Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of ischaemic stroke onset is established and approved treatment. Endovascular thrombectomy, although highly effective in reducing stroke disability and potentially mortality, is only indicated in large artery occlusion, feasible in a minority of patients, and is most commonly used in addition to iv thrombolysis. In spite of these combined revascularisation therapies, up to 40% of treated patients will be functionally dependent or die within three months.Importantly, only 13% of all patients with acute ischaemic stroke receive reperfusion therapies in Sweden.
Two important complications of ischaemic stroke and its acute treatment are haemorrhage into the infarcted tissue and cerebral oedema. Experimental data suggest that haemorrhage and oedema may be caused by an injury of the blood brain barrier (BBB) in the area with reduced circulation following an arterial occlusion. Activation of PDGF-CC by tPA, endogenously released by endothelial cells or exogenously used as iv thrombolysis treatment, leads to damage of BBB integrity by activating the PDGF-alpha receptor in the endothelial wal. Imatinib, a tyrosine kinase inhibitor restores disrupted BBB by blocking PDGF-CC mediated signalling, reduces the final infarct size and lowers the risk of haemorrhage after iv thrombolysis treatment, if initiated within the first hours.Restoring BBB function leads to 1) reduced inflow into the brain parenchyma of blood and large plasma molecules, reducing haemorrhage and oedema, and 2) reduced invasion of white blood cells which, according to some reports, may aggravate the infarct. In a phase 2 pilot study (N=60), we have demonstrated that Imatinib is safe and well tolerated in patients treated with IV thrombolysis after acute ischemic stroke. Interestingly, we found that high-dose Imatinib (800 mg per day) for 6 days significantly reduced the neurological deterioration compared to control which was a pre-defined secondary end point of the study. tPA is available endogenously and activated in a thrombogenic state. Therefore, we have widened the inclusion criteria and planned to perform a confirmatory phase 3 RCT in acute ischaemic stroke patients treated with or without IV thrombolysis.