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linical practice guidelines published by both the Ameri- in the placebo group. Symptomatic intracerebral hemorrhage
can Heart Association and American Stroke Association (ICH) within 36 hours occurred in 6.4% of rtPA patients versus
(AHA/ASA) in 2007, and the American College of Chest 0.6% of placebo patients (P < 0.001), and mortality was similar
Physicians in 2008, recommend the use of the throm- in both groups at 3 months (P = 0.30). Of note, half of the study
bolytic agent recombinant tissue plasminogen activator (rtPA) for patients were treated within 90 minutes of stroke symptom onset.
the treatment of acute ischemic stroke (AIS) in eligible patients A later subgroup analysis of the trial demonstrated that treatment
(1, 2). Approved by the US Food and Drug Administration (FDA) with rtPA within 90 minutes of stroke symptom onset resulted in
in 1996 for treatment of AIS, intravenous rtPA (or alteplase) is the more favorable outcomes (odds ratio [OR], 2.11; 95% confidence
only thrombolytic agent approved for this indication to date (3). interval [CI], 1.33–3.55) when compared to rtPA initiated within
Due to the extremely small timeframe in which a patient is eligible 90 to 180 minutes (OR, 1.69; 95% CI, 1.09–2.62) (8).
to receive rtPA, it is estimated that only 3% to 5% of stroke suf-
ferers reach a hospital in time to be considered for this treatment EXPANDED CRITERIA FOR rtPA USE
(4). This small number is discouraging because “the ultimate goal As mentioned above, the short 3-hour timeframe in which a
of early reperfusion therapy is to reduce or prevent brain infarc- patient is eligible for treatment with rtPA is a major contribut-
tion and thereby minimize the long term disability, neurologic ing factor to the relatively small number of patients who receive
impairment, and stroke-related mortality” (2). As stroke is the this medication (4). When the European Medicines Agency
third most frequent cause of death in the USA, killing 137,000 approved use of rtPA in Europe in 2002, the agency requested
people each year, mortality reduction could potentially spare the that two follow-up studies be conducted. Conducted first, the
lives of a large number of patients (5). This article briefly reviews SITS-MOST trial confirmed rtPA to be as safe and effective
the evidence supporting the use of rtPA for AIS and focuses on within 3 hours of onset of AIS in practice as in trials (9).
important new literature that has impacted practice since the The second follow-up study evaluated the use of rtPA be-
publication of the current AIS guidelines. yond the 3-hour timeframe. ECASS III, a double-blind, mul-
ticenter, parallel-group trial conducted between July 2003 and
BACKGROUND November 2007 (10), included patients 18 to 80 years of age
The initial European Cooperative Acute Stroke Study with a clinical diagnosis of stroke who were able to receive the
(ECASS), published in 1995, studied rtPA at a higher dose
(1.1 mg/kg, maximum dose 100 mg) and in a longer timeframe From the Department of Pharmacy Services, Baylor University Medical Center
from stroke symptom onset (within 6 hours) than in subsequent at Dallas.
studies, which led to currently approved and accepted rtPA dosing Corresponding author: Jennifer M. Roth, PharmD, BCPS, Department of
and usage criteria (6). The multicenter trial was conducted in 75 Pharmacy Services, Baylor University Medical Center at Dallas, 3500 Gaston
European hospitals and included 620 patients. In ECASS, rtPA Avenue, Dallas, Texas 75246 (e-mail: Jennifer.Roth@BaylorHealth.edu).
July 2011 Recombinant tissue plasminogen activator for the treatment of acute ischemic stroke 259