Risk of Hemorrhage after Alteplase: Secondary Analysis

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Whiteley WN, Emberson J, Lees KR, et al. "Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis". Lancet Neurol. 2016. 15(9):925-33.
PubMedFull text

Clinical Question

For patients that receive alteplase within 4.5 hours of acute ischemic stroke, what are the proportional and absolute effects of the drug on intracerebral haemorrhage, mortality, and functional impairment?

Bottom Line

Major Points

Guidelines

Design

  • Meta-analysis of individual patient information from 9 trials:
  • N=6756
    • Alteplase (n=3391)
    • Placebo (n=3365)
  • Analysis: Intention To Treat, logistic regression
  • Primary outcome: Intracerebral haemorrhage defined as
    • Type 2 parenchymal haemorrhage by 7 days after randomisation,
    • Safe Implementation of Thrombolysis in Stroke Monitoring Study’s (SITS-MOST) haemorrhage, or
    • fatal intracerebral haemorrhage within 7 days

Population

Inclusion Criteria

  • Inclusion was based on the individual 9 included trials

Exclusion Criteria

  • Exclusion was based on the individual 9 included trials

Baseline Characteristics

Summary from total population

  • Treatment delay(h)
    • ≤3: 23%
    • >3 to ≤4.5: 41%
    • >4.5: 35%
    • Missing: 1%
  • Age(years)
    • ≤80: 74%
    • >80: 26%
  • Stroke Severity(NIHSS[9])
    • ≤4: 10%
    • >4 to ≤10: 37%
    • >10 to ≤15: 22%
    • >15 to ≤21: 20%
    • >21: 9%
    • Missing: 2%
  • Women: 45%
  • History of Comorbidities:
    • Hypertension: 60%
    • Stroke: 18%
    • Diabetes Mellitus: 16%
    • Atrial Fibrillation: 24%
  • Antiplatelet use: 33%
  • Weight(kg), Mean: 75
  • Blood Pressure, Mean (mmHg)
    • Systolic 154(22)
    • Diastolic 83(14)

Interventions

  • Alteplase vs. placebo

Outcomes

Comparisons are alteplase vs. control, Odds-Ratio(95% Confidence Interval)

Primary Outcomes

Type 2 Parenchymal Haemorrhage within 7 days
6.8% vs. 1.3%, 5.55(4.01-7.70)
SITS-MOST Haemorrhage (Safe Implementation of Thrombolysis in Stroke Monitoring Study) within 7 days
3.7% vs. 0.6%, 6.67(4.11-10.84)
Fatal Intracranial Haemorrhage within 7 days
2.7% vs. 0.4%, 7.14(3.98-12.79)

Secondary Outcomes

Mortality after intracerebral haemorrhage
Functional Outcome 90-180 days following intracerebral haemorrhage

Subgroup Analysis

Adverse Events

Criticisms

Funding

  • UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh

Further Reading

  1. Hacke W et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995. 274:1017-25.
  2. Sandercock P et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3): a randomised controlled trial. Lancet 2012. 379:2352-63.]
  3. Davis SM et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008. 7:299-309.
  4. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 1995. 333:1581-7.
  5. Hacke W et al. 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. 352:1245-51.
  6. Hacke W et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 2008. 359:1317-29.
  7. 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. 33:493-5.
  8. Clark WM 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. JAMA 1999. 282:2019-26.
  9. http://www.nihstrokescale.org