ISIS4: Fourth International Study of Infarct Survival

1
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 66985.

2
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)

3
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, 2Plt0.0001)
• 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

4
ISIS-4 Fourth International Study of Infarct
Survival- RESULTS continued -
Mortality in days 035
Deaths
2500
P0.02
NS
NS
better
better
worse
2000
1500
1000
Placebo
(n29,022)
500
Captopril
(n29,028)
0
0
7
14
21
28
35
0
7
14
21
28
35
0
7
14
21
28
35
Days after randomization
ISIS-4 Collaborative Group. Lancet 1995 345
66985.
5
ISIS-4 Fourth International Study of Infarct
Survival- RESULTS continued -
Mortality and odds reduction in days 035
Odds ratio
Odds
2P
Placebo
Treatment
and
reduction or
95 CI
increase
Deaths/n
Captopril
2088/29,028
2231/29,022
7 odds

0.02
Mortality ()
7.19
7.69
reduction







Deaths/n
Mononitrate
2129/29,018
2190/29,032
3 odds

NS
Mortality ()
7.34
7.54
reduction






Deaths/n
Magnesium
2216/29,011
2103/29,039
6 odds
NS
Mortality ()
7.64
7.24
increase
0.75
1.0
1.25
ISIS-4 Collaborative Group. Lancet 1995 345
66985.
6
ISIS-4 Fourth International Study of Infarct
Survival- RESULTS continued -
Other clinical events reported with captopril up
to day 35
Placebo
Captopril
Excess/1000
2P
n29,022
n29,028
(SD)
No. ()
No. ()
Dizziness
110 (0.39)
155 (0.54)
1.6 (0.6)
lt0.01
With profound hypotension
30 (0.11)
83 (0.29)
1.9 (0.4)

lt0.001
Renal dysfunction
170 (0.60)
316 (1.11)
5.1 (0.8)
lt0.001
Mild
74 (0.26)
130 (0.46)
2.0 (0.5)
lt0.001
Moderate
23 (0.08)
68 (0.24)
1.6 (0.3)
lt0.001
Severe
13 (0.05)
26 (0.09)
0.5 (0.2)
ISIS-4 Collaborative Group. Lancet 1995 345
66985.
7
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