ISIS-2: Streptokinase and Aspirin in Acute Myocardial Infarction (1988)

“Streptokinase alone and aspirin alone each produced a highly significant reduction in 5-week vascular mortality. The combination of streptokinase and aspirin was significantly better than either agent alone.”

  • The ISIS-2 Collaborative Group

1. Publication Details

  • Trial Title: Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2
  • Citation: ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349-360. DOI: 10.1016/s0140-6736(88)92833-4
  • Published: August 13, 1988, in The Lancet
  • Author: The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
  • Funding: British Heart Foundation; UK Medical Research Council; and others.

2. Keywords

  • Acute Myocardial Infarction, Fibrinolysis, Thrombolysis, Streptokinase, Aspirin, Antiplatelet Therapy, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with suspected acute myocardial infarction (AMI) (Population), does treatment with intravenous streptokinase, oral aspirin, or both (Intervention) compared to double placebo (Comparison) reduce 5-week vascular mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: By the mid-1980s, the “open artery” hypothesis—the idea that dissolving the coronary thrombus was the key to treating a heart attack—was gaining traction. Fibrinolytic agents like streptokinase were promising, but their true effect on survival was unproven. Similarly, aspirin’s antiplatelet effects were known, but its role in the acute phase of an MI was not definitively established.
  • Knowledge Gap: There was a critical need for a very large, simple, randomized trial to determine if these widely available and inexpensive therapies, either alone or in combination, could save lives on a massive scale.
  • Proposed Hypothesis: The authors hypothesized that both streptokinase and aspirin would be superior to placebo in reducing vascular mortality, and that the combination would be superior to either agent alone.

5. Study Design and Methods

  • Design: A very large, multicenter, international, prospective, 2×2 factorial, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 417 hospitals in 16 countries.
  • Trial Period: Enrollment ran from March 1985 to December 1987.
  • Population:
    • Inclusion Criteria: Adult patients with a suspected acute MI within 24 hours of symptom onset, for whom the treating clinician was substantially uncertain whether or not to use a fibrinolytic or antiplatelet agent.
    • Exclusion Criteria: Clear indications for or contraindications to either of the study treatments.
  • Intervention: Patients were randomized in a factorial design to one of four groups:
  • Streptokinase: A 1-hour intravenous infusion of 1.5 million units of streptokinase plus an aspirin placebo tablet.
  • Aspirin: A daily 162.5 mg enteric-coated aspirin tablet for 1 month plus a streptokinase placebo infusion.
  • Combination: Both active streptokinase and active aspirin.
  • Double Placebo: Both streptokinase placebo and aspirin placebo.
  • Control: The double placebo group served as the control.
  • Management Common to Both Groups: All other aspects of care were at the discretion of the treating clinicians.
  • Power and Sample Size: The trial was designed to be large enough to detect a clinically meaningful difference in mortality with a high degree of statistical certainty.
  • Outcomes:
    • Primary Outcome: Vascular mortality at 5 weeks.
    • Secondary Outcomes: Included all-cause mortality, reinfarction, and stroke.

6. Key Results

  • Enrollment and Baseline: 17,187 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Both streptokinase and aspirin independently and significantly reduced 5-week vascular mortality. The effect of the combination was additive and highly significant.
    • Placebo: 12.0% mortality
    • Aspirin alone: 9.4% mortality (23% risk reduction vs. placebo)
    • Streptokinase alone: 9.2% mortality (25% risk reduction vs. placebo)
    • Streptokinase + Aspirin: 8.0% mortality (42% risk reduction vs. placebo)
  • Secondary Outcomes: The combination therapy also significantly reduced the rates of reinfarction and stroke.
  • Adverse Events: Streptokinase was associated with a small but significant increase in the risk of cerebral hemorrhage (stroke). Aspirin was associated with a small increase in minor bleeding.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of vascular death among the four groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the odds ratios for each comparison.
  • Interpretation of Key Statistic(s):
    • P-value: The p-values for the mortality reduction with aspirin alone, streptokinase alone, and the combination were all highly statistically significant (p<0.00001).
  • Clinical Impact Measures (for Combination vs. Placebo):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 12.0% – 8.0% = 4.0%.
      • Clinical Meaning: For every 100 patients with acute MI treated with both streptokinase and aspirin, 4 additional deaths were prevented at 5 weeks.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.04 = 25.
      • Clinical Meaning: You would need to treat 25 patients with both streptokinase and aspirin to prevent one additional death.
  • Subgroup Analyses: The benefits were consistent across a wide range of patient subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled, factorial design is the gold standard and provided a massive amount of high-quality, definitive data on two separate interventions.
  • Generalizability: The pragmatic design with very broad inclusion criteria and enrollment across 16 diverse countries makes the findings highly generalizable to almost all patients with suspected acute MI.
  • Statistical Power: The enormous sample size provided definitive power to detect even small but clinically important differences in mortality.
  • Patient-Centered Outcomes: The primary outcome of vascular mortality is a robust, objective, and highly relevant endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable.
  • Other: The study used streptokinase, which has since been largely replaced by newer fibrinolytic agents, but the principle of early reperfusion remains the same.

10. Conclusion of the Authors

  • The authors concluded that both intravenous streptokinase and oral aspirin provide a clear and significant mortality benefit in acute MI, and that their effects are largely additive.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided the definitive evidence that established both fibrinolysis and aspirin as the cornerstones of early management for acute myocardial infarction, a standard of care that saved countless lives and persists to this day (though fibrinolysis has been largely superseded by primary PCI where available).
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult patients with suspected acute MI within 24 hours of symptom onset.
    • Actionable Intervention: Administer aspirin immediately and consider early fibrinolytic therapy if primary PCI is not available.
    • Expected Benefit: The combination therapy can be expected to prevent approximately one death for every 25 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that streptokinase is the best fibrinolytic, only that it is effective.
  • Implementation Caveats: The key is early administration. The benefits of both therapies are greatest when given as soon as possible after symptom onset.

12. Context and Related Studies

  • Building on Previous Evidence: The ISIS-2 trial (1988) was a direct successor to the GISSI-1 trial (1986), which had first shown a benefit for streptokinase. ISIS-2 confirmed this finding and definitively established the additional, independent benefit of aspirin.
  • Influence on Subsequent Research: The definitive positive result of this trial solidified the “open artery” hypothesis and led to the development of newer fibrinolytic agents and, ultimately, to the trials comparing fibrinolysis to primary PCI (e.g., DANAMI-2 (2003)).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary questions.
  • Future Directions: The success of this trial spurred decades of research into optimizing reperfusion therapy for acute MI, leading to the current era of primary PCI.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing two simple, inexpensive, and widely available therapies for one of the leading causes of death worldwide.
  • Methods: The very large, multicenter, double-blind, factorial RCT design was of the highest quality. The pragmatic “uncertainty principle” for enrollment was a key strength that allowed for a very large and generalizable study population.
  • Results: The study reported a statistically significant and clinically profound benefit for both interventions, with a clear additive effect. The NNT of 25 for the combination therapy represents a major public health impact.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine and a classic example of how a large, simple, pragmatic trial can definitively answer a major clinical question and change practice on a global scale.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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