Abstract
Introduction
Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) versus placebo. ATTR-CM has historically been considered a predominantly male disease, and women are underrepresented in prior studies. Sex-specific data in contemporary patients treated with tafamidis remain limited.
Methods
Data from two cohorts were pooled: an early-access cohort (NCT02791230) and patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS; NCT00628745) in 2019–2023. This analysis evaluated sex-related differences in clinical characteristics and all-cause mortality, adjusting for age, cohort, baseline New York Heart Association (NYHA) class, and wild-type (ATTRwt-CM) versus variant (ATTRv-CM) disease.
Results
Overall, 1924 patients treated with tafamidis were included (1476 from the early-access cohort and 448 from THAOS), of whom 214 (11.1%) were women. A smaller proportion of women than men had ATTRwt-CM (59.8% vs. 88.9%), whereas a greater proportion had ATTRv-CM (40.2% vs. 11.1%; p < 0.0001). Women were more frequently of African descent (23.9% vs. 7.4%; overall p < 0.001). Age at enrollment, age at symptom onset, and time from symptom onset to diagnosis were similar between sexes (p > 0.05). Women appeared more symptomatic at baseline, with a higher proportion in NYHA class III/IV (37.7% vs. 29.4%; overall p = 0.036) and classified as National Amyloidosis Centre stage II/III (68.1% vs. 47.7%; overall p = 0.023), despite similar N-terminal pro–B-type natriuretic peptide levels (p > 0.05). In adjusted analyses, women had a higher estimated glomerular filtration rate than men (β [men vs. women] = − 10.61; p < 0.001). Over a mean follow-up of 1.5 years, men had a higher risk of all-cause mortality than women (adjusted hazard ratio [men vs. women], 1.60, 95% CI 1.12–2.30).
Conclusions
In this analysis of contemporary patients with ATTR-CM treated with tafamidis, women represented a small proportion of the overall population, and a greater proportion had ATTRv-CM compared with men. Although women appeared more symptomatic at presentation, men had a higher risk of all-cause mortality.
Trial Registration
ClinicalTrials.gov identifiers: NCT02791230 and NCT00628745.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40119-026-00475-3.
Keywords: ATTR-CM, Real-world evidence, Sex, Tafamidis
Key Summary Points
| Why carry out this study? |
| Prior evidence suggests that men and women with transthyretin amyloid cardiomyopathy (ATTR-CM) may differ in their clinical presentation. |
| This analysis evaluated the impact of sex on key clinical variables and all-cause mortality in a contemporary cohort of patients with ATTR-CM treated with tafamidis. |
| What was learned from this study? |
| A greater proportion of women than men had variant ATTR-CM, and women appeared to have greater functional limitation at baseline. |
| However, adjusted and subgroup analyses suggested that baseline differences were largely driven by genotype and other clinical factors rather than sex. |
| Men had a higher risk of all-cause mortality after adjusting for age, genotype, and baseline disease severity. |
Introduction
Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by extracellular deposition of misfolded transthyretin (TTR) amyloid fibrils in the myocardium, leading to progressive heart failure, arrhythmias, and reduced survival [1–3]. ATTR-CM may occur as a result of wild-type TTR deposition (ATTRwt-CM) or hereditary TTR variants (ATTRv-CM), both of which are associated with substantial morbidity and mortality [4, 5].
Tafamidis is a TTR stabilizer approved to treat patients with ATTR-CM that is administered once daily. It has demonstrated a statistically significant reduction in mortality at 30 months compared with placebo [6]. Clinical trial and real-world data describing outcomes in patients treated with tafamidis have been reported, including results from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT; NCT01994889) and the Transthyretin Amyloidosis Outcomes Survey (THAOS; NCT00628745), an ongoing, global, longitudinal registry of patients with transthyretin amyloidosis [6–8].
ATTR-CM has traditionally been viewed as a disease predominantly affecting older men, although the proportion of women varies across cohorts and genotypes [9, 10]. Emerging data suggest important sex-related differences in clinical presentation and phenotype. In patients with ATTRwt-CM, women tend to present at an older age and may have distinct clinical characteristics compared with men [10, 11]. Prior THAOS analyses have identified sex-related differences across the ATTR-CM spectrum; in a cohort of 1386 patients with ATTRwt-CM, women represented only 6% of the population and had less severe cardiac involvement but greater functional limitation than men [12]. Additional THAOS analyses have shown that the proportion of women with ATTRwt-CM increases with age, whereas myocardial involvement in ATTRv-CM may be more frequent and more pronounced in men [13, 14].
