Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
Cardiovascular Diseases, Heart Failure, Heart failure with Preserved Ejection Fraction, NT-proBNP, 6 MWT, KCCQ, SF-36, NYHA Class, LCZ696, Enalapril, Valsartan, Angiotensin-Converting Enzyme Inhibitors (ACEi), Angiotensin II Type 1 Receptor Blockers (ARB), Renin Angiotensin System Inhibitors (RASi)
Brief summary
The purpose of this study is to demonstrate the superiority of LCZ696 over individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF).
Detailed description
This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF \> 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e. enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.
Interventions
DRUGsacubitril/valsartan
Sacubitril/valsartan is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg, respectively in tablet form to be taken orally
DRUGEnalapril
Enalapril is available as 2.5 mg, 5 mg, and 10 mg tablet form to be taken orally
DRUGValsartan
Valsartan is available as 40 mg, 80 mg, 160 mg tablet form to be taken orally
DRUGPlacebo to match sacubitril/valsartan
Placebo to match LCZ696 50 mg, 100 mg, 200 mg tablet form to be taken orally
DRUGPlacebo to match enalapril
Placebo to match enalapril 2.5 mg, 5 mg, 10 mg tablet form to be taken orally
DRUGPlacebo to match valsartan
Placebo to match valsartan 40 mg, 80 mg, 160 mg tablet form to be taken orally
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
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Left ventricular ejection fraction (LVEF) \>40% by echo within 6 months prior to study entry or during the screening epoch * Symptom(s) of heart failure (HF) requiring treatment with diuretics (including loop, or thiazide diuretics, or mineralocorticoid antagonist \[MRAs\]) for at least 30 days prior to study entry * NYHA class II-IV * Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram. * NT-proBNP \> 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or \>600 pg/mL for patients with AF * KCCQ clinical summary score \< 75 * Patients on ACEi or ARB therapy must have a history of HTN
Exclusion criteria
* Any prior measurement of LVEF ≤ 40%, under stable conditions * Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention (PCI) within 3 months or an elective PCI within 30 days prior to study entry * Any clinical event within the 6 months prior to Visit 1 that could have reduced the LVEF (eg MI, coronary artery bypass graft \[CABG\]), unless an echo measurement was performed after the event confirming the LVEF to be \>40% * Current (within 30 days from Visit 1) acute decompensated HF requiring therapy. * Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or LCZ696 * History of hypersensitivity to LCZ696 or its components * Patients with a known history of angioedema * Walk distance primarily limited by non-cardiac comorbid conditions at study entry * Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) \<10 g/dL males and \< 9.5 g/dL females, or body mass index (BMI) \> 40 kg/m\^2. * Systolic blood pressure (SBP) ≥ 180 mmHg at study entry, or SBP \>150 mmHg and \<180 mmHg at study entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP \< 110 mmHg at study entry. * Patients with HbA1c \> 7.5% not treated for diabetes * Patients with prior major organ transplant or intent to transplant (ie on transplant list) * eGFR \< 30 ml/min/1.73 m\^2 as measured by MDRD at screening * Serum potassium \> 5.2 mmol /L (or equivalent plasma potassium value) at study entry * History or presence of any other disease with a life expectancy of \< 3 years * Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12 | Baseline, week 12 | To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF |
| Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24 | Baseline, week 24 | Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24 | Baseline, Week 24 | Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. |
| Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24 | Baseline, Week 24 | The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. |
| Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24 | Baseline, Week 24 | The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 worst-100 best). |
| Change From Baseline in NYHA Functional Class at Week 24 | Baseline, week 24 | NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: improved, unchanged, and worsened, defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively. |
| Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24 | Baseline, Week 24 | Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status. |
Countries
Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Colombia, Czechia, Denmark, Estonia, France, Germany, Guatemala, Hungary, India, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Peru, Portugal, Romania, Russia, Serbia, Slovakia, Spain, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).
Pre-assignment details
A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).
