Tenecteplase vs Alteplase for Stroke

Susan Jeffrey

March 23, 2012

March 23, 2012 — Results of a small phase 2B trial comparing tenecteplase with alteplase for the treatment of ischemic stroke showed better perfusion and clinical outcomes with tenecteplase when patients were selected using computed tomography (CT) perfusion imaging.

In a window of upto 6 hours after symptom onset, a higher dose of genetically engineered mutant tissue plasminogen activator, tenecteplase (TNKase, Genentech), was found superior to a lower dose and to standard dose alteplase (Activase, Genentech) for all efficacy outcomes, including absence of serious disability at 90 days.

"The results of this study suggest that it is appropriate to proceed to a phase 3 trial of telecteplase vs alteplase in the time window that is currently approved for stroke thrombolysis," the researchers, with first author Mark Parsons, MD, from the department of neurology at the John Hunter Hospital Hunter Medical Research Institute at the University of Newcastle in Australia, conclude.

The trial results are published in the March 22 issue of the New England Journal of Medicine.

Alteplase 'Far From Ideal'

Currently, intravenous alteplase given within 3 hours of symptom onset is the only drug approved by the US Food and Drug Administration (FDA) for treatment of ischemic stroke. That treatment window was recently lengthened to 4.5 hours according to an American Heart Association/American Stroke Association science advisory, based on results of the European Cooperative Acute Stroke Study 3 (ECASS 3) study, though the FDA has not yet approved the extended window.

However, the authors write, "alteplase is far from ideal, with incomplete and often delayed reperfusion in many patients."

Tenecteplase, "has some pharmacokinetic advantages over alteplase," they note. This agent is already used to treatment myocardial infarction (MI), but a previous study showed a lower dose than that used for MI provided the best balance of efficacy and risk. In a nonrandomized pilot trial, these same researchers found stroke patients selected using CT perfusion who received tenecteplase at a dose of 0.1 mg/kg had better outcomes on imaging, including better reperfusion and less infarct growth, and greater early clinical improvement than those treated with a standard dose of alteplase.

In the present study, Dr. Parsons and colleagues randomly assigned 75 patients within 6 hours of symptom onset to receive either alteplase at the standard dose of 0.9 mg/kg of body weight, or tenecteplase in 1 of 2 doses, 0.1 mg/kg or 0.25 mg/kg of body weight. To find patients most likely to benefit from treatment, the authors note, eligibility criteria included a perfusion lesion at least 20% greater than the infarct core on CT perfusion imaging at baseline, and an associated vessel occlusion on CT angiography.

Coprimary endpoints were the proportion of the perfusion lesion that was found to be reperfused at 24 hours on perfusion-weighted magnetic resonance imaging, and clinical improvement at 24 hours on the National Institutes of Health Stroke Scale (NIHSS).

At baseline, the mean NIHSS score for these patients was 14.4 ± 2.6, and time to treatment was 2.9 ± 0.8 hours.

"Together, the 2 tenecteplase groups had greater reperfusion (P = .004) and clinical improvement (P < .001) at 24 hours than the alteplase group," the researchers write.

Table. Coprimary Outcomes: Alteplase vs Tenecteplase (Both Doses)

Endpoint Alteplase Tenecteplase 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

NIHSS = National Institutes of Health Stroke Scale; SD = standard deviation

"The improved reperfusion and clinical response with tenecteplase did not come at a cost of increased intracranial hemorrhage," they note. No significant difference was seen in intracranial bleeding or other adverse events between groups.

A dose-response was also seen, with the higher dose of tenecteplase superior to both the lower dose and to alteplase for all efficacy outcomes, including absence of disability at 90 days that was seen in 72% of the combined tenecteplase patients vs 40% with alteplase (P = .02).

Their results suggest a phase 3 trial within the 3-hour time window approved for alteplase is in order, they conclude, and suggest that the dose-response they saw justifies use of the 0.25 mk/kg dose of tenecteplase as the comparator.

