Stroke is the leading cause of adult long-term disability in the United States and the third leading cause of death, following heart disease and cancer. The outcome of ischemic stroke is generally determined by the natural course with applied supportive methods. The use of tissue plasminogen activator (tPA) is an effort to intervene in this natural progression to disability and death.
Osborn and associates reviewed the large trials of thrombolytic therapy in the treatment of patients with ischemic stroke. A previous meta-analysis of several trials of thrombolytic therapy demonstrated a higher risk of mortality in patients who received thrombolytic therapy than in patients who did not, but individual study variations make this conclusion questionable. Careful examination of individual thrombolytic trials to discern differences might indicate a particularly beneficial treatment protocol. Specific parameters from the studies include (1) thrombolytic agent administered, (2) interpretation of computed tomographic (CT) scans before initiation of treatment, (3) time between stroke-symptom onset and therapy administration, (4) dose of thrombolytic agent, (5) use of ancillary medication and (6) blood pressure.
Three major thrombolytic agents have been used in the treatment of ischemic stroke: streptokinase, a purified preparation of a bacterial protein with a half-life of about 23 minutes; tPA, a recombinant tissue plasminogen activator that results in reduced fibrinogen levels with a half-life of about five minutes; and ancrod, a serine protease inhibitor that reduces fibrinogen levels. The CT brain scan must ascertain the absence of hemorrhage before thrombolytic therapy is initiated. Accuracy and protocols used for this CT scan interpretation are major factors in study outcome.
Trials suggest that tPA should be administered to patients within three hours after onset of stroke symptoms—a time frame included in the U.S. Food and Drug Administration label for this agent. Some studies had a permissible time frame after onset of stroke symptoms of up to six hours. Study comparisons show that there is a relatively short therapeutic window for ischemic brain tissue survival, with the exact time measurement uncertain.
A dose of 0.9 mg per kg of tPA demonstrated efficacy and served as the standard regimen in all of the trials using this thrombolytic agent. Future studies may show that lower or individualized dosages may be equally safe and effective. The use of ancillary medication (e.g., antiplatelet drugs and anticoagulants) in conjunction with thrombolytic therapy appears to be unwise in patients within 24 hours after a stroke, although further research is needed to examine this point. Further study is also needed to determine the upper limit of blood pressure that would exclude the administration of thrombolytic therapy.
The authors conclude that at three months post stroke, patients who had been treated with a dosage of 0.9 mg per kg of tPA within three hours of onset of stroke symptoms demonstrated neurologic improvement without an increase in mortality. The results achieved with streptokinase are poor. Early results using ancrod up to three hours of onset of stroke symptoms appear promising; this drug is not currently available in the United States. A CT scan is essential in evaluating for a hemorrhagic event, which contraindicates thrombolytic therapy. Physicians should initiate this form of thrombolytic therapy only if the training and administration protocols are available.