Development and external validation of prognostic models to predict sudden and pump-failure death in patients with HFrEF from PARADIGM-HF and ATMOSPHERE

Abstract

Background: Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF).

Objective: Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies.

Methods: We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial.

Results: NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE.

Conclusion: We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death.

Trial registration number: PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658.

Keywords: Device; Heart failure; Model; Pump failure death; Risk; Sudden death.

Conflict of interest statement

Li Shen and Brian Claggett have nothing to disclose. ATMOSPHERE and PARADIGM-HF were funded by Novartis and all authors (except Li Shen and Brian Claggett) or their institutions were paid by Novartis for their participation in one or both of these trials. Jianjian Gong, Marty Lefkowitz and Victor Shi are employees of Novartis.

© 2021. The Author(s).

Figures

Fig. 1

Observed vs. predicted cumulative incidence curves for sudden death and pump failure death by quartile of risk scores based on the corresponding models in PARADIGM-HF. A Sudden death model; B pump failure death model. Red solid lines are predicted cumulative incidence curves based the corresponding models, and black dotted lines are the observed cumulative incidence curves based on Aalen–Johansen estimators. Q1 the quartile 1, Q2 the quartile 2, Q3 quartile 3, Q4 quartile 4

Fig. 2

Observed vs. predicted cumulative incidence curves for sudden death and pump failure death by quartile of risk scores based on the corresponding models from PARADIGM-HF in ATMOSPHERE. A Sudden death model; B pump failure death model. Red solid lines are predicted cumulative incidence curves based the corresponding models, and black dotted lines are the observed cumulative incidence curves based on Aalen–Johansen estimators. Q1 the quartile 1, Q2 the quartile 2, Q3 quartile 3, Q4 quartile 4

Fig. 3

Distributions of risk scores for sudden death and pump failure death and its relation to the corresponding cumulative incidence within 3 years in PARADIGM-HF. A The risk score and the corresponding cumulative incidence based on sudden death model; B The risk score and the corresponding cumulative incidence based on pump failure death model. The columns are the histogram of the risk score for mode-specific death, the left axis shows the percent of patients in each column. The red line is the cumulative incidences of mode-specific death for the corresponding risk scores