Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies

Inclusion Criteria:

1. Hospital admission within the 72 hours prior to Screening for acute heart failure withdyspnea at rest and pulmonary congestion on chest X-ray, and other signs and/orsymptoms of heart failure such as edema and/or positive rales on auscultation.
2. All measures within 24 hours prior to Randomization of systolic blood pressure ≥ 100mmHg, and of heart rate ≥ 60 bpm.
3. All measures within 24 hours prior to Randomization of serum potassium ≤ 5.0 mEq/L (mmol/L).
4. Biomarker criteria for persistent congestion:
5. At Screening, NT-proBNP > 2,500 pg/mL.
6. At the time of Randomization (within 2 days prior to discharge), NT-proBNP > 1,500pg/mL (to ensure the persistence of congestion) that has decreased by more than 10%compared to Screening (to ensure the acuity of the index episode).
7. At 1 week prior to admission, at Screening, and at Visit 2 (just prior toRandomization) either (a) <= ½ the optimal dose of ACEi/ARB/ARNi (see Table)prescribed, no beta-blocker prescribed, and <= ½ the optimal dose of MRA prescribed or (b) no ACEi/ARB/ARNi prescribed, <= ½ the optimal dose of beta-blocker prescribed, and <= ½ the optimal dose of MRA prescribed.
8. Written informed consent to participate in the study.

Exclusion Criteria:

1. Age < 18 or > 85 years.
2. Clearly documented intolerance to high doses of beta-blockers.
3. Clearly documented intolerance to high doses of renin-angiotensin system (RAS)blockers (both ACEi and ARB).
4. Mechanical ventilation [not including continuous positive airway pressure (CPAP)/bilevel positive airway pressure (BIPAP)] in the 24 hours prior to Screening.
5. Significant pulmonary disease contributing substantially to the patients' dyspnea suchas forced expiratory volume during the 1st second (FEV1)< 1 liter or need for chronicsystemic or nonsystemic steroid therapy, or any kind of primary right heart failuresuch as primary pulmonary hypertension or recurrent pulmonary embolism.
6. Myocardial infarction, unstable angina or cardiac surgery within 3 months, or cardiacresynchronization therapy (CRT) device implantation within 3 months, or percutaneoustransluminal coronary intervention (PTCI), within 1 month prior to Screening.
7. Index Event (admission for AHF) triggered primarily by a correctable etiology such assignificant arrhythmia (e.g., sustained ventricular tachycardia, or atrialfibrillation/flutter with sustained ventricular response >130 beats per minute, orbradycardia with sustained ventricular arrhythmia <45 beats per minute), infection,severe anemia, acute coronary syndrome, pulmonary embolism, exacerbation of chronicobstructive pulmonary disease (COPD), planned admission for device implantation orsevere non-adherence leading to very significant fluid accumulation prior to admissionand brisk diuresis after admission. Troponin elevations without other evidence of anacute coronary syndrome are not an exclusion.
8. Uncorrected thyroid disease, active myocarditis, or known amyloid or hypertrophicobstructive cardiomyopathy.
9. History of heart transplant or on a transplant list, or using or planned to beimplanted with a ventricular assist device.
10. Sustained ventricular arrhythmia with syncopal episodes within the 3 months prior toscreening that is untreated.
11. Presence at Screening of any hemodynamically significant valvular stenosis orregurgitation, except mitral or tricuspid regurgitation secondary to left ventriculardilatation, or the presence of any hemodynamically significant obstructive lesion ofthe left ventricular outflow tract.
12. Active infection at any time during the AHF hospitalization prior to Randomizationbased on abnormal temperature and elevated white blood cells (WBC) or need forintravenous antibiotics.
13. Stroke or transient ischemic attack (TIA) within the 3 months prior to Screening.
14. Primary liver disease considered to be life threatening.
15. Renal disease or estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 [asestimated by the simplified Modification of Diet in Renal Disease (MDRD) formula] atScreening or history of dialysis.
16. Psychiatric or neurological disorder, cirrhosis, or active malignancy leading to alife expectancy < 6 months.
17. Prior (defined as less than 30 days from screening) or current enrollment in acongestive heart failure (CHF) trial or participation in an investigational drug ordevice study within the 30 days prior to screening
18. Discharge for the AHF hospitalization anticipated to be > 14 days from admission, orto a long-term care facility. Randomization must occur within 12 days followingadmission and within 2 days prior to anticipated discharge.
19. Inability to comply with all study requirements, due to major co-morbidities, socialor financial issues, or a history of noncompliance with medical regimens, that mightcompromise the patient's ability to understand and/or comply with the protocolinstructions or follow-up procedures
20. Pregnant or nursing (lactating) women.