Clot Factors Most Responsive to Thrombolysis in Stroke

Pauline Anderson

September 26, 2018

Greater thrombus permeability, a more distal thrombus location, and longer time to assessment are factors associated with outcomes of recanalization of an arterial occlusion in patients with acute ischemic stroke receiving intravenous tissue plasminogen activator (tPA, alteplase), results of a new study show.

"One of the most interesting findings of the study was that patients with a porous clot, say, a clot that has some contrast getting into it on the CT angiogram, have a very significant rate of early recanalization — around 50% — with the drug alone," Andrew M. Demchuk, MD, director, Calgary Stroke Program, professor, Departments of Clinical Neurosciences and Radiology, University of Calgary, Alberta, Canada, and chair in stroke research, Heart and Stroke Foundation, told Medscape Medical News.

"If they don't have a porous clot, the rate is much lower early on, in the range of 10%," he said.

The findings should help guide treatment and triage decisions in patients with acute ischemic stroke, said Demchuk.

"The original goal of the study was just to better understand tPA, but as it turns out, it provides context for physicians to make more informed decisions around the options to treat stroke," he said.

The study was published online September 11 in JAMA.

Treatments for acute ischemic stroke now include thrombectomy (mechanical removal of the clot) within 6 hours of symptom onset, as well as administration of thrombolytics, such as IV tPA, within 4 to 5 hours.

This multicenter, prospective cohort study included 575 patients (median age, 72 years; 51.5% men) who had had an acute ischemic stroke and for whom intracranial thrombus was visible on CT angiography (CTA).

All patients underwent head and neck CTA at baseline. The median time from when the patient was last known to be well to baseline CTA was 114 minutes.

Of the total, 47.8% of patients received IV tPA only, 33.9% received IV tPA plus endovascular thrombectomy, 8.3% received endovascular thrombectomy alone, and 9.9% received conservative treatment or standard medical management.

Conservative treatment might have included aspirin and typical stroke unit care, said Demchuk. It was offered to patients who were not eligible for either tPA or thrombectomy.

Investigators assessed the extent of intracranial thrombus using the clot burden score. A score of 0 implies complete occlusion of the ipsilateral anterior circulation vessels, while a score of 10 indicates no occlusion.

Thrombus Permeability

To assess thrombus permeability (responsiveness to tPA), investigators used the residual flow grade. Grade 0 indicates no contrast permeation of thrombus; grade 1 indicates contrast permeating diffusely through thrombus; and grade 2 indicates a hairline lumen or streak of well-defined contrast within the thrombus, extending through part or the entire length.

The primary outcome was successful recanalization, defined as a revised arterial occlusion scale (rAOL) score of 2b or 3 on repeat CTA or conventional cerebral angiogram obtained within 6 hours of initial CTA.

An rAOL score of 2b indicates partial or complete recanalization of the primary thrombus with occlusion in minor distal vascular branch or partial recanalization of the primary thrombus with no thrombus in the vascular tree at or beyond the primary occlusive thrombus. A score of 3 indicates complete recanalization of the primary occlusive thrombus with no clot in the vascular tree beyond.

An imaging expert blinded to all clinical information read all images.

Successful recanalization occurred in 27.3% overall, including in 30.4% who received IV tPA and 13.3% who did not, with a difference of 17.1% (95% confidence interval [CI], 10.2% - 25.8%).

Among patients who received tPA, the following factors were associated with recanalization outcomes:

  • higher residual flow grade (thrombus permeability): grade 2 (66.7%) vs grade 0 (24.1%) (odds ratio [OR], 7.03; 95% CI, 3.32 - 14.87; P < .001);

  • time from treatment start to recanalization assessment (OR, 1.28 for every 30-min increase in time; 95% CI, 1.18 - 1.38; P < .001); and

  • more distal thrombus location: distal (for example, middle or anterior cerebral artery) (42.5%) vs internal carotid artery (10.9%; OR, 5.18; 95% CI, 1.95 - 13.76; P = .001).

"The one type of clot that was extremely difficult to open was the carotid artery clot, the biggest type," even if the artery was porous, commented Demchuk. "That's really where mechanical thrombectomy becomes very important."

