Safe and Effective Administration of Tenecteplase in Pediatric Patients for Acute Ischemic Stroke

Authors: Elizabeth Davis, PharmD, BCPS, BCPP¹; Brian Hazelrigg, PharmD¹; Sarah Schepers, PharmD, BCPS¹; Jan Kornilow, MD, FACEP, FAAEM, FAEMS, FAOM, MDI^1,2; Hal Dickson, MD¹; Andrew Flack, MD¹; John Wulff, MD¹

Author Affiliations:
¹Indiana University Health Ball Memorial Hospital; Muncie, IN
²Indiana University School of Medicine; Muncie, IN

Abstract

Pediatric acute ischemic stroke (AIS) is an uncommon presentation to the emergency department (ED). Currently, the recommended fibrinolytic treatment option for pediatric AIS is alteplase, and there is limited safety, efficacy, or dosing information for Tenecteplase in the pediatric population.^1,2 Some health systems are choosing to switch fibrinolytic therapy for adult AIS to Tenecteplase due to its favorable dosing, administration, and pharmacokinetic profile. This presents a challenge with ED staff becoming more unfamiliar with alteplase and leading to a possible knowledge gap in management of pediatric stroke. This case report describes two successful administrations and neurologic recovery post Tenecteplase administration for pediatric AIS.

Introduction

Acute ischemic strokes in the pediatric population are relatively uncommon and often get misdiagnosed, given the wide range of etiologies for symptom presentation. The incidence of pediatric stroke is estimated to range from 2.5-13 per 100,000 per year, with increasing incidence each year.^3,4 Currently, the recommended fibrinolytic agent for confirmed AIS in the pediatric population is alteplase.¹ While alteplase still does not have FDA approval for use in pediatric stroke, there is available safety data supporting its use in this population. The study by Amlie-Lefond et al. provided safety data on 26 children treated with alteplase, where no patients developed symptomatic intracranial hemorrhage (SICH). An estimated risk of SICH was calculated to be 2.1%.⁵ In the study by Kossorotoff et al. SICH was observed in 1.8% of patients enrolled, further citing low bleed risk in this population.⁶ Tenecteplase is a fibrin-specific tissue-type plasminogen activator that binds to fibrin rich clots and converts plasminogen to plasmin.^7,8

Clinical trials in adult patients have shown Tenecteplase to be non-inferior to alteplase, with similar safety profiles, further supporting its use.^9,10,11,12 Given its advantageous administration, dosing and pharmacokinetic profile, Tenecteplase has become the agent of choice for AIS in the adult population at some stroke centers. Currently, there is limited safety, efficacy, or dosing information for Tenecteplase in the pediatric population.^13,14 Table 1 provides a current summary of the available literature regarding the use of Tenecteplase in pediatrics. These two additional case reports add to the literature where Tenecteplase may be considered as a safe alternative fibrinolytic therapy for pediatric AIS.

Case Reports

Case 1

A 15-year-old male with past medical history significant for fibromyalgia, migraines, and depression, presented via EMS to the ED due to abrupt onset of loss of strength in the face, left upper and lower extremities, and slurred speech, with brief improvement then worsening. The patient denied headache and reported no atypical symptoms with previous migraines. The patient’s last known normal was 60 minutes prior to arrival. Vital signs on arrival were as follows: oral temperature 37°C, heart rate of 81 beats/min, respiratory rate 16 breaths/min, blood pressure 131/102 mmHg, blood glucose of 94, and weight of 96.3kg. Initial NIH Stroke Scale (NIHSS) score on arrival was 11 for left sided facial droop, dysarthria, and left sided hemiparesis. Computed tomography (CT) scan showed no acute intracranial hemorrhage or evidence of acute large territorial infarct. Computed tomographic angiography (CTA) of the head/neck showed no major intracranial or cervical artery occlusion or significant stenosis.

The pediatric neurology team was consulted at an associated level 1 pediatric hospital who recommended transfer for further monitoring. The patient was still experiencing significant deficits and was assessed by in-house neurology staff. The use of fibrinolytic therapy was then discussed with the patient and guardians. The patient and guardians wished to proceed with fibrinolytic therapy. All labs were within normal limits and blood pressure prior to administration was 121/83 mmHg. No absolute contraindications to Tenecteplase identified. Tenecteplase 0.25mg/kg (24mg) was given, with a door to needle time of 1 hour and 12 minutes. The patient was then transferred to a pediatric hospital for continued monitoring.

