IV Alteplase Therapy Up to 4.5 Hours After Acute Ischemic Stroke Onset

Abstract and Introduction

Abstract

Purpose. The efficacy and safety of i.v. alteplase up to 4.5 hours after acute ischemic stroke (AIS) onset were evaluated.
Summary. Stroke is the leading cause of disability in the elderly, and i.v. alteplase (recombinant tissue plasminogen activator) is the only Food and Drug Administration (FDA)-approved thrombolytic agent for the treatment of AIS. Alteplase has been shown to decrease the percentage of patients disabled by a stroke. Until recently, the use of alteplase was only recommended within 3 hours of the onset of AIS symptoms. However, two clinical trials published in 2008 demonstrated that therapy with i.v. alteplase remains safe and effective when given 3–4.5 hours after AIS onset. Although FDA has not yet approved expanding the time interval to 4.5 hours for treatment with i.v. alteplase, the American Stroke Association recently published a statement recommending administration of alteplase in eligible patients 3–4.5 hours after symptom onset. There is clinical evidence supporting the safety and efficacy of i.v. alteplase administration to eligible patients who present within 4.5 hours of AIS symptom onset. Treatment with alteplase decreases the likelihood of disability from an AIS and is not associated with an increased rate of mortality. Expanding the time window for treatment with alteplase would likely increase the percentage of AIS patients who are able to receive alteplase and thus ultimately decrease the percentage of those left disabled from an AIS.
Conclusion. Evidence supports the safety and efficacy of i.v. alteplase administration to eligible patients within 4.5 hours of AIS symptom onset.

Introduction

Stroke is the third leading cause of death in the United States and is the leading cause of disability in the elderly. The estimated cost of stroke-related medical costs and disability for Americans in 2010 will be about $73.7 billion.^[1] Ischemic stroke, which occurs due to obstruction of a blood vessel that carries oxygen and nutrients to the brain, accounts for about 83% of all strokes. Hemorrhagic stroke, which occurs due to a ruptured blood vessel within the brain, accounts for about 17%.^[1]

Thrombolytic therapy is the only medical treatment option for acute ischemic stroke (AIS). While anti-platelet therapy with aspirin has been shown to decrease the risk of early recurrent stroke when initiated within 48 hours of ischemic stroke onset, it does not actually treat the stroke that has already occurred.^[2,3] I.V. alteplase (recombinant tissue plasminogen activator) is the only thrombolytic agent with Food and Drug Administration (FDA)-approved labeling for the treatment of AIS. Alteplase acts by binding to fibrin in a clot and converting the entrapped plasminogen to plasmin, which initiates local fibrinolysis with limited systemic proteolysis.^[4]

Alteplase received marketing approval from FDA in 1996 after the National Institute of Neurological Disorders and Stroke (NINDS) published the results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial.^[5] This study found that patients treated with alteplase within three hours of ischemic stroke symptom onset were at least 30% more likely to have minimal or no disability three months later versus patients who received placebo. This study also found that patients treated with alteplase had an increased rate of symptomatic intracerebral hemorrhage (ICH); however, there was not a significant difference in mortality between the two treatment groups. The dose of i.v. alteplase used in the NINDS study (0.9 mg per kilogram of body weight, maximum of 90 mg) became the FDA-approved dosage for the treatment of AIS. The extensive inclusion and exclusion criteria used in the study formed the basic criteria for selecting patients who qualify for alteplase treatment (appendix).^[4]

Recently, two prospective clinical trials found that alteplase was safe and effective in AIS patients when given 3–4.5 hours after symptom onset.^[7,8] While the 2007 American Heart Association/American Stroke Association Guidelines for the Early Management of Adults with Ischemic Stroke and the 2008 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (which were published before the results of these two studies were available) only recommended thrombolytic therapy with i.v. alteplase in eligible patients within 3 hours of clearly defined ischemic stroke onset, the American Heart Association and the American Stroke Association recently published a science advisory statement that recommended expanding the time for administration of alteplase to eligible patients with AIS to 4.5 hours after symptom onset.^[2,3,6] The exclusion criteria for treatment during the extended time period recommended by the American Heart Association and the American Stroke Association are slightly more extensive than the criteria for those treated within 3 hours after stroke. These additional exclusion criteria are also listed in the appendix. This article reviews the current literature for the safety and efficacy of i.v. alteplase in patients 3–4.5 hours after ischemic stroke onset.

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