Diuretic Dose and NYHA Functional Class Are Independent Predictors of Mortality in Patients With Transthyretin Cardiac Amyloidosis

Abstract

Background: With increasing diagnoses and available treatment options for transthyretin amyloidosis cardiomyopathy (ATTR-CM), risk stratification of ATTR-CM patients is imperative.

Objectives: We hypothesized that diuretic dose and New York Heart Association (NYHA) functional class are independent predictors of mortality in ATTR-CM and would be incrementally additive to existent risk scores.

Methods: Consecutive ATTR-CM patients referred to a single center were identified. Adjusted Cox proportional hazards models determined the association between diuretic dose (furosemide equivalent in mg/kg) at time of diagnosis and the primary outcome of all-cause mortality. The incremental value of adding diuretic dose and NYHA functional class to existing ATTR-CM risk scores was assessed for discrimination and calibration.

Results: 309 patients were identified, with mean age 73.2 ± 9.8 years, 84.1% male, and 66% wild type. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality (unadjusted hazard ratio: 2.12 per 1-mg/kg increase, [95% confidence interval: 1.71 to 2.61] and fully adjusted hazard ratio: 1.43 [95% confidence interval: 1.06 to 1.93]). Testing previously published ATTR risk scores, adding diuretic dose as categories (0 mg/kg, >0 to 0.5 mg/kg, >0.5 to 1 mg/kg, and >1 to 2 mg/kg) improved the area under the curve of the Mayo risk score from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787 while preserving calibration. Adding NYHA functional class further improved the area under the curve to 0.798 and 0.816, respectively.

Conclusions: Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients and provide incremental value to existing ATTR-CM risk scores.

Keywords: cardiac amyloidosis; heart failure; transthyretin.

Graphical abstract

Figure 1

Kaplan-Meier Curves for Freedom From All-Cause Mortality (A) Kaplan-Meier curves are shown for diuretic dose categories. (B) New York Heart Association functional class; (C) Mayo risk score categories; (D) UK risk score categories; and (E) Seattle Heart Failure Model (SHFM) score rounded to the nearest integer. For each model, comparison between groups was statistically significant with log-rank p < 0.001.

Figure 2

Time-Dependent ROC for All-Cause Mortality (A) Receiver-operating characteristic (ROC) curves are shown. Mayo risk score alone, Mayo score with addition of diuretic dose, and Mayo score with diuretic dose + New York Heart Association (NYHA) functional class. Adding diuretic dose to the Mayo score increased the area under the curve (AUC) from 0.693 to 0.767 and additionally adding NYHA functional class, increased it to 0.798. (B) UK risk score alone, UK score with addition of diuretic dose, and UK score with diuretic dose + NYHA functional class. Adding diuretic dose to the UK score increased the AUC from 0.711 to 0.787 and additionally adding NYHA functional class, increased it to 0.816.

Figure 3

Kaplan-Meier Curves for Freedom From All-Cause Mortality for the Fully Adjusted Models After Adding Diuretic Dose and NYHA Functional Class The final models were each divided into 3 risk groups (1 to 3, 4 to 6, and 7 to 9 points). (A) Mayo score + diuretic dose + NYHA functional class. (B) UK score + diuretic dose + NYHA functional class. For each model, comparison between groups was statistically significant with log-rank p < 0.001.

Central Illustration

Incremental Benefit of Adding Diuretic Dose and New York Heart Association Functional Class to Existing Transthyretin Amyloidosis Cardiomyopathy Risk Models for All-Cause Mortality Adding diuretic dose + New York Heart Association (NYHA) functional class to the Mayo transthyretin amyloidosis (ATTR) score improved the time-dependent area under the curve (AUC) from 0.693 to 0.798. Adding diuretic dose + NYHA functional class to the UK ATTR score improved the time-dependent AUC from 0.711 to 0.816.