ISIS2: Second International Study of Infarct Survival

1
ISIS-2 Second International Study of Infarct
Survival

• Purpose
• To assess the effects of intravenous
  streptokinase (SK) and oral aspirin, alone and in
  combination, shortly after suspected acute MI
• Reference
• The ISIS-2 collaborative group. Randomized trial
  of intravenous streptokinase, oral aspirin, both,
  or neither among 17,187 cases of suspected acute
  myocardial infarction ISIS-2. Lancet 1988ii
  34960.

2
ISIS-2 Second International Study of Infarct
Survival- TRIAL DESIGN -

• Design Multicenter, multinational, randomized,
  double-blind, placebo-controlled
• Patients 17,187 patients with suspected MI in
  previous 24h patients with history of stroke or
  GI hemorrhage/ulcer were excluded
• Follow up and primary endpoint Median 15 months
  follow up. Primary endpoint vascular mortality
• Treatment
• Patients randomized to one of four groups
• SK (1.5 million U over 60 min) and aspirin (160
  mg/day for 1 month)
• SK (1.5 million U over 60 min) and placebo
  matching aspirin
• Placebo matching SK and aspirin (160 mg/day for 1
  month)
• Placebo matching SK and placebo matching aspirin

3
ISIS-2 Second International Study of Infarct
Survival- RESULTS -

• Significant reduction in 5-week vascular
  mortality for
• SK or aspirin compared with matched placebo,
  regardless of therapy with the other agent or its
  placebo
• Combination therapy compared with SK alone,
  aspirin alone or combination placebo
• Effects of SK and aspirin on 5-week vascular
  mortality appeared additive and independent
• Reduction in all-cause mortality significant at
  median 15 months for each agent and for
  combination (2Plt0.001)
• With SK, greater benefit if therapy given early
  (04h) rather than late (524h)
• With SK, excess reinfarction and major/minor
  bleeds with aspirin, excess minor bleeds but
  reduced reinfarction and stroke
• Combination associated with excess major/minor
  bleeds but with greater reduction in reinfarction
  and stroke than either agent alone

4
ISIS-2 Second International Study of Infarct
Survival- RESULTS continued -

Vascular mortality over 35 days individual
therapies
1029
1016
Cumulative
1000
1000
(12.0)
(11.8)
no. of
vascular
804
800
800
791
(9.4)
deaths
(9.2)
600
600
Placebo
Placebo
infusion
tablets
400
400
SK
Aspirin
Odds reduction
Odds reduction
200
200
25, SD 4
23, SD 4
2Plt0.00001
2Plt0.00001
50
50
0
7
14
21
28
35
0
7
14
21
28
35
Days after randomization
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
5
ISIS-2 Second International Study of Infarct
Survival- RESULTS continued -

Vascular mortality at 35 days in four treatment
arms and combination
Vascular mortality () at 35 days
Aspirin
Placebo
Streptokinase
8.0
Placebo
13.2
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
6
ISIS-2 Second International Study of Infarct
Survival- RESULTS continued -

Estimates of 12- and 24-month survival
Estimated surviving
Placebo
infusion
Placebo
tablets
Placebo
infusion
and tablets
100
100
100
SK
Aspirin
95
95
95
90
90
90
85
85
85
80
80
80
70
70
70
0
12
24
0
12
24
0
12
24
Months after randomization
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
7
ISIS-2 Second International Study of Infarct
Survival- RESULTS continued -

Reduction in odds of vascular death in days 035,
by time from pain onset
Time of randomization
SK
Placebo
Aspirin
Placebo
(hours from pain onset)
better
better
better
better
01
2
3
4
Subtotal for 04
512
1324
Subtotal for 524
Total for 024
0.5
1.0
1.5
0.5
1.0
1.5
Odds ratio and 95CI
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
8
ISIS-2 Second International Study of Infarct
Survival- RESULTS continued -

Effects of SK and aspirin on clinical events
SK allocation
Aspirin allocation
Combination therapy
Placebo
Clinical
Placebo
SK
Aspirin
Both
SK and
infusion
event
tablets
placebos
aspirin
(n8595)
(n8600)
(n8592)
(n8587)
(n4300)
(n4292)
Reinfarction
202
238
284
156
123
77
Major bleed
18
46
33
31
11
24






(transfused)
Minor bleed
81

297
163
215
33
167






(not transfused)
Stroke
67
61
81
47
45
25
(excluding TIA)
The ISIS-2 collaborative group.
Lancet 1988 ii 34960.
9
ISIS-2 Second International Study of Infarct
Survival- SUMMARY -

• Early therapy with SK and aspirin in patients
  with MI
• Individually and in combination significantly
  reduced all-cause mortality
• In combination demonstrated additive effect