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Characteristics of Early-Stage Cardiac Transthyretin Amyloidosis
Quick Takes
- In patients with an early diagnosis of transthyretin amyloid cardiomyopathy not on disease-modifying therapy, NT-proBNP levels are a powerful predictor of survival.
- Patients with very early disease (low NT-proBNP level and diuretic use) when compared to a limited matched general population control have similar mid-term survival, though high cardiovascular morbidity at baseline.
- The role for disease-modifying therapies is unclear in this early stage but may have benefit.
Study Questions:
What is the natural history of patients diagnosed with early-stage transthyretin amyloid cardiomyopathy (ATTR-CM) not on disease-modifying therapies?
Methods:
This was a retrospective, observational study of all patients with ATTR-CM seen at two large European amyloidosis centers, the National Amyloidosis Centre (NAC) in the United Kingdom (UK) and the Amyloidosis Mondor Network in France, between 2009–2020. Patients needed to meet all three inclusion criteria: 1) wild-type TTR or p.Val142Ile TTR genotype, 2) NAC ATTR Stage I biomarkers at diagnosis (N-terminal pro–B-type natriuretic peptide [NT-proBNP] ≤3000 ng/L and estimated glomerular filtration rate [eGFR] ≤45 mL/min/1.73 m2), and 3) no disease-modifying therapy use. Only the p.Val142Ile TTR pathogenic variant was included in order to focus on patients with predominant cardiac involvement. Patients were also further subclassified as having NAC ATTR Stage Ia disease (furosemide equivalent diuretic dose of <0.75 mg/kg + NT-proBNP ≤500 ng/L or ≤1000 ng/L with atrial fibrillation) and Ib disease (all other Stage I patients). Routine evaluation was completed at diagnosis and then at 6- to 12-month intervals. Clinical outcomes assessed were death and cardiovascular morbidity, which included the presence of atrial fibrillation, cerebrovascular accident, permanent pacemaker, diuretic requirement, and New York Heart Association (NYHA) class II or greater symptoms.
Results:
A total of 879 patients were included in the analysis, with 71% (n = 623) from the UK and 29% (n = 256) from France. There were 12% (n = 109) with Stage Ia and 88% (n = 770) with Stage Ib disease. The median follow-up was 21 months (interquartile range [IQR], 8-40).
When looking at patient survival, 14% (n = 120) of patients had died leading to an overall median estimated survival of 87 months (95% confidence interval [CI], 63—not met). Multivariable analysis identified higher NT-proBNP, NAC ATTR Stage Ib, pathogenic variant TTR genotype, and higher troponin T at time of diagnosis as independent predictors of mortality. Higher NT-proBNP level was the most important predictor (hazard ratio [HR], 4.36; 95% CI, 1.69-11.30; p = 0.002). When stratified by stage subgroup, median estimated survival for patients with Stage Ib disease was 75 months (95% CI, 57-93) compared to Stage Ia disease at >100 months (HR, 5.06; 95% CI, 1.23-20.87; p = 0.025). In the UK cohort, there was no significant difference in mid-term survival of Stage Ia patients when compared to matched UK general population controls (p = 0.297).
Baseline cardiovascular morbidity in patients with Stage Ia ATTR amyloidosis was high and in general worsened during the study. The following trends were noted from diagnosis to follow-up:
- Diuretic use increased from 39% at diagnosis to 56%.
- Prevalence of atrial fibrillation increased from 31% to 40%.
- NYHA class II or greater symptoms increased from 62% to 82%.
- Cerebrovascular accident or transient ischemic attack increased from 8% to 15%.
- Permanent pacemaker implants increased from 13% to 20%.
- Median increase in NT-proBNP of 145 ng/L/year (IQR, 47-440).
- Median decrease in eGFR of 2.8 mL/min/1.73 m2/year (IQR, 0-7).
Conclusions:
In patients with NAC Stage I ATTR-CM not on disease-modifying therapy, elevated cardiac biomarkers, a pathogenic variant genotype, and Stage Ib disease independently predicted reduced survival. Patients with Stage Ia disease had mid-term survival that was comparable to the general population, though patients had high cardiovascular morbidity at baseline that worsened during follow-up.
Perspective:
Little is known about the natural history and prognosis of patients with an early diagnosis of ATTR-CM, though understanding this is important, as awareness of the disease and better diagnostic strategies are helping to identify more patients in this early phase. In the era of disease-modifying therapies, this knowledge will help with determining the ideal time to initiate drug therapy.
This study revealed several important insights. NT-proBNP concentration was a powerful independent predictor of mortality, making it a very useful test to frame overall risk when deciding on therapies and having discussions with patients. It was also interesting to note that patients with Stage Ia disease in the UK cohort had a comparable estimated survival to a matched UK general population control, though baseline cardiovascular morbidity was high and increased throughout the study. This suggests a potential role for disease-modifying therapies even in a very early stage to slow the progression of cardiovascular disease, but the impact on mortality is unclear. Further studies will be needed to explore these questions and examine the generalizability of these findings to different populations.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Amyloidosis, Amyloidosis, Familial, Amyloid Neuropathies, Familial, Arrhythmias, Cardiac, Atrial Fibrillation, Biomarkers, Cardiomyopathies, Diuretics, Furosemide, Genotype, Glomerular Filtration Rate, Heart Failure, Ischemic Attack, Transient, Natriuretic Peptide, Brain, Pacemaker, Artificial, Prealbumin, Stroke, Troponin T, Vascular Diseases
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