Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: Rationale for and design of the randomized, double-blind PARALLEL-HF study Academic research paper on "Clinical medicine"

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Original article

Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: Rationale for and design of the randomized, double-blind PARALLEL-HF study

Hiroyuki Tsutsui (MD, PhD, FJCC)3'*, Shinichi Momomura (MD, PhD, FJCC)b, Yoshihiko Saito (MD, PhD, FJCC)c, Hiroshi Ito (MD, PhD, FJCC)d, Kazuhiro Yamamoto (MD, PhD, FJCC)e, Tomomi Ohishif, Naoko Okinof, Weinong Guo (MD, PhD)g

a Department of Cardiovascular Medicine, Kyushu University, Fukuoka, Japan b Cardiovascular Division, Jichi Medical University, Saitama Medical Center, Saitama, Japan c First Department of Internal Medicine, Nara Medical University, Kashihara, Japan

d Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan e Department of Molecular Medicine and Therapeutics, Tottori University, Yonago, Japan f Novartis Pharma K.K., Tokyo, Japan

g Novartis Pharmaceutical Corporation, East Hanover, NJ, USA

ABSTRACT

Background: The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan. Methods and design: This is a multicenter, randomized, double-blind, parallel-group, active controlled study of 220 Japanese HFrEF patients. Eligibility criteria include a diagnosis of chronic HF (New York Heart Association Class II-IV) and reduced ejection fraction (left ventricular ejection fraction <35%) and increased plasma concentrations of natriuretic peptides [N-terminal pro B-type natriuretic peptide (NT-proBNP) >600 pg/mL, or NT-proBNP >400 pg/mL for those who had a hospitalization for HF within the last 12 months] at the screening visit. The study consists of three phases: (i) screening, (ii) singleblind active LCZ696 run-in, and (iii) double-blind randomized treatment. Patients tolerating LCZ696 50 mg bid during the treatment run-in are randomized (1:1) to receive LCZ696 100 mg bid or enalapril 5 mgbid for 4 weeks followed by up-titration to target doses ofLCZ696 200 mg bid or enalapril 10 mgbid in a double-blind manner. The primary outcome is the composite of cardiovascular death or HF hospitalization and the study is an event-driven trial.

Conclusions: The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study and aims to assess the efficacy and safety of LCZ696 in Japanese HFrEF patients.

© 2016 The Authors. Published by Elsevier Ltd on behalf of Japanese College of Cardiology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ARTICLE INFO

Article history:

Received 22 July 2016

Received in revised form 14 October 2016

Accepted 2 November 2016

Available online xxx

Keywords: LCZ696

Sacubitril/valsartan Japanese

Heart failure with reduced ejection fraction Neprilysin

* Corresponding author at: Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Fax: +81 92 642 5374.

E-mail address: htsutsui@cardiol.med.kyushu-u.ac.jp (H. Tsutsui).

http://dx.doi.org/10.1016/jjjcc.2016.11.011

0914-5087/© 2016 The Authors. Published by Elsevier Ltd on behalf of Japanese College of Cardiology. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Chronic heart failure (HF) is a major public health problem and global burden associated with high mortality rates, frequent hospitalizations, and poor quality of life [1]. Worldwide prevalence of HF is estimated to be as high as 26 million and is more frequent with increasing age (prevalence rates of HF >10% in the elderly, >70 years) [1,2]. HF affects nearly 1-2 million people from Japan and prevalence rates are expected to rise by 40% by 2050 [3-5]. The increase in incidence of HF in Japan has been attributed to a rapidly aging population and a largely westernized lifestyle [5,6].

