IST

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IST Collaborative Group. "The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke". The Lancet. 1997. 349(9065):1569-1581.
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Clinical Question

In patients with acute ischemic stroke, what is the efficacy of aspirin and of subcutaneous heparin in decreasing morbidity and mortality?

Bottom Line

The administration of aspirin within 48 hours of ischemic stroke onset reduces the risk of 14-day recurrence and the combined outcome of nonfatal stroke or death.

Major Points

IST and Chinese Acute Stroke Trial[1] (1997) trials are two of the largest trials to study aspirin in acute ischemic stroke. The International Stroke Trial (IST) demonstrated a 28% reduction in 14-day recurrence of ischemic stroke, and a 9% reduction in the combined outcome of nonfatal stroke or death at 14 days. This was similar to CAST, which demonstrated a 14% reduction in all-cause mortality at 4 weeks. Together, IST and CAST demonstrated that aspirin led to a reduction of 11 nonfatal strokes or deaths per 1,000 patients in the first few weeks among patients with acute ischemic stroke with a NNT of 91.

Guidelines

2014 AHA/ASA Secondary Stroke Prevention Guidelines [2]

  • For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet agents rather than oral anticoagulation is recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I; Level of Evidence A).
  • Aspirin (50–325 mg/d) monotherapy (Class I; Level of Evidence A) or the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (Class I; Level of Evidence B) is indicated as initial therapy after TIA or ischemic stroke for prevention of future stroke. (Revised recommendation)
  • Clopidogrel (75 mg) monotherapy is a reasonable option for secondary prevention of stroke in place of aspirin or combination aspirin/dipyridamole (Class IIa; Level of Evidence B). This recommendation also applies to patients who are allergic to aspirin.
  • The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, relative known efficacy of the agents,and other clinical characteristics (Class I; Level of Evidence C).
  • The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Class IIb; Level of Evidence B). (New recommendation in 2014 Update)
  • The combination of aspirin and clopidogrel, when initiated days to years after a minor stroke or TIA and continued for 2 to 3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention after ischemic stroke or TIA (Class III; Level of Evidence A).
  • For patients who have an ischemic stroke or TIA while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered, no single agent or combination has been adequately studied in patients who have had an event while receiving aspirin (Class IIb; Level of Evidence C).
  • For patients with a history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to VKA therapy is uncertain for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events (Class IIb; Level of Evidence C).
  • Unstable angina and coronary artery stenting represent special circumstances in which management may warrant DAPT/VKA therapy. (New Recommendation in 2014 Update)

Design

  • Multicenter, open, 2x3 factorial, randomized controlled trial
  • N=19,435
    1. Aspirin and medium-dose heparin (n=2,430)
    2. Aspirin and low-dose heparin (n=2,432)
    3. Aspirin and avoid heparin (n=4,858)
    4. Avoid aspirin and medium-dose heparin (n=2,426)
    5. Avoid aspirin and low-dose heparin (n=2,429)
    6. Avoid aspirin and avoid heparin (n=4,860)
  • Setting: 467 centers in 36 countries
  • Enrollment: January 1991 to May 1996
  • Follow-up: 6 months

Population

Inclusion Criteria

  • Suspected acute ischemic stroke with onset less than 48 h previously

Exclusion Criteria

  • Intracranial hemorrhage by CT imaging
  • Contraindications to heparin or aspirin
  • Clear indications for heparin or aspirin
  • Small likelihood of worthwhile benefit (eg, symptoms seemed likely to resolve completely within few hours or patient was severely disabled before stroke)
  • High risk of adverse effects (eg, hypersensitivity to aspirin, active peptic ulceration or recent GI bleeding, or already on long-term oral anticoagulants)

Baseline Characteristics

  • Median time to randomization: 19 hours
    • Within 3h: 4%
    • Within 6h: 16%
    • Within 12h: 37%
    • Within 24h: 66%
  • Age:
    • <50 years: 5%
    • 50-59 years: 11%
    • 60-69 years: 23%
    • 70-79 years: 35%
    • >80 years: 26%
  • Male: 54%
  • Atrial fibrillation: 16%
  • Systolic BP (mmHg):
    • <140: 18%
    • 140-59: 28%
    • 160-79: 26%
    • >180: 28%
  • Stroke syndrome:
    • Total anterior: 24%
    • Partial anterior: 40%
    • Posterior: 12%
    • Lacunar: 24%
  • CT scan before randomization: 67% (of which 49% showed infarction)
  • Aspirin within previous 3 days: 20%
  • Heparin within previous 24 hours: 2%

