Heart Failure With Preserved Ejection Fraction (HFpEF)
Conditions
Keywords
Heart failure with preserved ejection fraction (HFpEF), Heart failure hospitalization, NYHA, NT-proBNP, Acute decompensated heart failure, Sacubitril/valsartan, Global evaluation of treatment effectiveness (GETE), Worsening Heart Failure
Brief summary
The effect of sacubitril/valsartan vs. valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF decompensation) who had been stabilized and initiated at the time of or within 30 days post-decompensation.
Detailed description
This study used a randomized, double-blind, double-dummy, active-controlled, parallel group design conducted across 100 centers in the US and Canada. The study duration was a maximum of 20 months (minimum follow up was 8 weeks). Randomized patients were deemed hemodynamically stabilized and needed to meet all inclusion and none of the exclusion criteria. Patients were randomized 1:1 to LCZ696 or valsartan. Initial dose at randomization was determined based on the patient's previous dose of or lack of ACEi/angiotensin receptor blocker (ARB) immediately prior to current worsening heart failure (WHF) event (heart failure with preserved ejection fraction \[HFpEF\]) decompensation, or at the time of post-decompensation randomization. LCZ696 dose or valsartan dose levels may have been increased to the targeted desired dose of 97/103 mg \[200 mg\] BID or valsartan 160 mg BID on an every 2-week basis or earlier based on clinical need and investigator judgment. Every effort was made to titrate to and maintain patients on the target dose level, as tolerated by the patient. To maintain the blinding, patients were required to take their assigned active treatment tablet along with placebo matching the opposite treatment BID. The protocol had 4 amendments. Protocol Version 00 (Original Protocol) included a double-blind phase through Week 8 followed by an open-label phase during Weeks 8 to 12. Protocol Amendment 01 omitted the open-label phase and followed patients for a maximum of 20 months in a double-blinded treatment phase. Throughout all protocol versions, the primary endpoint remained the time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from Baseline to Weeks 4 and 8. The most recent protocol amendment (Amendment 04) reduced the sample size to approximately 450 patients (from 800) with 85% power for the primary endpoint, deemphasizing the statistical power for key secondary clinical endpoints; however, clinical events were still assessed as secondary endpoints. No efficacy analyses include OPEN LABEL' data. After Protocol Amendment 01, the open-label option was removed from the study, only the 233 patients randomized in the Double-blind Phase Sacubitril+ Valsartan (LCZ696) and the 233 patients randomized in the Double-blind Phase Valsartan arms were included in the efficacy analysis.
Interventions
DRUGsacubitril/valsartan
Sacubitril/valsartan (LCZ696) was available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily
DRUGvalsartan
Valsartan was available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily
DRUGsacubitril/valsartan matching placebo
Sacubitril/valsartan (LCZ696) matching placebo was available as tablet form to be taken orally, twice daily
DRUGvalsartan matching placebo
Valsartan matching placebo was available as tablet form to be taken orally, twice daily
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 99 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study 2. Patients \>=18 years of age, male or female 3. Current hospitalization for Worsening Heart Failure (WHF) (HFpEF decompensation), or within 30 days of discharge following a WHF event (defined as hospitalization, emergency department (ED) visit or out-of-hospital urgent HF visit, all requiring IV diuretics). Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray). Eligible patients were randomized after IV diuresis for HFpEF is given (and no earlier than 36 hours from their last ACEi dose if applicable) and within 30 days post-decompensation after presentation with acute HFpEF decompensation and meeting the following definitions of hemodynamic stability: Randomized patients were hemodynamically stable defined in this study as: 1. SBP \>=100mmHg for the preceding 6 hours prior to randomization; no symptomatic hypotension 2. No increase (intensification) in IV diuretic dose within last 6 hours prior to randomization 3. No IV inotropic drugs for 24 hours prior to randomization 4. No IV vasodilators including nitrates within last 6 hours prior to randomization 4. HFpEF with most recent LVEF \> 40% (within past 3 months) 5. Elevated NT-proBNP or BNP at the time of acute HFpEF decompensation or post-decompensation screening (and within 72 hours for out-of-hospital randomization, if applicable): 1. Patients not in Atrial Fibrillation(AF) at the time of biomarker assessment: NT-proBNP \>= 500pg/mL or BNP \>= 150 pg/mL; patients in AF at the time of biomarker assessment: NT-proBNP \>= 1000pg/mL or BNP \>= 300 pg/mL 2. Patients recruited in-hospital were randomized based on the qualifying local lab value in-hospital NT-proBNP or BNP value. 3. Patients enrolled post-decompensation can be randomized based on their NT-proBNP or BNP value in the following way: i. if enrolling in post-decompensation setting then need eligible screening/local NTproBNP/BNP within 72 hours of randomization. The test value could be from recent hospitalization if within 72 hours or ii. would require (re)drawing NT-proBNP or BNP labs in post-decompensation setting if the lab value is not already available within the last 72 hours). 6\) Has not taken an ACEi for 36 hours prior to randomization