Despite these observations, data on sex-related differences in contemporary patients treated with tafamidis remain limited. This analysis examined the association of sex with clinical characteristics and outcomes in patients with ATTRwt-CM and ATTRv-CM treated with tafamidis.
Methods
Data Sources and Patients
This analysis used data pooled from two cohorts: tafamidis-treated patients from THAOS and an early-access cohort. THAOS (NCT00628745) was a global, longitudinal, observational phase 4 study of patients with transthyretin amyloidosis and asymptomatic carriers of pathogenic TTR variants. Patients who were currently or previously treated with tafamidis, as well as patients naïve to tafamidis treatment, were eligible to enroll. Patients in THAOS were not receiving any other investigational treatment for ATTR-CM, and data were censored during any period when a patient participated in another clinical study. Further details of the design of THAOS and eligibility criteria have been published [15]. This analysis included all patients enrolled in THAOS between 2019 and 2023 (corresponding with enrollment of the early-access cohort and regulatory approval of tafamidis) who had a predominantly cardiac or mixed phenotype at enrollment and received tafamidis at the approved dose (tafamidis meglumine 80 mg or tafamidis free acid 61 mg) during participation in THAOS. Patients in THAOS could have initiated tafamidis treatment prior to or after enrollment.
Upon completion of ATTR-ACT, patients could enroll in an open-label, long-term extension (LTE) study to receive tafamidis for up to 60 months (NCT02791230) [16]. The early-access cohort was an independent arm of the LTE study, initiated following a protocol amendment in 2018. Patients with ATTR-CM were able to receive early access to the approved dose of tafamidis for up to 60 months. Standard-of-care therapies were permitted to continue along with study treatment, except for protocol-specified prohibited medications [17]. Patients in the early-access cohort were treated between 2018 and 2023.
Both studies were approved by the independent review board or ethics committee at each participating center and were conducted in accordance with the concepts laid out in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent.
Variables and Statistical Analyses
Baseline was the date of study enrollment or tafamidis initiation for THAOS, and the date of tafamidis initiation for the early-access cohort. Baseline demographics and clinical and cardiac characteristics are reported as number (percentage) for categorical data and mean, standard deviation (SD), median, and 10th and 90th percentiles for continuous data.
Differences between men and women in categorical variables were assessed using the Chi-square test, and differences in continuous variables (means) were assessed using the t test. The relationship between clinical and cardiac variables and sex (men vs. women [reference]) was analyzed using linear and logistic regression models for continuous and categorical dependent variables, respectively. Models were adjusted for age, cohort, baseline New York Heart Association (NYHA) class (except when NYHA class was the dependent variable), and TTR genotype. Kaplan–Meier survival plots were generated for time to all-cause mortality, stratified by sex and compared using the log-rank test. All surviving patients were censored at their last follow-up visit. Cox proportional hazards models were used to evaluate all-cause mortality, with sex, age, study, baseline NYHA class, and TTR genotype as factors, providing sex-specific (men vs. women) hazard ratios (HRs) with 95% confidence intervals (CIs). Genotype-stratified analyses were conducted in subgroups of patients with ATTRv-CM and patients with ATTRwt-CM. All data analyses were conducted using statistical software SAS version 9.4.
Results
Patient Demographics and Clinical Characteristics at Enrollment
This analysis included 1924 patients treated with tafamidis (1476 from the early-access cohort and 448 from THAOS), of whom 214 (11.1%) were women and 1710 (88.9%) were men (Table 1). Patients were enrolled across 77 study sites in 19 countries. Among women and men, respectively, mean age at enrollment was 77.2 and 76.7 years, mean age at symptom onset was 74.3 and 73.7 years, and mean time from symptom onset to diagnosis was 48.3 and 47.1 months, with no significant differences observed by sex (Table 1). A greater proportion of women vs. men were of African descent (23.9% vs. 7.4%), whereas a greater proportion of men vs. women were white (88.0% vs. 66.2%). A smaller proportion of women than men had ATTRwt-CM (59.8% vs. 88.9%), whereas a greater proportion had ATTRv-CM (40.2% vs. 11.1%). Women also had a lower mean estimated glomerular filtration rate (eGFR; 48.8 vs. 58.4 ml/min/1.73 m2) than men (Table 2). Medical history was generally comparable between women and men, although women had a lower rate of carpal tunnel syndrome (4.7% vs. 10.6%) and tendon rupture (0% vs. 2.7%). Mean follow-up was 1.5 years in both groups.
