Real-World Clinical Evidence With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy　― A Contemporary Review ―

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a cause of heart failure with preserved ejection fraction in older adults. Tafamidis, a transthyretin stabilizer, is the first disease-modifying therapy approved for ATTR-CM. Although its efficacy was demonstrated in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) trial, real-world data are essential to evaluate its effectiveness across broader and more diverse patient populations. This review synthesizes real-world evidence on tafamidis, including patient characteristics, diagnostic and therapeutic delays, and clinical outcomes such as mortality, hospitalization, cardiac biomarker trends, imaging findings, and functional capacity. Compared with clinical trial participants, real-world patients are generally older, often present with more advanced disease, and initiate treatment later in the disease course. Nevertheless, observational studies from Japan and other countries consistently show that tafamidis is associated with improved survival, reduced heart failure hospitalizations, stabilization of cardiac structure and biomarkers, and preservation of physical function – especially when therapy is started early. Accumulating such data will be crucial for optimizing patient care, particularly in the context of future treatment strategies involving emerging agents such as a next-generation oral transthyretin stabilizer and a subcutaneously administered RNA interference therapeutic. This review aims to bridge the gap between clinical trial findings and routine practice, supporting informed decision-making in the management of this progressive and underdiagnosed condition.

In recent years, transthyretin amyloid cardiomyopathy (ATTR-CM) has emerged as a key cause of heart failure with preserved ejection fraction (HFpEF), especially in older adults.^1,2 Characterized by the extracellular deposition of misfolded transthyretin (TTR) protein within the myocardium, this disease manifests with progressive heart failure, arrhythmias, conduction disturbances, and sometimes extracardiac symptoms such as carpal tunnel syndrome and autonomic neuropathy.^3–5 ATTR-CM exists in 2 primary forms: wild-type (ATTRwt), which is age-related and non-hereditary, and hereditary (variant, hATTR), caused by mutations in the TTR gene. Once considered rare, ATTR-CM is now increasingly recognized, especially due to advances in diagnostic imaging and awareness campaigns.

Tafamidis, a TTR tetramer stabilizer, is the first disease-modifying drug approved for ATTR-CM. Its clinical utility was established by the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) in 2018, which demonstrated significant survival benefits and reductions in cardiovascular hospitalizations.⁶ However, the trial population consisted of carefully selected patients, largely limited to individuals with mild to moderate functional impairment. In contrast, patients encountered in routine clinical practice often present with more advanced disease stages, greater comorbid burden, or atypical phenotypes. Consequently, real-world evidence has become essential to evaluate the generalizability and practical utility of tafamidis in broader clinical settings. Furthermore, novel agents such as a next-generation oral TTR stabilizer and a subcutaneously delivered RNA interference (RNAi) therapeutic are anticipated to be available. As the therapeutic landscape expands, a better understanding of tafamidis use and its clinical impact in real-world populations will be essential to guide optimal treatment selection and individualized care strategies in the future.

This review aims to provide a comprehensive synthesis of the real-world application of tafamidis in managing ATTR-CM and to bridge the gap between clinical trial evidence and daily clinical practice. This approach also serves to inform future research and guide clinical decision-making in the management of cardiac amyloidosis, particularly in aging societies.

Real-World Evidence: Patient Characteristics and Initiation

Real-world data on tafamidis use in ATTR-CM reveal a patient population that differs in meaningful ways from those enrolled in clinical trials. In practice, most patients are elderly males with wild-type ATTR (ATTRwt), and many initiate therapy at an advanced stage of disease. Multiple registry studies and observational cohorts have reported that the average age at diagnosis ranges between 75 and 80 years, with a consistent male predominance exceeding 80%.^7–9 In some studies, the impact of tafamidis treatment on mortality was evaluated in octogenarians.^10,11 Left ventricular wall thickness is typically increased, often above 15 mm, and biomarkers such as N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) are elevated in the majority of patients, indicating significant cardiac involvement at the time of diagnosis.

A notable finding across real-world cohorts is the delay in diagnosis.^12–14 Many patients experience non-specific symptoms such as general fatigue, dyspnea, or lower extremity edema, which may initially be attributed to hypertensive heart disease or diastolic dysfunction. This often results in diagnostic delays of a year or more, during which time structural and functional deterioration may occur. Although bone scintigraphy,¹⁵ cardiac magnetic resonance imaging and cardiac computed tomography¹⁶ have improved non-invasive diagnostic capabilities, access and interpretation remain inconsistent, particularly in community settings.

