Efficacy and safety of adjunctive eptifibatide or argatroban versus control for acute ischemic stroke: A systematic review and network meta-analysis of randomized control trials

Abstract Introduction: Acute ischemic stroke is a major cause of disability and mortality, with treatment mainly limited to intravenous alteplase thrombolysis. Eptifibatide, a glycoprotein IIb/IIIa inhibitor, and argatroban, a direct thrombin inhibitor, show potential as adjunctive or alternative treatments to improve outcomes. Given the lack of direct comparative studies, this network meta-analysis aims to assess the efficacy and safety of eptifibatide and argatroban in acute ischemic stroke management. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines. A literature search was executed across PubMed, Scopus, Embase, and Google Scholar databases up to July 2025, comparing outcomes between argatroban, eptifibatide, and control groups. Data analysis was performed using R (version 4.5.1) in RStudio, with packages netmeta, gemtc, BUGSnet, and bnma. Both frequentist and Bayesian methods assessed efficacy indirectly. A random effects model was selected based on study characteristics. Results: Across seven randomized controlled trials (RCTs), 1,856 participants were included. Of these, 498 patients received argatroban, 467 received eptifibatide, and 891 were assigned to the control group. Our meta-analysis produced the following results: Functional Independence (mRS 0-1):Eptifibatide showed superior odds versus control (OR 1.12 [0.65-1.95]) and Argatroban (OR 1.82 [0.61-5.45]), with wide confidence intervals. Argatroban versus control yielded OR 1.05 [0.59-1.86], indicating uncertainty. Bayesian analysis showed minimal effect for Control versus Argatroban = -0.046 [-0.65, 0.59], and slight advantage for Control versus Eptifibatide = 0.205 [-0.37, 0.78], with uncertainty. SUCRA ranked Eptifibatide highest (76.45%, Rank 1 [0.66]), followed by control (39.99%) and Argatroban (33.56%). No inconsistency was detected (p > 0.05). Symptomatic Intracranial Hemorrhage (sICH): Eptifibatide showed reduced likelihood of sICH versus control (OR 0.50 [0.18-1.40]), while Argatroban showed comparable risk (OR 0.97 [0.42-2.23]). Eptifibatide versus Argatroban favored Eptifibatide (OR 0.49 [0.15-1.60]). Bayesian estimates were: Control versus Argatroban = -0.024 [-1.3, 1.17]; Control versus Eptifibatide = -1.01 [-2.6, 0.24]; Eptifibatide versus Argatroban = 0.98 [-0.61, 2.83]. SUCRA ranked Eptifibatide highest (91.44%, Rank 1 [0.86]), with Argatroban (31.03%) above control (27.53%). Inconsistencies were non-significant, except Argatroban versus Control (difference -6.19, p = 0.03). All-Cause Mortality (90 days): Control showed better odds over Eptifibatide (OR 0.63 [0.28-1.41]) and Argatroban (OR 0.62 [0.26–1.48]); Eptifibatide vs Argatroban showed OR 0.42 [0.13-1.42], all uncertain. Bayesian values: Control vs Argatroban = -0.02454 [-1.30, 1.18]; Control vs Eptifibatide = -1.012 [-2.60, 0.24]; Eptifibatide vs Argatroban = 0.2006 [-1.15, 1.36]. SUCRA ranked Eptifibatide highest (76.45%), followed by Control (39.99%) and Argatroban (33.56%). Node splitting showed disagreement between direct, indirect, and network evidence. Inconsistency was insignificant, except Eptifibatide vs Control (difference -2.67, p = 0.06). Discussion:This network meta-analysis shows eptifibatide confers advantages across stroke outcomes, including functional independence, symptomatic intracranial hemorrhage (sICH), and mortality. As a GP IIb/IIIa inhibitor, eptifibatide may better modulate blood flow and platelet aggregation, shown by improved neurological recovery and reduced sICH risk. While argatroban showed benefit over control, its thrombin inhibition mechanism may be less effective compared to eptifibatide's reperfusion outcomes. These findings are supported by SUCRA rankings, which place eptifibatide ahead of argatroban and control in functional independence and sICH reduction, though intervention groups lagged in mortality outcomes. Despite statistical uncertainty, the trend favored eptifibatide. These results suggest eptifibatide holds promise for acute ischemic stroke. Although uncertainty remains, consistent trends advocate for further large-scale trials to validate these findings and support clinical decisions.