Is Tenecteplase Ready for Prime Time in Acute Stroke?

Whether the evidence supports wider use of tenecteplase (TNKase; Genentech)—a thrombolytic agent with an indication for acute MI—as an alternative to alteplase (Activase; Genentech) for the treatment of acute ischemic stroke was hashed over by two well-known combatants during the virtual International Stroke Conference 2021 this week.

Jeffrey Saver, MD (University of California, Los Angeles), argued that data from several small trials show that tenecteplase not only provides noninferior outcomes compared with alteplase, but also has some practical advantages. That includes single-bolus administration, which avoids the hour-long infusion required for alteplase and may speed the transfer of patients who need thrombectomy to another center.

“Tenecteplase is ready for prime time,” Saver said.

But Patrick Lyden, MD (University of Southern California, Los Angeles), countered that the head-to-head studies performed to date are not sufficient to prove that tenecteplase stands up well to alteplase, at least when it comes to how patients do 3 months after treatment. Lyden helped lead the NINDS trial, published in 1995, which established the efficacy of alteplase for improving clinical outcomes for patients with acute ischemic stroke.

“We don’t have the definitive phase III trial that we need,” Lyden said, adding that “we do not yet know the optimal dose.”

Despite the fact that tenecteplase lacks an approved indication for acute ischemic stroke and a conclusive head-to-head trial has not yet been completed, some centers are starting to adopt tenecteplase based on its ease of use.

Steven Warach, MD (University of Texas at Austin), who gave a separate talk describing his center’s switch from alteplase to tenecteplase as the preferred thrombolytic for acute stroke in September 2019, recounted something E. Clarke Haley, MD (University of Virginia, Charlottesville), another leader of the NINDS trial, told him last year: “The ongoing trials are necessary and important, but to justify the switch to tenecteplase, it only needs to be noninferior to alteplase.”

‘More Than Sufficient Evidence’

Arguing in favor of tenecteplase, Saver noted that it is a “designer drug,” a variant of alteplase modified to have a longer half-life, increased fibrin specificity and resistance to PAI-1 inactivation, and decreased thrombin activation. “As a result, it is designed to give more reperfusion, faster reperfusion, reduced bleeding, and one-time bolus administration,” he said.

Saver provided a list of several desirable attributes that would support adoption of a novel drug in routine clinical practice, describing how tenecteplase checks all the boxes with a well-characterized mechanism of action, strong preclinical data, and evidence of safety and efficacy in a closely related condition (acute MI).

Moreover, its administration in a 1-minute bolus—as opposed to the 1-hour infusion for alteplase—is a distinct advantage. Most paramedics are not equipped to handle an infusion pump, which would be necessary to transfer a patient to a thrombectomy-capable center during an alteplase infusion, so use of tenecteplase instead would allow for immediate transfers in more cases.

This feature of tenecteplase is especially important during the COVID-19 pandemic, Saver said, because it avoids the need for someone to come in repeatedly to check an infusion pump, a process associated with increased use of personal protective equipment and a greater risk of infection for both patients and hospital staff.

The evidence is there to support its use, too, Saver said. In an updated meta-analysis of five head-to-head RCTs with a total of 1,585 patients, also reported at the meeting, the proportion of patients who were disability-free—modified Rankin Scale (mRS) score of 0 to 1—at 3 months was similar in the tenecteplase and alteplase arms (58.1% vs 54.6%). Noninferiority criteria were met for that outcome, as well as other functional status endpoints, symptomatic intracranial hemorrhage, and mortality. If 1,000 patients are given tenecteplase instead of alteplase, the most likely estimate is that 36 more patients will recover without disability and the worst possible estimate is that four fewer would be nondisabled, Saver reported.

Also bolstering the case for tenecteplase, he said, is that it has been included as an option in practice guidelines covering about half of the world’s population; has received “implicit endorsement” from the US Food and Drug Administration by its addition to the protocol of an ongoing trial as a standard-of-care thrombolytic; and has been adopted in routine care in some places. Earlier this month, Saver pointed out, tenecteplase was added to ambulances of the Los Angeles EMS agency and to the UCLA mobile stroke unit.

“There is more than sufficient evidence to make this reasonable to use in clinical practice,” Saver concluded.

Missing the Definitive Trial

Lyden began his counterargument by pointing to a commentary he published in the International Journal of Stroke about a decade ago. In it, he writes that tenecteplase, though it shows promise and has potential advantages over alteplase, cannot be recommended for routine use in acute ischemic stroke because the correct dose is unknown. He says a large, multicenter RCT with proper randomization and blinding is needed to compare the two agents.

During the debate, Lyden indicated his view is not that different in 2021. Alteplase is a proven thrombolytic that works out to a long time window, can be enhanced through the use of image-guided selection criteria, and is supported by multiple trials that used the 3-month mRS score as the primary outcome, he said.

On the other hand, the five trials included in the meta-analysis cited by Saver did not have the 3-month mRS score as a primary outcome. Lyden said efficacy at the 3-month time point is the key question.

Thus, Lyden said, claiming the noninferiority of tenecteplase versus alteplase in terms of reperfusion is “perfectly appropriate and we can all agree, but a claim of noninferiority for a 3-month Rankin outcome simply stretches ‘credulibility.’”

In his rebuttal, Saver latched onto Lyden’s concession that tenecteplase has been proven noninferior in terms of its ability to dissolve clots. “If you think that these lytics work by opening arteries, Dr. Lyden just agreed that it’s equally good,” Saver said. “If you think these work by some other mechanism, go ahead, keep using alteplase. But for the clot openers, TNK’s okay.”

Is Noninferiority All You Need?

Providing some context to the debate was a talk by Shelagh Coutts, MD (University of Calgary, Canada), who is the principal investigator of the ongoing TEMPO-2 trial comparing tenecteplase with standard-of-care antiplatelet therapy in patients with minor ischemic stroke. She reviewed the trials comparing tenecteplase with alteplase conducted so far, and acknowledged that they have been limited, primarily by small sample sizes.

What we need to do better as a stroke community is stop thinking we know the answer when we don’t and stop giving opinions. Shelagh Coutts

Overall, the data derived from these studies regarding the safety and efficacy of tenecteplase are exciting and suggestive that it might be a better drug, but, Coutts said, “I don’t think we have proof yet.”

She called for more data. “To change the entire juggernaut of systems all over the world, we need good data. And let’s just prove it. Let’s do these trials quickly,” she said, noting that several trials are ongoing with sizes ranging from 456 to 1,870 participants.

“My plea is randomize the patients,” Coutts urged. “What we need to do better as a stroke community is stop thinking we know the answer when we don’t and stop giving opinions. And let’s just turn into trial machines and get data and improve our care for our patients.”

Ultimately, though, tenecteplase doesn’t have to provide superior outcomes compared with alteplase, Coutts said, agreeing with the sentiment conveyed by Warach. “I always say that whatever happens in the trials, as long as tenecteplase is as good as [alteplase], that’s going to be enough, because a single bolus for drip and ship for going to [endovascular therapy] is much, much easier for everybody involved.”

Data presented by Warach seem to confirm that advantage for tenecteplase. After tenecteplase was adopted as the standard of care at his center, times to treatment fell, transfer times dropped, and there were fewer unfavorable outcomes at discharge and similar rates of favorable outcomes. And, Warach reported, there was estimated pharmacy cost savings over 1 year of about $400,000 due to the lower cost per dose of tenecteplase.

At the end of the debate, an informal poll with more than 500 votes showed that 75% of respondents felt tenecteplase is ready for use in clinical practice, with a minority disagreeing.