A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure with Preserved Ejection Fraction

Importance: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP. Objective: To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF. Design, Setting, and Participants: Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation. Main Outcomes and Measures: Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials. Results: Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48%), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6%), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range-1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P <.001) and calibration (Hosmer-Lemeshow; χ²= 4.6; P =.46) were strong. Discrimination (AUC ≥ 0.84; P <.001 for all) and calibration (Hosmer-Lemeshow χ²= 2.8; P =.84; Hosmer-Lemeshow χ²= 4.4; P =.35; Hosmer-Lemeshow χ²= 2.5; P =.78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score. Conclusions and Relevance: A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community. Further validation in larger and more diverse populations is needed.