Below is a compilation of landmark studies in the field of thrombolysis in acute ischemic stroke .
NINDS (NEJM.1995) is a double blinded RCT done to assess the rTPA. Study proved that despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three month.
ECASS (JAMA. 1995) a multicentric, double blind RCT done to evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke.Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction.
ECASS II (Lancet. 1998) multicentric,placebo controlled, double blinded, RCT done to assess the safety and efficacy if rTPA within 6hours of onset.The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials.
ATLANTIS Trial - Part A (Stroke. 2000 ) was done focusing on evaluating the safety and efficacy of rtPA given between 0 and 6 hours after stroke onset.This study found no significant rtPA benefit on any of the planned efficacy end points at 30 and 90 days in patients treated between 0 and 6 hours after stroke onset. These negative results apply to patients treated after 3 hours, because only 15% of the patients were enrolled before 3 hours. The risk of symptomatic intracerebral hemorrhage was increased with rtPA treatment, particularly in patients treated between 5 and 6 hours after onset. These results do not support the use of intravenous rtPA for stroke treatment >3 hours after onset.
ATLANTIS Trial - Part B (JAMA.1999) was done to test the efficacy and safety of rt-PA in patients with acute ischemic stroke when administered between 3 and 5 hours after symptom onset. This study found no significant rt-PA benefit on the 90-day efficacy end points in patients treated between 3 and 5 hours. The risk of symptomatic ICH increased with rt-PA treatment. These results do not support the use of intravenous rt-PA for stroke treatment beyond 3 hours.
ATLANTIS Trial (Stroke 2002) (Prespecified subgroup analysis)they evaluated 61 patient in ATLANTIS Study group received rTPA within 3 hours. Study also found that despite a significant increase in the rate of symptomatic intracranial hemorrhage, tPA-treated patients were more likely to have a very favorable outcome (score of 1) on the National Institutes of Health Stroke Scale at 90 days.
ECASS III(N ENGL J MED. 2008) tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.Study found that As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage.
ATTEST Trial (2015) is a randomised, open label, blinded end point done to assess the efficacy and safety of tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) within 4·5 h of stroke onset in a population not selected on the basis of advanced neuroimaging, and to use imaging biomarkers to inform the design of a definitive phase 3 clinical trial.The study found that there was no significant difference was noted for percentage of pneumbra salvaged 68% for tenecteplase and 68% for alteplase group. Serious adverse events didnot differ in both groups.
MRCLEAN (N ENGL J MED. 2015) is a multicentric RCT done to assess the effect of intraaterial thrombolysis.In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe.
NOR-TEST (2017) is a randomised, open label, blinded end point done in 13 stroke units in Norway. It is done to investigate safety and efficacy of tenecteplase (0.4 mg/kg) v/s alteplase (0.9mg/kg) in patients with acute stroke presenting within 4.5h (n=1100. Primary outcome defined as mRS score 0-1 at 3 months was achieved in 64% in tenecteplase group and 63% in alteplase group.Serious adverse events were similar in both groups. Study concluded that tenecteplase was not superior to alteplase and showed similar safety profile.
WAKE-UP Trial (N Engl J Med 2018) is a multicentric RCT done to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days.
EXTEND-1A TNK (Int J Stroke. 2018) assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial. Study concluded that tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden.
EXTEND Trial (N Engl J Med 2019) is a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep).The trial found that use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo.
EXTEND-IA TNK Part II (JAMA.2020)To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. The study suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke.
NORTEST 2 Part-A (Lancet. 2022). The NOR-TEST trial showed that 0·4 mg/kg tenecteplase had an efficacy and safety profile similar to that of a standard dose (0·9 mg/kg) of alteplase, albeit in a patient population with a high prevalence of minor stroke. The aim of NOR-TEST 2 was to establish the non-inferiority of tenecteplase 0·4 mg/kg to alteplase 0·9 mg/kg for patients with moderate or severe ischaemic stroke. prematurely terminated study (terminated to fulfil the prespecified safety criteria), tenecteplase at a dose of 0·4 mg/kg yielded worse safety and functional outcomes compared with alteplase.
TRACE (Stroke Vasc Neurol. 2022) is a multicentre, prospective, randomised, open-label, blinded end-point, phase II study compared three tiers of 0.1, 0.25, 0.32 mg/kg rhTNK-tPA (to a maximum of 40 mg) with standard 0.9 mg/kg rt-PA (to a maximum of 90 mg) in patients who were eligible for intravenous thrombolysis.Similar to the Caucasians, rhTNK-tPA was well tolerated in Chinese patients with AIS at all doses administered within 3 hours of symptom onset.
ACT Trial (2022) is a multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial done to determine whether tenecteplase (0.25mg/kg) increase reperfusion compared to alteplase(0.9mg/kg). Study concluded that IV tenecteplase is a reasonable alternative to alteplase for all patients presenting with AIS.
TWIST Trial (Lancet Neurol. 2023) is aimed to determine whether thrombolytic treatment with intravenous tenecteplase given within 4·5 h of awakening improves functional outcome in patients with ischaemic wake-up stroke selected using non-contrast CT. In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging.
TRACE-2 (2023) In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial was done to establish the non-inferiority of tenecteplase to alteplase in AIS.Study found that tenecteplase was non-inferior to alteplase in people with ischaemic stroke who were eligible for standard intravenous thrombolytic but ineligible for or refused endovascular thrombectomy.
TRACE-3 (N Engl J Med 2024) is a randomised trial done in china were patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). Treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher.
TIMELESS (N Engl J Med 2024) is a multicentric, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well.Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo.
ORIGINAL Trail (JAMA.2024) is a RCT done to determine whether tenecteplase is noninferior to alteplase for patients with acute ischemic stroke (AIS) eligible for intravenous thrombolysis within 4.5 hours after stroke onset.In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile.
