Abstract
The basic science of cerebral ischemia is complex and involves multiple systems. As reviewed elsewhere, hypoperfusion, excitotoxicity, inflammation, and apoptosis are the main disease mechanisms that are tackled by pharmacological interventions. A large number of agents and strategies has been developed to change the pathophysiological cascade. While it has been a rather easy task to find agents that would work in the experimental setting, translation into the clinic has been a major problem. After more than two decades of dedicated clinical trials, only a single agent, rt-PA, has been approved by national agencies for routine use. This review will discuss pitfalls of prior clinical trials and the promise of upcoming strategies in clinical testing.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
The Abciximab in Ischemic Stroke Investigators (2000) Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke 31:601–609
Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth GU, Grau AJ, Green F, Grond-Ginsbach C, Schwaninger M (2003) Multiple levels of regulation of the interleukin-6 system in stroke. Stroke 34:1864–1870
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41
Bamford J, Sandercock P, Dennis M, Burn J, Warlow C (1991) Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337:1521–1526
Bonita R, Beaglehole R (1988) Recovery of motor function after stroke. Stroke 19:1497–1500
Brott T, Adams HP Jr, Olinger CP, Marier JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, et al (1989) Measurements of acute cerebral infarction: a clinical examination scale. Stroke 20:864–870
Caro JJ, Huybrechts KF (1999) Stroke treatment economic model (STEM): predicting long-term costs from functional status. Stroke 30:2574–2579
Dawson DA, Wadsworth G, Palmer AM (2001) A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke. Brain Res 892:344–350
Di Napoli M, Papa F, Bocola V (2001a) C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 32:917–924
Di Napoli M, Papa F, Bocola V (2001b) Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 32: 133–138
Elting JW, Suiter GA, Kaste M, Lees KR, Diener HC, Hommel M, Versavel M, Teelken AW, De Keyser J (2002) AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels. Stroke 33:2813–2818
Fagan SC, Morgenstern LB, Petitta A, Ward RE, Tilley BC, Marler JR, Levine SR, Broderick JP, Kwiatkowski TG, Frankel M, Brott TG, Walker MD (1998) Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology 50:883–890
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F (1999) Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in acute cerebral thromboembolism. JAMA 282:2003–2011
Grotta J (2001) Combination therapy stroke trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis 12:258–263
Hacke W, Bluhmki E, Steiner T, Tatlisumak T, Mahagne MH, Sacchetti ML, Meier D (1998) Dichotomized efficacy end points and global end-point analysis applied to the ECASS intention-to-treat data set: post hoc analysis of ECASS I. Stroke 29:2073–2075
Hacke W, Kaste M, Olsen TS, Bogousslavsky J, Orgogozo JM, Committee ftEE (2000) Acute treatment of ischemic stroke. Cerebrovasc Dis 10 [Suppl 3]:22–33
Herrmann O, Tarabin V, Suzuki S, Attigah N, Prinz S, Schneider A, Coserea I, Monyer H, Brombacher F, Schwaninger M (2003) Regulation of body temperature and neuroprotection by endogenous interleukin-6 in focal cerebral ischemia. J Cereb Blood Flow Metab 23:406–415
Jonas S, Aiyagari V, Vieira D, Figueroa M (2001) The failure of neuronal protective agents versus the success of thrombolysis in the treatment of ischemic stroke. The predictive value of animal models. Ann N Y Acad Sci 939:257–267
Kay R, Wong KS, Yu YL, Chan YW, Tsoi TH, Ahuja AT, Chan FL, Fong KY, Law CB, Wong A (1995) Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 333:1588–1593
Kidwell CS, Liebeskind DS, Starkman S, Saver JL (2001) Trends in acute ischemic stroke trials through the 20th century. Stroke 32:1349–1359
Lees KR (2002) Neuroprotection is unlikely to be effective in humans using current trial design: an opposing view. Stroke 33:308–309
Lyden P, Jacoby M, Schim J, Albers G, Mazzeo P, Ashwood T, Nordlund A, Odergren T (2001) The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurology 57:1199–1205
Lyden P, Shuaib A, Ng K, Levin K, Atkinson RP, Rajput A, Wechsler L, Ashwood T, Claesson L, Odergren T, Salazar-Grueso E (2002) Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke 33:122–128
Muir KW (2002) Heterogeneity of stroke pathophysiology and neuroprotective clinical trial design. Stroke 33:1545–1550
NINDS rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587
Rankin J (1957) Cerebral vascular accidents in patients over the age of 60. Scott Med J 2:200–215
Reith J, Jorgensen H, Pedersen P, Nakayama H, Raaschou H, Jeppesen L, Olsen T (1996) Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 347:422–425
Samsa GP, Matchar DB (2001) Have randomized controlled trials of neuroprotective drugs been underpowered? An illustration of three statistical principles. Stroke 32:669–674
Schellinger PD, Fiebach JB, Jansen O, Ringleb PA, Mohr A, Steiner T, Heiland S, Schwab S, Pohlers O, Ryssel H, Orakcioglu B, Sartor K, Hacke W (2001) Stroke magnetic resonance imaging within 6 h after onset of hyperacute cerebral ischemia. Ann Neurol 49:460–469
Schellinger PD, Fiebach JB, Hacke W (2003) Imaging-based decision making in thrombolytic therapy for ischemic stroke: present status. Stroke 34:575–583
Sherman DG, Atkinson RP, Chippendale T, Levin KA, Ng K, Futrell N, Hsu CY, Levy DE (2000) Intravenous ancrod for treatment of acute ischemic stroke. The STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA 283:2395–2403
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J (1988) Interobserver agreement for the assessment of handicap in stroke patients. Stroke 19:604–607
Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R (2000) Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators. Ann Neurol 48:713–722
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Schwaninger, M., Ringleb, P., Hacke, W. (2004). Design Issues in Selected Recent or Ongoing Stroke Trials. In: Dirnagl, U., Elger, B. (eds) Neuroinflammation in Stroke. Ernst Schering Research Foundation Workshop, vol 47. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-05426-0_11
Download citation
DOI: https://doi.org/10.1007/978-3-662-05426-0_11
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-05428-4
Online ISBN: 978-3-662-05426-0
eBook Packages: Springer Book Archive