A Randomized Controlled Trial of Lactobacillus GG in ...



Parsons et al. A randomized trial of Tenecteplase vs. Alteplase for Acute Ischemic Stroke | |

|Background |The only approved thrombolytic agent for acute ischemic stroke is IV alteplase (tPA). | |

| |Tenecteplase (TNK), a genetically engineered mutant tissue plasminogen activator (already used for MI) is an | |

| |alternative thrombolytic agent. | |

| |Theoretical advantages of TNK: Higher fibrin specificity, reduced binding affinity to plasminogen activator | |

| |inhibitor (PAI-1), a longer half-life, and a rapid single bolus infusion. | |

|Rationale |tPA leads to incomplete and delayed reperfusion in many patients. | |

| |TNK has some pharmacokinetic advantages over tPA | |

| |Dose ranging study of TNK in stroke tx showed that 0.4 mg/kg dose was associated with excess intracranial | |

| |hemorrhage. | |

| |Nonrandomized pilot trial showed that TNK dose of 0.1 mg/kg had superior outcomes on imaging and clinical | |

| |improvement vs. tPA dose of 0.9 mg/kg | |

|Objective |To compare standard dose of tPA with 2 different doses of TNK in patients with acute ischemic stroke. |The study asked a clearly focused |

| |1° hypothesis: TNK is superior to tPA with respect to one or both coprimary outcomes (% reperfusion and changes in |question. |

| |the NIHSS score at 24 hrs) | |

|Trial Design |Phase 2 B trial, randomized, open, blinded trial. Central block randomization by means of central telephone service |Randomized |

| |in blocks of 15 patients. |Treating clinician aware of |

| |Trial conducted from 2008-2011, 3 large stroke centers in Australia |treatment assignments |

| |CT perfusion and angiographic imaging used to select patients who would be the most likely to benefit from early | |

| |reperfusion (i.e. patients with large-vessel occlusion and a perfusion lesion at least 20% greater than the infarct |Allocation concealment performed |

| |core on CT perfusion imaging). | |

| | | |

| |Assessors of imaging outcomes and trained observers unaware of tx assignment and clinical information. | |

|Patient Population |With acute ischemic stroke selected based on CT perfusion and angiographic imaging. | Exclusion Criteria? Lots of pts |

| |2768 patients screened for participation. 75 underwent randomization (See page 4). |excluded |

| |Specific additional advanced imaging criteria: Large # of patients who were eligible for thrombolysis on the basis | |

| |of standard clinical and noncontrast CT were excluded. |Differences b/w groups with respect|

| |Significant differences between groups: tPA group had fewer people with diabetes, fewer smokers and a lower mean |to baseline characteristics |

| |blood glucose level. | |

| | |Small sample size |

|Eligibility |Inclusion Criteria: |tPA group seemed to have more |

| |First ever hemispheric ischemic stroke who were > 18 years of age |proximal middle cerebral artery |

| |NIHSS > 4 (National Institutes of Health Stroke Scale) |occlusions strokes vs. TNK group. |

| |mRS < 2 (modified Rankin scale) | |

| |Exclusion Criteria: | |

| |Standard contraindications to tPA, Specific imaging exclusion criteria | |

| |Specific Selection Criteria: | |

| |A perfusion lesion of at least 20% > than the infarct core on CT perfusion imaging at baseline and an associated | |

| |vessel occlusion on CT angiography. | |

|Intervention |Before randomization: CT perfusion and angiographic imaging |6 hours? |

| |Time of administration of thrombolytic: within 6 hours after onset of stroke | |

| |MRI @ 24 hours after treatment and 90 days for assessment of imaging outcomes | |

| | | |

| |75 patients underwent randomization: 3 groups of 25 each received tPA (0.9 mg/kg), TNK (0.1 mg/kg) and TNK (0.25 | |

| |mg/kg) | |

|Outcomes |1° imaging efficacy outcome: Reperfusion at 24 hr |Trial end points modified before |

| |1° clinical efficacy outcome: Improvement in NIHSS score b/w baseline and 24 hr |the end of the trial. |

| |2° imaging efficacy outcome: Infarct growth at 24 hr and at 90 days, complete recanalization at 24 hr, complete or |1° outcome Reperfusion changed from|

| |partial recanalization at 24 hr |absolute volume change to |

| |2° imaging safety outcome: Large parenchymal hematoma, any parenchymal hematoma, symptomatic intracranial hematoma |proportional change. |

| |2° clinical efficacy outcome: major neurologic improvement at 24 hr (reduction of >8 in NIHSS score), excellent |Infarct growth replaced “mismatch |

