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Health Systems Start Transition to New Approach for Treating Ischemic Stroke

By Dorothy Brooks

Alteplase (tPA) has been a mainstay to treat ischemic stroke. When given within hours of an episode, evidence has shown the clot-busting medication can improve outcomes. But what if there was a drug that could deliver similar, and possibly even better, outcomes for a subset of stroke patients without some of the logistical hurdles associated with alteplase?

Tenecteplase (tNK) has been used for years, but not to treat ischemic stroke. Investigators have studied whether the drug can be used safely in stroke patients and at what dose. Many experts believe those questions have been answered. With evidence mounting suggesting tNK offers certain advantages over alteplase, some large health systems have decided to start using tNK instead.

University Hospitals in Cleveland began using tNK in all its primary stroke centers in June, but this was after months of preparation for the transition, particularly among frontline providers. While the change is significant, experts predict it is a transition most larger health systems likely will make this year, with smaller community hospitals expected to follow in the years to come.

“After looking at the evidence, we looked at the logistics,” explains Amrou Sarraj, MD, FAHA, director, Comprehensive Stroke Center and Stroke Systems at University Hospitals. “It had to fit what we do; it had to fit our model.”

Sarraj and colleagues concluded tNK would offer multiple advantages, especially considering the way stroke patients are cared for within the University Hospitals Health System. “This is not a single hospital where patients come and we treat them. We have 14 primary ... stroke-ready hospitals across northeast Ohio,” Sarraj says. “Patients come to the closest stroke hospital, they get treated, and if they have a higher level of care need, such as in the case of a large vessel occlusion or the need for clinical monitoring, then they come to the main campus at Cleveland Medical Center.”

When such transfers are required, tNK works especially well because it is given as a single IV bolus for five seconds. Conversely, tPA requires a one-hour infusion. “When you arrange for a transfer, you don’t have to worry about the tPA running during the transfer and all of the issues that can happen with the tubing,” Sarraj observes. “I have seen several cases where the patient arrived, but the tubing didn’t work, so the patient didn’t get the dose of tPA.”

Although studies have demonstrated the outcomes of stroke patients treated with tNK are similar or noninferior to those treated with alteplase, there may be advantages for treating large vessel occlusions with tNK. In a comparison of the two treatments, the primary outcome was recanalization or restored blood flow before thrombectomy. More than twice as many patients who received tNK (22%) achieved recanalization before thrombectomy vs. patients who received alteplase (10%).1

Sarraj adds while patients with large vessel occlusions only comprise about 25% of all stroke patients, these incidents produce the highest level of disability. Longer-range studies must be conducted, but it seems there is a potential for improved outcomes with tNK.

The reason why tNK may work better on larger clots is because the drug includes what Sarraj refers to as a higher affinity for fibrin, a protein that plays an essential role in blood clotting. This feature may enable tNK to dissolve clots more effectively.

Although it might seem simply using a different thrombolytic agent would be an easy switch, it involves months of training and preparation. “We have had years of emergency physicians and nurses who were trained and practiced using tPA. You don’t flip the switch overnight,” Sarraj says. “We have excellent emergency department physicians, but they have to understand [the science], and they have to buy in.”

Such a change requires considerable effort in a large health system. “We needed to train every single ED physician, every single ED nurse, ICU [personnel] — everybody who may be involved at 14 hospitals,” Sarraj says. “That takes a lot of time and work, but you have to make sure that at 2 a.m., somebody doesn’t come [in and order] tPA.”

For example, if someone administered tNK using the dosage indicated for tPA, it would be a disaster. While Sarraj notes such incidents have been reported, they have not occurred at University Hospitals. “The tPA order is gone from our information technology. If someone tries to order tPA, they can’t,” Sarraj says.

Another hurdle includes going through the health system’s legal department. It is a valid concern, considering the FDA has yet to approve tNK to treat ischemic stroke. However, Sarraj notes FDA action tends to lag behind other guidelines.

“The American Heart Association Guidelines [approving tNK for ischemic stroke] are very powerful and intelligent, and they are written by physicians who know very well how to read the science,” he says.2

Sarraj is anticipating the results of an ongoing trial concerning whether tNK is beneficial beyond the current 4.5-hour window currently in place for treatment. The creators of the TIMELESS trial are comparing patients treated with placebo with those receiving tNK from 4.5 hours up to 24 hours following an ischemic stroke.3

“If that shows a benefit, then we have cleared the window, which is currently at 4.5 hours to maybe change that so that thrombolysis can be given up to 24 hours [following a stroke],” Sarraj says. “That would be a big deal and a big change.”

