This post hoc analysis of a randomized clinical trial examines data for patients according to the New York Heart Association class of their heart failure symptoms at baseline to evaluate the health status benefit of tafamidis vs placebo.
Key Points
Question
Do patients with transthyretin (ATTR) cardiac amyloidosis and New York Heart Association (NYHA) class III symptoms at baseline derive health status benefit with tafamidis vs placebo?
Findings
In this post hoc analysis of a randomized clinical trial of tafamidis in ATTR cardiac amyloidosis, heart failure–related health status benefits were noted for patients taking tafamidis, including those with NYHA class III symptoms at baseline.
Meaning
Patients with ATTR cardiac amyloidosis should be considered for tafamidis therapy to improve their health status over placebo regardless of NYHA class.
Abstract
Importance
Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms.
Objective
To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms.
Design, Setting, and Participants
This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries.
Interventions
Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo.
Main Outcomes and Measures
Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class.
Results
Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo.
Conclusions and Relevance
In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo.
Trial Registration
ClinicalTrials.gov Identifier: NCT01994889
Introduction
Transthyretin (ATTR) cardiac amyloidosis is an increasingly recognized phenotype of heart failure with preserved ejection fraction1,2 that carries a particularly poor prognosis. The TTR protein stabilizer tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations at 30 months in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT).3 The key secondary end points of 6-minute walk distance and patient-reported health status (as measured by Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS]) were also better with tafamidis relative to placebo. In a follow-up analysis of ATTR-ACT, tafamidis similarly reduced deterioration in the 4 domains of the KCCQ-OS score, demonstrating that tafamidis had a positive effect on social and physical limitations, symptom burden, and quality of life.4
ATTR-ACT included patients with symptoms in New York Heart Association (NYHA) classes I through III, and subgroup analysis showed that patients with NYHA class III symptoms experienced more cardiovascular-related hospitalizations than those with NYHA class I or II symptoms, suggesting that patients with NYHA class III symptoms had less benefit from tafamidis. While improving the health status of patients with ATTR amyloidosis is a key goal of treatment, the effect of tafamidis on health status in patients with baseline NYHA class III symptoms is important yet unknown. We hypothesized that patients treated with tafamidis had significant stabilization or improvement in health status compared with placebo, including patients with baseline NYHA class III symptoms.
Methods
ATTR-ACT was a randomized, placebo-controlled, multinational clinical trial of tafamidis vs placebo in patients with ATTR cardiac amyloidosis.3 The study followed the Declaration of Helsinki and the International Conference on Harmonization Good Clinical practice guidelines and was approved by the institutional review boards of each institution. All patients provided informed consent.
In brief, patients aged 18 to 90 years were eligible for enrollment in ATTR-ACT if they had NYHA class I-III heart failure symptoms and adequate functional capacity (>100-m walk distance on the 6-minute walk test). Race and ethnicity data were collected at enrollment via self-report by the patients and categorized as Asian, Black, White, and other (for races and ethnicities that did not fit the preceding 3 categories). Randomization occurred on a 2:1:2 basis (tafamidis meglumine, 80 mg; tafamidis meglumine, 20 mg; or placebo).
The final analysis was stratified by TTR genotype (variant or wild type) and baseline NYHA class (I-II vs III). The primary outcome was the hierarchical combination of death and frequency of cardiovascular-related hospitalization as analyzed using the Finkelstein-Schoenfeld method, with heart transplant and cardiac mechanical assist device implantation treated the same as death for the purposes of the analysis.3,5
In the current study, heart failure–related health status was quantified by KCCQ-OS score, which includes symptom frequency, physical limitations, social limitations, and quality-of-life domains.6 Scores range from 0 to 100, with 100 signifying better health status. Established KCCQ-OS score change thresholds were used to define clinical response: large to very large improvement or decline was a change of at least 20 points, moderate to large improvement or decline was a change from 10 to less than 20 points, small improvement or decline was a change from 5 to less than 10 points, and no change was an improvement or decline by less than 5 points.6 Stable or improved health status was defined as a decrease in KCCQ-OS score by more than 5 points. Outcomes were observed at 6 months, 12 months, 18 months, 24 months, and 30 months. The proportion of patients in each KCCQ-OS responder group was calculated for the overall cohort and also stratified by baseline NYHA class.
