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

A Multi-center, Randomized, Double-blind, Active-controlled, Parallel-group Phase 3 Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Ramipril on Morbidity and Mortality in High Risk Patients Following an Acute Myocardial Infarction (AMI)

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.

Study Overview

• Status: Completed
• Conditions: Acute Myocardial Infarction
• Intervention / Treatment: Drug: LCZ696 (sacubitril/valsartan); Drug: Placebo of ramipril; Drug: Valsartan; Drug: Ramipril; Drug: Placebo of LCZ696; Drug: Placebo of valsartan

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.

• Study Type: Interventional
• Enrollment (Actual): 5669
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1602ABQ
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  • Buenos Aires, Argentina, B1846BMF
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  • Buenos Aires, Argentina, C1405CNF
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  • Buenos Aires, Argentina, C1428DCO
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  • Buenos Aires, Argentina, C1430EGF
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  • Cordoba, Argentina, X5003DCP
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  • Cordoba, Argentina, X5000
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  • Cordoba, Argentina, X5004BAL
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  • Cordoba, Argentina, X5006CBI
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  • Corrientes, Argentina, W3400
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  • Formosa, Argentina, P3600
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  • San Luis, Argentina, D5702JRS
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  • Santa Fe, Argentina, S3000FUJ
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  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1280AEB
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    • La Plata, Buenos Aires, Argentina, B1900AWT
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  • Caba
    • Buenos Aires, Caba, Argentina, C1078AAI
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  • Provincia De Salta
    • Ciudad de Salta, Provincia De Salta, Argentina, A4406BPF
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  • San Miguel De Tucuman
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    • Rosario, Santa Fe, Argentina, C2000DSR
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    • Rosario, Santa Fe, Argentina, S2000DSV
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    • Herston, Queensland, Australia, 4029
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    • Murdoch, Western Australia, Australia, 6150
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  • Graz, Austria, 8036
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  • Salzburg, Austria, 5020
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  • St Poelten, Austria, 3100
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  • Brasschaat, Belgium, 2930
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  • Antwerpen
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  • Jud Iasi
    • Iasi, Jud Iasi, Romania, 700732
      • Novartis Investigative Site
  • Mures
    • Targu Mures, Mures, Romania, 540124
      • Novartis Investigative Site
  • ROM
    • Braila, ROM, Romania, 810249
      • Novartis Investigative Site
    • Suceava, ROM, Romania, 727525
      • Novartis Investigative Site
  • Timis
    • Timisoara, Timis, Romania, 300362
      • Novartis Investigative Site
• Russian Federation
  • Barnaul, Russian Federation, 656038
    • Novartis Investigative Site
  • Kemerovo, Russian Federation, 650002
    • Novartis Investigative Site
  • Krasnodar, Russian Federation, 350086
    • Novartis Investigative Site
  • Moscow, Russian Federation, 121359
    • Novartis Investigative Site
  • Moscow, Russian Federation, 127644
    • Novartis Investigative Site
  • Moscow, Russian Federation, 115516
    • Novartis Investigative Site
  • Moscow, Russian Federation, 117292
    • Novartis Investigative Site
  • Moscow, Russian Federation, 121552
    • Novartis Investigative Site
  • Murmansk, Russian Federation, 183047
    • Novartis Investigative Site
  • N.Novgorod, Russian Federation, 603005
    • Novartis Investigative Site
  • Nizhnii Novgorod, Russian Federation, 603126
