Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode. (PIONEER-HF)

Novartis

Status and phase: Completed; Phase 4

Conditions: Acute Heart Failure

Treatments: Drug: enalapril matching placebo; Drug: Enalapril; Drug: sacubitril/valsartan (LCZ696); Drug: sacubitril/valsartan (LCZ696) matching placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02554890

CLCZ696BUS01

Details and patient eligibility

About

The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).

Enrollment: 887 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.

2. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.

3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:

   • SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
   • No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
   • No i.v. inotropic drugs for 24 hours prior to randomization
   • No i.v. vasodilators including nitrates within last 6 hours prior to randomization

4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of >40%.

5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.

Key Exclusion Criteria:

1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
2. Enrollment in any other clinical trial involving an investigational agent or investigational device.
3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
5. Requirement of treatment with both ACE inhibitor and ARB.
6. eGFR < 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
7. Serum potassium > 5.2 mEq/L at screening.
8. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices
9. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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887 participants in 2 patient groups

sacubitril/valsartan (LCZ696)

Experimental group

Description:

Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack).

Treatment:

Drug: sacubitril/valsartan (LCZ696)

Drug: enalapril matching placebo

Enalapril

Active Comparator group

Description:

Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)

Treatment:

Drug: sacubitril/valsartan (LCZ696) matching placebo

Drug: Enalapril