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Fifteen Years of Publication: Then And Now
Where Advances Are Revolutionizing Stroke Treatment



STROKE EXPERTS cite among the advances in the past 15 years expanded anticoagulant therapies, longer time-to-needle times for tPA, telemedicine, and endovascular therapy.

Leading stroke experts look back at the research advances over the last 15 years in diagnosis and treatment — from the emergence of novel anticoagulants to thrombectomy and the growth of telemedicine.

By 2001, several clinical studies testing acute stroke treatments had failed to show efficacy, and there was a strong push to prevent secondary stroke. By then, it was already established that aspirin and other antiplatelet drugs play an important role in the secondary prevention of ischemic stroke.

But stroke specialists were divided about which agents work best: Was warfarin more effective than aspirin in preventing stroke after an initial stroke?

The results of the Warfarin versus Aspirin Recurrent Stroke Study (WARSS), the largest clinical trial comparing aspirin to warfarin, were eagerly awaited, but the findings did not settle the controversy: As reported in the July/August 2001 issue of Neurology Today, warfarin and aspirin both worked equally well. [See: Aspirin and Warfarin Compared for Recurrent Stroke in Large Trial,”]


Indeed, in the years since that first report, the discussion has broadened greatly beyond warfarin and aspirin. Since then, several other novel oral anticoagulants (NOACs) have been reported as alternative treatments for stroke prevention, particularly in patients with atrial fibrillation who are at high risk for cardioembolism, said Ralph L. Sacco MD, FAAN, president-elect of the AAN and the Olemberg chair of neurology and executive director of the McKnight Brain Institute at the University of Miami in Florida.

“These NOACS are more selective in addressing the clotting cascade by inhibiting thrombin or factor Xa and reducing the risk of thromboembolism — the first alternatives to warfarin in 40 years,” he told Neurology Today. “They are easier to use, do not require regular blood monitoring, and have less drug and food interactions compared to warfarin. Bleeding risk has generally been less than warfarin with most of these agents.”

To date, four NOACs have been approved for primary and secondary prevention of stroke in patients with atrial fibrillation: dabigatran (a direct thrombin inhibitor), rivaroxaban, apixaban, and endoxaban (direct Factor Xa inhibitors).

“We should have even more results from some ongoing stroke trials with NOACs within the next five years,” Dr. Sacco added. “Fifteen years after WARSS, we have a whole new class of drugs that can help prevent stroke.”


Tissue plasminogen activator (tPA), federally approved by the Food and Drug Administration (FDA) in 1996, and the more recent development of endovascular treatments like thrombectomy, have been the most dramatic change in stoke care over the last 25 years, said Kevin N. Sheth, MD, FAAN, associate professor of neurology and neurosurgery and division chief of neurocritical care and emergency neurology at Yale University School of Medicine, New Haven.

“tPA was the first and only drug approved for treating stroke, and it changed stroke care in neurology in many ways. It was the first time we had a therapy for stroke that could reduce the possibility of lasting problems in such patients,” said Dr. Sheth.

Importantly, he noted, subsequent studies have demonstrated that the initial three-hour treatment window for tPA can be expanded to 4.5 hours, and some studies, primarily in Europe, suggest that this window might be even be longer, he told Neurology Today.

“Emergency department [ED] nonbelievers have increasingly become believers, and this has given rise to entire new systems of stroke care,” he said.

“Indeed, the entire stroke care infrastructure has changed dramatically over the last 15 years, largely as the result of the adoption of tPA,” said James Grotta, MD, FAAN, director of stroke research and the mobile stroke program at Memorial Hermann Hospital in Houston, Texas. “The establishment of stroke centers and creation of benchmarks for quality improvement in delivering tPA by our EDs has changed stroke care in most hospitals,” he said.


In support of the treatment modality that time equals brain, telemedicine has become one of the most significant advances in stroke response and treatment since 2001, said Dr. Grotta. Furthermore, he said, “the availability of experts to coordinate care by telemedicine has helped expand the use of tPA, and now there are stroke specialists on call around the clock to provide expertise to thousands of emergency rooms.”

ED physicians can now link up with experts via telemedicine who can help guide them through administering tPA. “I can cover care for 20 EDs or so without being physically present on-site. This is technically a pretty easy treatment at any ED, but patient selection is critical. Telemedicine can bring an expert to each stroke patient reaching an emergency room.”

In Texas, he said, one year after telemedicine was established at three or four centers, more than 800,000 additional patients have had access to an ED capable of providing expertly guided stroke treatment, which is especially important because so many patients in Texas live in more rural areas.

Mobile units are also changing the delivery of care and leading to more patients having access to earlier treatment in the throes of a stroke, he said. “These units use telemedicine to provide on-board stroke expertise to interpret the CT scan and oversee administration of tPA and other stroke therapies in the pre-hospital stage much faster than is possible when patients had to arrive at an ED,” said Dr. Grotta.


Perhaps the most recent game changer in the stroke world is the development and use of stent retrievers, Dr. Sheth said, noting that the initial few trials had disappointing results. Since then, he said, newer devices were designed, and subsequent studies were cut short when efficacy was clearly demonstrated. There are now several FDA-approved devices, and virtually all stroke centers offer endovascular treatments for acute stroke.


DR. JAMES GROTTA: “The establishment of stroke centers and creation of benchmarks for quality improvement in delivering tPA by our emergency departments (EDs) has changed stroke care in most hospitals... Furthermore, the availability of experts to coordinate care by telemedicine has helped expand the use of tPA, and now there are stroke specialists on call around the clock to provide expertise to thousands of emergency rooms.”

In 2012, the FDA approved the Trevo Pro Retriever (Stryker Corp) and later that year, two other devices were approved — the Penumbra System (Penumbra Inc.) and the Solitaire FR Revascularization Device (Covidien).

“Like tPA, the sooner we use stent retrievers the better,” said Dr. Sacco. Patients can benefit up to six hours after the initial event, and studies are now underway to see whether the window can be extended.

“Now we have multiple approaches and more studies of other options are underway,” added Dr. Sheth.

This has not been a small effort, he added, but one that has evolved into multiple research efforts, with considerable support from the National Institutes of Health and a lot of funding from pharmaceutical and device manufacturers.

“Even so, we still need more support for catheterization laboratories,” he said. “We also need to look at other options to restore brain function after stroke. There have been many studies to triage stroke patients, but not enough patients have access to these treatments. This will require another reorganization of stroke care systems.”


“The pace of these [and other changes] is accelerating, and it has been wonderful to have witnessed this evolution,” especially given emerging evidence that vascular disease is much more prevalent than previously thought, said Vladimir Hachinski, MD, FAAN, distinguished professor of neurology and epidemiology and chairman of clinical neurological sciences at the University of Western Ontario's John P. Roberts Research Institute, in London, Ontario.

“For each diagnosed vascular stroke, there are an estimated five ‘silent’ strokes that affect cognition, and it is important to realize that vascular disease happens before either stroke or the onset of dementia.”

Newer prevention and treatment strategies have helped reduce stroke and dementia incidence and deaths after transient ischemic attacks by 26 percent, he said.

“We are beginning to realize that not only strokes but many dementias are vascular,” he added. “A recent autopsy study of 6,205 individuals found that 61 percent of those with frontotemporal dementia had a vascular component, and that vascular disease played a role in 80 percent of patients with Alzheimer's disease,” he said. “To me this is a major finding.”



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This article on stroke is part of a continuing series, “Fifteen Years of Publication: Then and Now” that looks back and ahead at some of the early research advances on brain repair first reported in 2001, the inaugural publication year of Neurology Today.


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