To assess the relative safety of istradefylline vs. other Parkinson’s Disease (PD) adjuncts based on randomized controlled trials (RCTs) and real-world evidence (RWE).
Istradefylline has demonstrated a significant reduction in “OFF” time when used as an adjunct to levodopa/carbidopa in patients with PD.
A systematic search for studies published until January 1st, 2024 was conducted. Relative safety was estimated using a Bayesian network meta-analysis (NMA) of RCTs and presented as OR [95% credible interval (CrI)]. Random and fixed-effect models were explored for all outcomes. Inconsistency was assessed through loop-specific approach and heterogeneity was evaluated by global I² statistic and between-study heterogeneity. Incidence rates of safety outcomes were summarized from RWE.
A total of 100 RCTs and 55 RWE publications met the predefined inclusion criteria, and 76 RCTs (n=22,967 patients) were included in NMA. Istradefylline demonstrated lower odds of hallucination (OR=0.25 [95%CrI: 0.06, 0.97]), treatment-emergent AEs (0.43 [0.25, 0.73]), treatment-related AEs (0.33 [0.19, 0.56]), serious AEs (0.56 [0.32, 0.99]), and withdrawals due to AEs (0.37 [0.19, 0.68]) vs. amantadine. Istradefylline demonstrated lower odds of hypotension vs. catechol-O-methyl transferase inhibitors (COMTis) (0.19 [0.03, 0.82]) and monoamine oxidase type B inhibitors (MAO-Bis) (0.09 [0.01, 0.52]), lower odds of dyskinesia (0.63 [0.40, 0.99]) vs. COMTis, and lower odds of nausea (0.57 [0.33, 0.99]) vs. dopamine agonists (DAs). In a sensitivity analysis of RCTs after year 2000, there was a reduction in the odds of dyskinesia (0.55 [0.38, 0.82]) and hallucination (0.41 [0.16, 1.00]) for istradefylline vs. DAs. RWE data were heterogenous but indicate that istradefylline displayed a lower incidence of dyskinesia compared with MAO‑Bis, somnolence compared with DAs and COMTis, nausea compared with all comparators, and peripheral edema and hallucinations compared with amantadine.
Overall, istradefylline exhibits a favorable safety profile compared to other PD adjunct therapies, as demonstrated by both RCTs and RWE.