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

Novartis

Status and phase: Completed; Phase 3

Conditions: Acute Myocardial Infarction

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT02924727

CLCZ696G2301

2016-002154-20 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 5,669 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age.

2. 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)

3. 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

4. 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

5. 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:

1. Known history of chronic HF prior to randomization
2. Cardiogenic shock within the last 24 hours prior to randomization
3. Persistent clinical HF at the time of randomization
4. Coronary artery bypass graft (CABG) performed or planned for index MI
5. Clinically significant right ventricular MI as index MI
6. Symptomatic hypotension at screening or randomization
7. Patients with a known history of angioedema
8. Stroke or transient ischemic attack within one month prior to randomization
9. Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy
11. Open-heart surgery performed within one month prior to randomization or planned cardiac surgery w/in the 3 months prior to randomization
12. eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening
13. Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at randomization
14. 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
15. Previous use of LCZ696
16. 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.
17. 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
18. Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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5,669 participants in 2 patient groups

LCZ696 (sacubitril/valsartan)

Experimental group

Description:

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.

Treatment:

Drug: Placebo of ramipril

Drug: Valsartan

Drug: LCZ696 (sacubitril/valsartan)

Ramipril

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo of LCZ696

Drug: Placebo of valsartan

Drug: Ramipril