Introduction

In 1995, the publication of the NINDS trial finally confirmed what had long been theorized but not proven: thrombolysis in acute ischemic stroke improves patient outcomes [1]. This groundbreaking success was a result of careful patient selection, risk mitigation and the use of an improved thrombolytic agent. Patients were treated within 3 h of stroke onset, significantly earlier than many previous trials. Strict selection criteria minimized the treatment of stroke-mimics. Computed tomography (CT), which was only widely available starting in the 1980s, enabled rapid identification and exclusion of intracerebral hemorrhage. Hemorrhage risk was further mitigated with strict blood pressure control and avoidance of early antiplatelet/anticoagulant medications. Lastly, alteplase had better fibrin specificity and less systemic side effects compared to prior thrombolytics.

Since 1995, additional trials and technological innovations have dramatically changed the landscape of acute ischemic stroke treatment. The thrombolytic treatment window expanded out to 4.5 h from stroke onset [2]. Imaging biomarkers are used to guide thrombolytic treatment in strokes with an unknown time of onset [3, 4]. Endovascular thrombectomy is used in select patients with large vessel occlusion [5,6,7]. One thing that has not changed: alteplase remains the only FDA-approved thrombolytic for the treatment of acute ischemic stroke.

Alteplase (Activase, tPA) is a biosynthetic form of human tissue-type plasminogen activator (tPA), an endogenous enzyme that catalyzes plasminogen cleavage into plasmin thereby facilitating fibrin breakdown. Tenecteplase (TNKase) is a genetically modified tPA designed to be administered as a bolus rather than continuous infusion. Bolus delivery enables rapid clot exposure to high enzyme concentrations facilitating rapid fibrinolysis thereby achieving earlier vessel recanalization and reperfusion [8]. Bolus administration of alteplase would necessitate an exceptionally large dose due to its short half-life. While alteplase exhibits some fibrin specificity, it still induces systemic fibrin activation, especially at higher concentrations, conferring increased risk of hemorrhage [9].

Development of Tenecteplase

Previous attempts at creating a fibrinolytic agent with a longer half-life sacrificed fibrinolytic activity. After testing multiple permutations of alteplase point mutations, a combination of three specific point mutations successfully created a variant with a longer half-life, increased fibrin specificity and increased resistance to plasminogen activator inhibitor 1 (PAI-1). PAI-1, expressed on the surface of platelets, inhibits clot breakdown. This variant was named TNK-tPA, “TNK” a reflection of its three-point mutations. It showed early promise in achieving its desired efficacy in rabbit studies where it induced 50% clot breakdown three times faster than tPA without causing significant systemic fibrinogen breakdown (Fig. 1) [8].

Tenecteplase was first studied clinically in acute myocardial infarction (MI). ASSENT-2 (Assessment of the Safety of a New Thrombolytic), a double blinded, randomized controlled trial comparing alteplase versus tenecteplase in acute MI showed equivalent 30-day mortality and rate of intracerebral hemorrhage (ICH) and a lower risk of non-cerebral hemorrhage with tenecteplase [12]. The practical advantages of a bolus administered thrombolytic combined with its promising safety profile quickly piqued the interest of the stroke community. Various trials investigating the safety and efficacy of tenecteplase in the acute ischemic stroke population have since been published with more underway.

Fig. 1
figure 1

Alteplase versus Tenecteplase. This figure compares the half-life [8, 10], treatment dose and duration [10], fibrin specificity, fibrinogen depletion and PAI-1 resistance [9, 11] of alteplase and tenecteplase. Abbreviations: PAI-1: plasminogen activator inhibitor—1

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Tenecteplase in Ischemic Stroke Clinical Trials

Tenecteplase Dose Optimization

Tenecteplase is administered at a dose of 0.5 mg/kg in the treatment of acute MI; however, additional studies were necessary to inform the optimal dose in the treatment of acute ischemic stroke. Selected studies comparing tenecteplase doses are summarized in Fig. 2. A Pilot Dose-Escalation Safety Study of Tenecteplase in Acute Ischemic Stroke [13] was notable for an increased rate of symptomatic ICH (sICH) at 0.5 mg/kg compared to 0.1, 0.2 and 0.4 mg/kg. TNK-S2B (Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke, not pictured) [17] compared tenecteplase doses of 0.1, 0.25 and 0.4 mg/kg to tPA. It was prematurely terminated; however, it was able to establish inferiority of the 0.4 mg/kg dose due to an increased rate of sICH (15.8%). TRACE (Safety and Efficacy of Tenecteplase versus Alteplase in Patients with Acute Ischaemic Stroke, Table 1) [18] compared tenecteplase doses of 0.1, 0.25 and 0.32 mg/kg with alteplase and observed a lower absolute rate of sICH in the 0.25 mg/kg tenecteplase group; however, there was no statistically significant difference in safety or efficacy between groups.

