EXTEND-IA TNK Trial: Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke
In patients with acute ischemic stroke from an ICA, M1, M2, or basilar occlusion eligible for endovascular thrombectomy within 4.5h of onset, does tenecteplase 0.25 mg/kg single bolus before EVT achieve more substantial reperfusion than alteplase 0.9 mg/kg infusion before EVT?
Campbell BCV et al. (NEJM 2018;378(17):1573-1582) · doi:10.1056/NEJMoa1716405 · 202 patients
Population
Included
- Ischemic stroke within 4.5 hours of symptom onset
- Large-vessel occlusion on CTA: internal carotid artery, first segment of MCA (M1), second segment of MCA (M2), or basilar artery
- Eligible for IV thrombolysis per standard contraindications
- Planned endovascular thrombectomy with arterial puncture able to commence within 6 hours of stroke onset
- No upper age limit
- No NIHSS restriction
- CT-perfusion mismatch (Tmax >6s lesion volume; core <70 mL, mismatch ratio >1.2) required for the first ~80 patients; criterion removed by protocol amendment October 2016
- Ischemic stroke able to receive intravenous thrombolysis within 4.5 hours after symptom onset
- Occlusion of the internal carotid artery, the first segment (M1) or second segment (M2) of the middle cerebral artery, or the basilar artery on CT angiography
- Eligible to undergo endovascular thrombectomy, with arterial puncture able to commence within 6 hours after stroke onset
- No upper age limit
- No restriction on clinical severity as assessed by the NIHSS (range 0 to 42)
- CT-perfusion mismatch for anterior-circulation strokes (hypoperfusion defined by Tmax greater than 6 seconds; ischemic core estimated by cerebral blood flow less than 30% of normal; mismatch ratio greater than 1.2, absolute mismatch volume greater than 10 mL, ischemic core volume less than 70 mL). This entry criterion was removed by protocol amendment on October 12, 2016, after approximately 80 patients had been enrolled.
Excluded
- Severe pre-existing disability (modified Rankin scale greater than 3 before stroke)
- Standard IV thrombolysis contraindications (recent surgery, active bleeding, untreated severe hypertension, etc.)
- Severe preexisting disability, defined as a modified Rankin scale score greater than 3
- Contraindication to intravenous thrombolysis with alteplase per standard criteria
Source: Campbell BCV et al., NEJM 2018· Retrieved 2026-06-09
Primary Outcome
Substantial reperfusion at initial angiographic assessment (surrogate angiographic endpoint)
Substantial reperfusion
Sequential gatekeeping: noninferiority met first (P=0.002; CI lower bound +2 pp, well above the −2.3 pp margin), then superiority met (P=0.03). NNT ≈ 9 for the angiographic surrogate. mRS 0–2 secondary did not reach significance (64% vs 51%, aOR 1.8, P=0.06); ordinal mRS shift favored TNK (cOR 1.7, P=0.04). 90-day mortality 10% vs 18% (aRR 0.5).
Study Arms
- Agent
- Tenecteplase
- Dose
- 0.25 mg/kg (max 25 mg)
- Route
- IV
- Frequency
- Single bolus
- Duration
- One-time
- Co-interventions
- Followed by standard endovascular thrombectomy
Bridging thrombolysis given before planned thrombectomy in large-vessel occlusion. Single-bolus administration permits initiation of inter-hospital transfer before a 1-hour infusion would finish. This is the 0.25 mg/kg dose, not the 0.4 mg/kg dose studied separately in EXTEND-IA TNK Part 2.
- Agent
- Alteplase
- Dose
- 0.9 mg/kg (max 90 mg)
- Route
- IV
- Frequency
- 10% as initial bolus, then remainder over a 1-h infusion
- Duration
- 60 minutes
- Co-interventions
- Followed by standard endovascular thrombectomy
Safety
Symptomatic ICH within 36h
1%
1%
Symptomatic ICH defined as parenchymal hematoma type 2 within 36 hours, combined with NIHSS increase of at least 4 points and clinical symptoms, centrally adjudicated by a blinded panel. 1 patient each arm (1% vs 1%). The TNK patient also received intravenous heparin during carotid endarterectomy. RR 1.0 (95% CI 0.1-15.9). Source: Campbell BCV et al., NEJM 2018, Table 2 p.1578.
90-day mortality
10%
18%
90-day mortality 10% TNK vs 18% alteplase. Adjusted RR 0.5 (95% CI 0.3-1.0, P=0.049). Adjusted OR 0.4 (95% CI 0.2-1.1, P=0.08). Nominally significant on RR but not on OR; authors did not claim a mortality benefit because the prespecified logistic-regression analysis did not reach significance. Source: Campbell BCV et al., NEJM 2018, Table 2.
Parenchymal hematoma
6%
5%
Parenchymal hematoma defined as intraparenchymal blood clot with mass effect. 6 (6%) TNK vs 5 (5%) alteplase. RR 1.2 (95% CI 0.4-3.8). No significant difference. Source: Campbell BCV et al., NEJM 2018, Table 2.
Trial Design
Type
- Investigator-initiated multicenter prospective RCT
- Open-label with blinded outcome assessment (PROBE design)
- 1:1 randomization stratified by site of vessel occlusion
- Sequential gatekeeping: noninferiority then superiority (NI margin -2.3 pp)
- Blinded adaptive sample-size re-estimation after 100 patients
Timeline
Enrolled March 2015 to October 2017
N
202
Enrollment
202 patients (101 TNK / 101 alteplase, ITT) at 12 Australian + 1 New Zealand sites. PROBE design (open-label, blinded outcome assessment). Enrolled March 2015 to October 2017. Blinded adaptive sample-size re-estimation after 100 patients set final size at 202. CT-perfusion mismatch entry criterion removed by amendment after ~80 patients. Published NEJM 2018.
ClinicalTrials.gov
NCT02388061Bedside Pearl
For an EVT-eligible LVO patient within 4.5 hours of onset, TNK 0.25 mg/kg as a single IV bolus (max 25 mg) achieved substantial angiographic reperfusion in 22% before EVT vs 10% with alteplase 0.9 mg/kg (absolute difference 12 pp, P=0.002 for NI, P=0.03 for superiority). Ordinal mRS shift favored TNK at 90 days (common OR 1.7, P=0.04). Symptomatic ICH 1% in both arms. The single-bolus administration also accelerates inter-hospital transfer logistics. TNK 0.25 mg/kg is the preferred IVT agent before EVT in modern practice (AHA/ASA 2026 §4.6.2 Class I, Level A).