Categorical variables are presented as a frequency and percentage and analyzed with the χ2 test. Continuous variables are expressed as mean (SD) or median (IQR) and analyzed by the t test and Wilcoxon rank sum test, respectively. Ordinal logistic regression models were generated for categorical responders at month 30 (after testing for proportional odds) based on change from baseline of KCCQ-OS score across the 8 KCCQ-OS response categories, including a category worse than “large to very large decline” for those with death, heart transplant, or cardiac mechanical support. All statistical tests were 2-sided, and P values less than .05 were considered significant. Statistical analysis was performed using SAS version 9.4.
Results
Of 441 patients in ATTR-ACT, the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group (n = 264) and 65.9 (21.7) in the placebo group (n = 177). The Table describes baseline characteristics of the 2 groups by NYHA class. A greater percentage of patients with NYHA class III symptoms were non-White and had hereditary ATTR amyloidosis compared with those with NYHA class I-II. Patients enrolled with NYHA class III symptoms reported lower KCCQ-OS scores and 6-minute walk distances and had higher troponin I and NT-proBNP values compared with patients with NYHA class I-II symptoms. There were no significant differences in baseline characteristics within the 2 treatment groups in both NYHA class I-II and class III subgroups (Table).
Table. Baseline Characteristics of the Study Cohorta.
| Characteristic | NYHA classes I and II (n = 300) | NYHA class III (n = 141) | ||||
|---|---|---|---|---|---|---|
| Tafamidis (n = 186) | Placebo (n = 114) | P value | Tafamidis (n = 78) | Placebo (n = 63) | P value | |
| Age, mean (SD), y | 74.5 (7.1) | 73.1 (6.5) | .09 | 74.7 (7.6) | 75.7 (6.8) | .38 |
| Sex, No. (%) | .50 | .74 | ||||
| Male | 175 (94.1) | 105 (92.1) | 66 (84.6) | 52 (82.5) | ||
| Female | 11 (5.9) | 9 (7.9) | 12 (15.4) | 11 (17.5) | ||
| Race and ethnicity, No. (%)b | .26 | .14 | ||||
| Asian | 10 (5.4) | 4 (3.5) | 3 (3.9) | 1 (1.6) | ||
| Black | 15 (8.1) | 16 (14.0) | 22 (28.2) | 10 (15.9) | ||
| White | 159 (85.5) | 94 (82.5) | 52 (66.6) | 52 (82.5) | ||
| Other | 2 (1.1) | 0 | 1 (1.3) | 0 | ||
| TTR genotype, No. (%) | .56 | .38 | ||||
| ATTRv | 34 (18.3) | 24 (21.1) | 29 (37.2) | 19 (30.2) | ||
| ATTRwt | 152 (81.7) | 90 (78.9) | 49 (62.8) | 44 (69.8) | ||
| BMI, mean (SD)c | 25.8 (3.5) | 25.9 (3.5) | .92 | 27.2 (4.3) | 27.2 (5.3) | >.99 |
| NT-proBNP, median (IQR), pg/mL | 2614 (1619-4236) | 2816 (1766-4360) | .57 | 4061 (2443-6798) | 4079 (2321-5269) | .43 |
| Troponin I, median (IQR), ng/mL | 0.13 (0.08-0.18) | 0.13 (0.08-0.18)d | .60 | 0.17 (0.12-0.29) | 0.14 (0.08-0.22) | .02 |
| eGFR, mean (SD), mL/min/1.73 m2 | 57.0 (14.2) | 55.1 (14.4) | .28 | 51.9 (21.8) | 51.1 (17.4) | .82 |
| KCCQ-OS score, mean (SD) | 74.5 (17.5) | 73.4 (18.5) | .59 | 50.0 (19.7) | 52.4 (20.7) | .48 |
| 6-min Walk distance, mean (SD), m | 389.0 (105.0) | 402.9 (106.4) | .27 | 258.8 (107.9) | 263.3 (108.1) | .80 |
Abbreviations: ATTRv, variant/hereditary ATTR amyloidosis; ATTRwt, wild-type ATTR amyloidosis; BMI, body mass index; eGFR, estimated glomerular filtration rate; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire Overall Summary; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; TTR, transthyretin.