Table 1.
Enrollment diagnosis and demographic characteristics by sex
| Characteristic | Women (n = 214) | Men (n = 1710) | p value |
|---|---|---|---|
| Age at enrollment (years) | |||
| Mean (SD) | 77.2 (9.2) | 76.7 (7.5) | 0.436 |
| Median (10th, 90th percentile) | 79.0 (65.9, 88.0) | 77.0 (67.0, 86.0) | |
| Age at symptom onset (years)a | n = 213 | n = 1704 | |
| Mean (SD) | 74.3 (10.9) | 73.7 (9.5) | 0.443 |
| Median (10th, 90th percentile) | 76.1 (61.1, 86.5) | 75.2 (61.5, 84.4) | |
| Duration of symptoms (years) | n = 202 | n = 1646 | |
| Mean (SD) | 1.2 (3.6) | 1.3 (4.0) | 0.674 |
| Median (10th, 90th percentile) | 0.0 (0.0, 3.0) | 0.0 (0.0, 4.4) | |
| Time from symptom onset to diagnosis (months) | n = 202 | n = 1645 | |
| Mean (SD) | 48.3 (21.0) | 47.1 (21.6) | 0.468 |
| Median (10th, 90th percentile) | 58.4 (3.6, 59.6) | 58.0 (2.6, 59.3) | |
| Follow-up time (years) | |||
| Mean (SD) | 1.5 (1.1) | 1.5 (1.1) | 0.893 |
| Median (10th, 90th percentile) | 1.4 (0.3, 3.3) | 1.1 (0.4, 3.4) | |
| Race/ethnicity, n (%) | n = 201 | n = 1658 | < 0.001 |
| White | 133 (66.2) | 1459 (88.0) | |
| African Descent | 48 (23.9) | 123 (7.4) | |
| American Hispanic | 0 | 1 (0.1) | |
| Latino American | 1 (0.5) | 1 (0.1) | |
| Asian | 15 (7.5) | 59 (3.6) | |
| Other | 4 (2.0) | 15 (0.9) |
Number of patients with available data indicated for variables with missing data
SD standard deviation
aFrom symptom onset to enrollment
Table 2.
Clinical characteristics by sex
| Characteristic | Women (n = 214) | Men (n = 1710) | p Value |
|---|---|---|---|
| TTR genotype, n (%) | < 0.0001 | ||
| Variant | 86 (40.2) | 190 (11.1) | |
| Wild-type | 128 (59.8) | 1520 (88.9) | |
| Carpal tunnel syndrome, n (%) | 10 (4.7) | 182 (10.6) | 0.006 |
| mBMIa (g/dl × kg/m2) | n = 169 | n = 1425 | |
| Mean (SD) | 1100.3 (235.3) | 1113.1 (195.5) | 0.497 |
| Median (10th, 90th percentile) | 1081.4 (818.1, 1422.9) | 1101.2 (886.9, 1361.1) | |
| eGFR (ml/min/1.73 m2) | n = 193 | n = 1617 | |
| Mean (SD) | 48.8 (20.2) | 58.4 (23.1) | < 0.001 |
| Median (10th, 90th percentile) | 45.6 (26.6, 72.5) | 55.8 (32.0, 88.9) | |
| Medical history, n (%) | |||
| Diabetes mellitus | 8 (3.7) | 55 (3.2) | 0.686 |
| Inflammatory arthritis | 1 (0.5) | 21 (1.2) | 0.326 |
| Osteoarthritis | 6 (2.8) | 68 (4.0) | 0.420 |
| Tendon rupture | 0 | 47 (2.7) | 0.008 |
| Joint replacementb | 0 | 3 (0.2) | 1.000 |
| Arthroplastyb | 4 (1.9) | 32 (1.9) | 1.000 |
| Rotator cuff repairb | 0 | 5 (0.3) | 1.000 |
| Lumbar spinal stenosisb | 9 (4.2) | 80 (4.7) | 0.864 |
| Trigger fingerb | 5 (2.3) | 44 (2.6) | 1.000 |
| Cerebrovascular accident/stroke | 3 (1.4) | 32 (1.9) | 0.628 |
| Autonomic neuropathy, n (%) | 14 (6.5) | 181 (10.6) | 0.065 |
Number of patients with available data indicated for variables with missing data
BMI body mass index, eGFR estimated glomerular filtration rate, mBMI modified body mass index, SD standard deviation, TTR transthyretin
amBMI is calculated by multiplying BMI (kg/m2) by serum albumin (g/l) to compensate for fluid accumulation
