Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis

Abstract

Background Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood–brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. Methods A Phase II randomised trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active) : 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). Results Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400 mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Non-serious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800 mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0–2) increased by 18% versus controls (61 vs. 79; P = 0.296). Conclusion This Phase II study showed that imatinib is safe and tolerable, and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomised trial is currently underway.

Predictors for Cerebral Edema in Acute Ischemic Stroke Treated With Intravenous Thrombolysis

“…10 Furthermore, animal studies and a pilot clinical study indicate that drugs that maintain the integrity of BBB may improve clinical outcome after acute ischemic stroke in tPA treated patients. 18,34,35 In our study, CED was associated with all types of SICH. Our data do not allow conclusions about the risk of CED in IVT patients versus non-IVT patients.…”

“…The main outcome measurement, presence of edema classified in three types, has been used previously in the ECASS-2 and ECASS-3 trials (although not mentioned in the final publication) 16,17 , in a phase II clinical trial of imatinib 18 and in an analysis of local data from…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…Directly after acute ischemic stroke, tissue plasminogen activator (tPA) is used for thrombolysis, but beyond a few hours-long time window of therapeutic opportunity, tPA treatment is associated with intracerebral hemorrhage, a consequence of induced BBB breakdown. Along similar lines, the tyrosine kinase inhibitor imatinib, an efficient inhibitor of PDGFR signaling, was reported to reduce neurological disability after ischemic stroke [176]. The mechanism of PRGFRaÀinduced BBB disruption is not understood, but intriguingly, the expression of Pdgfra is largely restricted to perivascular fibroblasts among the different cell types of the NVU [17].…”

“…The mechanism of PRGFRaÀinduced BBB disruption is not understood, but intriguingly, the expression of Pdgfra is largely restricted to perivascular fibroblasts among the different cell types of the NVU [17]. Along similar lines, the tyrosine kinase inhibitor imatinib, an efficient inhibitor of PDGFR signaling, was reported to reduce neurological disability after ischemic stroke [176]. As discussed above, pericytes are important for the constriction of capillaries and reduced CBF observed in the post-stroke situation [39,40].…”

Fibrinolysis: from blood to the brain

“…It was further demonstrated that the protein tyrosine kinase inhibitor, imatinib ('Gleevec'), that works downstream of the PDGF-CC activated PDGFRa1 receptor in perivascular astrocytes, inhibited the ability of t-PA to open the BBB [66]. This striking finding has recently led to clinical trials testing the effectiveness of imatinib in patients with ischaemic stroke, with positive preliminary findings [67].…”