Fig. 2
figure 2

Tenecteplase dose optimization: a review of clinical trials. This figure reviews selected clinical trials which compare different doses of tenecteplase in the treatment of acute ischemic stroke. Trials included are Pilot Dose Escalation Safety Study [13], TEMPO-1 [14], TNK EXTEND-IA Part 2 [15], CHABLIS-T [16]. * Complete recanalization strongly associated with excellent functional outcome (mRS 0–1) RR 1.65 p = 0.026. Key: Stopwatch: time since stroke onset included in the study; Brain: NIHSS included in the study; Camera: imaging requirements for inclusion; Telescope: primary endpoint. Abbreviations: NIHSS: National Institutes of Health Stroke Scale; sICH: symptomatic intracerebral hemorrhage; CTA: computed tomography angiography; IAO: intracranial arterial occlusion; SAE: serious adverse events; ICA: internal carotid artery; M1/2: segments 1 and 2 of the middle cerebral artery; mTICI: modified thrombolysis in cerebral infarction (score from 0–3 where 0 is no perfusion and 3 is full perfusion); RR: relative risk; ACA: anterior cerebral artery; w/o: without; mRS: modified rankin scale

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Table 1 Tenecteplase versus alteplase in ischemic stroke: a summary of completed clinical trials
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The remaining studies focused on patients in various time windows with an intracranial arterial occlusion at presentation. TAAIS (A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke, Table 1) [19] compared tenecteplase doses of 0.1 and 0.25 mg/kg to alteplase in patients with an intracranial arterial occlusion and perfusion mismatch. There were improved 90-day outcomes in the 0.25 mg/kg compared to the tPA group (72% vs 40%, p = 0.02) with no difference in rate of adverse events. Additionally, a higher reperfusion and recanalization rate was seen in the 0.25 mg/kg compared to the 0.1 mg/kg group with a higher rate of excellent recovery at 90 days (p = 0.01). TEMPO-1 (Tenecteplase-Tissue-Type Plasminogen Activator Evaluation for Minor Ischemic Stroke With Proven Occlusion) [14] which focused on patients with mild stroke in an extended time window found superior complete vessel recanalization with 0.25 mg/kg compared to 0.1 mg/kg with no significant difference in the rate of adverse events. A higher rate of sICH was noted with 0.4 mg/kg with no improvement in vessel recanalization when compared to 0.25 mg/kg in EXTEND-IA TNK Part 2 (Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke) [15]. However, notable patients enrolled in EXTEND-IA TNK Part 2 had a higher baseline NIHSS. Results from CHABLIS-T (CHinese Acute Tissue-Based Imaging Selection for Lysis In Stroke -Tenecteplase) presented at the International Stroke Conference in 2022 noted late window patients with optimal imaging perfusion mismatch had no improvement in complete reperfusion with 0.32 mg/kg when compared to 0.25 mg/kg tenecteplase [16]. 0.25 mg/kg is the tenecteplase dose adopted by most clinical trials moving forward.

