Transthyretin cardiac amyloidosis (ATTR-CM) is an increasingly recognized cause of heart failure with preserved ejection fraction (HFpEF) in older adults.1,2 However, real-world data from middle-income countries remain limited.3 In Türkiye, diagnostic pathways generally follow international guideline recommendations, but access to disease-modifying therapies is strongly influenced by national reimbursement rules, which require specific biomarker thresholds and defined disease stages.4 Tafamidis, the first approved transthyretin stabilizer, has demonstrated benefit in clinical trials,5 yet its real-world use and impact under these constraints have not been fully described. In this letter, we report the diagnostic characteristics and twelve-month clinical outcomes of patients with ATTR-CM in the Black Sea region of Türkiye, comparing those treated with tafamidis with untreated patients in routine clinical practice.
We prospectively followed 120 consecutive adults with ATTR-CM diagnosed and managed at two tertiary centers in the Black Sea region between 2023 and 2025. Diagnosis was based on a guideline-aligned non-invasive algorithm, which included echocardiography with strain analysis, serum and urine immunofixation with free light chain assays to exclude light chain amyloidosis, and technetium-labeled bone scintigraphy. Genetic testing was performed to distinguish wild-type from hereditary transthyretin disease.6 All patients were discussed in a multidisciplinary team. Tafamidis eligibility and reimbursement followed National Social Security Institution criteria for ATTR-CM, which require patients to have NT-proBNP levels > 600 pg/mL, New York Heart Association functional class I–III with a six-minute walk distance > 100 m, left ventricular wall thickness ≥ 12 mm, no prior heart or liver transplantation, preserved renal function (estimated glomerular filtration rate ≥ 30 mL/min/1.73 m²), and a modified body mass index (BMI) (BMI × serum albumin) > 600.
Among the cohort, 57 patients received tafamidis, while 63 remained untreated despite confirmed ATTR-CM diagnosis. Baseline clinical characteristics were largely comparable between the two groups, including age, sex distribution, functional status, comorbidities, and echocardiographic findings, although untreated patients tended to have higher natriuretic peptide concentrations (Table 1). Several diagnostic "red flag" features were frequently observed, such as atypical HFpEF presentations, discordance between electrocardiographic voltage and left ventricular wall thickness, and intolerance to commonly used rate-limiting agents. A geographical pattern was also evident: patients residing farther from tertiary centers generally experienced longer delays in diagnosis, highlighting the impact of regional accessibility on timely disease recognition.
The primary outcome was the composite of cardiovascular death or heart failure hospitalization over twelve months. Tafamidis use was associated with a lower risk of this composite endpoint compared with no tafamidis (log-rank p = 0.021; hazard ratio, 0.66; 95% confidence interval: 0.46–0.95), as illustrated in the Kaplan–Meier curve in Figure 1. Secondary outcomes, including heart failure hospitalization and intensification of outpatient diuretic therapy, also favored the tafamidis group. These associations remained consistent in prespecified adjusted analyses using inverse probability of treatment weighting and in sensitivity analyses that accounted for competing risks and restricted mean survival time at twelve months. Over 12 months of follow-up, the composite endpoint occurred in 28.6% of untreated patients and 14.0% of those receiving tafamidis, corresponding to an absolute risk reduction of 14.5% and a number needed to treat of 7 to prevent one additional composite event.
These findings align with emerging international real-world data from European, Japanese, and Hellenic cohorts, which consistently demonstrate that tafamidis treatment is associated with fewer clinical events and more stable functional status in patients with ATTR-CM.7-10 At the same time, our results highlight several context-specific challenges in Türkiye. First, the positive correlation between distance to the hospital and time to diagnosis suggests that patients in rural areas reach specialist care later, despite presenting with characteristic diagnostic red flags.4,11,12 Second, a substantial proportion of patients who fulfilled diagnostic criteria could not initiate tafamidis because they did not meet strict reimbursement thresholds based on natriuretic peptide levels and disease stage, or because they had advanced heart failure, active malignancy, or preferred not to start long-term therapy.13 Taken together, these observations indicate that both system-level and patient-level factors may restrict timely initiation of disease-modifying treatment, even when clinical suspicion and diagnostic pathways are appropriately established.
This letter has several limitations. The findings are based on two tertiary centers in a single region, with a modest sample size and a twelve-month follow-up. Treatment allocation was non-randomized and partly influenced by reimbursement criteria; thus, residual confounding may persist. Therefore, the observed associations should not be interpreted as evidence of causal benefit.
Nonetheless, this regional experience provides a concise snapshot of how ATTR-CM is diagnosed and managed in routine practice in Türkiye. Tafamidis treatment was associated with fewer early composite clinical events over twelve months in patients who could initiate therapy, whereas many others were denied access due to strict biomarker thresholds or late presentation. These findings underscore a nationwide need to reduce diagnostic delays, expand access to non-invasive diagnostic tools, and revise reimbursement criteria to align treatment availability with guideline-based recommendations. Simultaneously, ongoing clinician education and structured collaboration between tertiary centers and peripheral hospitals will be crucial to ensure that advances in amyloidosis care translate into equitable outcomes across the country.
Acknowledgments: The authors would like to express his sincere gratitude to Prof. Dr. Stefano Perlini (University of Pavia, Italy) for his valuable scientific review and expert feedback on the manuscript. His insight greatly enhanced the quality and academic rigor of this work.
Ethics Committee Approval: The study protocol was approved by the Ordu University Non-Interventional Scientific Research Ethics Committee (approval number: 296, date: 12.09.2025).
Informed Consent: Written informed consent to participate was obtained from all patients included in this study.
Authorship Contributions: Concept- S.D.; Design- S.D.; Supervision- S.D., O.O.Ş., N.B.; Materials- S.D.; Data Collection or Processing- S.D.; Analysis and/or Interpretation- S.D., N.B.; Literature Review- S.D., O.O.Ş.; Writing- S.D., O.O.Ş., N.B.; Critical Review- S.D., N.B.
Conflict of Interest: The authors declare that they have no conflict of interest.
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