Over the past 30 years, alteplase has been the cornerstone of acute ischemic stroke treatment. In 1995, the NINDS trial was the first to demonstrate that alteplase, when administered within 3 hours of stroke onset, improved functional outcomes (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995). In 2008, the ECASS-III trial showed benefit up to 4.5 hours after symptom onset, leading to an extension of the treatment window (Hacke, 2008). More recently, the indications for alteplase have been further expanded. With the use of advanced imaging techniques, it is now possible to identify patients with a last-known-well time of up to 12 or even 24 hours, or with an unknown time of onset, in whom alteplase can be used safely and effectively (Thomalla, 2018; Ma, 2019; Zhou, 2025). However, alteplase has some limitations. The complex administration, consisting of an initial bolus and continuous infusion, and the modest fibrin specificity, prompted the search for an alternative drug. Tenecteplase, a genetically modified tissue plasminogen activator, has a greater fibrin specificity and may therefore achieve higher rates of recanalization. Tenecteplase has a longer half-life, allowing a single bolus administration. The combination of easier administration and the potential for higher efficacy makes tenecteplase an option for replacing alteplase in daily practice.

Summary of Findings

Population: Patients with acute stroke

Intervention: Treatment with IV tenecteplase

Comparator: Treatment with IV alteplase

_{^1. Imprecision: serious. Due to overlap of the upper or lower limit of the 95% confidence interval with the minimal clinically important difference.}

_{^2. Imprecision: very serious. Due to overlap of the upper and lower limit of the 95% confidence interval with the minimal clinically important difference.}

Description of studies

One systematic review was included in the analysis of the literature. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

The systematic review and meta-analysis of Palaiodimou (2024) aimed to assess the efficacy and safety of tenecteplase (TNK) versus tissue plasminogen activator (TPA) during intravenous thrombolysis for acute ischemic stroke (AIS) within the first 4.5 hours after onset. The authors searched MEDLINE and Scopus for RCTs from inception to 16 May 2024. Studies involving adult patients with AIS who were eligible for intravenous thrombolysis within 4.5 hours of symptom onset, treated with 0.25 mg/kg TNK versus 0.9 mg/kg TPA, and reporting functional outcomes at follow-up were included. No restrictions on language or other criteria were imposed, and the reference lists of published articles and international conference abstracts were manually reviewed to ensure the bibliography was comprehensive. Observational cohort studies, uncontrolled studies, case series, case reports, commentaries, editorials, and narrative reviews were excluded. In total, 11 studies were included. Outcomes of interest were functional recovery, mortality, and symptomatic intracranial hemorrhage.

Table 2. Characteristics of included studies

_{*For further details, see risk of bias table in the appendix}

Results

1. Functional outcome (crucial)

1.1 Excellent functional recovery
Palaiodimou (2024) included eleven studies that reported excellent functional outcome at 3 months defined as a modified Rankin Scale (mRS) score ≤1 (Figure 1a). In total, 1980 of the 3722 patients (53.2%) who received tenecteplase had excellent functional outcome at 3 months as compared to 1855 of the 3679 patients (50.4%) who received alteplase (RR=1.05, 95%CI 1.01 to 1.10). This corresponded to an absolute risk difference of 0.02 (95%CI 0.00 to 0.04). This is non-inferior. 

_{Figure 1a. Excellent functional recovery}

1.2 Good functional outcome
Palaiodimou (2024) included eleven studies that reported good functional outcome at 3 months defined as mRS ≤2 (Figure 1b). In total, 2571 of the 3722 patients (69.1%) who received tenecteplase had good functional outcome at 3 months as compared to 2468 of the 3678 patients (67.1%) who received alteplase (RR=1.03, 95%CI 0.99 to 1.07). This corresponded to an absolute risk difference of 0.02 (95%CI -0.00 to 0.04). This is non-inferior.

_{Figure 1b. Good functional outcome}

2. Mortality (crucial)

Palaiodimou (2024) included eleven studies that reported mortality at 3 months (Figure 2). In total, 325 of the 3775 patients (8.6%) who received tenecteplase died as compared to 331 of the 3747 patients (8.8%) who received alteplase (RR=0.97, 95%CI 0.82 to 1.15). This corresponded to an absolute risk difference of -0.00 (95%CI -0.02 to 0.02).This is non-inferior.

_{Figure 2. Mortality}

3. Symptomatic Intracranial haemorrhage (important)

Palaiodimou (2024) included eleven studies that reported symptomatic intracranial haemorrhage (Figure 3). Eighty-five of the 3786 patients (2.2%) who received tenecteplase had symptomatic intracranial haemorrhage as compared to 75 of the 3749 (2.0%) who received alteplase (RR=1.12, 95%CI 0.83 to 1.53). This corresponded to an absolute risk difference of 0.01 (95%CI -0.02 to 0.05). This is non-inferior.

 _{Figure 3. Symptomatic intracranial haemorrhage}

A systematic review of the literature was performed to answer the following question(s):

• Is tenecteplase safe and effective as a thrombolytic compared to alteplase in patients with an acute ischaemic stroke <4.5 hours after the onset of symptoms?
• Is tenecteplase safe and effective as a thrombolytic compared to alteplase in patients with an acute ischaemic stroke 4.5-12 hours after the onset of symptoms, or if the time of onset is unknown, in patients selected with additional imaging?

Table 1. PICO

Relevant outcome measures

The guideline panel considered functional outcome and mortality rates as critical outcome measures for decision making; and symptomatic intracranial hemorrhage and degree of reperfusion as an important outcome measure for decision making.

The guideline panel defined the outcome measures as follows:

• Functional outcome: excellent functional outcome (mRS 0-1) or good functional outcome (mRS 0-2) at 90 days.
• Mortality: death (mRS 6) at 90 days.
• Symptomatic intracranial haemorrhage (sICH) at 24–48 h.
• Degree of Reperfusion: defined as grade 2b or 3 on the modified Treatment in Cerebral Ischemia (mTICI) scale (reperfusion of greater than 50% in the involved ischaemic territory).

The guideline panel defined an absolute difference of 3% for functional outcome (RD <-0.03 or >0.03) and 1% for mortality, symptomatic intracranial haemorrhage and reperfusion (RD <-0.01 or >0.01) as a minimal clinically (patient) important difference. *Non-inferiority was concluded when the upper bound of the confidence interval remained below the prespecified limit.

_{*‘Non-inferiority design’ = een onderzoeksopzet waarbij het doel is om aan te tonen dat een nieuwe behandeling of interventie niet slechter is dan de bestaande standaardbehandeling, binnen een vooraf gedefinieerde marge.}

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 2018 to 6-6-2025 for systematic reviews and RCTs. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from the following primary search concepts: (1) brain infarction (2) Tenecteplase. Duplicates were removed using EndNote software. After deduplication a total of 313 records were imported for title/abstract screening. Initially, ten studies were selected based on title and abstract screening. After reading the full text, nine studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and one systematic review was included.

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