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

Pharmacoeconomics. 2020 Mar;38(3):285-296. doi: 10.1007/s40273-019-00859-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bias
  • Cost-Benefit Analysis
  • Decision Making
  • Defibrillators, Implantable / economics*
  • Humans
  • Middle Aged
  • Models, Economic*
  • Mortality / trends*
  • Myocardial Infarction / economics*
  • Myocardial Infarction / mortality
  • Myocardial Infarction / therapy
  • Outcome Assessment, Health Care / economics*
  • Outcome Assessment, Health Care / statistics & numerical data
  • Proportional Hazards Models
  • Quality-Adjusted Life Years
  • Randomized Controlled Trials as Topic / economics