IJCDS

Introduction

Acute ischemic stroke (AIS) is a significant cause of morbidity and mortality in the United States [1].  The 2019 American Heart Association (AHA)/American Stroke Association (ASA) Guidelines for the Early Management of Patients with AIS recommend intravenous (IV) thrombolytic therapy for patients presenting within 4.5 hours of symptom onset [2]. Thrombolysis serves to prevent further cerebral ischemic damage and restore intracranial blood flow to the affected area [3]. While alteplase has been the historic standard of care, these guidelines also state that tenecteplase may be considered in select patient groups [2].

Tenecteplase, a thrombolytic approved by the United States Food and Drug Administration for ST-elevation myocardial infarction and AIS (as of March 4, 2025), offers several advantages over alteplase, including IV push administration and potential cost savings [4]. Additionally, due to genetic modification of tissue plasminogen activator (t-PA), tenecteplase has a 15-fold higher fibrin specificity and a 6-fold prolonged plasma half-life compared to alteplase [5]. This theoretically leads to more effective thrombus targeting. Tenecteplase also exhibits increased resistance to plasminogen activator inhibitor 1 (PAI-1) [5].  The increase in PAI-1 resistance allows the thrombolytic effect to be achieved with a lower dose of medication. Coupled with higher fibrin specificity, these attributes of the drug may lead to a lower risk of bleeding complications following administration [5].

Bleeding complications, such as intracranial hemorrhage (ICH), including hemorrhagic conversion following AIS, may lead to significant morbidity or mortality. During AIS, there is an early disruption in the blood-brain barrier secondary to an increase in the enzyme matrix metalloproteinase-9 (MMP-9) [6]. The increase in MMP-9 may allow blood to leak into brain tissue, causing hemorrhagic transformation [6]. Any patient with AIS is at risk for an ICH; however, the timeframe for this risk may vary depending on the interventions received. In patients who receive a thrombolytic, hemorrhagic conversion is often noted within the first 24 hours, with a decreasing risk after 36 hours [6]. If the patient undergoes a mechanical thrombectomy, there is a higher risk of hemorrhagic transformation within the first 24 hours [6].

There is evidence to suggest that tenecteplase may be as safe and efficacious as alteplase. The ATTEST trial, published in 2015, examined penumbral salvage in adult patients with supratentorial AIS receiving alteplase or tenecteplase 0.25 milligrams per kilogram (mg/kg) and identified no difference in penumbral salvage or serious adverse events [7]. NOR-TEST then analyzed thrombolytic-eligible adults who received alteplase or tenecteplase 0.4 mg/kg for functional outcomes (Modified Rankin Scale; mRS) at 3 months and showed no difference in efficacy with a similar safety profile, even at a higher tenecteplase dose [8].  EXTENDIA TNK narrowed the population to include only thrombectomyeligible adults with AIS secondary to a large vessel occlusion [9]. Tenecteplase 0.25 mg/kg was superior to alteplase for the primary outcome of reperfusion of >50% of involved ischemic territory or absence of retrievable thrombus at time of initial angiographic assessment (22% vs. 10%, 95% CI 1.1 to 4.4) [9].  Additionally, patients who received tenecteplase had significantly better 90day functional outcomes without an increased risk of bleeding [9].  The largest trial to date, the AcT trial, included 1,600 adult patients and found that tenecteplase was non-inferior to alteplase for the primary outcome of mRS of 0–1 at 90–120 days (36.9% vs. 34.8%, 95% CI -2.6 to 6.9) [10]. Additionally, no difference in symptomatic ICH or 90-day mortality was noted [10].

Based on the previous literature, the preferred thrombolytic agent for AIS at the trial site, an academic medical center and nationally certified Primary Stroke Center, transitioned from alteplase to tenecteplase in July 2023. The purpose of this study was to examine the safety of tenecteplase compared to alteplase in patients with AIS.

