By: Avery Tolliver, PharmD; PGY1 Pharmacy Resident
Mentor: Blake Rosenfelder, PharmD; Clinical Pharmacy Specialist
Mercy Hospital, Springfield, MO
Program Number: 2022-04-07
Approved Dates: April 1, 2022-October 1, 2022
Pending Approval for Contact Hours: One Hour(s) (1) CE(s) per session
Acute ischemic strokes (AIS) are one of the leading causes of death for Americans. In the United States around 795,000 people suffer from strokes each year, leading to significant morbidity and mortality.1 The American Heart Association’s (AHA) and American Stroke Association’s (ASA) joint guidelines on the early management of AIS has for many years recommended the use of the fibrinolytic medication alteplase for select ischemic stroke patients who can be treated within 4.5 hours of symptom onset. AHA/ASA AIS guidelines prior to the 2019 revision did not recommend the use of fibrinolytics other than alteplase. In the 2019 guideline revision AHA/ASA changed their recommendations, suggesting the use of tenecteplase over alteplase could be reasonable in patients without contraindications for intravenous (IV) fibrinolysis that are also eligible to undergo mechanical thrombectomy.2 The updated recommendation was a result of newly published studies comparing tenecteplase and alteplase. Since the publication of the 2019 guidelines, additional studies have shown the efficacy of tenecteplase for ischemic strokes and have further supported its use. These studies, along with shortages of alteplase, have increased the medical community’s interest in and use of tenecteplase. The following discussion of the evidence supporting tenecteplase for AIS and comparing it to alteplase will better prepare pharmacists to treat ischemic stroke patients and answer tenecteplase related questions from their multidisciplinary teams.
Tenecteplase vs. Alteplase
Alteplase (brand name Activase) and tenecteplase (brand name TNKase) are thrombolytic agents that have been approved by the Food and Drug Administration (FDA) for the treatment of ST-elevation myocardial infarction (STEMI).3,4 Alteplase is also FDA approved for acute ischemic stroke and pulmonary embolism, but these are off-label uses for tenecteplase. Alteplase is one of the most used thrombolytic agents and gained FDA approval in 1989, afterwards came the approval of tenecteplase in 2000.3,4
Tenecteplase and alteplase are in the same drug class causing them to have similarities but also to have pharmacokinetic and pharmacodynamic differences. Both agents work by binding to fibrin and converting plasminogen to plasmin initiating fibrinolysis of a thrombus.3 Alteplase, a recombinant tissue plasminogen activator (tPA), varies from tenecteplase (TNK-tPA) by modifications of three molecular sites. The three molecular modifications were engineered to give tenecteplase a longer half-life compared to alteplase.5 Tenecteplase has a biphasic initial half-life of 20 to 24 minutes and terminal half-life of 90 to 130 minutes which is longer than alteplase’s initial half-life of 5 minutes and terminal half-life of 27 to 46 minutes.3,4 Additionally, tenecteplase’s three molecular modifications allow for higher fibrinogen specificity and enhanced resistance to plasminogen activator inhibitor-1 compared to alteplase.5 Although pharmacokinetically different in some ways alteplase and tenecteplase are both hepatically metabolized.3,4
Due to the structural and pharmacokinetic differences between tenecteplase and alteplase their dosing strategies are different from one another. For the indication of AIS, a total dose of 0.9 mg/kg of alteplase is given IV, with 10% of the dose given as a bolus over one minute followed by the remaining 90% of the dose given by continuous infusion over 60 minutes.3 The maximum dose of alteplase for AIS is 90 mg. The complex administration of bolus and continuous infusions is due to alteplase’s short half-life and is avoided with tenecteplase’s longer half-life. For tenecteplase the AHA/ASA guideline recommended AIS dosing is 0.25 mg/kg with a maximum of 25 mg given as a single IV bolus over 5 seconds.2,3 The difference in tenecteplase dosing for the FDA-approved STEMI indication and the off-label AIS indication should be noted. The tenecteplase dosing for STEMI is based on weight ranges, and doses range from 30 to 50mg, which is approximately 0.5 mg/kg; however, the dose is still administered as a single bolus over 5 seconds. Neither tenecteplase nor alteplase require dose adjustments for renal or hepatic impairment.3
Although these two thrombolytic agents are dosed differently, they are supplied in similar ways and are expensive. Alteplase comes in kits from the manufacturer, Genentech, with 50 mg or 100 mg vials of alteplase.3,4 The kits contain sterile water for injection and a transfer device to reconstitute the vials. Additionally, alteplase vials include a hanging loop to allow administration of the dose from the vial. The 50 mg alteplase kit costs around $5,300 and the 100 mg kits cost around $10,500 each. Tenecteplase is also supplied by Genentech, and a 50 mg kit contains a 50 mg vial of tenecteplase, sterile water for injection, and syringe for reconstituting the vial and bolus administration. The tenecteplase kit costs around $7,500. One precaution to be aware of when preparing and administering tenecteplase is that it is incompatible with dextrose solutions; lines must be flushed with saline prior to and after administration. Alteplase is compatible with 5% dextrose and 0.9% saline.3,4 Additionally, the packaging for tenecteplase kits is designed to highlight the dosing for a STEMI. As a consequence, this could result in a substantial overdose if STEMI dosing is used when treating an AIS.
Along with other commonalities, tenecteplase and alteplase have similar adverse drug reactions. The major adverse drug reactions for both agents include a variety of hemorrhagic complications. Tenecteplase has high rates of hematomas (12.3%), hemorrhage (21.8%), renal artery hemorrhage (3.7%), and gastrointestinal hemorrhage (1.9%). Alteplase has high rates of intracranial hemorrhage (within 90 days 15%), gastrointestinal hemorrhage (5%), and genitourinary tract hemorrhage (4%). Neither of the agents have black box warnings or risk evaluation and mitigation strategies (REMS) programs.3,4
Recent Tenecteplase AIS Studies
The 2019 revision to the AHA/ASA acute ischemic stroke guidelines stated that tenecteplase could be used over alteplase for patients without contraindications for IV fibrinolysis and who are eligible to undergo mechanical thrombectomy.2 This new recommendation was a result of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) published in April of 2018.6 The EXTEND-IA TNK trial was a prospective, randomized, blinded outcome trial. Ischemic stroke patients included in the trial were within 4.5 hours of symptom onset and had large-vessel occlusion of the internal carotid, middle cerebral, or basilar artery. Patients also had to be eligible for IV thrombolysis and endovascular thrombectomy. Included patients were randomized to tenecteplase at a dose of 0.25 mg/kg (maximum 25 mg) or alteplase at a dose of 0.9 mg/kg (maximum 90 mg). The primary outcome investigated was substantial reperfusion, defined as the restoration of blood flow to more than 50% of the affected area or an absence of retrievable thrombus in the target vessel. The primary outcome was observed in 22 patients (22%) who received tenecteplase and 10 patients (10%) who received alteplase (P=0.002 for noninferiority). For the secondary outcome of modified Rankin scale (mRs) score at 90 days the tenecteplase group had a median score of 2 compared to the median score of 3 for the alteplase group (P=0.04). This outcome suggests a better functional outcome with tenecteplase compared to alteplase. However, there was no significant difference shown in early neurologic improvement measured by median National Institutes of Health Stroke Scale (NIHSS) scores at 24 hours. The NIHSS score at 24 hours for the tenecteplase group was 3 and NIHSS score was 6 for the alteplase group (P=0.06). The results of EXTEND-IA TNK show that tenecteplase is noninferior to alteplase in restoring perfusion for proximal cerebral artery occlusions and tenecteplase could lead to better functional outcomes for AIS patients.6
The EXTEND-IA TNK trial showed noninferiority of the 0.25 mg/kg (25 mg maximum) dose of tenecteplase compared to alteplase for AIS. However, during the recruitment phase of the EXTEND-IA TNK trial the results of the Norwegian Tenecteplase Stroke Trial (NOR-TEST) were published and NOR-TEST used 0.4 mg/kg of tenecteplase. NOR-TEST, a phase 3, randomized, open-label, superiority trial was published in August 2017.7 Ischemic stroke patients with measurable deficits on the NIHSS, admitted within 4.5 hours of symptom onset or within 4.5 hours of awakening with symptoms, and eligible for IV thrombolysis were eligible for the NOR-TEST study. Patients were randomized to two groups, an alteplase group receiving standard dosing and a tenecteplase group receiving 0.4 mg/kg (maximum 40 mg) as a single bolus. The primary end point evaluated was excellent functional outcome at 3 months measured as a mRs score of 0 to 1. In the tenecteplase group 354 (64%) achieved the primary outcome compared to 345 (63%) in the alteplase group (P=0.52). For the secondary outcome of intracranial hemorrhage (ICH) 24 to 48 hours after thrombolytic treatment, 47 (9%) patients in the tenecteplase group suffered from ICH compared to 50 (9%) in the alteplase group (P=0.82). Death at 3 months was also reported showing 29 (5%) deaths in the tenecteplase group compared to 26 (5%) in the alteplase group (P=0.68).7 The NOR-TEST trial did not show tenecteplase to be superior to alteplase for treatment of AIS. However, the NOR-TEST trial did show that the higher tenecteplase dose of 0.4 mg/kg had a similar safety profile to alteplase.
Following the EXTEND-IA TNK and NOR-TEST trial publications a meta-analysis of 5 randomized trials was performed to determine if evidence supported tenecteplase being noninferior to alteplase for acute ischemic stroke.8 The formal meta-analysis published in May 2019 looked at the primary efficacy end point of disability free outcome, measured as a mRs score of 0 to 1, at 3 months post stroke. All alteplase patients received the standard AIS dosing, and tenecteplase patients received one of three doses as a one-time bolus, 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), or 0.4 mg/kg (68.6%). Data from all 5 trials contributed to the primary outcome of disability free outcomes in 57.9% of tenecteplase patients compared to 55.4% of alteplase patients. The random-effects meta-analysis showed a risk difference of 4% (95% CI, -1% to 8%) falling within the noninferiority criteria for the primary outcome. For the secondary analysis of functional independence, measured as a mRs score of 0 to 2 at 3 months, data was available from 4 of 5 trials. The data showed the rate of independence was 71.9% in the tenecteplase group compared to 70.5% in the alteplase group, with a risk difference of 8% (95% CI, -4 to 20%) showing noninferiority. For the safety outcomes of symptomatic ICH and death, data was available for all 5 trials. ICH occurred in 3% of tenecteplase patients and 3% of alteplase patients. Mortality occurred at 3 months in 7.6% of tenecteplase patients compared to 8.1% of alteplase patients. Overall, this combined clinical trial data indicates that tenecteplase given for the treatment of AIS is noninferior to alteplase when measuring disability free outcomes and poses no greater safety risk.8
In addition, another systemic review with meta-analysis exploring the use of tenecteplase for thrombolysis in stroke patients was published in 2021.9 The meta-analysis included eight studies involving a total of 2031 patients that underwent thrombolysis for AIS. Tenecteplase showed an increase in recanalization rate (ARD =0.11, 95% CI [0.01;0.02]) and early neurological improvement (ARD=0.10, 95% CI [0.02;0.17]) compared to alteplase. Also, tenecteplase demonstrated an increase in good (mRs 0-2) and excellent (mRs 0-1) functional outcomes; however, these improvements were not statistically significant. Safety outcomes for this meta-analysis also showed no difference in ICH or mortality between tenecteplase and alteplase.9 This systemic review with meta-analysis reinforces the results of prior studies and further strengthens the AHA/ASA guideline recommendation on the use of tenecteplase.
