Thrombolytic therapy for acute ischemic stroke.
Available evidence of thrombolysis in acute ischemic stroke comes from a series of recent trials conducted in patients with acute stroke, and from a meta-analysis published in the Cochrane Library. The objective of this paper is to review the literature on tolerability and efficacy of thrombolytic therapy in patients with acute ischemic stroke, to find out what the level of evidence is for each thrombolytic drug, and what should consequently be done in the routine practice. This review is based on a bibliographic search of published meta-analyses of randomized trials, published randomized trials, and ongoing randomized trials, with the outcomes of disability, death, and symptomatic intracerebral hemorrhages (fatal or non-fatal). Our primary end-point is a combination of death and disability, in terms of "death or dependency", with dependency defined as a modified Rankin Score (mRS) of >/=3. The level of evidence for the efficacy of a thrombolytic treatment is considered sufficient if there is both a statistically significant effect in the meta-analysis of all randomized trials, without statistically significant heterogeneity, together with one adequately powered and designed conclusive trial. Streptokinase has a clearly harmful effect, without any demonstrated benefit and must not be used in patients with acute ischemic stroke. The level of evidence of an effect of intra-arterial pro-urokinase to reduce death or dependency is low, available data are sparse (only 220 patients), the estimation of its real efficacy and tolerability remains unclear, and its use in clinical practice is not presently justified. The efficacy of alteplase has been incompletely demonstrated because the results vary across trials and type of outcomes (death, death or dependency), and the cut-off of the disability scale. There is a significant heterogeneity in the effect on death or dependency. However, we can conclude that there is a beneficial effect, but its clinical application is limited because of the absence of adequate criteria to identify patients most likely to benefit from treatment. Overall the use of alteplase in patients with acute stroke was associated with some benefit, but it significantly increased total mortality in two trials. Given the observed confidence interval (CI), the results are compatible with, in the best situtation, 203 advoided death or dependency and 61 avoided death per 1000 treated patients, and at worst 77 avoided death or dependency and 38 extra deaths per 1000 treated patients. Further trials aimed at validating more discriminant selection criteria are mandatory.
Cornu
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Service de Pharmacologie Clinique EA 643, Claude Bernard University, Lyon, France. Catherine.Cornu@chu-lyon.fr
Amsallem
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Serradj-Jaillard A
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D000208:Acute Disease; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D015201:Meta-Analysis as Topic; D011358:Product Surveillance, Postmarketing; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013300:Streptokinase / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D013300:Streptokinase; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase