NINDS (1995): Double-blinded, randomized controlled trial of 624 patients with acute ischemic stroke to determine if administration of tPA within 3 h of stroke onset reduces morbidity and mortality. The trial was divided into two parts. Part 1 tested whether tPA led to neurologic improvement within 24 h. Part 2 assessed outcomes at 3 months. No significant difference in outcomes was seen in Part 1 (24 h), but a benefit was seen for tPA patients in Part 2 as compared to placebo. The trial found that administration of tPA within 3 h of stroke onset improved clinical outcomes at 3 months in all four measures (Barthel Index, Modified Rankin Scale , Glasgow Outcome Scale, NIHSS ), but had no effect on mortality. NNT to prevent significant disability: 8. Symptomatic intracerebral hemorrhage occurred in 6.4 % of patients that received tPA (Marler et al. NEJM, 1995).

ECASS III (2008): Double-blinded, randomized controlled trial of 821 patients with acute ischemic stroke to determine the efficacy and safety of tPA 3–4.5 h after stroke onset. Stricter exclusion criteria: previous stroke and concomitant diabetes, National Institutes of Health Stroke Scale (NIHSS ) >25, age >80, and warfarin use (irrespective of INR). The study found that patients in the tPA group were more likely to have favorable outcomes compared to the placebo group (52.4 % vs. 45.2 %; odds ratio, 1.34; 95 % confidence interval [CI], 1.02–1.76; P = 0.04). NNT to prevent significant disability: 14. The incidence of symptomatic intracerebral hemorrhage occurred in 2.4 % of patients that received tPA (Hacke et al. 2008).

PROACT (1998) and PROACT II (1999): The initial study demonstrated recanalization efficacy and safety of intra-arterial recombinant pro-urokinase for angiographically documented proximal MCA occlusion within 6 h of symptom onset (del Zoppo et al. Stroke, 1998). PROACT II showed treatment with IA r-proUK within 6 h significantly improved outcome at 90 days (Furlan et al. JAMA, 1999).

MERCI (2005): Studied safety and efficacy of MERCI embolectomy device (Merci Retriever) in patients with acute ischemic stroke with large intracranial vessel occlusion, who presented within 8 h of symptom onset, and thus were not eligible for tPA . The device achieved a 48 % successful recanalization rate in patients where the device was deployed, and 7.8 % of patients had symptomatic intracranial hemorrhage (Smith et al. Stroke, 2005).

MULTI MERCI (2008): Studied safety and efficacy of newer generational MERCI Retriever in patients with acute ischemic stroke with large intracranial vessel occlusion who received IV tPA , as well as adjuvant intra-arterial (IA) tPA (up to 24 mg) following thrombectomy. Newer generational devices were associated with higher rates of recanalization (57 % successful recanalization rate and 70 % after adjunctive IA therapy). However, the differences did not achieve statistical significance. Symptomatic ICH occurred in 9.8 % patients (Smith et al. Stroke, 2008).

PENUMBRA Trial (2009): Studied safety and efficacy of the Penumbra system in patients with acute ischemic stroke with large intracranial vessel occlusion, presenting within 8 h of symptom onset. Patients who presented within 3 h who received IV tPA had to have persistence of symptoms despite lytic therapy. The Penumbra system achieved 81.6 % successful recanalization rate, with 11.2 % symptomatic ICH (Stroke, 2009).

IMS III (2013): Randomized multicenter trial that compared outcomes of individuals with acute ischemic stroke treated with IV tPA and endovascular therapy (IA tPA + mechanical clot retraction) within 3 h of symptom onset versus those that received IV tPA alone. The study found there was no significant difference in good outcomes (modified rankin scale, mRS ≤ 2 at 90 days), mortality rates, or rate of symptomatic ICH between the two groups. Criticisms against the trial include the poor recanalization rate in the interventional arm possibly due to the use of older generational devices and the slow recruitment rate of the trial (Broderick et al. 2013).