Earlier Tenecteplase AIS Studies
The recent randomized controlled trials and meta-analysis are being used to support the AHA/ASA guideline changes, but they are not the only studies supporting the use of tenecteplase for AIS. There are three older randomized controlled studies that are also frequently referenced. The first being Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke published in 2010.10 This study is a randomized, multi-center, double-blind trial comparing tenecteplase and alteplase in AIS patients within 3 hours of symptom onset. The study compared tenecteplase 0.1 mg/kg, 0.25 mg/kg, and 0.4 mg/kg to alteplase. Specifically looking into the co-primary outcomes of proportion of poor outcomes (mRs 4-6) and proportion of good outcomes (mRs 0-1). The study was terminated early, however, the results reported out showed the 0.1 mg/kg tenecteplase group to have the least poor outcomes with only 7 (22.6%) compared to 10 (32.3%) in the alteplase group. The 0.25 mg/kg tenecteplase group had the most good outcomes with 15 (48.4%), followed by the 0.1 mg/kg group with 14 (45.2%), and the alteplase group only had 13 (41.9%).10 This study continues to show the trend of tenecteplase having similar outcomes to alteplase for AIS and possibly having fewer poor outcomes.
Another phase IIB, randomized, open-label, blinded trial that is commonly referenced is A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke by Parsons, et al.11 The study included AIS patients within six hours of symptom onset with presence of intracranial occlusion of the anterior cerebral, middle cerebral, or posterior cerebral arteries on computed tomography (CT) angiography. Patients were randomized to one of three groups: 0.1 mg/kg (maximum 10 mg) tenecteplase, 0.25 mg/kg (maximum 25 mg) tenecteplase, or alteplase. The co-primary outcomes investigated were the percentage of the perfusion lesion that was reperfused 24 hours after treatment and clinical improvement at 24 hours measured by NIHSS scores. Reperfusion at 24 hours occurred in 79.3% ± 28.8% of the tenecteplase patients compared to 55.4% ± 38.7% of the alteplase patients (P=0.004). While the improvement in NIHSS scores between baseline and 24 hours was around 3 ± 6.3 hours in the alteplase group compared to 8.0 ± 5.5 hours in the tenecteplase group (P<0.001). This study is limited by its small enrollment of 75 patients in total, however, it shows greater reperfusion and greater clinical improvement in the tenecteplase group compared to alteplase.11
The third trial, ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischemic Stroke: a phase 2, randomized, open-label, blinded endpoint study), is commonly referenced and is the foundation for a current on-going study.12 Eligible AIS patients had to have measurable deficits shown by the NIHSS score, be within 4.5 hours of symptom onset, and be eligible for IV thrombolysis. Patients were randomized to 0.25 mg/kg (maximum 25 mg) tenecteplase or standard dose alteplase. The primary outcome investigated was the percentage of hypo-perfused tissue salvaged at 24 to 48 hours post treatment. This was measured by pre and post treatment CTs. There was no significant difference in the primary outcome between tenecteplase (68%) and alteplase (68%). There were also no statistically significant secondary outcomes. However, there was a trend towards more early neurological improvement at 24 hours in the tenecteplase group with 19 (40%) compared to the alteplase group at 12 (24%), and a trend toward a higher proportion of good neurological outcomes (mRs 0-1) at 90 days in the tenecteplase group 13 (28%) compared to alteplase 10 (20%).12 The outcomes of this trial once again support previously discussed studies.
