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International Stroke Conference

Access daily, concise peer-reviewed reports from the International Stroke Conference selected by the Neurology Today editors.

Friday, February 21, 2020

LOS ANGELES—Directly performing endovascular clot retrieval may be as good as performing the procedure along with the use of tissue plasminogen activator (tPA), researchers reported here at the American Heart Association/American Stroke Association International Stroke Conference 2020.

At 90 days, 59.4 percent of the patients who underwent direct clot removals achieved a modified Rankin Scale score of 0–2 compared with 57.3 percent of patients who were treated with both tPA and endovascular therapy, reported Kentaro Suzuki, MD, PhD, a lecturer in the department of neurology at Nippon Medical School Hospital in Tokyo, Japan.

However, Dr. Suzuki noted that the lower limits of the confidence intervals fell outside the pre-specified boundary for non-inferiority, so the researchers were unable to declare that treatment with endovascular therapy alone was non-inferior to the standard-of-care—treatment with both the clot-buster agent and direct endovascular therapy.

The Japanese research team reported, however, was that there were fewer episodes of intracranial hemorrhage of any kind with the direct endovascular treatment. Of the 101 patients assigned to the endovascular therapy, 34 bleeding episodes of any kind were observed compared with 52 bleeding episodes among the 103 patients who were assigned to receive tPA plus endovascular clot retrieval in the so-called SKIP trial (p=0.02). Eight symptomatic intracranial bleeds occurred in patients who had the direct endovascular therapy compared with 12 such bleeds among those who received the standard-of-care treatment (p=0.48).

"We feel that giving alteplase to dissolve clots is not necessary, and mechanical clot removal can be performed immediately," said Dr. Suzuki. "If we skip alteplase, we can perform mechanical thrombectomy with a low risk of bleeding."

Commenting on the study, Ralph L. Sacco, MD, MS, FAAN, FAHA, chair and professor of neurology at the Miller School of Medicine at the University of Miami, told Neurology Today At the Meetings, "Right now, the guidelines suggest that we give patients tPA and then do clot removal on top of that."

"In this study, the Japanese researchers really showed that the two treatments were equivalent—that endovascular mechanical clot retrieval plus tPA was as good as clot removal without tPA—and that one treatment was not better than the other. However, they did find that there was significantly less bleeding with the endovascular retrieval alone," Dr. Sacco said.

"We know that the most important thing in stroke is to open the vessel, and however you can, to open that vessel quickly," he said. "If you have access to a comprehensive stroke center and you can get your door-to-perfusion time down to an hour or less, and if tPA makes that timing worse, then sometimes it would make sense to go directly to endovascular clot retrieval. It would depend on access and timing. The standard of care remains tPA and then endovascular clot retrieval, but if you are at a comprehensive stroke unit, you might go directly to endovascular treatment."

Dr. Sacco said endovascular therapy for removing the clots has improved over the years. "The original studies took too long and the devices were difficult to use. Now we have better devices and can proceed more quickly to remove the blockages. When you can open that vessel quickly you can make a huge impact on outcome."

Drs. Suzuki and Sacco had no disclosures.

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ISC Abstract LB18: Suzuki K, Matsumaru Y, Takeuchi M, et al. The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and MI occlusion (SKIP Study).

Friday, February 21, 2020

LOS ANGELES—Patients who received the common anti-fibrinolytic agent tranexamic acid for bleeding in stroke showed a trend towards reduced growth of ongoing intracerebral hemorrhage, researchers suggested here at the American Heart Association/American Stroke Association International Stroke Conference 2020.

In the randomized, phase 2 trial, referred to as STOP-AUST, researchers treated patients when they were able to identify the so-called spot sign on imaging scans—indicating that bleeding into the brain is continuing, reported Nawaf Yassi, MBBS, PhD, consultant neurologist at Royal Melbourne Hospital in Australia.

