ATLANTIS

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Albers GW, et al. "ATLANTIS trial: results for patients treated within 3 hours of stroke onset. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.". Stroke. 2002. 33(2):493-485.
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Clinical Question

Patients that present within three hours of acute ischemic stroke symptom onset, does alteplase compared to placebo allow more patients to achieve complete recovery?

Bottom Line

Following an acute ischemic stroke, treatment with alteplase within three hours of symptom onset appears beneficial but still comes with some risk of hemorrhage and death.

Major Points

As with the European Cooperative Acute Stroke Study trials (ECASS I)[1] (ECASS II) [2] and the National Institute of Neurologic Disorders (NINDS) trial,[3] the ATLANTIS trials (ATLANTIS B)[4] have shown less benefit when thrombolytic treatment is given past the 3 hour mark. When provided within three hours, patients have improved outcomes but this offers little decrease in the rates of hemorrhage and death compared to placebo. ECASS III went on to demonstrate benefit of alteplase up to 4.5 hours after despite previous findings.

Guidelines

Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines (2015, adapted) [5]

  • Eligible patients: those who can receive IV tPA within 4·5 h of the onset of stroke symptoms (ECASS III) in accordance with criteria adapted from NINDS [Evidence Level A]
  • All eligible patients should receive IV tPA ASAP after presentation [Evidence Level A]
    • target time door-to-needle <60 min
    • median time in 90% of treated patients of 30 min [Evidence Level B]
  • tPA dosing following the American Stroke Association guidelines:
    • 0.9 mg/kg (max 90 mg total dose): 10% (0.09 mg/kg) IV bolus over 1min, remaining 90% (0.81 mg/kg) as IV infusion over 60 min [Evidence Level A]

AHA/ASA Early management of acute ischemic stroke (2013, adapted) [6]

  • Intravenous tPA for selected patients up to 3 hours after onset of ischemic stroke (Class I Level A)
  • Eligible patients should receive tPA as quickly as possible, ideally within 60 minutes of hospital arrival (Class I Level A)
  • Intravenous tPA for selected patients between 3-4.5 after onset of ischemic stroke (Class I Level B)

Design

  • Sub-group Analysis of two Multicenter, double-blind, randomized, placebo controlled trials
  • N=755 (ATLANTIS population)
    • Population within 3 hours (n=61)
      • Alteplase (0.9mg/kg) (n=23)
      • Placebo (n=38)
  • Setting: 140 university and community hospitals in the United States
  • Enrollment: December 1993 - July 1998
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome:
    •  % patient with complete recovery (NIHSS[7] score ≤1) at 90 days
  • Secondary Outcomes:
    • Assessment at 90 days:
      • Global outcome test (not defined)
      • Barthel Index[8] score ≥95
      • Modified Rankin Scale[9] score ≤1
      • Glasgow Outcome Scale[10] score of 1

Population

Inclusion Criteria

  • Age 18-79
  • Clinical diagnosis of ischemic stroke with measurable neurological deficit
    • language
    • motor function
    • cognition
    • gaze
    • vision
    • neglect
  • Patients as part of Part A and B of ATLANTIS who received treatment within 3 hours of symptom onset

Exclusion Criteria

Clinical

  • Coma, severe obtunded, fixed eye deviation, complete hemiplegia
  • Minor stoke symptoms (<4 NIHSS, normal speech/visual)
  • Major symptoms rapidly resolving at time of randomization
  • Previous stroke within 6 weeks
  • Previous intracranial/subarachnoid hemorrhage, neoplasm, arteriovenous malformation, aneurysm
  • Clinical presentation suggestive of subarachnoid hemorrhage despite normal CT
  • Hypertension
    • SBP >185 mmHg
    • SBP >110 mmHg
  • Presumed Septic Emboli
  • Presumed pericarditis / presence of ventricular thrombus or aneurysm related to recent acute MI
  • within 30 days:
    • Surgery or biopsy of parenchymal organs
    • trauma with internal injuries or ulcerative wound
    • active or recent hemorrhage
    • Pregnancy / Lactation / Parturition
  • Head trauma within 90 days
  • Hereditary or acquired hemorrhagic diathesis
  • Baseline labs
    • Glucose <2.8 mmol/L [<50 mg/dL] OR >22.2mmol/L [>400mg/dL]
    • Platelet <100 000
    • hematocrit <0.25
  • Other serious / advanced /terminal illness
  • Any other condition where investigator feels would pose significant hazard to the patient if alteplase is used
  • Current participation in other drug treatment trial

Cerebral Computed Tomographic(CT) Scan

  • High density lesion consistent with hemorrhage of any degree
  • Evidence of significant mass effect with midline shift
  • Subarachnoid hemorrhage
  • Parenchymal hypodenisty, loss of gray/white matter distinction, and/or effacement of cerebral sulk in >33% of the middle cerebral artery territory

