Tenecteplase in Minor Stroke: Does Vessel Occlusion Change the Answer? — TEMPO-2 Secondary Analysis

Clinical Question (PICO)

In adults with minor acute ischemic stroke (NIHSS 0–5) within 12 hours and either intracranial arterial occlusion or a concordant focal perfusion deficit, does IV tenecteplase 0.25 mg/kg, compared with standard care without thrombolysis, improve return to pre-stroke functional status at 90 days? This prespecified secondary analysis examined complete occlusion, near occlusion, and no visible occlusion with a focal perfusion abnormality; exploratory treatment interactions were also examined within these strata.

Bottom Line

Baseline vessel status did not identify a subgroup with a demonstrated 90-day benefit from tenecteplase. Responder rates were 76.4% versus 73.8% without visible occlusion, 66.3% versus 80.4% with near occlusion, and 71.3% versus 72.5% with complete occlusion (tenecteplase versus control); adjusted risk ratios were 1.03, 0.85, and 1.00, respectively. These data do not resolve treatment for disabling deficits or the relatively uncommon large-vessel occlusion with mild symptoms.

Design

Trial type: Prespecified, exploratory secondary analysis of TEMPO-2, a multicenter randomized, open-label, blinded-endpoint superiority trial (PROBE); imaging was centrally assessed by a reader blinded to clinical information.
N: 886 randomized in the parent trial; 881 evaluable here (2 consent withdrawals and 3 unavailable/unevaluable scans).
- Tenecteplase: 431 (123 no visible occlusion, 92 near occlusion, 216 complete occlusion).
- Standard care: 450 (130 no visible occlusion, 102 near occlusion, 218 complete occlusion).
Randomization: 1:1 in the parent trial; its minimization algorithm used age, sex, NIHSS, and onset-to-randomization time, variables included in adjusted analyses. These occlusion-status strata were not separately randomized.
Setting: 48 hospitals in Australia, Europe, North America, South America, and Asia.
Enrollment: Dates not reported in this secondary-analysis article; consult the parent TEMPO-2 report for the recruitment interval.
Mean follow-up: The specified endpoint was at 90 days; mean observed follow-up was not reported.
Analysis: Intention to treat within baseline-imaging strata; adjusted Poisson generalized linear models with robust standard errors for risk ratios, Cox model for mortality. No multiplicity correction. Missing primary outcomes after loss to follow-up were counted as non-response; two consent withdrawals were not imputed.
Primary outcome: Responder at day 90: mRS 0–1 if pre-stroke mRS was 0–1, or mRS 0–2 if pre-stroke mRS was 2, assessed by a blinded investigator.

Population

Inclusion Criteria

Age at least 18 years; acute ischemic stroke with NIHSS 0–5; pre-stroke mRS 0–2; presentation within 12 hours of last known well.
Concordant angiographic intracranial occlusion or a locally identified focal CT/MR perfusion abnormality; no established infarct concordant with acute symptoms; baseline ASPECTS at least 7.

Exclusion Criteria

Standard contraindications to intravenous thrombolysis other than the extended time window; patients lacking evaluable baseline imaging or withdrawing consent were excluded from this analysis.
Full screening exclusions are in the parent protocol, not enumerated in this secondary report.

Baseline Characteristics (overall or representative arm)

Median baseline NIHSS was 2 (IQR 1–3) in each treatment arm of each imaging stratum; median ages across strata and arms were 70–74 years.
Complete occlusion: 434 patients; 16.8% large-vessel, 76.0% medium-vessel, 7.1% vertebrobasilar occlusion. Near occlusion: 194 patients; 15.5%, 77.3%, and 7.2%, respectively. No visible occlusion with perfusion abnormality: 253 patients.
Within complete occlusion, tenecteplase recipients were older and more often hypertensive than controls; in near occlusion, control-arm onset-to-treatment times were longer.

Interventions

Tenecteplase: IV 0.25 mg/kg once, with otherwise standard stroke-unit care.
Control: No thrombolysis; clinician-selected single or dual antiplatelet therapy or anticoagulation per usual care, plus standard stroke-unit care. The article does not provide a uniform antithrombotic regimen for this comparator.

Outcomes

Primary Outcome (return to pre-stroke mRS category or better at 90 days; prespecified vessel-status strata):

No visible occlusion / focal perfusion abnormality: 94/123 (76.4%) with tenecteplase vs 96/130 (73.8%) with control; adjusted RR 1.03 (95% CI 0.90–1.18), absolute difference +2.6 percentage points.
Near occlusion: 61/92 (66.3%) vs 82/102 (80.4%); adjusted RR 0.85 (95% CI 0.71–1.01), absolute difference −14.1 points. The unadjusted RR was 0.82 (95% CI 0.69–0.98); the adjusted interval includes 1.
Complete occlusion: 154/216 (71.3%) vs 158/218 (72.5%); adjusted RR 1.00 (95% CI 0.89–1.12), absolute difference −1.2 points.
P values: Subgroup-specific primary-outcome P values are not reported in the article. Do not treat the near-occlusion unadjusted interval or nominal secondary-endpoint P values as a prespecified efficacy finding.

