Differential Vascular and Endocrine Effects of Valsartan/Sacubitril in Heart Failure With Reduced Ejection Fraction

NCT ID: NCT03168568

Last Updated: 2020-11-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 79 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-04
• Study Completion Date: 2020-09-05

Brief Summary

The objective of this study is to evaluate whether valsartan/sacubitril leads to a superior improvement in endothelial function and endocrine status compared to valsartan alone.

Detailed Description

Valsartan/sacubitril (Entresto®; LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that has recently been approved for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). The drug consists of a 1:1 complex of the angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril. In a recent randomized controlled trial in patients with heart failure and reduced ejection fraction (PARADIGM-HF), valsartan/sacubitril significantly reduced all-cause and cardiovascular mortality as well as hospitalizations for heart failure compared to enalapril. The precise reason why combined angiotensin receptor and neprilysin blockade is superior to ACE blockade is still unclear and knowledge of the mechanisms involved would provide further insight which patients with symptomatic heart failure will particularly benefit from valsartan/sacubitril. On the one hand, many of the peptides affected by neprilysin blockade act on vascular endothelial cells. On the other, neprilysin inhibition may induce significant endocrine changes with a shift to more favorable hormonal profile in HFrEF patients. Detailed studies on the vascular and endocrine effects of valsartan/sacubitril in humans are lacking so far. The investigators hypothesize that valsartan/sacubitril results in an incremental improvement of endothelial dysfunction and endocrine imbalance over valsartan in patients with heart failure with reduced ejection fraction.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Valsartan/Sacubitril

Valsartan-Sacubitril 50mg/100mg twice daily, titrated to 200mg twice daily p.o. Duration of product administration: 3 months

Group Type: EXPERIMENTAL

Valsartan/Sacubitril or placebo

Intervention Type: DRUG

tablet (double dummy)

Valsartan

Valsartan 40mg/80mg twice daily, titrated to 160mg twice daily p.o Duration of product administration: 3 months

Group Type: ACTIVE_COMPARATOR

Valsartan or placebo

Intervention Type: DRUG

tablet (double dummy)

Interventions

Valsartan/Sacubitril or placebo

tablet (double dummy)

Intervention Type: DRUG

Valsartan or placebo

tablet (double dummy)

Intervention Type: DRUG

Other Intervention Names

Entresto®; LCZ696; Diovan®

Eligibility Criteria

Inclusion Criteria

1. Patients ≥ 18 years of age, male or female, with a diagnosis of symptomatic heart failure (NYHA class II-IV) per ESC heart failure guidelines

2. LVEF ≤ 40%

3. Established guideline-recommended therapy with an ACEI, ARB and a beta-blocker, as clinically indicated and tolerated, at stable doses for at least 3 weeks prior to inclusion.

Exclusion Criteria

1. History of hypersensitivity or allergy to any of the study drugs

2. History of angioedema.

3. Sitting systolic blood pressure <90 mmHg at Visit 1 (screening) or Visit 2 (randomization)

4. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).

5. Estimated GFR < 20 mL/min/1.73m2

6. Serum potassium > 5.5 mmol/L at Visit 1 (screening) or Visit 2 (randomization).

7. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1.

8. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 3 months after Visit 1.

9. Implantation of a cardiac resynchronization therapy device (CRTD) within 2 months prior Visit 1 or intent to implant a CRTD within next 3 months.

10. History of heart transplant, on a transplant list or with ventricular assistance device (VAD).

11. Presence of significant endocrine diseases.

12. Presence of active acute infectious diseases.

13. Known narrow-angle glaucoma

14. Known epilepsy

15. Cimino-shunt operation on both arms

16. Pregnancy, intention thereof during study; lack of sufficient contraception; breastfeeding

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

University of Zurich

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University Heart Center Zurich

Zurich, , Switzerland

Countries

Switzerland

References

Nagele MP, Haider T, Kreysing L, Barthelmes J, Nebunu D, Rossi VA, Hebeisen M, Sudano I, Ruschitzka F, Flammer AJ. Vascular Endothelial Effects of Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction: Randomized Controlled Trial. JACC Adv. 2024 Nov 13;3(12):101392. doi: 10.1016/j.jacadv.2024.101392. eCollection 2024 Dec.

Reference Type: DERIVED

PMID: 39606217 (View on PubMed)

Other Identifiers

VASCEND

Identifier Type: -

Identifier Source: org_study_id