**4. Intravenous tissue plasminogen activator**

A milestone in the management of ischemic stroke occurred in 1995 when the National Institute of Neurological Disorders and stroke rt-PA Stroke Study (NINDS) showed that administering intravenous recombinant tissue plasminogen activator (tPA) within 3 hours of symptoms onset had favorable outcomes in stroke management [46]. Intravenous tPA is a thrombolytic agent used to break down a clot [47]. In particular, it converts the inactive plasminogen into plasmin a proteolytic enzyme that breaks down fibrin [47]. The NINDS study was a randomized, double-blind trial with patients either randomized to receiving intravenous tPA or placebo, within 3 hours of the onset of symptoms [46]. The results of the study showed that neurological improvement was similar between the two groups 24 hours after treatment and better in the group that received intravenous tPA at three months [46]. The major adverse effect in the treatment group was symptomatic intracerebral hemorrhage within 36 hours after treatment that occurred in 6.4% of the treatment group versus 0.6% of the placebo group (P < 0.001) [46].

The European Cooperative Acute Stroke Study (ECASS) I published in 1995 was a randomized controlled study that divided subjects into two groups those receiving 1.1 mg per kg of body weight of intravenous tPA or placebo [48]. Patients were included in the study if they presented within 6 hours from onset of symptoms and had moderate to severe neurological deficit [48]. Patients receiving intravenous tPA had better mRS at 90 days and better neurological recovery in comparison to the placebo group [48]. The incidence of intracerebral hemorrhage and mortality rate was similar between the groups [48]. However, the group receiving intravenous tPA had a higher incidence of large intracerebral hemorrhage [48].

Other randomized controlled studies including the ECASS II in 1998 and the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) B in 1999 urged against the use of intravenous tPA beyond 3 hours in management of ischemic stroke [49, 50]. This conclusion was based on the high incidence of intracerebral hemorrhage that was observed in those who received intravenous tPA [49, 50].

In 2008, ECASS III study, a randomized controlled study, showed that administration of intravenous tPA to patients with ischemic stroke up to 4.5 hours after the onset of stroke symptoms was beneficial [51]. Patients were randomly assigned to either receive intravenous tPA or placebo and the median time for administration of the medication was 3 hours and 59 minutes [51]. The study showed that the group that received tPA had better outcomes than the placebo group (52.4% vs. 45.2%, confidence interval (CI), 1.02 to 1.76; P = 0.04) [51]. Both incidences of any intracerebral hemorrhage and symptomatic intracerebral hemorrhage were higher in the treatment group versus the placebo group with results being 27% vs. 17.6%, P = 0.001 and 2.4% vs. 0.2%, P = 0.008 respectively [51]. Mortality and other serious adverse events were similar between the groups [51].

Intracerebral hemorrhage following intravenous tPA remains a concern that can lead to devastating results. To decrease the risk of intracerebral hemorrhage following intravenous tPA, the American Heart Association and American Stroke Association issued guidelines with strict criteria for which patients are eligible for receiving intravenous tPA [52]. Other limitations to consider is that larger and more proximally located thrombi might not respond to intravenous tPA [53]. It has been

reported that restoration of blood flow in large vessel occlusion after intravenous tPA ranges between 10 and 30% depending on the large vessel that is occluded [53].

Given the limitations of intravenous tPA other avenues for management of ischemic stroke were needed. The Prourokinase (Prolyse) in Acute Cerebral Thromboembolism (PROACT II) study, a randomized controlled study aimed to determine the effects of administrating intraarterial recombinant prourokinase (r-proUK) compared to heparin within 6 hours of onset of symptoms [54]. The PROACT II study showed an increase in recanalization rate and improvement in modified Rankin score in patients treated with r-proUK versus those who were treated with heparin alone [54]. The major limitation of r-proUK was an increase in intracerebral hemorrhage 24 hours after administration that was associated with neurological deterioration (10% in treatment group versus 2% in control group, P < 0.06) [54].

Another medication that has been considered for the management of acute ischemic stroke is tirofiban [55]. Tirofiban is a glycoprotein IIb/IIIa platelet receptor antagonist [55]. The Safety of Tirofiban in acute Ischemic Stroke (SaTIS) trial aimed to determine whether tirofiban could be used for the treatment of acute ischemic stroke [55]. SaTIS was a prospective, open-labeled treatment, blinded outcome reading multicenter trial [55]. Patients that were included in the study had an NIHSS between 4 and 18 and received either intravenous tirofiban or placebo up to 48 hours from onset of symptoms [55]. There was no difference between the two groups in terms of intracerebral hemorrhage or neurological outcome up to five months of treatment [55]. Five months following intervention mortality was lower in the treatment group [55].