Tranexamic acid is frequently used to treat people who experience bleeding due to trauma, surgery, tooth removal, nosebleeds, and heavy menstruation. In the STOP- AUST study, 50 patients who exhibited the spot sign were randomized to intravenous tranexamic acid and 50 to placebo within 4.5 hours of symptom onset.

Among the findings, intracerebral hemorrhage growth of 33 percent or of at least 6 mL above baseline volume occurred in 22 patients receiving tranexamic acid and in 26 patients on the placebo, a reduction in the risk of an expanding volume of 28 percent; the difference was not statistically significant, however, possibly due to the small sample size (p=0.41), Dr. Yassi reported in his late-breaker presentation.

About 56 percent of the patients who received tranexamic acid after 90 days had either returned to their baseline modified Rankin Scale status or had a score between 0–2, indicating minimal deficits from the stroke. About 46 percent of patients on the placebo achieved those results (p=0.31), the researchers reported.

Dr. Yassi said major adverse events such as thromboembolism or death were not statistically significantly different between the two groups. One patient who received tranexamic acid had a thromboembolic event compared with two patients who were taking he placebo. Thirteen deaths occurred in those taking tranexamic acid compared with eight among those taking a placebo, he reported.

Dr. Yassi suggested that while the results were not significant, additional studies should be considered with tranexamic acid. "Further trials using tranexamic acid are ongoing and focusing on ultra-early treatment—within two hours. This is where the greatest opportunity for intervention appears to be," he said. "Tranexamic acid is inexpensive, safe, and widely available. Our results and others provide great impetus for further, focused research using this treatment."

Commenting on the results of STOP-AUST, Mark  J. Alberts, MD, chief of neurology at Hartford Hospital and physician-in-chief at Ayer Neuroscience Institute in Connecticut, told Neurology Today At the Meetings, "Although this trial did not see a significant outcome, with the small numbers of patients—50 people in each arm—the fact that they saw positive trends is encouraging. This does have the potential to change therapy."

Dr. Alberts said the spot sign can be observed on a contrast CT scan that indicates that there is ongoing bleeding—that blood is actively being pumped into the brain. "This is a population that you want to intervene in. There is a very high potential for these patients to get worse due to this bleeding activity. In intracerebral hemorrhages, it is all about size and location."

"We absolutely should continue investigations with this agent," said Bruce I. Ovbiagele, MD, MSc, FAAN, professor of neurology and associate dean at the University of California, San Francisco. "The result we have seen does align with what we know: that time equals brain so earlier treatment should be investigated. This type of stroke is associated with very poor outcomes, so any kind of investigation that tries to figure out how we can screen out those at higher risk and arrest the stroke is very important."

However, Dr. Ovbiagele said that he would not use tranexamic acid in his patients at this time outside of a clinical trial. "I am very much an evidence-based physician, but I would hope we would have trials here that can look at this agent."

He added that he didn't see any indication that treatment with tranexamic acid caused harm.

Drs. Yassi, Alberts, and Ovbiagele had no disclosures.

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ISC Abstract LB20: Meretoja A, Yassi N, Churilov L, et al. The spot sign and tranexamic acid on preventing ICH growth—Austalasia Trial (STOP-AUST): A multicenter, randomized double-blind, placebo-controlled trial.

Friday, February 21, 2020

LOS ANGELES—Specialized mobile stroke unit ambulances outfitted with CT machines appear to make a difference in how well patients recover from stroke, researchers reported here at the American Heart Association/American Stroke Association International Stroke Conference 2020.

Heinrich Audebert, MD, professor of neurology at the Center for Stroke Research at Charité-Universitätsmedizin in Berlin and the senior author of the Berlin Prehospital Or Usual Delivery trial, reported that 63 percent of patients treated in the mobile stroke unit were discharged with a modified Rankin Scale score of 0–2 compared with 57 percent of the patients who were treated with usual care, but not in a stroke unit vehicle. That translated to a 26 percent reduction in disability among those patients, which was statistically significant (p=0.003).

