Tenecteplase vs Alteplase in Acute Ischemic Stroke

Background: At my shop we have changed wholesale to the use of tenecteplase over alteplase for acute ischemic stroke meeting criteria for thrombolytic therapy.  This was based on a systematic review and meta-analysis of 6 RCTs and 2 observational trials showing improved reperfusion and early neurologic improvement with tenecteplase compared to alteplase (Link is HERE).  Despite the available evidence, questions remain on the efficacy and appropriate dose of tenecteplase. There are now two more trials comparing tenecteplase to alteplase in acute ischemic stroke: TASTE-A and NOR-TEST 2, Part A.

Why Tenecteplase over Alteplase:

• Cheaper
• Higher fibrin specificity
• Can be administered as a single bolus (due to longer half-life than alteplase)
• Allows for more rapid treatment without the need for infusion pumps

TASTE-A

TASTE-A is a single system trial looking at mobile stroke units (ambulances with built in CT scanners, neurologist-led multidisciplinary team) to enable prehospital treatment of acute ischemic strokes.

Paper: Bivard A 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. PMID: 35525251 (Access on Read by QxMD)

Clinical Question: Does the use of prehospital tenecteplase result in a smaller volume perfusion lesion on hospital arrival compared to the use of alteplase.

What They Did:

• Phase 2, randomized, open-label, blinded-endpoint, trial
• Performed in Melbourne and five tertiary hospitals
• Patients within 4.5 hours of system onset evaluated by a single mobile stroke unit (MSU) were randomized to:
  • Standard of care: Alteplase 0.9mg/kg (max 90mg) – 10% as a bolus over 1min and 90% as an infusion over 1hr
  • Intervention: Tenecteplase 0.25mg/kg (max 25mg) – IV bolus over 10sec

Outcomes:

• Primary: volume of perfusion lesion on arrival at hospital (Assessed by CT-perfusion imaging)
• Secondary Efficacy:
  • Percent reperfusion (difference between baseline hospital CT perfusion imaging and 24hr perfusion imaging)
  • Infarct core growth (difference between baseline hospital CT perfusion imaging and 24hr MRI)
  • Reduction in NIHSS (Difference between pretreatment score on the MSU and scores on arrival at the receiving hospital and at 24hrs post treatment)
• Secondary Safety:
  • Modified Rankin Scale (mRS) score of 5 or 6 at 90d
  • Symptomatic intracerebral hemorrhage (sICH)
  • Any hemorrhage within 36hrs
  • Death at 90d

Inclusion:

• Adult patients (Age ≥18 years of age)
• Acute ischemic stroke
• Eligible for thrombolytic therapy
• Independent mobility before stroke
• Pre-stroke mRS of 3 or less

Exclusion:

• Standard contraindications to IV thrombolysis

Results:

• 104 patients enrolled and randomized
  • Screened 530 patients
  • Only 162 were eligible for thrombolysis of which 104 (64%) were enrolled in the trial
  • Median age: 73 years (Range 61 to 83)
  • Median NIHSS at baseline: 8 (Range 5 to 14)
  • 94 patients got CTA of Head/Neck on MSU
    • 46 had LVO
  • Median time from stroke onset to treatment = 95min
  • 19% of patients treated within 60mim of symptom onset
  • 80% of patients had a prestrike mRS of 0
• Perfusion Lesion Volume (Primary Outcome):
  • Alteplase: 35mL (Range 18 to 76)
  • Tenecteplase: 12mL (Range 3 to 28)
  • Adjusted incidence rate ratio: 0.55; 95 % CI 0.37 to 0.81; p = 0.0030
  • Median NIHSS reduction between MSU and ED arrival were better with tenecteplase vs alteplase (1 vs 0), however at 90d there was no significant differences in any mRS (OR 1.03; 95% CI 0.51 to 2.09; p = 0.93)
• mRS of 5 to 6 at 90d:
  • Alteplase: 20%
  • Tenecteplase: 15%
  • Adjusted OR: 0.70; 95% CI 0.23 to 2.16; p = 0.54
• Death at 90d
  • Alteplase: 10%
  • Tenecteplase: 9%
  • Adjusted OR: 1.12; 95% CI 0.26 to 4.90; p = 0.88
• No cases of symptomatic ICH within 36hrs in either group
• 90d Serious Adverse Events:
  • Alteplase: 8%
  • Tenecteplase: 5%
• Patients treated with tenecteplase had shorter time from MSU CT imaging to initiation of thrombolytic treatment (median 13min; Range 9 to 18) compared to alteplase (median 19min; Range 14 to 27)
• 24 patients went on to have thrombectomy (13 tenecteplase vs 11 alteplase)
  • 90% reperfusion at 24 hours overall
  • 91% reperfusion at 24 hours tenecteplase
  • 83% reperfusion at 24 hours alteplase 