Baseline Characteristics

Presented as Placebo(n=38) vs. tPA(23); P-value

  • Age, y
    • Mean(SD): 66(10.7) vs. 66(10.4); NS
    • Median(Range): 68(41-93) vs. 66(46-80)
  • Female, No.(%): 16(42) vs. 4(27); 0.05
  • Caucasian, %: 84 vs. 95; NS
  • Co-mobidites, %
    • Hx Smoking: 72 vs. 87; NS
    • Myocardial infarction: 31 vs. 26; NS
    • Atrial fibrillation: 16 vs. 22; NS
    • Congestive heart failure: 16 vs. 4; NS
    • Diabetes: 16 vs. 17; NS
    • Prior stroke: 16 vs 22; NS
  • Time to treatment, min
    • Mean(SD): 144(33) vs. 161(21); NS
    • Median(Range): 144(52-180) vs. 169(97-180)
  • Baseline NIHSS score, distribution, n (%)
    • 3–7: 9(24) vs. 8(36); NS
    • 8–14: 13(34) vs. 6(27)
    • 15–21: 16(42) vs. 5(23)
    • >21: 0(0) vs. 3(14)

Interventions

  • IV tPA 0.9mg/kg
  • Placebo

Outcomes

Comparisons are Placebo(n=38) vs. tPA(n=23), OR(95% CI); P-value.

Primary Outcomes

Proportion of patient with NIHSS score ≤1 at 90 days, %
26.3 vs. 60.9, 4.4(1.4-13.2); 0.01

Secondary Outcomes

Not all scales completed for all patients: mRS(n=33), GOS(n=26)

Global Outcome Test, [OR(95% CI)]
"in favour of tPA": 2.0(0.8-4.9); NS
Barthel Index (≥95) at 90 days
57.9 vs. 65.2, 1.4(0.5-4.0); NS
modified Rankin Scale (≤1) at 90 days
45.5 vs. 61.1, 1.9(0.6-6.1); NS
Glasgow Outcome Scale at 90 days
46.2 vs. 56.3, 1.5(0.4-5.3); NS
NIHSS Score breakdown at 90 days, %
0-1: 26 vs. 61, NR
2-8: 50 vs. 13, NR
>8: 19 vs. 9, NR
Death: 5 vs. 17, NR

Subgroup Analysis

Proportion of patients with NIHSS ≤1 at 90 days, stratified by baseline stroke severity(NIHSS Score), %
≤10(n=30): 56 vs. 79, 2.9(0.6-14.3); NR
>10(n=31): 5 vs. 33, 10.5(0.9-120.3); NR

Adverse Events

Comparisons are Placebo(n=38) vs. tPA(n=23), No.(%); P-value.

  • Symptomatic Intracranial Hemorrhage (ICH) through Day 10: 0(0) vs. 3(13); 0.05
  • Asymptomatic ICH through Day 10: 0(0) vs. 2(8.7); NS
  • Fatal ICH: 0(0) vs. 3(13); 0.05
  • Fatal brain herniation without hemorrhage: 2(5.3) vs. 1(4.3); NS
  • Death at 30 days: 2(5.3) vs. 4(17.4); NS
  • Death at 90 days: 2(5.3) vs. 4(17.4); NS

Criticisms

  • This is a meta-analyzed subgroup analysis of parts A and B of ATLANTIS
    • Secondary outcomes NS likely due to under-powering from doing a subgroup analysis
  • Some outcomes not collected for all patients
  • The “Global Outcome Test” was not defined as a secondary outcomes, so even if it favours the treatment arm, unclear what that means
  • Imbalance of stroke severity between groups (more moderate strokes in placebo group, more mild and severe in treatment group)

Funding

Funded by Genetech,[11] a subsidiary of Roche. Two authors received honouria and one was a former employee of Genetech.

Further Reading

  1. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274: 1017–1025.
  2. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II): Second European- Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245–1251.
  3. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.
  4. 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 ran- domized controlled trial: Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282:2019–2026.[1]
  5. Casaubon, L. K., Boulanger, J.-M., Blacquiere, D., Boucher, S., Brown, K., Goddard, T., Gordon, J., Horton, M., Lalonde, J., LaRivière, C., Lavoie, P., Leslie, P., McNeill, J., Menon, B. K., Moses, B., Penn, M., Perry, J., Snieder, E., Tymianski, D., Foley, N., Smith, E. E., Gubitz, G., Hill, M. D., Glasser, E., Lindsay, P. and Heart and Stroke Foundation of Canada Canadian Stroke Best Practices Advisory Committee (2015), Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015. International Journal of Stroke [2]
  6. Jauch EC, et al. "Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association." Stroke. 2013;44:870-947.[3]
  7. NIH Stroke Scale[4]
  8. Barthel Index[5]
  9. Modified Rankin Scale[6]
  10. Glasgow Outcome Scale[7]
  11. Genetech website[8]