Chronic Heart Failure
Conditions
Keywords
Chronic Heart Failure, Cardiovascular death, CHF hospitalization, morbi-mortality trial, outcome study, endpoint driven, plasma renin activity, renin angiotensin aldosterone system, direct renin inhibitors, BNP, KCCQ, eGFR, (NYHA class II to IV) with elevated, BNP and reduced LVEF
Brief summary
The study will evaluate the efficacy and safety of both aliskiren monotherapy and aliskiren/enalapril combination therapy as compared to enalapril monotherapy, on morbidity and mortality in patients with chronic heart failure (NYHA Class II - IV.
Interventions
DRUGEnalapril
Enalapril 10 mg film-coated tablet and administered orally.
DRUGAliskiren
Aliskiren 150 mg titrated to 300 mg film-coated tablet and administered orally.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients eligible for inclusion in this study had to fulfill all of the following criteria: 1. Patients ≥ 18 years of age, male or female. 2. Patients with a diagnosis of chronic heart failure (NYHA Class II - IV): 1. LVEF ≤ 35% at Visit 1 (local measurement, within the past 6 months assessed by echocardiography, multiple uptake gated acquisition scan (MUGA), computerized tomography(CT) scan, magnetic resonance imaging (MRI) or ventricular angiography) 2. Elevated BNP or NT-proBNP at Visit 1: BNP ≥ 150 pg/mL (or BNP ≥ 100 pg/mL and unplanned hospitalization for HF within the last 12 months prior to Visit 1) (according to local measurement). OR NT-proBNP ≥ 600 pg/mL (or NT-proBNP ≥ 400 pg/mL and unplanned hospitalization for HF within the last 12 months prior to Visit 1) (according to local measurement). 3. Patients had to be treated with an ACEI at a stable dose enalapril 10 mg daily at least or any other ACEI, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; based on equivalent doses, for at least 4 weeks prior to Visit 1 4. Patients had to be treated with a beta-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to visit 1 (for patients not on target dose, according to local guidelines, or in absence of that medication, the reason should be documented). 5. Written informed consent to participate in the study and ability to comply with all requirements.
Exclusion criteria
Patients with any of the following were to be excluded from participation in the study: 1. History of hypersensitivity to any of the study drugs including history or allergy to ACEIs as well as known or suspected contraindications to the study drugs or previous history of intolerance to high doses of ACEIs during up- titration process. 2. Patients treated concomitantly with both an ARB and an aldosterone antagonist in addition to study drug at Visit 1. 3. Current acute decompensated HF (defined as an acute exacerbation of a chronic heart failure status manifested by typical signs and symptoms of HF like dyspnea, fatigue etc., that may require IV therapy with diuretics, vasodilators and/or inotropic drugs). 4. Symptomatic hypotension and/or less than 95 mmHg systolic blood pressure (SBP) at Visit 1 and/or less than 90 mmHg SBP at Visit 4. 5. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months prior to Visit 1. 6. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1. 7. Right heart failure due to severe pulmonary disease. 8. Patients with Diabetes Mellitus.
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 End of Study (78 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 |
|---|---|---|
| Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | Baseline, Month 12 | Change from baseline to Month 12 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. |
| All Cause Death | up to end of study (78 months) | Number of patients - All-cause death. All-cause death is common in Heart Failure HF patients this measures how many patients had this event. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Colombia, Costa Rica, Czechia, Denmark, Dominican Republic, Estonia, Finland, France, Germany, Greece, India, Ireland, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States, Venezuela
Participant flow
Pre-assignment details
During Active Run-in period, patients received enalapril for step 1 & 2 and then aliskiren on top of the max tolerated dose of enalapril for step 3. Patients who completed the run in were randomized in a 1:1:1 ratio to one of the 3 treatment arms (aliskiren/enalapril combination therapy, aliskiren monotherapy, or enalapril monotherapy).
Participants by arm
| Arm | Count |
|---|---|
| Combination Aliskiren / Enalapril Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally. | 2,340 |
| Aliskiren Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. | 2,340 |
| Enalapril Enalapril monotherapy -10 mg film-coated tablet and administered orally. | 2,336 |
| Total | 7,016 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 713 | 768 | 753 |
| Overall Study | H.A. Request | 26 | 23 | 19 |
| Overall Study | IRB request | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 11 | 6 | 11 |
| Overall Study | Missing study completion information | 5 | 4 | 6 |
| Overall Study | Patient's request | 21 | 17 | 11 |
| Overall Study | Vital Status at study end N/A | 8 | 10 | 10 |
| Overall Study | Vital Status known (alive) at study end | 2 | 3 | 3 |
| Overall Study | Vital Status unknown at study end | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Combination Aliskiren / Enalapril | Aliskiren | Enalapril | Total |
|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 11.65 | 63.3 years STANDARD_DEVIATION 12.06 | 63.3 years STANDARD_DEVIATION 11.71 | 63.2 years STANDARD_DEVIATION 11.81 |
| Sex: Female, Male Female | 494 Participants | 532 Participants | 499 Participants | 1525 Participants |
| Sex: Female, Male Male | 1846 Participants | 1808 Participants | 1837 Participants | 5491 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1,698 / 2,347 | 1,605 / 2,348 | 1,623 / 2,345 |
| serious Total, serious adverse events | 1,466 / 2,347 | 1,504 / 2,348 | 1,501 / 2,345 |
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 End of Study (78 months)
Population: Full Analysis Set (FAS) - All randomized patients with exception of mis-randomized patients that took no study drug and patients from the sites with major GCP violations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Aliskiren / 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 | 512 participants |
| Combination Aliskiren / 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 | 770 participants |
| Combination Aliskiren / 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 | 430 participants |
| Aliskiren | 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 | 562 participants |
| Aliskiren | 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 | 791 participants |
| Aliskiren | 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 | 442 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 | 808 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 | 452 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 | 547 participants |
Comparison: (superiority)p-value: 0.172495% CI: [0.85, 1.03]Regression, Cox
Comparison: (superiority) Non-Diabetic patientsp-value: 0.457995% CI: [0.85, 1.07]Regression, Cox
p-value: 0.036895% CI: [0.9, 1.1]Regression, Cox
Comparison: (superiority)p-value: 0.911895% CI: [0.9, 1.1]Regression, Cox
Secondary
All Cause Death
Number of patients - All-cause death. All-cause death is common in Heart Failure HF patients this measures how many patients had this event.
Time frame: up to end of study (78 months)
Population: Full Analysis Set (FAS) - All randomized patients with exception of mis-randomized patients that took no study drug and patients from the sites with major GCP violations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Aliskiren / Enalapril | All Cause Death | 595 participants |
| Aliskiren | All Cause Death | 654 participants |
| Enalapril | All Cause Death | 646 participants |
Secondary
Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score
Change from baseline to Month 12 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 12
Population: Full Analysis Set (FAS) - All randomized patients with exception of mis-randomized patients that took no study drug and patients from the sites with major GCP violations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Combination Aliskiren / Enalapril | Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | -5.04 KCCQ Score | Standard Error 0.56 |
| Aliskiren | Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | -6.03 KCCQ Score | Standard Error 0.57 |
| Enalapril | Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score | -5.01 KCCQ Score | Standard Error 0.55 |