Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
chronic heart failure, cardiovascular death, hospitalization, outcome study, BNP, KCCQ, eGFR
Brief summary
The study will evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure (NYHA Class II - IV and EF =\< 35%).
Interventions
DRUGLCZ696 200 mg BID
LCZ696 200 mg BID
Enalapril 10 mg BID
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must give written informed consent before any assessment is performed. * Outpatients ≥ 18 years of age, male or female. * Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction (EF =\< 35%) and elevated BNP. * Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks. * Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks.
Exclusion criteria
* Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. * History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs. * Previous history of intolerance to recommended target doses of ACEIs or ARBs * Known history of angioedema. * Requirement of treatment with both ACEIs and ARBs. * Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy). * Symptomatic hypotension and/or a SBP \< 100 mmHg. * Estimated GFR \< 30 mL/min/1.73m2 as measured by the simplified MDRD formula * Serum potassium \> 5.2 mmol/L. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | up to 51 months | Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients - All-cause Mortality | up to 51 months | Number of patients - All-cause mortality. All-cause mortality is common in Heart Failure HF patients this measures how many patients had this event. The data is on FAS population up to March 31, 2014 |
| Number of Patients Reported With Adjudicated Primary Causes of Death | up to 51 months | Number of patients reported with adjudicated primary causes of death. The data is on Randomization population up to March 31, 2014 |
| Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | Baseline, Month 8 | Change from baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. |
| Number of Patients With First Confirmed Renal Dysfunction | up to 51 months | Number of patients with first confirmed renal dysfunction |
| Percentage of Participants With New Onset of Atrial Fibrillation (AF) | up to 51 months | Percentage of participants with New Onset of Atrial Fibrillation The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis). |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Dominican Republic, Ecuador, Estonia, Finland, France, Germany, Guatemala, Hong Kong, Hungary, Iceland, India, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Venezuela
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period | 4,209 |
| Enalapril single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period | 4,233 |
| Total | 8,442 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 724 | 844 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | patient's request | 15 | 13 |
Baseline characteristics
| Characteristic | LCZ696 | Enalapril | Total |
|---|---|---|---|
| Age, Continuous | 63.78 years STANDARD_DEVIATION 11.52 | 63.82 years STANDARD_DEVIATION 11.25 | 63.80 years STANDARD_DEVIATION 11.385 |
| Sex: Female, Male Female | 888 Participants | 959 Participants | 1847 Participants |
| Sex: Female, Male Male | 3321 Participants | 3274 Participants | 6595 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2,479 / 4,203 | 2,594 / 4,229 |
| serious Total, serious adverse events | 1,937 / 4,203 | 2,142 / 4,229 |
Outcome results
Primary
Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization
Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF.
Time frame: up to 51 months
Population: Full Analysis Set (FAS) included all randomized patients but the following two exclusions: 6 patients who did not qualify for randomization but were inadvertently randomized into the study and did not receive double-blind study medication; 37 patients because they were randomized at sites that were closed due to serious GCP violations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 | Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | Primary Composite | 914 participants |
| LCZ696 | Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | CV death | 558 participants |
| LCZ696 | Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | 1st HF Hospitalization | 537 participants |
| Enalapril | Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | Primary Composite | 1117 participants |
| Enalapril | Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | CV death | 693 participants |
| Enalapril | Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization | 1st HF Hospitalization | 658 participants |
Secondary
Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score
Change from baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
Time frame: Baseline, Month 8
Population: FAS included all randomized patients with two exclusions: 6 pts who did not qualify for randomization but were misrandomized into the study and did not receive study meds; 37 pts because they were randomized at sites that were closed due to serious GCP violations The analysis included all FAS patients with at least one KCCQ data up-to Month 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 | Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | -2.99 KCCQ Score | Standard Error 0.364 |
| Enalapril | Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | -4.63 KCCQ Score | Standard Error 0.364 |
Secondary
Number of Patients - All-cause Mortality
Number of patients - All-cause mortality. All-cause mortality is common in Heart Failure HF patients this measures how many patients had this event. The data is on FAS population up to March 31, 2014
Time frame: up to 51 months
Population: Full Analysis Set (FAS) included all randomized patients but the following two exclusions: 6 patients who did not qualify for randomization but were inadvertently randomized into the study and did not receive double-blind study medication; 37 patients because they were randomized at sites that were closed due to serious GCP violations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 | Number of Patients - All-cause Mortality | 711 participants |
| Enalapril | Number of Patients - All-cause Mortality | 835 participants |
Secondary
Number of Patients Reported With Adjudicated Primary Causes of Death
Number of patients reported with adjudicated primary causes of death. The data is on Randomization population up to March 31, 2014
Time frame: up to 51 months
Population: Randomized set (RAN): Consisted of all patients who received a randomization number, regardless of receiving trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Number of patients who died | 714 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Fatal MI | 25 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Pump Failure | 147 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Sudden Death | 251 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Presumed Sudden Death | 26 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Presumed CV Death | 67 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Fatal Stroke | 30 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Pulmonary Embolism | 4 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - CV procedural | 3 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Other CV Death | 7 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Infection | 36 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Malignancy | 41 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Renal | 1 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Accidental | 13 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Pulmonary | 7 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Suicide | 4 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - GI | 16 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Other Non-CV death | 2 participants |
| LCZ696 | Number of Patients Reported With Adjudicated Primary Causes of Death | Unknown Death | 34 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - GI | 10 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Number of patients who died | 837 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Other CV Death | 6 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Fatal MI | 33 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Pulmonary | 13 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Renal | 1 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Pump Failure | 185 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Infection | 34 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Sudden Death | 311 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Unknown Death | 33 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Presumed Sudden Death | 23 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Malignancy | 41 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Presumed CV Death | 95 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Suicide | 1 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Fatal Stroke | 34 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Other Non-CV death | 4 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - Pulmonary Embolism | 3 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | Non-CV death - Accidental | 6 participants |
| Enalapril | Number of Patients Reported With Adjudicated Primary Causes of Death | CV Death - CV procedural | 4 participants |
Secondary
Number of Patients With First Confirmed Renal Dysfunction
Number of patients with first confirmed renal dysfunction
Time frame: up to 51 months
Population: Full Analysis Set (FAS) included all randomized patients but the following two exclusions: 6 patients who did not qualify for randomization but were inadvertently randomized into the study and did not receive double-blind study medication; 37 patients because they were randomized at sites that were closed due to serious GCP violations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 | Number of Patients With First Confirmed Renal Dysfunction | 94 participants |
| Enalapril | Number of Patients With First Confirmed Renal Dysfunction | 108 participants |
Secondary
Percentage of Participants With New Onset of Atrial Fibrillation (AF)
Percentage of participants with New Onset of Atrial Fibrillation The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis).
Time frame: up to 51 months
Population: The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 | Percentage of Participants With New Onset of Atrial Fibrillation (AF) | 3.15 Percentage of participants |
| Enalapril | Percentage of Participants With New Onset of Atrial Fibrillation (AF) | 3.15 Percentage of participants |