eHighlights 2020

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.”

 

Endovascular therapy with versus without intravenous tissue plasminogen activator compared in acute stroke with ICA and M1 occlusion

During the Closing Main Event at the ASA International Stroke Conference 2020 in Los Angeles, researchers of Late-Breaking Science found:

  • SKIP shows direct EVT has similar outcomes, less bleeding than bridging IVT therapy.
  • Nurse case managers improve post-stroke blood pressure control.
  • STOP-AUST finds potential benefit for tranexamic acid in ultra-early post-hemorrhagic stroke window.
  • CAS-CARE finds adding cilostazol to antiplatelet therapy inhibits in-stent restenosis.
  • Follow-up analysis of AUGUSTUS shows elevated risk for bleeding with aspirin in patients with prior stroke, TIA or TE.
  • First experience in robotic neurovascular interventions opens door to remote procedures.

SKIP shows direct EVT has similar outcomes, less bleeding than bridging IVT therapy

The debate over direct endovascular venous treatment, thrombectomy, for stroke versus bridging therapy with intravenous treatment, thrombolysis, before EVT is one step closer to resolution. The SKIP study (The Randomized Study of Endovascular Therapy With Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion) showed that patients who received only EVT had nearly identical outcomes as patients who had bridging tPA, then EVT. Patients who received EVT alone had significantly fewer intracranial bleeding events versus patients who first received tPA.

“We did not prove noninferiority of direct EVT to bridging therapy with respect to favorable outcomes,” said Kentaro Suzuki, MD, Nippon Medical School in Tokyo, Japan. “However, there was no difference in treatment effects between the two groups, and bleeding was significantly less with direct mechanical thrombosis.”

“We really didn’t know if tPA was needed before thrombectomy to recanalize large vessel disease,” Suzuki said. “Or if using tPA just delayed recanalization and reperfusion in these patients.”

The investigator-initiated trial randomized 204 patients at 20 centers in Japan to EVT or tPA plus EVT. The odds ratio for intracranial hemorrhage was 0.50 in favor of direct EVT. There was no difference in 90-day mortality and favorable outcomes were seen for 59.4% of the direct EVT group and 57.3% of the bridging group.

Nurse case managers improve post-stroke blood pressure control

Hypertension management is key to secondary stroke prevention and both home BP telemonitoring (HBPTM) and nurse case management can improve BP control. The Comparative Effectiveness of Home BP Telemonitoring (HBPTM) Plus Nurse Case Management Versus HBPTM Alone Among Minority Stroke Survivors study shows that the combination of HBPTM and NCM is superior to HBPTM alone in low income African American and Hispanic patients in New York City.

“These findings provide strong evidence for the implementation of NCM and HBPTM in minority populations,” said Gbenga Ogedegbe, MD, MPH, FACP, Dr. Adolph & Margaret Berger Professor of Medicine at the NYU Grossman School of Medicine. “Policymakers and health plans now have the information to implement these strategies in minority patients with stroke and uncontrolled hypertension,” he said.

Researchers randomized 450 stroke survivors with uncontrolled hypertension from comprehensive stroke centers and primary care practices at six public hospitals and three academic centers in New York City.

Patients performed home BP monitoring at least three times weekly for 12 months. Readings were sent wirelessly to a secure server and reported to their physicians before each clinic appointment. Half the group also received NCM phone calls weekly for the first two months, biweekly for the next two months and monthly through month 12.

Mean SBP fell significantly for both groups, but the NCM group had double the decline compared to the HBPTM-only group.

STOP-AUST finds potential benefit for tranexamic acid in ultra-early post-hemorrhagic stroke window

A novel treatment for hemorrhagic stroke, tranexamic acid (TXA) shows promise if it can be delivered early enough. The Spot Sign and Tranexamic Acid on Preventing ICH Growth – Australasia Trial (STOP-AUST) found a non-significant numerical reduction in ICH growth with TXA treatment delivered within 4.5 hours from the onset of symptoms. But treatment delivered within three hours of onset showed a 59% risk reduction for ICH growth, and treatment delivered within two hours showed 81% reduction in risk.

“These trends toward significant efficacy in the ultra-early time window warrant further exploration,” said Nawaf Yassi MBBS, BSc (Med), PhD, consultant neurologist at the Royal Melbourne Hospital and research fellow at the Melbourne Brain Centre and Florey Institute of Neuroscience and Mental Health at the University of Melbourne in Australia. “Such trials are currently underway in Australia and in Asia,” he said.

TXA, a reversible direct inhibitor of plasminogen lysine binding sites, has an excellent safety record in clinical and trial use for trauma, perioperative and other bleeding. Imaging shows that hematoma growth is more likely early in hemorrhagic stroke, prompting this trial of early TXA use.

One hundred patients who could be treated within 4.5 hours of onset were randomized to TXA or placebo. Hematoma size was assessed by CT scan 24 hours later and at 90 days. Physical and neurological function were also assessed at 90 days.

There were no safety concerns with TXA, Yassi said, and no difference in effect by subgroup analysis except time of administration.

