IST: International Stroke Trial: Aspirin and/or Subcutaneous Heparin Within 48h of Acute Ischaemic Stroke (Sandercock et al., 1997)
In patients within 48 hours of suspected acute ischaemic stroke, does aspirin 300 mg/day and/or subcutaneous unfractionated heparin reduce death or dependence at 6 months? Factorial 2x2 design enrolling 19,435 patients across 36 countries — one of the largest stroke trials ever conducted.
Sandercock PAG et al. (Lancet 1997;349:1569-1581) · doi:10.1016/S0140-6736(97)04011-7 · 19,435 patients
Population
Included
- Suspected acute ischaemic stroke with onset less than 48 hours before randomisation
- No evidence of intracranial haemorrhage on prior CT, or. If CT not yet available. Clinical grounds gave physician reasonable certainty stroke was ischaemic
- No clear indication for or contraindication to heparin or aspirin (uncertainty principle)
- Patient eligible regardless of stroke severity, age, sex, or stroke subtype
- A patient was eligible if, in the view of the responsible physician, there was evidence of an acute stroke (irrespective of severity) with onset less than 48 hours previously, no evidence of intracranial haemorrhage, and no clear indications for or contraindications to heparin or aspirin
- The fundamental criterion for eligibility was simply that the physician was uncertain whether or not to administer either or both of the trial treatments to that particular patient
- All patients were to be CT scanned to exclude intracranial haemorrhage, before randomisation where possible, and in comatose patients a CT was mandatory; a non-comatose patient could be randomised before CT if there was likely to be a long delay in getting the CT scan and if, on clinical grounds, the physician considered the stroke very likely to be ischaemic
Excluded
- Symptoms likely to resolve completely within a few hours
- Severely disabled before the stroke
- High risk of adverse effects from aspirin (hypersensitivity, active peptic ulceration, recent gastrointestinal bleeding)
- Already on long-term oral anticoagulants
- Only a small likelihood of worthwhile benefit, for example the symptoms seemed likely to resolve completely within a few hours, or the patient was severely disabled before the stroke
- A high risk of adverse effects, for example hypersensitivity to aspirin, active peptic ulceration, or recent gastrointestinal bleeding
- Already on long-term oral anticoagulants
Source: Sandercock PAG et al., Lancet 1997;349:1569-1581· Retrieved 2026-06-09
Primary Outcome (aspirin comparison)
14-day death or non-fatal recurrent stroke (aspirin 300 mg/day vs avoid aspirin)
Negligible absolute difference
14-day death or non-fatal recurrent stroke
Adjusted 6-month death or dependence: 14 fewer per 1000 (2p=0.03 after adjustment for baseline prognosis). Heparin (any dose) showed no net 6-month benefit and increased 14-day haemorrhagic stroke (1.2% vs 0.4%, 2p<0.00001) — IST is the foundational RCT evidence against routine therapeutic-intensity heparin in acute ischaemic stroke.
Study Arms
- Agent
- Aspirin (acetylsalicylic acid)
- Dose
- 300 mg daily
- Route
- Oral, nasogastric, rectal (300 mg suppository), or intravenous (100 mg lysine salt)
- Frequency
- Once daily
- Duration
- 14 days or until prior discharge
- Co-interventions
- Allocation was independent of the heparin randomisation in the factorial design. At discharge, clinicians were advised to consider long-term aspirin for all patients
Aspirin limb of the factorial 2x2 design (Sandercock Lancet 1997 Methods). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2.8% vs 3.9%) with no significant excess of haemorrhagic strokes, so the reduction in death or non-fatal recurrent stroke (11.3% vs 12.4%, 2p=0.02) was a small but real net benefit. Taken with CAST, supports early aspirin in acute ischaemic stroke.
- Agent
- No aspirin (open-label control, no placebo)
- Route
- Not applicable
- Co-interventions
- Patients allocated to avoid aspirin were considered non-compliant if they received any antiplatelet therapy in hospital within 14 days of randomisation. NSAIDs other than aspirin were permitted
Open-label control limb for the aspirin comparison. No placebo tablets were used. Source: Sandercock Lancet 1997.
