Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
Heart failure, preserved ejection fraction, diastolic heart failure
Brief summary
The purpose of this study was to evaluate the effect of LCZ696 compared to valsartan in the reduction of cardiovascular death and heart failure(HF) hospitalizations in patients with HF with preserved ejection fraction.
Detailed description
This was a multicenter, randomized, double-blind, parallel group, active-controlled, study to evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction. Specifically, the study evaluated the effect of sacubitril/valsartan compared to the active comparator valsartan in the reduction of the rate of CV death and total HF hospitalizations in patients with HFpEF. The trial consisted of two periods: (1) a single-blind treatment run-in epoch that lasted from 3 to 8 weeks, in which patients received valsartan 80 mg bid, followed by sacubitril/valsartan 100 mg bid and (2) a double-blind randomized treatment epoch (sacubitril/valsartan 200 mg bid or valsartan 160 mg bid). In this study, investigators were responsible for assessing and submitting all events which could potentially fulfill the criteria for the primary, secondary, or other clinical endpoints to a Clinical Endpoint Committee (CEC). Investigator reported events were assessed by the CEC for adjudication. For angioedema or angioedema-like events, investigators completed an Adjudication Questionnaire for an Angioedema-like Event form. All angioedema reports were forwarded to an Angioedema Adjudication Committee (AAC) by Novartis for assessment.
Interventions
DRUGLCZ696
LCZ696 50mg, 100mg and 200 mg dosage strengths will be available for dose adjustments.
DRUGValsartan
Valsartan 40mg, 80mg and 160mg dosage strengths will be available for dose adjustments.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Left ventricular ejection fraction (LVEF) ≥45% by echo during screening epoch or within 6 months prior to study entry. * Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF at least 30 days prior to study entry. * Current symptom(s) of HF (NYHA class II-IV) * Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram. * Elevated NT-proBNP
Exclusion criteria
* Any prior measurement of LVEF \< 40%. * Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention within 3 months or and elective PCI within 30 days prior to entry. * Any clinical event within the 6 months prior to entry could have reduced the LVEF (e.g., MI, CABG), unless an echo measurement performed after the event confirms a LVEF ≥45%. * Current acute decompensated HF requiring therapy. * Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor. * Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) \<10 g/dl, or body mass index (BMI) \> 40 kg/m2. * Systolic blood pressure (SBP) ≥ 180 mmHg at entry, or SBP \>150 mmHg and \<180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP \< 110 mmHg at entry. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Total follow up time (up to 57 months) | The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association \[NYHA\] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction \[LVEF\] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ) | Baseline, 8 months | The KCCQ is a validated instrument for self-assessment of quality of life and health status in heart failure (HF) patients. The clinical summary score, which is derived from the physical limitations and heart failure (HF) symptoms domains of the KCCQ is a valid measure for assessing the patient's health aspects that may be influenced by CV medications. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. Evaluation of change from baseline to month 8 in KCCQ a most sensitive, specific, and responsive health-related quality of life measure for heart failure symptoms and physical limitations. |
| Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Baseline, 8 months | Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a heart failure's (HF) patients' level of functionality based on the signs and symptoms of HF exhibited by the patient. |
| Participants With First Occurrence of a Composite Renal Endpoint | Randomization to total follow-up time (up to 57 months) | Analyis of composite renal endpoint defined as renal death, or reaching ESRD, or ≥50% decline in eGFR relative to baseline, using Cox's proportional hazards model. |
| All-cause Mortality | Randomization to total follow up time (up to 57 months) | Analysis for all-cause mortality using Cox's proportional hazards model. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Denmark, Finland, France, Germany, Greece, Guatemala, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Romania, Russia, Serbia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
4822 patients were randomized at 755 sites in 43 countries. 2419 participants were randomized into the LCZ696 treatment group and 2403 were randomized into the valsartan treatment group.
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients followed by Valsartan 80 mg bid for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of LCZ696 during the double blind period was 200 mg bid | 2,419 |
| Valsartan Single Blind Run-in Period (3-8 weeks): Prior optional valsartan run-in 40 mg bid for 1-2 weeks for some patients, followed by Valsartan 80 mg bid. for 1-2 weeks followed by LCZ696 100 mg bid for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients could only be randomized from the run-in period if they met all of the run-in safety criteria. Target dose of Valsartan during the double blind period was 160 mg bid | 2,403 |
| Total | 4,822 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 347 | 356 |
| Overall Study | Lost to Follow-up | 13 | 14 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Valsartan | LCZ696 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1988 Participants | 2004 Participants | 3992 Participants |
| Age, Categorical Between 18 and 65 years | 415 Participants | 415 Participants | 830 Participants |
| Race/Ethnicity, Customized Asian | 310 Participants | 297 Participants | 607 Participants |
| Race/Ethnicity, Customized Black | 50 Participants | 52 Participants | 102 Participants |
| Race/Ethnicity, Customized Caucasian | 1958 Participants | 1975 Participants | 3933 Participants |
| Race/Ethnicity, Customized Native American | 23 Participants | 28 Participants | 51 Participants |
| Race/Ethnicity, Customized Other | 61 Participants | 67 Participants | 128 Participants |
| Race/Ethnicity, Customized Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 1244 Participants | 1247 Participants | 2491 Participants |
| Sex: Female, Male Male | 1159 Participants | 1172 Participants | 2331 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 347 / 2,419 | 357 / 2,402 | 704 / 4,821 |
| other Total, other adverse events | 2,005 / 2,419 | 1,995 / 2,402 | 4,000 / 4,821 |
| serious Total, serious adverse events | 1,424 / 2,419 | 1,416 / 2,402 | 2,840 / 4,821 |
Outcome results
Primary
Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations.
