Tissue Plasminogen Activator for Acute Ischemic Stroke (Alteplase, Activase®)

Overview

stroke - blood clot

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)

Timeline

1946

Danish researchers describe enzyme that will become known as tissue plasminogen activator(tPA).4

NIH logo NINDS logo
1949

Early studies during the 1950s-1970s test other clot-dissolving agents.3

NIH logo
1976-1980

Belgian researchers isolate tPA from a melanoma cell line in large quantities and show that it can dissolve blood clots in animal models.5,6

image of cell culture
Shutterstock
1982

Academic and industry researchers express recombinant tPA, enabling purification in amounts sufficient for commercial use.8

Academic and industry researchers express recombinant tPA, enabling purification in amounts sufficient for commercial use.
NINDS
1982-1987

Small-7 and then large-scale clinical trials test tPA in heart attack patients.9,10,11

NIH logo
1986

FDA approves tPA for treatment of acute myocardial infarction, or heart attack.12

1984-1991

Several studies report the efficacy of tPA in animal models of stroke with improved outcomes and low risk of hemorrhage when treatment is delivered early.13,14,15,16,17,18

NIH logo NINDS logo
efficacy of tPA in animal models of stroke
Shutterstock
1986-1991

Pilot clinical trials test tPA in stroke patients, including the first studies to develop organized stroke teams and protocols for treatment within three hours of symptom onset.19,20,21,22

NIH logo NINDS logo
organized stroke teams and protocols for treatment within three hours of symptom onset
Shutterstock
1994

Pivotal Phase III trial demonstrates the safety and efficacy of tPA for acute ischemic stroke.25,27

NIH logo NINDS logo
Pivotal Phase II trial demonstrates the safety and efficacy of tPA for acute ischemic stroke.
Shutterstock
1995

FDA approves tPA for the treatment of acute ischemic stroke.

Food and Drug Administration logo
FDA.gov
1997

Researchers estimate $4 million in savings for every 1,000 acute ischemic stroke patients treated with tPA.29

NIH logo NINDS logo
2000

NINDS launches Know Stroke public education campaign.30

NIH logo NINDS logo
Know Stroke Campaign. Know the Signs. Act in TIme.
stroke.nih.gov
1997-2000

Postmarketing studies show benefits of tPA treatment in community hospital settings when rapid treatment protocols are followed.28

2014

Clot-retrieval devices are shown to be more effective than tPA alone for strokes involving clots in large arteries.31

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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  2. Ma J, Ward EM, Siegel RL, Jemal A. Temporal Trends in Mortality in the United States, 1969-2013. JAMA. 2015 Oct 27;314(16):1731-9. PMID: 26505597

  3. 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)

  4. Astrup T, Permin PM. Fibrinolysis in animal organism. Nature 1947;159:68 1–2. PMID: 2034226 (Denmark, source not given)

  5. Collen D, Billiau A, Edy J, De Somer P. Identification of the human plasma protein which inhibits fibrinolysis associated with malignant cells. Biochim Biophys Acta. 1977 Sep 29;499(2):194-201. PMID: 198009 (Belgium, private support)

  6. Matsuo O, Rijken DC, Collen D. Thrombolysis by human tissue plasminogen activator and urokinase in rabbits with experimental pulmonary embolus. Nature. 1981 Jun 18;291(5816):590-1. PMID: 7195468 (Belgium, private support)

  7. Van de Werf F, Ludbrook PA, Bergmann SR, Tiefenbrunn AJ, Fox KA, de Geest H, Verstraete M, Collen D, Sobel BE. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med. 1984 Mar 8;310(10):609-13. PMID: 6537987 (NIH/NHLBI grant HL17646, private support)

  8. Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature. 1983 Jan 20;301(5897):214-21. PMID: 6337343 (Genentech)

  9. Collen D, Topol EJ, Tiefenbrunn AJ, Gold HK, Weisfeldt ML, Sobel BE, Leinbach RC, Brinker JA, Ludbrook PA, Yasuda I, et al. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. Circulation. 1984 Dec;70(6):1012-7. PMID: 6388898 (Genentech)

  10. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985 Apr 4;312(14):932-6. PMID: 4038784 (NIH/NHLBI contract; Genentech, tPA)

  11. Dalen JE, Gore JM, Braunwald E, Borer J, Goldberg RJ, Passamani ER, Forman S, Knatterud G. Six- and twelve-month follow-up of the phase I Thrombolysis in Myocardial Infarction (TIMI) trial. Am J Cardiol. 1988 Aug 1;62(4):179-85. PMID: 3135737 (NIH/NHLBI contract; Genentech, tPA)

  12. U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed May 4, 2017.

  13. Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science. 1985 Dec 13;230(4731):1289-92. PMID: 3934754 (Private support; NINDS-supported investigator)

  14. Penar PL, Greer CA. The effect of intravenous tissue-type plasminogen activator in a rat model of embolic cerebral ischemia. Yale J Biol Med. 1987 May-Jun;60(3):233-43. PMID: 3111108 (NIH/NINDS, grants NS10174, NS19430)

