ISIS-4: Fourth International Study of Infarct Survival
Purpose
To assess the separate and combined effects on all-cause mortality of adding early captopril, mononitrate and magnesium sulphate to conventional treatment of patients with definite or suspected acute MI
Reference
Fourth International Study of Infarct Survival Collaborative Group. ISIS-4: A randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669–85.
ISIS-4: Fourth International Study of Infarct Survival - TRIAL DESIGN -
Design: Multicenter, multinational, randomized, partial double-blind, placebo-controlled, 2 x 2 x 2 factorial study
Patients: 58,050 patients hospitalized within 24h of suspected acute MI; patients with cardiogenic shock or persistent severe hypertension excluded
Follow up and primary end point: Median 15 months follow up. Primary endpoint all-cause mortality
Treatment: All patients received three study treatments, each being randomly assigned to active or placebo within each treatment:
Oral captopril 50mg twice daily or placebo, for 28 days (blinded)
Oral controlled-release isosorbide mononitrate 60mg twice daily or placebo, for 28 days (blinded)
Intravenous magnesium sulfate as 8 mmol bolus over 15 min then 72 mmol over 24 h, or no infusion (open)
ISIS-4: Fourth International Study of Infarct Survival - RESULTS -
With captopril, compared with control:
Significant reduction in 5-week mortality (7% odds reduction, 2P = 0.02)
Survival advantage maintained over 12 months: 5.4 fewer deaths/1000 (88.01 vs. 87.47% survival)
No significant increase in 5-week reinfarction, heart failure or death due to cardiogenic shock
Significant increase in hypotension warranting termination of captopril (10.0 vs. 4%, 52 excess/1000, 2P<0.0001)
Significant increase in in mild/moderate (but not severe) renal dysfunction and dizziness with/without profound hypotension
Mononitrate: well tolerated and, compared with control, was associated with a non-significant reduction in 5-week mortality; 12-month follow up indicated no survival advantage
Magnesium: non-significant increase in 5-week mortality; no survival advantage on 12-month follow up
ISIS-4: Fourth International Study of Infarct Survival - RESULTS continued -
Days after randomization
Deaths
Mortality in days 0–35
0
7
14
21
28
35
0
2500
2000
1500
1000
500
Placebo
(n=29,022)
Captopril
(n=29,028)
ISIS-4 Collaborative Group. Lancet 1995; 345: 669–85.
0
7
14
21
28
35
0
7
14
21
28
35
P=0.02
better
NS
better
NS
worse
ISIS-4: Fourth International Study of Infarct Survival - RESULTS continued -
2P
Deaths/n
Mortality (%)
Deaths/n
Mortality (%)
Deaths/n
Mortality (%)
Captopril
Mononitrate
Magnesium
2088/29,028
7.19
2129/29,018
7.34
2216/29,011
7.64
2231/29,022
7.69
2190/29,032
7.54
2103/29,039
7.24
0.02
NS
NS
7% odds
reduction
3% odds
reduction
6% odds
increase
Mortality and odds reduction in days 0–35
Placebo
Treatment
Odds ratio
and
95% CI
Odds
reduction or
increase
ISIS-4 Collaborative Group. Lancet 1995; 345: 669–85.
0.75
1.0
1.25
ISIS-4: Fourth International Study of Infarct Survival - RESULTS continued -
2P
Dizziness
With profound hypotension
Renal dysfunction
Mild
Moderate
Severe
110 (0.39)
30 (0.11)
170 (0.60)
74 (0.26)
23 (0.08)
13 (0.05)
155 (0.54)
83 (0.29)
316 (1.11)
130 (0.46)
68 (0.24)
26 (0.09)
1.6 (0.6)
1.9 (0.4)
5.1 (0.8)
2.0 (0.5)
1.6 (0.3)
0.5 (0.2)
<0.01
<0.001
<0.001
<0.001
<0.001
Other clinical events reported with captopril up to day 35
Placebo
n=29,022
No. (%)
Captopril
n=29,028
No. (%)
Excess/1000
(SD)
ISIS-4 Collaborative Group. Lancet 1995; 345: 669–85.
ISIS-4: Fourth International Study of Infarct Survival - SUMMARY -
In patients with suspected or definite acute MI:
Early treatment with captopril reduced all-cause mortality at 35 days and during long-term follow up
Mononitrate conferred no survival advantage in the short or long term
Magnesium conferred no survival advantage, in contrast with earlier and smaller studies