Tafamidis initiation in the real world is commonly delayed, even after diagnosis. Administrative procedures, reimbursement systems, and limited clinical familiarity with amyloidosis treatment can all contribute to treatment lag.¹⁷ In several cohort studies, more than half of the patients began tafamidis therapy in New York Heart Association (NYHA) class III or higher, a stage at which the therapeutic impact may be attenuated.⁹

Those who began therapy in NYHA class I–II generally showed better clinical stabilization and less biomarker progression.^18,19 However, treatment efficacy has been demonstrated even in patients initiated on tafamidis at NYHA class III,²⁰ as well as in patients who were switched from placebo to active drug in the long-term extension of the ATTR-ACT trial.²¹ These findings suggest that tafamidis should not be withheld in NYHA class III or more advanced cases, as long as the patient meets the eligibility criteria.

Comparison of patient characteristics in the ATTR-ACT clinical trial and observational real-world studies of tafamidis are shown in Table 1. Real-world populations tend to be older, have more comorbidities, and present with more advanced disease than participants in randomized controlled trials. Early diagnosis and prompt initiation of therapy remain challenges in routine clinical practice. Overall, real-world evidence underscores the importance of early recognition and prompt treatment initiation. Systematic screening in high-risk populations, such as elderly men with unexplained heart failure or increased wall thickness, may facilitate timely diagnosis and optimize the benefits of tafamidis therapy.

Table 1.

Comparison of Patient Characteristics in ATTR-ACT and Real-World Studies of Tafamidis

Characteristic	ATTR-ACT6	Real-world studies7–11
Age (years)	Mean ~75 years	Often older (late 70 s to early 80 s)
NYHA functional class	Approximately 2/3 were Class I–II	Higher proportion in Class II–III
Disease duration at diagnosis	Shorter (due to enrollment criteria)	Often delayed diagnosis (longer disease duration)
Comorbidities	Fewer comorbidities	More frequent
TTR mutation status	Wild-type and hereditary included	Predominantly wild-type ATTR
Cardiac biomarkers (NT-proBNP, troponin)	Relatively lower baseline values	Frequently elevated at baseline
Imaging parameters (LVEF, LV wall thickness)	Mild to moderate involvement	Often advanced structural abnormalities

ATTR-ACT, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; LV, left ventricle; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association.

Clinical Outcomes in Real-World Studies

Mortality and Hospitalization

Most real-world studies confirm the mortality benefit of tafamidis, although the magnitude of benefit tends to be less pronounced compared with that observed in the ATTR-ACT trial.⁶ In a large retrospective analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS), tafamidis-treated patients showed a significantly higher survival rate over 30 and 42 months compared with untreated patients, with an absolute difference exceeding 15% at each time point.⁷ The benefit was most pronounced among those without severe functional limitation or advanced cardiac remodeling at baseline.

Moreover, a real-world study from Japan reported that tafamidis reduced both all-cause mortality and heart failure-related hospitalizations over a median follow up of 18 months.⁸ Importantly, the divergence in survival curves between treated and untreated groups became more apparent beyond 12 months, highlighting the need for sustained treatment and longer observation to capture the full therapeutic effect.

While these observational studies are subject to inherent limitations such as selection bias and confounding by indication, they collectively demonstrate that tafamidis is associated with improved clinical outcomes in a broad range of patient populations. However, the degree of benefit may vary based on timing of therapy initiation, baseline disease severity, and comorbid conditions. These findings emphasize the importance of early diagnosis and prompt treatment initiation to optimize outcomes in patients with ATTR-CM.

Cardiac Imaging

Real-world studies have demonstrated that tafamidis may stabilize or even modestly reverse structural cardiac changes in patients with ATTR-CM, as evidenced using imaging modalities.

In a retrospective analysis of 45 patients with ATTR-CM, the study by Giblin et al. compared 23 individuals receiving tafamidis with 22 untreated controls over a 12-month period.²² The tafamidis-treated group showed significantly less deterioration in global longitudinal strain (GLS), with a median decline of 0.3%, compared with a median decline of 1.1% in the untreated group. Moreover, measures of the myocardial work index and efficiency deteriorated to a lesser extent, suggesting a stabilizing effect on myocardial contractile function.

A study conducted by Ichikawa and colleagues evaluated the impact of tafamidis on cardiac morphology in 41 patients with biopsy-confirmed ATTR-CM.²³ After an average treatment duration of 16 months, no significant changes were observed in echocardiographic parameters, indicating stabilization of cardiac structure. This effect was consistent across various subgroups, including older individuals and those with advanced disease, suggesting that tafamidis may attenuate cardiac remodeling regardless of disease severity at baseline.

