–1.28), respectively, in the sacubitril/valsartan core group and 1.70 (1.40–2.05) and 1.53 (1.26–1.86), respectively, in the enalapril core group. The geometric mean (95% CI) for cGMP/BNP ratio at Month 12 for the sacubitril/valsartan core group was 2.31, whereas that for the enalapril core group was 3.12 (Supplementary Figure 3).
Changes in Echocardiographic ParametersOverall, some improvements were observed in cardiac structure and function at Month 12 in both groups (Supplementary Table 2). Patients in the sacubitril/valsartan core group had a numerically higher mean (±SD) reduction in LA volume index at Month 12 than those in the enalapril core group (−3.3±11.7 vs. −1.5±12.4 mL/m2, respectively). An absolute LVEF increase of >3% was observed at Month 12 in both the sacubitril/valsartan and enalapril core groups. The mean change in LV end-systolic/diastolic volume indices was comparable between the groups. Changes in NT-proBNP concentrations did not correlate with changes in echocardiographic parameters from OLE baseline to Month 12.
SafetyOverall, 90% of patients (n=135) had ≥1 AE, and the incidence was comparable between the sacubitril/valsartan core group and enalapril core group (88.6% [n=70] vs. 91.6% [n=65], respectively; Table 2). Most of the AEs reported were mild (39.3%) or moderate (34.7%) in severity. The most commonly reported AEs were nasopharyngitis (24.7%), cardiac failure (22.7%), hypotension (14.7%), and renal impairment (12.0%). AEs related to the study drug were reported in 14.7% of patients, with the most commonly reported AEs (≥2%) being hypotension (9.3%) and renal impairment (2.7%); ≥1 SAEs were reported in 42.7% of patients (n=64), with cardiac failure (15.3%; n=23) being the most commonly reported SAE. Overall, 21.5% (n=17) of patients in the sacubitril/valsartan core group and 8.5% (n=6) of patients in the enalapril core group experienced cardiac failure. Six deaths were reported during the OLE, of which 5 were attributed to CV events and 1 to infection (Supplementary Table 3).
| Sac/Val core group (n=79) |
Enalapril core group (n=71) |
Total (n=150) |
|
|---|---|---|---|
| No. patients with ≥1 AE | 70 (88.6) | 65 (91.6) | 135 (90.0) |
| Individual AEs | |||
| Nasopharyngitis | 19 (24.1) | 18 (25.4) | 37 (24.7) |
| Cardiac failure | 22 (27.9) | 12 (16.9) | 34 (22.7) |
| Hypotension | 9 (11.4) | 13 (18.3) | 22 (14.7) |
| Renal impairment | 12 (15.2) | 6 (8.5) | 18 (12.0) |
| Ventricular tachycardia | 7 (8.9) | 3 (4.2) | 10 (6.7) |
| Hyperkalemia | 5 (6.3) | 5 (7.0) | 10 (6.7) |
| Constipation | 6 (7.6) | 4 (5.6) | 10 (6.7) |
| Anemia | 7 (8.9) | 2 (2.8) | 9 (6.0) |
| Hepatic function abnormal | 6 (7.6) | 3 (4.2) | 9 (6.0) |
| Cough | 7 (8.9) | 1 (1.4) | 8 (5.3) |
| Hypokalemia | 6 (7.6) | 2 (2.8) | 8 (5.3) |
| Diabetes | 6 (7.6) | 2 (2.8) | 8 (5.3) |
| Insomnia | 4 (5.1) | 4 (5.6) | 8 (5.3) |
| Arthralgia | 3 (3.8) | 4 (5.6) | 7 (4.7) |
| Contusion | 3 (3.8) | 4 (5.6) | 7 (4.7) |
| Back pain | 3 (3.8) | 4 (5.6) | 7 (4.7) |
| Atrial fibrillation | 6 (7.6) | 0 | 6 (4.0) |
| Cataract | 2 (2.5) | 4 (5.6) | 6 (4.0) |
| Pneumonia | 4 (5.1) | 1 (1.4) | 5 (3.3) |
| Diarrhea | 4 (5.1) | 1 (1.4) | 5 (3.3) |
| Dehydration | 3 (3.8) | 2 (2.8) | 5 (3.3) |
| Rhinitis allergic | 3 (3.8) | 2 (2.8) | 5 (3.3) |
| Cerebral infarction | 2 (2.5) | 3 (4.2) | 5 (3.3) |
| Delirium | 2 (2.5) | 3 (4.2) | 5 (3.3) |
| Dental caries | 2 (2.5) | 3 (4.2) | 5 (3.3) |
Data are presented as n (%). The sacubitril/valsartan (sac/val) core group consisted of patients who received sac/val in the core study and continued to receive sac/val in the OLE part. The enalapril core group consisted of patients who received enalapril in the core study and then switched to sac/val in the OLE part. AE, adverse event. Other abbreviations as in Table 1.