Strengths:

• Randomized clinical trial
• Assessors of imaging outcomes and 90d functional outcomes were blinded to treatment allocation
• Intention-to-treat analysis which is more in line with real life practice (as opposed to per protocol analysis)
• Funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report
• Had a prespecified robustness analysis for patients with non-zero perfusion lesion volume which was in agreement with the primary outcome. This reinforces a true treatment effect with tenecteplase compared to alteplase in perfusion lesion volume (an imaging-based outcome)

Limitations:

• Single system trial using mobile stroke units which may limit generalizability to other systems that do not have mobile stroke units
• MSU treating team was not masked to treatment allocation
• Perfusion lesion volume (primary outcome) is an imaging-based outcome not a patient-oriented outcome (i.e. survival and/or neurologic outcome)
• Don’t know pre-treatment volume of perfusion lesion (Unclear if there was a change or if just lower volume to start in one group)
• Tenecteplase groups was less sick at baseline

Author Conclusion: “Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted.  This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care”

Bottom Line: In patients who qualify for thrombolysis in a system using mobile stroke units, tenecteplase leads to faster thrombolysis, smaller post-treatment perfusion lesions, and improved early clinical recovery compared to alteplase.  However, it is unclear if mobile stroke units or the use of tenecteplase lead to improved patient oriented longer term neurologic outcomes based on this one study.

NOR-TEST 2, Part A

NOR-TEST [3], is the only phase 3 trial evaluating tenecteplase in ischemic stroke.  In this trial 0.4mg/kg of tenecteplase was compared to 0.9mg/kg of alteplase in patients presenting ≤4.5hrs from symptom onset.  The trial enrolled 1100 patients and showed similar efficacy and safety outcomes of tenecteplase.  The biggest issue with the trial is the majority of patients had either mild stroke symptoms or stroke mimics, both of which have good prognosis making it difficult to draw any robust conclusions from this trial in all stroke comers.  Additionally, the optimal dose of tenecteplase has not yet been established.

Paper: Kvistad CE 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. PMID: 35525250 (Access on Read by QxMD) 

Clinical Question: Is 0.4mg/kg of tenecteplase non-inferior to 0.9mg/kg of alteplase in patients with moderate to severe acute ischemic stroke?

What They Did:

• Phase 3, multicenter randomized, open-label, blinded endpoint, non-inferiority trial
• Performed at 11 hospitals with stroke units in Norway
• Patients randomized to:
  • Standard care: Alteplase 0.9mg/kg (max 90mg; 10% of dose as initial bolus followed by 90% in a 1hr)
  • Intervention: Tenecteplase 0.4mg/kg (Max dose of 40mg) as a bolus (Higher dose than TASTE-A 0.25mg/kg)
    • Part B of this trial is using the lower dose 0f 0.25mg/kg
  • Used a non-inferiority margin of 3%
  • Trial stopped early due to safety reasons

Outcomes:

• Primary: Favorable functional outcome (mRS 0 to 1) at 3 months
• Secondary:
  • Any ICH within 24 to 48hrs of treatment
  • Symptomatic ICH occurring within 24 to 48hrs of treatment
  • Major neurological improvement at 24hrs (Reduction in NIHSS of at least 4 points at 24hours compared to baseline)
  • Poor functional outcome (mRS 5 or 6) at 3 months
  • Death at 3 months

Inclusion:

