Restriction of Pharmacoepidemiologic Cohorts to Initiators of Medications in Unrelated Preventive Drug Classes to Reduce Confounding by Frailty in Older Adults

Nonexperimental studies of the effectiveness of seasonal influenza vaccine in older adults have found 40%-60% reductions in all-cause mortality associated with vaccination, potentially due to confounding by frailty. We restricted our cohort to initiators of medications in preventive drug classes (statins, antiglaucoma drugs, and beta blockers) as an approach to reducing confounding by frailty by excluding frail older adults who would not initiate use of these drugs. Using a random 20% sample of US Medicare beneficiaries, we framed our study as a series of nonrandomized "trials" comparing vaccinated beneficiaries with unvaccinated beneficiaries who had an outpatient health-care visit during the 5 influenza seasons occurring in 2010-2015. We pooled data across trials and used standardized-mortality-ratio-weighted Cox proportional hazards models to estimate the association between influenza vaccination and all-cause mortality before influenza season, expecting a null association. Weighted hazard ratios among preventive drug initiators were generally closer to the null than those in the nonrestricted cohort. Restriction of the study population to statin initiators with an uncensored approach resulted in a weighted hazard ratio of 1.00 (95% confidence interval: 0.84, 1.19), and several other hazard ratios were above 0.95. Restricting the cohort to initiators of medications in preventive drug classes can reduce confounding by frailty in this setting, but further work is required to determine the most appropriate criteria to use.