Multistate Model to Predict Heart Failure Hospitalizations and All-Cause Mortality in Outpatients With Heart Failure With Reduced Ejection Fraction: Model Derivation and External Validation

Abstract

Background: Outpatients with heart failure (HF) who are at high risk for HF hospitalization and death may benefit from early identification. We sought to develop and externally validate a model to predict both HF hospitalization and mortality that accounts for the semicompeting nature of the 2 outcomes and captures the risk associated with the transition from the stable outpatient state to the post-HF hospitalization state.

Methods and results: A multistate model to predict HF hospitalization and all-cause mortality was derived using data (n=3834) from the HEAAL study (Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan), a multinational randomized trial in symptomatic patients with reduced left ventricular ejection fraction. Twelve easily and reliably obtainable demographic and clinical predictors were prespecified for model inclusion. Model performance was assessed in the SCD-HeFT cohort (Sudden Cardiac Death in Heart Failure Trial; n=2521). At 1 year, the probability of being alive without HF hospitalization was 94% for a typical patient in the lowest risk quintile and 77% for a typical patient in the highest risk quintile and this variability in risk continued through 7 years of follow-up. The model c-index was 0.72 in the derivation cohort, 0.66 in the validation cohort, and 0.69 in the implantable cardiac defibrillator arm of the validation cohort. There was excellent calibration across quintiles of predicted risk.

Conclusions: Our findings illustrate the advantages of a multistate modeling approach, providing estimates of HF hospitalization and death in the same model, comparison of predictors for the different outcomes and demonstrating the different trajectories of patients based on baseline characteristics and intermediary events.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00000609 and NCT00090259.

Keywords: death; heart failure; hospitalization.

© 2016 American Heart Association, Inc.

Figures

Figure 1

Flow diagram of model development cohort selection and illness-death multistate model transitions. Selection of model development cohort and the number of participants with each of the illness-death multistate model transitions. HEAAL, Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan; NYHA, New York Heart Association; HF, heart failure

Figure 2

Prediction probabilities for the patient with the median risk from each quintile of risk for transition 2. The development cohort was divided into quintile of predicted risk for transition 2 (from prevalent heart failure to death). The median patient from each quintile was selected and the predicted probabilities of being alive without heart failure hospitalization, alive after heart failure hospitalization, dead after heart failure hospitalization and dead without heart failure hospitalization are shown. Patient A is the median risk patient in quintile 1 (lowest risk), patient B quintile 2, patient C quintile 3, patient D quintile 4 and patient E quintile 5 (highest risk).

Figure 3

Observed cumulative incidence of being in each health state by quintiles of predicted risk in the derivation cohort. Quintile 1 (Q1) refers to the lowest risk quintile and quintile 5 (Q5) refers to the highest risk quintile. HFH refers to heart failure hospitalization. Patients were divided into quintile of predicted risk of transition 2 and the cumulative incidence of being in each health state was plotted.

Figure 4

Quintiles of predicted probability and observed outcomes in the non-ICD medical therapy arms of the SCD-HeFT external validation cohort at 1, 2 and 5 years of follow up. Patients were divided into quintile of predicted risk of transition 2 . Quintile 1 (Q1) refers to the lowest risk quartile and quintile 5 (Q5) refers to the highest risk quartile. HFH refers to heart failure hospitalization.

Figure 5

Quintiles of predicted probability and observed outcomes in the ICD arm of the SCDHeFT external validation cohort at 1, 2 and 5 years of follow up. Patients were divided into quintile of predicted risk of transition 2. Quintile 1 (Q1) refers to the lowest risk quartile and quintile 5 (Q5) refers to the highest risk quartile. HFH refers to heart failure hospitalization.