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. 2021 Nov 14;42(43):4455-4464.
doi: 10.1093/eurheartj/ehab579.

Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial

Stuart J Pocock  1 , João Pedro Ferreira  2   3 , John Gregson  1 , Stefan D Anker  4 , Javed Butler  5 , Gerasimos Filippatos  6 , Nicholas D Gollop  7 , Tomoko Iwata  8 , Martina Brueckmann  7   9 , James L Januzzi  10   11   12 , Adriaan A Voors  13 , Faiez Zannad  2 , Milton Packer  14   15
Affiliations

Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial

Stuart J Pocock et al. Eur Heart J. .

Abstract

Aims: The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials.

Methods and results: In EMPEROR-Reduced, 33 candidate variables were pre-selected. Multivariable Cox regression models were developed using stepwise selection for: (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, and (iii) cardiovascular mortality. A total of 3730 patients were followed up for a median of 16 months, 823 (22%) patients had a primary outcome and 515 (14%) patients died, of whom 389 (10%) died from a cardiovascular cause. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last HF hospitalization, longer time since HF diagnosis, lower systolic blood pressure, New York Heart Association (NYHA) Class III or IV, higher heart rate and peripheral oedema were key predictors (eight variables in total, all P < 0.001). The primary outcome risk score discriminated well (c-statistic = 0.73), with patients in the top 10th of risk having an event rate >9 times higher than those in the bottom 10th. Empagliflozin benefitted patients across risk levels for the primary outcome. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality, followed by NYHA Class III or IV and ischaemic aetiology (four variables in total, all P < 0.001). The mortality risk model presented good event discrimination for all-cause and cardiovascular mortality (c-statistic = 0.69 for both). These simple models were externally validated in the BIOSTAT-CHF study, achieving similar c-statistics.

Conclusions: The combination of NT-proBNP and hs-cTnT with a small number of readily available clinical variables provides prognostic assessment for patients with HFrEF. This predictive tool kit can be easily implemented for routine clinical use.

Trial registration: ClinicalTrials.gov NCT03057977.

Keywords: Heart failure; High-sensitivity cardiac troponin T; NT-proBNP; Risk score.

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Figures

None
EMPEROR-Reduced risk model. CI, confidence interval; HF, heart failure; hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
Figure 1
Figure 1
(A) N-terminal pro B-type natriuretic peptide, (B) high-sensitivity cardiac troponin T, (C) systolic blood pressure, and (D) heart rate: their independent contributions according to fifths of their distributions to risk of the primary outcome (a composite of time-to-first heart failure hospitalization or cardiovascular death). CI, confidence interval; hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro B-type natriuretic peptide.
Figure 2
Figure 2
Observed vs. predicted events by tenths of the risk score distribution. Hosmer–Lemeshow goodness-of-fit test P = 0.473 for the primary outcome (A) and P = 0.053 for all-cause mortality (B), indicating adequate calibration. CI, confidence interval.
Figure 3
Figure 3
Hazard ratios and rate differences for the primary outcome (empagliflozin vs. placebo) according to thirds of the risk score distribution. CI, confidence interval; HR, hazard ratio.
Figure 4
Figure 4
Mortality risks for N-terminal pro B-type natriuretic peptide (A) and high-sensitivity cardiac troponin T (B): their independent contributions according to fifths of their distribution. CI, confidence interval; hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro B-type natriuretic peptide.
Figure 5
Figure 5
Incidence rates per 100 patient-years of (A) the primary outcome and (B) all-cause death for patients simultaneously grouped in thirds of N-terminal pro B-type natriuretic peptide and high-sensitivity cardiac troponin T. hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro B-type natriuretic peptide
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