Heart Failure
Conditions
Keywords
Heart failure with reduced left ventricular ejection fraction, LVEF, Cardiac dysfunction, Heart muscle dysfunction, Left ventricular (LV) dilation, Left ventricular hypertrophy, HF, AHF, CHF, CCF, acute heart failure, chronic heart failure, congestive heart failure, congestive cardiac failure
Brief summary
This is a phase IV, prospective, randomized, double-blind, double-dummy, parallel-group study. The study assessed the effects of 6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency of cardiac work in patients with NYHA II-III heart failure (HF) and reduced systolic function using 11C-acetate positron emission tomography (PET) and echocardiography.
Detailed description
Subjects were randomized into valsartan or sacubitril/valsartan arms in a 1:1 ratio. Regardless of the treatment arm a subject is in, the study drug was up-titrated to the highest tolerated dose level during the scheduled study visits. The different strengths of the two study drugs were not identical in appearance so the possible dose modification(s) during the treatment period could not be performed in a blinded manner. Subjects started on valsartan 80 mg BID or sacubitril/valsartan 100 mg BID dose and there was only one scheduled up-titration visit after the randomization. Exception for this were the subjects that were on valsartan 160 mg BID dose during the run-in phase. These subjects were randomized directly to valsartan 160 mg BID or sacubitril/valsartan 100 mg BID. Subjects that were randomized to valsartan arm had similar visit after which they continued on the same dose. For subjects that were randomized from valsartan 160 mg BID to sacubitril/valsartan 100 mg BID the dose was up-titrated to 200 mg BID if clinically possible. The total duration for each patient was planned to be about 14 weeks but could be longer if required for scheduling purposes . The longest participation, from signing of ICF until end of study, was 26 weeks.
Interventions
DRUGsacubitril/valsatran
sacubitril/valsatran 100 or 200 mg BID
DRUGvalsartan
Valsartan 80 or 160 mg BID
placebo to valsartan 80 or 160 BID
DRUGplacebo to sacubitril/valsartan
placebo to sacubitril/valsartan 100 or 200 mg BID
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 40-80 years of age * Chronic HF with reduced EF (left ventricle EF 25-35%) and NYHA class II-III symptoms. * Systolic BP 110-160 mm Hg * Optimal standard HF therapy according to European Society of Cardiology (ESC) guidelines at a stable dose for at least 4 weeks before the screening visit.
Exclusion criteria
* Estimated glomerular filtration rate (eGFR) \< 45 ml/min * Serum potassium \> 5.2 mmol/l and creatinine \>1.5 x ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Energetic Efficiency | Baseline, Visit 3 (approximately Week 8) | Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan. Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono Where * SBP : Systolic blood pressure during PET * SV : Stroke volume (Echocardiography) * HR : Heart rate * Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) * LV mass: Left ventricular mass Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed. No imputation of missing data was performed. |
| Change From Baseline in Myocardial Energetic Efficiency | Baseline, Visit 3 (approximately Week 8) | Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan. Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono Where * SBP : Systolic blood pressure during PET * SV : Stroke volume (Echocardiography) * HR : Heart rate * Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) * LV mass: Left ventricular mass Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed. No imputation of missing data was performed. |
| Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | Baseline, Visit 3 (approximately Week 8) | In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as: Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy. |
| Change From Baseline in Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | Baseline, Visit 3 (approximately Week 8) | In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as: Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy. |
Countries
Finland
Participant flow
Pre-assignment details
The patients who signed the ICF entered the screening/run-in period of the study. After the screening evaluations and confirmation of eligibility, the patients were allocated randomization numbers and randomized to receive the treatment assigned to each number in a blinded manner.
Participants by arm
| Arm | Count |
|---|---|
| Sacubitril/Valsartan subjects receive sacubitril/valsartan 100 mg orally twice daily (BID). The dose is then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration is not possible). | 27 |
| Valsartan subjects receive 80 mg orally twice daily (BID). The dose is then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration is not possible) | 28 |
| Total | 55 |
Baseline characteristics
| Characteristic | Sacubitril/Valsartan | Valsartan | Total |
|---|---|---|---|
| Age, Continuous | 63.1 years STANDARD_DEVIATION 10.1 | 64.4 years STANDARD_DEVIATION 7.5 | 63.8 years STANDARD_DEVIATION 8.8 |
| Race/Ethnicity, Customized White | 27 Participants | 28 Participants | 55 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 22 Participants | 21 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 28 |
| other Total, other adverse events | 4 / 27 | 5 / 28 |
| serious Total, serious adverse events | 1 / 27 | 0 / 28 |
Outcome results
Primary
Change From Baseline in Myocardial Energetic Efficiency
Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan. Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono Where * SBP : Systolic blood pressure during PET * SV : Stroke volume (Echocardiography) * HR : Heart rate * Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) * LV mass: Left ventricular mass Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed. No imputation of missing data was performed.