Methods

This Institutional Review Board-approved, single-center, retrospective cohort study reviewed patients admitted between June 30, 2022, and June 30, 2024. Patients were identified via an electronic medical record query and manual chart review. Eligible patients were those who were at least 18 years old and who received tenecteplase or alteplase for AIS. Patients were excluded if they were incarcerated pregnant or if they received the thrombolytic for an indication other than AIS. For AIS, tenecteplase was dosed at 0.25 mg/kg (maximum 25 mg) and alteplase was dosed at 0.9 mg/ kg (maximum 90 mg).

The primary outcome of this study was the incidence of major bleeding within 24 hours of receiving a thrombolytic. Major bleeding was defined as a new ICH on follow-up imaging or the need for blood transfusion due to an acute decrease in hemoglobin of at least 2 g/dL. Secondary outcomes included any bleeding event during admission, hypersensitivity reactions, angioedema, intensive care unit (ICU) length of stay, and in hospital-mortality. Baseline characteristics collected for each patient included age, weight, height, body mass index (BMI), gender, race, National Institutes of Health Stroke Scale (NIHSS) at admission, Modified Rankin Scale (mRS) at admission, blood glucose at admission, international normalized ratio (INR), and home medications of interest.

Data was analyzed using descriptive statistics for demographic data, and the primary outcome was analyzed using Fisher’s exact test. Other nominal data were analyzed using Fisher’s exact test or chi-square test, as appropriate. Continuous data were analyzed using the Mann-Whitney U test. A P-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using IBM® SPSS® Statistics for Windows (version 28.0, Armonk, NY).

Results

An initial patient list generated from the electronic medical record identified 125 thrombolytic administrations within the study period. After screening for inclusion and exclusion criteria, there were 71 eligible patients (Figure 1). Of the patients included, 42 patients (59%) received tenecteplase and 29 patients (41%) received alteplase.

Figure 1: Flow chart showing final cohort assignments for patients based on inclusion and exclusion criteria.

Baseline characteristics were compared between patients receiving tenecteplase and alteplase (Table 1). There was a significant difference noted when comparing baseline NIHSS (8 vs. 5, P = 0.04). All other characteristics were non-significant. When assessing past medical history, five patients in the tenecteplase group had a history of atrial fibrillation compared to zero patients in the alteplase group (12% vs. 0%, P = 0.074). Likewise, more patients in the tenecteplase group had a past medical history of stroke [n = 15 (35.7%) vs. n = 8 (27.6%), P = 0.472]. When assessing home medications, three patients in the tenecteplase group and one in the alteplase group were prescribed anticoagulation outpatient.

Table 1: Baseline Characteristics

The primary outcome, major bleeding within 24 hours of thrombolytic administration, occurred in six patients in the tenecteplase group and one in the alteplase group (14% vs. 3%, P = 0.228; (Table 2)). Major bleeding events included hemorrhagic transformation (tenecteplase n = 4), parenchymal hematoma (tenecteplase n = 1, alteplase n = 1), and subarachnoid hemorrhage (tenecteplase n = 1). No patients met the definition of major bleeding secondary to blood transfusion requirements. Other bleeding events during admission were experienced by two patients who received tenecteplase and one who received alteplase (any bleeding event during admission: n = 8 (19%) vs. n = 2 (7%), P = 0.511). The additional bleeding events in the tenecteplase group were scattered petechial hemorrhage within the subarachnoid space at greater than 24-hours and superficial bleeding, bruising, and vaginal bleeding. In the alteplase group, a patient developed a supraorbital hematoma post-alteplase administration in the setting of presenting secondary to a fall with facial trauma. The median ICU length of stay was two days (IQR 1-3) for both groups (P = 0.983). Two in-hospital deaths occurred in the tenecteplase group, and zero deaths occurred in the alteplase group (5% vs. 0%, P = 0.510). None of the deaths were attributable to the thrombolytic administration. There were no reported incidences of angioedema or hypersensitivity reactions in the study population.

Table 2: Primary and Secondary Outcomes