Acute Myocardial Infarction
Conditions
Keywords
Spontaneous AMI, HF hospitalization, outpatient HF, LV systolic dysfunction, pulmonary congestion, STEMI, NSTEMI, randomized clinical trial, LCZ696, ramipril
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.
Interventions
LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively
DRUGRamipril
Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules
Matching placebo of LCZ696 tablets
DRUGPlacebo of ramipril
Matching placebo of ramipril capsule
DRUGValsartan
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
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, India, Israel, Italy, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
A total of 5669 patients were randomized in a 1:1 ratio to the sacubitril/valsartan treatment group and the ramipril treatment group at 493 sites in 41 countries. A total of 8 patients were mis-randomized, 4 from each treatment group. One of the mis-randomized patients of the ramipril group died. The Full analysis set (FAS) was comprised of 5661 patients.
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 (Sacubitril/Valsartan) Following randomization, patients received LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily).
Patients were 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, received a valsartan bridge for one day. These patients received two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment. | 2,830 |
| Ramipril Following randomization, patients received Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily).
Patients were 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 immediately started on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients received two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo. | 2,831 |
| Total | 5,661 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 221 | 247 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Mis-randomized (one mis-randomized patient in the Ramipril group also died) | 4 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Ramipril | LCZ696 (Sacubitril/Valsartan) | Total |
|---|---|---|---|
| Age, Customized <65 years | 1451 Participants | 1386 Participants | 2837 Participants |
| Age, Customized ≥65 years | 1380 Participants | 1444 Participants | 2824 Participants |
| Age, Customized <75 years | 2324 Participants | 2286 Participants | 4610 Participants |
| Age, Customized ≥75 years | 507 Participants | 544 Participants | 1051 Participants |
| Race/Ethnicity, Customized Asian | 478 Participants | 475 Participants | 953 Participants |
| Race/Ethnicity, Customized Black | 40 Participants | 35 Participants | 75 Participants |
| Race/Ethnicity, Customized Caucasian | 2138 Participants | 2125 Participants | 4263 Participants |
| Race/Ethnicity, Customized Native American | 45 Participants | 45 Participants | 90 Participants |
| Race/Ethnicity, Customized Other | 105 Participants | 128 Participants | 233 Participants |
| Race/Ethnicity, Customized Pacific Islander | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown | 21 Participants | 22 Participants | 43 Participants |
| Sex: Female, Male Female | 700 Participants | 663 Participants | 1363 Participants |
| Sex: Female, Male Male | 2131 Participants | 2167 Participants | 4298 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2,834 | 3 / 2,835 | 220 / 2,820 | 244 / 2,816 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 1,769 / 2,820 | 1,770 / 2,816 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 1,146 / 2,820 | 1,126 / 2,816 |
Outcome results
Primary
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
Time frame: From randomization to first occurrence (up to approximately 43 months)
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | Primary Composite | 338 Count of Participants |
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | First Heart Failure (HF) Hospitalization | 170 Count of Participants |
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | Cardiovascular (CV) Death | 168 Count of Participants |
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | First Outpatient Heart Failure (HF) | 39 Count of Participants |
| Ramipril | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | Cardiovascular (CV) Death | 191 Count of Participants |
| Ramipril | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | Primary Composite | 373 Count of Participants |
| Ramipril | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | First Outpatient Heart Failure (HF) | 57 Count of Participants |
| Ramipril | Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | First Heart Failure (HF) Hospitalization | 195 Count of Participants |
Comparison: First HF Hospitalizationp-value: 0.167995% CI: [0.7044, 1.0629]Cox's Proportional Hazard Model
Comparison: First Outpatient HFp-value: 0.066795% CI: [0.4546, 1.0266]Cox's Proportional Hazard Model
Comparison: Primary Compositep-value: 0.165995% CI: [0.7778, 1.0441]Cox's Proportional Hazard Model
Comparison: CV Deathp-value: 0.203195% CI: [0.7104, 1.0754]Cox's Proportional Hazard Model
Secondary
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 frame: Time from randomization to death (approximately up to 43 months)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | All-cause Mortality for Full Analysis Set (FAS) | 213 Participants |
| Ramipril | All-cause Mortality for Full Analysis Set (FAS) | 242 Participants |
Comparison: All-Cause Deathp-value: 0.155695% CI: [0.7279, 1.052]Cox's Proportional Hazard Model
Secondary
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 frame: Time from randomization to first occurrence (approximately up to 43 months)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke | 315 Participants |
| Ramipril | Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke | 349 Participants |
Comparison: CV death, Non-fatal spontaneous MI or Non-fatal strokep-value: 0.178595% CI: [0.7734, 1.0489]Cox's Proportional Hazard Model
Secondary
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 frame: Time from randomization to first occurrence (up to approximately 43 months)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization | 308 Participants |
| Ramipril | Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization | 335 Participants |
Comparison: CV death or HF hospitalizationp-value: 0.250795% CI: [0.7824, 1.0662]Cox's Proportional Hazard Model
Secondary
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 frame: Time from randomization to first occurrence (approximately up to 43 months)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF | 201 Participants |
| Ramipril | Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF | 237 Participants |
Comparison: HF hospitalization or Outpatient HFp-value: 0.073295% CI: [0.6979, 1.0163]Cox's Proportional Hazard Model
Secondary
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 frame: Time from randomization to end of study (approximately up to 43 months)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | Total Number of Confirmed Composite Endpoints | 416 Events |
| Ramipril | Total Number of Confirmed Composite Endpoints | 455 Events |
Comparison: Total Number of Confirmed Composite Endpointsp-value: 0.045295% CI: [0.7018, 0.9961]Negative Binomial regression model
Post Hoc
All Collected Deaths
Pre-treatment deaths were collected from randomization to the day before first dose of study medication, for a maximum duration of 5 days. On-treatment and post-treatment safety follow-up deaths were collected from first dose of study medication to 30 days after the last dose of study medication. All deaths refer to the sum of pre-treatment, on-treatment and post-treatment safety follow-up deaths.
Time frame: Pre-treatment: Up to 5 days before Day 1. On-treatment and post-treatment safety follow up: up to 4 years
Population: All subjects to whom study treatment was assigned by randomization, regardless of whether or not treatment was administered
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 (Sacubitril/Valsartan) | All Collected Deaths | pre-treatment deaths | 1 Participants |
| LCZ696 (Sacubitril/Valsartan) | All Collected Deaths | On-treatment deaths and extended safety follow-up | 220 Participants |
| LCZ696 (Sacubitril/Valsartan) | All Collected Deaths | All deaths | 221 Participants |
| Ramipril | All Collected Deaths | pre-treatment deaths | 3 Participants |
| Ramipril | All Collected Deaths | On-treatment deaths and extended safety follow-up | 244 Participants |
| Ramipril | All Collected Deaths | All deaths | 247 Participants |