Long-term outcomes associated with istradefylline versus catechol-O-methyltransferase inhibitors in patients with Parkinson's disease: a nationwide real-world cohort study

Background: Istradefylline, a selective adenosine A_2A receptor antagonist, is approved as an adjunct to levodopa in Parkinson's disease, but its long-term effects on clinically meaningful outcomes are unclear. Objective: We aimed to compare the association of istradefylline versus catechol-O-methyltransferase (COMT) inhibitors with mortality, treatment escalation, and disease progression in levodopa-treated Parkinson's disease. Methods: We conducted a nationwide cohort study emulating a target trial using the DeSC claims database in Japan. Patients aged ≥50 years with levodopa-treated Parkinson's disease between 2014 and 2023 were included. Strategies were initiation of istradefylline versus COMT inhibitors. Primary outcomes were all-cause mortality, levodopa-equivalent daily dose (LEDD) escalation to ≥1100 mg, and dementia or psychosis. Secondary outcomes were fractures, cardiovascular events, pneumonia, and depression. Intention-to-treat and per-protocol effects were estimated using Cox models with propensity score–based overlap weighting. Results: We identified 3190 istradefylline and 7986 COMT inhibitor initiators. In intention-to-treat analysis, istradefylline was associated with lower risks of mortality (hazard ratio [HR] 0.91; 95 % CI 0.84–0.99) and LEDD escalation (HR 0.83; 95 % CI 0.73–0.94). Associations were stronger in per-protocol analysis (mortality: HR 0.84, 95 % CI 0.72–0.97; LEDD escalation: HR 0.71, 95 % CI 0.59–0.84). Istradefylline was linked to higher fracture risk (intention-to-treat HR 1.13, 95 % CI 1.02–1.25; per protocol HR 1.23, 95 % CI 1.07–1.41). No differences were observed for dementia, psychosis, or other outcomes. Conclusions: Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A_2A antagonists.