Study of Efficacy and Safety of LCZ696 in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction
Condition: Heart Failure With Reduced Ejection Fraction (HF-rEF)
MeSH terms: Heart Failure
Intervention: LCZ696; Enalapril; Placebo to LCZ696; Placebo to Enalapril
Intervention description: The target dose during the study was LCZ696 200 mg bid given orally. LCZ696 was supplied as 50 mg, 100 mg and 200 mg film-coated tablets.; The target dose during the study was enalapril 10 mg bid given orally. Enalapril was provided as 2.5 mg, 5 mg, and 10 mg tablets.; LCZ696 Placebo 50 mg, 100 mg and 200 mg film-coated tablets; Enalapril Placebo 2.5 mg, 5 mg and 10 mg tablets
Intervention MeSH terms: Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 225.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: chronic heart failure; cardiovascular death; hospitalization; outcome study; worsening heart failure; NT-proBNP; NYHA; KCCQ; HF-rEF

Summary:

      The purpose of this study was to assess the effect of LCZ696 at a target dose of 200 mg
      b.i.d. compared to enalapril 10 mg b.i.d., in addition to the background heart failure (HF)
      treatment, on delaying time to first occurrence of either cardiovascular (CV) death or HF
      hospitalization events in Japanese patients with stable chronic heart failure (CHF), New York
      Heart Association (NYHA) classes II-IV and reduced ejection fraction (left ventricular
      ejection fraction (LVEF) ≤ 35%).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent must be obtained before any assessment is performed.

          -  Outpatients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction:

          -  LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using
             echocardiography, MUGA, CT scanning, MRI or ventricular angiography is also
             acceptable, provided no subsequent measurement above 35%)

          -  NT-proBNP ≥ 600 pg/ml at Visit 1 OR NT-proBNP ≥ 400 pg/ml at Visit 1 and a
             hospitalization for HF within the last 12 months (according to central laboratory
             measurements)

          -  Patients must be on an ACEI or an ARB at a stable dose for at least 4 weeks before
             Visit 1.

          -  Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at
             a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented if
             patients reported contraindications or intolerance).

          -  An aldosterone antagonist should also be considered in all patients, taking account of
             renal function, serum potassium and tolerability. If given, the dose of aldosterone
             antagonist should 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 should also be considered e.g. cardiac resynchronization
             therapy and an implantable cardioverter-defibrillator in selected patients, as
             recommended by guidelines.

        Exclusion Criteria:

          -  History of hypersensitivity to any of the study drugs or to drugs of similar chemical
             classes, ACEIs, ARBs, NEP inhibitors as well as known or suspected contraindications
             to the study drugs.

          -  Previous documented history of intolerance to ACEIs or ARBs.

          -  Known history of angioedema.

          -  Requirement of treatment with both ACEIs and ARBs.

          -  Current acute decompensated HF (exacerbation of chronic HF manifested by signs and
             symptoms that may require intravenous therapy).

          -  Symptomatic hypotension and/or a SBP < 100 mmHg at screening or < 95 mmHg at the end
             of run-in.

          -  Estimated GFR < 30 mL/min/1.73 m2 as measured by the Japanese formula at screening, or
             the end of run-in or > 35% decline in eGFR between screening and end of run-in
             (according to local measurements).

          -  Serum potassium > 5.2 mmol/L (mEq/L) at screening or > 5.4 mmol/L (mEq/L) at the end
             of run-in (according to local measurements).

          -  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.

          -  Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months
             prior to Visit 1.

          -  Symptomatic bradycardia or second (except asymptomatic Wenckebach block) or third
             degree heart block without a pacemaker.

          -  Presence of hemodynamically significant mitral and/or aortic valve disease, except
             mitral regurgitation secondary to left ventricular dilatation.

          -  Presence of other hemodynamically significant obstructive lesions of left ventricular
             outflow tract, including aortic and sub-aortic stenosis.

          -  Presence of bilateral renal artery stenosis.