Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke

Recent trials of plasminogen activators in acute ischaemic stroke underscore the delicate balance between promise of benefit and risk. Attempts to manage clinical outcome by systemic infusion of recombinant tissue plasminogen activator (rt-PA) have so far had mixed success.1 2 The benefits seen in the National Institutes of Neurological Diseases and Stroke (NINDS) trial of rt-PA in acute ischaemic stroke were a significant absolute improvement in disability outcome.2 3 However, the risks in that study and in the European Cooperative Acute Stroke Study (ECASS)1 included further disability and mortality associated with haemorrhagic consequences of the plasminogen activator (PA).1 2 Three recent studies of streptokinase in acute ischaemic stroke were terminated because of safety concerns.4-9 In all five trials, the risk of symptomatic haemorrhage associated with the PA was significantly increased over placebo (table 1). In addition, approaches which effect recanalisation of documented cerebral arterial thrombotic occlusions by intravenous or intra-arterial PA infusion have yet to be rigorously shown to promote overall benefit, although anecdotal evidence suggests that individual patients may improve clinically.10-24 The reasons are practical. The perceived risks, those of angiography and the interventional procedures required for intra-arterial PA delivery, have not been fully evaluated,25 although the relative risks of diagnostic angiography are low.26-28 Clearly, this assessment hides many important differences in PA behaviour, study design and conduct, patient populations, diagnostic and therapeutic procedures, disease severity, comorbidity, and a host of other potential contributors. None the less, concerns which may erode the promise of benefit of thrombolytic agents in acute ischaemic stroke include the accentuation of innate risks associated with the evolution of ischaemic injury after the stroke event itself.29-34 These include early mortality caused by severe brain oedema and the development of haemorrhagic transformation which causes clinical deterioration or …