Emerging Therapies in Ischemic Stroke Management

Emerging Therapies in Ischemic Stroke Management

Kaste Markku , Tatlisumak Turgut
Published: US Neurology - Volume 4 - Issue I
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Pharmaceutical Recanalization Therapies
When given within three hours of stroke onset in well-selected eligible patients, intravenous (IV) thrombolysis with realtime plasminogen activator (rt-PA) has become the cornerstone of hyperacute stroke therapy. This follows approvals by the US Food and Drug Administration (FDA) in 1996 and the European Medicines Agency (EMEA) in 2002. Although effective, the therapy has several limitations, including certain contraindications, a short application time window, fear of hemorrhagic complications, which may lead to physicians refraining from using rt-PA, the lack of the necessary health service infrastructure in many developed countries, and the fact that not all patients benefit from IV thrombolysis. Recanalization rates with IV thrombolysis range between 20 and 66% (average 46% for all occlusions) depending on the occlusion site, size and consistency of the thromboembolic material, and several other factors. 1 Even if recanalization is achieved, reocclusion associated with clinical deterioration may occur.

Only 4–5% of all ischemic stroke patients in the developed world receive IV thrombolysis. According to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) registry, in Finland more ischemic stroke patients receive thrombolysis per million inhabitants than in any other EU country, and the emergency room of Helsinki University Central Hospital provides more thrombolysis than any other European hospital. However, even in Finland stroke patients do not have equal opportunities for thrombolysis. For benefits to be achieved, a number needed to treat (NNTT) of seven2 was determined, and for hazards to occur a number needed to harm (NNTH) of one in 1003 has been calculated.

The earlier thrombolysis is given, the better the outcome; however, not all stroke patients arrive early enough and thus the current three-hour time window is often too short. In addition to making thrombolysis available for more patients, several other treatments need to be developed. A recent analysis suggested that the benefit of IV thrombolysis continues up to 4.5 hours.4 The European Co-operative Acute Stroke Study III (ECASS III) is a multinational, controlled, randomized study in which patients are randomized to placebo or standard IV rt-PA in a time-frame of three to 4.5 hours from stroke onset. ECASSS III will bring more certainty to the question of whether patients benefit from IV thrombolysis between three and 4.5 hours after stroke. Attempts have been made to further extend the time window for IV thrombolysis with the use of modern brain imaging modalities such as diffusion–perfusion magnetic resonance imaging (MRI) and perfusion computed tomography, with promising success. These modalities may help patient selection for thrombolysis after three hours after the onset of symptoms.

Intra-arterial (IA) thrombolysis may be more effective than IV thrombolysis, especially in cases of large artery occlusions such as internal carotid, basilar, or proximal middle cerebral artery occlusions with extensive thrombus. IA thrombolysis leads more often to recanalization compared with IV thrombolysis (63 versus 46% for all vessels) and is associated with a similar rate of intracranial hemorrhages to IV thrombolysis.1 IA thrombolysis with pro-urokinase was beneficial even up to six hours after stroke onset in one study,5 but it was not approved by the FDA. A combined approach of IV and IA thrombolysis in open trials has been found to be better than IV thrombolysis, with a similar hemorrhagic complication rate to IV thrombolysis alone.6,7 A large randomized trial is warranted.

Novel thrombolytic agents including desmoteplase, tenecteplase, and reteplase have longer half-lives, higher fibrin specificity, and a higher resistance to PA inhibitor-1. Originally isolated from vampire bat saliva, IV desmoteplase was given in randomized trials three to nine hours after stroke onset to patients with a substantial region of penumbra. The first two trials delivered promising results,8,9 but the most recent efficacy trial could not confirm their results. A mutant form of rt-PA, tenecteplase, was found to be safe in a small study when given IV at 0.1–0.5mg/kg within three hours of stroke onset.10 A randomized phase IIb trial comparing three different doses of tenecteplase with standard IV rt-PA within three hours of the time window is under way. Reteplase can be administered as a bolus, and was superior to standard rt-PA in myocardial infarction. Experience with reteplase in stroke patients remains limited.

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