Comparative safety of istradefylline in Parkinson’s disease: A systematic review of randomized controlled trials and real-world studies

• An up-to-date assessment of comparative safety of PD adjuncts was conducted by NMA. • Istradefylline had numerically lower odds of TEAEs/TRAEs vs other adjuncts included. • All estimates excluding the null value from the 95 % CrI favored istradefylline. • Istradefylline exhibited a favorable safety profile relative to other adjuncts. Istradefylline offers a novel mechanism (adenosine A 2A receptor antagonism) to treat OFF episodes in Parkinson’s disease (PD). It may potentially offer improved tolerability versus other adjuncts, but comparative safety data are lacking. A systematic review and Bayesian network meta -analysis (NMA) incorporating RCTs of PD adjuncts until January 10, 2024, was conducted to estimate relative safety. Inconsistency was assessed and heterogeneity evaluated by global I 2 -statistic and between-study heterogeneity. Incidences of safety outcomes were summarized from RWE identified according to the same criteria. 100 RCTs and 55 RWE publications were identified; 76 RCTs were included in NMAs. Istradefylline demonstrated lower odds of serious AEs (odds ratio [OR] = 0.56; 95 % CrI: 0.32, 0.99), treatment-emergent AEs (0.43; 0.25, 0.73), treatment-related AEs (0.33; 0.19, 0.56), hallucinations (0.25; 0.06, 0.97), and withdrawal due to AEs (0.37; 0.19, 0.68) versus amantadine. Istradefylline showed lower odds of dyskinesia (0.63; 0.41, 0.99) and hypotension (0.19; 0.03, 0.82) versus catechol- O -methyl transferase inhibitors (COMTi), lower odds of nausea (0.58; 0.33, 0.99) versus dopamine agonists (DA), and lower odds of hypotension (0.09; 0.01, 0.52) versus monoamine oxidase-B inhibitors (MAO-Bi). Sensitivity analysis of RCTs published since 2000 found a reduction in odds of dyskinesia and hallucinations for istradefylline versus DA. RWE were heterogeneous but demonstrated lower incidence of certain AEs with istradefylline, specifically dyskinesia (versus MAO-Bi), somnolence (versus DA and COMTi), peripheral edema and hallucinations (versus amantadine), and nausea (versus all comparators). Istradefylline exhibits a favorable safety profile versus other PD adjuncts, as demonstrated by RCTs and RWE.