Estimating influenza vaccine effectiveness using an active comparator reduces bias due to confounding by frailty

Background: Estimating influenza vaccine effectiveness using an unvaccinated comparison group generally results in biased effect estimates with exaggerated beneficial associations.

Objectives: To quantify the reduction of bias when using an active comparator rather than an unvaccinated comparator to estimate preinfluenza season mortality among patients receiving chronic hemodialysis.

Methods: Using data from Medicare's end‐stage renal disease program (2009‐2013), we compared the risk of all‐cause mortality among adult recipients of high‐dose vaccine (HDV) versus standard‐dose vaccine (SDV), HDV versus none, and SDV versus none. We required continuous hemodialysis from May 1 to Jul 31 and ascertained insurance status and patient characteristics from Feb 1 to Jul 31. Follow‐up began on Aug 1 and ended at the earliest of all‐cause mortality, receipt of second influenza vaccine or unknown influenza vaccine type, modality switch, end of Medicare as primary payer, or start of influenza season. To quantify confounding bias, analyses were restricted to the preinfluenza season, when protective effects of vaccination should not yet be observed. We estimated standardized mortality ratio‐weighted cumulative incidence functions using Kaplan‐Meier methods and calculated risk differences (RD) and risk ratios (RRs) between groups.

Results: Of 350 921 eligible patients contributing 825 642 unique patient preinfluenza seasons, 0.8% received HDV, 70.5% received SDV, and 28.7% remained unvaccinated. Compared with unvaccinated patients, HDV recipients (RR, 0.60; 95% CI, 0.51‐0.70) and SDV recipients (RR, 0.72; 95% CI, 0.70‐0.75) demonstrated a decreased risk of mortality during the preinfluenza period. The effect estimate was attenuated in the comparison of HDV versus SDV recipients (RR, 0.89; 95% CI, 0.77‐1.03). RD estimates were similar.

Conclusions: Using an active comparator yielded less biased results than an unvaccinated comparator, as indicated by attenuated protective effect estimates of the association between influenza vaccination and all‐cause mortality prior to influenza season. Future vaccine‐effectiveness and safety studies should consider the active comparator design to reduce bias due to differences in underlying health status between vaccinated and unvaccinated individuals.