HF with reduced ejection fraction (HFrEF) is a common presentation of HF accounting for 50-60% of HF patients [3,79]. Evidence-based treatment strategies for HFrEF include angio-tensin-converting enzyme inhibitors (ACEls), angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs), all of which have been shown to improve clinical outcomes in HFrEF patients [10,11]. The prognosis of patients with HF remains poor despite the use of these standard-of-care pharmacotherapies. ln a recent report on the prognosis of HF patients from Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART-2; 2006-2010), the 3-year mortality rate was 14.6% [12]. In addition, the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) reported a mortality rate of 19.3% during a mean 2.4-year follow-up period of patients hospitalized with worsening HF [3]. These Japanese real-world HF registry data underscore the need for a novel therapeutic approach over current standard-of-care to improve the clinical outcomes in HFrEF patients.

Sacubitril/valsartan (LCZ696; sacubitril valsartan sodium hydrate in Japan) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNl) with a novel mode of action. Following oral administration, LCZ696 delivers systemic exposure to neprilysin inhibitor sacubitril (a pro-drug) and an angiotensin ll type l receptor [AT1] blocker valsartan [13]. It acts by simultaneous inhibition of neprilysin (via sacubitrilat, the active metabolite of sacubitril) and inhibition of the effects of angiotensin ll (via valsartan). The therapeutic cardiovascular (CV) and renal effects of LCZ696 in HF are possibly attributed to the enhancement of endogenous peptides that are degraded by neprilysin, such as natriuretic peptides (NPs), and concomitant inhibition of the detrimental effects of angiotensin ll [14]. The PARADIGM-HF study, a phase Ill global outcome trial, compared the efficacy and safety of LCZ696 (target dose: 200 mg bid) with the standard-of-care, ACEl enalapril (target dose: 10 mg bid) in patients with HFrEF and demonstrated the superiority of LCZ696 over enalapril in reducing mortality and morbidity in patients with HFrEF. LCZ696 was well-tolerated and the overall frequency of adverse events was comparable to enalapril [15]. LCZ696 has been approved for the treatment of patients with HFrEF in more than 60 countries/regions worldwide and also recently received Class lB recommendation by ACC/AHA/HFSA and ESC HF management guidelines [2,16-18].

The prospectively designed phase lll PARALLEL-HF (Prospective comparison of ARNl with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to provide the clinical efficacy and safety data of LCZ696 in Japanese patients with HFrEF. lt is designed to align with the Japanese guideline requirement for drug approval and observe a similar trend of clinical efficacy of LCZ696 compared to enalapril, as the PARADlGM-HF study, on morbidity and mortality in Japanese HFrEF patients.

Trial design and methods

The present study is a multicenter, randomized, double-blind, parallel-group, active controlled study to assess the efficacy and

safety of LCZ696 compared to enalapril on morbidity and mortality in Japanese patients with chronic HFrEF (at approximately 50 study sites in Japan; ClinicalTrials.gov: NCT02468232).

Patients

The patient eligibility criteria of the PARALLEL-HF study are largely similar to the PARADlGM-HF study population: adult chronic HF patients [New York Heart Association (NYHA) Class ll-lV] with reduced left ventricular ejection fraction (LVEF <35%) who receive stable doses of ACEl or ARB prior to study entry. The key inclusion and exclusion criteria are listed in Table 1.

Study design

The study consists of three phases: (i) screening; (ii) singleblind active treatment run-in; and (iii) double-blind randomized treatment (Fig. 1); the study visits and assessments are also illustrated in Fig. 2.

Screening (Visit 1)

About 370 patients are expected to be screened in order to randomize 220 patients (110 patients in each treatment group). All patients are assessed for their eligibility to enter the active treatment run-in according to the inclusion/exclusion criteria.

Single blind active treatment run-in (Visit 2)

Patients meeting the eligibility criteria at screening enter the single-blind active treatment run-in and receive LCZ696 50 mg bid for 2 weeks. Before starting the first dose of LCZ696, ACEls or ARBs are discontinued for approximately 36-hour washout period and thereafter; however, any other background medications for chronic HF are continued at this stage. At the end of the run-in period, only patients who are able to tolerate LCZ696 according to the following criteria are eligible for the double-blind, randomized treatment period: (1) serum potassium <5.4 mmol/L (mEq/L); (2) estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 and eGFR reduction <35% compared to screening; (3) no symptomatic hypotension and systolic blood pressure (SBP) >95 mmHg; (4) no postural symptoms or any adverse events that preclude continuation according to the investigator's judgment.