• Adult patients (≥18 years of age)
• Living independently before stroke
• Suspected acute ischemic stroke
• NIHSS ≥6
• Eligible for thrombolysis
• Within 4.5hrs of symptom onset
• Also included patients with signs or symptoms on awakening or an unknown onset of stroke signs if MRI showed a mismatch between diffusion-weighted imaging and fluid attenuated inversion recovery (FLAIR)
• Patients undergoing thrombectomy were included if receiving thrombolysis as a bridging therapy

Exclusion:

• Standard contraindications to IV thrombolysis
• Large areas of hypodense ischemic changes on baseline CT
• Pre-stroke modified Rankin scale ≥3
• Pregnant or breast feeding

 Results:

• 216 patients enrolled
  • Trial stopped early after a safety review showed an imbalance in the rates of symptomatic intracranial hemorrhage between treatment groups
• Favorable Functional Outcome (mRS 0 to 1 – Primary Outcome):
  • Tenecteplase: 32%
  • Alteplase: 51%
  • Unadjusted OR: 0.45; 95% CI0.25 to 0.80; p = 0.0064
• Any ICH
  • Tenecteplase: 21%
  • Alteplase: 7%
  • Unadjusted OR: 3.68; 95% CI 1.49 to 9.11; p = 0.0031
• 3 Month Mortality:
  • Tenecteplase: 16%
  • Alteplase: 5%
  • Unadjusted OR: 3.56; 95% CI 1.24 to 10.21; p = 0.013
• Symptomatic ICH:
  • Tenecteplase: 6%
  • Alteplase: 1%
  • Unadjusted OR: 6.57; 95% CI 0.78 to 55.62; p = 0.061

Strengths:

• 1^st phase 3 randomized clinical trial investigating the safety and efficacy of 0.4mg/kg tenecteplase in patients with moderate to severe stroke
• Outcome assessment at 3 months was blinded
• All patients enrolled were followed up within 14 days of the end of the 3 month follow up period
• Doctors and nurses in the stroke unit treating the patients during the post-thrombolysis hospital stay during the follow-up period were blinded to treatment group
• Funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report 

Limitations:

• Doctors and nurses providing care were not blinded to treatment
• Used a modified-intention-to-treat analysis (excluded patients who did not qualify for thrombolysis after randomization or who withdrew informed consent) which does not mimic real world practice (would need a non-modified full intention-to-treat analysis)
• Due to low number of patients unable to do sub-group safety analyses
• Groups not balanced at baseline, favoring the alteplase group
  • Patients were older
  • Less frequently had a mRS of 0 on admission
  • More ischemic stroke diagnosis, and less stroke mimic diagnosis
  • More patients in the alteplase arm were mRS 0 to 1 at baseline
• Primary outcome (modified Rankin Score) is subjective and has been previously shown to have low inter-rater reliability
• Initially a superiority trial but this was changed at some point to a non-inferiority trial

Author Conclusion: “In this prematurely terminated study (terminated to fulfill the prespecified safety criteria), tenecteplase at a dose of 0.4mg/kg yielded worse safety and functional outcomes compared with alteplase.  Our study consequently could not show that 0.4mg/kg tenecteplase is non-inferior to alteplase in moderate and severe ischaemic stroke.  Future stroke trials should assess a lower dose of tenecteplase versus alteplase in patients with moderate or severe stroke.”

Bottom Line: In patients with moderate to severe acute ischemic stroke tenecteplase at a dose of 0.4mg/kg resulted in worse favorable functional outcomes at 3 months in addition to higher rates of ICH, and mortality.

Discussion:

