ISIS-4 results

Source: ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group: ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669-685

Summary: Canadian Medical Association Journal 1996; 154: 527

In the Fourth International Study of Infarct Survival (ISIS-4) 58 050 patients with suspected acute myocardial infarction (AMI) were given, in addition to recommended anti-platelet and fibrinolytic therapies, 1 month of oral captopril (angiotensin-converting enzyme [ACE] inhibitor) therapy (6.25 mg initial dose, titrated up to 50 mg twice daily) or matching placebo, 1 month of oral controlled-release mononitrate therapy (30 mg initial dose, titrated up to 60 mg once daily) or matching placebo, or intravenous magnesium sulfate for 24 hours (8 mmol initial bolus, followed by 72 mmol) or no placebo. The study treatments were started within 2 hours after commencement of fibrinolytic therapy. The primary outcome measure was 5-week total mortality analysed on an intention-to-treat basis.

In the first 5 weeks patients in the captopril group had a 7% (standard deviation [SD] 3%) proportional reduction in the odds of death (p = 0.02), representing 4.9 (SD 2.2) fewer deaths per 1000 than in the placebo group. Small excesses in the incidence of heart block and cardiogenic shock and a significant increase in patient withdrawal from treatment because of severe hypotension (52 excess per 1000, p < 0.0001) were also found in the captopril group.

The 3% (SD 3%) proportional reduction in the odds of death in the first 5 weeks for patients in the mononitrate group was not significant. An excess of 15 (SD 2) per 1000 patients (p < 0.0001) treated with mononitrate experienced hypotension severe enough to warrant termination of treatment.

Among the patients who received intravenous magnesium therapy, there was a 6% (SD 3%) proportional increase in the 5-week odds of death. This was not statistically significant but does rule out the large survival advantage suggested by smaller trials. Most patients in previous trials of magnesium therapy did not receive fibrinolytic therapy; however, such patients in ISIS-4 (over 17 000 subjects) had no survival advantage. Small but significant increases in heart failure (p < 0.001), cardiogenic shock (p < 0.01) and death due to cardiogenic shock (p < 0.001) were seen in the magnesium group, mostly during or just after the infusion period. An excess of 11 (SD 2) patients per 1000 had hypotension severe enough to require termination of treatment.

Taken with the results of other randomized trials of early ACE inhibitor therapy, the ISIS-4 results demonstrate that this therapy can effect a significant reduction in mortality for at least 1 year after AMI. This benefit appeared to be greater in high-risk groups. Hypotension resulting from captopril therapy was not associated with an increase in mortality, and an observed excess of renal dysfunction was not considered severe. This treatment may thus be considered in a wide range of patients with suspected AMI without obvious contraindications.

| CMAJ February 15, 1996 (vol 154, no 4) |