Objective:

To evaluate clinical trials, systematic reviews, and meta-analyses assessing pharmacologic interventions used alongside tenecteplase or alteplase to prevent intracranial hemorrhage in acute ischemic stroke.

Background:

Tenecteplase (TNK) is an effective fibrin-specific thrombolytic used in acute ischemic stroke management. However, the risk of intracerebral hemorrhage (ICH) remains a major safety concern. Several adjunctive pharmacologic agents have been investigated to mitigate hemorrhagic transformation during reperfusion therapy, but their efficacy and safety remain uncertain.

Design/Methods:

A review of available literature, including randomized controlled trials (RCTs), systematic reviews, and meta-analyses, was conducted. Studies examining adjunctive drugs
administered during or shortly after thrombolysis were included. Data were synthesized
narratively with emphasis on ICH prevention, safety, and functional outcomes.

Results:

A total of approximately 30 studies were identified, including several RCTs and systematic reviews evaluating neuroprotective or vasculoprotective agents given with thrombolysis: MMP inhibitors (otaplimastat, minocycline): Both agents were well-tolerated without increasing ICH risk. Otaplimastat showed no significant reduction in hemorrhage rates,while meta-analysis of 7 RCTs of minocycline (n≈426) showed a non-significant trend toward improved outcomes without excess bleeding. Immunomodulators (fingolimod): A pilot RCT (n=47) demonstrated smaller hemorrhage volumes and better 90-day functional recovery when fingolimod was added to alteplase.PAR-1 agonist (3K3A-APC): The RHAPSODY phase-2 trial showed a trend toward fewer intracranial hemorrhages (67% vs 86% placebo, P=0.046) with preserved safety. Other agents (edaravone, imatinib, uric acid): Small studies suggested possible neurovascular protection but lacked clear evidence of hemorrhage reduction. Across all studies, no adjunct therapy conclusively prevented symptomatic ICH. Systematic reviews confirmed overall safety of adjuncts but inconsistent efficacy.

Conclusions:

Current evidence suggests that adjunctive neuroprotective and vasculoprotective agents can be safely co-administered with thrombolytics such as tenecteplase or alteplase, but none have definitively reduced intracranial hemorrhage risk. Fingolimod and 3K3A-APC show the most promise and warrant further investigation in larger, TNK-specific randomized trials.