The Effects of Sacubitril/Valsartan on Cardiac Oxygen Consumption and Efficiency of Cardiac Work in Heart Failure Patients

Phase 4

Completed

Conditions: Heart Failure

Interventions: Drug: sacubitril/valsatran
Drug: valsartan
Drug: placebo to valsartan
Drug: placebo to sacubitril/valsartan

Registration Number: NCT03300427

Lead Sponsor: Novartis Pharmaceuticals

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
sacubitril/valsartan	sacubitril/valsatran	subjects received sacubitril/valsartan 100 mg orally twice daily (BID). The dose was then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration was not possible).
sacubitril/valsartan	placebo to valsartan	subjects received sacubitril/valsartan 100 mg orally twice daily (BID). The dose was then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration was not possible).
valsartan	valsartan	subjects received 80 mg orally twice daily (BID). The dose was then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration was not possible)
valsartan	placebo to sacubitril/valsartan	subjects received 80 mg orally twice daily (BID). The dose was then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration was not possible)

Primary Outcome Measures

Name	Time	Method
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.