Final results of the EXTEND-IA TNK trial, suggesting better outcomes with tenecteplase than alteplase in the treatment of acute ischemic stroke, have now been published in the New England Journal of Medicine.
The study, which was first presented at the International Stroke Conference in Los Angeles, California, in February, showed that tenecteplase given before thrombectomy was associated with a higher incidence of reperfusion and possibly also better functional outcome than alteplase among patients with a large-vessel occlusion treated within 4.5 hours after symptom onset.
In the paper, the researchers, led by Bruce Campbell, MD, Royal Melbourne Hospital, Australia, note that alteplase is given as an infusion over a period of approximately 1 hour and has been associated with a low rate of reperfusion for large-vessel occlusion before thrombectomy in several trials. Tenecteplase is a genetically modified variant of alteplase with greater fibrin specificity and a longer half-life that permits bolus administration.
For the study, 202 patients eligible for thrombectomy were randomly assigned to receive tenecteplase (at a dose of 0.25 mg/kg; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg/kg; maximum dose, 90 mg) within 4.5 hours after symptom onset.
The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. This occurred in 22% of the patients treated with tenecteplase vs 10% of those treated with alteplase (incidence ratio, 2.2; 95% confidence interval [CI], 1.1 – 4.4; P = .002 for noninferiority; P = .03 for superiority).
Tenecteplase also resulted in a better 90-day functional outcome than alteplase (median modified Rankin Scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 – 2.8; P = .04).
Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group.
The authors explain that they expected the effect on the clinical outcome of endovascular thrombectomy to obscure any potential difference between tenecteplase and alteplase and therefore chose the technical efficacy of substantial reperfusion for the primary outcome.
However, patients in the tenecteplase group had significantly better functional outcomes than those in the alteplase group in an ordinal analysis of the modified Rankin Scale scores but not according to the proportion of patients who were left with minimal or no deficit or to the proportion of patients with early clinical improvement of their stroke deficit.
The authors point out that most patients who are treated with thrombolysis do not have reperfusion of the occluded vessel before thrombectomy. The incidence of reperfusion of 10% that was observed with alteplase in the present trial was similar to the 11% seen in the EXTEND-IA trial of alteplase plus endovascular thrombectomy. That trial included patients with a distribution of vessel occlusions similar to the one in the present trial.
The researchers suggest that the ability to administer tenecteplase in a single bolus, as compared with the 1-hour infusion of alteplase, may be of practical benefit in patients with stroke with large-vessel occlusion who are transported between, as well as within, hospitals to access endovascular thrombectomy.
Finding the Optimal Dose
They point out that the dose of tenecteplase (0.25 mg/kg) was chosen on the basis of previous data that showed better outcomes with this dose thanwith a dose of 0.1 mg/kg.
Noting that another recent study (NOR-TEST) has found — contrary to a previous dose-finding trial — that a higher dose of 0.4 mg/kg was not associated with an increased incidence of symptomatic intracerebral hemorrhage, they suggest this higher dose may be beneficial in patients with large-vessel occlusion given the large clot burden. This dose is being studied in a new trial (EXTEND-IA TNK Part 2).
In an accompanying editorial, Alison E. Baird, MD, SUNY Downstate Medical Center, New York City, says the additional thrombectomy procedures that were averted with tenecteplase in the present trial highlight the benefit and convenience of this therapy as compared with alteplase.
But she cautions that further trials are needed with clinically relevant primary outcome measures.
Baird adds that the current trial has paved the way for tenecteplase to provide an alternative or replacement for alteplase in patients undergoing bridging therapy for acute stroke and to avoid thrombectomy procedures in some patients.
And she notes that two other ongoing trials (TASTE and ATTEST2) are evaluating tenecteplase vs alteplase in stroke patients not expected to proceed to thrombectomy.
“Changes to practice would require not only further demonstration that tenecteplase is noninferior or superior in clinical efficacy to alteplase but also evidence of convenience, accessibility, affordability, and practicality,” she concludes. “Tenecteplase could tick all these boxes.”
The EXTEND IA trial was supported by grants from the National Health and Medical Research Council of Australia, the Royal Australasian College of Physicians, the Royal Melbourne Hospital Foundation, the National Heart Foundation of Australia, and the Stroke Foundation of Australia, by infrastructure funding from the state government of Victoria, and by an unrestricted grant from Medtronic.
N Engl J Med. Published April 26, 2018. Abstract, Editorial
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