A new staging system for cardiac transthyretin amyloidosis

Background

Transthyretin cardiac amyloidosis (ATTR) is an infiltrative and progressive disease caused by the extracellular deposition of transthyretin (TTR) in the heart. ATTR could be caused by non-mutated TTR, leading to wild-type ATTR or by more than 120 TTR known variants, responsible for hereditary transthyretin cardiac amyloidosis (hATTR)⁽¹⁾. Although TTR mutations are relatively rare, the most frequent variant of hATTR cardiomyopathy is TTR V122I, present in up to 3-4% of African or Afro-Caribbean individuals⁽²⁾.

Non-invasive techniques like bone DPD scintigraphy and cardiac magnetic resonance (CMR) have contributed to an increase in the recognition of ATTR during the last years. This has also prompted a new non-invasive diagnostic algorithm⁽³⁾, supporting the diagnosis when histology is difficult to obtain or is not feasible. Although there are no specific therapies to halt the progression of ATTR as yet, clinical trials exploring different compounds are underway.

Despite the advances in the understanding, recognition and drug development, data from ATTR patients have come until recently from small cohorts and there was no much data on follow-up. Therefore, the real natural history of ATTR is not clearly known.

The authors’ aim was to establish and validate a new prognostic staging both for wtATTR and hATTR patients.

Methods

A total of 869 patients with ATTR and heart failure from the UK National Amyloidosis Centre (NAC) were included. Among them, 553 were wild-type ATTR patients and 326 where hereditary ATTR patients. Patients with V30M TTR variant were excluded from the analysis.

Values from two biomarkers, NTproBNP and estimated GFR (eGRF), derived using the MDRD (Modification of Diet in Renal Failure) equation, were collected from all patients at baseline.

The staging system was then validated in a cohort of unrelated 318 ATTR patients from the Mondor Amyloidosis Network in France.

Results

Median survival in the whole cohort was 57 months (95% CI: 49.1-60.4 months).

NTproBNP > 3000 ng/L and eGFR < 45ml/min/1.73m² were found to be significantly associated with death by univariable analysis and patients were stratified in 3 stages based on NTproBNP and eGRF. Stage I was defined as NTproBNP £ 3000 ng/L and eGFR ³ 45 mL/min whereas Stage III was considered when NTproBNP was > 3000 ng/L and eGFR < 45mL/min. The rest were Stage II.

Median survival in patients at Stage I was 69.2 months (95% CI: 62.9-indeterminable), 46.7 months (95% CI: 40.2-57) at Stage II, whereas Stage III patients presented a survival of 24.1 months (95% CI: 21.2-29.6; p<0.0001). Among these patients, hazard ratio for death after adjusting for age was 3.8 (95% CI: 2.73-5.28, p<0.001), compared to Stage I.

In wtATTR patients, median survival in patients at Stage II patients was 49.2 months (95% CI: 41.3-indeterminable) whereas Stage III patients presented a survival of 32.7 months (95% CI: 23.4-37) (p<0.0001 Stage I vs. II and p=0.0003 Stage II vs. Stage III). Among these patients, hazard ratio for death after adjusting for age was 2.26 (95% CI: 1.51-3.36, p<0.001) and 4.37 (95% CI: 2.80-6.83, p< 0.001), compared to Stage I, respectively.

The majority of patients with hATTR were carriers of V122I variant of Afro-Caribbean origin. In this subgroup of patients, median survival in patients at Stage I was 54.4 months (95% CI: 31.1-indeterminable), at Stage II 28.8 months (95% CI: 23.6-45.1) and 17.7 months (95% CI: 11.5-22.3) at Stage III. Among these patients, hazard ratio for death after adjusting for age was 1.91 (95% CI: 1.17-3.12; p=0.009) and 3.48 (95% CI: 1.94-6.27, p<0.001), compared to Stage I, respectively.

In the validation cohort, including 318 patients (186 wtATTR, 68 V122I and 64 with other variants), median survival in patients at Stage I was 69.2 months, at Stage II 35 months and 20.5 months at Stage III. Among these patients, hazard ratio for death after adjusting for age was 3.36 (95% CI: 1.79-6.29, p<0.001) and 6.92 (95% CI: 3.45-13.87, p< 0.001), compared to Stage I, respectively.

Conclusion

The simple staging system proposed by Gillmore et al. includes two accessible biomarkers and could be used to establish the prognosis in both wtATTR and hATTR. Staging in ATTR is desirable given the utility in forthcoming clinical trials with disease-modifying drugs.

