Intravenous thrombolysis for patients with ischaemic stroke on antiplatelet therapy: a blessing in disguise?

Treatment with intravenous tissue plasminogen activator (tPA) is one of the most effective therapies for acute ischaemic stroke within 4.5 h of onset [1,2]. A feared complication of thrombolysis is the occurrence of symptomatic intracerebral hemorrhage (ICH) which occurs in 2–6% of the patients. Identification of risk factors for ICH after thrombolysis is of importance to exclude the patients who are at increased risk of bleeding complications. It is still a matter of debate whether the patients using antiplatelet (AP) agents at stroke onset can be safely treated with tPA. In this issue of the European Journal of Neurology, Dorado et al. report their experiences with tPA treatment in patients with and without prior AP therapy [3]. They found an increased risk of parenchymal hemorrhage in patients on AP therapy (25% versus 9.36%). The rate of symptomatic ICH was not significantly higher in AP-treated patients (11.1% versus 4.9%). No differences in functional outcome measures were observed between the two groups. These results are in line with some previous studies [4–6], who found an increased risk of symptomatic ICH but no different functional outcomes in patients with prior AP therapy. In one of these studies, AP therapy even increased the odds of a good functional outcome, after adjustment for confounders [5]. Data from a large multicenter study, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) also showed a slight but significant increase in symptomatic ICH in patients on aspirin [7]. In the same cohort, prior AP treatment did not affect functional outcome in the multivariable analysis. A subgroup analysis of different AP regimens (aspirin, clopidogrel, dipyridamole, or combination therapy) yielded no other results, although the combination of aspirin and clopidogrel in particular was associated with symptomatic ICH. None of the different AP regimens was associated with a poor outcome or increased mortality (data presented at the European Stroke Conference 2009 Stockholm). But how may AP therapy increase the risk of ICH after tPA? tPA is a strong fibrinolytic agent which breaks down the fibrin matrix of the thrombus. During acute cerebral ischaemia, there is also a damaging of the endothelium. Platelets are essential for the repair of this process. So, it seems plausible that inhibiting platelets in case of endothelial damage may increase the risk of ICH. However, we do not know whether this risk applies to all patients with AP or whether this occurs more to a specific subgroup of patients, for example in patients with leukoaraiosis or cerebral small-vessel disease. Although it is often assumed that ICH occurs after reperfusion, Saqqur et al. found that persistence of arterial occlusion was associated with symptomatic ICH [8]. It is known from Doppler studies that early reocclusion frequently occurs after initially successful recanalization [9]. Because aspirin remains biologically active for 4–6 days, a potential beneficial effect of AP therapy during thrombolysis may be explained by the prevention of early reocclusion. This hypothesis is confirmed by an observation that patients on aspirin experienced less often early deterioration than patients naı̈ve to aspirin [10]. So can we safely treat patients on AP therapy with tPA and does it has an additional beneficial effect? Likely, some of these questions will be answered by an ongoing randomized controlled trial in the Netherlands which investigates the safety and efficacy of 300 mg of IV aspirin after the tPA bolus (ARTIS trial ISRCTN NTR822). Patients naı̈ve to AP are included and randomized to tPA/placebo or to tPA/300 mg IV aspirin. The incidence of symptomatic ICH and functional outcome is assessed after 3 months. This study will hopefully answer whether aspirin will enhance the effect of thrombolysis, and whether the combination of the two drugs is safe. In the meantime, the study of Dorado et al. confirms that it seems safe to treat patients with ischaemic stroke on AP therapy with tPA.