UC Stroke Team Revolutionized Stroke Treatment for the World in 1990s — Here’s How

By Joseph Broderick, MD
Director, University of Cincinnati Gardner Neuroscience Institute
Professor of Neurology,
UC College of Medicine

Prior to the breakthrough accomplishments of the University of Cincinnati Stroke Team, stroke was both untreatable and the third leading cause of death in the United States. Approximately 8 out of 10 strokes are of the ischemic kind. Tissue plasminogen activator (tPA) dissolves blood clots that block blood flow resulting in tissue death.

Through the team’s leadership, hundreds of thousands of lives that would have otherwise resulted in death or debilitation have been heroically saved due to the development, testing and implementation of medical (tPA) and endovascular reperfusion therapies for acute ischemic stroke.

In addition to introducing these therapies to the world, the UC Stroke Team’s determination to educate the healthcare and nonmedical communities on stroke recognition and assessment led to the development of the globally accepted National Institutes of Health Stroke Scale in the mid-1980s and the F.A.S.T. method of communicating the warning signs of stroke to the public.

From watchful waiting to a trauma approach

In the early 1980s, stroke patients were often not assessed until 12–24 hours after arrival to the hospital, since (a), there was no consistent, reliable assessment of acute stroke patients by physicians and other healthcare personnel and (b), no treatment existed for stroke. As a result, prehospital and hospital logistical stroke-response systems were not configured for administering treatment that would have required rapid delivery to be effective.

When tPA was first proposed as a reperfusion therapy for acute stroke as part of an effort by the National Institute of Neurological Disorders and Stroke (NINDS) in 1986, the timeline for treatment for the pilot trial was set at 90 minutes from onset of symptoms — a threshold that had never occurred in any stroke trial or clinical setting in the world. The success of tPA would be dependent upon advancements in both logistical systems and rapid diagnostic assessment of stroke.

To address these challenges, the UC team formed the first multidisciplinary stroke team comprising stroke neurologists, emergency medicine physicians, neuroradiologists and trauma nurses. In addition, rather than just treating patients at the academic medical center, Drs. Thomas Brott, Joseph Broderick, William Barsan and colleagues created a SWAT team-method to treat patients at regional community hospitals across Greater Cincinnati.

The NIH Stroke Scale, the Prehospital Cincinnati Stroke Scale, the F.A.S.T Scale

In the mid-1980s, Dr. Brott and his UC colleagues developed the NIH Stroke Scale as a rapid tool to assess stroke patients by physicians and nurses. This scale is now used worldwide to assess stroke patients clinically, providing a common language for stroke severity that enables critical decision making throughout the care of the acute stroke patient. While the NIH Stroke Scale was a major clinical advancement, an even quicker and simpler tool was needed for the prehospital personnel who first assess potential stroke patients. Drs. Broderick, Brott and Rashmi Kothari worked with their colleague investigators at UC to develop the Prehospital Cincinnati Stroke Scale for prehospital personnel to rapidly identify potential stroke patients in the field and accelerate their transport to the hospital and subsequent treatment. In establishing a trauma approach to assessment and treatment of acute stroke patients, this team was the first to use cell phone technology to coordinate assessment and treatment of the stroke patient while driving to the hospital. And, for the first time anywhere in the world, patients were undergoing brain imaging to rule out brain hemorrhage and being treated with tPA within 90 minutes from symptom onset.  

Most recently, Dr. Broderick and colleagues developed the Cincinnati Stroke Triage Assessment Tool (C-STAT) that differentiates patients with more severe stroke in the prehospital setting who should be triaged to hospitals where thrombectomy can be performed.

The Cincinnati team adapted the Prehospital Cincinnati Stroke Scale to educate the public about stroke warning signs and what to do if they are present. This F.A.S.T. Scale is now used worldwide by the public to recognize stroke warning signs and to call the emergency medical service number. The F.A.S.T. Scale is the core message in the American Heart and American Stroke Association efforts to educate the public concerning recognition of acute stroke.

FDA approval of tPA — first treatment for acute stroke

The innovative methods of Drs. Brott and Broderick and colleagues led to the treatment of stroke patients using tPA. More than five-sevenths (71%) of the patients in the pilot three-center tPA trial were treated at the University of Cincinnati and associated community hospitals. Since this novel treatment was delivered substantially earlier than any other prior trial or in any emergency department at that time, the trial data were met with great skepticism by the medical community. This pilot trial laid (a), the groundwork for the dose of tPA and (b), a model for treatment logistics in the emergency department at the additional seven institutions that participated in the subsequent NINDS-funded randomized trial of tPA for acute stroke during 1991–1994. As a result, the trial demonstrated the effectiveness of tPA for acute ischemic stroke within three hours of onset, and the FDA approved its use in 1996, one year after publication of the trial in the New England Journal of Medicine. These developments changed stroke from an untreatable human disease to an eminently treatable one, and throughout the world, prehospital and hospital treatment of all types of acute stroke began to change.