Exclusion criteria
1. Any clinical event within the 90 days prior to randomization that could have reduced the LVEF (i.e., myocardial infarction (MI), coronary artery bypass graft (CABG), unless an echo measurement was performed after the event confirming the LVEF to be \> 40% 2. Entresto™ (sacubitril/valsartan) usage within the past 60 days 3. eGFR \< 20ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization 4. Serum potassium \> 5.2 mEq/L at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization 5. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within 30 days prior to randomization 6. Probable alternative diagnoses that in the opinion of the investigator could account for the patient's HF symptoms (i.e. dyspnea, fatigue) such as significant pulmonary disease (including primary pulmonary HTN), anemia or obesity. 7. Isolated right HF in the absence of left-sided structural heart disease 8. History of hypersensitivity (i.e. including angioedema), known or suspected contraindications, or intolerance to any of the study drugs including ARNIs (i.e. sacubitril/valsartan), and/or ARBs 9. Patients with a known history of angioedema due to any etiology 10. Patients with a history of heart transplant or LVAD, currently on the transplant list, or with planned intent to implant LVAD or CRT device within the initial three months of enrollment during the trial 11. A cardiac or non-cardiac medical condition other than HF with an estimated life expectancy of \< 6 months 12. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including suspected or confirmed amyloid heart disease (amyloidosis) 13. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate \> 110 bpm 14. Clinically significant congenital heart disease felt to be the cause of the patient's symptoms and signs of HF 15. Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention within the duration of the trial 16. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study 17. Known hepatic impairment (as evidenced by total bilirubin \> 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices 18. Participation in any other clinical trial involving investigational agents or devices within the past 30 days 19. Current confirmed COVID19 infection 20. Past COVID19 infection with persistent symptom burden suspected due to COVID19 (further defined in Section 5.2). 21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug and for 7 days off of study drug. Highly effective contraception methods are defined in protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8 | Baseline, Average of Week 4 and Week 8 | To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to weeks 4 and 8 in heart failure with preserved ejection fraction (HFpEF) patients with a worsening heart failure event (HFpEF decompensation) who have been stabilized for and initiated at the time of or within 30 days post-decompensation. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. The change from baseline to average of Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week - 8/Baseline. NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure. Baseline value was the last non-missing assessment of plasma NT-proBNP before the first administration of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EAC Adjudicated Recurrent Composite Events | Up to Week 84 | This endpoint calculated the cumulative number of the following composite events over time: * CV death * recurrent HF hospitalizations * recurrent urgent HF visits The time to these recurrent events was analyzed using the semi-parametric proportional rates model (abbreviated as LWYY model). The exposure-adjusted rate per 100 subject years (EAR) was calculated diving the total number of events by 100 subject years (total exposure up to event/censoring). The role of the Endpoint Adjudication Committee (EAC) was to ensure that all treatment outcomes were judged uniformly, using standard criteria and processes. Events that occurred in the double-blind treatment phase are included in the analysis. |
| Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function | Up to Week 84 | This endpoint calculated the incidences of a composite endpoint of worsening renal function defined as: * renal death (from adverse events data) * reaching end-stage renal disease (ESRD) (Sustained eGFR \<15mL/min/m2, chronic dialysis, or renal transplant) * ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline \[using central laboratory measurements (scheduled or unscheduled visits)\] The Investigator-reported AE and central laboratory data was used to identified event of interest in this secondary endpoint. Events that occurred in the randomized double-blind treatment phase were included in the analysis. |
| Proportional Change in NT-proBNP From Baseline to Week 8 | Baseline and Week 8 | This endpoint intended to assess the effect of sacubitril/valsartan vs. valsartan on change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to Week 8. NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline. |
| Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Up to 84 weeks | This hierarchical composite endpoint consists of 4 ordered components: 1. Time to CV death, 2. Number and times of HF hospitalizations during follow-up, 3. Number and times of urgent HF visits during follow-up, 4. Time averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8. This endpoint was analyzed estimating the unmatched win ratio by comparing every participant in the sacubitril/valsartan arm to every participant in the valsartan arm to determine a winner (unmatched pairing method). For every pair, a patient is labelled a 'winner' (i.e. achieve a better clinical outcome) or a 'loser'. Otherwise they are considered tied. The reported unit is the total wins or ties for each treatment group from performing such a hierarchical comparison. |
| Dosing Levels and Discontinuations | Randomization, Week 8, Week 24 | The dosing level has been summarized by treatment group and in-/out-of-hospital randomization status. The dose levels used were: Dose Level 1: 40 mg valsartan or 24/26 mg \[50 mg\] LCZ696, BID; Dose Level 2: 80 mg valsartan or 49/51 mg \[100 mg\] LCZ696, BID; Dose Level 3: 160 mg valsartan or 97/103 mg \[200 mg\] LCZ696, BID Patients counted as Off Treatment are those who prematurely permanently discontinued study treatment but continued with visits. Patients counted as No Treatment are those who permanently discontinued with both study treatment and study visits |
| Incidence of Adverse Events of Special Interest (AESI) During Treatment | Up to week 84 | This endpoint intended to calculate the incidence of the following adverse events of special interest (AESI) during treatment: Symptomatic hypotension, Hyperkalemia (potassium \> 5.5 mEq/L), Angioedema and worsening renal function (defined as an increase in serum creatinine of ≥ 0.5 mg/dL and worsening of the eGFR by at least 25%) |
| Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8 | Baseline, Week 4 and Week 8 | This endpoint intended to assess the effect of sacubitril/valsartan vs. valsartan on change from baseline in high sensitivity (hs)-Troponin at Weeks 4 and 8. Analysis was repeated for both the visits, Week 4 and Week 8 separately. Hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions. The change from baseline to Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week 4 or Week 8/Baseline. |
Countries
Canada, United States
Participant flow
Recruitment details
Of 586 patients screened for the study, 467 patients were randomized to receive treatment, and 466 randomized patients were treated. The study had 90 sites in the US and 10 sites in Canada
Pre-assignment details
Patients were randomized 1:1 to sacubitril/valsartan or valsartan. Randomized patients were deemed hemodynamically stabilized and needed to meet all inclusion and none of the exclusion criteria. At the randomization visit, all eligible patients were randomized via interactive response technology to one of the treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| Sacubitril/Valsartan (LCZ696) Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg twice daily (Dose Level 3). | 233 |
| Valsartan Study treatment was titrated to the target dose of valsartan 160 mg twice daily (Dose Level 3). | 233 |
| Total | 466 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind | Adverse Event | 4 | 0 | 0 |
| Double-Blind | Death | 18 | 26 | 0 |
| Double-Blind | Lost to Follow-up | 6 | 7 | 0 |
| Double-Blind | Physician Decision | 9 | 5 | 0 |
| Double-Blind | Subject decision | 24 | 13 | 0 |
| Open-Label | Adverse Event | 0 | 0 | 7 |
| Open-Label | Physician Decision | 0 | 0 | 1 |
| Open-Label | Technical problems | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sacubitril/Valsartan (LCZ696) | Valsartan | Total |
|---|---|---|---|
| Age, Continuous | 69.2 years STANDARD_DEVIATION 11.95 | 70.5 years STANDARD_DEVIATION 11.56 | 69.8 years STANDARD_DEVIATION 11.76 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Black | 50 Participants | 52 Participants | 102 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 176 Participants | 176 Participants | 352 Participants |
| Sex: Female, Male Female | 121 Participants | 121 Participants | 242 Participants |
