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Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA. 2020 Feb 20. pii: 2761799. doi: 10.1001/jama.2020.1511. (Original study)
Abstract

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase.

Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke.

Design, Setting, and Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria.

Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy.

Main Outcomes and Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death.

Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]).

Conclusions and Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.

Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.

Ratings
Discipline Area Score
Emergency Medicine 6 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Neurology 6 / 7
Hemostasis and Thrombosis 5 / 7
Comments from MORE raters

Emergency Medicine rater

Tenecteplase(or any thrombolytic medication) before mechanical thrombectomy is primarily a Stroke-Neurology level decision. EM physicians should not make this decision unilaterally without Stroke-Neurology, so this research is primarily of indirect relevance for Emergency Medicine.

Emergency Medicine rater

This is a well done randomized controlled trial comparing two doses of tenecteplase in patients with a stoke from a large vessel occlusion seen within 4.5 hours from onset. The two doses are 0.25 and 0.4 mg/kg. The trial was well done and showed no statistically significant difference in clinical or radiologic outcome; although, the symptomatic intracranial hemorrhage was 4.7% vs. 1.3% in the 0.4% and 0.25% mg/kg groups, respectively, a statistically non-significant difference. The conclusion of the authors appears to be that the lower dose is preferable.

Emergency Medicine rater

This is an extremely important study. There was residual uncertainty in the dosing of tenecteplase (TNK) for large vessel stroke. This study provides strong evidence (in a small sample) that 0.25 mg of TNK works just as well as 0.4 mg. Reperfusion at the time of thrombectomy was exactly the same. The distribution of functional outcomes on the modified Rankin was slightly better numerically (not different statistically). This strongly suggests that future study of different doses is not needed. TNK offers huge advantages over alteplase for patients having thrombectomy. It is given as a single bolus, so in contrast to alteplase, there is no chance of a problem with a one-hour infusion. When transferring patients, there is no messing with moving alteplase to an ambulance pump. TNK should replace tPA for anyone that appears to have large vessel stroke (arguably, it can simply replace tPA for all ischemic stroke).

Emergency Medicine rater

This is a well conducted RCT attempting, albeit somewhat indirectly, a relevant question yet to be addressed by national clinical guidelines. The study results should inform clinician's decision on initiation of intravenous thrombolytics at a reduced dose, to potentially minimize devastating intracranial bleeding. The fact that unadjusted RR of ICH with higher dose thrombolytics is triple of the reduced dose, should direct future studies to further elaborate on this matter.

Hemostasis and Thrombosis rater

As an Internal Medicine clinician with added certification in lipidology, I participate in Stroke Team Services. Although limited by size and open-label design, this trial is an important negative trial testing the superiority of tenecteplase. Its main utility, however, is limited to the stroke neurologists, interventionalists, and institutional P&T decision-makers.

Hospital Doctor/Hospitalists rater

An excellent study with very well done research. Although the authors note that the study is not sufficiently powered, the homogeneity of selected patients for either of the intervention groups means that the results could be extrapolated to a larger population and, as the authors mention, to patients with smaller strokes. The imagery is appropriate, relevant, and representative of the study. Overall, great quality work.

Internal Medicine rater

Head-to-head trial of the 2 candidate doses for tenecteplase (0.4mg/kg vs 0.25mg/kg) with no difference in efficacy. This is interpreted as the 0.4 dose not providing any additional benefit over the 0.25 dose. The authors note that they were significantly under powered to detect 3-5% clinically meaningful difference (would have needed 2400-6400 patients as opposed to the 300 that they randomized), but the primary outcome was identical at 19.3% in each group, so the observed results are likely reliable. With respect to side effects, however, the rate of intracranial bleeding with 0.4 vs 0.25 was 4.7% vs 1.3% with a p-value of 0.12. To me, this suggests the additional statistical power would have resulted in a meaningful difference in the safety outcome. Probably of more utility to neurology, but internists should maintain at least an awareness of the state of the art in this common condition.

Neurology rater

This randomized trial compared two doses of tenecteplase in persons with large-artery occlusion before endovascular therapy. Part 1 of the study showed that tenecteplase has a higher reperfusion/recanalization rate than alteplase. The study has limited relevance since regulatory agencies in most countries, including the U.S., have not approved tenecteplase as a treatment in acute ischemic stroke. This is a dosing comparison in which neither dose was superior in efficacy or safety. Society guidelines are already either recommending or considering treatment with tenecteplase instead of alteplase. This study will add to the evidence regarding the use of tenecteplase in acute ischemic stroke. There are ongoing studies that directly compare tenecteplase to standard alteplase.

Neurology rater

This RCT along with other previous trials is at the edge of changing treatment from tPA to TNK.
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