Tenecteplase versus Alteplase in Ischemic Stroke

Completed Clinical Trials

Completed trials evaluating the safety and efficacy of tenecteplase versus alteplase in the treatment of ischemic stroke are summarized in Table 1. ATTEST (Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis) [20] and NOR-TEST (Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway) [21] both failed to establish tenecteplase superiority to alteplase however did show similar safety outcomes between groups. NOR-TEST 2 [23] notably showed worse functional and safety outcomes with tenecteplase compared to alteplase, however the tenecteplase dose used (0.4 mg/kg) was higher than in most other studies and additionally patients enrolled in this trial had moderate to severe stroke (NIHSS > 5). The recently published AcT (Intravenous Tenecteplase Compared with Alteplase for Acute Ischaemic Stroke in Canada) trial [24] showed that tenecteplase was noninferior to alteplase in routine clinical practice when treating patients who meet standard criteria for IVT. TAAIS [19] and EXTEND-IA TNK (Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke) [22] showed that patients selected with imaging criteria supportive of a large vessel occlusion had improved functional outcomes when treated with tenecteplase compared to alteplase. In EXTEND-IA TNK, the improved functional outcomes with tenecteplase were seen when comparing median 90 day modified rankin scale (mRS) (2 vs 3, cOR 1.7, P < 0.04). Additionally, there was a lower risk of mortality in patients treated with tenecteplase in EXTEND-IA TNK (aOR 0.4), otherwise safety outcomes were similar between groups. TASTE-A (Comparison of Tenecteplase with Alteplase for the Early Treatment of Ischaemic Stroke in the Melbourne Mobile Stroke Unit) [25] showed improved reperfusion in patients who were treated with tenecteplase compared to alteplase in a mobile stroke unit (lesion size 12 mL vs 35 mL, p < 0.003) with similar safety outcomes. Most recently TRACE II [26] published in 2023 showed noninferior functional outcomes in patients with moderate to severe stroke (NIHSS > 4) who were ineligible for or refused EVT when treated with tenecteplase versus alteplase, with no significant difference in safety outcomes.

Ongoing Clinical Trials

Ongoing trials evaluating the safety and efficacy of tenecteplase versus alteplase in the treatment of acute ischemic stroke are summarized in Table 2. Most ongoing trials are using a tenecteplase dose of 0.25 mg/kg except for 3 T Stroke II (Thrombolysis Treated With TNK-tPA in Acute Ischemic Stroke Patients) [28] which is also investigating the higher dose of 0.4 mg/kg. All of these studies are being conducted in the traditional treatment time window (< 4.5 h) and using standard criteria for IVT administration. 3 T STROKE-II is notably investigating more severe strokes as it requires a minimum NIHSS of 6 for enrollment.

Table 2 Tenecteplase versus alteplase in ischemic stroke: a summary of ongoing clinical trials
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Tenecteplase in the Delayed Time Window

Completed and ongoing trials evaluating the safety and efficacy of tenecteplase in the treatment of ischemic stroke in the delayed time window (4.5—12 or 24 h from time of last known well) are summarized in Table 3. TWIST (Tenecteplase in Wake-up Ischaemic Stroke Trial) [31] is the only trial that has been completed so far. It compared tenecteplase with standard treatment (no intravenous thrombolysis) in patients presenting within 4.5 h of a wake-up stroke selected by non-contrast CT (Computed Tomography) head alone. Results showed no improvement in functional outcome at 90 days with numerically more sICH in the tenecteplase group however this did not reach statistical significance. This trial was limited by the publication of results from other extended window thrombolysis trials and the increased use of endovascular thrombectomy (EVT) during the trial period which may have affected results.

Table 3 Tenecteplase in late window ischemic stroke: a summary of completed and ongoing clinical trials
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The other 8 ongoing trials are investigating the use of tenecteplase in the extended window with varying image based and stroke severity selection criteria. TIMELESS (thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase) [32], ETERNAL-LVO (Extending the Time Window for Tenecteplase by Effective Reperfusion in Patients With Large Vessel Occlusion) [33], CHABLIS-T II [34], TRACE III [36] and RESILIENT (Randomization to Extend Stroke Intravenous ThromboLysis In Evolving Non-Large Vessel Occlusion With TNK) [39] require perfusion mismatch for enrollment whereas TEMPO-2 [35] and POST-ETERNAL (Extending the Time Window for Tenecteplase by Recanalization of Basilar Artery Occlusion in Posterior Circulation Stroke) [38] only require evidence of intracranial arterial occlusion (IAO) and ROSE-TNK (MRI-guided thrOmbolysis for Stroke bEyond Time Window by TNK) [37] requires diffusion weighted imaging (DWI)-Flair mismatch on magnetic resonance imaging (MRI) except in mild stroke where IAO is required. Of note, RESILIENT excludes patients with IAO and TEMPO-2, TRACE III and ROSE-TNK exclude patients planned to undergo endovascular thrombectomy (EVT). TIMELESS, CHABLIS-T II and TRACE III are focusing on patients with moderate to severe stroke based on NIHSS whereas TEMPO-2 is focusing on patients with milder stroke and transient ischemic attack. Notably ROSE-TNK has completed recruitment and its results are eagerly awaited.

