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

Study Overview
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Brief Summary
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The study will assess the effects of 6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on cardiac oxygen consumption and 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.

Official Title
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Controlled Trial on the Short-term Effects of Sacubitril/Valsartan Therapy on Cardiac Oxygen Consumption and Efficiency of Cardiac Work in Patients With NYHA II-III Heart Failure and Reduced Systolic Function Using 11C-acetate Positron Emission Tomography and Echocardiography

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: sacubitril/valsatran
* Drug: valsartan
* Drug: placebo to valsartan
* Drug: placebo to sacubitril/valsartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sacubitril/valsartan<br>Participants will be randomized to two treatment arms in a 1:1, double blinded fashion. Two strengths of sacubitril/valsartan will be available for use after randomization, 49 mg sacubitril/51 mg valsartan and 97 mg sacubitril/103 mg valsartan. After randomization, subjects in this arm will receive sacubitril/valsartan 100 mg orally twice daily (BID). The dose will be then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration is not possible). Dose modifications are allowed until week 4 after the randomization. In order to be eligible for the final assessments, the subject has to tolerate the 100 mg BID dose at the minimum. In total, participants will be on sacubitril/valsartan for a minimum of 8 weeks and a maximum of 10 weeks. | Drug: sacubitril/valsatran<br>* sacubitril/valsatran 100 or 200 mg BID<br>Drug: placebo to valsartan<br>* placebo to valsartan 80 or 160 BID<br>|
| Active Comparator: valsartan<br>Participants will be randomized to two treatment arms in a 1:1, double blinded fashion. In this arm, Valsartan 80 mg and 160 mg will be used as comparative drug, taken orally BID at home. Depending on the screening/run-in dose the subjects in this arm will get either valsartan 80 mg BID or valsartan 160 mg BID. During the treatment period the dose of valsartan will be up-titrated to the highest tolerated dose (160 mg BID) or maintained at 80 mg BID if up-titration is not possible. Dose modifications are allowed until week 4 after the randomization. In order to be eligible for the final assessments, the subject has to tolerate at least 80 mg BID dose of valsartan. The treatment phase will be a minimum of 8 weeks, and a maximum of 10 weeks. | Drug: valsartan<br>* Valsartan 80 or 160 mg BID<br>Drug: placebo to sacubitril/valsartan<br>* placebo to sacubitril/valsartan 100 or 200 mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in cardiac oxygen consumption and efficiency of cardiac work | Change from baseline in cardiac oxygen consumption and efficiency of cardiac work after 6 weeks of stable sacubitril/valsartan therapy compared to that of in patients on valsartan therapy using 11C-acetate positron emission tomography (PET). | baseline, at week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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