Participants by arm
| Arm | Count |
|---|---|
| Sacubitril/Valsartan (LCZ696) All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. | 1,281 |
| Individualized Medical Therapy (IMT) Comparator Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). | 1,285 |
| Total | 2,566 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Death | 23 | 17 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Technical problems | 5 | 1 |
| Overall Study | Withdrawal by Subject | 19 | 25 |
Baseline characteristics
| Characteristic | Sacubitril/Valsartan (LCZ696) | Individualized Medical Therapy (IMT) Comparator | Total |
|---|---|---|---|
| Age, Customized <65 years | 196 Participants | 221 Participants | 417 Participants |
| Age, Customized >=65 years | 1085 Participants | 1064 Participants | 2149 Participants |
| Race/Ethnicity, Customized Asian | 56 Participants | 59 Participants | 115 Participants |
| Race/Ethnicity, Customized Black | 11 Participants | 16 Participants | 27 Participants |
| Race/Ethnicity, Customized Caucasian | 1112 Participants | 1117 Participants | 2229 Participants |
| Race/Ethnicity, Customized Native American | 39 Participants | 33 Participants | 72 Participants |
| Race/Ethnicity, Customized Other | 59 Participants | 56 Participants | 115 Participants |
| Race/Ethnicity, Customized Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 643 Participants | 658 Participants | 1301 Participants |
| Sex: Female, Male Male | 638 Participants | 627 Participants | 1265 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 23 / 1,280 | 17 / 1,284 | 40 / 2,564 |
| other Total, other adverse events | 964 / 1,280 | 832 / 1,284 | 1,796 / 2,564 |
| serious Total, serious adverse events | 186 / 1,280 | 191 / 1,284 | 377 / 2,564 |
Outcome results
Primary
Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24
Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002.
Time frame: Baseline, week 24
Population: Subset of Full Analysis Set: This outcome measure was analyzed on patients with a Baseline 6MWD from 100 meters to 450 meters.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24 | 9.6935 Meters |
| Individualized Medical Therapy (IMT) Comparator | Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24 | 12.1920 Meters |
p-value: 0.416495% CI: [-8.5267, 3.52297]Mixed Models Analysis
Primary
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12
To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF
Time frame: Baseline, week 12
Population: Full Analysis Set: This outcome measure represents patients with non-missing change from baseline in log transformed NT-proBNP at Week 12. The model was fitting using change from baseline in log transformed NT-proBNP, and produced a difference in mean change from baseline in log transformed NT-proBNP, which was then transformed back to geometric mean ratio to baseline using an exponential transformation.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12 | 0.8218 Ratio |
| Individualized Medical Therapy (IMT) Comparator | Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12 | 0.9828 Ratio |
Comparison: Week 12p-value: <0.000195% CI: [0.7987, 0.8754]Mixed Models Analysis
Secondary
Change From Baseline in NYHA Functional Class at Week 24
NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: improved, unchanged, and worsened, defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively.
Time frame: Baseline, week 24
Population: Full Analysis Set: This outcome measure represents patients with both a baseline NYHA class and NYHA class at the visit observed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in NYHA Functional Class at Week 24 | Improved | 23.62 Percentage of Participants |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in NYHA Functional Class at Week 24 | Unchanged | 72.23 Percentage of Participants |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in NYHA Functional Class at Week 24 | Worsened | 4.15 Percentage of Participants |
| Individualized Medical Therapy (IMT) Comparator | Change From Baseline in NYHA Functional Class at Week 24 | Worsened | 4.31 Percentage of Participants |
| Individualized Medical Therapy (IMT) Comparator | Change From Baseline in NYHA Functional Class at Week 24 | Improved | 24.00 Percentage of Participants |
| Individualized Medical Therapy (IMT) Comparator | Change From Baseline in NYHA Functional Class at Week 24 | Unchanged | 71.68 Percentage of Participants |
p-value: 0.831495% CI: [0.8122, 1.182]Proportional cumulative odds model
Secondary
Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24
The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 worst-100 best).
Time frame: Baseline, Week 24
Population: Full Analysis Set: This outcome measure represents patients with non-missing change from baseline in SF-36 PCS at Week 24.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24 | 2.5405 Scores on a scale |
| Individualized Medical Therapy (IMT) Comparator | Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24 | 2.6975 Scores on a scale |
p-value: 0.63795% CI: [-0.8093, 0.4953]Mixed Models Analysis
Secondary
Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24
The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
Time frame: Baseline, Week 24
Population: Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24 | 12.3399 Scores on a scale |
| Individualized Medical Therapy (IMT) Comparator | Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24 | 11.8168 Scores on a scale |
p-value: 0.479195% CI: [-0.9258, 1.972]Mixed Models Analysis
Secondary
Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24
Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
Time frame: Baseline, Week 24
Population: Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24 | 15.49 Percentage of participants |
| Individualized Medical Therapy (IMT) Comparator | Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24 | 16.69 Percentage of participants |
p-value: 0.529495% CI: [0.6461, 1.2518]longitudinal binary logistic regression
Secondary
Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24
Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
Time frame: Baseline, Week 24
Population: Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24 | 67.94 Percentage of participants |
| Individualized Medical Therapy (IMT) Comparator | Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24 | 65.70 Percentage of participants |
p-value: 0.493895% CI: [0.8287, 1.476]longitudinal binary logistic regression