Update: what evidence supports intravenous tenecteplase for the treatment of acute ischemic stroke?

Introduction
Stroke remains a leading cause of death and long-term disability in the United States, and nearly 90% of all strokes that occur are ischemic in nature.1 Intravenous thrombolysis with alteplase has been the standard of care for reperfusion therapy in patients with ischemic stroke who present within 4.5 hours after the onset of symptoms.2 Alteplase is approved by the United States Food and Drug Administration as a thrombolytic agent for treatment of patients with acute ischemic stroke; however, off-label use of tenecteplase for this indication is gaining popularity. Tenecteplase is an attractive alternative to alteplase for thrombolysis due to its longer half-life and shortened dosing duration, higher fibrin selectivity, resistance to inhibition from plasminogen activator inhibitor-1, and reduced overall cost.3,4 Tenecteplase is also included in current practice guidelines for early management of acute ischemic stroke as an alternative to alteplase in select patient populations.5

A frequently asked question (FAQ) was published in January 2022 (available here) with information on the use of tenecteplase for the treatment of acute ischemic stroke.6 At the time the FAQ was published, the author found that the existing literature generally supported similar efficacy and safety of alteplase and tenecteplase for treatment of acute ischemic stroke, but concluded that additional research was needed to define optimal dosing of tenecteplase and further determine its role for treatment of acute ischemic stroke. Since the publication of the FAQ, additional literature has been published that may help to answer some of these questions.7,8 Thus, the purpose of this FAQ update is to summarize updated literature on the use of tenecteplase for thrombolytic treatment of acute ischemic stroke.

Literature review
Two additional randomized trials evaluating tenecteplase for acute ischemic stroke have been published since the initial FAQ was published in January 2022. Most recently, Bivard et al published TASTE-A, a phase 2, open-label, blinded endpoint, randomized trial conducted in Australia.7 The trial included 104 adults with hemispheric ischemic stroke within 4.5 hours prior to presentation and a modified Rankin scale (mRS) score of 3 or less. The trial occurred on a single mobile stroke unit (MSU) that transferred enrolled patients to 1 of 5 hospitals in Australia for follow-up care. The median (interquartile range [IQR]) National Institutes of Health Stroke Scale (NIHSS) score of enrolled patients was 8 (5-14) at baseline. Patients were randomized to receive standard dose intravenous alteplase (0.9 mg/kg [maximum 90 mg] administered with 10% as a bolus and the remaining 90% as a 1-hour infusion) or tenecteplase 0.25 mg/kg (maximum 25 mg) administered as a bolus over 10 seconds. The primary endpoint, volume of the perfusion lesion, was found to be significantly reduced with tenecteplase (median 12 mL; IQR, 3 to 28 mL)  compared to alteplase (35 mL; IQR, 18 to 76 mL; adjusted incidence rate ratio, 0.55; 95% confidence interval [CI], 0.37 to 0.81; p=0.030). Tenecteplase was also superior to alteplase for the secondary endpoint of median reduction in NIHSS score from the pretreatment score obtained on the MSU to the posttreatment score obtained at the hospital’s emergency department (median reduction with alteplase, 0 [IQR, 0 to 3]; median reduction with tenecteplase, 1 [IQR, 0 to 6]; adjusted difference, 1; 95% CI, 0.1 to 1.9; p=0.030). Ten percent of patients treated with alteplase and 9% of patients treated with tenecteplase died; no patients in either group experienced symptomatic intracranial hemorrhage (ICH) within 36 hours of receiving thrombolytic therapy.

The second trial, NOR-TEST 2, part A, was a phase 3, open-label, randomized, blinded endpoint, noninferiority trial that included 216 adult patients with clinically suspected moderate to severe (baseline NIHSS score of ≥6) acute ischemic stroke within 4.5 hours prior to hospitalization who were eligible to receive thrombolytic therapy.8 The median (IQR) NIHSS score of enrolled patients was 11 (8-17) at baseline. Patients were randomized to receive standard dose intravenous alteplase  or tenecteplase 0.4 mg/kg (maximum 40 mg) administered as a bolus. The primary endpoint measured was a favorable functional outcome at 3 months, which was defined either by a mRS score of 0 to 1 or a return to baseline mRS score if the prestroke mRS score was 2. Tenecteplase was considered noninferior to alteplase for this outcome if the lower bound of the two-sided 95% CI for the absolute difference was more than   -3%. At 3 months, 32% of patients treated with tenecteplase and 51% of patients treated with alteplase achieved the primary endpoint (unadjusted risk difference, -0.19; 95% CI, -0.33 to -0.06); thus, tenecteplase did not show noninferiority to alteplase for this endpoint. Intracranial hemorrhage and symptomatic intracranial hemorrhage both occurred more frequently among patients treated with tenecteplase (21% and 6%, respectively) compared to those who received alteplase (7% and 1%, respectively). The trial was terminated early due to this increased bleeding rate in the tenecteplase group. The adjusted odds ratio (OR) was 3.54 (95% CI, 1.40 to 8.99) for ICH and 5.91 (95% CI, 0.69 to 50.68) for symptomatic ICH. Sixteen percent of patients treated with tenecteplase died compared to 5% of patients treated with alteplase (adjusted OR, 2.94; 95% CI, 0.97 to 8.89).