| Sex: Female, Male Male | 112 Participants | 112 Participants | 224 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 18 / 233 | 26 / 233 | 0 / 50 |
| other Total, other adverse events | 161 / 233 | 165 / 233 | 14 / 50 |
| serious Total, serious adverse events | 119 / 233 | 117 / 233 | 3 / 50 |
Outcome results
Primary
Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8
To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to weeks 4 and 8 in heart failure with preserved ejection fraction (HFpEF) patients with a worsening heart failure event (HFpEF decompensation) who have been stabilized for and initiated at the time of or within 30 days post-decompensation. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. The change from baseline to average of Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week - 8/Baseline. NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure. Baseline value was the last non-missing assessment of plasma NT-proBNP before the first administration of study drug.
Time frame: Baseline, Average of Week 4 and Week 8
Population: Full analysis set: All patients to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received. Patients with missing baseline NT-proBNP and/or missing data from both Weeks 4 and 8 were not included in the primary analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8 | 0.7200 Geometric Mean Ratio |
| Valsartan | Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8 | 0.8425 Geometric Mean Ratio |
p-value: 0.049295% CI: [0.7307, 0.9994]ANCOVA
Secondary
Dosing Levels and Discontinuations
The dosing level has been summarized by treatment group and in-/out-of-hospital randomization status. The dose levels used were: Dose Level 1: 40 mg valsartan or 24/26 mg \[50 mg\] LCZ696, BID; Dose Level 2: 80 mg valsartan or 49/51 mg \[100 mg\] LCZ696, BID; Dose Level 3: 160 mg valsartan or 97/103 mg \[200 mg\] LCZ696, BID Patients counted as Off Treatment are those who prematurely permanently discontinued study treatment but continued with visits. Patients counted as No Treatment are those who permanently discontinued with both study treatment and study visits
Time frame: Randomization, Week 8, Week 24
Population: Full analysis set: All patients included in the double-blind phase to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Dose Level 1 | 62 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | No Treatment | 27 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Dose Level 2 | 9 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Dose Level 2 | 29 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Dose Level 3 | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Off Treatment | 10 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | No Treatment | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Dose Level 1 | 29 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Off Treatment | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Dose Level 1 | 12 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Dose Level 1 | 18 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | No Treatment | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Dose Level 2 | 15 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Dose Level 2 | 5 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Dose Level 3 | 22 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Dose Level 2 | 22 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | No Treatment | 3 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Dose Level 3 | 32 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Off Treatment | 2 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Dose Level 3 | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Dose Level 1 | 10 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | No Treatment | 19 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Dose Level 2 | 8 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Dose Level 3 | 48 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Dose Level 3 | 16 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Off Treatment | 3 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | No Treatment | 3 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Off Treatment | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Off Treatment | 1 Participants |
| Sacubitril/Valsartan (LCZ696) | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Dose Level 1 | 133 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Off Treatment | 4 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Dose Level 1 | 130 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Dose Level 2 | 32 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Dose Level 3 | 0 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | No Treatment | 0 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) | Off Treatment | 0 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Dose Level 1 | 40 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Dose Level 2 | 23 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Dose Level 3 | 48 