Double-blind randomized treatment (Visit 3)

Patients who are able to tolerate LCZ696 50 mg bid during the run-in are randomized to receive LCZ696 100 mg bid or enalapril

5 mg bid for 4 weeks and thereafter up-titrated, if tolerated, to target doses of LCZ696 200 mg bid or enalapril 10 mg bid (1:1) in a double-blind manner. Patient randomization is stratified by the N-terminal pro B-type natriuretic peptide (NT-proBNP) levels measured at the time of screening (<1600 pg/mLor >1600 pg/mL).

During the double-blind treatment period, patients are allowed to continue to receive all background HF therapies such as b-blockers and/or MRAs, but not ACEls or ARBs. Study visits are scheduled at Weeks 2, 4, 8, 12, and Month 6 during the first

6 months of the randomized treatment period and every 4 months thereafter.

A 36-hour wash-out period of LCZ696 is instituted at the beginning of the double-blind treatment; this period is established to prevent an overlap of the LCZ696 administered during the run-in period with enalapril and minimize the potential risk of occurrence of angioedema.

Patients who cannot tolerate the intermediate or target doses of study drug after randomization can be down-titrated to lower dose

JCc-I^Noo,^,

Table 1

Key inclusion and exclusion criteria.

Key inclusion criteria

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CRT-D, cardiac resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy pacemaker; CT, computerized tomography; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MRA, mineralocorticoid receptor antagonist; MUGA, multiple gate acquisition scan; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; VAD, ventricular assist device.

Single-blind run-in period

LCZ696

Screenin^ 50 mg bid

LCZ696 100 mg bida

Enalapri l 5 mg bida [""

Double-blind treatment period

Visit 1 2

Time -4 / -3 W -2W

LCZ696 200 mg bidb

Enalapril 10 mg bidb

Every4 m up to end of studyc

Fig. 1. Study design. W, week; M, month.a Down-titration to lower dose level (LCZ696,50 mg bid or enalapril 2.5 mg bid) is allowed if not tolerated during the first 4 weeks.ь Dose adjustment (LCZ696,50-100 mgbid or enalapril 2.5-5 mgbid) is permitted if not tolerated at the target dose, i.e. LCZ696,200 mgbid or enalapril 10 mgbid during the double-blind treatment period.c Projected duration of the trial is 40 months. Actual duration of the trial is event-driven.

levels of LCZ696 (100 mg or 50 mgbid) or enalapril (5 mgor2.5 mg bid) at the investigator's discretion after considering whether any other relevant non-disease-modifying therapy such as calcium channel blockers, diuretics, nitrates, or a-blockers were to be discontinued to rectify the situation. The dose levels of disease-modifying drugs such as b-blockers and MRAs may be modified to facilitate maintenance of the study drug if they are suspected to cause adverse events. Every attempt should be made to rechallenge the patients, at the investigator's discretion, in order to maintain as many patients as possible on the target or maximally tolerated dose of the study drug during the course of the doubleblind phase of the study. All clinical events which meet the primary or secondary endpoints as described below are assessed by a Clinical Endpoint Committee for adjudication.

Study objectives

Primary objective

The purpose of this study is to assess the effect of LCZ696 at a target dose of 200 mg bid compared with enalapril at a target dose of 10 mg bid in addition to background HF treatments, in delaying the time to first occurrence of the composite endpoint defined as either CV death or HF hospitalization.