Tenecteplase and Endovascular Thrombectomy

Table 4 summarizes ongoing and planned trials studying tenecteplase with endovascular thrombectomy. Most are investigating the degree of reperfusion achieved with intra-arterial (IA) tenecteplase infused directly after EVT. BRETIS-TNK (Boosting REcanalization of Thrombectomy for Ischemic Stroke by Intra-arterial TNK) [40] is investigating IA tenecteplase infusion selectively in patients with TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification stroke subtype of large artery atherosclerosis. INSIST-TNK [41] (Improving Neuroprotective Strategy for Ischemic Stroke With Poor Recanalization After Thrombectomy by Intra-arterial TNK), TECNO (Intra-arterial Tenecteplase for Noncomplete Reperfusion of Intracranial Occlusions) [42] and ALLY (Adjunctive Intra-arterial Tenecteplase Following Mechanical Thrombectomy Pilot Trial) [43] are investigating IA tenecteplase infusion in patients with incomplete reperfusion after attempted EVT. BRIDGE-TNK (Endovascular Treatment With Versus Without Intravenous rhTNK-tPA in Stroke) [46] and DIRECT-TNK (Endovascular Treatment Alone or Preceded by Systemic Thrombolysis With Tenecteplase in Ischemic Stroke) [44] are investigating functional outcomes after intravenous (IV) tenecteplase compared to no tenecteplase or placebo prior to EVT in the standard 4.5 h window. DIRECT-TNK focuses on moderate to severe stroke based on NIHSS. Notably BRETIS-TNK has completed recruitment and its results are eagerly awaited.

Table 4 Tenecteplase and endovascular thrombectomy in ischemic stroke: a summary of ongoing trials
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Nonrandomized Studies

Selected non-randomized studies evaluating alteplase versus tenecteplase in the treatment of acute ischemic stroke are summarized in Table 5 and a summary of major findings are presented in Fig. 3. Mahawish et al. [47] transitioned the New Zealand stroke network comprising 8 hospitals from alteplase to tenecteplase due to its likely superior large vessel recanalization in the setting of New Zealand’s geographic barriers to endovascular thrombectomy. A retrospective analysis of registry data was notable for a greater odds of 90 day mRS 0–2 with tenecteplase (63.5% vs 60% aOR 2.16) and a shorter median door-to-needle time (53 min vs 63.5 min, p = 0.01). Outcomes were otherwise not significantly different. Significantly more patients who received tenecteplase underwent thrombectomy, this was adjusted for in the analysis. Zhong et al. [48] analyzed outcomes in patients treated with thrombolysis for acute ischemic stroke across five stroke centers in New Zealand. As three of the centers transitioned to tenecteplase and two were still using alteplase, they could compare outcomes data between groups treated during the same period. They found no significant difference in treatment times, functional outcomes, or symptomatic hemorrhage between groups. Hall et al. [49] evaluated the effect of switching from alteplase to tenecteplase on treatment times at their stroke center. They found a significant improvement in door-to-needle time after switching to tenecteplase (41 min vs 58 min, p < 0.01). Other workflow metrics were unchanged between time periods arguing against temporal confounders. There was no significant difference in sICH between groups. A Prospective Observational Study of Tenecteplase versus Alteplase in Routine Clinical Practice analyzed workflow metrics and patient outcomes across a 10-hospital regional stroke network in Texas before and after switching from alteplase to tenecteplase [50]. Analysis showed an improved median door-to-needle time after switching to tenecteplase (42 min vs 48 min, p = 0.004). In patients transferred for endovascular thrombectomy, median door-in-door-out times at the initial hospital improved after switching to tenecteplase (difference of 22 min, p = 0.05). A significant reduction was noted in the time from arrival at the initial hospital to the start of EVT in transfer patients treated with tenecteplase versus alteplase (144 min vs 184 min, p = 0.03). Metrics for transferred patients who did not receive a thrombolytic prior to transfer were unchanged between groups arguing against temporal confounders. There was a non-inferior rate of favorable outcomes at discharge including discharge to home and independent ambulation. There was a lower rate of sICH in the tenecteplase group (1.7% vs 2.8%) which did not meet a strict non-inferiority margin however in a subgroup analysis comprising only patients treated per 2019 AHA/ASA acute ischemic stroke treatment guidelines, the lower rate of sICH (0.7% vs 2.3%) was non-inferior. Interestingly this study also noted an increase in net favorable outcomes in the tenecteplase group (36.8% vs 27.4%, p = 0.02). The CERTAIN cohort registry, an international collaboration, contains patient data from 25 stroke networks including over 100 thrombolysis capable stroke centers in New Zealand, Australia and the USA [51]. The primary outcome of their analysis was symptomatic ICH. The rate of sICH in patients treated with alteplase was two times that seen in patients treated with tenecteplase (3.6% vs 1.8%, p < 0.001). There was a consistently significant difference in the rate of sICH when groups were adjusted for potential confounders including age, sex, NIHSS and thrombectomy. There was a higher mortality rate in the unadjusted TNK group however this was not statistically significant when adjusted for confounding factors (aOR 1.18, p = 0.147).

