Clinical trial NCT06712030: Effect of Angiotensin Receptor/Neprilysin Inhibitors on Transthyretin Cardiac Amyloidosis and Heart Failure with Reduced Ejection Fraction
Official title: Effect of Pharmacological Treatment with Angiotensin Receptor/Neprilysin Inhibitors on Transthyretin Cardiac Amyloidosis and Heart Failure with Reduced Ejection Fraction (SAVA-TTR)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)
Keywords: Heart failure
Reduced ejection fraction
Angiotensin receptor/neprilysin inhibitors
Sacubitril valsartan
Lead sponsor: Puerta de Hierro University Hospital
Sponsor class: OTHER
First posted: 2024-12-02
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in left ventricular systolic function (%) assessed by echocardiogram.
timeFrame: 12 months
Secondary outcomes:
measure: Change in left ventricular systolic function assessed by global longitudinal strain (GLS)
timeFrame: 12 months
measure: Change in E/e' ratio measured by echocardiogram.
timeFrame: 12 months
measure: Change in functional capacity assessed by 6-minute walk test
timeFrame: 12 months
measure: Change in quality of life according to the Kansas City Cardiomyopathy Questionnaire
timeFrame: 12 months
measure: Change in N-terminal pro-B-type natriuretic peptide (NTproBNP) biomarker level.
timeFrame: 12 months
measure: Proportion of patients experiencing cardiovascular hospitalizations.
timeFrame: 12 months
measure: Proportion of patients experiencing adverse events
timeFrame: 12 months
measure: Proportion of patients discontinuing treatment
timeFrame: 12 months
measure: Proportion of patients experiencing all-cause mortality.
timeFrame: 12 months
Other outcomes:
Locations:
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
Study officials:
affiliation: Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, Madrid, Spain
name: Esther Gonzalez Lopez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: