Randomized Trial of Tenecteplase Versus Alteplase for Acute Ischemic Stroke - Tenecteplase Versus Alteplase for Acute Ischemic Stroke

Apr 10, 2012
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Australian National Health and Medical Research Council
Date Published:
01/01/2012
Date Updated:
04/10/2012
Original Posted Date:
04/10/2012
References

Description:

Current guidelines recommend that intravenous alteplase (tPA) be administered for systemic fibrinolysis in patients presenting with acute ischemic stroke within 3 hours (Grade I) and within 4.5 hours (Grade IIC) of onset of symptoms. Tenecteplase (TNK) is a genetically modified version of tPA that has some pharmacokinetic benefits over tPA. The current phase II trial sought to compare outcomes in patients with acute ischemic stroke randomized to receive two low doses of TNK versus standard dose of tPA.

Hypothesis:

Intravenous low-dose TNK would be superior to standard-dose intravenous tPA in patients presenting with acute ischemic stroke.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age ≥18 years
  • First hemispheric stroke
  • NIHSS score >4
  • Premorbid modified Rankin score of ≤2
  • Presence of intracranial occlusion in the anterior cerebral, middle cerebral, or posterior cerebral artery on CT angiography (CTA) 
  • Infarct-core lesion on CT perfusion maps of cerebral blood volume had to be less than one third of the territory of the MCA or less than one half of the territory of the anterior cerebral or posterior cerebral artery

    Number of screened applicants: 2,768
    Number of enrollees: 75
    Duration of follow-up: 90 days
    Mean patient age: 70
    Percentage female: 50%

Exclusions:

  • Standard contraindications to intravenous fibrinolytic therapy
  • Acute internal-carotid-artery and vertebrobasilar occlusions on CTA

Primary Endpoints:

  • Percentage of the perfusion lesion that was reperfused 24 hours after treatment, as assessed on perfusion-weighted magnetic resonance imaging
  • Extent of clinical improvement at 24 hours, as measured by the change on the NIHSS score from before treatment to 24 hours after treatment

Secondary Endpoints:

  • Extent of infarct growth at 24 hours and at 90 days
  • Vessel recanalization at 24 hours

Drug/Procedures Used:

Patients were randomly assigned in a 1:1:1 ratio to the standard dose of tPA (0.9 mg/kg, the first 10% administered as an initial bolus and the remainder over a 1-hour period, with a maximum dose of 90 mg) or to TNK (0.1 mg/kg, administered as a single bolus, with a maximum dose of 10 mg; or 0.25 mg/kg, administered as a single bolus, with a maximum dose of 25 mg).

Concomitant Medications:

Antiplatelet agents (45%), anticoagulants (4%)

Principal Findings:

A total of 75 patients were randomized, 25 each to the two TNK and one tPA arms. About 20% had diabetes mellitus, and 38% had prior atrial fibrillation. The mean National Institutes of Health Stroke Scale (NIHSS) score was about 14.4, with a mean time to treatment from onset of symptoms of about 3 hours (2.7 hours for tPA and 3.1 hours for TNK). Only three patients were treated between 3 and 4.5 hours. The occlusion was usually in the proximal portion of S1 of the middle cerebral artery (MCA) (35%), distal portion of S1 of the MCA (30%), or S2 (14%).

The two co-primary endpoints: reperfusion at 24 hours (79.3% vs. 55.4%, p = 0.004) and improvement in NIHSS score between baseline and 24 hours (8.0 vs. 3.0, p < 0.001), were both superior in the TNK arms (pooled) as compared with tPA. Complete or partial recanalization of the infarct vessel at 24 hours was also superior (88% vs. 68%, p = 0.05). Clinically, good or excellent outcome at 90 days was more frequent in the TNK arms (72% vs. 44%, p = 0.02). On subgroup analysis, most outcomes were individually better in the 0.25 mg/kg TNK arm as compared with tPA (including 72% with excellent recovery at 90 days). Other than clinical improvement at 24 hours, other outcomes were similar between the 0.1 mg/kg TNK and tPA arms.

The safety endpoints of intracranial hematoma (4% vs. 12%, p = 0.33) and any parenchymal hematoma (6% vs. 20%, p = 0.11) were both lower in the TNK arms. Overall mortality rates were similar (8% vs. 12%, p = 0.68), as were the number of patients with poor outcome at 90 days (10% vs. 28%, p = 0.09). Bleeding outcomes were similar between the two TNK arms compared with tPA individually.

Interpretation:

The results of this trial indicate that intravenous TNK is superior to tPA for systemic thrombolysis in patients presenting with acute ischemic stroke within the therapeutic window. No increases in bleeding events were noted in this trial with TNK, although the sample size was small. On subgroup analysis, a dose of 0.25 mg/kg of TNK seemed to have the highest efficacy, with no increase in bleeding events. An earlier trial with 0.4 mg/kg of TNK had been stopped due to increased bleeding. Phase III trials are ongoing on this topic, and are eagerly awaited.

One major limitation of this trial is its generalizability—of more than 2,700 patients with acute stroke that were screened, only 22% were eligible for intravenous thrombolysis. Of these, only 21% further met the computed tomography (CT) selection criteria outlined in this trial. Eventually, only 3% of all screened patients could be randomized.

References:

Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012;366:1099-107.

Keywords: Stroke, Follow-Up Studies, Fibrinolytic Agents, Hematoma, Posterior Cerebral Artery, Middle Cerebral Artery, Time-to-Treatment, Intracranial Hemorrhages, Patient Selection, Tomography, Blood Volume, Fibrinolysis, Atrial Fibrillation, Tissue Plasminogen Activator, Diabetes Mellitus, Hemorrhage


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