• We already reviewed a systematic review with meta-analysis on the comparison of Tenecteplase vs Alteplase in acute ischemic stroke on REBEL EM (Link is HERE)
  • Included 8 trials (6 RCTs & 2 observational trials) with 2031 patients
  • No difference in good functional outcomes (mRS 0 to 2) at 3 months
  • But Tenecteplase showed better recanalization (NNT = 9) and early neurologic improvement (NNT = 10)
  • Additionally, there was no difference in ICH, symptomatic ICH, or mortality
  • Bottom Line: Tenecteplase appears to be a reasonable alternative to alteplase with a similar safety profile with the added benefits of improving early neurologic improvement and recanalization (both surrogates of survival with good functional outcomes)
• In the TASTE-A trial, patients receiving tenecteplase on the MSU unit resulted in faster treatment, smaller post-treatment perfusion lesion volume, greater early clinical recovery, and no difference in safety concerns (hemorrhage or death) compared to alteplase.
  • Interestingly the authors focus on faster treatment and early improvement, but seam to completely ignore the fact that at 90 days there was no difference in neurologic outcomes at 90d by stating their study wasn’t powered for this (It also wasn’t powered for early improvement in neurologic status nor safety outcomes – i.e. secondary outcomes which are generally hypothesis generating)
  • Also, of note 18% of patients in the alteplase group and 25% of patients in the tenecteplase group had a ZERO-volume perfusion lesion on arrival to the receiving hospital (This could be due to the ultra-early thrombolysis, BUT could also be due to inclusion of stroke mimics)
• The original NOR-TEST trial (Published 2017) [3], enrolled adult patients with suspected acute ischemic stroke who were eligible for thrombolysis and admitted within 4.5hrs of symptom onset or within 4.5hrs of awakening with symptoms.
  • Patients were randomized to receive tenecteplase 0.4mg/kg (max 40mg) or alteplase 0.9mg/kg (max 90mg)
  • 1100 patients were randomized (however the majority had minor strokes)
  • The primary outcome was excellent neurologic outcome (mRS o to 1 at 3 months)
  • The primary outcome was achieved in 64% of patient in the tenecteplase arm and 63% in the alteplase arm by 3 months
  • The rate of death was 5% in both arms at 3 months
  • Authors concluded that tenecteplase was not superior to alteplase in efficacy and showed a similar safety profile
• NOR-TEST 2, Part A, compared 0.4mg/kg of tenecteplase to 0.9mg/kg of alteplase in patients with moderate to severe acute ischemic stroke ≤4.5hrs.
  • The trial was terminated early due to the high rate of bleeding and mortality with the 0.4mg/kg tenecteplase dosing
  • Favorable functional outcome at 3 months occurred less frequently in patients allocated to tenecteplase compared to alteplase
  • Additionally, rates of ICH, poor functional outcome, and mortality were all higher in the tenecteplase group compared to alteplase
  • Of note the 1% symptomatic intracranial hemorrhage rate seen in this trial is much lower than previous trials showing anywhere from 3 to 6%
• NOR-TEST 2, Part B, not yet published will be comparing 0.25mg/kg of tenecteplase to 0.9mg/kg of alteplase in patients with moderate to severe acute ischemic stroke ≤4.5hrs 

Clinical Take Home Point:

• The evidence for thrombolysis in general is not robust (only two positive trials – NINDS II and ECASS III), however patient selection practices have changed over the past few years with the use of CT angiogram, perfusion imaging, and mechanical thrombectomy for large vessel occlusions (i.e. there may be a population that benefits from thrombolysis, however this remains to be proven)
• Tenecteplase is cheaper than alteplase, can be administered as a single bolus (due to longer half-life than alteplase) allowing for more rapid treatment without the need for infusion pumps
• 0.4mg/kg of tenecteplase has had mixed results when compared to alteplase, and should not be used to treat acute ischemic stroke at this time
• 0.25mg/kg of tenecteplase could be the dose of choice for acute ischemic stroke that has thus far shown better recanalization rates and early neurologic improvement with a similar safety profile to alteplase, however evidence for long term neurologic outcomes still remain obscure. Hopefully, the NOR-TEST 2, Part B trial will help elucidate more patient oriented outcomes

References:

1. Bivard A 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. PMID: 35525251 (Access on Read by QxMD)
2. Kvistad CE 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. PMID: 35525250 (Access on Read by QxMD)
3. Logallo N et al. Tenecteplase Versus Alteplase for Managemetn of Acute Ischaemic Stroke (NOR-TEST): A Phase 3, Randomised, Open-Label, Blinded Endopoint Trial. Lancet Neurol 2017. PMID: 28780236 

For More Thoughts on This Topic Checkout:

• REBEL EM: Tenecteplase for Thrombolysis of AIS?

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

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