The study results underscore the efficacy of tPA for certain clots, said Demchuk. "If a clot is too big, tPA is less likely to work, so it's really best, and ideal, for those more distal clots, smaller clots, and porous clots."

Demchuk noted that tPA also seems to continue to be active well beyond its half life. "The drug aids the body's ability to dissolve the clot, even after it's long gone from the system," he said.

Additional Comfort

The new results should provide "additional comfort" for physicians by showing that tPA "is actually working," especially for porous clots, said Demchuk. As it stands, some physicians are reluctant to use tPA because of the small risk, perhaps 5%, of a bleed in the brain, he said.

Demchuk stressed that the new results "add further fuel to the need to do a CT angiogram," which is not always performed. "This provides one more reason to do it, and we should be doing it, to identify candidates for thrombectomy."

Information provided by CTA helps determine whether patients are likely to respond to tPA or need alternative treatment, added Demchuk.

"CTA is sort of the new standard of care," because of the availability of thrombectomy, he said. "We need to know if there's a large clot in the brain. If there is, then the patient generally will go for thrombectomy."

Dr Bijoy Menon (left) and Dr Andrew Demchuk (right).

The study results "add another layer of information" for clinicians to make decisions regarding stroke treatment, lead author Bijoy K. Menon, MD, stroke neurologist and associate professor of neurology, Department of Clinical Neuroscience, University of Calgary, told Medscape Medical News.

"The more information we have, the more informed our decisions will be," said Menon.

Such information could help predict which patients are most suitable for transfer to a comprehensive stroke center for endovascular therapy and which can remain at the primary stroke center, said Menon.

For example, he said, knowing that the likelihood of treating a large clot with tPA in the first few hours is "very low," physicians can make arrangements for quick transfer to a dedicated center with thrombectomy capability.

"We may try to administer tPA, but the focus now is to shift that patient over as soon as possible," he said.

On the other hand, it may not make sense to transfer a 90-year-old nursing home resident to a comprehensive stroke center that could be miles away if there's a "high chance" that by the time the patient arrives, the clot "would have opened up" with tPA, said Menon.

New thrombolytics are being investigated, as is combining such drugs with ultrasound, but Demchuk questions the pursuit of these approaches if today's tPA is "working really well on its own."

Consistent Findings

Asked to comment, S. Claiborne Johnston, MD, PhD, vice president for medical affairs and Frank and Charmaine Denius Distinguished Dean's Chair, Dell Medical School, University of Texas at Austin, said that the findings are "interesting" but perhaps not surprising, as they're "consistent with our understanding of the pathophysiology of emboli."

Johnston said he's not sure how the new results will be used clinically, "since the risk factors identified are never strong enough to make it unnecessary to proceed to angiography in any subgroup."

Patrice Lindsay, PhD, director, Systems Change and Stroke Program, Heart and Stroke Foundation, offered an additional comment.

The study is "important" and "reconfirms the critical role" of tPA in acute stroke treatment, said Lindsay.

"Alteplase is an effective treatment for acute stroke and should be available and offered to all patients who meet criteria," she said.

Such criteria are outlined in the new Heart and Stroke Canadian Best Practice recommendations for acute stroke management.

To maximize the benefits of tPA, all patients who show signs of stroke should as soon as possible undergo a CT scan with angiography, with use of contrast dye to better visualize the blood vessels in the brain, said Lindsay.

"This imaging helps select the best candidates for tPA and also identifies patients who may benefit from endovascular thrombectomy, with or without tPA," he said.

The new guidelines for acute stroke management extend the time window for endovascular therapy for select patients, said Lindsay.

The guidelines, in addition to this new study, "provide new hope for patients presenting later and those in more rural and remote areas," she said.

The study was funded by an operating grant from the Canadian Institutes of Health Research. Dr Demchuk reports receiving honoraria for CME events from Medtronic. Dr Menon reports holding a patent on a system and method for assisting in decision making and triaging for acute stroke patients. Dr Johnston reports no relevant financial relationships.

JAMA. Published online September 11, 2018. Abstract

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