Determining the optimal dose of tenecteplase before endovascular thrombectomy

Researchers in the Thursday Main Event Late-Breaking Science session during the ASA International Stroke Conference in Los Angeles found:

  • No advantage to higher tenecteplase dose.
  • ESCAPE-NA1 shows neuroprotective benefits.
  • Multifocal transcranial rotating magnet stimulation helpful in chronic ischemic stroke.
  • WOVEN highlights need for restenosis improvement in ICAD.
  • B_PROUD shows positive effect of mobile stroke units on functional outcomes.

No advantage to higher tenecteplase dose

The first randomized controlled trial to compare tenecteplase dosing found no difference in adverse events, cerebral reperfusion or in functional outcomes for 0.40 mg/kg prior to endovascular thrombectomy compared to a 0.25 mg/kg dose. The trial was conducted in patients with large vessel occlusion, hypothesizing that patients with a larger stroke burden would be more likely to benefit from larger thrombolytic dosing.

“It is unlikely in our opinion that patients with small vessel occlusions would require a larger dose of tenecteplase than the large vessel disease patients in this trial,” said Bruce Campbell, BMedSci, PhD, professor of medicine at the University of Melbourne in Australia and co-principal investigator of the EXTEND-1A TNK II trial. “There is no advantage to increasing the dose to 0.4 mg/kg; however, there is a window of safety in case of any inadvertent overestimation of the patient’s weight.”

The 2019 AHA guidelines for thrombolysis recommend tenecteplase 0.25 mg/kg for large vessel occlusion and 0.40 mg/kg for mild stroke without large vessel occlusion, reflecting the state of the evidence at the time of writing. The EXTEND-IA TNK II trial randomized 300 ischemic stroke patients to either 0.40 mg/kg or 0.25 mg/kg tenecteplase (slide 16) within 4.5 hours of symptom onset.

The trial was published simultaneously in JAMA.

ESCAPE-NA1 shows neuroprotective benefits

Neuroprotection is a tempting target for stroke treatment, but no clinical trials have shown benefit in stroke. Until nerinetide.

“We have provided perhaps the first evidence of some clinical benefit from neuroprotection,” said Michael Hill, MD, professor of clinical neuroscience, community health sciences, medicine and radiology at the University of Calgary and director of the stroke unit for the Calgary Stroke Program in Canada. “In patients who did not receive alteplase, we saw a reduction in infarct volume, a 44% reduction in mortality and an 18% increase in the likelihood of modified Rankin score of 0-2.”

The trial compared nerinetide, with neuroprotective activity in cell cultures, rodents, primates and humans undergoing neurovascular repair of intracranial aneurysms, against placebo in ischemic stroke. Patients at 48 global sites received drug or placebo within 30 minutes of randomization and alteplase following current stroke guidelines. A total of 659 patients received alteplase and 446 patients did not.

The overall trial showed no difference between nerinetide and placebo, Hill said. Only patients who did not receive alteplase showed neuroprotective effects. Studies showed a significant reduction in peak serum nerinetide levels and area under the curve in patients treated with alteplase.

“Alteplase was activating proteases that were chewing up the drug,” Hill said.

ESCAPE-NA1 was published simultaneously in Lancet.

Multifocal transcranial rotating magnet stimulation helpful in chronic ischemic stroke

The wearable Transcranial Rotating Permanent Magnet Stimulation (TRPMS) device shows clinical benefit in chronic ischemic stroke. A single center sham-controlled trial in 29 patients showed statistically significant improvements on BOLD fMRI as well as improvement physical functioning measures.

“TRPMS looks like a neoprene swim cap with six stimulators,” said David Chiu, MD, Elizabeth Blanton Wareing Chair in the Eddy Scurlock Stroke Center of Houston Methodist Hospital and professor of neurology at Weill Cornell Medical College. “It is attached to a controller and driven by a smart phone app.”

Multifocal Transcranial Rotating Permanent Magnet Stimulation in Chronic Ischemic Stroke: A Phase 1 / 2A Randomized Clinical Trial, randomized 29 patients to TRPMS treatment or sham for 40 minutes, five days a week, for four months.

Patients in the treatment arm had a significantly greater increase in the number of active voxels on fMRI immediately after treatment compared to sham (p=0.038), one month after treatment (p=0.024) and a higher proportion of patients with ˃15% increase in active voxels (p=0.025).
MRI outcomes correlated with functional outcomes. Active treatment patients showed significant increase in gait velocity and numerical improvement in Fugl-Meyer upper extremity, action research arm test, grip strength and NIH stroke scale scores. There was no improvement in pinch strength scores.

WOVEN highlights need for restenosis improvement in ICAD

Twelve-month results of on-label use of the Wingspan stent in patients with intra-cranial atherosclerotic disease (ICAD) underline the problem of restenosis following stenting. The Wingspan One-Year Vascular Events and Neurologic Outcomes (WOVEN) trial found that most patients, (83%) had restenosis and 16.8% had restenosis of 70% or greater.

The mean time to restenosis was five months, and patients were managed medically, with angioplasty, stenting or some combination. Restenosis was the primary cause of stroke during the first year after stenting.

“WOVEN is the largest on-label, long-term study follow-up to date,” said Michael J. Alexander, MD, professor and vice chair of neurology and co-director of the Comprehensive Stroke Center at Cedars-Sinai Medical Center in Los Angeles. “We clearly have work to do in restenosis.”

WOVEN was initiated by investigators in the post-marketing WEAVE trial of one-month event rates mandated by the FDA. Of the 24 WEAVE sites, 15 sites participated in WOVEN.

While the WOVEN 12-month event rate is similar to the 12-month event rate following aggressive medical therapy in the SAMMPRIS trial, the WOVEN periprocedural complication rate is very low: 2.6%. The total one-year WOVEN stroke and death rate is 8.5%, lower than the 12.2% rate reported in SAMMPRIS.

“WOVEN also shows that further randomized clinical trials are needed for ICAD between stenting and medical treatment,” Alexander said.

B_PROUD shows positive effect of mobile stroke units on functional outcomes

One of the largest studies of mobile stroke units showed significant associations with higher rates of thrombolysis in patients with acute cerebral ischemia without contraindications for thrombolysis. MSUs are also associated with reduced time to treatment and improved functional outcomes after three months.

“The effects of thrombolysis and thrombectomy are highly time dependent,” said Heinrich J. Audebert, professor of neurology at the Center for Stroke Research Berlin at Charité Berlin in Germany. “We see a clear difference in outcomes when an MSU is dispatched compared to usual ambulance transport to the hospital.”

Researchers in Berlin equipped three ambulances with mobile CT and point-of-care lab equipment to support prehospital thrombolysis. It was known that MSU utilization could shorten time to treatment, but it was not clear that MSUs could improve functional outcomes.

The Berlin Prehospital or Usual Delivery of Stroke Care (B_PROUD) compared MSU transport (654 patients) versus non-MSU transport (683 patients) in Berlin from 2017 to 2019. MSU patients were 26% more likely to have a low modified Rankin Score three months post-stroke compared to ambulance patients.

“Just waiting until patients arrive at hospital is not enough anymore,” Audebert said. “There may be different ways to advance treatment into the prehospital field. It may be that we should apply neuroprotective as well.”