Systematic review of ATTR: cardiac amyloidosis, survival, and effects of treatment
Prevalence and clinical outcomes of transthyretin amyloidosis: a systematic review and meta-analysis
Introduction and methods
In transthyretin-mediated (ATTR) amyloidosis, instability of the TTR protein due to genetic or degenerative factors may lead to deposition of TTR monomers in vital organs such as the heart . Currently, systematic evidence on the prevalence and clinical outcomes of this disease is lacking.
Aim of the study
The study aim was 3-fold: (1) to better understand the prevalence of cardiac amyloidosis in various patient subgroups, (2) to provide survival estimates for wild-type ATTR (wtATTR) and different hereditary ATTR (hATTR) genotypes, and (3) to explore the effects of novel ATTR therapeutics on the natural course of disease.
The authors performed a systematic review of the literature published in MEDLINE before 31 December 2021 to investigate the prevalence of cardiac amyloidosis and all-cause mortality (at 1, 2, and 5 years) in ATTR patients. A total of 62 studies (n=277,882 patients) reporting the prevalence of cardiac amyloidosis were identified. Data on ATTR mortality were extracted from 95 studies (n=18,238 ATTR patients). Subgroup analyses were performed for ATTR subtype, hATTR genotypes, and treatment subgroups.
- The prevalence of cardiac amyloidosis was high in patients with clinical suspicion of this condition (1 7%–71%) and carriers of TTR mutations (3%–85%).
- The prevalence was also high among patients with unexplained LV hypertrophy or a hypertrophic cardiomyopathy phenotype (2%–34%), patients with HFpEF (14%–29%), and elderly with aortic stenosis (13%).
- Statistical heterogeneity between studies was high (I²=98%; P<0.0001).
- Compared with patients with hATTR, patients with wtATTR were older (mean age: 67.1 vs. 77.1 years; Q=42.1; P=7 × 10⁻¹⁰) and more frequently male (Q=88.9; P=5 × 10⁻²⁰ ).
- The pooled estimate of 2-year survival for the natural disease course was 73.3% (95%CI: 70.9%–75.7%), although this varied between countries (61%–85%; Q=68.56; P=3.5 × 10⁻⁹ ). Statistical heterogeneity between studies was high (I²=97% ; P<0.01) and was not eliminated by country or continent subgroup analysis.
- The pooled estimated 2-year survival was 70.4% (95%CI: 66.9%–73.9%) for non-subtyped ATTR, 76.0% (95%CI: 73.0%–78.9%) for wtATTR, and 77.2% (95%CI: 74.0%–80.4%) for hATTR.
- Despite wtATTR patients being older, the wtATTR subtype was independently associated with higher survival rates compared with the hATTR subtype at 1 year (z=2.291; P=0.022) and 2 years (z=2.650; P=0.008) in meta-regression analysis adjusted for age, sex, and study sample size.
- All-cause mortality at 2 and 5 years was higher among patients with “cardiac” hATTR mutations (i.e., Val122Ile and Thr60Ala) and lower among patients with Val30Met mutations compared with wtATTR patients (both P=10⁻¹⁵).
Effect of treatment
- Compared with the natural disease course (i.e., patients receiving supportive standard of care or symptomatic treatment for HF), survival was higher in patients treated with novel ATTR therapeutics (tafamidis or patisiran) at both 2 years (72.4%; 95%CI: 69.8%–74.9% vs. 79.9%; 95%CI: 74.4%–85.3%; P<0.05) and 5 years (45.8%; 95%CI: 41.5%–50.1% vs. 64.0%; 95%CI: 50.1%–78.0%; P<0.05).
This systematic literature review showed that the prevalence of cardiac amyloidosis was high in patients with unexplained LV hypertrophy or a hypertrophic cardiomyopathy phenotype, HFpEF patients, and elderly with aortic stenosis. The wtATTR subtype was associated with longer survival compared with the hATTR subtype, although all-cause mortality was lower in hATTR patients with a Val30Met mutation (which is associated with early disease onset and late cardiac involvement). The survival rate was also higher in patients receiving novel ATTR therapeutics compared with the natural disease course.
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