One patient in the enalapril core group reported hyperkalemia as an SAE. AEs that led to study discontinuation were reported in 5.3% of patients (n=8; 4 patients from each group; Supplementary Table 4). Overall, 23.3% of patients (n=35) had ≥1 AE requiring dose adjustment or interruption of study treatment, the most reported being hypotension (10.0%; n=15) and cardiac failure (4.0%; n=6). In terms of AEs of special interest, the overall incidence of hypotension, renal impairment, and hyperkalemia-related AEs was 22.7% (n=34), 12.7% (n=19), and 7.3% (n=11), respectively (Supplementary Table 5). Hyperkalemia was the most frequent hyperkalemia-related AE and was reported in 6.7% of patients; no patients discontinued study treatment due to hyperkalemia-related AEs. The most commonly reported AEs leading to discontinuation of study treatment were renal impairment (2.0%), cardiac failure (1.3%), and hypotension (1.3%). Approximately 26.7% of patients (n=40) had a ≥25% decline in estimated glomerular filtration rate (eGFR) from OLE baseline, but the decline in eGFR was not statistically significant between groups (Supplementary Figure 4). Approximately 8.7% of patients (n=13) had a >50% increase in serum creatinine concentrations. Overall, 8.7% of patients had elevated total bilirubin concentrations and 4.7% had elevated alanine or aspartate transaminase concentrations during the OLE period. During the OLE, 2 patients experienced angioedema/angioedema-like events; neither of these cases were confirmed as angioedema by the Angioedema Adjudication Committee.
This OLE demonstrated that long-term treatment with sacubitril/valsartan at doses of up to 200 mg, b.i.d., was safe and well tolerated in Japanese patients with chronic HFrEF. Most patients reached the target dose of sacubitril/valsartan 200 mg, b.i.d., at Week 8; most were maintained at 200 mg, b.i.d., at Month 4. Two-thirds of all patients received the target dose of sacubitril/valsartan 200 mg, b.i.d., at the last visit. Overall, no trend of worsening of HF was observed a year following the initiation of open-label sacubitril/valsartan; NYHA classification remained unchanged in most patients. The key parameters for cardiac structure and function remained unchanged or improved numerically. Among the cardiac biomarkers related to cardiac and renal function/injury and associated comorbidities, NT-proBNP concentrations were maintained when patients were treated continuously with sacubitril/valsartan or improved when patients were switched from enalapril to sacubitril/valsartan.
In the present study, there was no obvious trend in changes in NT-proBNP concentrations in the sacubitril/valsartan core group, whereas BNP and urine cGMP concentrations were increased in the enalapril core group. This reflects the mode of action of sacubitril/valsartan. It is recognized that sacubitril/valsartan treatment is associated with an initial decrease in NT-proBNP.19 The PARALLEL-HF study showed that early and sustained reductions in NT-proBNP from baseline were observed with sacubitril/valsartan compared with enalapril.16 Prospective studies in HFrEF outpatients show that sacubitril/valsartan induces “hemodynamic recovery”, together with reductions in NT-proBNP concentrations and improvement of NYHA class.20–22 Similar results are observed with real-world studies,23 and these results are in agreement with observations made during the present OLE, where a trend for improvement in NYHA classification and a rapid reduction in NT proBNP were observed in the early stage following switching, which was sustained for ≥1 year.