Secondary objectives

The key secondary objectives are (1) to assess the effect of LCZ696 100 mg bid and 200 mg bid on the changes in NT-proBNP from baseline to predefined time points of Weeks 4 and 8 and Month 6; to assess the effect of LCZ696 compared with

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Visits «

Screening

Single-blind treatment run-in period

Assessments

At screening

Patient screening according to inclusion and exclusion criteria

Demography and medical history, physical exam and vital signs

HF and CV history, concomitant medications, NYHA class, echocardiography, ECG, NT-proBNP (for eligibility), complete laboratory assessments, AEs/SAEs

Double-blind randomized treatment period

Treatment run-in

Start of run-in: Physical exam, vital signs, concomitant medications, NYHA class, KCCQ questionnaire, plasma/serum biomarkers, AEs/SAEs

End of run-in: all above assessments + eligibility as per inclusion and exclusion criteria

Randomized treatment

At all visits: Physical exam, concomitant medications, NYHA class, endpoint information, AE/SAEs, vital signs (at all visits between Week 2 and EOS)

At Weeks 0, 8; Months 6, 18, 30 and EOS: KCCQ questionnaire, patient global assessment

At Weeks 4, 8; Months 6, 18, 30 and EOS: Complete laboratory assessments

At Weeks 2, 4, 8; Months 6, and 18: Plasma/serum biomarkers

Fig. 2. Study visits and assessments. AE, adverse event; CV, cardiovascular; ECG, electrocardiogram; EOS, end of study; KCCQ, Kansas city cardiomyopathy questionnaire; HF, heart failure; M, month; NT-proBNP, N-terminal prohormone B-type natriuretic peptide; NYHA, New York Heart Association; SAE, serious adverse event; W, week.

enalapril on (2) the time to first occurrence of CV death, HF hospitalization, or intensification of treatments due to documented episodes of worsening HF defined as worsening signs and symptoms of HF requiring the addition of a new drug for HF treatment, initiation of intravenous treatment, increase of loop diuretic dose (i.e. an increment of >20 mg/day furosemide or equivalent) for persistent use for >4 consecutive weeks, or institution of mechanical or circulatory support such as mechanical ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump, or ventricular assist device; (3) changes in NYHA classification from baseline to predefined time points (Weeks 4 and 8 and Month 6); (4) changes in the clinical summary score for HF symptoms and physical limitations, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at Week 8 and Month 6; and (5) to assess the safety and tolerability of LCZ696 compared to enalapril.

Other secondary objectives are to assess the effect of LCZ696 compared with enalapril on the following: (1) the rate of composite of CV death and total (first and recurrent) HF hospitalizations; (2) changes in the clinical composite score (assessed by NYHA classification and patient global assessment) at Month 6; (3) the time to all-cause mortality; (4) the number of patients hospitalized and number of hospital admissions (all-cause and cause-specific); (5) healthcare resource utilization (number of days/stays in ICU, number of rehospitalizations and emergency room visits for HF, etc.); (6) changes in cardiac and other biomarkers from baseline to Weeks 4 and 8 and Month 6 (e.g. NT-proBNP, aldosterone, cystatin-C, high-sensitivity troponin T); biomarkers related to fibrosis or remodeling such as amino-terminal propeptide of procollagen type I (PINP) and type III (PIIINP) are measured during the run-in visit and at Month 18.

Safety monitoring

Patients are assessed at each study visit for hyperkalemia, symptomatic hypotension, renal dysfunction, potential angioe-dema, and all the adverse events and serious adverse events per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance of conducting clinical trials in human subjects.

All suspected angioedema events will be adjudicated by an independent Angioedema Adjudication Committee.

Statistical analysis and sample size calculation

The sample size is determined to ensure at least 80% probability of observing a hazard ratio (12/1i) of <1, where 11 and 12 are hazards of the enalapril and LCZ696 treatment groups, respectively, and to support the consistency between this study and PARADIGM-HF. Assuming a 20% hazard reduction in the primary endpoint (composite of CV death and HF hospitalization) in LCZ696 over enalapril, approximately 57 primary endpoint events will be required. Assuming an annual event rate of 13% in the enalapril group, an enrollment period of 22 months and a follow-up period of 18 months for the last enrolled patient, a total sample size of 220 patients is required to obtain approximately 57 primary endpoint events.