Table 5 Tenecteplase versus alteplase in ischemic stroke: a summary of selected nonrandomized studies
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Fig. 3
figure 3

Tenecteplase versus alteplase: results from meta-analyses. This figure reviews results from selected meta-analyses comparing tenecteplase with alteplase in the treatment of acute ischemic stroke. Meta-analyses included are: Tenecteplase versus Alteplase for Management of Acute Ischemic Stroke [52], Evidence That Tenecteplase is Noninferior to Alteplase for Acute Ischemic Stroke [53], Intravenous Thrombolysis With Tenecteplase in Patients With Large Vessel Occlusions [54], Off-Label Use of Tenecteplase for the Treatment of Acute Ischemic Stroke [55], * According to definition in each study. Abbreviations: h: hours; mRS: modified rankin scale (score from 0 to 6 where 0 is asymptomatic, 1 is symptomatic but no disability, 2 is slightly disabled but independent, 3 is dependent for some activities but independent with gait, 4 is dependent for bodily needs and gait, 5 is requires constant nursing and 6 is dead)

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Meta-Analyses

Selected meta-analyses are summarized in Table 6. Kheiri et al. [52] and Burgos and Saver [53] both completed a meta-analysis of the same 5 randomized controlled clinical trials comparing alteplase and tenecteplase but differed in their analytic framework. Kheiri B et al. completed a superiority analysis that was notable for an increased rate of complete recanalization in patients treated with tenecteplase (OR 2.01 (1.04–3.87), p = 0.04) and neurological improvement at 24–72 h (OR 1.43 (1.01–2.03), p = 0.05). There was no significant difference in 3-month functional outcomes, symptomatic ICH, or mortality between groups. Burgos AM et al. completed a noninferiority analysis that was notable for a noninferior rate of excellent 3-month functional outcomes (mRS 0–1) in the tenecteplase group and no significant difference in symptomatic ICH or mortality between groups. This was the first meta-analysis to establish non-inferiority of tenecteplase to alteplase in the treatment of ischemic stroke. Katsanos et al. [54] conducted a meta-analysis of 4 randomized controlled trials of alteplase versus tenecteplase specifically focusing on patients presenting with a large vessel occlusion. A higher rate of complete recanalization was seen in the tenecteplase group (OR 3.05 (1.73–5.4), p = 0.0001). There also was a higher rate of neurological improvement at 3 months (cOR 2.06 (1.15–3.69), p = 0.02) and a higher rate of good functional outcome at 3 months in patients treated with tenecteplase (OR 2.06 (1.15–3.69), p = 0.02). Differences in sICH and mortality were inconclusive between groups. Katsanos et al. [55] also completed a meta-analysis of nonrandomized studies comparing alteplase with tenecteplase in the treatment of acute ischemic stroke in real world clinical practice. This analysis was notable for an increased rate of complete vessel recanalization (aOR 2.38 (1.18–4.81), p = 0.02), early neurological improvement (aOR 7.6 (1.97–29.41), p = 0.003) and 3-month functional outcome (aOR 1.6 (1.08–2.37), p = 0.02) in patients treated with tenecteplase. There was no significant difference in the rate of sICH between groups.