In a prospective investigation led by Dobner et al., 36 patients treated with tafamidis underwent cardiac magnetic resonance imaging at baseline and again after 12 months.²⁴ The analysis revealed preserved biventricular function and a significant reduction in left ventricular (LV) mass, from 184.7±47.7 g to 176.5±44.3 g (P=0.011), in the tafamidis group. In contrast, untreated patients showed no such improvement. These results further support the potential of tafamidis to preserve myocardial structure and function in a real-world clinical setting. Taken together, these findings suggest that tafamidis therapy administered over 12–18 months may lead to stabilization, or modest improvement, of key cardiac structural and functional parameters, including LV wall thickness and GLS, in patients with ATTR-CM.

Emerging real-world studies have begun to explore the effects of tafamidis on atrial function in patients with ATTR-CM.²³ While no statistically significant changes were observed in left atrial volume index (LAVI) or left atrial global longitudinal strain (LA-GLS), these parameters remained stable throughout the study period, suggesting that tafamidis may help prevent further atrial remodeling. Building on these findings, Nishizawa et al. conducted a study involving patients with ATTRwt-CM.²⁵ Over a 12-month period, they observed that tafamidis treatment led to significant improvements in both left atrial reservoir and conduit strains, as measured using speckle-tracking echocardiography. These findings are particularly relevant given the high prevalence of atrial fibrillation and diastolic dysfunction in this population. Although most clinical outcomes studies have focused on ventricular parameters, these results indicate that tafamidis may also contribute to atrial functional preservation when initiated early in the disease course.

Cardiac Biomarkers

In addition to imaging, circulating cardiac biomarkers such as hs-cTnT and NT-proBNP have been widely used in clinical practice to assess disease severity and therapeutic response in ATTR-CM.

Real-world data consistently indicate that tafamidis therapy helps stabilize these biomarkers, particularly when initiated early in the disease course. A study by Oghina et al. assessed the evolution and prognostic value of NT-proBNP and hs-cTnT in patients with ATTR-CM before and after tafamidis treatment.²⁶ The study found that in the cohort treated with tafamidis, the slopes of log-transformed NT-proBNP and hs-cTnT levels stabilized over time, suggesting that tafamidis may halt the progression of cardiac stress markers.

Similarly, Nakamura et al. investigated the prognostic impact of increased cardiac troponin I levels during tafamidis therapy in patients with transthyretin cardiac amyloidosis.²⁷ The study concluded that an increase in cardiac troponin I levels was independently associated with worse clinical outcomes, indicating that stable troponin levels during tafamidis treatment may reflect a favorable response.

Recent real-world evidence from Kumamoto University highlights the importance of cardiac biomarkers in monitoring tafamidis efficacy. In a longitudinal study of 258 patients with ATTR-CM, Kuyama et al. found that baseline hs-cTnT was a strong independent predictor of all-cause mortality.²⁸ Long-term tafamidis treatment attenuated the progression of hs-cTnT and BNP levels, indicating its stabilizing effect on myocardial injury. Complementing this, Kuyama et al. demonstrated that an increase in hs-cTnT or BNP during the first year of tafamidis therapy was associated with significantly worse outcomes, including death and heart failure hospitalization.²⁹

These findings underscore the utility of serial hs-cTnT and BNP measurements as prognostic tools to monitor the therapeutic response and guide clinical management in real-world settings.

Functional Capacities

Maintaining physical function is a key therapeutic goal in the management of ATTR-CM, as the disease is progressive and often results in a marked decline in exercise capacity and overall quality of life. Several real-world and prospective studies have demonstrated its potential to attenuate functional decline.

In a prospective study, medical therapy with tafamidis was associated with the preservation of physical performance in patients with ATTR-CM, as assessed using cardiopulmonary exercise testing (CPET) over a 12-month period.³⁰ Patients with less advanced disease at baseline (NYHA class I–II) exhibited improvements in peak oxygen uptake (V̇O₂) and ventilatory efficiency, while patients with more advanced disease maintained stable parameters. These findings suggest that early initiation of tafamidis may contribute to preserving exercise capacity, especially in patients with milder disease.

A Japanese single-center study provided additional evidence on the effect of tafamidis therapy on exercise tolerance in patients with wild-type ATTR-CM.³¹ Over a 6-month follow-up period, tafamidis-treated patients showed stabilization in 6-min walk test distance, and a subset of individuals with lower baseline walking distance experienced improvement. Notably, no significant decline was observed across the cohort, indicating that tafamidis may prevent progressive deterioration in physical function.

