Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials

BACKGROUND Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment. METHODS We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage. FINDINGS Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 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 favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002). INTERPRETATION The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

[1]  Stephen Rose,et al.  Diffusion‐ and perfusion‐weighted MRI response to thrombolysis in stroke , 2002, Annals of neurology.

[2]  R. Gibbons,et al.  The impact of time to thrombolytic treatment on outcome in patients with acute myocardial infarction , 2000, Heart.

[3]  J. Baron,et al.  Treatment of acute ischemic stroke. Challenging the concept of a rigid and universal time window. , 1995, Stroke.

[4]  S Hamilton,et al.  The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. , 2000, Stroke.

[5]  G. Albers,et al.  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. , 1999, JAMA.

[6]  H. Schouten,et al.  Interobserver agreement for the assessment of handicap in stroke patients. , 1988, Stroke.

[7]  J. Broderick,et al.  Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke. The TPA Bridging Study Group. , 1993, Stroke.

[8]  J. M. Wardlaw,et al.  Thrombolytic Therapy With Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke: Where Do We Go From Here? A Cumulative Meta-Analysis , 2003, Stroke.

[9]  G. Albers,et al.  Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. , 2000, JAMA.

[10]  Lippincott Williams Wilkins,et al.  Multicenter Trial of Hemodilution in Ischemic Stroke — Background and Study Protocol , 1985, Stroke.

[11]  M. Kaste,et al.  Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS) , 1995, JAMA.

[12]  R. Califf,et al.  Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the global use of strategies to open occluded arteries in Acute Coronary Syndromes (GUSTO-IIb) trial. , 1999, Circulation.

[13]  Gruppo Italiano per lo Studio della Soprawivenza nell'Inf Miocardico.,et al.  EFFECTIVENESS OF INTRAVENOUS THROMBOLYTIC TREATMENT IN ACUTE MYOCARDIAL INFARCTION , 1986, The Lancet.

[14]  Mahoney Fi,et al.  FUNCTIONAL EVALUATION: THE BARTHEL INDEX. , 1965 .

[15]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[16]  M. Kaste,et al.  Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II) , 1998, The Lancet.

[17]  J. Grotta,et al.  Early stroke treatment associated with better outcome: the ninds rt-pa stroke study , 2000, Neurology.

[18]  Johan Herlitz,et al.  Indications for fibrinolytic therapy in suspected acute myocardial infarction : collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients , 1994 .

[19]  J. Marler,et al.  Measurements of acute cerebral infarction: a clinical examination scale. , 1989, Stroke.

[20]  A. Alexandrov,et al.  Timing of recanalization after tissue plasminogen activator therapy determined by transcranial doppler correlates with clinical recovery from ischemic stroke. , 2000, Stroke.

[21]  R. Knill-Jones,et al.  Observer variability in assessing impaired consciousness and coma. , 1978, Journal of neurology, neurosurgery, and psychiatry.

[22]  K. Welch,et al.  Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1997, Archives of neurology.