This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

Amyloidosis Conferences



Identifying ATTR-CM: are we doing enough?

Take-home messages
  • The epidemiology of ATTR-CM is not well-characterised and the incidence may be underestimated
  • Accurate and early diagnosis is important, as effective therapy options are available
  • Diagnosis of ATTR-CM has increased over time, and this may be a result of increased use of bone scintigraphy among cardiologists
  • Although ATTR-CM diagnoses are increasing, patient phenotype at diagnosis does not suggest an increase in early diagnoses and many patients may remain undiagnosed

Transthyretin-mediated amyloidosis with cardiomyopathy (ATTR‑CM) is a rare and ultimately fatal disease, caused by the myocardial deposition of misfolded transthyretin (TTR) fibrils. Patients suffer from progressive heart failure (HF), complicated by conduction disorders and arrhythmias.1 Patients with ATTR‑CM can be treated with tafamidis, a stabiliser of the TTR tetramer that has been shown to improve survival and quality of life for patients. This effect is thought to be greater in earlier stages of the disease, as treatment in patients with NYHA class I/II HF was associated with decreased mortality and hospitalisations compared with patients with NYHA class III HF, highlighting the need for accurate and timely diagnosis.2

Evidence presented at the European Society of Cardiology (ESC) Congress 2021 suggests that there is an increased awareness of ATTR‑CM and that diagnosis rates are increasing - but are we doing enough?

Is ATTR-CM being diagnosed early enough?

Despite increased awareness of ATTR‑CM over the years, it is unclear if cases are being diagnosed in earlier stages of disease. At the congress, Dr Pranav Chandrashekar presented a study that set out to test this by analysing phenotypic trends on presentation with ATTR‑CM over time.

116 patients with ATTR‑CM* who visited an amyloidosis centre between 2005 and 2020 were stratified into three time periods, based on the date of diagnosis:

  • early (pre-2016, n=21)
  • mid (2016-2018, n=46)
  • recent (2018-2020, n=49)

The study compared the diagnostic method used, patient demographics, and presence of cardiac biomarkers or transthoracic echocardiograph (TTE) features that raise suspicion of ATTR-CM, between each group.

The method of diagnosis changed significantly (p<0.05) between the early time period group (cardiac biopsy: 57%; PYP scan: 5%) and the recent time period group (cardiac biopsy: 4%; PYP scan: 84%), likely due to increased education on the utility of bone scintigraphy for the diagnosis of ATTR‑CM.

The number of diagnoses for ATTR-CM increased over the time periods studied, however this did not correlate with a change in clinical phenotype at diagnosis. Almost all parameters studied, including percentage of patients with NYHA class I/II, the median daily diuretic dose, biomarkers such as troponin T and NT-pro BNP, and TTE characteristics such as left ventricular mass index, showed no significant difference across the time periods. The only parameter that changed significantly was the age at diagnosis which increased from 71 years in the early time period to 78 years in the recent time period. Women represented the minority of patients across all time periods (range 4%-10%).

Despite the increased awareness of ATTR‑CM, Dr Chandrashekar remarked, the lack of major changes in the clinical phenotype on presentation in the patients studied challenges the assumption that patients with ATTR‑CM are being identified earlier with milder phenotypes. Furthermore, the very low percentage of women in this sample suggests that women with ATTR‑CM remain largely undiagnosed. Given the availability of effective treatments for ATTR-CM, Dr Chandrashekar concluded that continued education and awareness of ATTR-CM red flags and diagnostic methods are needed to achieve better outcomes in this population.

*ATTR‑CM diagnosis was established based on the standard criteria of confirmed ATTR variant + typical TTE features; histological confirmation endomyocardial biopsy; or typical diffuse cardiac tracer uptake on bone scintigraphy while ruling out light chain amyloidosis.

Is ATTR-CM being underdiagnosed?

The prevalence of ATTR-CM is not well characterised, and recent studies suggest that it may be underestimated in older adults with HF and other conditions associated with ageing.1,3 In another talk at the congress, Professor Thibaud Damy addressed the relatively understudied epidemiology of ATTR-CM, presenting results from a retrospective, observational study using real-world French data collected between 2011 and 2017.

The E-PACT study aimed to estimate the prevalence and incidence of ATTR-CM and to describe the demographic characteristics of patients and patient survival. As there is no ICD-10 marker code for ATTR-CM, patients were originally included if they had E85 (the ICD-10 code for amyloidosis) and then excluded if:

  • they had no relevant cardiac condition
  • had suspected AL amyloidosis
  • were younger than 50 years old

Over the period studied, the prevalence of ATTR-CM was 5,042 cases (0.8/ 100,000) and the incidence of new cases was 4,815 (0.5/ 100,000). The incidence rate increased by more than three times from 2011 to 2017, reaching 1,225 new cases in 2017, and Professor Damy attributed this to an improvement in the diagnostic pathway in France and communications to help cardiologists identify ATTR-CM using bone scintigraphy.

In the study, the sex ratio was 2:1 for men to women (overall 67% vs 33%), in keeping with what was expected. Median survival was 33.7 months overall, with minor differences between genders; the probability of survival was 0.69 at 1-year post-diagnosis, 0.58 at 2 years, 0.48 at 3 years and 0.41 at 4 years.

The results presented by Professor Damy were consistent with existing data concerning the frequency of amyloidosis, despite patients only being included if they had been previously diagnosed with amyloidosis. It is likely therefore, Professor Damy said, that the data he presented are an underestimation, and the actual prevalence of the disease is higher. That the incidence of ATTR-CM consistently increased between 2011 and 2017 also suggests that there are many undiagnosed patients and Professor Damy stated that the annual growth is still very important in France, especially in the context of new therapies.

AL: amyloid light chain; ICD: International Statistical Classification of Diseases and Related Health Problems; NT-pro BNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Health Association; PYP: pyrophosphate

Based on: Chandrashekar P, Rashdan L et al. Phenotypic presentation trends of transthyretin amyloid cardiomyopathy: are we getting better? Presented at the European Society of Cardiology Congress, 27-30 August 2021; Damy T, Bourel G et al. Epidemiology of transthyretin amyloid cardiomyopathy (ATTR-CM) in France, a study based on the systeme national des donnees de sante (SNDS) the French nationwide claims database. Presented at the European Society of Cardiology Congress, 27-30 August 2021

  1. Rozenbaum M H, Large S et al. Impact of delayed diagnosis and misdiagnosis for patients with transthyretin amyloid cardiomyopathy (ATTR-CM): a targeted literature review. Cardiol Ther 2021;10(1):141-159
  2. Maurer M S, Schwartz J H et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379(11):1007-1016
  3. Ruberg F L, Grogan M et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 2019;73(22):2872-2891

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