Dosing of Tenecteplase for AIS
Considering the results of the NOR-TEST trial using tenecteplase doses of 0.4 mg/kg (maximum of 40mg) and the EXTEND-IA trial using 0.25 mg/kg (maximum of 25 mg), the EXTEND-IA trial researchers performed the EXTEND-IA TNK Part 2 trial to determine the optimal dosing of tenecteplase in AIS patients.13 EXTEND-IA TNK Part 2 is a randomized, open-label, blinded end point trial of AIS patients within 4.5 hours of symptom onset determined to have large vessel occlusion of the intracranial internal carotid, middle cerebral, or basilar artery. Additionally, patients had to be eligible for IV thrombolysis and endovascular thrombectomy. Eligible patients were randomized to either 0.4 mg/kg (40 mg maximum) of tenecteplase or 0.25 mg/kg (25 mg maximum) of tenecteplase. Substantial reperfusion defined as restoring blood flow to more than 50% of the involved territory or an absence of retrievable intracranial thrombus was the primary outcome investigated. The primary outcome occurred in 29 (19.3%) of the patients in the 0.4 mg/kg tenecteplase group and 29 (19.3%) of those receiving 0.25 mg/kg of tenecteplase (P=0.89). Additionally, the analysis of the secondary outcomes showed no significant differences between groups for mRs scores at 90 days and early neurological recovery. More notably the safety outcome showed no significant difference in symptomatic ICH with 7 (4.7%) of 0.4 mg/kg patients having symptomatic ICHs compared to 2(1.3%) of the 0.25 mg/kg patients (P=0.12). Also, no difference was seen in mortality with 26 deaths in the 0.4 mg/kg group and 22 deaths in the 0.25 mg/kg group (P=0.35). The EXTEND-IA TNK Part 2 trial showed no significantly improved cerebral reperfusion with 0.4 mg/kg of tenecteplase compared to 0.25 mg/kg prior to endovascular thrombectomy in patients with large vessel occlusion ischemic strokes.13 EXTEND-IA TNK Part 2 results further support the use of the 0.25 mg/kg (max 25 mg) dose recommended by the AHA/ASA guidelines.2
Whether or not tenecteplase should be used in place of alteplase for AIS is still a difficult question to answer with the current data from small sample size studies. However, there are several studies currently being performed that will give more insight into this question when completed. One on-going study is the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST2) which is looking at functional outcome at 90 days, measured by the modified Rankin Scale, to determine if tenecteplase is superior in efficacy to alteplase.14 A similar study is The Norwegian Tenecteplase Stroke Trial 2 (NOR-TEST 2) which is looking into the safety and efficacy of 0.4mg/kg of tenecteplase versus alteplase for AIS patients within 4.5 hours of symptom onset, awakening with stroke symptoms, or bridge therapy before thrombectomy. The primary endpoint is functional outcome at 90 days measured with the mRs.15 Another on-going study is the Alteplase Compared to Tenecteplase in Patients with Acute Ischemic Stroke (AcT) trial to see if 0.25 mg/kg (max 25 mg) IV tenecteplase is non-inferior to IV alteplase in patients with AIS. Like the other ongoing studies, the primary outcome is functional outcome between days 90 to 120 based on the mRs.16 These are a few of the in-progress studies looking into the efficacy and safety of tenecteplase compared to alteplase for AIS patients. These studies have the potential to further define tenecteplase’s place in therapy for AIS patients.
Tenecteplase has many positive attributes making it a more ideal choice than alteplase for thrombolysis in AIS patients. Its molecular modifications allow higher fibrinogen specificity, enhanced resistance to plasminogen activator inhibitor 1, and a longer half-life compared to alteplase. These qualities allow bolus administration of tenecteplase which is faster and less error prone than the bolus and infusion administration of alteplase. The bolus administration of tenecteplase also allows non-thrombectomy hospitals faster door-in to door-out times for those patients that require thrombolysis followed by thrombectomy at a qualified institution. Finally, in addition to faster administration, tenecteplase is less costly than alteplase by approximately $3,000 dollars per dose.
Tenecteplase’s pharmacokinetic profile is ideal for AIS patients, and study results are starting to reinforce that fact. The studies reviewed show tenecteplase has comparable efficacy to alteplase in AIS patients with large vessel occlusions and could lead to better functional outcomes. Tenecteplase, compared to alteplase in one meta-analysis, also showed non-inferiority in disability free outcomes and increased functional independence. Another meta-analysis reported increased recanalization rates and early neurological improvement with tenecteplase compared to alteplase. All of these studies are showing positive results in favor of using tenecteplase for patients who are candidates for IV thrombolysis and mechanical thrombectomy. In addition to positive outcomes, the studies also indicate that tenecteplase’s safety profile is similar to alteplase’s profile in regard to adverse drug reactions. Although currently reported studies already illustrate promising results in favor of tenecteplase, the results of on-going studies will further define tenecteplase efficacy and place in therapy for AIS.
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