Non-contrast enhanced CT scans (NECT) are recommended in all patients suffering AIS. NECT excludes parenchymal hemorrhage and can assess for other exclusion criteria for rt-TPA such as widespread hypoattenuation [16]. NECT is however insensitive in detecting acute and small infarctions, especially in the posterior fossa. A “subtle” sign of cerebral ischemia within the first few hours of symptom onset on NECT is loss of gray-white differentiation. This sign may be manifest as a loss of distinction among the basal ganglia or as a blending of the densities of the cortex and underlying white matter [16]. Another sign of cerebral ischemia is swelling of the gyri that produce sulcal effacement. Another useful CT sign is that of increased density within the occluded artery, such as the hyperdense middle artery (MCA) sign. Diffusion-weighted MRI imaging (DWI) is currently the most sensitive and specific technique for the diagnosis of AIS. DWI imaging has a sensitivity of 88–100 % in the diagnosis of AIS within minutes of symptom onset. CT perfusion and MRI perfusion and diffusion imaging allow measurement of the size of the infarct core and the penumbra. However, reperfusion therapy based on the mismatch between infarct size and penumbra has not been proven to improve outcome [17].

The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial demonstrated that rt-PA given to patients within 3 h of the onset of stroke resulted in an 11–13 % absolute increase in the chance of minimum or no disability at 3 months [18]. Studies with a longer time window for enrollment have demonstrated a higher mortality in the treatment group, largely due to an increased incidence of intracerebral hemorrhage. In the European Cooperative Acute Stroke Study (ECASS) patients with moderate to severe acute ischemic strokes were randomized (<6 h) to placebo or rt-PA. Patients with infarction involving more than one third of the middle cerebral artery territory on CT scan were excluded. At 30 days there was a higher mortality in the rt-PA group (17.9 % vs. 12.7 %) [19]. Large parenchymal hemorrhages were increased threefold in the rt-PA group. In the second European Cooperative Acute Stroke Study (ECASS II) no benefit for rt-PA was demonstrated; furthermore, treatment differences were similar whether patients were treated within 3 h or 3–6 h [20]. ECASS III reported the results of a study in which alteplase (0.9 mg/kg) or placebo was administered between 3 and 4.5 h after the onset of acute ischemic stroke [21]. Patients with severe stroke were excluded from this trial. Although mortality did not differ between groups, more patients has a favorable outcome with alteplase than with placebo (52.4 vs. 45.2 %; OR 1.34 95 % CI 1.02–1.76, p = 0.04). The Third International Stroke Trial (IST-3) randomized 3,035 patients to 0.9 mg/kg rt-TPA or placebo within 6 h of suffering an AIS; this study had no exclusion criteria based on age [22]. Patients who had a clear indication for rt-TPA were commonly treated with rt-TPA; hence this study included patients with clinical equipoise. In this study, 53 % of the patients were older than 80 years (an exclusion criteria in previous studies). Furthermore, 38 % of patients received rt-TPA after a delay of 3.0–4.5 h while 33 % received therapy after a delay of 4.5–6.0 h. At 6 months, 37 % of patients in the rt-TPA group as compared to 35 % in the control group were alive and independent (primary outcome variable; NS). However, an ordinal analysis demonstrated a significant shift in the Oxford Handicap Score (OHS) towards a favorable outcome with thrombolytic therapy (OR 1.27; 95 % CI 1.10–1.47). It is noteworthy that patients over the age of 80 years appeared to benefit the most from rt-TPA, emphasizing that age alone should not be used as a “contraindication” to treatment with rt-TPA. Furthermore, only patients treated within 3 h of the onset of the ictus benefited from treatment with rt-TPA. Wardlaw performed an updated meta-analysis which included data from the IST-3 trial [23]. This meta-analysis included 12 trials (7,012 patients) of rt-TPA given within 6 h of the onset of stroke symptoms. rt-TPA significantly increased the odds of being alive and independent at final follow up (46.3 % vs. 42.1 %, OR 1.17, 95 % CI 1.06–1.29, p = 0.001). However, the benefit of rt-TPA was noted only in patients given rt-TPA within 3 h. There was a trend towards an increased risk of death for patients treated between 3 and 6 h (OR 1.16; 95 % CI 1.00–1.35; p = 0.06). Symptomatic ICH occurred in 7.7 % of patients receiving rt-TPA as compared to 1.8 % in the placebo group. These data suggest that suitable patients with AIS treated within 3 h of the onset of symptoms benefit from treatment with rt-TPA (see contraindications below). The use of rt-TPA beyond this narrow window is controversial. To help resolve the time to treatment issue, Lees et al. performed a pooled analysis investigation time to treatment and outcome [1]. This meta-analysis predated the publication of the IST-3 study. The adjusted odds for a favorable 3 months outcome were 2.55 (95 % CI 1.44–4.52) for 0–90 min, 1.64 (1.12–2.40) for 91–180 min, 1.34 (1.06–1.68) for 181–270 min (4.5 h) and 1.22 (0.92–1.61) for 271–360 min in favor of rt-TPA. This data would suggest that “selected” patients (low risk of bleeding) may benefit from TPA up to 4.5 h and that the risks outweigh the benefits beyond 4.5 h. Drug regulatory authorities have taken contradictory actions with regards to the extended treatment window for rt-TPA, with the European Medicines Agency expanding the approval to 4.5 h while the US FDA have declined to do so [16]. The most recent guidelines (January 2013) published by the AHA/ASA state “Intravenous rt-TPA is recommended for administration to eligible patients who can be treated in the time period of 3–4.5 h after stroke onset (Class 1; Level of evidence B) [16]. In addition to the exclusion criteria for patients treated within 3 h (listed below), the AHA/ASA include the following additional exclusion criteria for treatment between 3 and 4.5 h: Age > 80 years, those taking an oral anticoagulant regardless of the INR, those with an NIHSS score > 25, >1/3 MCA territory stroke and those with a history of both stroke and diabetes.

The most recent guidelines from the AHA/ASA suggest the following inclusion and exclusion criteria for thrombolytic therapy [16]:

Inclusion Criteria

Exclusion criteria

Relative exclusion criteria (risk and benefits must be carefully considered on a case by case basis)

Angioedema is estimated to occur in between 1 and 5 % of patients who receive rt-TPA. The angioedema is usually mild, transient and contralateral to the ischemic hemisphere. Empiric treatment with H2RA’s, anti-histamines and corticosteroids are recommended [16].

The International Stroke Trial (IST) randomized (using a factorial design) over 19,000 patients within 48 h of an AIS to 14 days of treatment with placebo, heparin (5,000 or 12,500 U q 12 hourly) or aspirin 300 mg daily [26]. Aspirin resulted in a 1.1 % absolute reduction in recurrent ischemic strokes at 14 days; both heparin regimens had no effect on outcome. Additional studies have demonstrated that heparin, low-molecular-weight heparin (LMWH) and heparinoids do not improve outcome following a stroke [27, 28].