    • Novartis Investigative Site
  • Rostov on Don, Russian Federation, 344068
    • Novartis Investigative Site
  • S.-Petersburg, Russian Federation, 192242
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197341
    • Novartis Investigative Site
  • Saint-Petersburg, Russian Federation, 194044
    • Novartis Investigative Site
  • Saratov, Russian Federation, 410012
    • Novartis Investigative Site
  • Sestroretsk, Russian Federation, 197706
    • Novartis Investigative Site
  • Sochy, Russian Federation, 354057
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 191014
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 191015
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 194291
    • Novartis Investigative Site
  • Tomsk, Russian Federation, 634012
    • Novartis Investigative Site
  • Yekaterinburg, Russian Federation, 620109
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
  • Singapore, Singapore, 529889
    • Novartis Investigative Site
  • Singapore, Singapore, 308433
    • Novartis Investigative Site
  • Singapore, Singapore, 169609
    • Novartis Investigative Site
  • Singapore, Singapore, 768828
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 833 48
    • Novartis Investigative Site
  • Kosice, Slovakia, 040 11
    • Novartis Investigative Site
  • Presov, Slovakia, 081 81
    • Novartis Investigative Site
  • SVK
    • Banska Bystrica, SVK, Slovakia, 974 01
      • Novartis Investigative Site
  • Slovak Republic
    • Bratislava, Slovak Republic, Slovakia, 826 06
      • Novartis Investigative Site
    • Nitra, Slovak Republic, Slovakia, 949 01
      • Novartis Investigative Site
• South Africa
  • Cape Town, South Africa, 7925
    • Novartis Investigative Site
  • Worcester, South Africa, 6850
    • Novartis Investigative Site
  • Cape Town
    • Pinelands, Cape Town, South Africa, 7405
      • Novartis Investigative Site
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7500
      • Novartis Investigative Site
    • George, Western Cape, South Africa, 6529
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Valencia, Spain, 46026
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
    • Sevilla, Andalucia, Spain, 41014
      • Novartis Investigative Site
  • Cadiz
    • Villamartin, Cadiz, Spain, 11650
      • Novartis Investigative Site
  • Castilla Y Leon
    • Leon, Castilla Y Leon, Spain, 24071
      • Novartis Investigative Site
  • Catalunya
    • Badalona, Catalunya, Spain, 08916
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Extremadura
    • Caceres, Extremadura, Spain, 10003
      • Novartis Investigative Site
  • Galicia
    • A Coruna, Galicia, Spain, 15006
      • Novartis Investigative Site
    • La Coruna, Galicia, Spain, 15006
      • Novartis Investigative Site
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Novartis Investigative Site
• Sweden
  • Goethenburg, Sweden, 413 45
    • Novartis Investigative Site
  • Helsingborg, Sweden, 252 20
    • Novartis Investigative Site
  • Helsingborg, Sweden, 25232
    • Novartis Investigative Site
  • Malmo, Sweden, 221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, 118 83
    • Novartis Investigative Site
  • Uppsala, Sweden, 751 85
    • Novartis Investigative Site
  • Vasteras, Sweden, 72189
    • Novartis Investigative Site
  • SE
    • Stockholm, SE, Sweden, 141 86
      • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Novartis Investigative Site
  • Lugano, Switzerland, 6903
    • Novartis Investigative Site
  • Luzern 16, Switzerland, CH 6000
    • Novartis Investigative Site
  • St Gallen, Switzerland, 9007
    • Novartis Investigative Site
• Taiwan
  • New Taipei, Taiwan, 22060
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Tainan, Taiwan, 71004
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
  • Yilan, Taiwan, 26058
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site
  • THA
    • Bangkok, THA, Thailand, 10330
      • Novartis Investigative Site
    • Khon Kaen, THA, Thailand, 40002
      • Novartis Investigative Site
• Turkey
  • Ankara-Cankaya, Turkey, 06100
    • Novartis Investigative Site
  • Istanbul, Turkey, 34304
    • Novartis Investigative Site
  • Istanbul, Turkey, 34865
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
  • Kucukcekmece Istanbul, Turkey, 34303
    • Novartis Investigative Site
  • Mersin, Turkey, 33343
    • Novartis Investigative Site
