Alternative Thrombolytics in Stroke: TNK, Reteplase, and Intra-Arterial Approaches

While intravenous alteplase remains the standard thrombolytic for acute ischemic stroke, several trials now support alternative agents and delivery strategies. This review highlights key studies investigating tenecteplase (TNK), reteplase, and intra-arterial (IA) thrombolysis following thrombectomy.

Tenecteplase (TNK)

Tenecteplase is a genetically engineered alteplase variant with higher fibrin specificity and longer half-life, allowing single bolus administration. It has shown promise in multiple RCTs:

• EXTEND-IA TNK Part 1: TNK 0.25 mg/kg led to higher early reperfusion rates and better functional outcomes than alteplase.
• EXTEND-IA TNK Part 2: Compared 0.25 vs 0.40 mg/kg TNK; the higher dose showed no additional benefit, confirming 0.25 mg/kg as optimal.

Reteplase (RAISE Trial)

The RAISE trial compared IV reteplase (18 mg + 18 mg) to standard alteplase within 4.5 hours of stroke onset:

• mRS 0–1 at 90 days: 79.5% (reteplase) vs 70.4% (alteplase); p < 0.001 for noninferiority, p = 0.002 for superiority
• Safety: Similar symptomatic ICH and mortality, slightly more minor ICH with reteplase

Clinical Pearl: Reteplase is promising but not yet FDA-approved for stroke.

Intra-Arterial Thrombolysis After Thrombectomy

Several recent trials evaluated IA thrombolytics as adjunct therapy following successful mechanical thrombectomy, targeting residual microthrombi or no-reflow phenomena.

CHOICE Trial (IA tPA)

The CHOICE trial evaluated intra-arterial alteplase following thrombectomy:

• Design: IA alteplase 0.225 mg/kg vs placebo post-thrombectomy (n=121)
• Result: mRS 0–1 at 90 days: 59.0% vs 40.4% (P = .047)
• No increase in symptomatic ICH or death

ANGEL-TNK (IA TNK)

The ANGEL-TNK trial tested intra-arterial tenecteplase in the extended window:

• Population: 255 patients, 4.5–24h from onset, LVO with ≥50% reperfusion
• Intervention: IA TNK 0.125 mg/kg post-thrombectomy
• Result: mRS 0–1 at 90 days: 40.5% vs 26.4% (P = .02)
• Safety: Similar ICH (5.6% vs 6.2%) and mortality (21%)

PEARL (IA tPA)

The PEARL trial further evaluated IA alteplase in a larger cohort:

• Design: IA alteplase 0.225 mg/kg vs standard care (n=324); 42% had prior IV thrombolysis
• Result: mRS 0–1 at 90 days: 44.8% vs 30.2% (RR 1.45)
• Safety: Comparable rates of ICH and mortality

Conclusion

With increasing evidence from multiple RCTs, both tenecteplase and reteplase show promise as alternatives to alteplase for acute ischemic stroke. Intra-arterial thrombolytics after thrombectomy also appear to enhance outcomes without added bleeding risk. As protocols evolve, these agents may become more integrated into personalized stroke reperfusion strategies.