Secondary Outcomes:

In complete occlusion, mRS 0–2 occurred in 81.0% vs 88.5% (adjusted RR 0.93, 95% CI 0.86–1.00; −7.5 points). Instrumental daily-living functioning was lower with tenecteplase in both near and complete occlusion; quality-of-life measures favored control in near occlusion. These are multiple, exploratory comparisons.
Parent-trial follow-up angiography found more recanalization with tenecteplase than control among patients with baseline occlusion (48% vs 22%), without a corresponding clinical benefit in this secondary analysis.
Within complete occlusion, an age-by-treatment interaction was reported (P < .001): adjusted RR 1.13 (95% CI 1.01–1.28) at age ≤80 and 0.60 (0.44–0.84) at >80. Sex (P = .024) and onset-time (P = .041) interactions were also reported, but their individual strata had no significant between-treatment differences. These nested, uncorrected analyses are hypothesis-generating, not selection rules.

Adverse Events / Safety:

Symptomatic ICH at 24 hours: no visible occlusion 2/123 (1.6%) vs 1/130 (0.8%); near occlusion 2/92 (2.2%) vs 0/102; complete occlusion 4/216 (1.9%) vs 1/218 (0.5%). These subgroup differences were not statistically significant.
Near occlusion: 90-day death 6/92 (6.5%) vs 0/102 (P = .010), serious adverse events 24/92 (26.1%) vs 14/102 (13.7%; P = .045). Both P values are nominal and uncorrected; the mortality mechanism cannot be attributed solely to sICH.

Figures

Distribution of 90-day modified Rankin scores by vessel-occlusion status and treatment — *Figure 1.* Distribution of the 90-day mRS in patients treated with tenecteplase versus control, stratified by vessel occlusion status. TNK = tenecteplase.

Forest plots of 90-day recovery by treatment across vessel-status subgroups — *Figure 2.* Forest plots of return to baseline neurological functioning or better, separately for (A) focal perfusion abnormality without visible occlusion, (B) near occlusion, and (C) complete occlusion. The article describes adjusted risk ratios for these subgroup analyses; see Methods for the full adjustment set.

Criticisms

The parent trial was randomized, but this secondary analysis was not powered for three imaging strata or their nested age/sex/time comparisons; uncorrected multiplicity makes isolated positive or harmful subgroup signals fragile.
Imbalances in age, hypertension, creatinine, and onset-to-treatment time within strata complicate inference despite adjustment. Occlusion groups also differed greatly in size; few had proximal LVO and none had basilar occlusion.
Missing primary outcomes after loss to follow-up were coded as failures, while two consent withdrawals and three imaging exclusions were removed. The article does not quantify all follow-up missingness here.
Comparator antithrombotics varied by clinician; the imaging criterion included focal perfusion deficits without a visible occlusion. The trial does not answer a pure IV-lysis-versus-DAPT or a thrombectomy-selection question.
The authors’ broad conclusion about all minor stroke should be narrowed at the bedside: mild NIHSS does not guarantee a nondisabling deficit, and the analysis cannot exclude a meaningful effect in the underrepresented mild proximal-LVO subgroup.

Funding

TEMPO-2 was supported by the Canadian Institutes for Health Research, Heart & Stroke Foundation of Canada, and British Heart Foundation. Boehringer Ingelheim provided the drug via a cost-recovery grant to the University of Calgary; the investigators describe the study as independent and report that the company had no role in design, analysis, or interpretation, though it could review the manuscript for medical/scientific accuracy and intellectual-property considerations. Registration: NCT02398656.

The paper

Authors. Räty S et al.
Title. Tenecteplase versus standard care for minor ischaemic stroke according to the baseline occlusion status in TEMPO-2 trial.
Journal. European Stroke Journal.
Year. 2026.
DOI. 10.1093/esj/aakag111
PMCID. PMC13573578

Deep Dive — click to expand

What this is

Published in September 2026, this prespecified secondary analysis asks whether TEMPO-2’s neutral overall result concealed a useful imaging-defined indication for tenecteplase in minor stroke. It did not: complete occlusion, near occlusion, and isolated perfusion abnormality all lacked a demonstrated primary-outcome advantage. The finding matters because an angiographic clot can feel like a compelling reason to lyse, even when the presenting deficit is mild and the balance of benefit and bleeding risk remains uncertain.