In the study, 749 patients were assigned to treatment based on the availability of three mobile stroke units in the metropolitan area of Berlin, and their outcomes were compared with 794 patients who received conventional care.

The mobile stroke units in Berlin are staffed with emergency medicine neurologists and equipped with a CT scanner and a lab designed to enable specific stroke treatment at the scene.

Dr. Audebert said 60 percent of patients assigned to the mobile stroke unit received clot-busting treatment with alteplase if a mobile stroke unit was available, compared with 48 percent of patients who received conventional treatment in the hospital; the time to treatment was shortened by an average of 20 minutes when a mobile stroke unit was dispatched; and the use of a mobile stroke unit reduced the likelihood and severity of disability and death at three months by 26 percent.

The difference between standard care and the mobile stroke units was not statistically significant, however, for the co-primary endpoint—that is, that patients required aid in getting around or were confined to long-term nursing care or had scores of 4–5 on the modified Rankin Scale. Dr. Audebert reported that 12.6 percent of the patients treated in the mobile stroke unit met the endpoint compared with 13.3 percent of the patients who received usual care (p=0.057).

The researchers reported that 7.1 percent of the patients who were in the mobile stroke unit died compared with 8.9 percent of the patients in the usual care group.

 "While we had anticipated better outcomes in the patients treated in the mobile stroke units, we are amazed by the magnitude of the effects," Dr. Audebert said. "It is obvious that clot-busting treatment is most effective if it is applied in the ultra-early phase of stroke, ideally within the first or 'golden hour' of symptom-onset."

Since treatment within the first hour of symptom-onset happens rarely in conventional care, Dr. Audebert said health care providers should consider ways to optimize treatment so it can begin while in route to the hospital.

"Stroke treatment is more effective the earlier it starts," he said. "Just waiting until the patient arrives at the hospital is not enough anymore."

Commenting on the study, Mitchell S. Elkind, MD, MS, FAAN, professor of neurology at Columbia University and president-elect of the American Heart Association, told Neurology Today At the Meetings, "This was one of the most exciting studies that were presented at the meeting because it has the potential to really change how we arrange our systems of care."

However, Dr. Elkind said that those changes are not just as simple as retrofitting ambulances. "You really can't just put a CT scanner in an ambulance. You have to design a vehicle from the ground up and it may not be necessary that all ambulances have these capabilities."

"While the results of the study were impressive, this still was done in just one city in Germany, and how it would work in the United States or other parts of the world remain a question. Whether it can work in urban, suburban, or in rural areas are things that have to be worked out. There are also questions about cost-effectiveness. These are not cheap vehicles; they will cost in the neighborhood of $1 million each, plus there is the cost of staffing them. We have to show that it is cost-effective if we are going to implement the use of these vehicles widely."

"We now have three mobile stroke units at New York Presbyterian Hospital, one on the east side of New York City, one on the west side, and one in Queens. I am not sure that we have proven yet that they can operate without philanthropy," he said.

Dr. Elkind said that the failure of the trial to show a significant impact in case of very devastating strokes was somewhat expected. "We saw in this trial that the mobile stroke unit decreased the time to getting thrombolysis by 20 minutes and increased the number of patients who received thrombolysis by 12 percent, but in a very devastating stroke—the modified Rankin Scale scores of 4–5—those differences in time shift may not be enough to make a difference in these individuals," he said.

The study was funded by the German Research Foundation and the Ministry of Education and Research. Dr. Audebert disclosed he has received research grants from Pfizer and honoraria from Pfizer, Bristol Myers Squibb, Bayer Vital, Boehringer Ingelheim, Takeda, and Novo-Nordisk. He has also receive research grants from Stiftung Deutsche Schlaganfall-Hilfe, Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft, and Innovationsfonds des Gemeinsamen Bundesausschusses. Dr. Jessup had no disclosures.

