Purpose <p>Clopidogrel (CPG)-based dual antiplatelet therapy (DAPT) is widely used prior to endovascular treatment of intracranial aneurysms to prevent procedural thromboembolic complications (TECs). Recently, newer-generation P2Y12 inhibitors – prasugrel and ticagrelor (PSG/TCG) – have emerged as potential alternatives. This meta-analysis aimed to evaluate the utility of PSG and TCG as first-line agents for DAPT by directly comparing their safety and efficacy with conventional CPG-based therapy.</p> Method <p>Relevant studies were extracted from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials by two independent reviewers. A random-effects model was used to compare the risk of TECs and hemorrhagic complications (HECs) between PSG/TCG-based and CPG-based DAPT, expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Subgroup analyses were performed to compare platelet reactivity, measured by platelet reaction unit (PRU) values, between the two groups.</p> Results <p>Six studies encompassing 1,071 patients were included. Compared with CPG-based DAPT, PSG/TCG-based DAPT was associated with a significantly lower risk of TECs (RR, 0.46; 95% CI, 0.23–0.93; <i>p</i> = 0.04) without a corresponding increase in HECs. Subgroup analysis demonstrated significantly lower PRU values in the PSG/TCG compared with the CPG group (<i>p</i> =0.01).</p> Conclusion <p>This meta-analysis shows that PSG/TCG-based DAPT offers superior thromboembolic protection without increased hemorrhagic risk, compared to conventional CPG-based regimens in endovascular treatment of intracranial aneurysms. These results suggest that PSG/TCG-based DAPT is worth considering as a treatment option in this setting, and prospective randomized trials are needed to confirm these results and to evaluate its role as a first-line option.</p>