Values presented are number (frequency) and analyzed using χ2, mean (SD) and analyzed using t test, or median (IQR) and analyzed using Wilcoxon rank sum test by normal approximation method.
Race and ethnicity data were collected at enrollment via self-report by the patients and categorized as Asian, Black, White, and other (for races and ethnicities that did not fit the preceding 3 categories).
Calculated as weight in kilograms divided by height in meters squared.
These values reflect 113 patients in this cohort because of 1 missing baseline value for troponin I.
More frequent categorical KCCQ-OS score improvements were noted for those treated with tafamidis regardless of NYHA class (Figure 1 and eTables 1-3 in Supplement 1). For patients who were treated with tafamidis, the odds of having a categorical improvement in KCCQ-OS score at 30 months was 2.4 times (95% CI, 1.6-3.4; P < .001) that of patients receiving placebo (Figure 1A). These improvements with tafamidis persisted in patients with NYHA class III symptoms at baseline (Figure 1C). In fact, 35% of NYHA class III patients alive at 30 months while taking tafamidis reported improved heart failure health status compared with 10% of those who received placebo.
Figure 1. Health Status Response at 30 Months as Indicated by Kansas City Cardiomyopathy Questionnaire Overall Summary Score.
Death and declining health status were more common in the placebo group, while improved health status was more common in the tafamidis group for the overall cohort and in patients with baseline New York Heart Association (NYHA) class I-II and NYHA class III symptoms. Responder analysis percentages reflect patients who were alive at 30 months. Heart transplant and cardiac mechanical assist device implantation were treated the same as death for the purposes of the analysis (percentages included for reference).
In patients alive at 30 months with available KCCQ-OS data, those taking tafamidis were 2.5 times more likely (95% CI, 1.4-4.5; P = .003) to have a 10-point improvement in KCCQ-OS score compared with those taking placebo, which was similar for both patients with NYHA class I-II symptoms (odds ratio [OR], 2.4; 95% CI, 1.1-5.1; P = .03) and NYHA class III symptoms (OR, 2.7; 95% CI, 1.1-6.6; P = .03). Cumulative distribution function curves further highlight this shift toward improvement with tafamidis vs placebo in the entire cohort and in those with baseline NYHA class III symptoms throughout the study period (eFigure in Supplement 1).
Overall, patients were more likely to be alive with stable or better health status when taking tafamidis vs placebo throughout the study period (37% vs 15% at 30 months; number needed to treat, 4.5), regardless of NYHA class (Figure 2).
Figure 2. Proportion of Patients Who Were Alive With Stable or Improved Health Status at Each Analysis Time Point.
At each study interval, stable or better health status, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score, demonstrated a benefit in patients who received tafamidis vs placebo. NYHA indicates New York Heart Association.
Discussion
In this post hoc analysis of ATTR-ACT, patients with ATTR cardiac amyloidosis and baseline NYHA class III symptoms were sicker and had worse mortality and cardiovascular hospitalization outcomes throughout the study period compared with patients with NYHA class I-II symptoms. However, treatment with tafamidis was associated with marked health status benefits, including more frequent improvements and less frequent declines in health status, as compared with placebo. Patients were more frequently alive with stable or improved health status if they were randomized to receive tafamidis. This study highlights the benefits of tafamidis in the overall cohort, as well as patients with baseline NYHA class III symptoms.