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ISC Abstract LB5: Ebinger M, Siegerink B, Kunz A, et al. Effects of pre-hospital acute stroke treatment as measured with the modified Rankin Scale; the Berline Pre-hospital Or Usual care Delivery (B_Proud) trial.

Friday, February 21, 2020

LOS ANGELES—The novel peptide nerinetide failed to improve clinical outcomes after endovascular thrombectomy among stroke patients in a randomized, phase 3 trial, researchers reported here at the American Heart Association/American Stroke Association International Stroke Conference 2020.

The study, referred to as ESCAPE-NA-1, evaluated the efficacy and safety of nerinetide in patients with acute ischemic stroke who do not achieve an independent lifestyle after endovascular thrombectomy.

Nerinetide was designed to perturb post-synaptic density protein 95 protein–protein interactions that lead to excitotoxic cell death in acute ischemia. In preclinical studies, nerinetide inhibited signaling that led to neuronal excitotoxicity, penetrated the blood-brain barrier after intravenous administration, and had reduced stroke damage in cultured neurons, mice, rats, and high-order primates, especially when ischemia was temporary and followed by adequate reperfusion.

Among 549 patients assigned to nerinetide, 61.4 percent achieved a modified Rankin Scale score of 0–2 at 90 days, compared with 59.2 percent of the 556 patients assigned to placebo (p=0.65), reported Michael D. Hill, MD, professor of clinical neurosciences and director of the stroke unit at the University of Calgary in Alberta.

In the trial, Dr. Hill and colleagues enrolled 1,105 patients, and found that in secondary outcomes, the results were also similar. Serious adverse events occurred equally between groups, according to the study, which was also published in The Lancet.

"Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo," Dr. Hill said.

Intriguingly, however, Dr. Hill reported an unexpected finding: "Among patients who were not treated with alteplase, we observed a treatment effect. This finding will require confirmation but suggests that neuroprotection in human stroke might be possible."

"We observed evidence to support a modification of nerinetide treatment effect by usual care alteplase treatment in an exploratory analysis," Dr. Hill said. "In the no-alteplase stratum, nerinetide was associated with improved outcomes, whereas no observed benefit was found in the alteplase stratum, with the absolute risk difference slightly but not significantly favoring placebo."

"The large magnitude of the effect of alteplase on nerinetide treatment response in humans was not predicted," he added. "This finding raises the possibility of a drug–drug interaction between alteplase and nerinetide that might have nullified the treatment effect of nerinetide in the alteplase stratum and to a 9 percent absolute benefit in the no-alteplase stratum. This absence of effectiveness of nerinetide in the alteplase stratum is biologically plausible."

In an editorial in The Lancet that accompanied Dr. Hill's study, Graeme J. Hankey, MBBS, professor of neurology at the University of Western Australia in Perth, suggested that while the current study with nerinetide did not prove that neuroprotective agents were beneficial after thrombectomy in stroke patients, it was not reason to lose faith.

"Clinicians and patients are encouraged to continue to participate in clinical trials of cytoprotection therapies for acute stroke so that their data are not lost but might contribute to a collective effort that will ultimately be rewarding for all."

Dr. Hankey suggested that there might be a signal of effectiveness among the patients not treated with alteplase. "While this could be a chance finding, the drug-drug interaction could have lessened the effectiveness in patients who did receive alteplase in the study."

NoNO of Toronto sponsored the trial, which was designed by the academic investigators and the sponsor. Funding also was provided by the Canadian Institutes for Health Research and Alberta Innovates.

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Hill MD, Goyal M, Menon BK, et al, for the ESCAPE-NA1 Investigators. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NAI): A multicentre, double-blind, randomised controlled trial. Lancet 2020;Epub 2020 Feb 20.

Hankey GJ. Comment. Nerinetide before reperfusion in acute ischaemic stroke: Déjà vu or new insights? Lancet 2020;Epub 2020 Feb 20.

