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

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 such as forced expiratory volume during the 1st second (FEV1)\< 1 liter or need for chronic systemic or nonsystemic steroid therapy, or any kind of primary right heart failure such as primary pulmonary hypertension or recurrent pulmonary embolism.
• •6. Myocardial infarction, unstable angina or cardiac surgery within 3 months, or cardiac resynchronization therapy (CRT) device implantation within 3 months, or percutaneous transluminal coronary intervention (PTCI), within 1 month prior to Screening.
• •7. Index Event (admission for AHF) triggered primarily by a correctable etiology such as significant arrhythmia (e.g., sustained ventricular tachycardia, or atrial fibrillation/flutter with sustained ventricular response \>130 beats per minute, or bradycardia with sustained ventricular arrhythmia \<45 beats per minute), infection, severe anemia, acute coronary syndrome, pulmonary embolism, exacerbation of chronic obstructive pulmonary disease (COPD), planned admission for device implantation or severe non-adherence leading to very significant fluid accumulation prior to admission and brisk diuresis after admission. Troponin elevations without other evidence of an acute coronary syndrome are not an exclusion.
• •8. Uncorrected thyroid disease, active myocarditis, or known amyloid or hypertrophic obstructive cardiomyopathy.
• •9. History of heart transplant or on a transplant list, or using or planned to be implanted with a ventricular assist device.
• •10. Sustained ventricular arrhythmia with syncopal episodes within the 3 months prior to screening that is untreated.
• •11. Presence at Screening of any hemodynamically significant valvular stenosis or regurgitation, except mitral or tricuspid regurgitation secondary to left ventricular dilatation, or the presence of any hemodynamically significant obstructive lesion of the left ventricular outflow tract.
• •12. Active infection at any time during the AHF hospitalization prior to Randomization based on abnormal temperature and elevated white blood cells (WBC) or need for intravenous 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 \[as estimated by the simplified Modification of Diet in Renal Disease (MDRD) formula\] at Screening or history of dialysis.
• •16. Psychiatric or neurological disorder, cirrhosis, or active malignancy leading to a life expectancy \< 6 months.
• •17. Prior (defined as less than 30 days from screening) or current enrollment in a congestive heart failure (CHF) trial or participation in an investigational drug or device study within the 30 days prior to screening
• •18. Discharge for the AHF hospitalization anticipated to be \> 14 days from admission, or to a long-term care facility. Randomization must occur within 12 days following admission and within 2 days prior to anticipated discharge.
• •19. Inability to comply with all study requirements, due to major co-morbidities, social or financial issues, or a history of noncompliance with medical regimens, that might compromise the patient's ability to understand and/or comply with the protocol instructions or follow-up procedures
• •20. Pregnant or nursing (lactating) women.