Tafamidis Reduces Mortality Rates In Cardiomyopathy Patients
Overview
The study explored the effectiveness of tafamidis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) across varying levels of left ventricular ejection fraction (LVEF). Conducted as part of the phase 3 ATTR-ACT trial and its subsequent long-term extension (LTE) study, patients were initially randomized to receive either tafamidis or a placebo for 30 months. After this period, participants could continue into the LTE study to receive tafamidis. The study evaluated all-cause mortality, which included death, heart transplants, or cardiac mechanical assist device implantation, from the start of the trial until the end of follow-up. This assessment compared patients who had continuous tafamidis treatment (80 mg meglumine or 61 mg free acid) with those who began tafamidis treatment later (initially given a placebo in ATTR-ACT, then switched to tafamidis in the LTE study), categorized by their baseline LVEF (<50% or ≥50%).
Findings showed that patients with a baseline LVEF of less than 50% (177 patients: 88 on tafamidis, 89 on placebo) generally exhibited more severe heart failure, included a higher percentage of Black individuals, and had a greater incidence of variant ATTR-CM compared to those with an LVEF of 50% or higher (171 patients: 85 on tafamidis, 86 on placebo). By the end of the follow-up period, which had a median duration of 60 to 64 months, all-cause mortality was numerically greater in the group with a baseline LVEF below 50%. Nevertheless, consistent with other supportive findings, continuous tafamidis treatment was linked to a 47% reduction in mortality risk compared to delayed tafamidis treatment, regardless of whether the baseline LVEF was below or above 50% (hazard ratio 0.53 [95% confidence interval 0.367–0.758]; p < 0.001 for LVEF <50%, and 0.53 [0.344–0.818]; p < 0.01 for LVEF ≥50%).
In conclusion, the study demonstrates that early initiation of tafamidis treatment significantly reduces mortality in patients with ATTR-CM, irrespective of their initial LVEF levels.
Introduction
Tafamidis has received global approval for treating transthyretin amyloid cardiomyopathy (ATTR-CM), based largely on the efficacy and safety outcomes from the 30-month, phase 3 ATTR-ACT trial. After completing ATTR-ACT, patients were able to participate in a long-term extension (LTE) study, which provided access to open-label tafamidis for up to 5 years or until the drug became commercially available in their region. This LTE study also offered valuable insights into the long-term effects of tafamidis treatment. The results from these studies consistently support the clinical benefits of tafamidis meglumine 80 mg and tafamidis free acid 61 mg for patients with ATTR-CM, including those with both wild-type and variant ATTR-CM, as well as across varying degrees of disease severity and age groups, including patients over 80 years old.
Patients with chronic heart failure are often classified by their left ventricular ejection fraction (LVEF) to guide treatment decisions and prognosis. Heart failure can occur with preserved ejection fraction (LVEF ≥50%), mildly reduced ejection fraction (LVEF 41–49%), or reduced ejection fraction (LVEF ≤40%). While ATTR-CM was traditionally associated with an LVEF ≥50%, more recent studies have shown that some patients present with an LVEF <50% at diagnosis. The ATTR-ACT trial did not select patients based on LVEF, though it did exclude those with New York Heart Association (NYHA) functional class IV. As a result, 50% of the trial participants had an LVEF <50% at enrollment (with 27% having mildly reduced ejection fraction and 22% having reduced ejection fraction). Two recent retrospective studies in the United States, each involving over 500 patients, also found that a significant proportion of patients were diagnosed with ATTR-CM with either mildly reduced or reduced ejection fraction. Reduced ejection fraction was more frequently observed among Black or African American patients, those with variant ATTR-CM, and those with NYHA functional class III or IV.
Tafamidis addresses the underlying cause of ATTR-CM and has demonstrated efficacy across all LVEF categories. Current treatment guidelines recommend tafamidis for patients with ATTR-CM regardless of their LVEF classification. However, there remains uncertainty about the comparative benefits of tafamidis in patients with mildly reduced or reduced ejection fraction versus those with preserved ejection fraction. Additionally, in some countries, such as Spain, tafamidis is not reimbursed for patients with an LVEF <50%.