The primary efficacy variable will be analyzed using Cox proportional hazards model with treatment and the stratification factor of screening NT-proBNP (<1600pg/mL, >1600pg/mL) as fixed-effect factors. The primary hypothesis to be tested is H10:12/ 11 >1 versus H1a: 12/11 <1, where 11 and 12 are hazards for enalapril treatment and LCZ696 treatment, respectively. The frequency of patients with composite primary endpoint events and the treatment exposure adjusted event rate will be provided for individual treatment arms.

Study management and committees

The executive committee provides the scientific leadership for the study design and oversees the conduct of the trial in collaboration with Novartis Pharma AG as the sponsor. An external and independent Data Monitoring Committee (DMC) has been appointed to monitor the conduct of the study and patient safety. The DMC will function independently of all other individuals associated with the conduct of this trial including investigators, sponsor personnel, and other committees overseeing the trial (such as the Ethics committee and Executive committee). The DMC consists of 6 members and will meet two times a year to review accumulating safety data after the first patient first visit (FPFV).

The Clinical Endpoint Committee for adjudication is responsible for classifying the fatal (CV and non-CV death) and non-fatal events (HF hospitalization, worsening HF requiring an intensification of outpatient treatment) according to the pre-specified definitions of the primary and secondary efficacy endpoints (Table 2).

Table 2

Definition of key clinical efficacy endpoints. Cardiovascular death

Discussion

HF accounts for up to 1-4% of all hospital admissions as a primary diagnosis in economically developed countries [1]. Although there has been significant progress in HFrEF management over the past two decades, there remains a substantial burden in mortality and morbidity in these patients. Several observational studies in Japan show similar patient burden in terms of prevalence of HF and associated mortality and morbidity, despite the increasing use of evidence-based therapies [3,4,6,19].

The rationale for the current PARALLEL-HF study stems from the strong evidence from PARADIGM-HF trial that demonstrated superior benefits of LCZ696 compared with enalapril in reducing CV mortality and morbidity risks in patients with HFrEF. PARADIGM-HF enrolled 1487 [~18%] patients from the Asia-Pacific region (although no patients from Japan were enrolled); a subgroup analysis showed consistent beneficial effects of LCZ696 compared to enalapril across various geographical regions [15,20]. Considering the robust evidence from the PARADIGM-HF trial and the lack of feasibility of conducting a stand-alone regional trial in Japan of similar statistical power and sample size, the requisite condition for authorization of LCZ696 in Japan requires a similar trend of efficacy in Japanese HFrEF patients as per the Japanese Guidelines for Clinical Evaluation of Drugs for Heart Failure and related Q&A document [21,22].

The design of the PARALLEL-HF study is aligned with the PARADIGM-HF study in that it facilitates interpretation of efficacy

and safety profiles of LCZ696 in Japanese patients with HFrEF. The PARALLEL-HF study design has several unique aspects. Patients with HFrEF and NYHA class II-IV on a stable dose of ACEI or ARB for 4 weeks prior to enrollment are eligible for enrolment, unlike the PARADIGM-HF trial where patients were required to be on a stable dose of an ACEI or ARB equivalent to enalapril 10 mg/day for 4 weeks. This is designed considering relatively lower daily doses for both the maximum approved and physician-prescribed dosage of ACEI and ARB in Japan, for example the maximum approved dose of enalapril for HF is 10 mg/day. It allows enrollment of a more representative HFrEF patient population in clinical practice in Japan.

