Acute Heart Failure
Conditions
Keywords
Acute, Heart Failure, reduced ejection fraction, NTproBNP, Heart failure with reduced ejection fraction (HFREF)
Brief summary
The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).
Interventions
sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
DRUGEnalapril
Enalapril tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.
DRUGsacubitril/valsartan (LCZ696) matching placebo
matching placebo of sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
enalapril matching placebo tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed. 2. Currently hospitalized for ADHF. 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) at time of hospitalization. 3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status: * SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension * No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization * No i.v. inotropic drugs for 24 hours prior to randomization * No i.v. vasodilators including nitrates within last 6 hours prior to randomization 4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of \>40%. 5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization. Key
Exclusion criteria
1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days. 2. Enrollment in any other clinical trial involving an investigational agent or investigational device. 3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor). 4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy. 5. Requirement of treatment with both ACE inhibitor and ARB. 6. eGFR \< 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening. 7. Serum potassium \> 5.2 mEq/L at screening. 8. 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 9. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1. 10. 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. 11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline | Baseline, Week 4 and Week 8 | To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) between week 4 and 8. Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Incidences of Hyperkalemia | 8 weeks of treatment | Hyperkalemia is defined as Potassium level \>5.5 mEq/L. Hyperkalemia is the medical term that describes a potassium level in your blood that's higher than normal. Potassium is a chemical that is critical to the function of nerve and muscle cells, including those in your heart. |
| Number of Patients With Incidences of Angioedema | 8 weeks of treatment | Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with difficulty in breathing. |
| Change From Baseline in High Sensitivity Troponin (Hs-Troponin) | Baseline, Week 4/Week 8 | time-averaged (Weeks 4 and 8) change from baseline in hs-troponin T. hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions. |
| Number of Patients With Incidences of Symptomatic Hypotension | 8 weeks of treatment | Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache. |
| Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio | Baseline, Week 4 and Week 8 | Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP to urinary creatinine ratio. Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning). |
| Change From Baseline in BNP to NTproBNP Ratio | baseline, Week 4 and Week 8 | Time-averaged (Weeks 4 and 8) change from baseline in BNP to NT-proBNP ratio. BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure. |
| N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8 | Baseline, Week 8 | BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure. Plasma NT-proBNP (pg/mL) values were Week 8 visit. |
| Change From Baseline in Urinary cGMP | Baseline, Week 4 and Week 8 | Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP. Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide) |
Countries
United States
Participant flow
Recruitment details
A total of 964 patients were screened for the study. Of these, 887 patients were randomized, 444 to enalapril and 443 to sacubitril/valsartan, and 875 randomized patients were treated.
Pre-assignment details
Patients were randomized 1:1 to sacubitril/valsartan or enalapril. At the end of the 8-week treatment period, all patients had a 36-hour washout from study treatment prior to starting the open-label extension to ensure that the blinding of the core study was maintained.
Participants by arm
| Arm | Count |
|---|---|
| Enalapril Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement.
Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack) | 441 |
| Sacubitril/Valsartan (LCZ696) Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement. Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack). | 440 |
| Total | 881 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind | Adverse Event | 45 | 51 |
| Double-blind | Death | 6 | 4 |
| Double-blind | Lost to Follow-up | 7 | 5 |
| Double-blind | Noncompliance with study treatment | 6 | 5 |
| Double-blind | Physician Decision | 4 | 3 |
| Double-blind | Protocol Violation | 1 | 1 |
| Double-blind | Subject/Guardian decision | 21 | 16 |
| Double-blind | Technical problems | 1 | 0 |
| Double-blind | Withdrawal by Subject | 5 | 6 |
| Open-label | Adverse Event | 0 | 30 |
| Open-label | Death | 0 | 1 |
| Open-label | Lost to Follow-up | 0 | 7 |
| Open-label | Physician Decision | 0 | 1 |
| Open-label | Subject/Guardian decision | 0 | 11 |
| Open-label | Technical problems | 0 | 1 |
| Open-label | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Enalapril | Sacubitril/Valsartan (LCZ696) | Total |
|---|---|---|---|
| Age, Customized <65 years | 232 Participants | 253 Participants | 485 Participants |
| Age, Customized ≥65 years | 209 Participants | 187 Participants | 396 Participants |
| Age, Customized < 75 years | 363 Participants | 370 Participants | 733 Participants |
| Age, Customized ≥75 years | 78 Participants | 70 Participants | 148 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants | 34 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 399 Participants | 405 Participants | 804 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 133 Participants | 113 Participants | 246 Participants |
| Sex: Female, Male Male | 308 Participants | 327 Participants | 635 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 436 | 10 / 439 | 6 / 828 | 16 / 851 |
| other Total, other adverse events | 139 / 436 | 153 / 439 | 65 / 828 | 199 / 851 |
| serious Total, serious adverse events | 132 / 436 | 117 / 439 | 104 / 828 | 191 / 851 |
Outcome results
Primary
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline
To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) between week 4 and 8. Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.
