A stroke occurs when the blood supply to brain tissue is blocked by a blood clot (ischemic stroke), or when a blood vessel in the brain ruptures (hemorrhagic stroke), causing brain cells to die and leading to functional impairments. Stroke is a leading cause of death and disability both globally and in the U.S., where approximately 800,000 people experience a stroke each year1.
Although stroke remains a critical health issue, better management of cardiovascular risk factors, greater awareness of symptoms, and prompt medical attention are helping to prevent strokes and improve outcomes. Accordingly, the death rate from stroke in the U.S. fell 77% between 1969 and 20132. Another major advance was the clot-dissolving medicine tPA (for tissue plasminogen activator), the first treatment for acute ischemic stroke to receive Food and Drug Administration (FDA) approval. Known by the generic name alteplase and marketed as Activase® (Genentech), tPA is given to patients through an IV in the arm, and it works by dissolving blood clots that block blood flow to the brain. When administered quickly after stroke onset (within three hours, as approved by the FDA), tPA helps to restore blood flow to brain regions affected by a stroke, thereby limiting the risk of damage and functional impairment.
NINDS played a major role in the development of tPA, from funding early studies that provided a rationale for its use, to leading pivotal clinical trials that supported the treatment’s FDA approval in 1996. Most notably, NINDS scientists recognized the importance of urgent treatment for acute stroke and pioneered efforts to develop protocols for assessing and treating patients with unprecedented speed. These efforts revolutionized stroke care, and the success of tPA set the stage for additional approved treatments after decades of little hope for effective interventions.
Print Overview and Timeline(pdf, 424 KB)
Danish researchers describe enzyme that will become known as tissue plasminogen activator(tPA).4
Academic and industry researchers express recombinant tPA, enabling purification in amounts sufficient for commercial use.8
FDA approves tPA for the treatment of acute ischemic stroke.
Researchers estimate $4 million in savings for every 1,000 acute ischemic stroke patients treated with tPA.29
Postmarketing studies show benefits of tPA treatment in community hospital settings when rapid treatment protocols are followed.28
History of Development
NINDS played a major role in the development of tPA, from funding early studies that provided a rationale for its use, to leading pivotal clinical trials that supported the treatment’s FDA approval in 1996.
Discovery of a clot-buster
Beginning in the 1950s, investigators first began to develop clot-dissolving, or thrombolytic, interventions for heart attacks and stroke. Early agents included the bacterial enzyme streptokinase and urokinase, an enzyme produced in the kidneys. However, both carried significant risks for dangerous internal bleeding, or hemorrhage, as they prevented clotting throughout the body.3 While tPA had also been discovered by this time,4 it was not extensively studied until the late 1970s, following a fortuitous finding that certain cancer cells grown in the lab produced large amounts of the enzyme.5 This allowed more thorough characterization, which showed that tPA acted preferentially at clots, a potentially major advantage over previously tested enzymes.6
The first studies demonstrating the clot-busting effects of tPA were conducted in the early 1980s, in animal models of coronary artery and other blockages and in a small number of heart attack patients,7 though not yet in stroke patients. The 1980s also ushered in a revolution in biotechnology. Scientists could now clone genes and directly express proteins in cell cultures, and Genentech researchers began producing recombinant tPA in sufficient quantities for future commercialization.8 In 1984, the National Heart, Lung, and Blood Institute (NHLBI) supported the first multicenter, randomized clinical trial using recombinant tPA in heart attack patients. This trial showed successful coronary artery opening in 75% of patients with limited adverse bleeding.9 Based on positive results in additional trials,10,11 the FDA approved tPA (alteplase, Activase®) for treating heart attack12 in 1987.
Restoring blood flow to brain
Meanwhile, NINDS researchers and others thought tPA might be used to treat stroke as well. Earlier failures with streptokinase and urokinase had discouraged further investigation of thrombolytic agents for stroke. However, researchers now understood that these trials had begun treatment too late to salvage oxygen-deprived brain tissue. Furthermore, since tPA carried less risk of internal bleeding, it could be given intravenously, as opposed to directly to an affected artery, a process that required additional time-consuming examination. By the late 1980s, several studies supported in part by NINDS had found that intravenous tPA could dissolve clots in animal models with limited risk of hemorrhage, but only if tPA was administered shortly after the clot blocked blood flow.13,14,15,16,17,18
In the early 1990s, reports of pilot trials of tPA in small numbers of stroke patients described artery opening and improved outcomes.19,20 In particular, two studies involving NINDS support and NINDS intramural investigators developed protocols for assessing and treating stroke patients within 90 minutes or less and three hours or less of symptom onset, based on earlier evidence of the window of opportunity to prevent irreversible damage.21,22 These pioneering studies radically increased the speed with which stroke patients could be diagnosed and treated. They also established that the effective dose of tPA for stroke was less than the standard dose for heart attack, further decreasing the risk for dangerous bleeding. Larger randomized, placebo-controlled studies followed,23,24 including the NINDS tPA Stroke Trial.25 In 1995, results from this pivotal trial showed that patients treated with tPA within three hours of symptom onset were at least 30 percent more likely than placebo-treated patients to have minimal or no disability for up to three months. Treatment with tPA was associated with a greater risk of bleeding in the brain, especially in patients with severe strokes. However, tPA treatment in such patients was still more likely than placebo to result in better outcomes, and mortality did not increase overall in tPA-treated patients.
Thanks in large part to the NINDS-supported trial, the FDA approved tPA26 for the treatment of ischemic stroke in 1996. Follow-up studies confirmed that tPA treatment outcomes observed in the NINDS trial persisted for up to one year,27 and postmarketing studies showed that community hospitals could achieve similar results with adherence to recommended protocols for rapid assessment and treatment.28 In addition, a study on cost benefits estimated $4 million in savings for every 1,000 patients treated with tPA, due to improved outcomes and reduced long term care costs.29
Building on tPA’s benefits
The implementation of rapid treatment protocols transformed acute stroke care in the U.S., even beyond contributing to the success of tPA. Hundreds of hospitals developed organized stroke teams and resources to become primary stroke centers for tPA treatment. On the heels of tPA’s approval, NINDS launched a public awareness and education campaign to help people recognize the signs and symptoms of stroke and understand the importance of getting to the hospital quickly. This successful Know Stroke campaign30 has reached millions through a variety of media and community programs, including programs for Spanish-speaking and minority communities.
NINDS and others have continued to support efforts to increase the use of tPA in eligible patients and improve treatment outcomes, including research on ways to mitigate the risk of bleeding in the brain and extend the time window for treatment. Moreover, the success of tPA motivated the search for additional acute stroke treatments, including interventions to remove large clots resistant to the clot-busting drug. In 2015, multiple clinical trials demonstrated the benefit of clot-retrieval devices as compared to tPA alone for the treatment of severe strokes affecting large arteries to the brain,31 prompting the FDA to expand approval for such devices32. Subsequent clinical trials sponsored by industry and NINDS showed that the time window for effective treatment with these devices can be extended to 16 hours or more in patients determined by brain imaging to have salvageable brain tissue.33,34.
List of References
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Reviewed in Barreto AD. Intravenous thrombolytics for ischemic stroke. Neurotherapeutics. 2011 Jul;8(3):388-99. PMID: 21638138 (NIH and private support, including NINDS grants NB06833 and NB03564)
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