An increase in BNP is a predictor of CV risk in patients treated with sacubitril/valsartan and early modest rises are generally expected with sacubitril/valsartan treatment. This generally reaches steady state or declines after several months of maintenance dosing. In a biomarker substudy of PARADIGM-HF, sacubitril/valsartan increased both urinary cGMP and plasma BNP concentrations.24 The relationship between sacubitril/valsartan and BNP concentrations is complex and depends on several factors, such as the dose, duration, and timing of sacubitril/valsartan therapy, as well as the study population and the baseline and follow-up concentrations of BNP and NT-proBNP. Variability in BNP response is observed and some studies have reported a decrease in BNP concentrations with sacubitril/valsartan treatment, particularly after a few months of treatment.25 The results of the present study indicate that there was a significant increase in NT-proBNP concentrations between Month 4 and Month 12 in the sacubitril/valsartan core group, but no significant change in BNP concentrations over the same period. The data do not provide a clear explanation as to whether the effect of sacubitril/valsartan was diminished during this time. In addition, the reason behind the observed differences between NT-proBNP and BNP in response to sacubitril/valsartan treatment is not evident. Further analysis or investigation would be required to determine the underlying factors influencing these findings. Literature evidence show that in patients with HFrEF, those with a decrease in NT-proBNP have better outcomes and favorable reverse ventricular remodeling.26–29 In the present extension study, the urine cGMP/BNP ratio was higher in the enalapril core group than in the sacubitril/valsartan core group, suggesting that the cGMP/BNP ratio increased when switching from enalapril to sacubitril/valsartan. The PIONEER-HF study showed that a higher urine cGMP/BNP ratio was associated with better outcomes and sacubitril/valsartan increased the urine cGMP/BNP ratio compared with enalapril.30 In the present study, a decline in eGFR was observed for both the sacubitril/valsartan and enalapril core groups; however, the difference was not statistically significant. Post hoc analysis of both PARADIGM-HF and PARAGON-HF showed that the decline in eGFR when transitioning to sacubitril/valsartan varied among patients but was generally minor and partially reversible in most cases.31 Moderate eGFR decline following the switch to sacubitril/valsartan did not consistently correlate with unfavorable outcomes.31
Echocardiographic parameters indicated better cardiac structure and function with sacubitril/valsartan than with enalapril at the OLE baseline. LVEF increased by >3% in both the sacubitril/valsartan and enalapril core groups at Month 12. This is consistent with other studies; an absolute improvement in LVEF of ≥5% is considered clinically relevant.23,32–35 These results emphasize the favorable impact of sacubitril/valsartan on LV remodeling and demonstrate that switching patients from ACEIs to sacubitril/valsartan is tolerable and safe, and leads to significant improvement in LV function. Real-world evidence suggests a positive correlation between improvement in LV function and QoL.32,36 No significant correlations were observed between changes in NT-proBNP concentrations and echocardiographic parameters from OLE baseline to Month 12.
The safety profile of sacubitril/valsartan in this OLE was comparable with that of the core study.16 The most commonly reported treatment-emergent AEs were nasopharyngitis, cardiac failure, hypotension, and renal impairment. Hypotension and renal impairment were the most frequent AEs suspected to be related to study treatment. These results are comparable with those reported in the 52-week long-term study with sacubitril/valsartan in Asian patients with hypertension.37 In that study, a case of angioedema was also reported, which led to treatment discontinuation; however, in the present OLE, no such cases were observed.37 The incidence of hyperkalemia observed in the present OLE was higher than that observed in a pooled real-world study (7% vs 2%);38 this may underline the infrequent potassium monitoring outside the randomized control trial context.
