Natural history study of early-stage transthyretin amyloid cardiomyopathy
Characteristics and natural history of early-stage cardiac transthyretin amyloidosis
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.
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