| |recovery (mRS= 0 or 1) at 90 days, excellent or good recovery (mRS= 0 to 2)at 90 days |salvage” (volume of penumbra that |

| |2° clinical safety outcome: poor outcome (mRS 5 or 6) at 90 days, death |did not grow into infarct) as 2° |

| |Post hoc secondary imaging outcome: volume reperfusion at 24 hr, mismatch salvage at 24 hr, mismatch salvage at 90 |outcome. |

| |days | |

| | |Post hoc analysis of original end |

| | |points performed |

|Statistics |Alpha level = 0.025 prespecified for 2 primary end points | |

| |Sample size calculated on the basis of pilot study, power set at 80% and an assumption of superiority with respect | |

| |to one of the two coprimary outcomes. | |

| | | |

| |Testing of 1⁰ hypotheses: Unadjusted student’s t-test of means. | |

| |Analysis repeated after adjustment for potential confounding baseline variables. | |

| |Testing of 2° outcomes with a nonparametric distribution: Wilcoxon rank-sum test. | |

| |Comparison of categorical variables: Chi-square test of proportions or Fisher’s exact test | |

|Results – Efficacy |Endpoint |Pooled TNK (50 patients) compared |

| |Alteplase |to tPA alone (25 patients), |

| |Tenecteplase |appropriate to compare? |

| |P Value | |

| | | |

| |Reperfusion at 24 hours (%, SD) | |

| |55.4 ± 38.7 | |

| |79.3 ± 38.7 | |

| |.004 | |

| | | |

| |Improvement in NIHSS score from baseline to 24 hours (points, SD) | |

| |3.0 ± 6.3 | |

| |8.0 ± 5.5 | |

| |< .001 | |

| | | |

| |Mean (+ SD) NIHSS score at baseline: 14.4+2.6 | |

| |Time to treatment: 2.9+0.8 hrs | |

| |Beneficial for 2° outcomes: Infarct growth was ↓, a higher proportion of patients had an excellent or good recovery | |

| |(mRS of 0-2 at 90 days (72% vs. 44%, P=0.02) | |

| | | |

| |Higher dose of TNK superior to lower dose and tPA for all efficacy outcomes. | |

| | | |

| |Excellent recovery (no clinically significant disability) in 72% vs. 40% in tPA (P=0.02) | |

| | | |

| |Lower dose of TNK vs. tPA: Greater clinical improvement at 24 hrs with lower dose (P=0.04), other efficacy outcomes | |

| |were equivalent | |

|Results – Safety |No significant between group differences in intracranial bleeding or other serious adverse events but more patients | |

| |had parenchymal hematoma in tPA grpup (4% vs. 16%) | |

|Authors’ conclusion|TNK associated with significantly better reperfusion and clinical outcomes vs. tPA in patients with stroke selected | |

| |on the basis of CT perfusion imaging. | |

|Bottom Line |The results do favor TNK but it is too early to draw any definitive conclusions. | |

|Application to |Results cannot be extrapolated to majority of patients who are eligible for thrombolysis. | |

|Clinical Practice | | |

| |6 hours of window to administer thrombolytic (only 3 patients were treated after 4.5 hrs)? Previous studies have | |

| |shown that 6 hour window is not effective or safe. | |

| | | |

| |Phase 3 trial should be conducted to determine whether same results can be established in a broader population of | |

| |patients | |

Appendix:

NIHSS (National Institute of Health Stroke Scale): 42 point scale that quantifies neurologic deficits in 11 categories, with higher scores indicating more severe deficits.

mRS (modified Rankin Scale (ranges from 0-6)

0: no symptoms, 1: minor but no clinically significant disability, 2: slight disability, 6: death

Recovery assessed with mRS:

Excellent recovery: Score of 0 or 1

Excellent or good recovery: 0-2

Poor outcome: 5 or 6

Mismatch salvage: Volume of mismatch on CT perfusion imaging at baseline that did not progress to infarction

Symptomatic intracranial hematoma: Large parenchymal hematoma and clinical worsening (an increase in the NIHSS score of > 4)

CT angiographic criterion: Presence of intracranial occlusion in anterior, cerebral, middle cerebral or posterior cerebral artery. Excluded patients with internal carotid artery and vertebrobasilar occlusions

CT perfusion criterion: Hemispheric perfusion lesion on transit-time maps that was at least 20% > infarct-core lesion, with a volume of at least 20 mL. The infarct-core lesion on CT perfusion maps of cerebral blood volume had to be < 1/3 rd the territory of the middle cerebral artery or < ½ the territory of the anterior cerebral or posterior cerebral artery.

References:

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

2. Jeffrey S. Tenecteplase vs. alteplase for stroke. Medscape [cited Apr 10 2012]. Available from:

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