Thrombolytic agents stroke

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

No direct comparison trials have been reported between the different thrombolytic agents in acute ischemic stroke. In a retrospective review of the results for acute stroke lAT performed at our center, we have found significantly higher rates of recanalization and good clinical outcome in the era in which lA UK was used versus the era in which UK was not available and lAT with rt-PA was the primary treatment. Conversely, in another retrospective study, Eckert et al. found no major difference between the recanalization rates of UK and rt-PA. 

Suarez Jl, Zaidat OO, Sunshine JL, Tarr R, Selman WR, Landis DM. Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes. Neurosurgery 2002 50 251-259 [discussion 259-260]. 

In situations where inappropriate clot formation results in the blockage of a blood vessel, the tissue damage that ensues depends, to a point, upon how long the clot blocks blood flow. Rapid removal of the clot can often minimize the severity of tissue damage. Thus, several thrombolytic (clot-degrading) agents have found medical application (Table 12.5). The market for an effective thrombolytic agent is substantial. In the USA alone, it is estimated that 1.5 million people suffer acute myocardial infarction each year, and there are another 0.5 million suffer strokes. 

E. Therapeutic response Activase, and other thrombolytic agents, used in a timely manner during an evolving myocardial infarction, decrease mortality and improve left ventricular function. Resolution of chest pain, resolution of baseline EKG changes, reduced total creatine phospho-kinase (CPK) release, and preserved left ventricular function are evidence of cardiac reperfusion. Activase, administered within the first 3 hours of ischemic stroke onset, has been shown to improve recovery. 

No preclinical studies of neuroprotectives plus hypothermia in permanent occlusion stroke models without thrombolysis have been reported. This is of particular importance because these permanent ischemia models may better simulate the events that occur clinically in the vast majority of stroke patients who do not receive reperfusion therapy with a thrombolytic agent. Such studies will be necessary before proceeding with clinical trials in stroke patients. 

Q9 Several pharmacological agents could theoretically be used to promote cerebral blood flow and potentially improve the outcome from a stroke. Are thrombolytic agents or anticoagulants likely to be suitable treatments for all cases of stroke ... 

Currently, the only treatment of patients with acute ischemic stroke is thrombolysis and restoration of blood flow [3,6,7]. Only a fraction of stroke patients benefits from this therapy [3,6,7], Therapeutic recanalization of an occluded cerebral artery is a risky option that can be applied only in the case of selected patients. The main limitation of cerebral thrombolysis is the narrow, 3-hour therapeutic window during which the thrombolytic agent has to be administered to be effective. Beyond this time limit, its effectiveness is neutralized by the high risk of cerebral hemorrhage [7], In acute stroke, only a small fraction of patients benefit from intravenous administration of recombinant tissue plasminogen activator, which is the only drug with proven effectiveness in reducing the size of infarct in humans [6],... 

With advances of adjunctive pharmacotherapy for PCI, multiple trials sought to confirm superiority of primary PCI to thrombolytic therapy in STEMI. In a review of 23 trials, primary PCI had better outcomes than thrombolytic therapy by reducing the combined endpoint of death, nonfatal reinfarction, and stroke (8% versus 14%), independent of the type of the thrombolytic agent used (124). 

C. Clinical Use The major application of the thrombolytic agents is in the emergency treatment of coronary artery thrombosis. Under ideal conditions (ie, treatment within 1—4 hours), these agents may cause prompt recanalization of the occluded vessel. Very prompt use (ie, within 3 hours of the first symptoms) of t-PA in patients with ischemic stroke appears to result in a significantly better clinical outcome. Cerebral hemorrhage must be positively ruled out before such use. The thrombolytic agents are also used in cases of multiple pulmonary emboli. 

The Cochran group performed a meta-analysis [52]. The analysis included those studies that used t-PA (NINDS, ECASS, and ECASS II), and also those studies that evaluated SK, MAST -I, MAST-E, and the Australian SK study. The meta-analysis included patients who were treated within 3 h after symptom onset. In this analysis, there were 126 fewer dead or dependent stroke patients for every 1,000 patients treated with thrombolytic agents. 

Evidence-based guidelines for time of stroke onset greater than 4.5 h Finally reviewing the evidence available, it was recommended that t-PA not be given to individuals beyond the 4.5 h of symptom onset. Furthermore, they recommended against the use of SK as an IV thrombolytic agent in acute ischemic stroke [77]. 

---