Time frame: Baseline, Week 4 and Week 8
Population: Full analysis set (FAS): consisted of all randomized patients with the exception for those patients who had not been qualified for randomization and had not received study treatment, but had been inadvertently randomized into the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline | 0.7466 pg/ml |
| Sacubitril/Valsartan (LCZ696) | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline | 0.5333 pg/ml |
p-value: <0.000195% CI: [0.6315, 0.808]ANCOVA
Secondary
Change From Baseline in BNP to NTproBNP Ratio
Time-averaged (Weeks 4 and 8) change from baseline in BNP to NT-proBNP ratio. BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.
Time frame: baseline, Week 4 and Week 8
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | Change From Baseline in BNP to NTproBNP Ratio | 0.9174 Ratio |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in BNP to NTproBNP Ratio | 1.3527 Ratio |
p-value: <0.000195% CI: [1.3752, 1.581]ANCOVA
Secondary
Change From Baseline in High Sensitivity Troponin (Hs-Troponin)
time-averaged (Weeks 4 and 8) change from baseline in hs-troponin T. hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions.
Time frame: Baseline, Week 4/Week 8
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | Change From Baseline in High Sensitivity Troponin (Hs-Troponin) | 0.7477 Ratio |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in High Sensitivity Troponin (Hs-Troponin) | 0.6345 Ratio |
p-value: 0.001195% CI: [0.7694, 0.9361]ANCOVA
Secondary
Change From Baseline in Urinary cGMP
Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP. Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide)
Time frame: Baseline, Week 4 and Week 8
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | Change From Baseline in Urinary cGMP | 0.9641 Ratio |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Urinary cGMP | 1.5895 Ratio |
p-value: <0.000195% CI: [1.4559, 1.8669]ANCOVA
Secondary
Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio
Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP to urinary creatinine ratio. Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning).
Time frame: Baseline, Week 4 and Week 8
Population: FAS
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio | 0.8258 Ratio |
| Sacubitril/Valsartan (LCZ696) | Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio | 1.1714 Ratio |
p-value: <0.000195% CI: [1.3248, 1.519]ANCOVA
Secondary
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8
BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure. Plasma NT-proBNP (pg/mL) values were Week 8 visit.
Time frame: Baseline, Week 8
Population: Full analysis set (FAS): consisted of all randomized patients with the exception for those patients who had not been qualified for randomization and had not received study treatment, but had been inadvertently randomized into the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8 | 0.6443 pg/ml |
| Sacubitril/Valsartan (LCZ696) | N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8 | 0.4596 pg/ml |
p-value: <0.000195% CI: [0.6171, 0.8245]ANCOVA
Secondary
Number of Patients With Incidences of Angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with difficulty in breathing.
Time frame: 8 weeks of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enalapril | Number of Patients With Incidences of Angioedema | 11 Participants |
| Sacubitril/Valsartan (LCZ696) | Number of Patients With Incidences of Angioedema | 1 Participants |
Secondary
Number of Patients With Incidences of Hyperkalemia
Hyperkalemia is defined as Potassium level \>5.5 mEq/L. Hyperkalemia is the medical term that describes a potassium level in your blood that's higher than normal. Potassium is a chemical that is critical to the function of nerve and muscle cells, including those in your heart.
Time frame: 8 weeks of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enalapril | Number of Patients With Incidences of Hyperkalemia | 41 Participants |
| Sacubitril/Valsartan (LCZ696) | Number of Patients With Incidences of Hyperkalemia | 51 Participants |
Secondary
Number of Patients With Incidences of Symptomatic Hypotension
Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache.
Time frame: 8 weeks of treatment
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enalapril | Number of Patients With Incidences of Symptomatic Hypotension | 56 participants |
| Sacubitril/Valsartan (LCZ696) | Number of Patients With Incidences of Symptomatic Hypotension | 66 participants |