CAS-CARE finds adding cilostazol to antiplatelet therapy inhibits in-stent restenosis

Researchers in Japan have shown early evidence of reduced in-stent restenosis in patients with carotid artery stents after adding a novel antiplatelet agent, cilostazol, to conventional antiplatelet agents.

Cilostazol is a phosphodiesterase 3 inhibitor with effects on vascular dilation, endothelial function and vascular smooth muscle cell proliferation.

“Adding cilostazol to other antiplatelet agents after carotid stenting inhibited in-stent restenosis for two years,” said Nobuyuki Sakai, MD, director of neurosurgery at Kobe City Medical Center General Hospital and director of neuroendovascular therapy at the Institute of Biomedical Research and Innovation in Kobe, Japan. “But we did not see improvements in mortality or bleeding events.”

The Cilostazol Versus Other Anti-platelet Drugs for the In-Stent Restenosis After Carotid Artery Stenting: The Carotid Artery Stenting -With Cilostazol Addition for Restenosis (CAS-CARE) trial randomized 699 patients to conventional antiplatelet therapy with or without cilostazol after carotid stenting; 631 patients were included in the final analysis. Patients were followed for 24 months and evaluated for in-stent restenosis ≥50%. Secondary endpoints included all-cause death, cardiovascular or hemorrhagic event, stroke and severe in-stent restenosis.

Cilostazol patients had a hazard ratio of 0.64 for in-stent restenosis at 24 months compared to patients on antiplatelet therapy alone, Sakai reported. But there was no difference in rates of stroke, cardiovascular disease, hemorrhagic event or mortality between the two groups.

Follow-up analysis of AUGUSTUS shows elevated risk for bleeding with aspirin in patients with prior stroke, TIA or TE

Aspirin is known to increase the risk of bleeding in atrial fibrillation patients with recent acute cardiac syndrome and/or percutaneous intervention compared to regimens without aspirin. A secondary analysis of the Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or PCI in Patients With Atrial Fibrillation and Prior Stroke (AUGUSTUS) trial found that aspirin and vitamin K antagonists pose an even greater bleeding risk for patients with prior stroke, TIA or thromboembolism. Apixaban, however, does not elevate bleeding risk.

“We know that patients with atrial fibrillation and a history of prior stroke, TIA or TE are at increased risk of recurrent strokes and major bleeding,” said Maria Cecilia Bahit, MD, chief of cardiology at INECO Neurosciencias in Rosario, Santa Fe, Argentina “Now we see that aspirin appears to have a more profound risk than was realized in these patients and should be avoided.”

AUGUSTUS randomized 4,614 patients taking a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist plus aspirin or placebo for six months. The primary analysis found that apixaban alone resulted in less bleeding and few deaths or hospitalizations versus a vitamin K inhibitor plus aspirin.

This secondary analysis confirmed those results in patients with a history of stroke, TIA or TE who are at elevated risk for bleeding. Apixaban is associated with less bleeding, death and hospitalization than aspirin or vitamin K inhibitors.

First experience in robotic neurovascular interventions opens door to remote procedures

Remote endovascular intervention is a reality. A surgical team in Toronto has successfully performed intracranial INR procedures to treat six patients with aneurysms with the operator and patient in different rooms.

“Remote stroke treatment is our next goal,” said Vitor Mendes Pereira, MD, professor of medical imaging and surgery at the Krembil Brain Institute at the University of Toronto in Canada. “Being able to routinely perform stroke care remotely could greatly ease the geographic disparities we now see in access to neuroendovascsular procedures.”

The Toronto team modified a CorPath GRX robot to the movements and devices used in intracranial neurovascular procedures. Patients had complex, wide-necked intracranial saccular aneurysms that required treatment with intracranial stenting and/or coiling. One of the cases used radial access to place a flow diverter. The other five patients had femoral access.

Robotic intervention allows for closer proximity and ergonomic visualization, automated robotic techniques, sub-millimeter measurement and positioning to within 1 mm by fixing devices during deployment, Pereira noted. And because links between operator and patient are electronic, there is no need for them to be located in the same room or even the same building. Another team has reported performing robotic PCI on five patients 20 miles away.

Pereira said all procedures were successful with no complications, no changes to baseline neurologic status and no conversions to manual procedures.

Mark your calendar for ISC21

The International Stroke Conference 2021 is scheduled for Feb. 10-12, 2021, in Denver, Colorado. The Pre-Conference Symposia and the State-of-the-Science Stroke Nursing Symposium will be held Feb. 9, the day prior to the beginning of ISC21.

Below, you will find the Call for Science submission dates and deadlines.

Abstracts

Submission opens: May 20, 2020
Submission closes: Aug. 25, 2020

Late-Breaking Science and Ongoing Clinical Trials Abstracts

Submission opens: Oct. 7, 2020
Submission closes: Nov. 4, 2020

The link to submit abstracts and/or session ideas can be found at strokeconference.org/submitscience on the applicable date above. Start planning now for the International Stroke Conference 2021.

Top