PARALLEL-HF trial includes an active run-in period of 2 weeks to ensure tolerability of minimum daily dose of LCZ696 50 mg bid. During the double-blind period, LCZ696 is initiated at 100 mg bid for 4 weeks followed by up-titration to 200 mg bid. Up-titration is not forced but rather according to patient safety and tolerability of LCZ696 and allows temporary dose interruption or dose reduction. This dosing scheme is based on observations in the recent TITRATION study which shows that a gradual up-titration of LCZ696 from 50 mg bid to 200 mg bid over 6 weeks increased the likelihood of reaching target doses in patients with prior exposure to low doses of ACEI/ARB [23]. In addition, this stepwise up-titration regime will generate biomarker efficacy data such as changes in NT-proBNP at predefined time points (Weeks 4 and 8 and Month 6) to assess the effect of LCZ696 100 mg and 200 mg bid doses on HF-related biomarkers.

The target dose of LCZ696 200 mg bid in the present study is selected because, (1) this daily dose regimen was generally well-tolerated in PARADlGM-HF [15] and TlTRATlON studies [23] in HFrEF patients taking lower daily doses of ACEl or ARB; (2) in a phase lll study in Japanese hypertensive patients (n = 1161), LCZ696 200 mg or 400 mg once-daily was well-tolerated [24]; and (3) the pharmacokinetics of ascending doses of LCZ696 (20600 mg) in healthy Japanese subjects were similar to that observed in Caucasian subjects [25].

The PARALLEL-HF study uses the same comparator drug of enalapril as in the PARADlGM-HF trial, which is also designed considering the appropriateness of the proposed dosage of the comparator in Japanese patients with HFrEF. The Japanese treatment guidelines for chronic HF recommend ACEl in all patients with HFrEF, unless contraindicated (evidence level A). Although the approved dose of enalapril in Japan is 5-10 mg/day, doses up to 20 mg/day are well-tolerated in Japanese patients with HFrEF [26,27].

The primary endpoint of a composite of CV death or HF hospitalization in the present study is in line with the Japanese guidelines for clinical evaluation of drugs for HF which state that treatment goals for chronic HF should improve vital prognosis and morbidity in patients with chronic HF, relieve subjective symptoms, and improve the quality of life [21,22]. This composite outcome is selected as it best reflects the mortality and morbidity burden of chronic HF and has also been used in other trials such as PARADlGM-HF, SHlFT, EMPHASlS-HF, and CHARM-Added [2831]. ln addition, stratification of patients by baseline NT-proBNP is implemented to ensure a balanced patient risk profile between the two treatment groups.

A number of secondary efficacy endpoints that are predefined in this study aim to provide complementary efficacy evaluations of HF morbidity, biomarkers, symptoms and functional capacity and will allow the assessment of efficacy of LCZ696 compared to enalapril based on the totality of primary and key secondary endpoints. Of note are two pre-defined secondary endpoints that are worthy of mention. The effect on NT-proBNP is characterized at two doses of LCZ696 (100 mg and 200 mg bid) from baseline to Weeks 4 and 8 and Month 6. NT-proBNP is a valid biomarker to assess the effects of LCZ696 as it is not a substrate of neprilysin such as B-type natriuretic peptide [14]. Change in NT-proBNP is of particular interest because NP concentrations have important prognostic implications in patients with HF. Elevated levels of NPs are associated with adverse outcomes in these patients and reduction in their levels is associated with improvement in left ventricular wall stress [32]. Another secondary endpoint of interest is the composite of CV death, HF hospitalization, and intensification of treatment due to worsening HF. While mortality and HF hospitalizations have been traditionally used as endpoints in most of the HF trials, there is growing awareness that other episodes of worsening HF should be recognized as an important morbidity event in the patient journey as they may suggest progression of the underlying pathophysiology, deteriorating clinical status, or less favorable prognosis in HF patients [33]. A recent post hoc analysis from PARADlGM-HF showed that manifestations of worsening HF, such as outpatient intensification of HF therapy and emergency department visits, have serious prognostic implications including an increased risk of all-cause mortality [34].

