Reassessing prasugrel’s boxed warning: a review of dose adjustment, platelet function testing, and platelet reactivity unit (PRU)-guided strategies in neurointervention

Prasugrel is a third-generation P2Y12 inhibitor that achieves faster, more consistent platelet inhibition than clopidogrel. Its use in the United States is limited by an U.S. Food and Drug Administration (FDA) boxed warning originating from TRITON-TIMI 38, which identified excess bleeding in patients aged 75 years or older, weighing less than 60 kg, or with prior stroke or transient ischemic attack. That warning was developed in cardiology cohorts treated with fixed doses, while contemporary practice has diversified. European trials show prasugrel can be at least as effective as alternative P2Y12 inhibitors when patients are selected appropriately. Japanese and Korean experience with low-dose regimens (20 mg loading/3.75-5 mg maintenance) suggests ischemic protection can be preserved with acceptable bleeding risk in smaller, higher-bleeding-risk populations. Neurointerventional series and meta-analyses in stent-assisted coiling and flow diversion report lower thromboembolic events and more predictable platelet inhibition, but the evidentiary signal is strongest in carefully selected patients with confirmed clopidogrel hyporesponsiveness or high on-treatment platelet reactivity treated with low-dose, platelet function-guided strategies. In these settings, hemorrhagic complication rates are generally similar to clopidogrel at low doses, although rare catastrophic intracranial hemorrhage has been described. This narrative review synthesizes cardiology and neurointerventional evidence to help clinicians interpret the boxed warning in context. The central message is to favor platelet function-guided and dose-adjusted therapy that targets a physiologic window of platelet reactivity, rather than relying on fixed cardiology dosing, and to prioritize prospective, neuro-specific studies that define optimal low-dose prasugrel strategies.