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association \[NYHA\] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction \[LVEF\] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.
Time frame: Total follow up time (up to 57 months)
Population: Full Analysis Set - This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 | Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Primary Composite Events | 894 Events |
| LCZ696 | Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Total Hospitalizations for heart failure | 690 Events |
| LCZ696 | Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Cardiovascular death | 204 Events |
| Valsartan | Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Primary Composite Events | 1009 Events |
| Valsartan | Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Total Hospitalizations for heart failure | 797 Events |
| Valsartan | Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations. | Cardiovascular death | 212 Events |
Comparison: Primary Composite Eventsp-value: 0.058795% CI: [0.7526, 1.0052]Proportional Rates Model (LWYY)
Comparison: Total Hospitalizations for heart failurep-value: 0.055695% CI: [0.7216, 1.0039]Joint Frality Model
Comparison: Cardiovascular Deathp-value: 0.624195% CI: [0.7863, 1.1551]Cox's proportional hazard model
Secondary
All-cause Mortality
Analysis for all-cause mortality using Cox's proportional hazards model.
Time frame: Randomization to total follow up time (up to 57 months)
Population: Full Analysis Set -This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LCZ696 | All-cause Mortality | 342 Participants |
| Valsartan | All-cause Mortality | 349 Participants |
Comparison: All-cause mortalityp-value: 0.684695% CI: [0.8352, 1.1255]Cox's proportional hazards model
Secondary
Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class
Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a heart failure's (HF) patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.
Time frame: Baseline, 8 months
Population: Full Analysis Set - This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints. However, this endpoint only includes those participants who had assessments completed for both Baseline and Month 8 visits; as that is the only way a change could be calculated and analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 | Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Improved (n=2316, 2302) | 347 Number of Participants |
| LCZ696 | Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Unchanged (n=2316, 2302) | 1767 Number of Participants |
| LCZ696 | Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Worsened (n=2316, 2302) | 202 Number of Participants |
| Valsartan | Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Improved (n=2316, 2302) | 289 Number of Participants |
| Valsartan | Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Unchanged (n=2316, 2302) | 1792 Number of Participants |
| Valsartan | Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class | Worsened (n=2316, 2302) | 221 Number of Participants |
Comparison: NYHA Class Changep-value: 0.003595% CI: [1.1294, 1.8552]Repeated measures cumulative odds model
Secondary
Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ is a validated instrument for self-assessment of quality of life and health status in heart failure (HF) patients. The clinical summary score, which is derived from the physical limitations and heart failure (HF) symptoms domains of the KCCQ is a valid measure for assessing the patient's health aspects that may be influenced by CV medications. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. Evaluation of change from baseline to month 8 in KCCQ a most sensitive, specific, and responsive health-related quality of life measure for heart failure symptoms and physical limitations.
Time frame: Baseline, 8 months
Population: Full Analysis Set-This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 | Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ) | -1.5073 Points on a scale | Standard Error 0.3709 |
| Valsartan | Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ) | -2.5338 Points on a scale | Standard Error 0.3729 |
Comparison: Clinical Summary Scorep-value: 0.05195% CI: [-0.0047, 2.0576]Mixed Models Analysis
Secondary
Participants With First Occurrence of a Composite Renal Endpoint
Analyis of composite renal endpoint defined as renal death, or reaching ESRD, or ≥50% decline in eGFR relative to baseline, using Cox's proportional hazards model.
Time frame: Randomization to total follow-up time (up to 57 months)
Population: Full Analysis Set -This was the primary efficacy population applied in efficacy analyses for all efficacy endpoints.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 | Participants With First Occurrence of a Composite Renal Endpoint | Composite renal endpoint | 33 Participants |
| LCZ696 | Participants With First Occurrence of a Composite Renal Endpoint | Renal Death | 1 Participants |
| LCZ696 | Participants With First Occurrence of a Composite Renal Endpoint | Reaching ESRD | 7 Participants |
| LCZ696 | Participants With First Occurrence of a Composite Renal Endpoint | >=50% decline in eGFR from baseline | 27 Participants |
| Valsartan | Participants With First Occurrence of a Composite Renal Endpoint | >=50% decline in eGFR from baseline | 60 Participants |
| Valsartan | Participants With First Occurrence of a Composite Renal Endpoint | Composite renal endpoint | 64 Participants |
| Valsartan | Participants With First Occurrence of a Composite Renal Endpoint | Reaching ESRD | 12 Participants |
| Valsartan | Participants With First Occurrence of a Composite Renal Endpoint | Renal Death | 1 Participants |
Comparison: Composite renal endpointp-value: 0.001495% CI: [0.3312, 0.7673]Cox's proportional hazards model
Comparison: Renal Deathp-value: 0.958895% CI: [0.0581, 14.861]Cox's proportional hazards model
Comparison: Reaching ESRDp-value: 0.248495% CI: [0.2272, 1.4672]Cox's proportional hazards model
Comparison: \>=50% decline in eGFR from baselinep-value: 0.000495% CI: [0.2798, 0.6942]Cox's proportional hazards model