Table 6 Tenecteplase versus alteplase in ischemic stroke: a summary of selected meta-analyses
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Conclusion

Tenecteplase has clear practical work-flow advantages over alteplase given its relative ease of preparation and administration. This translated into objective improvements in treatment times in three different nonrandomized, real-word clinical studies [47, 49, 50]. A 40-min improvement in time from presentation to thrombectomy in transfer patients treated at an outside hospital was noted in one study after the transition to tenecteplase [50]. This metric was attributed to local practices that preclude patient transfer with an ongoing alteplase infusion and may not generalize to all centers. However, in similar practice settings it would have a significant impact on patient outcomes as for every 4-min delay from presentation to reperfusion, 1 of every 100 patients has a worse disability outcome (mRS increase by 1 or more) [56].

Beyond practical advantages, tenecteplase has established non-inferiority to alteplase in the treatment of acute ischemic stroke [53]. The patients in this meta-analysis notably had milder strokes (median NIHSS 7) mostly treated within 4.5 h of onset. While there is no reason to think tenecteplase would perform significantly worse in more severe strokes or delayed time windows, additional data from patients in these subgroups will help clarify. Notably a meta-analysis of patients with large vessel occlusion showed they were more likely to have good functional outcomes (mRS 0–2) when treated with tenecteplase than alteplase (OR 2.06 (1.15–3.69), p = 0.02) [50].

0.25 mg/kg continues to gain support as the ideal tenecteplase dose for treatment of ischemic stroke. Higher doses have been associated with increased risk of symptomatic hemorrhage [13, 17, 18, 22] without significant additive benefit. Superior vessel recanalization was seen with 0.25 mg/kg compared to 0.1 mg/kg (52% vs 39%) with no difference in the rate of serious adverse events [14]. All ongoing clinical trials reviewed here are using 0.25 mg/kg except for one [28] which also has a 0.4 mg/kg arm.

Improved vessel recanalization with tenecteplase has been noted in multiple trials. 3 meta-analyses reviewed here [52, 54, 55] showed a 2–threefold increase in the rate of complete vessel recanalization with use of tenecteplase compared to alteplase. This is a significant finding since each grade in improved vessel recanalization has been associated with an increased number of quality adjusted life years [57]. Accordingly, the 2019 ASA/AHA stroke guidelines have a class IIb recommendation that it may be reasonable to choose tenecteplase 0.25 mg/kg over alteplase in patients eligible for both IVT and EVT [58].

There is a lot of interest in the efficacy of tenecteplase in the delayed window and wake-up stroke population as reflected in the number of ongoing clinical trials [31,32,33,34,35,36,37,38,39]. One trial has been completed so far investigating tenecteplase in wake-up stroke [31]; however, its interpretation is limited as patients were selected using non-contrast head CT which is not currently considered standard of care in this population. Interestingly, there was no significant difference in the rate of sICH in patients who received tenecteplase versus no thrombolytic.

Clinical trials have shown a significantly higher rate of sICH with tenecteplase 0.5 mg/kg [13] and a significantly higher rate of sICH and mortality with tenecteplase 0.4 mg/kg [23] compared to alteplase. The current 2019 ASA/AHA stroke guidelines have a class IIb recommendation that tenecteplase 0.4 mg/kg might be considered as an alternative to alteplase in patients with minor neurological impairment and no large vessel occlusion [58]. However, this was before the results of NOR-TEST 2 were published, therefore this recommendation may change. Tenecteplase 0.25 mg/kg and 0.1 mg/kg have not been associated with a significant increase in sICH or mortality. In the CERTAIN cohort registry, the rate of sICH in patients treated with alteplase was notably two times that seen in patients treated with tenecteplase (3.6% vs 1.8%, p < 0.001) [51]. Interestingly tenecteplase 0.25 mg/kg was associated with a lower mortality rate than alteplase when administered prior to thrombectomy [22].

It should be noted that all completed trials used a prospective, randomized, open label, blinded outcome (PROBE) design except for TNK-S2B which was a double blinded randomized controlled trial that was prematurely terminated. All ongoing trials are also using a PROBE design except for TIMELESS and RESILIENT which are double blinded, randomized controlled trials. While a PROBE trial design is cost-effective and pragmatic in the clinical setting, it can lead to bias as the treating physician and patient/family are not blinded to treatment group allocation. This is especially important when outcome measures are patient reported such as the 90 days modified rankin score. Ideally future trials would be conducted in a double blinded fashion. When PROBE trial design is implemented, it would be beneficial to report outcomes that are more objective and therefore less subject to bias such as vessel recanalization and final infarct volume [59].

Overall, the available data supports the safe use of tenecteplase in the treatment of acute ischemic stroke in clinical practice.