Stroke: neither aspirin or heparin clearly reduced death or dependency.

Clinical bottom line (level 1b-)

  1. Patients with acute ischaemic stroke who were given aspirin had no clear difference in than those not given aspirin, but had slightly fewer deaths plus recurrent strokes (NNT = 57 at 6 months) .
  2. Patients given heparin had no clear difference in death than those not given heparin, and there was no difference in deaths plus recurrent strokes.
International Stroke Trial Collaborative Group : Lancet 1997; 349: 1569-1581
Expires November 2002

The study

Unblinded concealed randomised trial with intention-to-treat
Setting: 467 hospitals, 36 countries

19435 patients (aged median about 73 years; 26% over 80, 54% male) acute ischaemic stroke diagnosed by computed tomography scan where possible or clinically, and within 48 hours of symptom onset

Excluded if
  • evidence of intracranial haemorrhage
  • small treatment benefit expected (eg. very severe stroke or transient ischaemic attack)
  • high risk of side effects (eg. hypersensitive to aspirin, or presence of peptic ulcer)
  • already on anticoagulants


    • Control Group: (n = ., . analysed): avoid aspirin (n=9715; 9646 analysed) or avoid heparin (n=9718; 9644 analysed)
    Experimental Group: (n = 9720, 9719 analysed): aspirin 300 mg daily for 14 days or until prior discharge
    Experimental Group: (n = 9717, 9716 analysed): unfractionated heparin 12,500 IU twice daily

    99.2% followed for 6 months

    The evidence

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death with aspirin 14 days 909
    (9.36%)    		 872
    (8.97%)    		 4.00%
    (-5.00% to 12.0%)    		 0.38%
    (-0.43% to 1.20%)    		 260
    (NNT = 84 to infinity;
    NNH = 234 to infinity)
    death with heparin 14 days 905
    (9.31%)    		 876
    (9.02%)    		 3.00%
    (-6.00% to 11.0%)    		 0.30%
    (-0.51% to 1.11%)    		 336
    (NNT = 90 to infinity;
    NNH = 195 to infinity)
    death or dependency with aspirin 6 months 6125
    (63.5%)    		 6000
    (61.7%)    		 3%
    (1% to 5%)    		 1.76%
    (0.40% to 3.13%)    		 57
    (32 to 250)
    death or dependency with heparin 6 months 6062
    (62.9%)    		 6063
    (62.4%)    		 1%
    (-1% to 3%)    		 0.46%
    (-0.91% to 1.82%)    		 220
    (NNT = 55 to infinity;
    NNH = 110 to infinity)
    dependency with heparin 6 months 3986
    (41.3%)    		 3898
    (40.4%)    		 2.00%
    (-1.00% to 5.00%)    		 0.90%
    (-0.49% to 2.29%)    		 111
    (NNT = 44 to infinity;
    NNH = 205 to infinity)

  • Analyses compared outcomes for immediate heparin versus avoid heparin, and immediate aspirin versus avoid aspirin. Outcomes for low versus medium dose heparin was one of a number of subsidiary analyses. A meta-analysis with the Chinese Acute Stroke Trial was pre-planned.

    • Comments

    1. Open trial although unlikely to have affected results since biases should have been cancelled out by including so many patients from so many centres.
    2. Applicability of results easy to use as inclusion criteria general.
    3. No difference in either treatments in sub-group analyses (AF or not, time to treatment, age, clinical stroke syndrome, initial blood pressure, whether CT was pre- or post- starting treatment).
    4. Although total deaths were similar in both heparin-treated and control groups, more patients died of haemorrhagic complications and fewer of ischaemic and embolic complications in the heparin-treated groups.
    5. 25000 IU/day heparin was much riskier than the 10000 IU/day regimen. When the lower dose was compared with placebo for the principal outcomes, a significantly lower early death or stroke rate was seen (10.8% vs 12%, p=0.02). There was no advantage in terms of death plus dependency after 6 months, however.

    Citation

    1. International Stroke Trial Collaborative Group , : The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569-1581
    Search Terms: stroke in Cochrane
    Contributor: Nick Shenker and Clare Wotton, November 1999
    Reviewer: Rowan Harwood

    Clinical Question.
    Patient acute ischaemic stroke
    Intervention or Exposure subcutaneous heparin or aspirin
    Comparison placebo
    Outcome death and dependency