Upon arrival to the pediatric ED the patient had almost complete symptom resolution, with only left lower extremity weakness, repeat NIHSS score of 2. Magnetic resonance imaging (MRI) 24 hours post Tenecteplase administration showed acute infarct involving the right caudate and putamen. The patient continued to improve with complete symptom resolution upon discharge. Post stroke workup included thrombotic studies, ECHO, and EEG. Thrombotic studies were within normal limits for antithrombin III, protein C & S. The patient was negative for Factor V Leiden or prothrombin gene mutation, antiphospholipid antibodies, beta-2 glycoprotein, and lupus anticoagulant were within normal limits. EEG showed no electrographic seizures or epileptiform discharges, and the ECHO showed normal cardiac anatomy and function. The patient was started on aspirin 325mg (3.3mg/kg) by mouth daily for secondary stroke prevention.

Case 2

A 17-year-old male with past medical history of reported heart murmur in early childhood presented via EMS to the ED due to rapid onset of slurred speech, light headedness, and significant right sided weakness while playing video games. The patient was last known to be normal approximately 40 minutes prior to arrival in the ED. The stroke team was subsequently activated based on the patient’s presentation. Vital signs on arrival were as follows: Oral temperature 37.6°C, heart rate of 107 beats/min, respiratory rate of 18 breaths/min, blood pressure of 110/83mmHg, blood glucose of 94mg/dL, and weight of 60.2kg. Initial NIHSS score on arrival was 5 for right-sided drift in both extremities and mild/moderate sensory loss. CT scan of the head showed no acute intracranial hemorrhage, mass effect, or evidence of acute large territorial infarct. CTA of the head and neck showed no large vessel occlusive disease. A point of care basic metabolic panel was done, and all labs returned within normal limits.

The patient was examined by house neurology staff and continued to exhibit significant one-sided weakness. At this time the use of fibrinolytics was discussed with the patient’s family given concern for acute ischemic stroke. Risk and benefits of fibrinolytic therapy were discussed with patient, grandmother, and father who agreed to proceed with Tenecteplase administration. No absolute contraindications to Tenecteplase were identified. Patient received 15mg (0.25mg/kg) with a door to needle time of approximately 34 minutes. Blood pressure prior to administration was 129/82 mmHg. The patient was subsequently transferred to an associated level 1 pediatric hospital for continued monitoring.

Upon arrival at level 1 pediatric hospital, the patient’s symptoms had mostly resolved, with a repeat NIHSS score of 0. MRI of the brain the next day (approximately 15 hours post symptom onset) showed a small acute infarct of the left periventricular region involving the left caudate body and extending into the left corona radiata. Post stroke work up including thrombotic studies, ECHO, and extremity dopplers. Thrombotic studies were within normal limits for AT III, protein C & S. The patient was negative for FVL or PT gene mutation, antiphospholipid antibodies, beta-2 glycoprotein, and lupus anticoagulant were within normal limits. The patient’s echocardiogram showed tiny secundum atrial septal defect with left to right shunting. Ultrasounds of all four extremities were performed to rule out additional thrombi that could have embolized causing the acute stroke but were all negative. The patient was started on aspirin 325mg (6mg/kg) by mouth daily for secondary stroke prevention. Patient discharged from hospital two days after transfer with return to neurologic baseline and plans for outpatient assessment for atrial septal defect closure with cardiology.

Discussion

The current literature surrounding Tenecteplase use in the pediatric population is limited. Both patients described were treated with single dose Tenecteplase at 0.25mg/kg. Both patients tolerated the treatment well with no complications and almost complete symptom resolution upon arrival to the pediatric ED. The decision to choose Tenecteplase over alteplase came down to several factors including availability of Tenecteplase in the ED vs an infusion that would have to be made and delivered to the ED, ease of administration, and familiarity of Tenecteplase by ED nurses, and patient specific factors such as age and weight. The current guidelines suggest vascular imaging with MRI/MRA to confirm large vessel occlusion and differentiate arterial ischemic stroke from hemorrhagic stroke or stroke mimics.¹ At our facility it is not feasible to obtain this imaging within 25 minutes, so a CT/CTA was performed prior to deciding if the patient was a candidate for fibrinolytic therapy. In both cases, deficits were severe and debilitating enough that Tenecteplase was administered prior to confirmatory MRI. The post stroke work up for Case 1 was inconclusive on the etiology of the stroke. This patient had a normal prothrombotic work up, as well as a normal ECHO and EEG. Case 2 also had a normal prothrombotic work up and negative extremity ultrasounds. This patient did have an abnormal ECHO, revealing an atrial septal defect, that can carry a risk of stroke as high as 10%.¹⁵

