Heart Failure and Reduced Ejection Fraction
Conditions
Keywords
Heart Failure, Reduced Ejection Fraction, Central Aortic Stiffness, Vascular, Echocardiogram, Aortic Stiffness
Brief summary
To determine whether treatment with sacubitril/valsartan provides a superior effect on aortic characteristic impedance compared to enalapril in patients with heart failure and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) after 12 weeks of treatment. The primary endpoint is the change in aortic characteristic impedance (Zc = dP/dQ in early systole) between baseline and Week 12.
Interventions
24/26mg, 49/51mg and 97/103mg oral, tablets.
DRUGEnalapril
2.5mg, 5mg, and 10mg, oral, tablets
matching placebo (2.5mg, 5mg and 10mg) oral, tablets
matching placebo (24/26mg, 49/51mg and 97/103mg) oral, tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* History of HTN and one of the following at BOTH screening and pre-randomization: 1. SBP \>105 mm Hg on antihypertensive medication. 2. SBP \>/= 140 mm Hg and NOT on antihypertensive medication. * NYHA class I-III heart failure and with reduced ejection fraction \</= 40%, as determined by any local measurement made within the past 12 months using echocardiography, MUGA, CT scanning, MRI, ventricular angiography or single-photon emission computed tomography (SPECT), provided no subsequent measurement above 40%. Patients who have had an intervening medical event (e.g. myocardial infarction) or procedure (e.g. revascularization, cardiac resynchronization), must have a reassessment of EF ≥ 3 months following the event to ensure that eligibility criteria are still met. * On stable doses of treatment with guideline-directed therapy, other than ACEis and ARBs prior to randomization. 1. If the patient is currently taking an ACEi, a 36-hour washout is required prior to randomization (Visit 2). 2. If the patient is currently taking an ARB, they must discontinue the ARB before initiation of study treatment however washout is not required. * On an optimal medical regiment of diuretics and background medications to effectively treat co-morbidities such as HTN, DM, and coronary artery disease. Key
Exclusion criteria
* History of hypersensitivity to any of the study drigs, including history of hypersensitivity to drugs of similar chemical classes, or allergy to ACEis, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs. * Previous history of intolerance to sacubitril and valsartan, ACEi or ARB standard of care doses despite appropriate and gradual up-titration. * History of angioedema, drug-related or otherwise. * Requirement of treatment with both ACE inhibitor and ARB. * Current or prior treatment with sacubitril and valsartan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Aortic Characteristic Impedance at Week 12 | Baseline, Week 12 | Aortic characteristic impedance, Zc, is the ratio of the change in pressure (dP)produced by a given change in flow (dQ) in early systole, i.e., Zc = dP/dQ. Zc is related directly to aortic wall stiffness and inversely to lumen area. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4 | pre-dose and 4 hours post dose at week 4 | Pearson correlation coefficient between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as U-cGMP/U-creatinine ratio (nmol/mmol) during both trough and 4 hours post-dose at Week 4 |
| Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | Baseline, Week 12 | Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) |
| Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain | Baseline, Week 12 | Parameter measured by echocardiography. |
| Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi) | Baseline, Week 12 | Parameter measured by echocardiography |
| Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging) | Baseline, Week 12 | Parameter measured by echocardiography |
| Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4 | Pre-dose and 4 hours post dose at week 4 | Pearson correlation coefficients between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as BNP (pg/ML) during both trough and 4 hours post-dose at Week 4 |
| Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF) | Baseline, Week 12 | Parameter measured by echocardiography |
| Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees) | Baseline, Week 12 | Parameter measured by echocardiography |
| Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi) | Baseline, Week 12 | Parameter measured by echocardiography |
| Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi) | Baseline, Week 12 | Parameter measured by echocardiography |
| Change From Basekine in Echocardiographic Measure: Mitral E/E' | Baseline, Week 12 | Parameter measured by echocardiography |
Countries
United States
Participant flow
Recruitment details
Of 892 patients screened for the study, 465 completed screening and were enrolled. Of the 465 randomized, 1 patient was randomized in error to the sacubitril/valsartan group and was not treated. The Full Analysis Set and Safety Set are based on 464 patients who received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Enalapril (Double-Blind Phase) minimum dose: 2.5mg, BID, oral, tablet. maximum dose: 10 mg, BID, oral tablet. All patients began on Dose Level 1 (2.5mg) and were titrated every two weeks to target Dose level 3 (10mg). | 233 |
| Sacubitril/Valsartan (Double-Blind Phase) minimum dose: 24/26mg, BID, oral, tablet. maximum dose: 97/103mg, BID, oral, tablet. All patients began on Dose Level 1 (24/26mg) and were titrated every two weeks to target Dose level 3 (97/103mg). | 231 |
| Total | 464 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 8 |
Baseline characteristics
| Characteristic | Sacubitril/Valsartan (Double-Blind Phase) | Enalapril (Double-Blind Phase) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 141 Participants | 133 Participants | 274 Participants |
| Age, Categorical Between 18 and 65 years | 90 Participants | 100 Participants | 190 Participants |
| Race/Ethnicity, Customized Asian | 2 articipants | 2 articipants | 4 articipants |
| Race/Ethnicity, Customized Black | 62 articipants | 53 articipants | 115 articipants |
| Race/Ethnicity, Customized Caucasian (White) | 166 articipants | 175 articipants | 341 articipants |
| Race/Ethnicity, Customized Native American | 0 articipants | 1 articipants | 1 articipants |
| Race/Ethnicity, Customized Other | 1 articipants | 0 articipants | 1 articipants |
| Race/Ethnicity, Customized Unknown | 0 articipants | 2 articipants | 2 articipants |
| Sex: Female, Male Female | 61 Participants | 48 Participants | 109 Participants |
| Sex: Female, Male Male | 170 Participants | 185 Participants | 355 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 233 | 1 / 231 | 5 / 454 |
| other Total, other adverse events | 32 / 233 | 43 / 231 | 42 / 454 |
| serious Total, serious adverse events | 21 / 233 | 17 / 231 | 40 / 454 |
Outcome results
Primary
Change From Baseline in Aortic Characteristic Impedance at Week 12
Aortic characteristic impedance, Zc, is the ratio of the change in pressure (dP)produced by a given change in flow (dQ) in early systole, i.e., Zc = dP/dQ. Zc is related directly to aortic wall stiffness and inversely to lumen area.
