Myocardial infarction: tPA reduced reinfarction and adverse effects, but caused more strokes than streptokinase.

Clinical bottom line (level 1b)

  1. Patients with a myocardial infarction who received aspirin and heparin compared with aspirin alone were more likely to have a bleed requiring transfusion (NNH = 390 at 35 days) , but not less likely to die, reinfarct or have a stroke.
  2. Patients who received tPA compared with streptokinase were less likely to reinfarct (NNT = 190 at 35 days) , have an allergic reaction (NNT = 36 at 35 days) or develop profound hypotension (NNT = 21 at 35 days) , but were more likely to have a stroke (NNH = 290 at 35 days) . There was no difference in mortality or a bleed requiring transfusion.
  3. Patients who received anistreplase compared with streptokinase were more likely to have an allergic reaction (NNH = 67 at 35 days) , but were not less likely to die, reinfarct or have a stroke.
ISIS-3 (Third International Study of Infarct Survival) Collaborative Group : Lancet 1992; 339 (8796): 753-770
Expires March 2003

The study

Unblinded ?concealed randomised trial with intention-to-treat
Setting: 914 acute hospitals in 20 countries

41299 patients (aged 39%, 60 or less; 26%, 70 or more, 73% male) with a suspected or definite myocardial infarction (within 24 hours of symptom onset)

Excluded if
  • contraindications to fibrinolytic therapy (e.g. high risk of bleeding), or low-risk of benefit


Note:
  • Patients were randomised in a 3x2 factorial design.


Control Group: (n = 20375, 20375 analysed): aspirin 162 mg po daily
Experimental Group: (n = 20400, 20400 analysed): aspirin 162 mg daily and heparin 12 500 units subcutaneously after 4 hours then twice daily for 7 days or until discharge
Experimental Group: (n = 13607, 13607 analysed): streptokinase 1.5 million units infused over 1 hour
Experimental Group: (n = 13569, 13569 analysed): tPA 0.04 million units/kg as an initial 1 minute bolus, 0.36 MU/kg over the next hour, then 0.067 MU/kg over 3 hours
Experimental Group: (n = 13599, 13599 analysed): anistreplase (APSAC) 30 units over 3 minutes

99% followed for 35 days
Outcome notes:
  • death : aspirin and heparin v. aspirin
  • reinfarction : aspirin and heparin v. aspirin
  • stroke : aspirin and heparin v. aspirin
  • transfused bleed : aspirin and heparin v. aspirin
  • death : tPA v. streptokinase
  • reinfarction : tPA v. streptokinase
  • stroke : tPA v. streptokinase
  • transfused bleed :
  • allergic reaction : tPA v. streptokinase
  • profound hypotension : tPA v. streptokinase
  • death : APSAC v. streptokinase
  • reinfarction : APSAC v. streptokinase
  • stroke : APSAC v. streptokinase
  • transfused bleed : APSAC v. streptokinase
  • allergic reaction : APSAC v. streptokinase
  • profound hypotension : APSAC v. streptokinase

The evidence

aspirin and heparin v. aspirin
Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
death 35 days 2189
(10.7%)		 2132
(10.5%)		 3%
(-3% to 8%)		 0.29%
(-0.30% to 0.89%)		 340
(NNT = 330 to infinity;
NNH = 110 to infinity)
reinfarction 35 days 707
(3.47%)		 645
(3.16%)		 9%
(-1% to 18%)		 0.31%
(-0.039% to 0.66%)		 320
(NNT = 2500 to infinity;
NNH = 150 to infinity)
stroke 35 days 240
(1.18%)		 261
(1.28%)		 -9%
(-29% to 9%)		 -0.10%
(-0.315% to 0.11%)		 -990
(NNT = 320 to infinity;
NNH = 890 to infinity)
transfused bleed 35 days 156
(0.77%)		 209
(1.02%)		 -34%
(-64% to -9%)		 -0.26%
(-0.44% to -0.08%)		 -390
(-1300 to -230)

tPA v. streptokinase
Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
death 35 days 1455
(10.6%)		 1418
(10.3%)		 2%
(-5% to 9%)		 0.24%
(-0.48% to 0.97%)		 410
(NNT = 210 to infinity;
NNH = 100 to infinity)
reinfarction 35 days 472
(3.43%)		 397
(2.89%)		 16%
(4% to 26%)		 0.54%
(0.12% to 0.95%)		 190
(100 to 810)
stroke 35 days 141
(1.02%)		 188
(1.37%)		 -34%
(-66% to -8%)		 -0.34%
(-0.60% to -0.09%)		 -290
(-1100 to -170)
transfused bleed 35 days 124
(0.90%)		 110
(0.80%)		 11%
(-15% to 31%)		 0.10%
(-0.12% to 0.32%)		 1000
(NNT = 850 to infinity;
NNH = 320 to infinity)
allergic reaction 35 days 496
(3.60%)		 110
(0.80%)		 78%
(73% to 82%)		 2.80%
(2.45% to 3.14%)		 36
(32 to 41)
profound hypotension 35 days 1626
(11.8%)		 976
(7.10%)		 40%
(35% to 44%)		 4.70%
(4.01% to 5.39%)		 21
(19 to 25)

anistreplase v. streptokinase
Outcome Time to outcome CEREERRRR
(95% CI)		ARR
(95% CI)		NNT
(95% CI)
death 35 days 1455
(10.6%)		 1448
(10.5%)		 0%
(-7% to 7%)		 0.05%
(-0.68% to 0.77%)		 2200
(NNT = 150 to infinity;
NNH = 130 to infinity)
reinfarction 35 days 472
(3.43%)		 483
(3.51%)		 -2%
(-16% to 10%)		 -0.08%
(-0.51% to 0.35%)		 -1200
(NNT = 200 to infinity;
NNH = 290 to infinity)
stroke 35 days 141
(1.02%)		 172
(1.25%)		 -22%
(-52% to 2%)		 -0.23%
(-0.48% to 0.02%)		 -440
(NNT = 210 to infinity;
NNH = 4100 to infinity)
transfused bleed 35 days 124
(0.90%)		 138
(1.00%)		 -11%
(-42% to 13%)		 -0.10%
(-0.33% to 0.13%)		 -980
(NNT = 300 to infinity;
NNH = 790 to infinity)
allergic reaction 35 days 496
(3.60%)		 702
(5.10%)		 -42%
(-58% to -27%)		 -1.50%
(-1.98% to -1.02%)		 -67
(-98 to -51)
profound hypotension 35 days 1626
(11.8%)		 1722
(12.5%)		 -6%
(-13% to 1%)		 -0.70%
(-1.47% to 0.07%)		 -140
(NNT = 68 to infinity;
NNH = 1500 to infinity)

Citation

  1. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group , : ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected myocardial infarction. Lancet 1992; 339 (8796): 753-770
Search Terms:
Contributor: Chris Ball and Clare Wotton, February 2000
Reviewer:

Clinical Question.
Patient myocardial infarction
Intervention or Exposure tPA, streptokinase, anistreplase (APSAC), aspirin and heparin
Outcome death, reinfarction, stroke, bleed, allergic reaction, hypotension