Key result
Istradefylline modestly reduces OFF time while preladenant and tozadenant show limited or uncertain efficacy.
Why the study?
The comparative efficacy and safety of different adenosine A2A receptor antagonists and doses for motor fluctuations in Parkinson's disease remained unclear.
Do adenosine A2A receptor antagonists improve OFF time, ON time, and UPDRS III scores without increasing adverse events in patients with Parkinson's disease?
Systematic Review (n=5,364)
Do adenosine A2A receptor antagonists improve OFF time, ON time, and UPDRS III scores without increasing adverse events in patients with Parkinson's disease?
Istradefylline 40 mg provides modest improvements in OFF and ON times for Parkinson's disease patients with motor fluctuations, while preladenant and tozadenant show limited efficacy.
Istradefylline 40 mg modestly reduces OFF time in fluctuating PD; extends RCT meta-evidence for selective A2A antagonism while questioning class-wide efficacy.
Background Adenosine A 2 A receptor antagonists—istradefylline, preladenant, and tozadenant—are adjunctive therapies for motor fluctuations in Parkinson’s disease (PD). However, the comparative efficacy and safety of different agents and doses remain unclear. Methods We conducted pairwise and dose-stratified network meta-analyses (NMA) of randomized controlled trials (RCTs) evaluating A 2 A antagonists regarding OFF time, ON time with troublesome dyskinesia, Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) scores, and adverse events (AEs). Random-effects models using restricted maximum likelihood (REML) accounted for within- and between-study variability. Heterogeneity and inconsistency were assessed using τ 2 , I 2 , and Q statistics. Results Pairwise meta-analysis showed significant reductions in OFF time versus placebo (mean difference [MD] = −0.35; 95% confidence interval [CI]: [−0.52, −0.18]), with benefits for istradefylline (MD = −0.29; 95% CI: [−0.57, −0.01]) and preladenant (MD = −0.36; 95% CI: [−0.56, −0.15]); tozadenant was ineffective. NMA of OFF time (11 RCTs, 45 comparisons) found modest benefits for istradefylline 20 mg (MD = −0.33; 95% CI: [−0.66, 0.01]) and 40 mg (MD = −0.47; 95% CI: [−0.83, −0.11]) with moderate-certainty evidence; preladenant and tozadenant showed low or very low certainty. For ON time with troublesome dyskinesia (6 studies, n = 1439), istradefylline 40 mg significantly increased ON time (MD = 0.61; 95% CI: 0.14–1.07), while 20 mg showed a positive trend; preladenant was ineffective. UPDRS III scores (8 RCTs, 31 comparisons) showed no significant improvements, with substantial heterogeneity ( τ 2 = 2.107; I 2 = 85.0%). In safety analyses (13 studies, n = 5364), istradefylline 20 mg (OR = 1.34; 95% CI: 1.04–1.72) and preladenant 10 mg (OR = 1.37; 95% CI: 1.05–1.80) increased AEs; other doses were similar to placebo. The network heterogeneity was low ( I 2 = 10.1%). Conclusions Istradefylline 40 mg provided modest improvements in the OFF and ON times with moderate-certainty evidence; preladenant and tozadenant showed limited or uncertain efficacy. No agents significantly improved UPDRS III scores, and some doses increased AEs. Evidence is constrained by heterogeneity, imprecision, and methodological limitations. High-quality, large RCTs are needed to clarify dose–response effects and confirm the clinical role of A 2 A antagonists in PD.
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Muneer et al. (2026) conducted a systematic review in Parkinson's disease (n=5,364). Adenosine A2A receptor antagonists (istradefylline, preladenant, tozadenant) vs. Placebo was evaluated on OFF time (MD -0.35, 95% CI -0.52, -0.18). Istradefylline 40 mg provided modest reductions in OFF time (MD -0.47; 95% CI -0.83 to -0.11) and increased ON time, while preladenant and tozadenant showed limited or uncertain efficacy.
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