Tenecteplase on Par With Alteplase, Randomized Trial Affirms

DALLAS -- Tenecteplase (TNKase) did as good a job at ischemic stroke thrombolysis as did alteplase (Activase) for patients presenting within 4.5 hours of symptom onset in the randomized TRACE-2 trial from China.

The proportion of patients with little to no disability at 90 days, as marked by a modified Rankin Scale (mRS) score of 0-1, was 62% with tenecteplase and 58% with alteplase (RR 1.07, 95% CI 0.98-1.16), meeting noninferiority criteria by excluding the likelihood of more than a 3.74% absolute risk difference.

Symptomatic intracranial hemorrhage risk was identical in the two groups at 36 hours (2% in both), Shuya Li, MD, of Beijing Tiantan Hospital at Capital Medical University in Beijing, reported at the American Stroke Association International Stroke Conference.

Mortality risk within 90 days likewise was similar with tenecteplase and alteplase (7% vs 5%; RR 1.31, 95% CI 0.86-2.01).

"This randomized controlled trial provides further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke," the researchers concluded in a paper published in conjunction with the presentation in The Lancet.

Two other large phase III trials, NOR-TEST 1 from Norway (using a higher 0.4 mg/kg dose of tenecteplase) and AcT from Canada (using the same 0.25 mg/kg dose as in TRACE-2) have also shown noninferiority to alteplase in acute ischemic stroke within 4.5 hours of symptom onset. However, the NOR-TEST 2 trial -- stopped early after enrollment of 216 patients -- had failed to show noninferiority of tenecteplase at the 0.4 mg/kg dose and actually showed poorer outcomes compared with alteplase.

The negative NOR-TEST 2 trial results had been chalked up to baseline imbalances in the treatment groups and the higher dose of tenecteplase that was administered, but there were calls for replication of the positive findings with the more common 0.25 mg/kg dose.

The TRACE-2 trial also clarified generalizability to Asian populations, Li noted.

Replication was nice, but "the reality is the field is already moving away from alteplase to tenecteplase," commented Mark Alberts, MD, chief of neurology at the Hartford Hospital in Connecticut.

His hospital system is one of the many in the midst of switching to tenecteplase, he said: "There are several driving forces. You have more and more studies supporting it, you have the simplicity of giving it via a bolus and not a bolus and drip, then you have the cost factor ... a very significant factor."

It also means easier transfer between hospitals for patients, noted an accompanying editorial in The Lancet led by Bijoy Menon, MD, of the University of Calgary in Alberta. Nevertheless, they agreed: "Similar or better patient outcomes and more efficient workflow at lower cost is the impetus that is needed to increase the use of intravenous thrombolysis in many low-income and middle-income countries. The actual economic benefits are, however, likely to be different between countries and will need further analyses."

Tenecteplase does not have a label indication for use in acute ischemic stroke, and it's not clear what it would take to get there, added Larry Goldstein, MD, co-director of the Kentucky Neuroscience Institute in Lexington and an American Heart Association volunteer expert. But if the FDA were to require a confirmatory U.S. trial, equipoise remains, given that the trials have shown noninferiority rather than superiority for the 0.25 mg/kg dose, he said.

The phase III trial randomized 1,430 adult ischemic stroke patients (mean age 65-67, about one-third female) eligible for thrombolysis at 53 sites in China to receive either tenecteplase at a dose of 0.25 mg/kg up to a maximum of 25 mg, given as a single IV bolus immediately upon randomization, or alteplase at a dose of 0.9 mg/kg up to a maximum of 90 mg, given as a 10% bolus and the rest over a 1-hour infusion.

The drug was given open-label. Enrolled patients had to present within 4.5 hours of symptom onset, have an NIH Stroke Scale (NIHSS) score of 5 to 25 (mean 7), and premorbid mRS of 0-1. Those expected to go for endovascular treatment were excluded.

Results from a per-protocol analysis were similar to the main findings from the modified intention-to-treat analysis.

Among the secondary findings, tenecteplase compared with alteplase yielded no significant differences in the following:

• Proportion with an mRS score of 0-2 at 90 days (73% vs 72%)
• Ordinal mRS at 90 days (1 in both groups)
• Improvement on NIHSS of ≥4 points or score ≥1 at 24 hours (50% vs 49%)
• European quality-of-life visual analog scale score (77.7 vs 76.4)
• Barthel index ≥95 (70% vs 69%)

No subgroups stood out for differential impact of one lytic versus the other.

Among the safety outcomes, symptomatic intracranial hemorrhage and any significant hemorrhage within 90 days both came out identical between groups, at 2% and 1%, respectively. Overall and serious adverse events were equally common as well (86% vs 87%, P=0.57; and 16% vs 15%, P=0.55).

Limitations of the study included the open-label design and exclusion of patients with more disabling strokes eligible for endovascular thrombectomy, "which might limit the generalizability of the findings to more severely affected patients who could have a higher risk of intracranial hemorrhage," the researchers noted.

Although the trial was done in an Asian population, the findings would likely be generalizable to the U.S. population, Alberts suggested.