ATLANTIS trial

Hacke W, Donnan G, Fieschi C, Kaste M, von Rummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S ATLANTIS Trials Investigators ECASS Trials Investigators NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 363 768-774. 

A pooled analysis of individual patient data from the NINDS, ECASS I and II and the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials (Hacke et al. 2004), which represents 99% of patients randomized in trials of rt-PA in stroke, has confirmed that benefit from thrombolysis decreases with time since stroke onset, being most beneficial if given within 90 minutes (odds ratio for favorable outcome of 2.8) (Fig. 21.1), although benefit was still present at 4.5 hours (now confirmed in ECASS III). However, it is clear that many patients will not benefit at this time point and, conversely, that other patients may benefit up to and beyond six hours in view of the fact that the ischemic penumbra may extend for much longer periods in some patients (Baron 2001). At present, only approximately 1% of UK patients receive thrombolysis (Intercollegiate Working Party on Stroke 2006) and 1-6% in North America. 

In the Alteplase ThromboLysis for Acute Non-interventional Therapy in Ischemic Stroke (ATLANTIS) Trials, patients were randomized to receive 0.9 mg/kg of rt-PA or placebo within 0-6 h (ATLANTIS-Part A n=I42) [44] or 3-5 h (ATLANTIS-Part B, n=547) [45] of stroke symptom onset. Except for time to treatment, enrollment criteria were very similar to those of... 

Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999 282 2019-2026 [see comment]. 

Three large randomized trials, the European Cooperative Acute Stroke Study (ECASS) parts I and II, and the Alteplase Thrombolysis for Acute Noninterven-tional Therapy in Ischemic Stroke (ATLANTIS), have investigated the efficacy of IV rt-PA in acute stroke beyond the 3-hour window. All three studies showed high rates of sICH complicating rt-PA treatment, and no overall efficacy of rt-PA. 

OR 1.81, 95% Cl 1.46-2.24), most of which were related to symptomatic intracranial hemorrhage (OR 3.37, 95% Cl 2.68. 22). In addition, a pooled analysis of six major randomized placebo-controlled IV rt-PA stroke trials (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) I and II, European Cooperative Acute Stroke Study (ECASS) I and II, and NINDS I and II), including 2775 patients who were treated with IV rt-PA or placebo within 360 minutes of stroke onset, confirmed the beneht up to 3 hours and suggested a potential beneht beyond 3 hours for some patients. The pattern of a decreasing chance of a favorable 3-month outcome as the time interval from stroke onset to start of treatment increased was consistent with the findings of the original NINDS study. ... 

The ATLANTIS, ECASS and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004 363 768-74. 

Abciximab in Ischemic Stroke Investigators (2000) Abciximab in acute ischemic stroke a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke 31 601-609 Albers GW, Clark WM (1999) For the ATLANTIS Study Investigators. The ATLANTIS rt-PA (Alteplase) acute stroke trial final results. Cerebrovasc Dis 9 126 Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A, Grotta JC (2001) Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy sonographic classification and short-term improvement. Circulation 103 2897-2902... 

ECASS /-// and ATLANTIS A-B trials The European Cooperative Acute Stroke Study (ECASS-I) enrolled 620 patients with acute ischemic stroke in whom treatment could be initiated within 6 h of stroke onset [42]. Patients were excluded if pretreatment CT showed signs of hemorrhage or major early infarction involving more than one-third of the MCA territory (diffuse sulcal effacement, poor differentiation between gray-white matter, and diffuse hypodensity). In a randomized double-blind study, patients either received placebo or IV t-PA (1.1 mg/kg to a maximum dose 100 mg 10% bolus followed by infusion over 1 h) and could not receive anticoagulants, antiplatelet, cerebroprotective. 

Pooled Data Analysis and Meta-Analysis A pooled analysis of the six initial major randomized placebo-controlled rV rt-PA stroke trials (ATLANTIS I and n, ECASS I and II, and NINDS I and n), including 2,775 patients who were treated with IV rt-PA or a placebo within 360 min of stroke onset, confirmed the benefit up to 3 h and suggested a potential benefit beyond 3 h for some patients [51]. Specifically, the odds of a favorable 3-month outcome were 2.8 (95% Cl 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favor of the rt-PA group. Interestingly, ICH was not associated with time from symptoms onset to treatment. 

ThomaUa, G., et al.. Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients comparison of a German multicenter study with the pooled data of ATLANTIS, ECASS, andNINDS tPA trials. Stroke, 2006. 37(3) p. 852-8. 

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