PARALLEL-HF began enrollment in June 2015, and completion of recruitment and follow-up is anticipated by 2018. ln conclusion, considering that LCZ696 exerts unique CV and renal effects in patients with HFrEF, the PARALLEL-HF study has been designed to assess the efficacy and safety of LCZ696 compared with enalapril in Japanese patients with HFrEF. lf our hypothesis proves correct that LCZ696 treatment provides similar improvements in clinical outcomes in Japanese HFrEF patients as

observed in PARADIGM-HF study, with an acceptable safety profile, this study may provide evidence for a newer and better therapeutic approach than the 'gold-standard' ACEI to Japanese patients with HFrEF.

Conflict of interest

H.T. has received speakers' bureau/honorarium from MSD, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi-Sankyo, Teijin Pharma, Nippon Boehringer Ingelheim, Bayer Yakuhin, Bristol-Myers Squibb, and research funds from Takeda Pharmaceutical, Bayer Yakuhin, Nippon, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sanofi, and Daiichi-Sankyo, honorarium for writing promotional material for Medical Review, and consultation fees from Novartis Pharma K.K.

S.M. has received speakers' bureau/honorarium from Mitsubishi Tanabe Pharma, Daiichi-Sankyo, Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Pfizer, Bayer Yakuhin, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Toa Eiyo, Actelion Pharmaceuticals Japan, Philips Respironics GK, Teijin Pharma, Medtronic Japan, St. Jude Medical, Boston Scientific Japan, and Torii Pharmaceutical, honorarium for writing promotional material for Medtronic Japan, Teijin Pharma, Kyowa Hakko Kirin, research funds from Mitsubishi Tanabe Pharma, Daiichi-Sankyo, Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Toa Eiyo, Actelion Pharmaceuticals Japan, Teijin Pharma, Medtronic Japan, St. Jude Medical, Abbott Japan, Nippon Boehringer Ingelheim, and Bayer Yakuhin, and consultation fees from Novartis Pharma K.K.

Y.S. has received research funds from Mitsubishi Tanabe Pharma, Shionogi, Daiichi-Sankyo, Takeda Pharmaceutical, and Otsuka Pharmaceutical, Baxter, consultation fees from Novartis Pharma K.K, and is affiliated with endowed departments sponsored by MSD.

H.I. has received speakers' bureau/honorarium 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, honorarium for writing promotional material for Daiichi-Sankyo, consultation fees from Novartis Pharma K.K, and is affiliated with an endowed department sponsored by Medtronic Japan.

K.Y. has received speakers' bureau/honorarium from Otsuka Pharmaceutical, Ono Pharmaceutical, Mitsubishi Tanabe Pharma, Toa Eiyo, Takeda Pharmaceutical, Medtronic, Bristol-Myers Squibb, Pfizer, research funds from St. Jude Medical Japan, Otsuka Pharmaceutical, Daiichi-Sankyo, Ono Pharmaceutical, Biotronik Japan, Japan Lifeline, Astellas, Sanwa Kagaku Kenkyusho, Boehringer Ingerlheim, Abbott Vascular Japan, Bayer Yakuhin, Teijin Pharma, Mitsubishi Tanabe Pharma, Novartis Pharma K.K., Fukuda Denshi, Taisho Toyama Pharmaceutical, Fukuda Life Tec, and consultation fees from Novartis Pharma K.K.

T.O., N.O., W.G. are employees of Novartis at the time of study conduct.

Funding

This study is sponsored by Novartis Pharma AG. Acknowledgments

The authors thank Suchitra Jagannathan (Novartis Ireland Ltd) and Syed Abdul Haseeb (Novartis Healthcare Pvt Ltd, Hyderabad,

JCc-I^No.o.P^,

India) for providing medical writing assistance and editorial support. 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.

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