乌鸦传媒

LOS ANGELES -- Tenecteplase (TNKase) used off-label as the routine standard for stroke thrombolysis at one Texas stroke network was both feasible and safe, according to the early experience switching from alteplase (Activase).

In the first 50 cases, the proportion discharged to home able to ambulate independently was 46.0% compared with 33.0% among the 327 treated with alteplase in the prior 2 years, Steven Warach, of the University of Texas at Austin, .

No deaths occurred within 7 days of treatment, and the 4.0% in-hospital all-cause mortality compared favorably with alteplase's 6.1%. There were no symptomatic hemorrhagic transformations and 10 cases of small asymptomatic intracranial hemorrhage.

Should tenecteplase be the standard of care was one of many questions from the audience. "Every hospital, every provider needs to evaluate the data for themselves and reach that conclusion," Warach concluded.

His group was swayed, he said, by the prior data suggesting tenecteplase was at least noninferior to alteplase (and actually superior for large vessel cases headed to mechanical thrombectomy in the EXTEND-IA TNK trial), by its rapid preparation and delivery times, and by the over $3,000 cost-savings per patient for the drug alone.

The nine acute care hospitals in the Ascension Texas system -- with two comprehensive stroke centers and two primary stroke centers, that together care for about 1,250 ischemic strokes and administer IV thrombolysis to 150 annually -- all switched at the same time. Alteplase remained an option for strokes past 4.5 hours' onset, albeit an inconvenient one as it was taken out of the emergency department.

Lytic eligibility criteria and monitoring afterward remained the same as with alteplase.

Another trial presented at an ISC late-breaking session and online in JAMA, the , compared two doses of tenecteplase in 300 patients with large vessel occlusion ischemic stroke prior to thrombectomy in 28 centers in Australia and New Zealand.

A 0.40 mg/kg dose didn't improve >50% reperfusion of the previously occluded vascular territory compared with 0.25 mg/kg (19.3% vs 19.3%, adjusted RR 1.03, P=0.89). None of the functional outcome measures differed between groups, nor did all-cause deaths or symptomatic intracranial hemorrhage, reported Bruce Campbell, PhD, of Australia's Royal Melbourne Hospital.

"We chose the right dose," Warach noted. His center opted for 0.25 mg/kg.

Overcoming Concerns

At least one other U.S. hospital has also made the switch, Warach said -- Oregon Health and Science University's clinical center in Portland.

In New Zealand, a number of centers on the southern island with a catchment population of 800,000 have moved to tenecteplase, said Teddy Wu, MBChB, PhD, of Christchurch Hospital in New Zealand, who spoke with 乌鸦传媒 at the session.

After 170 cases in the last year and a half, there have only been two PH2 intracranial hemorrhages by the Heidelberg classification and a total of three symptomatic hemorrhages, he said. "But it's pretty safe, it's safer than what we had experienced with alteplase."

In the U.S., though, defensive medicine with an eye on legal concerns looms larger.

"People are still wary if you use a drug off-label and there is a complication when you have a drug that's on-label, you have to go and really defend why you did that," commented Larry Goldstein, MD, of the University of Kentucky in Lexington.

On the other hand, the guidelines say tenecteplase "could be considered," with a level 2b recommendation, he acknowledged in an interview.

"It always crosses people's minds," Warach agreed. However, "when I've discussed this with all of our stakeholders at our facility, legal didn't actually raise the objection. There are so many medicines we use that are not FDA approved for that indication, and it's really physician judgment and discretion. Even using alteplase 3 to 4-and-a-half [hours after stroke onset] is off-label."

Tenecteplase is still only and distributed in 50-mg vials.

Prospects for Tenecteplase

A single 5-minute bolus is a real advantage over bolus plus infusion, said Louise McCullough, MD, PhD, of the University of Texas Health Science Center at Houston, who was a moderator at the ISC late-breaking session. "You get the CT scan, no bleed; you get the tenecteplase, you're done. If you give the tPA [tissue plasminogen activator, alteplase], there's still an hour-long drip which really can slow down transfer."

The faster the reperfusion the better, and Warach's study -- while small -- supported the speed rationale for tenecteplase: with an intent to treat door-to-needle time of 50 versus 57 minutes overall and 47 versus 60 minutes for patients first seen at primary stroke centers. Based on the small number of patients who needed transfer for endovascular therapy, the door-in to door-out times were 85 versus 110 minutes.

Also, with tenecteplase "you know you're giving the full dose," Warach said, noting that people can be so keen to get the bolus of alteplase in they forget to have the infusion ready and then there's a gap.

With alteplase's 6-minute half life, "if you wait 5 minutes [between bolus and starting infusion], most of it is gone, you never actually achieve that serum concentration again, so the bolus is quite a big issue," Campbell noted.

What About Cost?

One advantage of tenecteplase is its lower cost relative to alteplase. But, said Campbell, "I hear people predicting that if it were really to be used [in stroke], the prices would probably equibrilate."

In New Zealand, for example, the price of tenecteplase rose over the space of 12 months by NZD$1,000 per vial, to where the cost savings is on the order of hundreds of dollars rather than thousands as in the U.S., Wu noted. "I was surprised."

"They're starting to get the idea it's happening," said Campbell. "It'll take a bit more time."

Nevertheless, he said, tenecteplase's clinical advantages would make its use worthwhile even if its cost rises to match alteplase.

While Genentech has raised the price of alteplase substantially over time and said in 2016 it was not interested in developing tenecteplase for stroke, it is now sponsoring the comparing tenecteplase to placebo in acute ischemic stroke patients who present from 4 to 24 hours after onset. Also, Wu, Campbell, and other groups are discussing pooling their data into a big international registry, Warach noted.