Time frame: Baseline, Visit 3 (approximately Week 8)
Population: Full analysis set (FAS): consisted of all randomized patients who had received at least one dose of study medication in the treatment period and had at least one post-baseline assessment of any efficacy endpoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in Myocardial Energetic Efficiency | 1679.8 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 9282.4 |
| Valsartan | Change From Baseline in Myocardial Energetic Efficiency | 2907.1 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 11571.5 |
Comparison: The study hypothesis is that short-term therapy with sacubitril/valsartan added on standard HF therapy improves cardiac efficiency in subjects with systolic HF.p-value: 0.759495% CI: [-6781.7, 4981.8]ANCOVA
Primary
Change From Baseline in Viable Myocardial Energetic Efficiency (Sensitivity Analysis)
In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as: Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy.
Time frame: Baseline, Visit 3 (approximately Week 8)
Population: Full analysis set (FAS): consisted of all randomized patients who had received at least one dose of study medication in the treatment period and had at least one post-baseline assessment of any efficacy endpoints.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sacubitril/Valsartan | Change From Baseline in Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | 1751.4 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 9098.1 |
| Valsartan | Change From Baseline in Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | 2674.3 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 11551.2 |
Comparison: The study hypothesis is that short-term therapy with sacubitril/valsartan added on standard HF therapy improves cardiac efficiency in subjects with systolic HF.p-value: 0.842295% CI: [-6365.5, 5214.5]ANCOVA
Primary
Myocardial Energetic Efficiency
Positron emission tomography (PET) imaging and echocardiography were performed before randomization (after a minimum of 4 weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg BID of sacubitril/valsartan. Cardiac efficiency was calculated based on the following formula: Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono Where * SBP : Systolic blood pressure during PET * SV : Stroke volume (Echocardiography) * HR : Heart rate * Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) * LV mass: Left ventricular mass Visit 3 was performed after the study treatment was on a stable dose for a minimum of 6 weeks. It could be performed before or after 8 weeks, based on when the last dose modification was performed. No imputation of missing data was performed.
Time frame: Baseline, Visit 3 (approximately Week 8)
Population: Full analysis set (FAS): consisted of all randomized patients who had received at least one dose of study medication in the treatment period and had at least one post-baseline assessment of any efficacy endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sacubitril/Valsartan | Myocardial Energetic Efficiency | Baseline (Day 1) | 48621.3 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 17001.4 |
| Sacubitril/Valsartan | Myocardial Energetic Efficiency | Visit 3 | 50301.0 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 20842.7 |
| Valsartan | Myocardial Energetic Efficiency | Baseline (Day 1) | 50035.7 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 18068.2 |
| Valsartan | Myocardial Energetic Efficiency | Visit 3 | 52942.8 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 19702.5 |
Primary
Viable Myocardial Energetic Efficiency (Sensitivity Analysis)
In addition to the derivation of the primary endpoint, an alternative formula was used, where the viable myocardial energetic efficiency was derived as: Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono Where vKmono is the viable myocardium clearance rate. This alternative parameter was included as a sensitivity analysis to exclude possible bias related to scar tissue in patients with ischemic myopathy.
Time frame: Baseline, Visit 3 (approximately Week 8)
Population: Full analysis set (FAS): consisted of all randomized patients who had received at least one dose of study medication in the treatment period and had at least one post-baseline assessment of any efficacy endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sacubitril/Valsartan | Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | Baseline | 48163.0 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 16719.8 |
| Sacubitril/Valsartan | Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | Visit 3 | 49914.4 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 20821.2 |
| Valsartan | Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | Baseline | 49575.6 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 18255.8 |
| Valsartan | Viable Myocardial Energetic Efficiency (Sensitivity Analysis) | Visit 3 | 52249.9 (((mmhg x ml x bpm) /g)/(1/min)) | Standard Deviation 19585.8 |