Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)
Conditions
Keywords
Heart failure, Reduced ejection fraction, Angiotensin receptor/neprilysin inhibitors, Sacubitril valsartan
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.
Interventions
Dose titration of Sacubitril/Valsartán to the maximum tolerated dose (maximum 97/103 mg)
Sponsors
Puerta de Hierro University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The analysis of the echocardiogram will be performed by evaluators blinded to the treatment and the timing of the imaging.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in left ventricular systolic function (%) assessed by echocardiogram. | 12 months | Measured by biplane method in percentage |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Change in left ventricular systolic function assessed by global longitudinal strain (GLS) | 12 months | Measure of longitudinal shortening as a percentage |
| 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 | — |
| Proportion of patients experiencing cardiovascular hospitalizations. | 12 months | — |
Countries
Spain
Contacts
Primary ContactEsther Gonzalez Lopez, MD, PhD
Outcome results
None listed