Background: 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.
Methods: We simulated a hypothetical cohort of patients with a generic disease that increased background mortality by a constant additive disease-specific rate. We quantified the bias in terms of the percentage change in life expectancy gains with the intervention under an oHR compared with a dsHR approach as a function of the cohort start age, the disease-specific mortality rate, dsHR, and the duration of the intervention's effect. We then quantified the bias in a cost-effectiveness analysis (CEA) of implantable cardioverter-defibrillators based on efficacy estimates from a clinical trial.
Results: For a cohort of 50-year-old patients with a disease-specific mortality of 0.05, a dsHR of 0.5, a calculated oHR of 0.55, and a lifetime duration of effect, the bias was 28%. We varied these key parameters over wide ranges and the resulting bias ranged between 3 and 140%. In the CEA, the use of oHR as the intervention's effectiveness overestimated quality-adjusted life expectancy by 9% and costs by 3%, biasing the incremental cost-effectiveness ratio by - 6%.
Conclusions: The use of an oHR approach to model the intervention's effectiveness beyond the time horizon of the trial overestimates its benefits. In CEAs, this bias could decrease the cost of a QALY, overestimating interventions' cost effectiveness.