Continuously Updated Estimation of Heart Transplant Waitlist Mortality

Abstract

Background: Heart transplant allocation in the United States is made on the basis of coarse tiers, defined by mechanical circulatory devices and therapy for advanced heart failure, updated infrequently as a patient's condition deteriorates. Thus, many patients die awaiting heart transplantation. What is needed is a tool that continuously updates risk of mortality as a patient's condition changes to inform clinical decision making.

Objectives: This study sought to develop a decision aid that aggregates adverse events and measures of end-organ function into a continuously updated waitlist mortality estimate.

Methods: From 2008 to 2013, 414 patients were listed for heart transplantation at Cleveland Clinic, Cleveland, Ohio. The endpoint was waitlist death. Pre-listing patient characteristics and events and laboratory results during listing were analyzed. At each event or measurement change, mortality was recomputed from the resulting model.

Results: There were 77 waitlist deaths, with 1- and 4-year survival of 85% and 57%, respectively. When time-varying events and measurements were incorporated into a mortality model, pre-listing patient characteristics became nonsignificant. Neurological events (hazard ratio [HR]: 13.5; 95% confidence interval [CI]: 7.63 to 23.8), new requirement for dialysis (HR: 3.67; 95% CI: 1.88 to 7.14), more respiratory complications (HR: 1.79 per episode; 95% CI: 1.23 to 2.59), and higher serum bilirubin (p < 0.0001) and creatinine (p < 0.0001) yielded continuously updated estimates of patient-specific mortality across the waitlist period.

Conclusions: Mortality risk for patients with advanced heart failure who are listed for transplantation is related to adverse events and end-organ dysfunction that change over time. A continuously updated mortality estimate, combined with clinical evaluation, may inform status changes that could reduce mortality on the heart transplant waiting list.

Keywords: heart failure; mathematical modeling; mechanical circulatory support; risk score.

FIGURE 1. Overall Survival on the Heart Transplant Waitlist or After Insertion of a Durable Mechanical Circulatory Support Device as Bridge to Transplant Before Listing

Each symbol represents a death positioned on the vertical axis by the Kaplan-Meier estimator; vertical bars are confidence limits equivalent to ±1 standard error. The solid line depicts parametric survival estimates enclosed within a dashed 68% confidence band equivalent to ±1 standard error. Numbers below the horizontal axis are patients remaining at risk. The inset shows an instantaneous risk of death (hazard function) on an expanded horizontal axis. The solid line depicts parametric estimates enclosed within a dashed 68% confidence band equivalent to ±1 standard error. Note the early peaking hazard and underlying constant hazard. Risk factors were simultaneously examined for each of these phases.

FIGURE 2. Individual Risk Profiles for Patients on the Heart Transplant Waitlist

Superimposed are events or laboratory values leading to elevation of calculated risk of mortality. (A) Patient alive at end of follow-up. (B) Patient who died on the waitlist. (C) Patient who received a heart transplant. T. Bili. = total bilirubin.

CENTRAL ILLUSTRATION. Method Used to Provide Continuously Updated Estimates of Mortality on the Heart Transplant Waitlist

This patient was in acute-on-chronic heart failure and developed acute renal failure from poor kidney perfusion. Milrinone and nitroprusside replaced an angiotensin-converting enzyme inhibitor, aldactone, and digoxin. Five days later, the patient was listed for heart transplantation. The next day, the patient received a durable left ventricular assist device for deteriorating cardiac function. Two and one-half weeks later, the patient experienced a number of episodes of transient visual disturbances neurologists attributed to thromboembolism. (A) This episode is seen as a large increase in instantaneous risk of mortality at 18 days, or 0.59 months. The underlying risk of death if all risk factors are set to zero is shown by the dashed line. Also shown are frequent blood draws for creatinine and bilirubin. Every change in these levels increases or decreases estimated mortality risk as the graph is updated. (B) The area beneath the hazard function is the cumulative hazard function, and the dashed line is the underlying cumulative hazard. (C) An equation (see Online Appendix) transforms cumulative hazard into an estimate of mortality at each moment in time. Notice that the underlying risk of death continues smoothly upward, but this curve is constantly being modified by either events or measurements reflecting end-organ function.