This study utilized the blood and first morning void (FMV) urine samples from the PARALLEL-HF study (core part). The PARALLEL-HF study (core part) was a multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled study to assess the effect of sacubitril valsartan at a target dose of 200 mg b.i.d. and enalapril 10 mg b.i.d. on cardiovascular (CV) mortality and morbidity in Japanese HF patients with reduced ejection fraction.

Inclusion Criteria:

1. Written informed consent was required before any assessment could be performed.

2. Male or female outpatients of ≥ 20 years of age (at the time of signing informed consent)

3. Patients with a diagnosis of congestive heart failure NYHA class II-IV and reduced ejection fraction:

   • LVEF ≤ 35% at Visit 1
   • NT-proBNP ≥ 600 pg/mL at Visit 1 OR NT-proBNP ≥ 400 pg/mL at Visit 1 and a hospitalization for HF within the previous 12 months

4. Patients were to be on an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) at a stable dose for at least 4 weeks before Visit 1.

5. Patients were to be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1.

6. An aldosterone antagonist was also to be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist was to be optimized according to guideline recommendations and patient tolerability, and should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for HF was also to be considered e.g., cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines.

Exclusion Criteria:

1. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes, ACEIs, ARBs, neutral endopeptidase (NEP) inhibitors as well as known or suspected contraindications to the study drugs.
2. Previous documented history of intolerance to ACEIs or ARBs.
3. Known history of angioedema.
4. Requirement of treatment with both ACEIs and ARBs.
5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).
6. Symptomatic hypotension and/or a systolic blood pressure (SBP) < 100 mmHg at Visit 1 (Screening) or < 95 mmHg at Visit 199 (end of run-in).
7. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as measured by the Japanese formula at Visit 1 (Screening) or Visit 199 (end of run-in) or > 35% decline in eGFR between Visit 1 and Visit 199 (according to local measurements).
8. Serum potassium > 5.2 mmol/L (mEq/L) at Visit 1 (Screening) or > 5.4 mmol/L (mEq/L) at Visit 199 (end of run-in) (according to local measurements).
9. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1.
10. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1.
11. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 months prior to Visit 1 or intent to implant such a device. Also, patients who had implantation of a conventional pacemaker or an ICD or had a revision of a pacemaker or other device leads within 1 month before Visit 1 are excluded.
12. History of severe pulmonary disease.

Data related to biomarkers and clinical assessment in the PARALLEL-HF study