Discussion
These 2 recent publications provide further insight into the optimal dosing of tenecteplase when used to treat patients with acute ischemic stroke. The results of NOR-TEST 2 showed reduced efficacy and an increased risk of harm when tenecteplase was administered at a dose of 0.4 mg/kg to patients with moderate to severe stroke.8 While the original NOR-TEST trial found similar safety and efficacy between standard dose alteplase and tenecteplase 0.4 mg/kg, the patients enrolled in NOR-TEST had less severe strokes than those in NOR-TEST 2, with a median NIHSS score of 4, and a portion of those patients were ultimately diagnosed with stroke mimic.6,8-10 The results of NOR-TEST 2 are consistent with the trial published by Haley et al in 2010, which found tenecteplase at a dose of 0.4 mg/kg to be inferior compared to alternate doses (0.1 mg/kg and 0.25 mg/kg) in the dose selection phase of the trial; tenecteplase 0.4 mg/kg was also found to have the highest rates of symptomatic ICH.6,8,10,11 The findings of the TASTE-A trial further support the efficacy of tenecteplase at a lower dose of 0.25 mg/kg.7,10

Conclusion
While the optimal dose of tenecteplase for treatment of acute ischemic stroke has not yet been determined, updated evidence has eliminated tenecteplase 0.4 mg/kg as a safe alternative to alteplase. This dose was associated with an increased risk of symptomatic ICH and reduced efficacy compared to alteplase at a standard dose when used to treat moderate to severe acute ischemic stroke. One additional published study conducted in a small number of patients with acute ischemic stroke further supports efficacy of tenecteplase at a lower dose (0.25 mg/kg) for treatment of acute ischemic stroke. Ongoing research will continue to define the optimal dose and place in therapy for tenecteplase for the treatment of acute ischemic stroke.

References

  1. Stroke facts. Centers for Disease Control and Prevention. Updated April 5, 2022. Accessed May 23, 2022. https://www.cdc.gov/stroke/facts.htm
  2. Oliveira-Filho J, Samuels OB. Approach to reperfusion therapy for acute ischemic stroke. In: Post TW, ed. UpToDate. UpToDate; 2022. Accessed May 23, 2022. www.uptodate.com
  3. Li G, Wang C, Wang S, Xiong Y, Zhao X. Tenecteplase in ischemic stroke: challenge and opportunity. Neuropsychiatr Dis Treat. 2022;18:1013-1026. doi:10.2147/NDT.S360967
  4. Potla N, Ganti L. Tenecteplase vs. alteplase for acute ischemic stroke: a systematic review. Int J Emerg Med. 2022;15(1):1. doi:10.1186/s12245-021-00399-w
  5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50(12):e344-e418. doi:10.1161/STR.0000000000000211
  6. Kadus V, Hartke P. What evidence supports intravenous tenecteplase for the treatment of acute ischemic stroke? University of Illinois at Chicago Drug Information Group. Published January 2022. Accessed May 23, 2022. https://dig.pharmacy.uic.edu/faqs/2022-2/january-2022-faqs/what-evidence-supports-intravenous-tenecteplase-for-the-treatment-of-acute-ischemic-stroke/
  7. Bivard A, Zhao H, Churilov L, et al. Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a phase 2, randomised, open-label trial. Lancet Neurol. 2022;21(6):520-527. doi:10.1016/S1474-4422(22)00171-5
  8. Kvistad CE, Næss H, Helleberg BH, et al. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022;21(6):511-519. doi:10.1016/S1474-4422(22)00124-7
  9. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781-788. doi:10.1016/S1474-4422(17)30253-3
  10. Coutts SB, Yu AYX. Tenecteplase for acute stroke: the thrombolysis puzzle. Lancet Neurol. 2022;21(6):496-497. doi:10.1016/S1474-4422(22)00172-7
  11. Haley EC Jr, Thompson JL, Grotta JC, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707-711. doi:10.1161/STROKEAHA.109.572040

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2022

The information presented is current as of May 23, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.