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

Fernando Alarid-Escudero, Karen M. Kuntz

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)285-296
Number of pages12
Issue number3
StatePublished - Mar 1 2020

Bibliographical note

Funding Information:
Dr Alarid-Escudero was supported by a grant from Fulbright-García Robles and the National Council of Science and Technology of Mexico (CONACYT) as part of Dr Alarid-Escudero’s doctoral program. Drs Kuntz and Alarid-Escudero were supported by a grant from the National Cancer Institute (U01-CA-199335) as part of the Cancer Intervention and Surveillance Modeling Network (CISNET). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies had no role in the design of the study, interpretation of results, or writing of the manuscript. The funding agreement ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report.

Publisher Copyright:
© 2019, Springer Nature Switzerland AG.


Dive into the research topics of 'Potential Bias Associated with Modeling the Effectiveness of Healthcare Interventions in Reducing Mortality Using an Overall Hazard Ratio'. Together they form a unique fingerprint.

Cite this