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Tenecteplase surpasses alteplase for thrombolysing acute ischemic stroke

 

Key clinical point: Tenecteplase thrombolysis produced better reperfusion than did alteplase.

Major finding: Robust reperfusion occurred in 22% of tenecteplase patients and in 10% of patients who received alteplase.

Study details: EXTEND-IA TNK, a multicenter, randomized trial with 202 patients.

Disclosures: The study was investigator initiated and funded chiefly by the Australian government. Medtronic provided an unrestricted grant for trial infrastructure but had no role in study design conduct or analysis. Dr. Campbell and Dr. Powers had no disclosures.

Source: Campbell B et al. ISC 2018, abstract LB2

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More data needed to cement tenecteplase’s role

In the EXTEND-IA TNK study, tenecteplase appeared to act better than alteplase and has the extra advantage of being administered as a bolus injection. Alteplase is delivered as a drip, and it’s often hard to get patients with an intravenous infusion out of the hospital quickly when you have to transport the patient. You need a nurse in the ambulance monitoring the drip. With tenecteplase you administer the bolus and can then send the patient without an intravenous line.

Dr. Jeffrey L. Saver, professor of neurology, UCLA Mitchel L. Zoler/Frontline Medical News
Dr. Jeffrey L. Saver
Two other trials of tenecteplase, compared with alteplase, are now underway, so we’ll soon have a much larger evidence base for tenecteplase. This is the first large, multicenter, randomized trial to show an advantage for tenecteplase, but it failed to show a significant advantage for change in NIH Stroke Scale score. The results show a strong signal of benefit, but we need additional data from other trials.

Jeffrey L. Saver, MD, is professor of neurology and director of the stroke unit at the University of California, Los Angeles. He has received research support and personal fees from Medtronic-Abbott and Neuravia. He made these comments in an interview.


 

REPORTING FROM ISC 2018

– Thrombolysis with tenecteplase beat alteplase on an acute imaging endpoint in patients with acute ischemic stroke who were on their way to also get thrombectomy in a randomized, multicenter study with 202 patients in Australia and New Zealand.

The results of the trial, called Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK), showed that when the patients underwent their initial angiogram after receiving thrombolysis and before their thrombectomy procedure, the percentage of patients with robust blood flow – a Thrombolysis in Cerebral Infarction (TICI) score of 2b or 3 or no retrievable thrombus – was 22% in the patients treated with tenecteplase 0.25 mg/kg and 10% among those who received alteplase 0.9 mg/kg. After adjustment, the 12% incremental change in robust reperfusion with tenecteplase calculated into a 2.6-fold higher rate of robust reperfusion, statistically significant for both noninferiority and for superiority, Bruce C. Campbell, MBBS, PhD, said at the International Stroke Conference, sponsored by the American Heart Association.

Dr. Bruce C. Campbell, professor of neurology at the University of Melbourne and head of hyperacute stroke at Royal Melbourne Hospital. Mitchel L. Zoler/Frontline Medical News
Dr. Bruce C. Campbell
However, the results failed to show a significant between-group difference for improvement in National Institutes of Health Stroke Scale score 3 days after enrollment, which occurred in 72% of the tenecteplase patients and in 69% who received alteplase. The 90-day modified Rankin Scale score was 0-2 or unchanged from baseline in 65% of the tenecteplase and 52% of the alteplase patients, a difference that came close to but did not reach statistical significance (P = .06). All patients enrolled were on track to undergo thrombectomy if their angiogram showed continued occlusion, but Dr. Campbell did not report the actual number of patients who underwent this intervention.


Tenecteplase is a genetically-modified tissue plasminogen activator with enhanced fibrin specificity that increases the drug’s half life and allows for bolus administration, unlike alteplase, which needs continuous infusion (CNS Drugs. 2015 Oct;29[10]:811-8). Tenecteplase also has a U.S. wholesale price that is about $3,000 cheaper per vial than alteplase, said Dr. Campbell, professor of neurology at the University of Melbourne and head of hyperacute stroke at Royal Melbourne Hospital.

But further data are needed before tenecteplase is ready for routine use, conceded Dr. Campbell, an assessment other experts agreed with. Dr. Campbell cited two studies in progress that are comparing tenecteplase with alteplase in acute ischemic stroke patients not headed for endovascular thrombectomy, as well as a study he is leading that compares the tenecteplase dose he just tested, 0.25 mg/kg, with a higher dose, 0.40 mg/kg.

William J. Powers, MD, professor and chair of neurology at the University of North Carolina in Chapel Hill. Mitchel L. Zoler/Frontline Medical News
Dr. William J. Powers
“I don’t think the data [that Dr. Campbell reported] are sufficient to say that tenecteplase is equivalent to alteplase. This was studied in a very select group of patients who had large vessel occlusions and were transported to receive mechanical thrombectomy,” said William J. Powers, MD, professor and chair of neurology at the University of North Carolina in Chapel Hill. Most of the data on the efficacy of thrombolysis in ischemic stroke patients have involved alteplase, he noted. Tenecteplase (TNKase) has Food and Drug Administration marketing approval only for treating patients with an acute MI. Alteplase (Activase) has FDA approval for treating acute ischemic stroke. Both drugs are marketed by Genentech.

Several reports have appeared in recent years suggesting that treatment with tenecteplase seems to be at least as good as alteplase in ischemic stroke patients. For example, a randomized trial with 75 ischemic stroke patients selected by imaging at three Australian centers showed that treatment with tenecteplase produced a significant 24% improvement in the rate of arterial reperfusion and an average 5-point improvement in NIH Stroke Scale score (N Engl J Med. 2012;366[12]:1099-107). And results from the NOR-TEST study recently showed that among 1,100 patients randomized at 13 Norwegian centers, the primary outcome of a 90-day modified Rankin Scale score of 0-1 was achieved by 64% of the tenecteplase patients and by 63% of those who received alteplase (Lancet Neurol. 2017 Oct;16[10]:781-8).

The EXTEND-IA TNK trial ran during 2015-2017 at 18 hospitals. All enrolled patients received their thrombolytic treatment within 4.5 hours of their stroke onset, and underwent endovascular thrombectomy within 6 hours of onset. The safety outcomes of death, symptomatic intracranial hemorrhage, and parenchymal hematoma occurred at statistically similar rates in both treatment arms.

The study was investigator initiated and funded chiefly by the Australian government. Medtronic provided an unrestricted grant for trial infrastructure but had no role in study design conduct or analysis. Dr. Campbell and Dr. Powers had no disclosures.

SOURCE: Campbell B et al. ISC 2018, abstract LB2.

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