ISIS Pilot

International Studies of Infarct Survival (1987)

Condition

Suspected myocardial infarction within 24 hours of symptom onset

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Objective

To investigate the efficacy and safety of streptokinase in the acute phase and heparin as well as ASA thereafter

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Trial design

Active treatment:

  • Comparison 1: streptokinase 1.5 MU i.v. over 1 hour (n=413)
  • Comparison 2: ASA 325 mg on alternate days for 28 days starting immediately
    (n=313)
  • Comparison 3: heparin 1000 IU/h i.v. for 48 hours starting 12 hours after
    the end of streptokinase infusion (n=314)

Control treatment:

  • Comparison 1: placebo infusion over 1 hour (n=206)
  • Comparison 2: placebo tablets for 28 days (n=306)
  • Comparison 3: no heparin (n=305)

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Endpoints

Efficacy endpoints: non-fatal myocardial reinfarction in hospital, death in hospital, death after discharge, stroke
Safety endpoints: bleeding requiring transfusion, minor bleeding, other adverse events (hypotension, tachycardia, allergic reaction, nausea)

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Trial participants

619 patients with suspected myocardial infarction (mean age 60 years) up to 24 hours after symptom onset

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Results

Comparison 1 (streptokinase vs. placebo):
Efficacy:
Non-fatal reinfarction occurred in 16 of 413 patients (3.9%) randomized to streptokinase and in 6 of 206 patients (2.9%) randomized to placebo. 31 patients (7.5%) receiving streptokinase died in hospital compared to 20 placebo patients (9.7%). After discharge, death occurred in 25 (6.1%) vs. 18 (8.7%) of the patients. After streptokinase, 2 patients (0.5%) experienced a stroke compared to 5 patients (2.4%) in the placebo group
Safety: 16% of the patients receiving streptokinase suffered minor bleeding events compared to 6% of the placebo patients. There were no significant differences in bleeding requiring transfusion between groups. Other adverse events, especially hypotension and nausea occurred more frequently in the streptokinase group

Comparison 2 (ASA vs. placebo):
Efficacy:
Non-fatal reinfarctions occurred in 10 of 313 patients (3.2%) given ASA compared to 12 of 306 patients (3.9%) given placebo. In hospital deaths were registered in 19 (6.1%) vs. 32 patients (10.5%), and deaths after discharge in 22 (7.0%) vs. 21 patients (6.9%) receiving ASA respectively placebo. 1 patient (0.3%) in the ASA group compared to 6 patients in the placebo group (2.0%) suffered a stroke
Safety: There was no significant increase in bruising or minor bleeding in the ASA group as well as in other adverse events compared to placebo

Comparison 3 (heparin vs. no heparin):
Efficacy:
7 of the 314 patients (2.2%) randomized to heparin vs. 15 of the 305 control patients (4.9%) suffered a non-fatal reinfarction in hospital. 25 patients (8.0%) in the heparin group vs. 26 control patients (8.5%) died in hospital, and 22 (7.0%) vs. 21 (6.9%) after discharge. In the heparin group, 5 patients (1.6%) experienced a stroke compared to 2 patients (0.7%) in the control group
Safety: Bruising and bleeding occurred in 14% of the patients given heparin and in 12% of the control patient. There was no difference in bleeding requiring transfusion between groups

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Summary

Comparison 1 (streptokinase vs. placebo): High-dose streptokinase infusion was associated with a non-significant increase in reinfarction rate and decrease in mortality during hospital stay and thereafter, as well as a significant reduction in stroke incidence. Streptokinase induced a significant increase in minor bleeding
Comparison 2 (ASA vs. placebo): ASA was associated with a non-significant decrease in non-fatal reinfarctions, deaths after discharge and strokes, as well as a significant reduction in hospital mortality. There were no significant differences in bleeding between ASA and placebo
Comparison 3 (heparin vs. no heparin): Heparin was associated with a non-significant decrease in reinfarction and a trend towards more strokes. There were no differences in hospital deaths and mortality after discharge. In the heparin group, a non-significant trend towards more bruising and minor bleeding was observed

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Reference

Collins R, Conway M, Alexopoulos D, Yusuf S, Sleight P, Brooks N, Bowes R,  Marshall A, Harding S, Maskell G, Sanderson J, Mittra B, Hunt D, Tibbutt D, Sterry H, Jackson D, Scrimgeour A, Lim L, Appleby P, Parish S, Peto R. Randomized factorial trial of high-dose intravenous streptokinase, of oral aspirin and of intravenous heparin in acute myocardial infarction. Eur Heart J 1987;8:634-642

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Corresponding author

Rory Collins, MD, ISIS, Radcliffe Infirmary, Oxford 0X2 6HE, U.K.

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