  • Sivas, Turkey, 58140
    • Novartis Investigative Site
  • Trabzon, Turkey, 61080
    • Novartis Investigative Site
  • Eskisehir
    • Meselik, Eskisehir, Turkey, 26480
      • Novartis Investigative Site
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Novartis Investigative Site
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • Bournemouth, United Kingdom, BH7 7DW
    • Novartis Investigative Site
  • Glasgow, United Kingdom, G51 4TF
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS1 3EX
    • Novartis Investigative Site
  • Leicester, United Kingdom, LE3 9QP
    • Novartis Investigative Site
  • Middlesbrough, United Kingdom, TS4 3BW
    • Novartis Investigative Site
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Novartis Investigative Site
  • Norwich, United Kingdom, NR4 7UY
    • Novartis Investigative Site
  • Worcester, United Kingdom, WR5 1DD
    • Novartis Investigative Site
  • Hampshire
    • Basingstoke, Hampshire, United Kingdom, RG24 9NA
      • Novartis Investigative Site
  • Lincolnshire
    • Lincoln, Lincolnshire, United Kingdom, LN2 5QY
      • Novartis Investigative Site
  • Northern Ireland
    • Craigavon, Northern Ireland, United Kingdom, BT63 5QQ
      • Novartis Investigative Site
  • West Dumbartonshire
    • Clydebank, West Dumbartonshire, United Kingdom, G81 4HX
      • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35243
      • Novartis Investigative Site
    • Birmingham, Alabama, United States, 35294-2041
      • Novartis Investigative Site
    • Huntsville, Alabama, United States, 35801
      • Novartis Investigative Site
  • Arizona
    • Gilbert, Arizona, United States, 85297
      • Novartis Investigative Site
  • California
    • Bakersfield, California, United States, 93301
      • Novartis Investigative Site
    • Carmichael, California, United States, 95608
      • Novartis Investigative Site
    • Los Alamitos, California, United States, 90720
      • Novartis Investigative Site
    • Northridge, California, United States, 91325
      • Novartis Investigative Site
    • Orange, California, United States, 92868
      • Novartis Investigative Site
    • San Francisco, California, United States, 94143
      • Novartis Investigative Site
    • Sylmar, California, United States, 91342
      • Novartis Investigative Site
  • Florida
    • Brandon, Florida, United States, 33511
      • Novartis Investigative Site
    • Hollywood, Florida, United States, 33312
      • Novartis Investigative Site
    • Jacksonville Beach, Florida, United States, 32050
      • Novartis Investigative Site
    • Ocala, Florida, United States, 34480
      • Novartis Investigative Site
  • Georgia
    • Cumming, Georgia, United States, 30041
      • Novartis Investigative Site
    • Johns Creek, Georgia, United States, 30024
      • Novartis Investigative Site
    • Thomasville, Georgia, United States, 31792
      • Novartis Investigative Site
  • Idaho
    • Boise, Idaho, United States, 83702
      • Novartis Investigative Site
    • Coeur d'Alene, Idaho, United States, 83814
      • Novartis Investigative Site
  • Indiana
    • Muncie, Indiana, United States, 47303-3400
      • Novartis Investigative Site
    • Munster, Indiana, United States, 46321
      • Novartis Investigative Site
    • Richmond, Indiana, United States, 47374
      • Novartis Investigative Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Novartis Investigative Site
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Novartis Investigative Site
    • Baton Rouge, Louisiana, United States, 70808
      • Novartis Investigative Site
    • Covington, Louisiana, United States, 70433
      • Novartis Investigative Site
    • Hammond, Louisiana, United States, 70403
      • Novartis Investigative Site
    • Slidell, Louisiana, United States, 70458
      • Novartis Investigative Site
  • Maine
    • Bangor, Maine, United States, 04401
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Novartis Investigative Site
    • Baltimore, Maryland, United States, 21218
      • Novartis Investigative Site
    • Rockville, Maryland, United States, 20850
      • Novartis Investigative Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Novartis Investigative Site
    • Kalamazoo, Michigan, United States, 49008
      • Novartis Investigative Site
    • Lansing, Michigan, United States, 48912
      • Novartis Investigative Site