James Grotta, MD, FAAN, was one of the investigators in the original tPA trial. He has long advocated for the use of tPA and is considered by colleagues a champion of the thrombolytic agent. But he also has looked at newer trials and has come to appreciate the advantages offered by tNK.

“When people started advocating for tNK a number of years ago ... I was always sort of propelled into the role of defending tPA,” says Grotta, director of stroke research at the Clinical Institute for Research Innovation at Memorial Hermann-Texas Medical Center in Houston. “We didn’t really have the data for tNK yet. It was all theoretical [at that point], and we had decades of experience with tPA as being very effective.”

More than a decade ago, the Memorial Hermann Texas Medical Center was the largest enrolling site for one of the first trials comparing tNK with tPA, a trial that ended early because there was excessive bleeding in the tNK group.4

“That was probably because of the dosage [of tNK] that we tested. The numbers in each group were too small to draw any conclusions,” says Grotta, founder and director of Houston’s Mobile Stroke Unit Consortium.

Grotta and other researchers discarded the idea of using tNK for ischemic stroke, but other investigations continued. Two recent studies prompted Grotta to reconsider tNK. One was the study Sarraj referenced, and the other was a Canadian study showing that when tNK was given at 0.25 mg/kg, researchers did not see excessive bleeding problems documented in patients who received larger dosages. “It showed that the use of tNK at the 0.25 dose was noninferior to tPA, and there was a large enough number of patients that it confirmed [what many investigators] were expecting,” Grotta says.5

Such evidence convinced Grotta that switching from alteplase to tNK for ischemic stroke is a good idea. He reports the Memorial Hermann Health System is in the process of making this transition. The logistical advantages will be helpful to clinicians operating the health system’s mobile stroke unit.

“When we start tPA on the mobile stroke unit, when the patient arrives to the ED — for one reason or another — the infusion part is interrupted,” Grotta explains, noting this happens roughly 8% of the time.

When this interruption occurs, clinicians cannot restart the infusion; they have to start another bolus of alteplase, which almost never happens in the ED, according to Grotta. “That doesn’t happen with tNK because it is just given as an initial bolus and doesn’t require an infusion,” he says. “That is a practical factor that supports the use of tNK.”

A related advantage is that for patients with difficult-to-access veins, clinicians may need to place only one IV when using tNK. That same IV can be used for other needed medicines once the initial bolus of tNK is administered.

“If a patient has high blood pressure and you have to get it controlled, then you have to have two IVs in when giving tPA,” Grotta explains. “It is actually recommended that you have two IVs in before you give tPA.”

As with University Hospitals in Cleveland, the process of switching to tNK at Memorial Hermann will take time. “Most large hospital systems like ours don’t just operate as a single hospital; they operate as a system. When they purchase drugs ... they buy for the whole system,” Grotta explains. “You have to change for all the hospitals in the health system — or at least the major hospitals in the health system — and that takes a bit of coordination.”

Care pathways must be developed and all appropriate personnel must receive training. “When giving tNK, you need to do it correctly,” Grotta says. “It is ineffective if given too little of the drug, and dangerous if given too much.”

Studies thus far have not demonstrated tNK to deliver superior outcomes than tPA, except in patients with large vessel occlusions. Still, Grotta notes there is the advantage of speed. “To me, the most important thing, whether you are using tNK or tPA, is getting the drug in faster and into more people,” he says. “You really should be able to treat faster with tNK.”

Grotta suspects most large academic health systems have either already switched to tNK or are planning to switch soon.

“My guess is that within a year, virtually all major medical centers will have switched,” he says. “It will take longer for the small community hospitals to switch, but they will.”


1. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med 2018;378:1573-1582.

2. Zhong CS, Beharry J, Salazar D, et al. Routine use of tenecteplase for thrombolysis in acute ischemic stroke. Stroke 2021;52:1087-1090.

3. Tenecteplase in stroke patients between 4.5 and 24 Hours (TIMELESS).

4. Haley EC Jr, Thompson JLP, Grotta JC, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial. Stroke 2010;41:707-711.

5. Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): A pragmatic, multicentre, open-label, registry-linked, randomized, controlled, non-inferiority trial. Lancet 2022;400:161-169.