Developing and validating models to predict sudden death and pump failure death in patients with heart failure and preserved ejection fraction

Abstract

Background: Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF.

Methods: Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials.

Results: The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68-0.75) and 0.78 (95% CI 0.75-0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination.

Conclusions: The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials.

Clinical trial registration: I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712.

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

Conflict of interest statement

No author has a disclosure relevant to the subject of this manuscript.

© 2020. The Author(s).

Figures

Fig. 1

Observed vs. predicted cumulative incidence curves for sudden death by tertile of the risk scores based on the sudden death models in I-Preserve. a Sudden death model 1, b sudden death model 2, c sudden death model 3, d sudden death model 4. Red solid lines are predicted cumulative incidence curves based on the corresponding models, and black dotted lines are the observed cumulative incidence curves based on Aalen–Johansen estimators

Fig. 2

Observed vs. predicted cumulative incidence curves for pump failure death by tertile of the risk scores based on the pump failure death models in I-Preserve. a Pump failure death model 1 or 2; b pump failure death model 3; c pump failure death model 4. Red solid lines are predicted cumulative incidence curves based on the corresponding models, and black dotted lines are the observed cumulative incidence curves based on Aalen–Johansen estimators

Fig. 3

Survival status at the end of follow-up in I-Preserve, according to baseline risk score for sudden death and pump failure death. Every patient has a score for both risk of pump failure death and risk of sudden death at baseline, plotted on the X and Y axis, respectively. The shaded areas show the outcome for each patient during follow-up, according to their scores (PFD pump failure death, OD other death, SD sudden death). As can be seen, patients who died suddenly (shown in red, clustered in the upper left quadrant of the figure) had a high score for risk of sudden death and low score for risk of pump failure death. The opposite was true for patients dying from pump failure (clustered in the lower right quadrant of the figure)

Fig. 4

Annual rates of modes of death in the highest tertile based on the sudden death model in I-Preserve and in the control group of SCD-HeFT. The range of the risk score in the highest tertile based on sudden death model 4 in I-Preserve was from 3.8 to 6.1 with the median value of 4.2