Korean Food and Drug Administration Just Approved Urokinase for Intraarterial Thrombolysis of Ischemic Stroke in Non-applicable Case of Intravenous Tissue Plasminogen Activator

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Vascular Neurology 2010;2:1-2 ISSN 2092-6855

This year, intraarterial (IA) urokinase (UK) injection is approved by Korean Food and Drug Administration (KFDA) in case of acute stroke and non-applicable case of intravenous (IV) tissue plasminogen activator (tPA) only.

The 2003 American Heart Association (AHA) guidelines con- cluded that IA administration of at least one specific thrombolytic agent, recombinant pro-urokinase, appears to be of some benefit in treatment of carefully selected patients with acute ischemic stroke secondary to occlusion of the middle cerebral artery (MCA). This conclusion was based on the results of a pro- spective, randomized, placebo-controlled phase III study test- ing the effectiveness of IA thrombolysis with pro-urokinase am- ong patients with stroke of <6 hours’ duration secondary to occlusion of the MCA. In the primary intent-to-treat analysis, 40%

of the 121 patients treated with recombinant pro-urokinase and 25% of the 59 control patients had a modified Rankin Scale score of 0 to 2 at 90 days (p=0.04). But intracranial hemorrhage with neurological deterioration within 24 hours of treatment oc- curred in 10% of patients treated with recombinant pro-uro- kinase and in 2% of the control group (p=0.06). Finally this st- udy prematurely terminated due to high cerebral hemorrhage.

The FDA has not approved the drug, and recombinant pro- urokinase is not currently available for clinical use.

Recently, controlled study of IA UK injection in Japanese group showed that primary outcome (m-Rankin score 0 to 2) was not differences between UK and control group. Cerebral hemorrhage was significantly higher at UK group. AHA guide line of acute stroke treatment (2007) has been established to determine the qualifications of physicians who can perform intra-arterial thrombolysis on the basis of recent statements from professional organizations and clinical trials.

Class I Recommendations

1) IA thrombolysis is an option for treatment of selected patients who have major stroke of <6 hours’ duration due to occlu- sions of the MCA and who are not otherwise candidates for IV recombinant tissue plasminogen activator (rtPA)(Class I, Level of Evidence B). This recommendation has not changed since previous guidelines.

2) Treatment requires the patient to be at an experienced st-

roke center with immediate access to cerebral angiography and qualified specialists of intervention. Facilities are encouraged to define criteria to credential individuals who can perform intraarterial thrombolysis (Class I, Level of Evidence C). This recommendation has been added since previous guidelines.

Class II Recommendation

1) IA thrombolysis is reasonable in patients who have con- traindications to use of IV thrombolysis, such as recent surgery (Class IIa, Level of Evidence C). This recommendation was not included in the previous guideline.

Class III Recommendation

1) The availability of IA thrombolysis should generally not preclude the IV administration of rtPA in otherwise eligible patients (Class III, Level of Evidence C). This recommendation has not changed from previous guidelines.

In case of IA UK injection, combination treatment of IV tPA and subsequent IA thrombolytic tPA treatment is not confirmed and still evaluated as interventional management of stroke III study. Thus, AHA guide line dose not recommend yet as a standard treatment. This years, report of combination therapy as IA UK after full does of rtPA showed that subgroup analysis between diffusion weighted image (DWI)/perfusion weighted image (PWI) mismatch in the rtPA group and DWI/PWI mismatch in the non-rtPA group also showed no statistical difference in recanalization rate, favorable clinical outcome, and mortality (χ² test, p>0.05), but the significant intra-cerebral hemorrage rate was high in the tPA group (χ² test, p<0.05).

Although it was just approved in Korea, IA UK injection should be strictly controlled by evidence based regulation. None- theless, it is regrettable that IA UK injection has been contained in the standard protocol and performed in some hospitals. UK, before approval by KFDA, was not legally permitted for IA thrombolysis of cerebrovascular occlusion, even in case of using as an off-label drug. In Korea, using off-label drugs regards ille- gal because public medical insurance system does not allow using off-label drug. It meets the conclusion that previous all IA thrombolysis was not appropriate treatment except Institutional Review Board (IRB) permitted research even favorable sense.

Korean Food and Drug Administration

Just Approved Urokinase for Intraarterial Thrombolysis of Ischemic Stroke in Non-applicable Case

of Intravenous Tissue Plasminogen Activator

online©MLComm

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Editorial

2 Vascular Neurology 2010;2:1-2

In Korea, indiscreet-IA UK treatment was performed in acute ischemic stroke and reported as a research papers without even IRB permission or with a consent which did not shown using non-approved drug. These issues have been intensely reported at press, Medical Tribunes as special issue, year of 2009. Fur- thermore, IA UK after full dose of tPA should not be used as a standard protocol, because KFDA approved only IA UK in case

of non applicable of IV tPA, and also is not confirmed yet by evidence-based medicine (AHA guideline 2007, Korean FDA drug information).

Conclusively, IA UK thrombolysis should be strictly considered to generalize to all acute stroke patients after failure of tPA thrombolysis, although controlled study of IA UK was recently reported and it was just approved in Korea.