Stroke, t-PA and the NINDS trial

“Tissue Plasminogen Activator for Acute Ischemic Stroke” – The National Institute for Neurologic Disorders and Stroke rt-PA Stroke Study Group, New England Journal of Medicine, December 14th, 1995

Introduction

Prior to the advent of intravenous thrombolytics, there was no direct treatment for ischemic strokes. The clot occluding the artery was allowed to sit in place and the area of brain deprived of blood flow, nutrients and oxygen was allowed to expand while the associated risk factors were controlled. Eventually the body would dissolve the clot (ironically, with it’s own “homemade” version of tissue plasminogen activator, or t-PA) and start the long road to recovery of brain function.

The difficulty with strokes is not mortality. In fact, people who die from large strokes due to massive clots are often dead before they reach a hospital or care facility. Preventing stroke mortality was only one component of the analysis conducted by these authors. Strokes cause disability. Depending on the region of the brain affected, strokes can cause weakness, inability to speak, inability to control emotions or any other mental function without killing, and often this is the most devastating result. Additionally, once disability has set in, the only treatment available is long term physical therapy, which is usually accompanied with large costs and uncertain outcomes. It is important to also note that there is a proportion of stroke patients who regain function of the affected brain region  without intervention. Often this indicates a smaller or less severe stroke, but even with advanced imaging at the initial assessment, it is difficult to characterize which patients will follow this course.

Results

This study assessed the risks and benefits of administering intravenous t-PA within 90 and within 180 minutes of onset of stroke symptoms. The patients were assessed at 24 hours after stroke and 3 months after stroke. The tools for assessment were a variety of scales that measured disability. For example, the NIH Stroke Scale looks at multiple physical exam findings, such as strength in one extremity, to determine how much brain function the patient has lost. Mortality was also compared after 3 months.

The following results from the study were statistically significant: In comparing groups who received t-PA within 90 minutes and placebo, more t-PA patients than placebo patients showed significant improvement within the first 24 hours. After 3 months, more patients who received t-PA within 180 minutes were disability free than patients who received placebo, and this result was the same when patient groups were broken down by age and type and severity of stroke. There was an increased risk of symptomatic intracranial bleeding in patients given t-PA during the first 36 hours, but there was no difference in mortality between patients receiving t-PA and placebo after 3 months.

Why We Do What We Do

This study clearly showed that t-PA increases the chance of eliminating disability after three months if it is administered in the first 3 hours after symptom onset. The authors of this study chose a very difficult outcome measurement – the total reduction of disability to baseline, regardless of how severe the stroke was initially. By validating t-PA in this setting, they make a very strong case for its general use in ischemic strokes across the board.

Intravenous t-PA was the first direct treatment of stroke and is still, 18 years after the NINDS trial, the only effective therapy that we have. It has trounced intravascular mechanical clot-busting, numerous surgical procedures and many other drugs, therapies and delivery mechanisms. Most importantly, it works. For the patients who emerge with no disability, it is not just a therapy, it is a stroke cure. The NINDS study did not just validate the use and effectiveness of t-PA. For those who understand the metrics and analysis properly, it is a sign of hope that someday we will be able to eliminate, and not just reduce, the debilitating disability that results from stroke.

Tissue plasminogen activator for acute ischemic stroke. The National Institute
of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995
Dec 14;333(24):1581-7. PubMed PMID: 7477192.
http://www.nejm.org/doi/full/10.1056/NEJM199512143332401