Association of early adjunctive dopaminergic therapy and 5-year mortality in Parkinson's disease: A nationwide cohort study

Background: Although dopaminergic therapy improves motor symptoms in Parkinson's disease (PD), the association between initial treatment strategy and long-term survival remains unclear. Objective: To examine the association between early dopaminergic therapy strategy and 5-year mortality in PD. Methods: We conducted a nationwide, population-based retrospective cohort study using the Korean National Health Insurance Service (NHIS)-Senior Cohort (2004-2019). Newly diagnosed PD patients were categorized into initial treatment groups: levodopa monotherapy versus levodopa with early adjunctive medications, including monoamine Oxidase B (MAO-B) inhibitor, dopamine agonist (DA), and catechol-O-methyltransferase (COMT) inhibitor. Machine learning-based analyses were performed to estimate adjusted differences in 5-year restricted mean survival time (RMST) for all-cause mortality accounting for measured demographic, socioeconomic, lifestyle, and clinical covariates, including levodopa equivalent daily dose and comorbidity burden. Results: Among 4949 patients, 2816 (56.9%) received levodopa only, 288 (5.8%) received levodopa with MAO-B inhibitor, 1645 (33.2%) with DA, and 200 (4.0%) with COMT inhibitor. Compared with levodopa monotherapy, early adjunctive therapy with a MAO-B inhibitor was associated with an increase in 5-year RMST (ΔRMST = 3.45 months; 95% CI, 1.92–4.98; P < 0.001). DA showed a smaller but similarly directed association (ΔRMST, 0.95 months; 95% CI, 0.09–1.82; P = 0.031). No significant association was observed for COMT inhibitors (ΔRMST, −1.64 months; 95% CI, −4.25–0.97; P = 0.217). Discussion: In this nationwide cohort study, early adjunctive dopaminergic therapy was associated with differences in 5-year mortality. These findings should be interpreted cautiously because treatment allocation likely reflected disease severity, frailty, cognition, and physician preference.