The International Stroke Trial: What “IS” the Best Therapy for Acute Ischaemic Stroke?

Original Citation

International Stroke Trial Collaborative Group.  The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997;349:1569-81.

Overall Study Question

The IST was a large (n=19,435) international study designed to determine the safety and efficacy of two widely used treatments for acute ischaemic stroke: unfractionated heparin and aspirin. Patients with acute stroke were eligible if they could be enrolled within 48 hours after a negative CT scan to receive either heparin 5000 u sc q12h (n=2,426) or heparin 12500 u sc q12h (n=2,432) or aspirin 300 mg daily (n=2,430), both heparin and aspirin (n=2,430), or neither drug (4,860).  The major endpoints of the study were death and other clinical events at 14 days, death and dependency at 6 months and intracranial and other hemorrhage.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  99.99% of patients were complete at the 14-day evaluation and 99.2% were complete at 6 months.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

No.  This trial was an open label study.

4. Were the groups similar at the start of the trial?

Unknown.  The breakdown of patient characteristics by treatment group at the beginning of the trial was not given.  The authors stated that groups were similar.

5. Aside from the experimental intervention, were the groups treated equally?

The use of non-trial treatments (including anti-edema, surgery and thrombolysis) was well balanced according to the authors (data not given).  Thirty-six different countries may have lead to regional differences in co-intervention. However, strict randomization protocol should have taken care of any differences. The compliance rates were good (88-94% for heparin and 93% for aspirin) but it was not broken out by region.

6. Overall, are the results of the study valid?

Yes.

What were the Results?

1. How large was the treatment effect? 

Patients who received aspirin had an absolute reduction in stroke recurrence at 14 days of 1.1% and there was no difference in hemorrhagic strokes.  Death or nonfatal stroke at 14 days was significantly less in the aspirin group (11.3% vs. 12.4%, p=0.02, NNT=91).

Patients who received heparin experienced a significant reduction in stroke recurrence within 14 days by 0.9%. However, patients who received heparin also experienced an increase in hemorrhagic strokes by 0.8%(absolute)in the same time frame. The increase in hemorrhagic strokes was dose-related.  There was no difference in the incidence of death or dependency at 6 months in the heparin group.

2. How precise was the estimate of the treatment effect?

Unable to extract confidence intervals from the paper.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Most clinicians have used the IST results as evidence supporting immediate initiation of aspirin in hospitalized acute ischemic stroke patients and some have used it as evidence to abandon all but rare use of full-dose unfractionated heparin in acute ischemic stroke.

2. Were all clinically important outcomes considered?

Yes.  Recurrent ischaemic stroke, hemorrhagic stroke, death or nonfatal stroke, pulmonary embolism and major extracranial bleed were all assessed at 14 days.  At six months, death and dependency were assessed.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes, with aspirin. Aspirin appeared to provide a reduction in recurrence without significantly increasing the risk of hemorrhagic stroke.  No, with subcutaneous heparin.  Although the heparin prevented recurrence within 14 days, there was a significant increase in hemorrhagic stroke as well.  This resulted in an overall neutral effect on death and dependency.

Commentary

When the results of the IST are combined with the results of the Chinese Acute Stroke Trial, one can support the recommendation to begin aspirin in all eligible acute ischemic stroke patients within 48 hours of symptom onset.  The use of unfractionated heparin remains controversial.  There is a strong-voiced minority who state that the IST study is flawed and patients who needed heparin were excluded (this was an exclusion criteria for this study).  Also, a small number of patients did not have a CT scan prior to enrolling.  This may have led to an overestimation of the risk of heparin.  Even when a more easily dosed and theoretically safer “heparinoid” compound was subsequently tried in ischaemic stroke in the TOAST trial, a similar result was obtained. The heparinoid did not offer any benefit, but was associated with increased risk.  Despite the fact that there is still no evidence to support the use of heparin in acute ischemic stroke, it remains in use and proponents favour further clinical trials to test immediate (i.e. within 6 hours) anticoagulation with this product.

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