Study LimitationsThe results of this OLE must be interpreted with caution because no comparator was used. The absence of a placebo-control group makes the interpretation of safety results a challenging task for such a high-risk cohort. The main objective of this extension part was to assess the long-term safety of sacubitril/valsartan treatment, and cardiovascular outcomes were not analyzed during the study period. Common to any extension study, patients entered voluntarily, and this voluntary enrollment may have potentially introduced a selection bias.
Long-term treatment with sacubitril/valsartan at doses up to 200 mg, b.i.d., was safe and well tolerated in both groups of patients (i.e., those who continued treatment with sacubitril/valsartan and those who were switched from enalapril to sacubitril/valsartan). NYHA classification was unchanged for most patients in both groups. Key echocardiographic parameters remained unchanged, and NT-proBNP concentrations were maintained when patients were treated continuously with sacubitril/valsartan or improved when patients were switched from enalapril. In conclusion, the long-term use of sacubitril/valsartan showed a positive risk-benefit profile in treating Japanese patients with chronic HFrEF.
The authors thank all the patients, investigators, and staff who participated in this study extension. The authors also thank Ritika Paul and Shalini Verma from Novartis Healthcare Private Ltd. (Hyderabad, India) for providing medical writing support in accordance with Good Publication Practice (GPP 2022) guidelines.
This study was funded by Novartis Pharmaceuticals Corporation.
H.T. was an Executive Committee Chair of PARALLEL-HF and has received consultation fees from Novartis Pharma K.K., Nippon Boehringer Ingelheim, Bayer Yakuhin, Ono Pharmaceutical; remuneration from MSD, Astellas Pharma, Pfizer, Bristol-Myers Squibb, Otsuka Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Bayer Yakuhin, Novartis Pharma K.K., Kowa Pharmaceutical, Teijin Pharma; research funding from Actelion Pharmaceuticals, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, IQVIA Services, Omron Healthcare; and scholarship funds from Astellas Pharma, Novartis Pharma K.K., Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, and MSD. S.M. was an Executive Committee Member of PARALLEL-HF and has received speakers bureau/honoraria from Ono Pharmaceutical, MSD, Nippon Boehringer Ingelheim. Y. Saito was an Executive Committee Member of PARALLEL-HF and has received research funds from Otsuka Pharmaceutical, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Takeda Pharmaceutical Co., Ltd., Nihon Medi-Physics Co., Ltd., LSI Medience Corporation; research expenses from Novartis Pharma K.K. and Roche Diagnostics; speakers bureau/honoraria from Otsuka Pharmaceutical, Daiichi Sankyo, Nippon Boehringer Ingelheim, Novartis Pharma K.K.; and consultation fees from Novartis Pharma K.K. H.I. was an Executive Committee Member of PARALLEL-HF and has received speakers bureau/honoraria from Takeda Pharmaceutical, Daiichi-Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, and Ono Pharmaceutical; research funds from Takeda Pharmaceutical, Daiichi-Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, Shionogi, Sumitomo Dainippon Pharma, and Ono Pharmaceutical; honoraria for writing promotional material for Daiichi-Sankyo; and consultation fees from Novartis Pharma K.K.; and is affiliated with an endowed department sponsored by Medtronic Japan. K.Y. was a Medical Advisor of PARALLEL-HF and has received speakers bureau/honoraria and research funds from Otsuka Pharmaceutical and Novartis Pharma K.K., as well as consultation fees from Novartis Pharma K.K. Y. Sakata was a Data Monitoring Committee Member of PARALLEL-HF and reports no conflicts of interest. T.O., P.K., and T.K. were employees of Novartis at the time of the study. H.T., K.Y., Y. Sakata, and H.I. are members of Circulation Journal’s Editorial Team.
All authors participated in the development and writing of the paper, reviewed and critically revised the manuscript for content, and approved the final version of the manuscript for submission.
The study protocol and all amendments were reviewed and approved by the independent ethics committee or institutional review board (IRB) for each center (e.g., Nihon University Hospitals Joint IRB [Reference no. 5010005002382]).
Elements of the information presented here are available at ClinicalTrials.gov (ID: NCT02468232). The deidentified participant data will not be shared.
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-23-0174
