The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Urinary Incontinence, Incident Parkinsonism, and Parkinson's Disease Pathology in Older Adults.

OBJECTIVE: To test the hypothesis that urinary incontinence (UI) is associated with incident parkinsonism in older adults. METHODS: We used data from 2,617 older persons without dementia. Assessment included baseline self-report UI and annual structured exam which assessed parkinsonian signs, motor performances, cognitive function, and self-report disabilities. We used a series of Cox proportional hazards models to examine the association of UI with parkinsonism and adverse health outcomes and a mixed-effect model to examine the association of UI with the annual rate of cognitive decline. In decedents, regression models were used to examine if UI proximate to death was related to postmortem indices of neuropathologies. RESULTS: At baseline, more than 45% of participants reported some degree of UI. Over an average of nearly 8 years of follow-up, UI was associated with incident parkinsonism (hazard ratio [HR] = 1.07, 95% CI = 1.02, 1.12), death (HR = 1.07, 95% CI = 1.03, 1.11), incident ADL disability (HR = 1.11, 95% CI = 1.07, 1.16), and incident mobility disability (HR = 1.07, 95% CI = 1.02, 1.13). UI was not related to incident MCI (HR = 1.02, 95% CI = 0.97, 1.07), incident AD dementia (HR = 1.00, 95% CI = 0.95, 1.05) or to the rate of cognitive decline (Estimate = -.002, standard error = .002, p = .167). In 1,024 decedents with brain autopsy, UI proximate to death was related to PD pathology (Lewy body pathology and nigral neuronal loss), but not Alzheimer's disease pathology or other age-related neuropathologies. CONCLUSION: UI in older adults is associated with incident parkinsonism and may identify older adults at risk for accumulating PD brain pathology.