The explanatory role of stroke as a mediator of the mortality risk difference between older adults who initiate first-versus second-generation antipsychotic drugs

Antipsychotic drugs are used to treat dementia-related symptoms in older adults, and observational studies show higher risks of death and stroke associated with the use of first-generation antipsychotic drugs (FGAs) compared with second-generation antipsychotic drugs (SGAs). However, the extent to which stroke explains the differential mortality risk between FGA use and SGA use in older adults is unclear. We followed those who initiated use of antipsychotic drugs (9,777 FGA users and 21,164 SGA users) aged 65 years or older, and who were enrolled in Medicare and either the New Jersey or Pennsylvania pharmacy assistance program during 1994 to 2005, over 180 days for the outcomes of stroke and death. We estimated direct and indirect effects by comparing 180-day mortality risks associated with the use of FGAs versus SGAs as mediated by stroke on the risk ratio scale, as well as the proportion mediated on the risk difference scale. FGA use was associated with marginally higher risks of stroke (risk ratio = 1.24, 95% confidence interval (CI): 1.01, 1.53) and death (risk ratio = 1.15, 95% CI: 1.08, 1.22) compared with SGA use, but stroke explained little (2.7%) of the observed difference in mortality risk. The indirect effect was null (risk ratio = 1.004, 95% CI: 1.000, 1.008), and the direct effect was equal to the total effect of antipsychotic drug type (FGA vs. SGA) on mortality risk (risk ratio = 1.15, 95% CI: 1.08, 1.22). These results suggest that the difference in mortality risk between users of FGAs and SGAs may develop mostly through pathways that do not involve stroke.