Tenecteplase in acute ischemic stroke: a new era in thrombolysis

Silva, Gisele Sampaio; Rocha, Eva; Pontes-Neto, Octávio Marques; Martins, Sheila Ouriques

doi:10.1055/s-0045-1808088

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Review Article • Arq. Neuro-Psiquiatr. 83 (5) • 2025 • https://doi.org/10.1055/s-0045-1808088 linkcopy

Tenecteplase in acute ischemic stroke: a new era in thrombolysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Tenecteplase (TNK) is a genetically engineered variant of alteplase, showing promise for acute ischemic stroke treatment. With a longer half-life and higher fibrin specificity, TNK enables more targeted and efficient clot dissolution. Clinical trials demonstrate potential advantages, including improved reperfusion rates and functional outcomes with lower systemic bleeding. Though not officially approved for this purpose by all regulatory agencies, TNK is used off-label and in acute stroke guidelines due to its ease of administration and effectiveness. The 0.25 mg/kg dosage within 4.5 hours of symptom onset was shown to be consistently effective and safe. Further trials are expected to identify patient subgroups that benefit most from TNK treatment. The present narrative review assesses the existing literature and evidence regarding the use of tenecteplase for the treatment of acute ischemic stroke.

Keywords
Ischemic Stroke; Thrombolytic Therapy; Tenecteplase

Medication	Alteplase	Tenecteplase
Synthesis	Recombinant version of tPA	Bioengineered version of alteplase
FDA approved indications	Acute ischemic stroke Myocardial infarction Acute pulmonary embolism	Myocardial infarction
EMA approved indications	Acute ischemic stroke Myocardial infarction Acute pulmonary embolism	Acute ischemic stroke Myocardial infarction
Administration	10% bolus followed by 1-h infusion	Single bolus
Fibrin specificity	Lower than Tenecteplase	14–15x higher than alteplase
Degradation	Less resistant to PAI-1	80x higher resistance to PAI-1
Plasma half-life	4–6 minute	17–20 min

