Simple score developed to predict increased risk of transthyretin amyloid cardiomyopathy in patients with heart failure with preserved ejection fraction

1. The simple score comprised of 3 clinical (age, male sex, hypertension diagnosis) and 3 echocardiographic (ejection faction, posterior wall thickness, relative wall thickness) variables predicts increased risk of transthyretin amyloid cardiomyopathy in patients with heart failure with preserved ejection fraction.

2. Clinically useful classification performance was noted for a score of 6 or more in clinically relevant transthyretin amyloid cardiomyopathy prevalence scenarios.

Evidence Rating Level: 2 (Good)

Study Rundown: Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by left ventricular (LV) wall thickening and manifests as clinical heart failure, usually with preserved ejection fraction. Heart failure with preserved ejection fraction (HFpEF) often affects older individuals with existing hypertensive heart disease, and LV wall thickening due to hypertrophy, and studies suggest a prevalence of ATTR-CM between 6-13% in this population of patients. The objective of this retrospective cohort study was to derive and validate a simple score to predict increased risk of ATTR-CM in patients living with HFpEF (ejection fraction ³ 40%). A total of 666 patients with HFpEF referred to the Mayo Clinic between May 2013 to August 2020 were included. The main outcomes were performance of the ATTR-CM score in all cohorts, and prevalence of high-risk ATTR-CM score in 4 multinational HFpEF clinical trials. The score range was between -1 to 10, and variables included clinical factors such as age, male sex and hypertension diagnosis, in addition to echocardiographic factors such as relative wall thickness (WT) more than 0.57, posterior WT ³ 12mm, and ejection fraction <60%. There were 4 different participant cohorts in this study: referral derivation (n=416), referral validation (n=250), community validation (286), and external validation (n=66). A clinically useful classification performance for a score of 6 or more in clinically relevant ATTR-CM prevalence scenarios was indicated through precision-recall curves and predictive value vs prevalence plots. Using 6 as a high-risk cutoff had a sensitivity of 93% and a specificity of 62%. Overall, a major strength of this study was the use of a community-based cohort and a more racially diverse external, referral validation cohort. A limitation to this study however was that the ATTR-CM score was derived in patients that were already suspected of having ATTR-CM, and hence the score might not perform similarly when applied to patients with HFpEF more broadly.

Click to read the study in JAMA Cardiology

Relevant Reading: Prevalence of transthyretin amyloid cardiomyopathy in heart failure with preserved ejection fraction

In-Depth [retrospective cohort]: A total of 666 patients were included in this study [median age 76; 333 [80%] males, and 380 [94%] were White). The median ejection fraction (EF) of included patients was 56% (IQR, 50%-63%). Participant cohorts included were referral derivation (n=416), referral validation (n=250), community validation (n=286), and external validation (n=66). Variables taken into consideration in the simple score included: age, male sex, hypertension diagnosis, ejection fraction <60%, posterior WT of 12mm or more and relative WT more than 0.57 with an AUC (95% CI) of 0.89 (0.86-0.92). The weighted ATTR-CM score constructed b estimates of the 6 score variables had a range of -1 to 10 with similar discrimination (AUC 0.88; 95% CI, 0.85-0.91). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P <.001) and calibration (Hosmer-Lemeshow; 𝑥² = 4.6; P = .46) were found to be strong. Discrimination (AUC ³ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow 𝑥² = 2.8; P = .84; Hosmer-Lemeshow 𝑥² = 4.4; P = .35; Hosmer-Lemeshow 𝑥² = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Additionally, model-based probabilities closely matched the observed prevalence for each of given score value (goodness-of-fit 𝑥² = 4.6; P = .46), which indicated robust calibration. A clinically useful classification performance for a score of 6 or more in clinically relevant ATTR-CM was indicated. Using 6 as a high-risk cutoff had a sensitivity of 93% and a specificity of 62%.

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