This post-hoc analysis aimed to evaluate long-term all-cause survival in patients with ATTR-CM who had either mildly reduced or reduced ejection fraction (LVEF <50% at baseline) or preserved ejection fraction (LVEF ≥50% at baseline) and were treated with either placebo or the approved tafamidis dose (80/61 mg) during the ATTR-ACT trial and its LTE study.
Method
The ATTR-ACT trial (NCT01994889) was a multicenter, international, double-blind, placebo-controlled, randomized, phase 3 study designed to assess the efficacy of tafamidis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Patients were randomized in a 2:1:2 ratio to receive either 80 mg or 20 mg of tafamidis meglumine, or a placebo, over a 30-month period. Randomization was stratified based on transthyretin (TTR) genotype (wild-type or variant) and NYHA functional class (I or II/III). Following the completion of the ATTR-ACT trial, eligible patients could join an open-label extension study (NCT02791230), receiving tafamidis for up to 60 months or until it became commercially available in their region. Patients who initially received tafamidis in ATTR-ACT continued the same treatment, while those on placebo were re-randomized 2:1 to receive either 80 mg or 20 mg of tafamidis meglumine, again stratified by TTR genotype. A protocol amendment in July 2018 transitioned all participants in the extension study to tafamidis free acid 61 mg, bioequivalent to 80 mg of tafamidis meglumine. Data from patients who received the 20 mg dose in ATTR-ACT were excluded from the analysis since this dose is not approved for treating ATTR-CM.
The trials adhered to ethical standards as outlined by the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines, with all participants providing informed consent.
This post-hoc analysis focused on evaluating the efficacy of the approved dose of tafamidis (meglumine 80 mg or free acid 61 mg) in patients who participated in either ATTR-ACT or the LTE study, categorized by baseline left ventricular ejection fraction (LVEF) (<50% or ≥50%). The analysis pooled data from both the ATTR-ACT and completed LTE studies, summarizing demographic and clinical characteristics for four subgroups: those with LVEF <50% or ≥50% at baseline, and whether they received continuous tafamidis treatment or were switched from placebo to tafamidis.
Efficacy comparisons between treatment groups within each LVEF category were conducted. The median follow-up time was calculated using Kaplan–Meier methods, and all-cause mortality was analyzed using a Cox proportional hazards model, accounting for treatment and TTR genotype. Changes from baseline in the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score were summarized over time, with additional assessments of 6MWT distance and NT-proBNP concentration up to Month 30. Statistical analyses included mixed models for repeated measures to evaluate treatment differences, incorporating fixed effects of treatment, visit, TTR genotype, and visit-by-treatment interaction.
This analysis underscores the importance of ongoing research into the treatment of ATTR-CM and provides insights into the potential benefits of tafamidis across different patient subgroups.
Inclusion Criteria
To be eligible for ATTR-ACT, patients aged 18-90 years had to have biopsy-confirmed ATTR-CM, an end-diastolic interventricular septal thickness >12 mm (assessed via echocardiography), and a history of heart failure, including at least one associated hospitalization or consistent clinical symptoms (NYHA functional class I-III). Additional requirements included an N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration ≥600 pg/ml, a 6-minute walk test (6MWT) distance >100 m, and an estimated glomerular filtration rate ≥25 ml/min/1.73 m². Patients were to be stable on standard heart failure therapy, without cardiovascular-related hospitalizations in the two weeks prior to baseline. Exclusion criteria included previous liver or heart transplants, or implantation of a cardiac mechanical assist device.
Result
The ATTR-ACT study enrolled 441 patients with transthyretin amyloid cardiomyopathy (ATTR-CM) across 13 countries between December 2013 and August 2015. Of these participants, 176 were assigned to receive 80 mg of tafamidis meglumine, while 177 received a placebo. The baseline left ventricular ejection fraction (LVEF) of these patients was documented, with 50% having an LVEF below 50% in both treatment groups. After 30 months, 108 patients continued with the tafamidis treatment in a long-term extension (LTE) study.