Trial name/Phase	Year published	Number of patients	Intervention	Inclusion criteria	Results	Safety outcomes
TNK-S2B¹² Phase IIB/III	2010	112	TNK: 0.1 mg/kg 0.25 mg/kg 0.4 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–3 hours. NIHSS: Aphasia score > 1, motor power > 1, vision > 2, or attention > 2.	No differences in 3-month functional outcome (mRS score ≥ 4) between remaining TNK doses and alteplase.	Symptomatic ICH: TNK 0.4 mg/kg: 3/19 (15.8%) TNK 0.25 mg/kg: 2/31 (6.5%) TNK 0.1 mg/kg: 0/31 (0%) r-tPA: 1/31 (3.2%)
TAAIS trial¹⁰ Phase IIB	2012	75	TNK: 0.1 mg/kg 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window 0–6 hours. NIHSS > 4 Maximum age: 85. Visible occlusion on CTA > 20% mismatch on CTP. Prestroke mRS: ≤ 2.	Pooled TNK groups (0.1 and 0.25 mg/kg) had greater reperfusion and clinical improvement at 24 hours compared with the alteplase group (79.3 ± 28.8% vs 55.4 ± 38.7%, p = 0.004 and (8.0 ± 5.5% vs 3.0 ± 6.3%, p < 0.001).	Symptomatic ICH: 3/25 (12%) alteplase and 2/50 (4%) TNK pooled. No differences in mortality were found at 90 days.
TEMPO-1¹³ Phase II	2015	50	TNK: 0.1 mg/kg 0.25 mg/kg	Time window: 0–12 hours. NIHSS ≤ 5. Visible occlusion on CTA.	66% had mRS 0–1 at 90 days. Recanalization rates were high in 0.1 mg/kg (39% complete and 17% partial) and 0.25 mg/kg (52% complete and 9% partial). Complete recanalization was significantly related to mRS 0–1 at 90 days (p = 0.026)	In 0.25 mg/kg group there was 1 symptomatic ICH (4%)
ATTEST¹⁴ Phase II	2015	104	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours. NIHSS: ≥ 1. Perfusion imaging: > 20% mismatch.	No significant differences for percentage of penumbra salvaged between TNK 68% (28/47) and alteplase 68% (23/49) groups (p = 0.81)	No differences were found in mortality and rates of symptomatic ICH
NOR-TEST¹⁵ Phase III	2017	1,050	TNK: 0.4 mg/kg r-tPA: 0.9 mg/kg	Time window 0–4.5 hours. NIHSS ≥ 1. Wake-up patients: DWI/FLAIR mismatch required. Prestroke mRS ≤ 2.	Superiority trial. Good functional outcome (mRS score ≤ 1) at 90 days achieved by 354/549 (64%) of tenectplase and 345/551 (63%) of alteplase groups, p = 0.52, with OR, 1.8 [0.84–1.38]	No difference in symptomatic ICH and overall mortality In moderate to severe strokes mortality increased in the TNK group (26.3% vs 9.1%; p = 0.045) at 90 days
EXTEND-IA TNK¹⁶ Phase II	2018	202	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours thrombolysis, EVT ≤ 6 hours. NIHSS: ≥ 1 ICA, M1, M2, or basilar artery occlusion on CTA or MRA Prestroke mRS ≤ 3.	The primary outcome (mTICI 2b or 3) occurred in 22/101 (22%) of patients treated with TNK vs 10/101 (10%) of those treated with r-tPA (p = 0.002 for non-inferiority; p = 0.03 for superiority)	No difference in symptomatic ICH or mortality
EXTEND-IA TNK part 2³⁰ Phase II	2020	300	TNK: 0.25 mg/kg 0.40 mg/kg	Time window: 0–4.5 hours. ICA, M1, M2, or basilar artery occlusion on CTA or MRA. TNK given before mechanical thrombectomy.	Reperfusion greater than 50% of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group. There were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups.	There were no significant differences in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, −5.6– 11.0%]) or symptomatic ICH (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, −0.5– 7.2%]).
AcT³³ Phase IIB/III	2022	1,600	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours.	mRS 0–1 at 90–120 days: 36.9% of patients in the TNK group and 34.8% patients in the alteplase group (meeting the prespecified non-inferiority threshold).	3.4% of patients in the TNK group and 3.2% of patients in the alteplase group had 24 h symptomatic ICH 15.3% in the TNK group and 15.4% in the alteplase group died within 90 days of starting treatment.
NOR-TEST 2A³² Phase III	2022	216 (stopped after safety review)	TNK: 0.4 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours. NIHSS ≥ 6. Wake-up patients: DWI/FLAIR mismatch required. Prestroke mRS ≤ 2.	mRS score of 0–1 at 90 days: 32% TNK vs 51% alteplase group (p = 0.006).	Any ICH: 21% in the TNK group and 7% in the alteplase group (p = 0.0031). Mortality at 3 months: 16% in the TNK group and 5% in the alteplase group (p = 0.013). Symptomatic ICH: 6% in the TNK group and 1% in the alteplase group (p = 0.061)
TRACE⁴⁸ Phase II	2022	240	TNK: 0.1 mg/kg 0.25 mg/kg 0.32 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–3 hours.	There was no difference in the improvement on National Institutes of Health Stroke Scale on day 14 in the 3 tiers and control group (63.3%, 77.2%, 66.7% vs 62.7%).	The number of sICH was 3 of 60 (5.0%) in the 0.1 mg/kg group, none in the 0.25 mg/kg group, 2 of 60 (3.3%) in the 0.32 mg/kg group and 1 (1.7%) of 59 in the r-tPA group. There were no significant between-group differences in severe adverse events
TASTE A¹⁷ Phase II	2022	104	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours.	On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3–28]) than with alteplase (35 mL [18–76]; adjusted incidence rate ratio 0.55, 95% CI 0.37–0.81; p = 0.0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0.70, 95% CI 0.23–2.16; p = 0.54)	Five (9%) patients allocated to tenecteplase, and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1.12, 95% CI 0.26–4.90; p = 0.88). No cases of symptomatic intracerebral hemorrhage were reported within 36 hours with either treatment.
TRACE-2¹⁸ Phase III	2023	1,430	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours. Prestroke mRS ≤ 1 NIHSS 5–25. Ineligible for mechanical thrombectomy.	mRS score of 0–1 at 90 days: 62% of the TNK group and 58% of the alteplase group (greater than the non-inferiority margin)	No difference in symptomatic ICH within 36 hours: 2% in the TNK group and 2% in the alteplase group. No difference in mortality within 90 days: 7% in the TNK group versus 5% in the alteplase group.