bResults from search of free text fields in medical history
In genotype-stratified analyses, women with ATTRwt-CM were older than men at enrollment (mean age: 80.7 vs. 77.6 years) and at symptom onset (mean age: 77.5 vs. 74.5 years; p < 0.001) (Table S1). Women with ATTRv-CM were also older than men at enrollment (mean age: 72.1 vs. 69.6 years) but no statistically significant difference in age at symptom onset was observed. In both subgroups, women had significantly lower mean eGFR (ATTRv-CM: 54.5 vs. 65.9 ml/min/1.73 m2; ATTRwt-CM: 45.0 vs. 57.5 ml/min/1.73 m2) (Table S2).
Cardiac Characteristics at Enrollment
The distribution of NYHA class and NAC stage differed significantly by sex, with a higher proportion of women vs. men in NYHA class III/IV (37.8% vs. 29.5%; overall p = 0.036) and NAC stage II/III (68.0% vs. 47.7%; overall p = 0.023) (Table 3). Mean NT-proBNP levels were similar between women and men (3459.8 and 3227.3 pg/ml, respectively). Women vs. men had a higher mean heart rate (74.8 vs. 71.6 beats/min; p = 0.006) as well as shorter mean PR (186.9 vs. 213.3 ms; p < 0.001), QRS (109.2 vs. 125.2 ms; p < 0.001), QT (423.7 vs. 440.8 ms; p < 0.001), and QTcF (453.6 vs. 465.1; p < 0.001) intervals.
Table 3.
Cardiac characteristics by sex
| Characteristic | Women (n = 214) | Men (n = 1710) | p value |
|---|---|---|---|
| NYHA class, n (%) | n = 204 | n = 1651 | 0.036 |
| I | 30 (14.7) | 248 (15.0) | |
| II | 97 (47.5) | 917 (55.5) | |
| III | 72 (35.3) | 470 (28.5) | |
| IV | 5 (2.5) | 16 (1.0) | |
| Presence of pacemaker/ICD, n (%) | 6 (2.8) | 72 (4.2) | 0.500 |
| NAC stage, n (%) | n = 47 | n = 434 | 0.023 |
| I | 15 (31.9) | 227 (52.3) | |
| II | 23 (48.9) | 137 (31.6) | |
| III | 9 (19.1) | 70 (16.1) | |
| NT-proBNP (pg/ml) | n = 47 | n = 439 | |
| Mean (SD) | 3459.8 (3981.8) | 3227.3 (3810.9) | 0.692 |
| Median (10th, 90th percentile) | 2195.0 (372.0, 9555.0) | 2028.0 (490.8, 7112.0) | |
| Heart rate (beats/min) | n = 200 | n = 1633 | |
| Mean (SD) | 74.8 (15.4) | 71.6 (13.5) | 0.006 |
| Median (10th, 90th percentile) | 73.0 (56.0, 96.0) | 70.0 (57.0, 89.0) | |
| PR interval (ms) | n = 119 | n = 789 | |
| Mean (SD) | 186.9 (46.1) | 213.3 (48.7) | < 0.001 |
| Median (10th, 90th percentile) | 180.0 (148.0, 238.0) | 208.0 (160.0, 275.0) | |
| QRS interval (ms) | n = 190 | n = 1521 | |
| Mean (SD) | 109.2 (27.7) | 125.2 (31.0) | < 0.001 |
| Median (10th, 90th percentile) | 99.5 (81.0, 146.5) | 121.0 (90.0, 168.0) | |
| QT interval (ms) | n = 189 | n = 1517 | |
| Mean (SD) | 423.7 (44.0) | 440.8 (46.3) | < 0.001 |
| Median (10th, 90th percentile) | 424.0 (368.0, 484.0) | 440.0 (382.0, 499.0) | |
| QTcF interval (ms) | n = 187 | n = 1512 | |
| Mean (SD) | 453.6 (34.7) | 465.1 (37.4) | <0.001 |
| Median (10th, 90th percentile) | 452.0 (412.0, 498.0) | 463.0 (419.0, 512.0) |
Number of patients with available data indicated for variables with missing data
ICD implantable cardioverter defibrillator, NAC National Amyloidosis Centre, NT-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association, SD standard deviation