Advancements in acute stroke treatment after tPA

While tPA for acute ischemic stroke revolutionized the field of acute stroke and systems of care in the late 1990s and 2000s, these trials and subsequent clinical practice showed that a substantial proportion of patients with larger ischemic strokes did not respond to intravenous (IV) tPA alone. To address this issue, the UC research team led by Drs. Broderick, Brott, Arthur Pancioli and Opeolu Adeoye developed two novel approaches to improve stroke reperfusion:

  1. Adding an IV infusion of the platelet G IIb/IIIa receptor drug (eptifibatide) to tPA, which prevents aggregation of platelets that could lead to clot formation.
  2. Combining IV tPA with immediate treatment of the remaining clot by interventional angiography (endovascular therapy).

The first approach with combined IV eptifibatide and tPA has been tested in three promising pilot trials and has been funded by the NINDS as a phase 3 trial in 2018. However, in 2015, the second approach of clot removal by endovascular therapy following IV tPA was resoundingly demonstrated to be more effective than IV tPA alone for patients with occlusions of large intracranial arteries.

Drs. Broderick and Brott and their colleagues first tested the combined IV tPA and endovascular approach in three pilot North American trials from 1994 to 2003, and subsequently in the largest randomized global trial of endovascular therapy (Interventional Management of Stroke [IMS] Ill) from 2006 to 2013. IMS III compared IV tPA alone starting within three hours of onset to IV tPA followed by endovascular therapy to remove remaining thrombus. The trial began prior to the widespread use of CT angiography to identify clots in large intracranial arteries and used FDA-cleared technology for thrombus removal that became available in 2004, 2008 and 2012 but incorporated these changes into the trial as they became available. While the overall trial using older clot removal technology was neutral, trial subjects with documentation of major arterial occlusion by CT angiogram at baseline benefited from endovascular therapy, as did subjects with the most severe strokes at one year. In addition, IMS I, II and III demonstrated the importance of time to reperfusion that mirrored the importance of time to treatment with IV tPA.

Prompted by the IMS Ill results, international colleagues of Drs. Broderick and Brott, who participated in IMS Ill, began five new trials in various countries from 2010–2013 that utilized the newest endovascular clot removal technology (stent retrievers). These trials, published from December 2014 through April 2015, demonstrated in patients with large intracranial arterial occlusions the effectiveness of endovascular therapy following IV tPA as compared to IV tPA alone.

In addition, Dr. Broderick led the National Coordinating Center for the NINDS-funded DEFUSE III Trial that was published in the New England Journal of Medicine in 2018. This trial demonstrated that patients with salvageable brain tissue identified by advanced brain imaging benefited remarkably from endovascular clot removal, extending the therapeutic time window for stroke therapy to 16 hours or more after onset of symptoms. Thus, these two scientifically proven treatments for acute ischemic stroke resulting from the UC Stroke team’s work, IV tPA and endovascular clot retrieval, revolutionized the treatment of acute stroke.

In addition to the innovative and fundamental advances in acute ischemic stroke treatments, the research team at UC first demonstrated that expansion of bleeding in the brain is common in patients with intracerebral hemorrhage during the first 3–4 hours after onset. This led to interventional trials of hemostatic agents (recombinant Factor VIIa) and blood pressure control for acute ICH and subsequent changes in blood pressure management for these patients. An NIH-funded global trial of rFVIIa treatment within two hours of stroke onset, headed by Dr. Broderick, started in 2019.

Continuing contributions to stroke investigation and treatment

As leaders of the largest population-based stroke study in the U.S., the UC Stroke Team led by Drs. Broderick, Kissela, Dawn Kleindorfer and Daniel Woo demonstrated the excess burden of stroke among African Americans as compared to whites, and have shown the change in stroke incidence rates over time. Drs. Broderick and Woo and colleagues initiated some of the earliest population studies of the genetic and environmental risk factors for intracerebral and subarachnoid hemorrhage and brain aneurysms that have advanced the understanding of both diseases. Most of the national statistics about stroke for the country supplied by the American Heart and Stroke Association are derived from the population data from Greater Cincinnati and Northern Kentucky.

Currently, Dr. Broderick is the Principal Investigator for the National Coordinating Center for the NIH StrokeNet that directs all NINDS-funded Phase II and Phase Ill trials of stroke therapy, prevention and recovery in the U.S. and is leading the development of global stroke trial networks. Currently, nine phase-3 and phase-2 trials are ongoing or starting in 2020.

Biggest impact in our hometown

Due to the UC Stroke Team’s innovative efforts to change stroke, one of humanity’s greatest and feared scourges, they have altered the disease from untreatable to treatable, with the largest impact within our hometown. We have provided acute stroke care to all of the region’s hospitals in person, and more recently by telemedicine, since the late 1980s.

In 2018, we had over 5,600 phone consultations from 33 regional emergency departments and hospitals and treated 560+ patients with tPA or endovascular clot removal. Since the beginning of our team in the 1980s, over 30,000 people in Greater Cincinnati and Northern Kentucky have participated in our research studies involving population studies, surveys about stroke and clinical trials.

And in 2020, we will deploy a mobile stroke unit in Greater Cincinnati that will be able to image the brain and deliver tPA and other treatment at a patient’s home or workplace within an hour of symptom onset and then bring them to the most appropriate hospital.

We look forward to partnering with our community during the next decade of stroke care in Greater Cincinnati and Northern Kentucky.

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