Comments

Transthyretin cardiac amyloidosis has been traditionally associated with a misdiagnosed entity with no specific treatment⁽⁴⁾. Nowadays trends are changing: we are currently witnessing an increase in the awareness and recognition of this disease thanks to the sensibility and specificity of new cardiac imaging techniques⁽⁵⁾, the possibility of non-invasive diagnosis⁽³⁾ and the development of new compounds on the horizon.

Based on the probable previous misdiagnosis, solid data on natural history has not been available.

ATTR has been traditionally considered a “benign” form of cardiac amyloidosis, with a slow progression rate, especially compared to AL. Nonetheless, in those diagnosed in later stages, a benign course could not be anticipated⁽⁶⁾. Available data in terms of prognosis were contradictory depending on centres and time of diagnosis. Therefore, it was difficult to answer patients enquiring about prognosis and what to expect⁽⁷⁾.

Mayo stage in AL amyloidosis was established in an attempt to facilitate the comparison between therapeutical interventions and the evaluation of randomized clinical trials by objective and consistent biochemistry criteria. It has been widely used since being reviewed in 2012, and includes two cardiac biomarkers, NTproBNP and troponin T and concentration of free light chains⁽⁸⁾.

In a similar way and despite the existence of less data on the role of NTproBNP and troponin compared to AL, Grogan et al. published in 2016 a staging system for wtATTR using NTproBNP and troponin T with similar cut-off values: NTproBNP>3000pg/mL and Troponin T>0.05ng/mL⁽⁹⁾. In this case, 360 patients followed at the Mayo Clinic with antemorten and histological diagnosis of wtATTR were included.

Gillmore’s proposed staging system is based on the largest published cohort of ATTR patients, with 869 patients included. Median age at diagnosis was similar between both groups. London’s staging system included hereditary ATTR patients for the first time as well as those ones with non-invasive diagnosis, probably including patients diagnosed earlier.  

Two widely available biomarkers were selected based on a previous study in which NTproBNP, eGFR, age, 6-min walk test performance, Troponin T, systolic blood pressure and New York Heart Association (NYHA) class were observed as independent prognostic factors in ATTR⁽¹⁰⁾. Troponin was excluded in an attempt to avoid the difficulty to standardised results given the different available assays. The exclusion of troponin could be discussed. Although its significance in ATTR could be different compared to AL amyloidosis, troponin has been shown to be an independent predictor beyond ischaemic heart disease, in the cardiomyopathy field and also in heart failure⁽¹¹⁾.

Focusing on NTproBNP and eGFR, there is obviously a correlation between both of them. NTproBNP is influenced by renal function and other factors including fluid status, other causes of cardiac disease and significantly by atrial fibrillation, quite common, especially in wtATTR⁽⁷⁾. BNP could be a better biomarker in this setting given its accuracy in renal failure. Nonetheless, an independent cut-point will be required.

One of the strengths of London’s system compared to Mayo staging is the inclusion of an external and unrelated validation cohort. Another one is the inclusion of hereditary ATTR patients, being V122I the predominant subgroup. Interestingly, previous reports had showed discrepancies in terms of prognosis of V122I patients. Results from the THAOS (Transthyretin Amyloid Outcome Survey) registry showed that survival in patients with V122Ile was not significantly different from survival in wtATTR individuals⁽¹²⁾. On contrast, single-centre data demonstrated a worse survival among V122I⁽¹³⁾. Despite its single-centre nature, 201 V122I patients were included in this study, with a similar proportion of V122I and wtATTR in the 3 stages. A slightly poorer prognosis was observed in V122I in the three stages. Median NTproBNP was higher in stage II and III in V122I compared to wtATTR. Hypothesis to support these differences include a more advanced disease, more aggressive profile or less efficacy of treatment.

Finally, patients with Val30Met TTR variant, one of the most frequent worldwide TTR variants, were excluded from the analysis given its predominant neurologic phenotype. Nonetheless, Val30Met patients also present with cardiac involvement, especially those with late-onset and this often limits their prognosis, even after liver transplantation. Analysis from Val30Met patients with cardiac involvement, from endemic and non-endemic areas, is missing.

Staging systems are desirable and required for clinical trials on cardiac involvement. Results from the first clinical trial with a stabilizer in patients with ATTR cardiomyopathy are expected throughout this year. Antisense oligonucleotide and siRNA therapies hopefully will be tested soon in cardiac ATTR and TTR removal by using antibodies is also an interesting approach under evaluation⁽¹⁴⁾.

The existence of two different staging systems raises the question of which of the two should be used. There is probably no straightforward answer and there is also the concern about whether both staging systems are simplifying too much⁽¹²⁾ a complex disease with different underlying physiopathological mechanisms. Therefore, more accurate prognostic tools would be desirable to better assess prognosis and treatment efficacy.