- Agent
- Unfractionated heparin
- Dose
- 5000 IU twice daily
- Route
- Subcutaneous
- Frequency
- Twice daily
- Duration
- 14 days or until prior discharge
- Co-interventions
- No routine coagulation monitoring (fixed-dose protocol). Allocation was independent of the aspirin randomisation
Low-dose heparin limb of the factorial design. Neither heparin regimen offered any clinical advantage at 6 months: the early reduction in recurrent ischaemic stroke was offset by a similar-sized increase in haemorrhagic stroke. The authors concluded that if heparin is used, the dose should not exceed 5000 IU subcutaneously twice daily. Source: Sandercock Lancet 1997.
- Agent
- Unfractionated heparin
- Dose
- 12,500 IU twice daily
- Route
- Subcutaneous
- Frequency
- Twice daily
- Duration
- 14 days or until prior discharge
- Co-interventions
- No routine coagulation monitoring (fixed-dose protocol). Allocation was independent of the aspirin randomisation
Medium-dose heparin limb. Compared with 5000 IU twice daily, the 12,500 IU twice-daily regimen was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12.6% vs 10.8%). Medium-dose heparin was harmful at the dose tested. Source: Sandercock Lancet 1997.
- Agent
- No heparin (open-label control, no placebo)
- Route
- Not applicable
- Co-interventions
- Patients allocated to avoid heparin were considered non-compliant if they received any heparin in hospital within 14 days of randomisation
Open-label control limb for the heparin comparison. No placebo was used. Source: Sandercock Lancet 1997.
Safety
14-day mortality (aspirin vs avoid)
9%
9.4%
Aspirin 9.0% vs avoid 9.4%. Non-significant reduction of 4 per 1000.
14-day transfused or fatal extracranial bleeds (aspirin vs avoid)
1.1%
0.6%
Aspirin 1.1% vs avoid 0.6% (2p=0.0004). +5 per 1000 transfused or fatal extracranial bleeds with aspirin in the presence of heparin; in the absence of heparin the excess was +2 per 1000 (NS).
14-day haemorrhagic stroke (aspirin vs avoid)
0.9%
0.8%
Aspirin 0.9% vs avoid 0.8%; no significant excess of haemorrhagic stroke with aspirin alone. Note: the heparin comparison is very different. Heparin (any dose) increased haemorrhagic stroke 1.2% vs 0.4% (2p<0.00001), with the medium-dose arm driving most of the excess. See safetyData for the full heparin profile.
Trial Design
Type
- Large, randomised, open-label (unblinded) trial with central minimisation-algorithm allocation
- Factorial 2x2 design: aspirin (any) vs avoid aspirin AND heparin (any dose) vs avoid heparin. Analysed independently
- 467 hospitals in 36 countries; pilot phase January 1991 – February 1993 (984 patients), main trial March 1993 – May 1996
- 6-month outcome assessment blinded in most countries (mailed validated questionnaire or telephone interview)
- Prospectively planned for joint analysis with the parallel Chinese Acute Stroke Trial (CAST, n≈20,000)
- Two-sided p values (2p) cited throughout; independent data monitoring committee reviewed interim analyses about once a year
Timeline
Enrolled January 1991 to May 1996; 6-month outcome 99.2% complete; 14-day outcome 99.99% complete. Published Lancet 1997 May 31.
N
19,435
Enrollment
19,435 patients at 467 hospitals in 36 countries. Pilot phase January 1991 to February 1993 (984 patients); main trial March 1993 to May 1996. Factorial 2x2: aspirin (any) vs avoid aspirin; heparin (any dose) vs avoid heparin — analysed independently. Open-label with central minimisation allocation; 6-month outcome blinded in most countries. Prospectively planned for joint analysis with CAST. Published Lancet 1997 May 31.
Bedside Pearl
IST (with CAST): in ~40,000 patients within 48h of acute ischaemic stroke, aspirin 160-325 mg reduces death or recurrent stroke by about 9 per 1000 with about 2 per 1000 excess symptomatic ICH. Routine therapeutic-intensity heparin shows no net 6-month benefit and increases haemorrhagic stroke. Give aspirin once ICH is excluded; do not give therapeutic heparin routinely. Delay aspirin 24h after IV thrombolysis.