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | No Treatment | 18 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 8 | Off Treatment | 5 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Dose Level 1 | 18 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Dose Level 2 | 16 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Dose Level 3 | 32 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | No Treatment | 11 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized In-Hospital ; Timepoint: Week 24 | Off Treatment | 1 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Dose Level 1 | 60 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Dose Level 2 | 11 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Dose Level 3 | 0 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | No Treatment | 0 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) | Off Treatment | 0 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Dose Level 1 | 21 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Dose Level 2 | 12 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Dose Level 3 | 20 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | No Treatment | 5 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 8 | Off Treatment | 1 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Dose Level 1 | 11 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Dose Level 2 | 10 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | Dose Level 3 | 15 Participants |
| Valsartan | Dosing Levels and Discontinuations | Participants Randomized Out-of-hospital; Timepoint: Week 24 | No Treatment | 9 Participants |
Secondary
EAC Adjudicated Recurrent Composite Events
This endpoint calculated the cumulative number of the following composite events over time: * CV death * recurrent HF hospitalizations * recurrent urgent HF visits The time to these recurrent events was analyzed using the semi-parametric proportional rates model (abbreviated as LWYY model). The exposure-adjusted rate per 100 subject years (EAR) was calculated diving the total number of events by 100 subject years (total exposure up to event/censoring). The role of the Endpoint Adjudication Committee (EAC) was to ensure that all treatment outcomes were judged uniformly, using standard criteria and processes. Events that occurred in the double-blind treatment phase are included in the analysis.
Time frame: Up to Week 84
Population: Full analysis set: All patients included in the double-blind phase to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | EAC Adjudicated Recurrent Composite Events | 63.519 events per 100 subject years |
| Valsartan | EAC Adjudicated Recurrent Composite Events | 76.189 events per 100 subject years |
p-value: 0.356395% CI: [0.5684, 1.2255]LWYY model
Secondary
Incidence of Adverse Events of Special Interest (AESI) During Treatment
This endpoint intended to calculate the incidence of the following adverse events of special interest (AESI) during treatment: Symptomatic hypotension, Hyperkalemia (potassium \> 5.5 mEq/L), Angioedema and worsening renal function (defined as an increase in serum creatinine of ≥ 0.5 mg/dL and worsening of the eGFR by at least 25%)
Time frame: Up to week 84
Population: Full analysis set: All patients included in the double-blind phase to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Symptomatic hypotension | 56 Participants |
| Sacubitril/Valsartan (LCZ696) | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Hyperkalemia | 45 Participants |
| Sacubitril/Valsartan (LCZ696) | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Angioedema | 0 Participants |
| Sacubitril/Valsartan (LCZ696) | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Worsening renal function | 50 Participants |
| Valsartan | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Worsening renal function | 72 Participants |
| Valsartan | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Symptomatic hypotension | 36 Participants |
| Valsartan | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Angioedema | 1 Participants |
| Valsartan | Incidence of Adverse Events of Special Interest (AESI) During Treatment | Hyperkalemia | 43 Participants |
Secondary
Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome
This hierarchical composite endpoint consists of 4 ordered components: 1. Time to CV death, 2. Number and times of HF hospitalizations during follow-up, 3. Number and times of urgent HF visits during follow-up, 4. Time averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8. This endpoint was analyzed estimating the unmatched win ratio by comparing every participant in the sacubitril/valsartan arm to every participant in the valsartan arm to determine a winner (unmatched pairing method). For every pair, a patient is labelled a 'winner' (i.e. achieve a better clinical outcome) or a 'loser'. Otherwise they are considered tied. The reported unit is the total wins or ties for each treatment group from performing such a hierarchical comparison.
