Effect of Angiotensin Receptor/Neprilysin Inhibitors on Transthyretin Cardiac Amyloidosis and Heart Failure with Reduced Ejection Fraction

Phase 3

Not yet recruiting

• Conditions: Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)
• Interventions: Drug: Sacubitril / Valsartan

• Registration Number: NCT06712030
• Lead Sponsor: Puerta de Hierro University Hospital

Brief Summary

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.

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 Timeline

• Status Verified: 2024-11
• Study First Submitted: 2024-11-19
• Study First Submitted QC: 2024-11-26
• Last Update Submitted: 2024-11-26
• Study First Posted: 2024-12-02
• Last Update Posted: 2024-12-02
• Study Start: 2025-01
• Primary Completion: 2027-04
• Study Completion: 2027-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 114

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).

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sacubitril/Valsartan	Sacubitril / Valsartan	Sacubitril/valsartan up to maximum tolerated dose

Primary Outcome Measures

Name	Time	Method
Change in left ventricular systolic function (%) assessed by echocardiogram.	12 months	Measured by biplane method in percentage

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Hospital Universitario Puerta de Hierro; 🇪🇸 Majadahonda, Madrid, Spain