NCT03300427 - The Effects of Sacubitril/Valsartan on Cardiac Oxygen Consumption and Efficiency of Cardiac Work in Heart Failure Patients | Crick

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

55

Conditions

Heart Failure

Interventions

sacubitril/valsatranDRUG

sacubitril/valsatran 100 or 200 mg BID

valsartanDRUG

Valsartan 80 or 160 mg BID

placebo to valsartanDRUG

placebo to valsartan 80 or 160 BID

placebo to sacubitril/valsartan

Eligibility

Sex: ALLMin age: 40 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Locations (1)

Novartis Investigative Site

Turku, Finland

Outcomes

Primary Outcomes

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)

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)

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.