Optimizing Thrombolysis for Acute Ischemic Stroke: Adjunct Therapies and Multiple Dosing Strategies

Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) are the keystones of current treatment for acute ischemic stroke. Most IVT candidates harbor medium or distal arterial occlusions, while EVT targets large artery occlusions. However, both treatments often fail to achieve sustained recanalization, microvascular reperfusion, and optimal clinical outcomes. Supplementing IVT with antithrombotic therapies has not shown consistent benefit, and alternative lytics such as tenecteplase provide, at best, a marginal improvement in outcome compared with alteplase. This review summarizes current evidence on multiple dosing strategies of IVT, including repeat administration of IVT in non-EVT candidates and IVT or intra-arterial thrombolytics in combination with EVT. We discuss the physiologic, pharmacokinetic, and clinical rationale for these approaches, highlight results from key clinical trials, and identify knowledge gaps to guide future research. Emerging data support novel fibrinolytic agents, sequential IVT dosing, and adjunct intra-arterial thrombolysis as promising strategies to enhance reperfusion and functional recovery while maintaining safety.