Interventions

  • CT performed prior to randomization where possible and in comatose patients
  • Active treatment received immediately after randomization and to continue for 14 days or until prior discharge
  • 2x3 factorial randomization
  • Heparin
    • SQ UFH 5,000u BID (n=4,860)
    • SQ UFH 12,500u BID (n=4,856)
    • Avoid heparin (n=9,718)
  • Aspirin
    • Aspirin 300mg daily (n=9,720)
    • Avoid aspirin (n=9,715)

Outcomes

Primary Outcomes

Mortality at 14 days
Heparin vs. avoid heparin: 9.0% vs. 9.3% (P=NS)
Medium- vs. low-dose heparin: 9.3% vs. 8.7% (P=NS)
Aspirin vs. avoid aspirin: 9.0% vs. 9.4% (P=NS)
Mortality, dependence, or incomplete recovery at 6 months
Heparin vs. "avoid heparin": 62.9% vs. 62.9% (P=NS)
Medium- vs. low-dose heparin: 62.6% vs. 63.1% (P=NS)
Aspirin vs. "avoid aspirin": 62.2% vs. 63.5% (2P=0.07), NNT 77
Complete recovery from stroke: 17.6% vs. 16.6% (2P=0.07), NNT 100

Secondary Outcomes

Symptomatic ICH within 14 days
Heparin vs. avoid heparin: 1.2% vs. 0.4% (2P<0.00001), NNH 125
Medium- vs. low-dose heparin: 1.8% vs. 0.7% (2P<0.00001), NNH 100
Aspirin vs. avoid aspirin: 0.9% vs. 0.8% (P=NS)
Ischemic stroke within 14 days
Heparin vs. avoid heparin: 2.9% vs. 3.8% (2P=0.005), NNT 111
Medium- vs. low-dose heparin: 3.2% vs. 2.6% (P=NS)
Aspirin vs. avoid aspirin: 2.8% vs. 3.9% (2P<0.001), NNT 91
Major extracranial hemorrhage within 14 days
Heparin vs. avoid heparin: 1.3% vs. 0.4% (2P<0.00001), NNH 111
Medium- vs. low-dose heparin: 2.0% vs. 0.6% (2P<0.00001), NNH 71
Aspirin vs. avoid aspirin: 1.1% vs. 0.6% (2P=0.0004), NNH 200
Pulmonary embolism within 14 days
Heparin vs. avoid heparin: 0.5% vs. 0.8% (2P=0.02)
Medium- vs. low-dose heparin: 0.4% vs. 0.7% (P=NS)
Aspirin vs. avoid aspirin: 0.6% vs. 0.8% (2P=0.08)
Mortality or nonfatal stroke at 6 months
Heparin vs. avoid heparin: 11.7% vs. 12.0% (P=NS)
Medium- vs. low-dose heparin: 12.6% vs. 10.8% (2P<0.01)
Aspirin vs. avoid aspirin: 11.3% vs. 12.4% (2P<0.05), NNT 91

Criticisms

  • No placebo control
  • Unblinded assessment of events
  • Open design

Funding

  • Governmental: UK Medical Research Council, the UK Stroke Association, and the European Union BIOMED-1 programme
  • Industry: Eli Lilly, Sterling Winthrop (now Bayer USA), Sanofi, and Bayer UK.
  • Geographically-specific:
    • Australia: National Heart Foundation grant
    • Canada: Nova Scotia Heart and Stroke Foundation grant
    • Czech Republic: IGA Ministry of Health grant
    • India: McMaster INCLEN program and the All India Institute of Medical Sciences
    • New Zealand: The Julius Brendel Trust and the Lottery Grants Board
    • Norway: Norwegian Council on Cardiovascular Disease and Nycomed

Further Reading

  1. Chen ZM et al. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke Lancet (1997): 349.9,066; 1-641.
  2. Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.