Friday, February 21, 2020

LOS ANGELES—A higher dose of tenecteplase did not improve reperfusion prior to thrombectomy for stroke patients with large blood vessel occlusion, researchers reported here at the American Heart Association/American Stroke Association International Stroke Conference 2020.

Of 150 patients who were treated with 0.40 mg/kg of tenecteplase, 29 of 150 (19.3 percent) achieved the primary endpoint of a greater than 50 percent improvement in reperfusion of blocked brain blood vessels compared with 29 of150 patients who were treated with 0.25 mg/kg (p=0.89), reported Bruce C.V. Campbell, MBBS, PhD, professor of neurology and head of stroke at the Royal Melbourne Hospital and University of Melbourne in Australia.

"The findings suggest that the 0.40 mg/kg dose of tenecteplase does not confer an advantage over the 0.25 mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned," Dr. Campbell reported at the meeting, during which the study was published online in JAMA Neurology.

While Dr. Campbell and colleagues suggested that the small sample size of the study would not detect a clinically meaningful improvement in the 5 percent range, the researchers also suggested that the results seen in the trial with 300 patients probably means that there would not be such a difference anyway.

The EXTEND-IA TNK Part 2 trial was an investigator-initiated, multicenter, randomized, open-label, blinded endpoint trial in patients with ischemic stroke due to large vessel occlusion of the intracranial internal carotid, middle cerebral, or basilar artery who were eligible for intravenous thrombolysis and endovascular thrombectomy within 4.5 hours of stroke onset.

Thrombectomy was not performed in patients with substantial reperfusion after thrombolysis, with the exception of four of 29 patients (14 percent) in the 0.40mg/kg group and four of 29 in the 0.25mg/kg group who had substantial reperfusion with residual thrombus that was managed with thrombectomy.

The analysis of secondary outcomes—a modified Rankin Scale score of 0–2 at 90 days and early neurological recovery—found favorable outcomes were not significantly different between the two dosed groups. Symptomatic intracranial hemorrhage occurred in seven patients (4.7 percent) in the 0.40 mg/kg group, four of which were associated with wire perforation during the endovascular procedure, and two patients (1.3 percent) in the 0.25 mg/kg group (p=0.12). There were 26 deaths in the 0.40 mg/kg group and 22 in the 0.25 mg/kg group (p-0.35).

Commenting on the study, Larry B. Goldstein, MD, FAAN, FAHA, Ruth L Works Professor and chair of neurology and co-director of the Kentucky Neuroscience Institute at the University of Kentucky, told Neurology Today At the Meetings, "A prior smaller study suggested that 0.10 mg/kg was not as effective as 0.25 mg/kg. As with other drugs, there may be an 'inverted U' dose-response curve­—that is, an increased benefit to a dose range and then decreased benefit with higher doses—or a threshold effect."

Dr. Goldstein noted that tenecteplase is not approved in the United States for use in thrombectomy, but he cited the latest guidelines by the American Heart Association Guidelines, which indicate "it may be reasonable to choose tenecteplase (single IV bolus of 0.25-mg/kg, maximum 25 mg) over intravenous alteplase in patients without contraindications for intravenous fibrinolysis who are also eligible to undergo mechanical thrombectomy. (Level IIb)."

The results of the study are unlikely to greatly change clinical practice in the United States, he said. "I do not believe that tenecteplase is being widely used 'off label' in the US for this purpose, and the guidelines do not recommend the higher dose."

Dr. Campbell reported receiving grants from the National Health and Medical Research Council and the National Heart Foundation during the conduct of the study. Dr. Goldstein had no competing interests.

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Campbell BCV, Mitchell PJ, Churilov L, et al, for the EXTEND-1A TNK Part 2 investigators. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: The EXTEND-IA TNK Part 2 randomized clinical trial. JAMA 2020;Epub 2020 Feb 20.