Time frame: Up to 84 weeks
Population: Full analysis set: All patients included in the double-blind phase to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time to CV death wins | 2170 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time to CV death ties | 50583 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of HF hospitalizations during follow-up wins | 6963 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of HF hospitalizations during follow-up ties | 37263 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of urgent HF visits during follow-up wins | 930 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of urgent HF visits during follow-up ties | 35761 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time-averaged proportional change in NT-proBNP wins | 9987 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time-averaged proportional change in NT-proBNP ties | 17431 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Overall wins | 20050 Pairwise comparisons |
| Sacubitril/Valsartan (LCZ696) | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Overall ties | 17431 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time-averaged proportional change in NT-proBNP ties | 17431 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time to CV death wins | 1536 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of urgent HF visits during follow-up ties | 35761 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time to CV death ties | 50583 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Overall ties | 17431 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of HF hospitalizations during follow-up wins | 6357 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Time-averaged proportional change in NT-proBNP wins | 8343 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of HF hospitalizations during follow-up ties | 37263 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Overall wins | 16808 Pairwise comparisons |
| Valsartan | Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome | Number and times of urgent HF visits during follow-up wins | 572 Pairwise comparisons |
p-value: 0.157895% CI: [0.934, 1.524]unmatched pairwise win-ratio
Secondary
Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8
This endpoint intended to assess the effect of sacubitril/valsartan vs. valsartan on change from baseline in high sensitivity (hs)-Troponin at Weeks 4 and 8. Analysis was repeated for both the visits, Week 4 and Week 8 separately. Hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions. The change from baseline to Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week 4 or Week 8/Baseline.
Time frame: Baseline, Week 4 and Week 8
Population: Full analysis set: All patients to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received. Patients with missing baseline hs-Troponin and/or missing data from both Weeks 4 and 8 were not included in the this analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8 | Week 4 | 0.8124 Geometric mean ratio |
| Sacubitril/Valsartan (LCZ696) | Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8 | Week 8 | 0.7545 Geometric mean ratio |
| Valsartan | Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8 | Week 4 | 0.9826 Geometric mean ratio |
| Valsartan | Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8 | Week 8 | 0.9310 Geometric mean ratio |
Comparison: Week 4p-value: <0.000195% CI: [0.76, 0.91]ANCOVA
Comparison: Week 8p-value: <0.000195% CI: [0.74, 0.89]ANCOVA
Secondary
Proportional Change in NT-proBNP From Baseline to Week 8
This endpoint intended to assess the effect of sacubitril/valsartan vs. valsartan on change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to Week 8. NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure. The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline.
Time frame: Baseline and Week 8
Population: Full analysis set: All patients to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received. Patients with missing baseline NT-proBNP and/or missing data from Week 8 were not included in the this analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Proportional Change in NT-proBNP From Baseline to Week 8 | 0.6778 Geometric mean ratio |
| Valsartan | Proportional Change in NT-proBNP From Baseline to Week 8 | 0.7275 Geometric mean ratio |
p-value: 0.476695% CI: [0.7661, 1.1329]ANCOVA
Secondary
Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function
This endpoint calculated the incidences of a composite endpoint of worsening renal function defined as: * renal death (from adverse events data) * reaching end-stage renal disease (ESRD) (Sustained eGFR \<15mL/min/m2, chronic dialysis, or renal transplant) * ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline \[using central laboratory measurements (scheduled or unscheduled visits)\] The Investigator-reported AE and central laboratory data was used to identified event of interest in this secondary endpoint. Events that occurred in the randomized double-blind treatment phase were included in the analysis.
Time frame: Up to Week 84
Population: Full analysis set: All patients included in the double-blind phase to whom study treatment was assigned by randomization and at least 1 dose of study treatment was received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sacubitril/Valsartan (LCZ696) | Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function | 34 events of worsening renal function |
| Valsartan | Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function | 46 events of worsening renal function |
p-value: 0.315595% CI: [0.2496, 1.5649]negative binomial regression model