A prospective study conducted by Shibata and colleagues explored the impact of tafamidis on exercise tolerance in patients with wild-type ATTR-CM using CPET over a 6-month period.³² The study found no significant overall change in peak oxygen uptake (peak V̇O₂), suggesting that tafamidis effectively stabilizes exercise capacity rather than improving it universally. However, a subgroup analysis revealed that patients with lower baseline peak V̇O₂ were more likely to experience improvement in exercise tolerance. This finding indicates that early identification and initiation of therapy in patients with reduced functional reserve may maximize the therapeutic benefits of tafamidis.

Comparison of clinical outcomes from the ATTR-ACT randomized controlled trial and real-world observational studies of tafamidis are shown in Table 2. Both settings demonstrate that early diagnosis and treatment are key to maximizing clinical benefits, including survival, symptom control, and functional preservation. Taken together, these real-world studies support the role of tafamidis in preserving functional capacity among patients with ATTR-CM. While exercise tolerance may not substantially improve in most patients, the ability to maintain physical function and prevent further decline is a clinically meaningful benefit.

Table 2.

Clinical Outcomes With Tafamidis in ATTR-CM: ATTR-ACT vs. Real-World Evidence

Outcome	ATTR-ACT6	Real-world studies7–9,22–32	Summary
All-cause mortality	Reduced by ~30% vs. placebo at 30 months	Reduced mortality, especially with early treatment	Benefit seen in both settings, more with early initiation
Cardiovascular hospitalizations	Fewer hospitalizations vs. placebo	Generally reduced; evident after ≥12 months of therapy	Hospitalization reduction confirmed in several cohorts
Functional capacity (6MWT, V̇O2)	Slower decline	Stabilized; improvement in early or lower-functioning patients	6MWT and CPET support functional preservation
Quality of life (KCCQ-OS)	Maintained	Improvement or stabilization reported	Reflects patient-perceived benefit
NT-proBNP/troponin	Slower biomarker progression	Stabilized or declined in early treated patients	Biomarker trends reflect clinical stabilization
Echocardiography/CMR imaging	Modest structural change	Stable or reduced LV mass/strain decline in several cohorts	Dependent on disease stage at treatment start
Adverse events	Similar to placebo	Well tolerated across real-world cohorts	Favorable safety profile in routine care

6MWT, 6-min walk test; ATTR-CM, transthyretin amyloid cardiomyopathy; CMR, cardiac magnetic resonance; CPET, cardiopulmonary exercise testing; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricle; NT-proBNP, N-terminal pro B-type natriuretic peptide; V̇O₂, oxygen uptake.

Ongoing Real-World Initiatives and Future Directions

Ongoing international registry studies continue to track patients treated with tafamidis, evaluating survival rates, functional capacity, and changes in biomarkers. These studies provide valuable insights into the real-world effectiveness of tafamidis, especially in understanding the benefits of early treatment initiation.

In particular, data from Japan has shown that tafamidis treatment stabilizes cardiac biomarkers such as NT-proBNP and hs-cTnT. Studies from Kumamoto University have demonstrated that patients starting tafamidis treatment early in the disease course experience significantly lower hospitalization rates due to heart failure, as well as slower disease progression.²⁸ This highlights the importance of early intervention in improving long-term outcomes. Looking ahead, there is a growing body of research focused on the impact of treatment delays on prognosis.³³ These real-world studies are likely to provide further evidence of the benefits of initiating tafamidis early in disease progression. Additionally, they will help elucidate how patients in different disease stages respond to treatment, ultimately refining therapeutic strategies.²⁹

Furthermore, multi-center and regional studies are expanding our understanding of tafamidis’ effects across different healthcare settings.⁷ These studies will offer insights into how regional differences and healthcare resources influence treatment outcomes, particularly in areas with limited access to advanced therapies. Ultimately, real-world data will play a pivotal role in refining individualized treatment strategies, maximizing the therapeutic benefits of tafamidis, and improving patient outcomes globally.

Conclusions

Tafamidis has become the cornerstone of ATTR-CM therapy, and real-world data largely corroborate its benefits, as demonstrated in randomized trials. Early detection and patient stratification remain key to maximizing benefit. Continued surveillance and broader inclusion in future real-world studies will be essential to optimize tafamidis therapy across diverse patient populations. Accumulating such data will be crucial for optimizing patient care, especially in the context of future treatment strategies involving emerging agents such as a next-generation oral TTR stabilizer and a subcutaneously administered RNAi therapeutic.

Disclosures

Y.I., K.T. have received remuneration for lectures from Pfizer Japan Inc. K.T. is a member of Circulation Report’s Editorial Team. The other authors declare they have no conflicts of interest.

Author Contributions

The authors used ChatGPT (OpenAI) to assist in language editing and organization of the manuscript. The final content was reviewed and approved by all authors, who take full responsibility for the accuracy and integrity of the work.