TWIST⁴³ Phase III	2023	578	TNK: 0.25 mg/kg control: no thrombolysis	Time window: wake-up strokes with limb weakness within 4.5 h of awakening. NIHSS ≥ 3 or aphasia. Non-contrast CT.	Treatment with tenecteplase was not associated with better functional outcome, according to mRS score at 90 days (adjusted OR 1.18, 95% CI 0.88–1.58; p = 0.27).	Mortality at 90 days did not significantly differ between groups: 10% in the TNK group and 8% in the control group (p = 0.37). Symptomatic ICH occurred in 2% of patients in the TNK group versus 1% in the control group (p = 0.28).
BRETIS-TNK Phase IIB	2023	26	AIS-LVO patients with large-artery atherosclerosis etiology	Intra-arterial TNK (4 mg) after microcatheter navigation through the clot was administered, followed by TNK (0.4 mg/min) given continuously for 20 minutes after the first retrieval attempt of EVT. Comparison: historical cohort from 2015 to 2019.	The first-pass successful reperfusion rate was higher in the TNK versus control group (53.8% versus 36%, p = 0.14), and the difference became statistically significant after propensity score matching (53.8% versus 23.1%, p = 0.03). There was a trend toward higher proportion of functional independence at 90 days in the TNK compared with the control group (50% versus 32%, p = 0.11)	There was no difference in symptomatic ICH between the TNK and control groups (7.7% versus 10.0%, p = 0.92).
ATTEST-2 Phase III	2023	1,858	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 4.5 hours.	90-day mRS score distribution: acOR 1.07 (95%CI 0.90–1.27); Non-inferiority p < 0.0001; Superiority p = 0.456	sICH (ECASS-3): 29/885 (3.3%) versus 21/891 (2.4%), OR 1.44 (95%CI 0.81–2.56), p = 0.212 mRS 5–6: 95/885 (10.7%) versus 111/891 (12.5%). Death: 68/885 (7.7%) versus 75/891 (8.4%), OR 0.96 (95%CI 0.69–1.33), p = 0.797
TIMELESS⁴⁰ Phase III	2024	458	TNK: 0.25 mg/kg Placebo	Time window: 4.5–24 hours. Prestroke mRS: ≤ 1. NIHSS: 5–25. MCA or ICA occlusion.	The adjusted common odds ratio for the distribution of scores on the mRS at 90 days for TNK as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; p = 0.45).	In the safety population, mortality at 90 days was 19.7% in the TNK group and 18.2% in the placebo group, and the incidence of symptomatic ICH was 3.2% and 2.3%, respectively.
TASTE³⁴ Phase III	2024	680	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours. Core on DWI/CTp < 70 mL. Penumbra mismatch. Ratio > 1.8 and > 15 mL volume.	Primary outcome: mRS 0–1 at 3 months (non-inferiority) - Intention to treat population: 57% TNK and 55% alteplase (OR 1.19; p = 0.03) - Per protocol population: 59% in TNK and 56% in rtPA (OR 1.27, p = 0.01)
TRACE-III⁴¹ Phase III	2024	506	TNK: 0.25 mg/kg Placebo	Time window: 4.5–24 hours. Prestroke mRS score < 1. Baseline NIHSS 6–25. Neuroimaging: ICA, MCA M1 or M2 occlusion confirmed by CTA/MRA, ICA, MCA M1 or M2 being responsible for signs and symptoms of acute stroke. Target mismatch profile on CTP or MRl + MR perfusion (ischemic core volume < 70 ml, mismatch ratio > 1.8, and mismatch volume > 15 ml).	Primary outcome: mRS 0–1 at 3 months: 33% in TNK group and 24% in rtPA group (p = 0.03)	Symptomatic ICH 3% vs 0.8% No difference in mortality.
TEMPO-2³⁶* Phase III	2024	886	TNK: 0.25 mg/kg Placebo	Time window: 0–12 hours. Prestroke mRS 0–2. NIHSS 0–5. lntracranial occlusion or focal perfusion abnormality ASPECTS > 6.	Primary outcome: return to baseline function (75% control and 72% TNK)
CHABLIS-T²⁹ Phase III	2024	86	TNK: 0.25 mg/kg 0.32 mg/kg	Time window: 4.5–24 hours. NIHSS > 5 CTA: IAO ICA, MCA M1/M2, ACA. Perfusion mismatch > 1.2, core < 70, penumbra > 10.	Primary outcome(major reperfusion without the occurrence of symptomatic ICH): 14 (32.6%) in the 0.25 mg/kg and 10 (23.3%) in the 0.32 mg/kg dosage. mRS 0–1 for 90 days. 12 (27.9%) in the 0.25 mg/kg and 21 (48.8%) in the 0.32 mg/kg dosage.	Similar rates of symptomatic ICH (4.3% vs 4.3%).
CHABLIS T II⁴²* Phase III	2024	224	TNK: 0.25 mg/kg Best medical treatment (including alteplase and thrombectomy when eligible)	Time window: 4.5–24 hours. Anterior large or medium vessel occlusion. Ischemic core volume < 70 mL, and penumbral mismatch > 10 mL measured on CTP.	The primary outcome was major reperfusion without symptomatic ICH at 24–48 hours. It was achieved in 33% of patients in the TNK group and 10% in best medical treatment group, with an adjusted risk ratio of 3.0 (95% CI, 1.5–5.7; p = 0.001). There were no significant differences between groups in secondary outcomes including NIHSS score at 24–48 hours, infarct growth at 3–5 days, and mRS score at 90 days.	There was no significant difference between groups regarding sICH at 24–48 hours, any intracranial hemorrhage, parenchymal hematoma type 2, and 90-day mRS 5–6.
ORIGINAL³⁵* Phase III	2024	1,489	TNK: 0.25 mg/kg r-tPA: 0.9 mg/kg	Time window: 0–4.5 hours.	The primary outcome was the proportion of patients with an mRS score of 0 to 1 at 90 days, with 72.7% of TNK-treated patients and 70.3% of alteplase-treated patients meeting that standard (adjusted risk ratio 1.02; 95% CI 0.96–1.09).	The rate of symptomatic intracranial hemorrhage was not significantly different between groups, irrespective of the definition use. Using ECASS III criteria, for example, the rate was 1.2% in both arms. There also were no differences between the TNK and alteplase arms in the rate of all-cause mortality at 90 days (4.6% vs 5.8%) or serious adverse events (15.8% vs 15.6%).

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[TFN1] Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator.