Ischemic brain tissue salvaged from infarction by the GP IIb/IIIa platelet antagonist tirofiban Abstract—In an open pilot study, the authors tested whether the nonpeptide glycoprotein (GP) IIb/IIIa antagonist tirofiban, a highly effective and selective blocker of platelet aggregation, prevents the transition of ischemic brain tissue into the infarct proper as defined by MRI (perfusion-weighted/T2- weighted) in patients with acute ischemic stroke. The infarct volume (T2 lesion after 1 week) was smaller in treated patients (n = 10) compared with matched control subjects (n = 10; p = 0.029) with similar initial perfusion deficit (TTP-maps). The authors conclude that GP IIb/IIIa antagonists have therapeutic potential in acute stroke therapy. NEUROLOGY 2002;58:474 –476 U. Junghans, MD; R.J. Seitz, MD; A. Ritzl, PhD; H.-J. Wittsack, PhD; G.R. Fink, MD; H.-J. Freund, MD; and M. Siebler, MD The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) recep- tor, a member of the integrin family, plays a key role in the process of platelet aggregation. Activated GP IIb/IIIa receptors bind fibrinogen molecules that than form bridges between adjacent platelets, thus facilitating subsequent platelet aggregation and ac- cumulation. In coronary ischemia, GP IIb/IIIa recep- tor antagonists have been demonstrated to be effective blockers of thrombocyte aggregation with proven clinical efficacy. 1 In several animal models of focal brain ischemia, use of GP IIb/IIIa antagonists led to a substantial reduction in infarct size resulting from decreased microthrombosis. 2,3 Moreover, recent data suggest that the chimeric Fab fragment abcix- imab (ReoPro, Lilly, Bad Homburg, Germany), the first GP IIb/IIIa inhibitor available, is a promising agent for improving acute stroke therapy. 4 In con- trast to abciximab, the nonpeptide GP IIb/IIIa antag- onist tirofiban (Aggrastat, Merck, Whithouse Station, NJ) has better clinical steering properties owing to its short elimination half-life (t 1/2 ~2 hours), which is of particular importance when, for example, endarterectomy or craniotomy need to be performed. Tirofiban also has fewer side effects (e.g., no allergenic potency). MRI has been shown to be a powerful clinical tool in the diagnostic workup of acute stroke. It reliably detects and differentiates fresh and chronic ischemic lesions and can now be used to detect perfusion defi- cits in acute stroke. 5 During the first hours of stroke evolution, hemodynamically compromised regions are generally considered to reflect ischemic brain tis- sue that may be recruited into the infarct over the next 24 to 48 hours. It has been demonstrated both experimentally and clinically that lesion growth de- pends on the severity of the respective perfusion def- icit. About one-half of the total perfusion deficit volume with a delay of 4 seconds in the time-to- peak (TTP) map of perfusion-weighted imaging (PWI) will undergo necrosis. 6 Experimental data now clearly show that reduced and delayed blood flow due to ongoing microthrombosis results in progression of ischemic areas and that platelets contribute substan- tially to microcirculatory disturbances. 3 In this open pilot study, we tested the hypothesis whether the highly selective nonpeptide GP IIb/IIIa antagonist tirofiban may help prevent the transition of ischemic brain tissue into the infarct proper as defined by MRI in patients with acute ischemic stroke. Patients and methods. Consecutive stroke patients with acute hemispheric neurologic symptoms were pro- spectively evaluated using contrast agent bolus tracking PWI within 24 hours of symptom onset as described ear- lier. 6 Turbo spin-echo T2-weighted images were recorded ~7 days later. After exclusion of cerebral bleeding (nega- tive MRI or CT results) each patient received a bolus injec- tion of 5,000 units of unfractionated heparin followed by continuous heparin adjusted to yield an activated partial thromboplastin time 2- to 2.5-fold above baseline levels, a standard therapeutic technique in our department. Ten patients (8 men; mean age 58 years, range 36 to 80 years) with stable or progressive symptoms were also treated IV with body weight–adjusted tirofiban 1 for at least 24 hours (range 1 to 3 days). Ten patients (6 men; mean age 59.1 years, range 27 to 77 years) treated with heparin only were matched with respect to age, sex, arterial territory, side, stroke etiology, and clinical score (European Stroke Scale, Barthel Index) and served as control subjects. Pa- tients treated with tirofiban were imaged 0.8 to 22.5 hours (median 3.6 hours) after symptom onset and the control subjects were imaged 0.7 to 14.5 hours (median 3.3 hours) after symptom onset. Volumes of the ischemic lesion (as assessed using PWI data obtained in the acute stage) and the infarct (as assessed using T2-weighted imaging after 7 days) were measured by two independent investigators (A.R., G.R.F.) blinded to clinical data (figure, for methods, see Neumann–Haefelin et al. 6 ). The study was approved by From the Department of Neurology (Drs. Junghans, Seitz, Ritzl, Fink, Freund, and Siebler) and Institute of Diagnostic Radiology (Dr. Wittsack), University Hospital Düsseldorf, Germany. Supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbe- reich 194), and Kompetenznetz Schlaganfall of the BMBF/Germany. Received February 16, 2001. Accepted in final form October 9, 2001. Address correspondence and reprint requests to Prof. Dr. M. Siebler, De- partment of Neurology, University Düsseldorf, Moorenstr. 5, 40225 Düssel- dorf, Germany; e-mail: siebler@uni-duesseldorf.de 474 Copyright © 2002 by AAN Enterprises, Inc.