They note though, that in this study, patients were selected using CT perfusion and angiography, and so a large number of patients who were eligible for thrombolysis on the basis of standard clinical and noncontrast CT scans were excluded.

"We therefore cannot extrapolate our results to the majority of patients who are eligible for thrombolysis," Dr. Parsons and colleagues conclude. "A phase 3 study would be needed to determine whether the efficacy of tenecteplase extends to this broader population of patients."

Cautious Assessment

Asked for comment on these new findings, Mark Alberts, MD, professor of neurology and director of the Stroke Program at Northwestern University and Northwestern Memorial Hospital in Chicago, Illinois, said the results were interesting, but was cautious in his assessment.

"I think this is a small but intriguing study," he told Medscape Medical News. "There are some significant limitations due to the small number of patients and the study design."

For example, there appeared to be more severe strokes and more proximal middle cerebral artery occlusions in the alteplase group, strokes that are known not to respond as well to any type of therapy, and have higher complication and lower recovery rates. "So with only a small number of patients in any group, only 25, it makes it hard to draw any definitive conclusions," he said.

In addition, Dr. Alberts had questions about the blinding, and pointed out that the study primary endpoint was changed during the study, from absolute volume change to proportional change, based on study results published in the meantime. Further, it is already known that alteplase in the 6-hour time window is "not particularly safe or effective."

Still, he said, "at the end of the day, the tenecteplase group seemed to do better, they seemed to have less bleeding complications, and more efficacy, but I think it would be very preliminary to draw any firm conclusions from it.

"I think the results are intriguing and may lead to a larger prospective, double-blind, randomized trial, of maybe tenecteplase vs alteplase with some logical time window," he said.

Philip B. Gorelick, MD, MPH, medical director at the Hauenstein Neuroscience Center, Saint Mary’s Health Care in Grand Rapids, Michigan, who also was not involved in the study, noted that the theoretical advantages of tenecteplase include higher fibrin specificity, reduced binding affinity to plasminogen activator inhibitor (PAI-1), a longer half-life, and a rapid single bolus infusion.

The current study, "may be considered a 'high-tech' one in that CT angiography was used to select eligible patients," he said, from those with intracranial occlusion of the anterior, middle, or posterior cerebral artery, and CT perfusion was used to find those patients with perfusion lesions at least 20% greater than the infarct core.

"In this small study of 25 patients per treatment group, time to treatment was slightly under 3 hours, baseline NIHSS scores were in the moderate range (mean of 14.4), and the tenecteplase groups had greater reperfusion and clinical improvement at 24 hours, but no significant between-group differences in intracranial bleeding or other serious adverse events,” Dr. Gorelick told Medscape Medical News. Complete, or at least partial or complete revascularization, also favored tenecteplase, as did most of the secondary outcomes, he noted.

"These data serve to encourage the development of a phase 3 study featuring tenecteplase," he said. He also cautioned that phase 2B study methodology is limited by relatively small numbers of participants, and other predictor variables that were not the focus of this particular study, such as the status of collateral blood flow, blood glucose levels, and complications such as infections, all of which may influence neurologic outcomes.

Furthermore, he adds, 90-day clinical outcomes are usually the gold standard or key primary outcome, and may be challenging to meet even though imaging outcomes are favorable.

"Since most of the phase 2B patients in this trial had middle cerebral artery occlusions, the next step to develop a phase 3 trial will be challenging, as one will need to consider incorporation of a mechanical clot retrieval device treatment arm, given the results of SWIFT," he added, referring to results of the Solitaire With Intention for Thrombectomy trial of the Solitaire clot retrieval system that was also recently approved by the FDA.

Recruitment to such a study may be made more difficult by the views of physician and regulators about thrombolytic medications and the use of clot retrieval devices, he said.

The study was funded by the Australian National Health and Medical Research Council. Disclosures for the researchers are available at www.nejm.org.

N Engl J Med. 2012;366:1099-1107. Abstract

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