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Aortic Characteristic Impedance at Week 12 | -0.7 dyne x sec/cm5 | Standard Error 5.5 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Aortic Characteristic Impedance at Week 12 | -2.9 dyne x sec/cm5 | Standard Error 5.5 |
p-value: 0.782795% CI: [-17.6, 13.2]ANCOVA
Secondary
Change From Basekine in Echocardiographic Measure: Mitral E/E'
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Basekine in Echocardiographic Measure: Mitral E/E' | 0.32 Ratio | Standard Error 0.36 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Basekine in Echocardiographic Measure: Mitral E/E' | -1.43 Ratio | Standard Error 0.36 |
Comparison: vs Enalaprilp-value: 0.000795% CI: [-2.76, -0.75]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain
Parameter measured by echocardiography.
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain | -0.21 Percentage | Standard Error 0.16 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Global Longitudinal Strain | -0.34 Percentage | Standard Error 0.16 |
p-value: 0.579295% CI: [-0.58, 0.33]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi)
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi) | 0.63 mL/m2 | Standard Error 0.44 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Atrial Volume Index (LAVi) | -2.17 mL/m2 | Standard Error 0.44 |
p-value: <0.000195% CI: [-4.02, -1.59]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF)
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF) | 1.30 Percentage | Standard Error 0.37 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Ventricular Ejection Fraction (LVEF) | 1.94 Percentage | Standard Error 0.38 |
p-value: 0.235495% CI: [-0.41, 1.68]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi)
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi) | -3.18 mL/m2 | Standard Error 0.61 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Ventricular End Diastolic Volume Index (LVEDVi) | -5.15 mL/m2 | Standard Error 0.62 |
p-value: 0.024295% CI: [-3.68, -0.26]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi)
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi) | -3.28 mL/m2 | Standard Error 0.55 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Left Ventricular End Systolic Volume Index (LVESVi) | -4.86 mL/m2 | Standard Error 0.56 |
p-value: 0.045295% CI: [-3.13, -0.03]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging)
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging) | -0.00 cm/sec | Standard Error 0.11 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Mitral Annular E' Velocity (Doppler Tissue Imaging) | -0.03 cm/sec | Standard Error 0.11 |
p-value: 0.861795% CI: [-0.33, 0.27]ANCOVA
Secondary
Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees)
Parameter measured by echocardiography
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees) | 0.03 Ea/Ees Ratio | Standard Error 0.01 |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in Echocardiographic Measure: Ventricular-vascular Coupling (Ea/Ees) | 0.02 Ea/Ees Ratio | Standard Error 0.02 |
p-value: 0.821595% CI: [-0.05, 0.04]ANCOVA
Secondary
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP)
Time frame: Baseline, Week 12
Population: Full Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Enalapril (Double-Blind Phase) | Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | 0.9500 pg/mL |
| Sacubitril/Valsartan (Double-Blind Phase) | Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | 0.6334 pg/mL |
p-value: <0.000195% CI: [0.5858, 0.7589]ANCOVA
Secondary
Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4
Pearson correlation coefficients between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as BNP (pg/ML) during both trough and 4 hours post-dose at Week 4
Time frame: Pre-dose and 4 hours post dose at week 4
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (pre-dose) | 0.022 Pearson's Correlation |
| Enalapril (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (post-dose) | -0.127 Pearson's Correlation |
| Sacubitril/Valsartan (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (pre-dose) | 0.070 Pearson's Correlation |
| Sacubitril/Valsartan (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: B-type Natriuretic Peptide (BNP) During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (post-dose) | 0.016 Pearson's Correlation |
Secondary
Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4
Pearson correlation coefficient between changes from baseline in aortic characteristic impedance (dyne x sec/cm5) and biomarker levels such as U-cGMP/U-creatinine ratio (nmol/mmol) during both trough and 4 hours post-dose at Week 4
Time frame: pre-dose and 4 hours post dose at week 4
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Enalapril (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (pre-dose) | 0.087 Pearson's correlation coefficient |
| Enalapril (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (post-dose) | 0.110 Pearson's correlation coefficient |
| Sacubitril/Valsartan (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (pre-dose) | 0.098 Pearson's correlation coefficient |
| Sacubitril/Valsartan (Double-Blind Phase) | Pearson Correlation Coefficient Between Change From Baseline in Aortic Characteristic Impedance and Biomarker Levels: cGMP/U-creatinine During Both Trough and 4 Hours Post-dose at Week 4 | Week 4 (post-dose) | 0.157 Pearson's correlation coefficient |