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The Argatroban and tPA Stroke Study

Published online by Cambridge University Press:  27 November 2007

Andrew D. Barreto  and
James C. Grotta
Andrew D. Barreto
Affiliation:
Department of Neurology, Stroke Division, The University of Houston-Texas, Houston, TX, USA; Email: [email protected]
James C. Grotta
Affiliation:
Department of Neurology, Stroke Division, The University of Houston-Texas, Houston, TX, USA; Email: [email protected]
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Extract

ABSTRACT

Background: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke is related to clot lysis and arterial recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. However, human data on this combination are limited. Design: We report an update of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose escalation, safety, and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 h. After standard dose intravenous rtPA administration, a 100-μg/kg bolus of argatroban followed by infusion of 1 μg/kg per min for 48 h was adjusted to a target partial thromboplastin time of 1.75 times baseline. Results: Twenty patients with middle cerebral artery occlusions (including 13 men) have been enrolled, with a mean ± SD age of 61 ± 13 years. Baseline median National Institute of Health Stroke Scale score was 12.5 (range, 3–25). The mean ± SD time from symptom onset to argatroban bolus administration was 177 ± 56 min. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 2 patients and there was 1 death. Recanalization was complete in 7 patients and partial in another 7, and reocclusion occurred in 4 within 2 h of rtPA bolus administration. Conclusion: The combination of low-dose argatroban and intravenous rtPA may be safe, and produce faster and more complete recanalization, but a larger cohort of patients is required to confirm this pilot study.

Keywords

acute strokeanticoagulationargatrobanthrombin inhibitorthrombolysis
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 35 - 47
Copyright
© 2008 Cambridge University Press

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References

Alexandrov, A.V., & Grotta, J.C. (2002). Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology, 59, 862–867.Google Scholar
Alexandrov, A.V., Burgin, W.S., Demchuk, A.M., El-Mitwalli, A., & Grotta, J.C. (2001). Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation, 103, 2897–2902.Google Scholar
Alexandrov, A.V., Demchuk, A.M., Burgin, W.S., Robinson, D.J., & Grotta, J.C. (2004a). Ultrasound-enhanced thrombolysis for acute ischemic stroke, phase I: findings of the CLOTBUST trial. Journal of Neuroimaging, 14, 113–117.Google Scholar
Alexandrov, A.V., Molina, C.A., Grotta, J.C., et al. (2004b). Ultrasound enhanced systemic thrombolysis for acute ischemic stroke. New England Journal of Medicine, 351, 2170–2178.Google Scholar
Alexandrov, A.V., Wojner, A.W., & Grotta, J.C. (2004c). CLOTBUST: design of a randomized trial of ultrasound-enhanced thrombolysis for acute ischemic stroke. Journal of Neuroimaging, 14, 108–112.Google Scholar
Arg-231 Clinical Study Report (1999). A Randomized, Single-Blind Study of Two Doses of Novastan Versus Heparin as Adjunctive Therapy to Recombinant Tissue Plasminogen Activator in Acute Myocardial Infarction: MINT Study. Houston, TX: Texas Biotechnology Corporation.
Ciccone, A., Abraha, I., & Santilli, I. (2007). Glycoprotein IIb-IIIa inhibitors for acute ischemic stroke. Stroke, 38, 1113–1114.Google Scholar
Demchuk, A.M., Burgin, W.S., Christou, I., et al. (2001). Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke, 32, 89–93.Google Scholar
Fiorelli, M., Bastianello, S., von Kummer, R., et al. (1999). Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke, 30, 2280–2284.Google Scholar
Hacke, W., Kaste, M., Fieschi, C., et al. (1998). Second European-Australian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet, 352, 1245–1251.Google Scholar
Hacke, W., Brott, T., Caplan, L., et al. (1999). Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology, 53, S3–S14.Google Scholar
Investigator's Brochure for Argatroban (2001). Houston, TX: Texas Biotechnology Corporation.
Jang, I.K., Gold, H.K., Leinbach, R.C., Fallon, J.T., & Collen, D. (1990). In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator. Circulation Research, 67, 1552–1561.Google Scholar
Jang, I.K., Brown, D.F., Giugliano, R.P., et al. (1999). A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (Tpa) in acute myocardial infarction: Myocardial Infarction with Novastan and TPA (MINT) study. Journal of the American College of Cardiology, 33, 1879–1885.Google Scholar
Kawai, H., Umemura, K., & Nakashima, M. (1995). Effect of argatroban on microthrombi formation and brain damage in the rat middle cerebral artery thrombosis model. Japanese Journal of Pharmacology, 69, 143–148.Google Scholar
Kobayashi, S., & Tazaki, Y. (1997). Effect of the thrombin inhibitor argatroban in acute cerebral thrombosis. Seminars in Thrombosis and Hemostasis, 23, 531–534.Google Scholar
Labiche, L.A., Al-Senani, F., Wojner, A.W., Grotta, J.C., Malkoff, M.A., & Alexandrov, V. (2003). Is the benefit of early recanalization sustained at 3 months? a prospective cohort study. Stroke, 34, 695–698.Google Scholar
LaMonte, M.P., Nash, M.L., Wang, D.Z., et al. (2004). Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study. Stroke, 35, 1677–1682.Google Scholar
Moledina, M., Chakir, M., & Gandhi, J.P. (2001). A synopsis of the clinical uses of argatroban. Journal of Thrombsis and Thrombolysis, 12, 141–149.Google Scholar
Morris, D.C., Zhang, L., Zhang, Z.G., et al. (2001). Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke. Stroke, 32, 2635–2640.Google Scholar
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995). Tissue plasminogen activator for acute ischemic stroke. New England Journal of Medicine, 333, 1581–1587.Google Scholar
Sugg, R.M., Pary, J.K., Uchino, K., et al. (2006). Argatroban tPA stroke study: study design and results in the first treated cohort. Archievs of Neurology, 63, 1057–1062.Google Scholar
Tamao, Y., & Kikumoto, R. (1997). Effect of argatroban, a selective thrombin inhibitor, on animal models of cerebral thrombosis. Seminars in Thrombosis and Hemostasis, 23, 523–530.Google Scholar
Tanaka, K.A., Szlam, F., Katori, N., Sato, N., Vega, J.D., & Levy, J.H. (2004). The effects of argatroban on thrombin generation and hemostatic activation in vitro. Anesthesia and Analgesia, 99, 1283–1289.Google Scholar
Tanaka, Y., Kawabata, S., Sin, R., et al. (1987). Therapeutic effect of argatroban (MD-805), antithrombotic agent, in the acute stage of cerebral thrombosis. Journal of Clinical and Therapeutic Medicine, 3, 133–142.Google Scholar
The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators (1998). Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA, 279, 1265–1272.Google Scholar
Walenga, J.M. (2002). An overview of the direct thrombin inhibitor argatroban. Pathophysiology of Haemostasis and Thrombosis, 32 (suppl. 3), 9–14.Google Scholar
www.clinicaltrials.gov Identifier: NCT00268762. Accessed September 28, 2007.
Wykrzykowska, J.J., Kathiresan, S., & Jang, I.K. (2003). Clinician update: direct thrombin inhibitors in acute coronary syndromes. Journal of Thrombsis and Thrombolysis, 15, 47–57.Google Scholar