Effect of Angiotensin Receptor/Neprilysin Inhibitors on Transthyretin Cardiac Amyloidosis and Heart Failure with Reduced Ejection Fraction (SAVA-TTR)

Effect of Pharmacological Treatment with Angiotensin Receptor/Neprilysin Inhibitors on Transthyretin Cardiac Amyloidosis and Heart Failure with Reduced Ejection Fraction (SAVA-TTR)

Prospective, randomized, multicenter, open-label clinical trial to evaluate the safety and efficacy of Sacubitril/Valsartan (Sac/Vals) compared to no initiation of the drug in patients with transthyretin cardiac amyloidosis (ATTR) and heart failure with reduced ejection fraction (LVEF ≤40%). The primary objective is to determine the impact of Sac/Vals treatment on systolic function by assessing the change in LVEF on echocardiogram at 12-month follow-up.

Study Overview

• Status: Not yet recruiting
• Conditions: Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)
• Intervention / Treatment: Drug: Sacubitril / Valsartan

Detailed Description

Transthyretin cardiac amyloidosis (ATTR) has emerged as a prevalent and underdiagnosed cause of heart failure (HF), affecting patients both with preserved left ventricular ejection fraction (LVEF) and with systolic dysfunction. It remains unclear whether this population benefits from standard treatments for HF with reduced LVEF or whether treatment with renin-angiotensin system inhibitors and neprilysin might even be harmful in ATTR.

The investigators plan to conduct a prospective, randomized, multicenter, open-label clinical trial to evaluate the safety and efficacy of Sacubitril/Valsartan (Sac/Vals), as recommended in current HF guidelines, versus no treatment in patients with ATTR and heart failure with reduced ejection fraction (HFrEF), including those with LVEF ≤40%.

Approximately 114 patients from four Spanish centers will be randomized 1:1 to receive Sac/Vals treatment (up to the maximum tolerated dose) or to not initiate the drug, with stratification by center and tafamidis treatment. It has been included a run-in period with a low dose of Sac/Vals to assess tolerance prior to randomization. Patients will have scheduled follow-up visits at 3, 6, and 12 months, during which clinical, functional, analytical, electrocardiographic, and echocardiographic variables will be evaluated.

The primary objective is to determine the impact of Sac/Vals treatment on systolic function in patients with ATTR and HFrEF by assessing the change in LVEF on echocardiogram at 12 months. Improvement in LVEF will be defined as an increase of ≥5% from the baseline echocardiogram to the 12-month follow-up.

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Esther Gonzalez Lopez, MD, PhD; Phone Number: +34 91 1916000; Email: egonzalezlopez@salud.madrid.org

Study Locations

• Spain
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro
      • Contact: Noemí Ramos López; Email: nramosl@cnic.es
      • Contact: Esther Gonzalez Lopez, MD, PhD; Phone Number: +34 91 1916000; Email: egonzalezlopez@salud.madrid.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients ≥ 18 years of age of both sexes.
• Patients diagnosed with ATTR cardiac amyloidosis as indicated in guidelines, both in its hereditary form (ATTRv) or wild-type form (ATTRwt).
• Patients initially evaluated or under follow-up in Cardiomyopathy/Heart Failure/Amyloidosis Units at participating centers.
• Heart failure and reduced ejection fraction: LVEF ≤40%, in functional class I, II, or III according to the New York Heart Association (NYHA).

Exclusion Criteria:

• NYHA Functional Class IV.
• Stage 4 and 5 chronic kidney disease (creatinine clearance by CKD-EPI <30 mL/min/1.73m²).
• Hyperkalemia (blood potassium levels > 5.4 mmol/L).
• Hypotension defined as systolic blood pressure (SBP) <100 mmHg on two consecutive measurements.
• Treatment with ACE inhibitors, ARBs, or sacubitril/valsartan at the time of enrollment.
• History of angioedema or hypersensitivity to ACE inhibitors or ARBs.
• Treatment with TTR gene silencers or diflunisal.
• Participation in another clinical trial.
• Pregnancy, breastfeeding, or fertile women unwilling to use adequate contraception throughout the study duration.
• Any condition that, in the investigator's opinion, compromises participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/Valsartan; Sacubitril/valsartan up to maximum tolerated dose	Drug: Sacubitril / Valsartan; Dose titration of Sacubitril/Valsartán to the maximum tolerated dose (maximum 97/103 mg)
No Intervention: No treatment; No initiation of Sacubitril/valsartan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular systolic function (%) assessed by echocardiogram.	Measured by biplane method in percentage	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular systolic function assessed by global longitudinal strain (GLS)	Measure of longitudinal shortening as a percentage	12 months
Change in E/e' ratio measured by echocardiogram.	Ratio between E wave (peak velocity of early diastolic blood flow across the mitral valve, measured using transmitral Doppler) and E' (E prime): velocity of early diastolic mitral annular motion, measured using tissue Doppler imaging.	12 months
Change in functional capacity assessed by 6-minute walk test	Distance covered over a time of 6 minutes in a flat surface in meters.	12 months
Change in quality of life according to the Kansas City Cardiomyopathy Questionnaire	0 to 100 scale, where 0 is the worst possible health status and 100 best possible health status.	12 months
Change in N-terminal pro-B-type natriuretic peptide (NTproBNP) biomarker level.	Measure in blood. Unit pg/ml.	12 months
Proportion of patients experiencing cardiovascular hospitalizations.		12 months
Proportion of patients experiencing adverse events	Including serious adverse event, grade 3-4 adverse event, adverse reaction, adverse event of special interest.	12 months
Proportion of patients discontinuing treatment		12 months
Proportion of patients experiencing all-cause mortality.		12 months

Collaborators and Investigators

• Sponsor: Puerta de Hierro University Hospital
• Investigators: Principal Investigator: Esther Gonzalez Lopez, MD, PhD, Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, Madrid, Spain

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: November 19, 2024
• First Submitted That Met QC Criteria: November 26, 2024
• First Posted (Estimated): December 2, 2024

Study Record Updates

• Last Update Posted (Estimated): December 2, 2024
• Last Update Submitted That Met QC Criteria: November 26, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Heart failure; Reduced ejection fraction; Sacubitril valsartan; Angiotensin receptor/neprilysin inhibitors
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Metabolic Diseases; Proteostasis Deficiencies; Heart Failure; Cardiomyopathies; Amyloidosis; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2024-515661-34-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Under agreement, individual or aggregated patient data could be shared with other scientific groups for scientific projects. Data can be shared only for scientific purposes and in full compliance with Personal Data Protection requirements in the EU.
• IPD Sharing Time Frame: After study scientific publication
• IPD Sharing Access Criteria: Under request to Study Chair
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No