Clinical trial NCT03190304: The Effect of Neprilysin (LCZ696) on Exercise Tolerance in Patients With Heart Failure
Official title: The Effect of NEPRIlysin (LCZ696) on EXercise TOLerance, Muscle Vasodilatation, Muscle Strength and Body Composition in Patients With Heart Failure - NEPRIExTol-HF Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Exercise Tolerance
Vasodilation
Body Composition
Muscle Strength
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
First posted: 2017-06-16
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: double-blind, randomized clinical trial
Primary purpose: TREATMENT

Brief summary: Studies with new drugs in the treatment of heart failure (HF), such as the combination of valsartan/sacubitril, also known as LCZ696, have demonstrated important clinical impact on the morbidity and mortality outcomes in HF population. However, the effect of LCZ696 on the pathophysiological mechanisms of HF such as exercise tolerance (peak VO2) and peripheral muscle blood flow is not known. Since LCZ696 is a new drug with promising effects on the treatment of HF, the objective of the present study will be to evaluate the effect of LCZ696 in patients with HF on: 1) peak VO2, 2) 6-minute walk test, 3) peripheral muscle blood flow, 4) muscle strength, and 5) body composition.

Detailed description: Heart failure (HF) with reduced ventricular ejection fraction is a disease that affects around 5.7 million people in the United States, with a mortality rate of approximately 50% within 5 years. HF is characterized by an exacerbation of the renin-angiotensin-aldosterone system (RAAS), which leads to an increase in sympathetic nerve outflow, peripheral vasoconstriction, and reduced functional capacity. Moreover, many clinical trials have been developed for the treatment of HF patients focused on inhibition of RAAS, such as enalapril. Nevertheless, hospitalization and mortality rates in this population are excessive. However, studies with new drugs, such as the combination of valsartan/sacubitril, also known as LCZ696, have demonstrated important clinical impact on the morbidity and mortality outcomes in HF population. However, the effect of LCZ696 on the pathophysiological mechanisms of HF such as exercise tolerance (peak VO2) and peripheral muscle blood flow is not known. Since LCZ696 is a new drug with promising effects on the treatment of HF, the objective of the present study will be to evaluate the effect of LCZ696 in patients with HF on: 1) peak VO2, 2) 6-minute walk test, 3) peripheral muscle blood flow, 4) muscle strength, and 5) body composition.

Eligibility criteria: Inclusion Criteria:

1. Symptomatic patients with heart failure (men and women) aged \>18 years,
2. Functional class II, III or IV by the New York Heart Association (NYHA)
3. Left ventricular ejection fraction \<35%
4. Ischemic and nonischemic etiology
5. Type B natriuretic peptide (BNP) \>150 pg/ml (or pro-BNP \[N-terminal-proBNP\] ≥ 600 pg / ml) or if the patient was hospitalized for cardiac decompensation within the preceding 12 months, BNP \>100 pg/ml (or N-terminal-proBNP ≥ 400 pg / ml)

Exclusion Criteria:

1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), or neprilysin inhibitors, as well as known or suspected contraindications to the study drugs.
2. Previous history of intolerance to recommended target doses of ACEIs or ARBs.
3. Known history of angioedema.
4. Requirement for treatment with both ACEIs and ARBs.
5. Current acute decompensated heart failure (exacerbation of chronic heart failure manifested by signs and symptoms that may require intravenous therapy).
6. Symptomatic hypotension.
7. Estimated glomerular filtration rate (eGFR) \<30%.
8. Serum potassium \>5.4 mmol/L.
9. Acute coronary syndrome, stroke, transient ischaemic attack, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within the 3 months.
10. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months.
11. Implantation of a cardiac resynchronization therapy (CRT) device within 3 months or intent to implant a CRT.
12. History of heart transplant or on a transplant list or with left ventricular (LV) assistance device.
13. History of severe pulmonary disease.
14. Diagnosis of peripartum- or chemotherapy-induced cardiomyopathy within the 12 months.
15. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months.
16. Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker.
17. Presence of haemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation.
18. Presence of other haemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis.
19. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including, but not limited to, any of the following: History of active inflammatory bowel disease during the 12 months. Active duodenal or gastric ulcers during the 3 months. Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine aminotransferase values exceeding 2x upper limit of normal, history of hepatic encephalopathy, history of oesophageal varices, or history of porto-caval shunt. Current treatment with cholestyramine or colestipol resins.
20. Presence of any other disease with a life expectancy of \<5 years.

Primary outcomes:
measure: Exercise tolerance
timeFrame: 6 months
Secondary outcomes:
measure: Walking distance
timeFrame: 6 months
measure: Muscle vasodilation
timeFrame: 6 months
measure: Muscle strength
timeFrame: 6 months
measure: Body composition
timeFrame: 6 months
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Marcelo Rodrigues dos Santos
state: SP
Study officials:
affiliation: Heart Institute (InCor), University of Sao Paulo Medical School
name: Antonio P Barretto, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dos Santos MR, Alves MNN, Jordao CP, Pinto CEN, Correa KTS, de Souza FR, da Fonseca GWP, Tomaz Filho J, Costa M, Pereira RMR, Negrao CE, Barretto ACP. Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study. Am Heart J. 2021 Sep;239:1-10. doi: 10.1016/j.ahj.2021.05.005. Epub 2021 May 14.