Abstract
BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial effects from observational data. METHODS: We used observational data from 5 580 participants enrolled in the Cardiovascular Health Study from 1989/1990 to 1999/2000. We conceptualized the cohort as an overlapping sequence of nonrandomized trials. We compared multiple selection (eligible population, prevalent users, new users) and analytic approaches (multivariable adjustment, inverse-probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State Examination (3MSE). RESULTS: When comparing prevalent users to nonusers (N = 2 772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95% CI: 0.05-0.63). Compared to prevalent user design, estimates from new user designs (eg, comparing eligible statin initiators to noninitiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N = 454), the annual 3MS change comparing statin initiators to noninitiators was -0.21 points/year (95% CI: -0.81 to 0.39). CONCLUSIONS: The association of statin use and cognitive decline is attenuated toward the null when using rigorous analytical approaches that more closely mimic randomized controlled trials. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.