Within the tafamidis group, 47 patients had begun the study with an LVEF below 50%, while 61 patients had an LVEF of 50% or higher. In the placebo group, which later transitioned to tafamidis in the LTE study, 35 patients started with an LVEF below 50%, and 47 with an LVEF of 50% or higher. Overall, 43% of patients entering the LTE study had an LVEF below 50%.
The baseline characteristics of patients with an LVEF below 50% were comparable across treatment groups. Most patients were male, aged around 73 to 75 years, and a significant portion were Black or African American. The majority of these patients had a New York Heart Association (NYHA) functional class of II or III, with just over a quarter diagnosed with variant transthyretin cardiomyopathy (ATTRv-CM), commonly associated with the V122I TTR variant. Median follow-up times were around 60 months in the tafamidis group and 64 months in the placebo group.
A higher percentage of patients with an LVEF below 50% were Black and had ATTRv-CM compared to those with LVEF above 50%. These patients also tended to have more severe symptoms and worse clinical outcomes, such as higher NT-proBNP levels and slightly lower estimated glomerular filtration rates.
The study found that tafamidis treatment led to a smaller increase in NT-proBNP levels at 12 months and a slower decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores from baseline compared to the placebo group, especially noticeable from month 12 onwards. At the 60-month mark, the tafamidis group had a significantly smaller reduction in KCCQ-OS scores and lower all-cause mortality compared to those who transitioned from placebo to tafamidis.
In the group with an LVEF of 50% or higher, tafamidis was associated with smaller declines in 6-minute walk test (6MWT) distances and NT-proBNP levels compared to placebo. The tafamidis group also experienced a significantly smaller reduction in KCCQ-OS scores over time and lower all-cause mortality rates at both 30 and 60 months.
The study concluded that tafamidis treatment significantly improved outcomes in ATTR-CM patients, regardless of baseline LVEF, with notable reductions in all-cause mortality and less deterioration in functional status as measured by the KCCQ-OS score.
Conclusion
Tafamidis is recommended for treating patients with transthyretin amyloid cardiomyopathy (ATTR-CM) regardless of their left ventricular ejection fraction (LVEF). However, in some regions, it is not yet reimbursed for patients with LVEF below 50%, possibly due to lower awareness of the disease and uncertainty about the treatment’s value in patients with reduced or mildly reduced ejection fraction compared to those with preserved ejection fraction.
This post-hoc analysis of participants from the phase 3 ATTR-ACT and LTE studies revealed that approximately 51% of patients had an LVEF below 50% at baseline. Despite these patients presenting with more severe disease, tafamidis showed similar efficacy in both groups, regardless of LVEF. This finding aligns with previous research indicating that heart failure with reduced or mildly reduced ejection fraction is a common presentation of ATTR-CM, particularly in Black patients and those with advanced hereditary ATTR-CM.
Patients with a baseline LVEF below 50% exhibited more severe symptoms, which likely contributed to a numerically higher long-term mortality rate and greater declines in quality of life compared to those with LVEF above 50%. Although the mortality rates varied slightly between the groups at 30, 60, and 5 years of follow-up, the risk of all-cause mortality was reduced by 47% across both groups throughout the studies.
Tafamidis was more effective in improving 6-minute walk test (6MWT) distances and NT-proBNP concentrations in patients with LVEF above 50%, likely due to their less advanced disease at baseline. However, despite the differences, tafamidis consistently slowed the decline in health-related quality of life across both LVEF groups. Therefore, the decision to initiate tafamidis treatment should not be based on LVEF alone.
The study faced several limitations, including a small patient population, particularly towards the end of follow-up, which reduced the power to compare groups. Additionally, the availability of certain assessments and the baseline differences in disease severity posed challenges in comparing LVEF groups. The study also likely underestimates tafamidis’ efficacy due to the crossover of placebo patients to tafamidis in the LTE phase. Further research, especially on different LVEF levels and including measures such as cardiovascular-related hospitalizations, would be beneficial to confirm these findings.
In conclusion, heart failure with reduced or mildly reduced ejection fraction is common among ATTR-CM patients. Tafamidis significantly reduced long-term all-cause mortality and deterioration in quality of life across both LVEF groups, underscoring its efficacy in treating ATTR-CM patients regardless of their LVEF.
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