Replication of the PARADIGM-HF Heart Failure Trial in Healthcare Claims Data.

Inclusion Criteria:

• Age 18 years or older
• NYHA functional class II-IV
• LVEF ≤ 35%

AND the following:

• Hospitalization for heart failure within the last 12 months

  • Treatment with a stable dose of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/day for at least 4 weeks before the screening visit; and treatment with a stable dose of a beta-blocker for at least 4 weeks prior to the screening visit, unless contraindicted or not tolerated
• Treatment with a stable dose of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/day for at least 4 weeks before the screening visit

AND the following:

• Treatment with a stable dose of a beta-blocker for at least 4 weeks prior to the screening visit, unless contraindicated or not tolerated

Exclusion Criteria:

• Known history of angioedema
• Requirement for treatment with both ACEIs and ARBs
• Current acute decompensated heart failure (exacerbation of chronic heart failure manifested by signs and symptoms that may require intravenous therapy)
• Symptomatic hypotension and/or a systolic blood pressure \<100 mmHg at Visit 1 (screening) or \<95 mmHg at Visit 3 or at Visit 5 (randomization)
• Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m2 at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or >35% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5
• Serum potassium >5.2 mmol/L at Visit 1 (screening) or >5.4 mmol/L at Visit 3 or Visit 5 (randomization)
• Acute coronary syndrome, stroke, transient ischaemic attack, cardiac, carotid, or other major cardiovascular surgery, PCI, or carotid angioplasty within the 3 months prior to Visit 1.
• Implantation of a cardiac resynchronization therapy (CRT) device within 3 months prior Visit 1 or intent to implant a CRT
• History of heart transplant or on a transplant list or with LV assistance device
• History of severe pulmonary disease
• Diagnosis of peripartum- or chemotherapy-induced cardiomyopathy within the 12 months prior to Visit 1
• Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1
• Documented ventricular arrhythmia within the 3 months prior to Visit 1

AND the following:

• Syncopal episodes within the 3 months prior to Visit 1

AND the following:

• Untreated ventricular arrhythmia within the 3 months prior to visit 1

OR the following:

• Untreated ventricular arrhythmia within the 3 months prior to visit 1
• Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
• Presence of haemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation
• Presence of other haemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including, but not limited to, any of the following:
• History of active inflammatory bowel disease during the 12 months before Visit 1

OR the following:

• Active duodenal or gastric ulcers during the 3 months prior to Visit 1

OR the following:

• Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine aminotransferase values exceeding 2× upper limit of normal at Visit 1, history of hepatic encephalopathy, history of oesophageal varices, or history of porto-caval shunt

OR the following:

• Current treatment with cholestyramine or colestipol resins
• Presence of any other disease with a life expectancy of 5 years
• Any Ivabradine use -- Approved in April 2015 (same year as Entresto)