Among patients with ATTRwt-CM, a higher proportion of women vs. men were in NYHA class III/IV (42.5% vs. 28.8%; overall p = 0.001) and NAC stage II/III (69.7% vs. 48.0%; overall p = 0.040), but no statistically significant differences were observed in NYHA class or NAC stage in patients with ATTRv-CM (Table S3).
Regression Analysis of Sex-Related Differences in Clinical and Cardiac Variables
After adjustment for age, cohort, and TTR genotype, women had significantly higher eGFR (β [men vs. women] = − 10.61; p < 0.001) and lower heart rate (β [men vs. women] = 2.60; p = 0.015) than men (Table 4). A similar pattern for eGFR was observed in patients with ATTRv-CM and in patients with ATTRwt-CM (Table S4).
Table 4.
Regression analyses of sex-related differences in clinical and cardiac variables
| Variable | Na | β coefficient (SE)b | p Value |
|---|---|---|---|
| mBMI (g/dl × kg/m2) | 1594 | 6.10 (16.856) | 0.717 |
| Heart rate (beats/min) | 1833 | 2.60 (1.070) | 0.015 |
| eGFR (ml/min/1.73 m2) | 1810 | − 10.61 (1.699) | < 0.001 |
| NT-proBNP (pg/ml)c | 486 | 622.07 (635.721) | 0.328 |
| Variable | N | Odds ratio (CI) | p Value |
|---|---|---|---|
| NYHA class (I–II vs. III–IV) | 1855 | 0.80 (0.60–1.07) | 0.125 |
BMI body mass index, CI confidence interval, eGFR estimated glomerular filtration rate, mBMI modified body mass index, NT-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association, SE standard error
aNumber with data for dependent variable
bSex (men vs. women [reference])
cNT-proBNP values were not transformed
All-Cause Mortality
A total of 34 women (15.9%) and 346 men (20.2%) died during the study, of whom 2 (5.9%) and 26 (7.5%) had a cardiovascular-related cause of death (Table S5). No statistically significant sex-based difference in all-cause mortality was observed (log-rank p = 0.178; Table 5; Fig. 1). However, after adjustment for age, study, baseline NYHA class, and TTR genotype, men had a significantly higher risk of all-cause mortality than women (HR [men vs. women] 1.60; 95% CI 1.12–2.30). No significant sex-based differences in all-cause mortality were observed in subgroups of patients with ATTRv-CM or ATTRwt-CM based on Kaplan–Meier analyses and after adjustment for baseline variables (Table S6).
Table 5.
All-cause mortality stratified by sex
| Women (n = 214) | Men (n = 1710) | |
|---|---|---|
| Number of deaths, n (%) | 34 (15.9) | 346 (20.2) |
| Number censored, n (%) | 180 (84.1) | 1364 (79.8) |
| Kaplan–Meier estimates of time to event (years) | ||
| Quartiles (95% CI) | ||
| 25% | 3.27 (1.74‒NE) | 2.13 (1.82‒2.42) |
| 50% | NE (3.79‒NE) | NE (NE‒NE) |
| 75% | NE (NE‒NE) | NE (NE‒NE) |
| HR (95% CI), men vs. womena | 1.60 (1.12‒2.30) | |
| Log-rank p value, men vs. women | 0.178 | |
CI confidence interval, HR hazard ratio, NE not estimable; NYHA New York Heart Association, TTR transthyretin
aCox proportional hazards models were used to evaluate all-cause mortality, with sex, age, study, baseline NYHA class, and TTR genotype as factors
Fig. 1.
Kaplan–Meier survival plots for all-cause mortality, by sex, hazard ratio. NE not estimable, TTR transthyretin
Discussion
In this pooled analysis of contemporary patients with ATTR-CM treated with tafamidis from THAOS and an early-access cohort, women represented a small proportion of the overall population. A greater proportion of women than men had ATTRv-CM, although ATTRwt-CM was more common in both sexes, and women were more frequently of African descent. These findings are consistent with prior reports demonstrating that women with ATTR-CM account for a higher proportion of patients with ATTRv-CM than with ATTRwt-CM [9, 18] and extend these observations to this population of patients treated with tafamidis. Given the higher prevalence of ATTRv-CM, particularly that associated with the V122I (p.V142I) variant, among patients of African ancestry [19, 20], the higher proportion of women of African descent observed in this cohort is also consistent with the known epidemiology of ATTRv-CM. These findings highlight the importance of considering genotype and ancestry when evaluating sex-related differences in ATTR-CM populations, as cohort composition may influence observed phenotypic differences.
Regarding disease presentation, women appeared more symptomatic at enrollment, with a higher proportion in NYHA class III/IV and more advanced NAC stage, despite similar NT-proBNP concentrations. These findings may reflect, at least in part, the persistent diagnostic gap reported in women with ATTR-CM. Prior studies have suggested that women with ATTR-CM are under-recognized and may experience delays in diagnosis because ATTR-CM, particularly ATTRwt-CM, has historically been considered a predominantly male disease and because existing diagnostic thresholds may be less sensitive in women [9, 11, 21]. Baseline differences in heart rate and other ECG variables were generally consistent with established sex differences seen in healthy populations [22], although women demonstrated shorter mean QT and QTcF intervals than men, a finding that contrasts with observations in healthy populations. However, most apparent sex-related differences observed in the pooled cohort were attenuated after stratification by genotype, with men and women having broadly similar symptom burden, biomarker profiles, and clinical characteristics. The only consistent differences were older age and lower eGFR in women.
Although Kaplan–Meier analyses showed no significant differences in mortality between men and women, men had a significantly higher risk of all-cause mortality during follow-up after adjusting for baseline factors. The difference between these analyses likely reflects confounding by baseline factors that differed between groups. Cause-of-death patterns were broadly comparable between sexes and do not suggest that differences in cardiovascular versus non-cardiovascular mortality explain the observed survival findings, although interpretation is limited by the substantial proportion of deaths with unknown cause. When examined within genotype subgroups, no statistically significant sex-based differences in all-cause mortality were observed. These findings suggest that differences in genotype distribution may have contributed to the overall mortality findings.
Women in this cohort appeared to have greater functional limitation at presentation despite similar NT-proBNP levels. This pattern may not be unique to ATTR-CM and has been described in broader heart failure populations, where women often report greater symptom burden and poorer quality of life despite comparable biomarker profiles and similar or more favorable survival outcomes [23–25]. The mechanisms underlying these differences remain incompletely understood but may relate to body size, comorbidity burden, exercise capacity, symptom perception, or referral patterns [26]. In the current cohort, similar NT-proBNP concentrations alongside more favorable survival in women suggest caution in interpreting functional status alone as a marker of more advanced biological disease.
This study has several limitations. The analysis was observational and included pooled data from two distinct cohorts. Women represented a relatively small proportion of the study population, limiting power for subgroup analyses. Residual confounding cannot be excluded, and follow-up duration was modest. In addition, inclusion was restricted to patients treated with tafamidis and may not reflect the broader untreated ATTR-CM population. Baseline NT-proBNP and NAC stage data were missing for a substantial proportion of patients, limiting interpretation of disease severity based on these measures. Missing baseline data for these variables and other markers of disease severity also limited the ability to control for such factors in the analysis of all-cause mortality. Baseline was defined differently across the two cohorts, potentially introducing heterogeneity in time zero and survival follow-up, as patients may have differed in disease duration and/or treatment exposure at the start of observation. Additionally, given the uneven distribution of genotype between men and women, adjustment for genotype may have resulted in over-controlling in multivariable analyses, and adjusted mortality findings should be interpreted with caution. Furthermore, the two studies differed in enrollment criteria and follow-up procedures. Although adjusted analyses accounted for study cohort, residual confounding related to patient selection and other factors cannot be excluded. Lastly, in the absence of a comparison group, these data did not allow for assessment of differential tafamidis efficacy by sex.
Conclusions
In conclusion, women remain underrepresented among contemporary patients with ATTR-CM treated with tafamidis, and a greater proportion had ATTRv-CM than men. Although women appeared more symptomatic at presentation, men had a higher risk of mortality when adjusting for baseline factors. Further studies are needed to better understand potential sex-related differences in diagnosis, referral patterns, and disease expression in ATTR-CM.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank all patients and investigators from the THAOS registry and the early access study for their important contributions to this study.
Medical Writing Assistance
Medical writing support was provided by Neel Misra-Davison, MSc, CMPP, of Engage Scientific Solutions and was funded by Pfizer.
Author Contribution
Conceptualization, investigation, and data collection: Marianna Fontana, Martha Grogan, Maria Generosa Crespo-Leiro, Mathew S. Maurer, Fabian aus dem Siepen, Mazen Hanna, Diego Delgado, Thibaud Damy, Margot K. Davis. Data curation and formal analysis: Martin Carlsson. Data interpretation and writing—review and editing: all authors.
Funding
This study and the Rapid Service Fee were sponsored by Pfizer.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Please direct any further inquiries to the corresponding author.
Declarations
Conflicts of Interest
Marianna Fontana: Consultancy and advisory board fees from Alexion, Alnylam, AstraZeneca, Attralus, BridgeBio, Caelum Biosciences, Cardior, Eidos, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Lexeo Therapeutics, Novo Nordisk, Pfizer, and Prothena and has received research grants from Alnylam, AstraZeneca, BridgeBio, and Pfizer, and has received a salary from a British Heart Foundation Intermediate Fellowship. Alberto Aimo: nothing to disclose. Martha Grogan: Research funding: Alnylam, Eidos, Janssen, Pfizer, and Novo Nordisk; license/patent pending from Anumana (algorithm to detect cardiac amyloidosis using AI ECG); advisory board: Alnylam, AstraZeneca, BridgeBio, Janssen, and Novo Nordisk. Maria Generosa Crespo-Leiro: Institutional grants from Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) and Pfizer; honoraria for advisory board participation from Novo Nordisk; travel grants from Pfizer; and personal fees for scientific lectures from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Novartis, and Vifor Pharma. Mathew S. Maurer: Grants and personal fees from Eidos, Ionis, Pfizer, and Prothena; grants from Alnylam; and personal fees from Akcea and GSK. Fabian aus dem Siepen: Speaker fees from Pfizer, Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Janssen, and consulting fees from Pfizer and Akcea Therapeutics. Mazen Hanna: Honoraria for advisory board participation from Akcea, Alexion Pharmaceuticals, Alnylam, BridgeBio, and Pfizer; and one-time speaker fees from Alnylam. Diego Delgado: Research grants and consultant for Pfizer, Alnylam and AstraZeneca. Martin Carlsson: Employee of and owns stock/stock options in Pfizer. Thibaud Damy: Consulting fees from Alnylam, GlaxoSmithKline, Pfizer, and Prothena; honoraria from Alnylam, Pfizer, and Prothena; research grants from GlaxoSmithKline and Pfizer; and clinical trial support from Alnylam, Ionis, and Pfizer. Margot K. Davis: Honoraria from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Novo Nordisk, and Pfizer; consulting fees from Alnylam Pharmaceuticals, Anthos, AstraZeneca, Bayer, BridgeBio Pharma Inc., Novo Nordisk, and Pfizer; research funding from Pfizer.
Ethics/Ethical Approval
Both studies were approved by the independent review board or ethics committee at each participating center and were conducted in accordance with the concepts laid out in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provided written informed consent.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Please direct any further inquiries to the corresponding author.