Potential Bias Associated with Modeling the Effectiveness of Healthcare Interventions in Reducing Mortality Using an Overall Hazard Ratio

Clinical trials often report intervention efficacy in terms of the reduction in all-cause mortality between the treatment and control arms (i.e., an overall hazard ratio [oHR]) instead of the reduction in disease-specific mortality (i.e., a disease-specific hazard ratio [dsHR]). Using oHR to reduce all-cause mortality beyond the time horizon of the trial may introduce bias if the relative proportion of other-cause mortality increases with age. We sought to quantify this oHR extrapolation bias and propose a new approach to overcome this bias.