1. Shadow Audit

The headline “no vessel-status interaction worth acting on” obscures a directional near-occlusion signal: the primary responder rate was 66.3% with tenecteplase versus 80.4% with control, a 14.1-point deficit, although the adjusted RR interval (0.71–1.01) crosses unity. Six versus zero deaths by 90 days in that stratum (nominal P = .010), and 24 versus 14 serious adverse events, add concern without proving causation. Conversely, the seemingly reassuring complete-occlusion neutral result mostly describes medium-vessel occlusions (76%), not proximal LVO; treating it as a definitive LVO result would hide the sample’s composition. The parent trial’s 48% versus 22% recanalization contrast did not translate into functional rescue here.

2. Inversion Engine

For tenecteplase to be justified because a vessel is visibly occluded, a clinically important 90-day benefit must emerge in a reproducible occlusion-defined population that this trial diluted or could not power, with benefit exceeding sICH risk. In complete occlusion the observed adjusted RR is 1.00 (95% CI 0.89–1.12); a true large benefit, such as a roughly 10-point absolute gain on a 72.5% control response rate, would require a risk ratio near 1.14, outside that whole-stratum interval, but could still be confined to the small proximal-LVO subset. For near occlusion the observed direction must reverse a 14.1-point absolute disadvantage before a positive net-benefit case even begins. These are interpretation thresholds, not formal power calculations or new trial estimates.

3. Second-Order Catalyst

The first practical mover is an acute-stroke pathway that currently interprets “CTA clot present” as sufficient authorization for lysis in an otherwise mild, nondisabling presentation. Add explicit documentation of disability, vessel location, perfusion findings, and thrombectomy candidacy, rather than allowing the imaging label alone to determine IV treatment. A protocol committee can audit such decisions promptly; it should not use this secondary analysis to withdraw thrombolysis from patients with disabling symptoms or to foreclose evaluation of mild proximal LVO.

4. Asymmetric Leverage

The leverage is in a frequent decision, not a spectacular subgroup cure: many patients arrive with NIHSS ≤5, and a small unnecessary-treatment rate across that denominator could mean avoidable hemorrhage, costs, and monitoring. But the converse asymmetry matters too: missing a genuinely disabling deficit or a threatened proximal-LVO patient can impose a much larger individual loss. The rational filter is clinical disability plus vascular anatomy, not an indiscriminate “mild stroke = no treatment” rule.

5. Paradigm Destroyer

This paper weakens the reflex “visible occlusion means tenecteplase must help” in unselected minor stroke. A two-sentence protocol edit: For NIHSS 0–5, do not use baseline intracranial occlusion or isolated perfusion abnormality by itself as the rationale for IV tenecteplase; document whether the deficit is disabling and evaluate proximal occlusion separately. If the deficit is disabling or proximal-LVO/endovascular eligibility is in question, obtain urgent stroke-team review under the applicable reperfusion pathway rather than applying this secondary analysis as an exclusion rule.

MVP — Minimum Viable Proof

In 881 imaging-evaluable TEMPO-2 patients with minor stroke, none of the three prespecified baseline-vessel-status strata showed an adjusted 90-day responder advantage for tenecteplase; the complete-occlusion stratum had adjusted RR 1.00 (0.89–1.12). That is sufficient to challenge occlusion alone as a treatment trigger, not sufficient to settle every disabling minor stroke or proximal-LVO case.

Best Combination

Read this against TEMPO-2’s neutral parent result and the prior minor-stroke comparisons of thrombolysis with non-thrombolytic regimens, including PRISMS and ARAMIS. It adds an imaging modifier that was often missing from earlier trials, while leaving large-vessel, disabling, and antithrombotic-regimen-specific questions for purpose-built analyses. Mechanistic recanalization is not a surrogate for patient-valued 90-day recovery, especially when most observed occlusions are distal.

Overvalue Warning

Do not turn the age >80 interaction (adjusted RR 0.60), near-occlusion mortality P = .010, or the complete-occlusion mRS 0–2 secondary endpoint into a proven causal subgroup rule: these are multiple exploratory comparisons without multiplicity adjustment.
Do not read “no benefit despite occlusion” as “never lyse a mild-NIHSS patient” or “proximal LVO does not matter”: the trial included few proximal LVOs, no basilar occlusions, and cannot replace a disability assessment.

Educational use notice. The Clotbust Review is dedicated to medical education. Figures from published articles are embedded for teaching purposes, with attribution to the original publication. We do not claim copyright over any embedded figure; all rights remain with the original publisher and authors under the article's published license. If you are a rights holder and would like a figure removed, please contact the editorial team. See our editorial notice for the full policy.