Does Recombinant t-PA Have a Role in AIS?

Author: Phillip S. Owen, PharmD, and Robert Lee Page II, PharmD, FASCP, BCPS

An estimated 700,000 patients experience a new or recurrent stroke each year. Approximately 500,000 of these cases are first attacks, and 200,000 of them are recurrent strokes. Although the incidence rates are higher in men than in women at a younger age, that difference disappears as people approach 75 years of age. The national impact of stroke can be devastating. It has been estimated that stroke currently costs the US health care system about $56.8 billion per year. The latest data calculate the mean lifetime cost per patient for ischemic stroke in the United States at $140,048, which includes inpatient care, rehabilitation, and follow-up care necessary for lasting deficits.1

Current Evidence

Acute ischemic stroke (AIS) is a diverse disease process; prediction of course, recovery, disability, or death is difficult. Diagnostic procedures for AIS—such as cerebral angiography—performed after event onset demonstrate that the majority of acute infarctions are arterial occlusions. In AIS, recombinant tissue plasminogen activator (t-PA) has been evaluated to reduce the risk of intracerebral hemorrhage (ICH) and to maximize the potential of recovery. Evidence supporting t-PA in AIS comes from 2 large, multicentered trials.

The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study was a double-blind, placebo-controlled, randomized trial that evaluated the safety and efficacy of t-PA in patients presenting with acute stroke, and it discerned the appropriate time to administer t-PA.2 The trial randomized 624 patients into 2 parts. Part 1 tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over baseline values in the score on the National Institutes of Health Stroke Scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 used a global test statistic to assess clinical outcome at 3 months, according to scores on the Barthel index (BI), the modified Rankin scale (MRS), the Glasgow outcome scale (GS), and the NIHSS. Favorable outcomes were defined as a BI score of ≥95, an MRS score of ≤1, a GS score of 1, and an NIHSS score of ≤1. Each group was assessed according to the time from the onset of stroke to the beginning of treatment: 0-90 minutes, 91-180 minutes, and 0-180 minutes.

For part 1, the investigators found no statistically significant differences between groups in the primary outcome. In part 2, the number of patients with favorable outcomes for each of the 4 primary outcome measures 3 months after stroke was higher in the t-PA group than in the placebo group, and only statistically significant in the patients randomized to receive t-PA in the <3-hour window. Even though benefit was demonstrated in patients who were treated with t-PA at 3 to 12 months after stroke, there was a 6.4% incidence of ICH in the treatment groups.

Despite endorsements by expert panels, such as the American College of Chest Physicians, there was great concern that the incidence of ICH in routine clinical practice may be higher. The FDA mandated that the Standard Treatment with Alteplase to Reverse Stroke (STARS) study be conducted to assess the safety profile and clinical outcomes obtained following the administration of intravenous t-PA therapy for acute stroke patients in clinical practice.3 This multicentered, prospective study followed the clinical course of nearly 400 patients with AIS. Primary outcome measures were the time intervals between stroke symptom onset, hospital arrival, and treatment with t-PA; pretreatment computed tomographic (CT) scan results; ICH; and major systemic bleeding. The trial revealed that the median time from stroke onset to treatment was 2 hours 44 minutes, and the median NIHSS score was 13. A baseline CT without stroke-specific abnormalities of the middle cerebral artery, a less severe baseline NIHSS score, an age of ≤85 years, and lower mean arterial pressure at baseline all were found to be predictors of favorable outcomes. Only 3% of the participants experienced symptomatic ICH, and the 30-day mortality rate was 13%. At 30 days after treatment, 35% had favorable outcomes, and 43% were functionally independent.

In contrast, other trials have not demonstrated findings similar to those of the NINDS and STARS studies. In fact, the following prospective, multicentered, randomized, double-blind, placebo-controlled trials could not distinguish a clinical benefit from the t-PA treatment groups and placebo groups. The European Cooperative Acute Stroke Study (ECASS) I and II were trials that used the same outcome measures and time strata as the NINDS.4,5 Both studies showed that the 3-hour cohort did not display any significant differences because of the small patient numbers (n = 80/group). Furthermore, the safety analysis of these 2 trials showed no significant difference in mortality between the groups and a significantly higher incidence of fatal ICH.

The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke trial tested the efficacy and safety of t-PA at 3 to 5 hours post stroke symptoms, using the NIHSS ≤1 at 90 days as the primary outcome measure. Secondary end points included excellent functional recovery at days 30 and 90 on the MRS, the BI, and the GS.6 The study was an intention- to-treat design that had 2 different arms, placebo and treatment. The patients, however, were randomized to 1 of 3 different time strata. There were 39 patients who were treated within 3 hours of symptom onset, 547 patients who were treated within 3 to 5 hours of symptom onset, and 24 patients who were treated >5 hours after symptom onset. This trial failed to find a significant difference in overall mortality between the t-PA group and the placebo group at 3 to 5 hours, despite an increased neurologic recovery in the treatment group between days 30 and 90.

Guidelines

Despite some question as to the exact magnitude of clinical benefit and the practicality that t-PA can offer in patients presenting with AIS, the general consensus is that the benefits, if given to specific patients, outweigh the risk. This sentiment is probably why the American Academy of Neurology, the American Heart Association, and the American College of Chest Physicians granted a grade 1A recommendation to the use of t-PA, but with strict inclusion and exclusion criteria. Most of the inclusion criteria can be generalized to the time from onset of symptoms to treatment, which should be <180 minutes; and baseline CT showing no evidence of ICH. The exclusion criteria are more specific for physiologic parameters, such as systolic blood pressure >185 mm Hg, diastolic blood pressure >110 mm Hg, and platelets <100,000/μL.7

Therefore, pharmacists either dispensing or recommending t-PA in the setting of AIS should obtain the most accurate time line from the onset to the point of treatment, gather patient-specific parameters to assist with appropriate patient selection, and consult with the neurologist to ensure that a CT has been performed, with the results being unremarkable for ICH.

Dr. Owen is a pharmacy practice resident at the University of Colorado Hospital. Dr. Page is an associate professor of clinical pharmacy and physical medicine/rehabilitation at University of Colorado Health Sciences Center, Schools of Pharmacy and Medicine.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@ascendmedia.com.