    • Petoskey, Michigan, United States, 49770
      • Novartis Investigative Site
    • Saginaw, Michigan, United States, 48601
      • Novartis Investigative Site
    • Southfield, Michigan, United States, 48075
      • Novartis Investigative Site
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Novartis Investigative Site
    • Robbinsdale, Minnesota, United States, 55422
      • Novartis Investigative Site
    • Saint Cloud, Minnesota, United States, 56303
      • Novartis Investigative Site
    • Saint Paul, Minnesota, United States, 55101
      • Novartis Investigative Site
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Novartis Investigative Site
    • Jackson, Mississippi, United States, 39216
      • Novartis Investigative Site
  • Missouri
    • Lee's Summit, Missouri, United States, 64064
      • Novartis Investigative Site
    • North Kansas City, Missouri, United States, 64116
      • Novartis Investigative Site
    • Springfield, Missouri, United States, 65804
      • Novartis Investigative Site
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Novartis Investigative Site
    • Lincoln, Nebraska, United States, 68526
      • Novartis Investigative Site
    • Omaha, Nebraska, United States, 68114
      • Novartis Investigative Site
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Novartis Investigative Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Novartis Investigative Site
  • New York
    • Flushing, New York, United States, 11355
      • Novartis Investigative Site
    • New York, New York, United States, 10016
      • Novartis Investigative Site
    • New York, New York, United States, 10029
      • Novartis Investigative Site
    • Valhalla, New York, United States, 10595
      • Novartis Investigative Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Novartis Investigative Site
    • Charlotte, North Carolina, United States, 28204
      • Novartis Investigative Site
    • Durham, North Carolina, United States, 27710
      • Novartis Investigative Site
  • North Dakota
    • Grand Forks, North Dakota, United States, 58201
      • Novartis Investigative Site
  • Ohio
    • Canton, Ohio, United States, 44710
      • Novartis Investigative Site
    • Cincinnati, Ohio, United States, 45220
      • Novartis Investigative Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Novartis Investigative Site
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16550
      • Novartis Investigative Site
    • Hershey, Pennsylvania, United States, 17033
      • Novartis Investigative Site
    • York, Pennsylvania, United States, 17403
      • Novartis Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29403
      • Novartis Investigative Site
    • Columbia, South Carolina, United States, 29203
      • Novartis Investigative Site
    • Greenville, South Carolina, United States, 29607
      • Novartis Investigative Site
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Novartis Investigative Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37917
      • Novartis Investigative Site
    • Nashville, Tennessee, United States, 37212
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75226
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • Webster, Texas, United States, 77598
      • Novartis Investigative Site
  • Virginia
    • Danville, Virginia, United States, 24541
      • Novartis Investigative Site
    • Falls Church, Virginia, United States, 22042
      • Novartis Investigative Site
    • Lynchburg, Virginia, United States, 24501
      • Novartis Investigative Site
    • Manassas, Virginia, United States, 20109
      • Novartis Investigative Site
  • Washington
    • Bellevue, Washington, United States, 98004
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: LCZ696 (sacubitril/valsartan); LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively; Drug: Placebo of ramipril; Matching placebo of ramipril capsule; Drug: Valsartan; Valsartan (VAL489) 40 mg and 80 mg tablets, two doses for 1 day to patients who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization
Active Comparator: 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.	Drug: Ramipril; Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules; Drug: Placebo of LCZ696; Matching placebo of LCZ696 tablets; Drug: Placebo of valsartan; matching placebo of valsartan for one day to patients who will be randomized to received ramipril

