Impact of Earlier Diagnosis in Cardiac ATTR Amyloidosis Over the Course of 20 Years

Abstract

Background: Diagnostic and therapeutic advances have led to much greater awareness of transthyretin cardiac amyloidosis (ATTR-CA). We aimed to characterize changes in the clinical phenotype of patients diagnosed with ATTR-CA over the past 20 years.

Methods: This is a retrospective observational cohort study of all patients referred to the National Amyloidosis Centre (2002-2021) in whom ATTR-CA was a differential diagnosis.

Results: We identified 2995 patients referred with suspected ATTR-CA, of whom 1967 had a diagnosis of ATTR-CA confirmed. Analysis by 5-year periods revealed an incremental increase in referrals, with higher proportions of patients having been referred after bone scintigraphy and cardiac magnetic resonance imaging (2% versus 34% versus 51% versus 55%, chi-square P<0.001). This was accompanied by a greater number of ATTR-CA diagnoses, predominantly of the wild-type nonhereditary form, which is now the most commonly diagnosed form of ATTR-CA (0% versus 54% versus 67% versus 66%, chi-square P<0.001). Over time, the median duration of associated symptoms before diagnosis fell from 36 months between 2002 and 2006 to 12 months between 2017 and 2021 (Mann-Whitney P<0.001), and a greater proportion of patients had early-stage disease at diagnosis across the 5-year periods (National Amyloidosis Centre stage 1: 34% versus 42% versus 44% versus 53%, chi-square P<0.001). This was associated with more favorable echocardiographic parameters of structure and function, including lesser interventricular septal thickness (18.0±3.8 mm versus 17.2±2.6 mm versus 16.9±2.3 mm versus 16.6±2.4 mm, P=0.01) and higher left ventricular ejection fraction (46.0%±8.9% versus 46.8%±11.0% versus 47.8%±11.0% versus 49.5%±11.1%, P<0.001). Mortality decreased progressively during the study period (2007-2011 versus 2012-2016: hazard ratio, 1.57 [95% CI, 1.31-1.89], P<0.001; and 2012-2016 versus 2017-2021: hazard ratio, 1.89 [95% CI, 1.55-2.30], P<0.001). The proportion of patients enrolled into clinical trials and prescribed disease-modifying therapy increased over the 20-year period, but even when censoring at the trial or medication start date, year of diagnosis remained a significant predictor of mortality (2012-2016 versus 2017-2021: hazard ratio, 1.05 [95% CI, 1.03-1.07], P<0.001).

Conclusions: There has been a substantial increase in ATTR-CA diagnoses, with more patients being referred after local advanced cardiac imaging. Patients are now more often diagnosed at an earlier stage of the disease, with substantially lower mortality. These changes may have important implications for initiation and outcome of therapy and urgently need to be factored into clinical trial design.

Keywords: amyloidosis; prognosis; transthyretin.

Figure 1.

Total number of patients referred with suspected ATTR-CA between 2002 and 2021, and the proportion of whom were subsequently diagnosed with ATTR-CA. Pie charts demonstrating the proportion of referrals made by different medical specialties between 2002 and 2021. AL amyloidosis indicates light-chain amyloidosis; and ATTR-CA, transthyretin cardiac amyloidosis.

Figure 2.

Referral pathway for patients referred to the National Amyloidosis Centre. A, Pie charts demonstrating the proportion of patients who were referred to the NAC with a suspected diagnosis of ATTR-CA after each local investigation. B, Pie charts demonstrating the proportion of patients who were subsequently diagnosed with ATTR-CA after each local investigation. C, Pie charts demonstrating the proportion of patients in whom a diagnosis of ATTR-CA was eventually excluded after each local investigation. CA indicates cardiac amyloidosis; CMR, cardiac magnetic resonance; and NAC, National Amyloidosis Centre.

Figure 3.

Number of patients diagnosed with each subtype of transthyretin cardiac amyloidosis between 2002 and 2021. ATTR-CA indicates transthyretin cardiac amyloidosis.

Figure 4.

Number of patients diagnosed with transthyretin cardiac amyloidosis between 2002 and 2021, and the proportion of patients with each NAC disease stage for each 5-year period. NAC indicates National Amyloidosis Centre.

Figure 5.

Survival in patients with ATTR cardiac amyloidosis over the 20-year study period. A, Error bars demonstrating the change in mean interventricular septal (IVS) wall thickness (error bars representing 2×95% CI of the mean) between 2002 and 2021. B, Error bars demonstrating the change in mean left ventricular ejection fraction (error bars representing 2×95% CI of the mean) between 2002 and 2021.

Figure 6.

Kaplan-Meier curves demonstrating the prognostic effect of the year of diagnosis between 2002 and 2021, followed by multivariable Cox proportional hazards regression analysis, adjusted for age, comparing the risk of death in each 5-year interval between 2002 and 2021. A, All patients with transthyretin cardiac amyloidosis (ATTR-CA). B, Patients with wild-type transthyretin cardiac amyloidosis (wild-type ATTR-CA-CA). C, Patients with p.(T80A) hereditary transthyretin cardiac amyloidosis (hATTR-CA). D, Patients with p.(V142I) hATTR-CA. HR indicates hazard ratio.