Is tenecteplase ready to replace alteplase to treat acute ischaemic stroke? The knowns and unknowns

Tenecteplase (TNKase, TNK-tPA or TNK) is a thrombolytic agent derived from the tissue plasminogen activator (tPA). It is a 527-amino acid glycoprotein developed by replacing three amino acids at the T, N and K positions of the glycoprotein structure of tPA under genetic recombinant technology. After replacing threonine 103 with asparagine, asparagine 117 with glutamine and a tetra-alanine at amino acids 296–299, TNK is about eightfold more potent in dissolving clot, 80-fold higher resistance to plasminogen activator inhibitor-1 and 14-fold enhanced relative fibrin specificity, and with a longer half-life (20 min).1 Hence, TNK is administered as a single intravenous bolus.

TNK 0.5 mg/kg intravenous bolus is the choice in treating acute myocardial infarction (MI),2 and was approved by the United States Food and Drug Administration in 2000. In comparison, the optimal dosages of TNK used alone or as a part of the bridging therapy remain to be further defined. For Caucasians patients with acute ischaemic stroke (AIS), TNK was tested at doses of 0.1, 0.25, 0.4 or 0.5 mg/kg.3–7

In the current issue of the journal, Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events (TRACE) trial tested three different doses of TNK versus standard dose of tPA in Chinese patients with AIS within 3 hours of onset.8 The trial is a dose selection phase II trial with a multicentre, prospective, randomised, open label, blinded-endpoint (PROBE) controlled design recruiting AIS patients with severity of National Institutes of Health Stroke Scale (NIHSS) 4–25. No difference in safety was revealed between different dose groups compared with tPA in terms of symptomatic intracerebral haemorrhage (sICH) events (5.0% in 0.1 mg/kg, 0.0% in 0.25 mg/kg, 3.3% in 0.32 mg/kg TNK and 1.7% in 0.9 mg/kg tPA; p=0.52). Also, no significant difference in any efficacy outcomes was observed. The study may be statistically underpowered due to a small sample size.

The Norwegian Tenecteplase Stroke Trial (NOR-TEST) showed a similar efficacy and safety profile between the TNK (0.4 mg/kg) and tPA in patients with mild AIS within 4.5 hours of onset.9 In its subgroup analysis, the distribution of favourable outcome and sICH were similar between treatment groups in patients with moderate and severe stroke. However, all-cause mortality in patients with severe strokes at 90 days was increased in the TNK group (26.3% vs 9.1%; p=0.045).10

Imaging assessment has been used as a surrogate marker to compare the efficacy of TNK to that of tPA. The Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) trial compared TNK 0.25 mg/kg to tPA 0.9 mg/kg in patients with AIS treated within 4.5 hours of onset. ATTEST failed to show a significant improvement of salvaged penumbra in the TNK group.11 The Australian-TNK trial required a large vessel occlusion on baseline CT angiography and substantial mismatch on baseline CT perfusion imaging to select patient for either TNK 0.1 or 0.25 mg/kg versus standard dose of tPA within 3 hours of onset.5 The trial showed better early neurological improvement, reperfusion and higher rates of favourable 90-day outcome in patients treated with 0.25 mg/kg of TNK. The pooled analysis of ATTEST and Australian-TNK trials showed that TNK-treated patients with a TICI (Treatment in Cerebral Ischemia Score) 0/1 occlusion had higher rate of complete recanalisation at 24 hours (71% vs 43%, p<0.001) and had better early clinical improvement and favourable 90-day outcomes.12 Further analysis stressed the importance of target perfusion mismatch.13 The EXTEND-IA TNK study showed that TNK (0.25 mg/kg) before thrombectomy was associated with a higher rate of reperfusion and better functional outcome than the standard dose of tPA in AIS patients with an large vessel occlusion (LVO), if treated within 4.5 hours of onset.14 EXTEND-IA TNK Part 2 showed that TNK doses of either 0.40 or 0.25 mg/kg had no difference in improving cerebral reperfusion prior to endovascular thrombectomy. However, sICH occurred in seven patients (4.7%) in the 0.40 mg/kg group compared with two patients (1.3%) in the 0.25 mg/kg group (risk ratio 3.50, 95% CI 0.74 to 16.62; p=0.12).6

With limited evidence, the 2019 AIS guideline of the American Heart/Stroke Association recommended TNK 0.4 mg/kg as an alternative to tPA in selected patients with AIS of minor neurological impairments and no major intracranial occlusion, while TNK 0.25 mg/kg for LVO patients prior to thrombectomy (both with level of evidence (LOE): B-R, and class of recommendation (COR): IIb).15

Current limited evidence supports no superiority of either dose over the other (0.25 mg/kg vs 0.4 mg/kg). Yet, dosage of 0.25 mg/kg is most frequently used in ongoing trials of TNK in AIS (table 1), with a support of its efficacy based on a recent network meta-analysis.16 In addition, TNK’s efficacy when used in patient with LVO was only seen with imaging-based endpoints, while its safety is comparable to tPA. Therefore, its solid effects in treating AIS remain to be studied. TNK is likely to have its role to treat AIS, but more data are needed for it to completely replace tPA.

A series of ongoing phase III trials will further address the efficacy and safety of TNK either within early or late time windows, with or without LVO (table 1). Particularly in China, the ongoing TRACE II trial is testing the efficacy of TNK 0.25 mg/kg (single bolus, max 25 mg) as opposed to standard dose of tPA.17 TRACE III will study TNK in AIS due to LVO with perfusion mismatch up to 24 hours of symptom onset.