SYNTHESIS (2013): Randomized trial comparing outcomes of individuals with acute ischemic stroke within 4.5 h of symptom onset to receive IV tPA or mechanical clot disruption or retrieval. The study found that treatment with endovascular therapy is not superior to IV tPA alone, and there were no differences in serious adverse events. Major critiques included the fact that there was no vascular imaging prior to randomization to identify large vessel occlusions and endovascular therapy was unorthodox and included clot disruption with micro-guidewire (Ciccone et al. 2013).

MR RESCUE (2013): Randomized trial comparing outcomes of individuals within 8 h of large vessel, anterior circulation strokes who underwent mechanical embolectomy versus IV tPA . All patients underwent CT or MR imaging to determine if the patient had a favorable penumbral pattern (small infarct core with significant salvageable tissue) or non-favorable pattern (large core with little to no salvageable tissue). The study found that embolectomy was not superior to standard care, nor was favorable penumbral imaging successful at identifying patients who could benefit from endovascular therapy. Major critiques included the use of older generational devices and low recanalization rates and the use of complex penumbral imaging software (Kidwell et al. 2013).

MR CLEAN (2015): Randomized controlled trial comparing outcomes in patients with acute ischemic stroke and large proximal vessel occlusion treated with IV tPA versus IV tPA plus embolectomy within 6 h. Patients were included after the identification of a large vessel proximal occlusion. The study found that selected patients with large proximal vessel occlusions treated with embolectomy plus within 6 h plus IV tPA was effective at improving independence (mRS) and reducing mortality without an increase in intracerebral hemorrhage (Berkhemer et al. 2015).

EXTEND-IA (2015): Randomized controlled trial comparing outcomes in patients with acute ischemic stroke and large proximal vessel occlusion, and using CT perfusion imaging, treated with IV tPA alone within 4.5 h plus endovascular therapy versus tPA alone. The study found that patients who received tPA and early endovascular treatment had improved reperfusion and functional outcomes (Campbell et al. 2015).

ESCAPE (2015): Randomized controlled trial comparing outcomes in patients with acute ischemic stroke and large proximal vessel occlusion, small infarct core, and moderate to good collateral circulation on imaging, to IV tPA plus endovascular treatment versus tPA alone. Patients were included up to 12 h after symptom onset. The study found that patients with small infarct core and moderate to good collateral circulation had improved outcomes and reduced mortality with tPA and rapid endovascular treatment (Goyal et al. 2015).

SWIFT-PRIME (2015): Randomized controlled trial comparing outcomes in patients with acute ischemic stroke and large proximal vessel occlusion treated with IV tPA alone versus tPA and endovascular treatment within 6 h. Patients were selected by identification of a small core infarct through penumbral software. M2 occlusions were excluded. The study found that patients who received IV tPA and thrombectomy within 6 h after onset had improved functional outcomes (Saver et al. NEJM, 2015).

MATCH (2004): Randomized trial comparing outcomes in patients with recent stroke or TIA treated with both aspirin and clopidogrel versus clopidogrel alone for a period of 18 months. The study failed to show further reduction of risk with combination therapy compared to clopidogrel alone (event rates were actually quite similar in both groups), but did show a much higher risk of major bleeding (Diener et al. Lancet, 2004).

CHARISMA (2006): Randomized primary prevention trial comparing outcomes in high-risk patients with known vascular disease but no history of ischemic events treated with aspirin and clopidogrel versus aspirin alone for 28 months. The study did not find that dual therapy reduced risk of future events, and did have higher bleeding rates. Post hoc subgroup analysis concluded that combination therapy was associated with fewer nonfatal strokes compared to aspirin (Bhatt et al. NEJM, 2006).

CHANCE (2013): Trial in Chinese patients with recent minor stroke or high-risk TIA randomized to aspirin and clopidogrel versus aspirin alone for a period of 90 days. The outcome was subsequent stroke. The study found that starting aspirin and clopidogrel within 24 h of symptom onset reduces the 90-day stroke incidence when compared to aspirin monotherapy without increasing bleeding rates (Wang et al. 2013).