  15. Zivin JA, Lyden PD, DeGirolami U, Kochhar A, Mazzarella V, Hemenway CC, Johnston P. Tissue plasminogen activator. Reduction of neurologic damage after experimental embolic stroke. Arch Neurol. 1988 Apr;45(4):387-91. PMID: 3128254 (NIH/NINDS, grants NS23323, NS23814; US Dept. of Veterans Affairs (VA); Genentech, tPA)

  16. Phillips DA, Fisher M, Smith TW, Davis MA. The safety and angiographic efficacy of tissue plasminogen activator in a cerebral embolization model. Ann Neurol. 1988 Apr;23(4):391-4. PMID: 3132892 (Private support – Genentech and other private)

  17. Lyden PD, Zivin JA, Clark WA, Madden K, Sasse KC, Mazzarella VA, Terry RD, Press GA. Tissue plasminogen activator-mediated thrombolysis of cerebral emboli and its effect on hemorrhagic infarction in rabbits. Neurology. 1989 May;39(5):703-8. PMID: 2496332 (NIH/NINDS, grant NS23814; VA; Burroughs Wellcome Co., tPA)

  18. Overgaard K, Sereghy T, Boysen G, Pedersen H, Diemer NH. Reduction of infarct volume and mortality by thrombolysis in a rat embolic stroke model. Stroke. 1992 Aug;23(8):1167-73; discussion 1174. PMID: 1636193 (Denmark, private support)

  19. Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology. 1992 Feb;42(2):289-98. PMID: 1736156 (Germany, source not given)

  20. von Kummer R, Hacke W. Safety and efficacy of intravenous tissue plasminogen activator and heparin in acute middle cerebral artery stroke. Stroke. 1992 May;23(5):646-52. PMID: 1579960 (Germany, source not given)

  21. Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992 May;23(5):632-40. PMID: 1579958 (NIH/NINDS, intramural and grants NS03342, NS32324, NS51007; Genentech, tPA)

  22. Haley EC Jr, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, Torner JC, Marler JR. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke. 1992 May;23(5):641-5. PMID: 1579959  (NIH/NINDS, grant number not given)

  23. Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology. 1992 May;42(5):976-82. PMID: 1579252 (Sumitomo Pharmaceuticals, Tokyo, Japan)

  24. Haley EC Jr, Brott TG, Sheppard GL, Barsan W, Broderick J, Marler JR, Kongable GL, Spilker J, Massey S, Hansen CA, et al. Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke. The TPA Bridging Study Group. Stroke. 1993 Jul;24(7):1000-4. PMID: 8322373 (Genentech; NINDS intramural)

  25. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. PMID: 7477192. LINK (NIH/NINDS, contracts NS02382, NS02374, NS02377, NS02381, NS02379, NS02373, NS02378, NS02376, NS02380; Genentech, tPA)

  26. U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1996/altegen061896L.htm. Accessed May 4, 2017.

  27. Kwiatkowski TG, Libman RB, Frankel M, Tilley BC, Morgenstern LB, Lu M, Broderick JP, Lewandowski CA, Marler JR, Levine SR, Brott T. Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. N Engl J Med. 1999 Jun 10;340(23):1781-7. PMID: 10362821

  28. Gladstone DJ, Black SE. Update on intravenous tissue plasminogen activator for acute stroke: from clinical trials to clinical practice. CMAJ. 2001 Aug 7;165(3):311-7. Review. PMID: 11517650 (Private and unknown funding sources)

  29. Fagan SC, Morgenstern LB, Petitta A, Ward RE, Tilley BC, Marler JR, Levine SR, Broderick JP, Kwiatkowski TG, Frankel M, Brott TG, Walker MD. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology. 1998 Apr;50(4):883-90. PMID: 9566367 (NIH/NINDS contracts NS02382, NS02374, NS02377, NS02381, NS02379, NS02373, NS02376, NS02378, and NS02380)

  30. Know Stroke Home: About the Campaign. Available at: https://stroke.nih.gov/about/index.htm. Accessed April 3, 2017.

  31. Furlan AJ. Endovascular therapy for stroke--it's about time. N Engl J Med. 2015 Jun 11;372(24):2347-9. PMID: 25882509

  32. U.S. Food and Drug Administration. FDA allows marketing of clot retrieval devices to reduce disability in stroke patients [FDA website]. September 2, 2016. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm519042.htm. Accessed April 3, 2017.

  33. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, Sila CA, Hassan AE, Millan M, Levy EI, Mitchell P, Chen M, English JD, Shah QA, Silver FL, Pereira VM, Mehta BP, Baxter BW, Abraham MG, Cardona P, Veznedaroglu E, Hellinger FR, Feng L, Kirmani JF, Lopes DK, Jankowitz BT, Frankel MR, Costalat V, Vora NA, Yoo AJ, Malik AM, Furlan AJ, Rubiera M, Aghaebrahim A, Olivot JM, Tekle WG, Shields R, Graves T, Lewis RJ, Smith WS, Liebeskind DS, Saver JL, Jovin TG; DAWN Trial Investigators. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. PMID: 29129157 (Private support - Stryker Neurovascular)

  34. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG; DEFUSE 3 Investigators. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Jan 24. PMID: 29364767 (NIH/NINDS, grants NS086487 and NS092076)