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization	A confirmed composite endpoint for this outcome measure includes cardiovascular death or heart failure hospitalization.	Time from randomization to first occurrence (up to approximately 43 months)
Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF	A confirmed composite endpoint includes first occurrence of heart failure hospitalization or outpatient heart failure	Time from randomization to first occurrence (approximately up to 43 months)
Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke	A confirmed composite endpoint for this outcome measure includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke	Time from randomization to first occurrence (approximately up to 43 months)
Total Number of Confirmed Composite Endpoints	A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, non-fatal spontaneous MI hospitalization, and non-fatal stroke hospitalization	Time from randomization to end of study (approximately up to 43 months)
All-cause Mortality for Full Analysis Set (FAS)	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.	Time from randomization to death (approximately up to 43 months)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Shah AM, Claggett B, Prasad N, Li G, Volquez M, Jering K, Cikes M, Kovacs A, Mullens W, Nicolau JC, Kober L, van der Meer P, Jhund PS, Ibram G, Lefkowitz M, Zhou Y, Solomon SD, Pfeffer MA. Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy. Circulation. 2022 Oct 4;146(14):1067-1081. doi: 10.1161/CIRCULATIONAHA.122.059210. Epub 2022 Sep 9.
• Mehran R, Steg PG, Pfeffer MA, Jering K, Claggett B, Lewis EF, Granger C, Kober L, Maggioni A, Mann DL, McMurray JJV, Rouleau JL, Solomon SD, Ducrocq G, Berwanger O, De Pasquale CG, Landmesser U, Petrie M, Leng DSK, van der Meer P, Lefkowitz M, Zhou Y, Braunwald E. The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial. Circulation. 2022 Dec 6;146(23):1749-1757. doi: 10.1161/CIRCULATIONAHA.122.060841. Epub 2022 Nov 2.
• Pfeffer MA, Claggett B, Lewis EF, Granger CB, Kober L, Maggioni AP, Mann DL, McMurray JJV, Rouleau JL, Solomon SD, Steg PG, Berwanger O, Cikes M, De Pasquale CG, Fernandez A, Filippatos G, Jering K, Landmesser U, Menon V, Merkely B, Petrie MC, Petrov I, Schou M, Senni M, Sim D, van der Meer P, Lefkowitz M, Zhou Y, Wang Y, Braunwald E. Impact of Sacubitril/Valsartan Versus Ramipril on Total Heart Failure Events in the PARADISE-MI Trial. Circulation. 2022 Jan 4;145(1):87-89. doi: 10.1161/CIRCULATIONAHA.121.057429. Epub 2021 Nov 19. No abstract available.
• Pfeffer MA, Claggett B, Lewis EF, Granger CB, Kober L, Maggioni AP, Mann DL, McMurray JJV, Rouleau JL, Solomon SD, Steg PG, Berwanger O, Cikes M, De Pasquale CG, East C, Fernandez A, Jering K, Landmesser U, Mehran R, Merkely B, Vaghaiwalla Mody F, Petrie MC, Petrov I, Schou M, Senni M, Sim D, van der Meer P, Lefkowitz M, Zhou Y, Gong J, Braunwald E; PARADISE-MI Investigators and Committees. Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction. N Engl J Med. 2021 Nov 11;385(20):1845-1855. doi: 10.1056/NEJMoa2104508. Erratum In: N Engl J Med. 2021 Dec 30;385(27):2592.

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2016
• Primary Completion (Actual): February 26, 2021
• Study Completion (Actual): February 26, 2021

Study Registration Dates

• First Submitted: October 4, 2016
• First Submitted That Met QC Criteria: October 4, 2016
• First Posted (Estimated): October 5, 2016

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 16, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: STEMI; NSTEMI; randomized clinical trial; LCZ696; Spontaneous AMI; HF hospitalization; outpatient HF; LV systolic dysfunction; pulmonary congestion; ramipril
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Valsartan; Sacubitril and valsartan sodium hydrate drug combination; Ramipril
• Other Study ID Numbers: CLCZ696G2301; 2016-002154-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No