Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI

Phase 3

Completed

Conditions: Acute Myocardial Infarction

Interventions: Drug: LCZ696 (sacubitril/valsartan)
Drug: Ramipril
Drug: Placebo of ramipril
Drug: Placebo of LCZ696
Drug: Placebo of valsartan
Drug: Valsartan

Registration Number: NCT02924727

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily.

Detailed Description: The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily, in addition to conventional post-AMI treatment, in reducing the occurrence of composite endpoint of CV death, HF hospitalization and outpatient HF (time-to-first event analysis) in post-AMI patients with evidence of LV systolic dysfunction and/or pulmonary congestion, with no known prior history of chronic HF.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5669

Inclusion Criteria

Male or female patients ≥ 18 years of age.
Diagnosis of spontaneous AMI based on the universal MI definition* with randomization to occur between 12 hours and 7 days after index event presentation. (*patients with spontaneous MI event determined to be secondary to another medical condition such as anemia, hypotension, or arrhythmia OR thought to be caused by coronary vasospasm with document normal coronary arteries are not eligible; patients with clinical presentation thought to be related to Takotsubo cardiomyopathy are also not eligible)
Evidence of LV systolic dysfunction and/or pulmonary congestion requiring intravenous treatment associated with the index MI event defined as:
- LVEF ≤40% after index MI presentation and prior to randomization and/or
- Pulmonary congestion requiring intravenous treatment with diuretics, vasodilators, vasopressors and/or inotropes, during the index hospitalization
At least one of the following 8 risk factors:
- Age ≥ 70 years
- eGFR <60 mL/min/1.73 m^2 based on MDRD formula at screening visit
- Type I or II diabetes mellitus
- Documented history of prior MI
- Atrial fibrillation as noted by ECG, associated with index MI
- LVEF <30% associated with index MI
- Worst Killip class III or IV associated with index MI requiring intravenous treatment
- STEMI without reperfusion therapy within the first 24 hours after presentation
Hemodynamically stable defined as:
- SBP ≥ 100 mmHg at randomization for patients who received ACEi/ARB during the last 24 hours prior to randomization
- SBP ≥ 110 mmHg at randomization for patients who did not receive ACEi/ARB during the last 24 hours prior to randomization
- No IV treatment with diuretics, vasodilators, vasopressors and/or inotropes during the 24 hours prior to randomization

Key

Exclusion Criteria

Known history of chronic HF prior to randomization
Cardiogenic shock within the last 24 hours prior to randomization
Persistent clinical HF at the time of randomization
Coronary artery bypass graft (CABG) performed or planned for index MI
Clinically significant right ventricular MI as index MI
Symptomatic hypotension at screening or randomization
Patients with a known history of angioedema
Stroke or transient ischemic attack within one month prior to randomization
Known or suspected bilateral renal artery stenosis
Clinically significant obstructive cardiomyopathy
Open-heart surgery performed within one month prior to randomization or planned cardiac surgery w/in the 3 months prior to randomization
eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening
Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at randomization
Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as esophageal varices
Previous use of LCZ696
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin) within the past 3 years with a life expectancy of less than 1year.
History of hypersensitivity to the study drugs or drugs of similar chemical classes or known intolerance or contraindications to study drugs or drugs of similar chemical classes including ACE inhibitors, ARB or NEP inhibitors
Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LCZ696 (sacubitril/valsartan)	Placebo of ramipril	Following randomization, patients will receive LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients will be required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will receive a valsartan bridge for one day. These patients will receive two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.
Ramipril	Placebo of valsartan	Following randomization, patients will receive the Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients will be required to take a total of two pills, (one capsule from the ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to ramipril who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will immediately start on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients will receive two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
Ramipril	Placebo of LCZ696	Following randomization, patients will receive the Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients will be required to take a total of two pills, (one capsule from the ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to ramipril who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will immediately start on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients will receive two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.
LCZ696 (sacubitril/valsartan)	LCZ696 (sacubitril/valsartan)	Following randomization, patients will receive LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients will be required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will receive a valsartan bridge for one day. These patients will receive two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.
LCZ696 (sacubitril/valsartan)	Valsartan	Following randomization, patients will receive LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients will be required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will receive a valsartan bridge for one day. These patients will receive two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment.
Ramipril	Ramipril	Following randomization, patients will receive the Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients will be required to take a total of two pills, (one capsule from the ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to ramipril who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will immediately start on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients will receive two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.

Primary Outcome Measures

Name	Time	Method
Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint	From randomization to first occurrence (up to approximately 43 months)	A confirmed composite endpoint includes cardiovascular (CV) death, heart failure (HF) hospitalization, or outpatient heart failure

Secondary Outcome Measures

Name	Time	Method
All-cause Mortality for Full Analysis Set (FAS)	Time from randomization to death (approximately up to 43 months)	All-cause mortality defined as deaths related to Cardiovascular (CV) and non-CV events for patients in the Full Analysis Set up to a cut-off date of 31-Dec-2020.
Total Number of Confirmed Composite Endpoints	Time from randomization to end of study (approximately up to 43 months)	A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, non-fatal spontaneous MI hospitalization, and non-fatal stroke hospitalization
Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization	Time from randomization to first occurrence (up to approximately 43 months)	A confirmed composite endpoint for this outcome measure includes cardiovascular death or heart failure hospitalization.
Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF	Time from randomization to first occurrence (approximately up to 43 months)	A confirmed composite endpoint includes first occurrence of heart failure hospitalization or outpatient heart failure
Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke	Time from randomization to first occurrence (approximately up to 43 months)	A confirmed composite endpoint for this outcome measure includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke