Women and men with ATTR-CM show different clinical patterns

Women with transthyretin amyloid cardiomyopathy (ATTR-CM) showed different clinical characteristics than men with the condition in pooled data from two previous studies of patients treated with Vyndamax (tafamidis).

Although women appeared more symptomatic at study enrollment, men had a significantly higher risk of death during follow-up after adjustment for baseline factors. And, despite representing about one in 10 study participants, the proportion with hereditary ATTR-CM (hATTR-CM) was nearly four times higher among women than men.

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Sept. 3, 2026 News by Marisa Horak, MS

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“Further studies are needed to better understand potential sex-related differences in diagnosis, referral patterns, and disease expression in ATTR-CM,” the researchers wrote.

The study, “Sex Differences in a Contemporary, Real-World Cohort of Patients with Transthyretin Amyloid Cardiomyopathy Treated with Tafamidis,” was published in Cardiology and Therapy. It was funded by Pfizer, which markets Vyndamax, and one of its authors is a company employee.

In ATTR-CM, a misfolded transthyretin protein forms toxic clumps, known as amyloid deposits, that build up in the heart muscle. This can lead to symptoms such as irregular heartbeats, heart failure, and reduced survival.

The condition is either hereditary, caused by mutations in the TTR gene, or wild-type (wtATTR-CM), which develops without an inherited gene mutation and typically occurs later in life.

ATTR-CM has traditionally been viewed as a disease that predominantly affects older men. As a result, women have historically been underrepresented in ATTR-CM research. But emerging evidence suggests important sex-related differences. For example, women with wild-type ATTR-CM tend to present at an older age and have distinct clinical characteristics.

Here, an international team of researchers set out to further investigate sex-related differences in people with ATTR-CM who were treated with Vyndamax in the two study cohorts.

Pooled studies included tafamidis-treated patients

The therapy, taken once daily as an oral capsule, is approved for adults with either type of ATTR-CM. In the European Union, tafamidis is sold as Vyndaqel. It works by stabilizing transthyretin, helping prevent new amyloid deposits from forming and slowing disease progression.

The team pooled data from two global studies. The first included an early-access cohort within a long-term extension study (NCT02791230) of the Phase 3 ATTR-ACT clinical trial (NCT01994889), whose results largely supported Vyndamax’s approvals for ATTR-CM.

The second was a Phase 4 observational study, called THAOS (NCT00628745), that included ATTR-CM patients treated with Vyndamax or with tafamidis meglumine, the older formulation sold as Vyndaqel. Pfizer discontinued the U.S. supply of Vyndaqel in 2025.

The analysis included 214 (11.1%) women and 1,710 (88.9%) men with ATTR-CM. A significantly greater proportion of women than men were of African descent (23.9% vs. 7.4%), while a greater proportion of men than women were white (88% vs. 66.2%). The proportion with hereditary ATTR-CM was nearly four times higher among women than men (40.2% vs. 11.1%).

“These findings highlight the importance of considering [genetics] and ancestry when evaluating sex-related differences in ATTR-CM populations,” the team wrote.

Although age at symptom onset did not differ significantly between women and men with hATTR-CM, symptoms appeared significantly later in women than men with wtATTR-CM (mean 77.5 vs. 74.5 years). Women with both forms of ATTR-CM were also significantly older than men at study enrollment.

In terms of heart characteristics, a significantly greater proportion of women than men with wtATTR-CM had greater functional limitation at enrollment (42.5% vs. 28.8%), as indicated by a higher New York Heart Association (NYHA) functional class.

Similarly, a significantly greater proportion of women than men with wtATTR-CM were classified in the more advanced National Amyloidosis Centre stages II or III (69.7% vs. 48%). Despite these differences, NT-proBNP levels, a heart stress biomarker, were similar between women and men with wild-type disease.

In comparison, no sex-related differences in these disease parameters were noted in the unadjusted genotype-stratified comparisons for those with hATTR-CM.

Genotype may help explain baseline differences

These findings may reflect, at least in part, diagnostic delays previously reported in women with ATTR-CM, particularly wtATTR-CM, as it has “historically been considered a predominantly male disease and because existing diagnostic thresholds may be less sensitive in women,” the researchers wrote.

Adjusted statistical analyses showed that across both disease forms, women had a significantly higher estimated glomerular filtration rate, a sign of better kidney function, than men. Women with wtATTR-CM also had a significantly lower heart rate than men.

Overall, 34 women (15.9%) and 346 men (20.2%) died over a mean follow-up of 1.5 years. Statistical analyses adjusted for age, study, baseline NYHA class, and TTR genotype indicated that men had a significantly higher risk, by 60%, of death from any cause than women.

Nevertheless, among those who died, cardiovascular-related causes accounted for a similar proportion of deaths in women and men (5.9% vs. 7.5%). The researchers said the overall cause-of-death patterns “do not suggest that differences in cardiovascular versus non-cardiovascular mortality explain the observed survival findings,” although a substantial proportion of deaths had an unknown cause.

Within both disease forms, all-cause mortality was numerically higher in men than women, but neither difference reached statistical significance, meaning the study could not rule out chance as an explanation.

“Although women appeared more symptomatic at presentation, men had a higher risk of mortality when adjusting for [initial] factors,” the researchers wrote, calling for further studies to better understand potential sex-related differences in ATTR-CM.