Tissue plasminogen activator (tPA) is one of the very few time-sensitive drugs in the realm of Neurology. It has been a standard of care for the management of acute ischemic stroke for so long that many of you may not know its origin story. Let’s go back in time to review how tPA became known as an effective clot-busting medication.
Tissue plasminogen activator (tPA) was discovered in the 1950s, however, it was not until the early 1980s that a recombinant tPA (Alteplase) was developed as a therapeutic agent. In 1987 it was approved by the FDA for the treatment of acute myocardial infarction. The ECASS and NINDS trials published weeks apart in 1995 were the landmark trials that led to the FDA approval of tPA for ischemic stroke the following year.
The ECASS trial was a randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial that administered tPA vs. placebo within 6 hours from the onset of acute stroke symptoms. The goal of this study was to see if patients who were given tPA had a lower rate of disability post-stroke than a placebo group by comparing modified Rankin scales (mRS) 90 days beyond treatment. An intention to treat (ITT) analysis resulted in no statistically significant difference between the two groups due to major protocol violations, however, a subgroup analysis of the “target population” showed that those given tPA had a statistically significant lower rate of disability.
The NINDS trial was a randomized, double-blind, placebo-controlled trial that compared the efficacy of tPA within 3 hours of symptoms onset. The study was completed in 2 parts between 1991 to 1994; Part 1 enrolled 291 patients and compared NIH stroke scale (NIHSS) changes at 24 hours, and Part 2 enrolled 333 patients and compared the clinical outcomes (Barthel index, mRS, Glasgow scale, and NIHSS) 3 months after the event. While the study did not demonstrate any statistically significant difference in NIHSS for patients treated with tPA compared to placebo within 24 hours in the Part 1 aspect of the study, Patients who received tPA in Part 2 of the study had better NIHSS and mRS at 90 days. Even though the risk of intracranial hemorrhage was higher in those who received tPA (6.4% vs. 0.6% (p<0.001)), the favorable primary outcomes and comparable 90-day mortality between tPA vs. placebo (5.8% vs. 5.4% (p<0.001)) made it apparent that the benefits of tPA outweigh the risks in certain populations.
It has been over 25 years since tPA was approved for the management of acute ischemic stroke and over that time Alteplase dominated the management of acute ischemic stroke. Now it seems that a newer thrombolytic, tenecteplase, is challenging its dominance, but we will save that discussion for a future post!
Feel free to review the landmark articles here and here!
Learn more about tPA here!
References:
- Astrup, T, Stage, A. Isolation of a Soluble Fibrinolytic Activator from Animal Tissue. Nature 170, 929 (1952). https://doi.org/10.1038/170929a0
- Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct 4;274(13):1017-25.
- 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. doi: 10.1056/NEJM199512143332401.