In ATTR-ACT and the open-label extension, tafamidis was shown to more than double the life expectancy (6.73 vs 2.85 years) and quality-adjusted life-years in patients with ATTR cardiac amyloidosis vs standard of care.7 Although there was no interaction with NYHA class and all-cause mortality in ATTR-ACT, patients with NYHA class III symptoms had more cardiovascular-related hospitalizations in the tafamidis cohort (P < .001 for interaction) compared with class II. This finding has raised questions about the overall benefit of tafamidis in patients with a greater symptom burden. The current post hoc analysis of ATTR-ACT highlights the positive health status benefits with tafamidis for all eligible patients, including those with baseline NYHA class III symptoms.
Limitations
This study is limited because it is a post hoc analysis of ATTR-ACT and was not powered to analyze outcomes specifically in patients with NYHA class III symptoms. Only 32% of the enrolled cohort was NYHA class III at baseline. Further studies of disease-modifying therapy in patients with NYHA class III symptoms are needed.
Conclusions
This post hoc analysis of a randomized clinical trial found that heart failure–related health status was better with tafamidis vs placebo in patients with ATTR cardiac amyloidosis regardless of NYHA class. Treatment with tafamidis should be considered for all patients with ATTR cardiac amyloidosis who meet the inclusion criteria for ATTR-ACT, including those with baseline NYHA class III symptoms.
eFigure. Cumulative distribution function curves in ATTR-ACT
eTable 1. Change in KCCQ-OS at 30 months
eTable 2. NYHA class 1 or 2 symptoms at baseline
eTable 3. NYHA class 3 symptoms at baseline
Data sharing statement
References
- 1.Sperry BW, Saeed IM, Raza S, Kennedy KF, Hanna M, Spertus JA. Increasing rate of hospital admissions in patients with amyloidosis (from the National Inpatient Sample). Am J Cardiol. 2019;124(11):1765-1769. doi: 10.1016/j.amjcard.2019.08.045 [DOI] [PubMed] [Google Scholar]
- 2.González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594. doi: 10.1093/eurheartj/ehv338 [DOI] [PubMed] [Google Scholar]
- 3.Maurer MS, Schwartz JH, Gundapaneni B, et al. ; ATTR-ACT Study Investigators . Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi: 10.1056/NEJMoa1805689 [DOI] [PubMed] [Google Scholar]
- 4.Hanna M, Damy T, Grogan M, et al. Impact of tafamidis on health-related quality of life in patients with transthyretin amyloid cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Am J Cardiol. 2021;141:98-105. doi: 10.1016/j.amjcard.2020.10.066 [DOI] [PubMed] [Google Scholar]
- 5.Maurer MS, Elliott P, Merlini G, et al. ; ATTR-ACT Study Investigators . Design and rationale of the phase 3 ATTR-ACT clinical trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Circ Heart Fail. 2017;10(6):e003815. doi: 10.1161/CIRCHEARTFAILURE.116.003815 [DOI] [PubMed] [Google Scholar]
- 6.Spertus JA, Jones PG, Sandhu AT, Arnold SV. Interpreting the Kansas City Cardiomyopathy Questionnaire in clinical trials and clinical care: JACC state-of-the-art review. J Am Coll Cardiol. 2020;76(20):2379-2390. doi: 10.1016/j.jacc.2020.09.542 [DOI] [PubMed] [Google Scholar]
- 7.Rozenbaum MH, Garcia A, Grima D, et al. Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies. Eur Heart J Qual Care Clin Outcomes. 2022;8(5):529-538.doi: 10.1093/ehjqcco/qcab031 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure. Cumulative distribution function curves in ATTR-ACT
eTable 1. Change in KCCQ-OS at 30 months
eTable 2. NYHA class 1 or 2 symptoms at baseline
eTable 3. NYHA class 3 symptoms at baseline
Data sharing statement