Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI
Condition: Acute Myocardial Infarction
MeSH terms: Myocardial Infarction; Infarction
Intervention: LCZ696 (sacubitril/valsartan); Ramipril; Placebo of LCZ696; Placebo of ramipril; Valsartan; Placebo of valsartan
Intervention description: LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively; Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules; Matching placebo of LCZ696 tablets; Matching placebo of ramipril capsule; 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; matching placebo of valsartan for one day to patients who will be randomized to received ramipril
Intervention MeSH terms: Valsartan; Ramipril; 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: 5669.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Spontaneous AMI; HF hospitalization; outpatient HF; LV systolic dysfunction; pulmonary congestion; STEMI; NSTEMI; randomized clinical trial; LCZ696; ramipril

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.
    

Eligibility 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