Dispenzieri, A

Abstract Background Tafamidis (meglumine 80 mg/free acid 61 mg) is approved to treat transthyretin amyloid cardiomyopathy (ATTR-CM). In the pivotal phase 3 study ATTR-ACT, tafamidis significantly reduced all-cause mortality (ACM) and cardiovascular-related hospitalisations in patients with ATTR-CM (1). Real-world data further extend and support the benefit of long-term tafamidis for improving survival in contemporary patients with ATTR-CM (2). Purpose To further compare survival in a contemporary, real-world, pooled, matched cohort of patients with ATTR-CM treated vs not treated with tafamidis, adjusted for potential prognosticators of treatment effect. Methods Data were pooled from 2 studies. One study included a contemporary cohort of patients with ATTR-CM who received early access to tafamidis in the ATTR-ACT long-term extension (LTE) study but did not participate in the parent study. The other study included a contemporary cohort of patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS; NCT00628745) with predominantly cardiac or mixed phenotype ATTR-CM enrolled between 2019–2023 who received tafamidis throughout the study or never received tafamidis. THAOS was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic gene carriers. Treated patients were pooled from the 2 studies; all received the approved dose of tafamidis. Untreated patients were from THAOS. A propensity score matching procedure was used to match treated and not treated patients 1:1 on 3 significant variables identified from a multivariate logistic regression analysis: baseline age, New York Heart Association (NYHA) class and phenotype (cardiac, mixed); other variables considered were sex, estimated glomerular filtration rate (eGFR), follow-up time and modified body mass index (mBMI). Results In all, 566 patients (283 treated, 283 not treated) were included; 85 treated patients were from the LTE study and 198 were from THAOS. In treated and not treated patients, respectively, median age at enrolment was 78.0 and 78.7 years, and 89.0% and 83.4% were male (Table). The estimated adjusted survival probabilities for ACM for treated vs not treated patients were 78.0% vs 67.9% at 30 months and 70.2% vs 57.9% at 42 months (Figure). The hazard ratio (HR) for time to event for ACM was 0.62 (95% CI 0.41–0.92), favouring tafamidis. Conclusions This matched-cohort analysis showed better survival in a contemporary, real-world cohort of patients with ATTR-CM receiving the approved dose of tafamidis vs those not treated. These findings further extend results of ATTR-ACT to contemporary populations of patients with ATTR-CM treated clinically with tafamidis. These data show greater effectiveness of tafamidis for ATTR-CM in clinical practice than observed in earlier clinical trials, which may reflect earlier diagnosis and treatment in contemporary patients.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1