Pediatric strokes and the medications used to treat them are largely understudied. As a result, there may be delays or errors in diagnosis, including the condition being mistaken as stroke mimics in the pediatric population.² It is estimated that 60-90% of patients presenting to the ED with an acute neurological syndrome have some condition other than stroke. The most common stroke mimics are migraine with aura, Bell’s palsy, and seizure with or without Todd’s paresis.^2,3 Common risk factors for pediatric AIS include arteriopathies, cardiac disease, inherited/acquired thrombophilia, inborn errors of metabolism, rheumatologic disease, sickle cell disease, malignancy, and congenital vascular syndromes.³ The low incidence of pediatric strokes, coupled with patients potentially presenting to non-pediatric specific facilities, can lead to delays in recognition and treatment. These delays can cause significant morbidity and mortality given the time sensitive nature of this condition. Delay in therapy can lead to sensorimotor deficits, behavioral problems, intellectual disability, language impairment, and epilepsy.³

Tenecteplase is listed as a reasonable alternative to alteplase, for treatment of AIS in adults, in the 2019 Guidelines for Management of Acute Ischemic Stroke.¹⁶ Previously the guidelines only referenced fibrinolytic agents for adult patients. The 2026 Guideline for the Early Management of Patients with Acute Ischemic Stroke specifically recommends alteplase in pediatric patients 28 days to 18 years with confirmed AIS presenting within 4.5 hours of symptom onset. The guideline also mentions there is some safety data that Tenecteplase may be safe in the pediatric population.¹ This study is limited to 11 children who received Tenecteplase with no significant adverse effects. This study did not look at efficacy, optimal dosing, or additional safety concerns.¹⁴ Alteplase has largely fallen out of favor, for use in adults, due to Tenecteplase having a simpler dose calculation, administration of intravenous push vs bolus and infusion, increased specificity for clot-bound fibrin, and increased resistance to plasminogen activator inhibitor-1.^7,8,13 Tenecteplase also has similar safety and efficacy when compared to alteplase, but no such data can currently be extrapolated to the pediatric population.^10,11,12 Pediatric patients are known to have developmental hemostasis, further complicating the use of fibrinolytic therapy in the pediatric population. Fibrin function and physiology are age dependent, tissue plasminogen activator (tPA) is less abundant in children, and plasminogen activator inhibitor is found at higher levels than in adults.^17,18 Theoretically, Tenecteplase may be more specific for fibrin in children compared to alteplase, given the higher levels of plasminogen activator inhibitor present in children compared to adults. More studies are needed to determine pharmacokinetic/dynamic information in pediatrics to determine optimal dosing for safety and efficacy.

While pediatric stroke work ups are challenging, having a plan in place for how to manage and possible treatment options are key to timely identification and treatment. In these patient cases our ED providers and neurologists were in communication with a pediatric center and corresponding pediatric neurologist, awaiting transfer of care post Tenecteplase administration. Emergency department pharmacists also played a vital role in medication selection and appropriate dosing for these patients.

Conclusion

There is limited data regarding the use of Tenecteplase in the pediatric population. As more emergency departments move toward using Tenecteplase as the fibrinolytic of choice in the adult population, this ultimately decreases the use and familiarity of alteplase, which is the traditional agent of choice for acute ischemic strokes in the pediatric population. These case reports add to the literature showing the safe and efficacious use of Tenecteplase for acute ischemic stroke in the pediatric population. More data regarding the safety and efficacy of Tenecteplase in the pediatric population is needed, preferably through randomized controlled trials. While each pediatric stroke case will need to be evaluated for use of Tenecteplase vs alteplase, Tenecteplase may be a reasonable option for adolescents meeting AIS criteria for fibrinolytic therapy.

Table 1: Literature review of Tenecteplase for AIS in pediatric populations

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