Natural history study of early-stage transthyretin amyloid cardiomyopathy

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis

Literature - Law S, Bezard M, Petrie A, et al. - Eur Heart J. 2022 May 24;ehac259. doi: 10.1093/eurheartj/ehac259

Introduction and methods

Background

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a challenging diagnosis. Due to recent improvements in diagnostic imaging techniques coupled with increased awareness of the disease among cardiologists, >50% of patients are now diagnosed with early-stage ATTR-CM [1-8]. However, the natural history of early-stage disease remains poorly characterized.

Aim of the study

The authors aimed to characterize the natural disease course and clinical outcome among patients with early-stage ATTR-CM (National Amyloidosis Centre (NAC) ATTR Stage I).

Methods

In this retrospective, multicenter, observational study, 879 patients with ATTR-CM who visited one of two large amyloidosis centers in the UK and France between August 2009 and July 2020 were included. Inclusion criteria were: (1) wild-type TTR gene sequence or TTR mutation encoding the known pathogenic p.V142I variant; (2) NAC ATTR Stage I biomarkers at time of diagnosis (NT-proBNP ≤3000 ng/L and eGFR ≥45 mL/min per 1.73 m2); and (3) no disease-modifying therapy during clinical follow-up.

Patients were systemically evaluated at diagnosis and thereafter at a 6–12-month intervals as clinically indicated up to 100 months, if possible.

Main results

Survival

Patients were stratified into two NAC ATTR disease stages: Stage Ia, defined as NT-proBNP level ≤500 ng/L (or ≤1000 ng/L in the presence of AF) and furosemide-equivalent diuretic dose <0.75 mg/kg (109 patients ; 12%); and Stage Ib, comprising all remaining Stage I patients (770 patients; 88%).
Among the patients with Stage Ib disease, estimated median survival was 75 months (95% CI: 57–93) compared with >100 months in those with Stage Ia disease (hazard ratio (HR) for death: 5.06; 95% CI: 1.23–20.87; P=0.025).
The most powerful independent predictor of mortality was NT-proBNP level at diagnosis (HR: 4.36; 95% CI: 1.69–11.30; P=0.002), followed by TTR genotype, and troponin T level.
Estimated survival among Stage Ia patients from the UK was comparable to that of UK general population controls (P=0.297).

Cardiovascular morbidity in Stage Ia

Among the 109 patients with Stage Ia at diagnosis—who were followed for median duration of 28 months (range: 8–46)—regular diuretic use increased (from 39% to 56%), as well as prevalence of NYHA class ≥II HF symptoms (from 62% to 82%), AF (from 31% to 40%), permanent pacemaker implants (from 13% to 20%), and CVA/TIA (from 8% to 15%).
In the 63 patients with Stage Ia disease who had a primary cardiovascular (CV) presentation, cardiac biomarkers, cardiac imaging results, and functional markers of cardiac disease were significantly worse than in the 46 patients with no primary CV presentation.
The most common CV presentations were cardiac failure (60%) and atrial arrhythmias (25%).
Of the 80 patients with biomarker results during follow-up, 21 (26%) went from Stage Ia to Stage Ib and 14 (18%) developed Stage ≥II disease.

Conclusion

In this natural history study, ATTR-CM patients with NAC ATTR Stage I could be further stratified according to NT-proBNP level and diuretic requirement at diagnosis. Despite good short- and mid-term survival, patients with Stage Ia showed significant CV morbidity.

The authors believe their “findings lend strong support to the argument for considering disease-modifying therapy with TTR stabilisers or TTR gene silencers at the time of identification of ATTR amyloid in patients with cardiac uptake by radionuclide imaging, even in patients without a primary cardiovascular presentation or overt heart failure symptoms.” However, they add, it remains to be determined whether this will reduce CV morbidity and prolong survival.

References

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Find this article online at Eur Heart J.