In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT.
Clinical trial registration ClinicalTrials.gov: NCT01994889 .
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive cardiac disease leading to death within a few years, typically due to cardiac causes including heart failure (HF) and sudden death. ATTR-CM remains both underdiagnosed and misdiagnosed. , Greater awareness of ATTR-CM, and what to expect during the course of the disease, could aid earlier diagnosis and improve treatment, which is crucial to facilitate effective patient care. In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with ATTR-CM. All-cause mortality was significantly lower with tafamidis (29.5%) than with placebo (42.9%), as was the rate of CV-related hospitalization (0.48 per year with tafamidis compared with 0.70 per year with placebo). There was also a reduction in all-cause mortality with tafamidis in patients with less and more severe disease and both hereditary and wild-type ATTR-CM. Further information on the causes of hospitalization and death may help guide physicians on what to expect when treating patients with ATTR-CM. We therefore evaluated the causes of CV-related deaths and hospitalizations in ATTR-ACT.
Methods
ATTR-ACT was a phase 3, multicenter, international, 3-arm, parallel-design, placebo-controlled, double-blind, randomized study for which the design has been previously published (NCT01994889). , Briefly, those eligible to enroll were patients aged ≥18 and ≤90 years with a diagnosis of ATTR-CM defined by the presence of either variant TTR (ATTRv), or wild-type amyloid (ATTRwt) and a medical history of HF with at least 1 prior hospitalization due to HF, or clinical signs and symptoms associated with HF (volume overload or elevated intracardiac pressures) that required treatment with a diuretic. Eligible patients also had end-diastolic intraventricular septal wall thickness >12 mm demonstrated by echocardiography, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration ≥ 600 pg/ml and confirmed the presence of amyloid deposits in biopsy tissue from cardiac and noncardiac sites. Patients were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or matching placebo once daily for 30 months, with analyses performed on the pooled tafamidis treatment group (combined tafamidis 80 mg and 20 mg groups) compared with placebo.
The primary efficacy endpoint of ATTR-ACT was a hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations comparing tafamidis with placebo. CV-related mortality (in which heart transplant or durable cardiac mechanical assist device (CMAD) implantation [for circulatory support] counted as death) and the rate of CV-related hospitalizations were also assessed by Cox proportional hazards model and Poisson regression analysis, respectively.
The study was approved by the independent review boards or ethics committees at each participating site and was conducted in accordance with the provisions of the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. All patients provided written informed consent.
The independent Endpoint Adjudication Committee conducted a blinded review of all potential study endpoints to determine whether investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. All cases of death during the study were reported to the Endpoint Adjudication Committee, which reviewed the case to determine the cause of death. Death due to any cause was included in the primary efficacy evaluation (together with a heart transplant and implantation of a durable CMAD, which were counted as death for the efficacy analyses). All deaths were reviewed to determine if they were CV-related or not, with CV-related causes recorded as HF, arrhythmia, myocardial infarction (MI), sudden death, stroke, and other CV causes (see Supplementary Table 1 ).
At each visit, it was reported by the investigator if the patient had been hospitalized (including the reason for hospitalization), with all hospitalizations reported to the Endpoint Adjudication Committee. Hospitalization for endpoint adjudication was defined as a nonelective admission to an acute care setting for medical therapy that resulted in at least a 24-hour stay (or a date change if the time of admission/discharge was not available). Hospitalization reports were also reviewed by the Endpoint Adjudication Committee to determine if they were CV-related or not, with CV-related causes recorded as HF, arrhythmia, MI, transient ischemic attack/stroke, and other CV causes (see Supplementary Table 2 ).
The hazard ratio for time to mortality was derived from a Cox proportional hazards model with genotype (ATTRv and ATTRwt) and New York Heart Association (NYHA) baseline classification (NYHA classes I and II combined, and NYHA class III) in the model. Frequency of all-cause hospitalization was compared using a Poisson regression model with treatment, genotype (ATTRv and ATTRwt), NYHA baseline classification (NYHA classes I and II combined, and NYHA class III), treatment-by-genotype interaction, and treatment-by-NYHA baseline classification interaction terms as factors adjusted for treatment duration.
Comorbidities, numbers of deaths, and hospitalizations are shown using descriptive statistics. Causes of hospitalization are shown with multiple occurrences of the same hospitalization admittance reason in a single patient counted once. For efficacy analyses and frequency of hospitalization, all hospitalizations in each patient are counted.
Results
As previously reported, demographic and clinical characteristics were similar in the tafamidis and placebo groups, with the majority of patients being male, with a mean age of 74 years, and over 75% ATTRwt. Most patients (approximately 60%) were NYHA class II with median NT-proBNP concentrations being approximately 3,000 pg/ml, and mean left ventricular ejection fraction approximately 48%. Patients had a number of CV-related comorbidities, with the most common being hypertension (54.9% of tafamidis patients; 47.5% of placebo patients), atrial fibrillation (53.0% tafamidis; 50.3% placebo), congestive cardiac failure (25.0% tafamidis; 27.7% placebo), and coronary artery disease (19.3% tafamidis; 22.6% placebo).
There was a significant 30.9% reduction in the risk of CV-related death with tafamidis compared with placebo ( Figure 1 ). The majority of deaths in the study were CV-related (103 of 144 total deaths, 71.5%). Total deaths were less frequent with tafamidis compared with placebo, as were both CV-related and non-CV-related deaths ( Table 1 ). All predefined causes of death were less frequent with tafamidis than with placebo ( Table 1 ). There was a nonsignificant 30.2% reduction in the risk of HF death with tafamidis ( Figure 1 ). Within each treatment group, the proportions of each cause of CV-related death were similar, with HF the most common cause of CV-related death, followed by sudden death.
| Deaths | Tafamidis (N = 264) | Placebo (N = 177) |
|---|---|---|
| Total deaths | 72 (27.3%) | 72 (40.7%) |
| CV-related deaths | 53 (20.1%) | 50 (28.2%) |
| Cause of CV-related death | ||
| Heart failure | 41 (15.5%) | 40 (22.6%) |
| Sudden death | 7 (2.7%) | 9 (5.1%) |
| Stroke | 0 | 1 (0.6%) * |
| Other CV | 5 (1.9%) † | 0 |
| Non-CV-related deaths | 14 (5.3%) | 13 (7.3%) |
| Indeterminate deaths | 5 (1.9%) | 9 (5.1%) |
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