Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2
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The landmark ISIS-2 trial demonstrated that early administration of intravenous streptokinase and oral aspirin independently and additively reduced 5-week vascular mortality in patients with suspected acute myocardial infarction.
Key Findings
Study Design
Study Limitations
Clinical Significance
ISIS-2 is one of the most historically important trials in cardiology. It unequivocally established aspirin and early thrombolytic therapy as life-saving, standard-of-care interventions for acute myocardial infarction. The finding that simply chewing an inexpensive aspirin tablet drastically reduces mortality revolutionized emergency cardiovascular care and remains a cornerstone of acute coronary syndrome management worldwide.
Historical Context
Prior to ISIS-2, standard care for acute myocardial infarction was largely supportive (prolonged bed rest, oxygen, pain relief), and in-hospital mortality was extremely high. Although GISSI-1 (1986) demonstrated a mortality benefit for streptokinase, the role of acute antiplatelet therapy was unproven until ISIS-2 definitively demonstrated its independent, profound synergistic survival benefit when combined with reperfusion therapy.
Guided Discussion
High-yield insights from every perspective
How do the mechanisms of action of streptokinase and aspirin complement each other in the pathophysiology of an acute myocardial infarction, explaining the additive mortality benefit seen in ISIS-2?
Key Response
Streptokinase is a thrombolytic that activates plasminogen to plasmin, degrading the existing fibrin mesh of a clot. Aspirin is an antiplatelet agent that irreversibly inhibits COX-1, preventing thromboxane A2 generation and subsequent platelet aggregation. Using both targets the two primary components of a coronary thrombus (fibrin and platelets), thereby preventing re-occlusion after initial lysis.
Although ISIS-2 established thrombolysis and aspirin as the standard of care for acute MI in 1988, how has the management of STEMI evolved, and in what specific clinical scenarios would a thrombolytic protocol still be indicated today?
Key Response
Primary percutaneous coronary intervention (PCI) has largely replaced thrombolysis for STEMI management due to superior reperfusion rates and lower bleeding risks. However, thrombolytic therapy (typically using newer fibrin-specific agents like tenecteplase, though streptokinase is used in resource-limited settings) remains a Class I indication when timely PCI within 120 minutes of first medical contact is unavailable.
In the ISIS-2 trial, the mortality benefit of streptokinase was highly dependent on the time from symptom onset to administration, whereas aspirin's benefit was less time-dependent. What is the pathophysiological basis for this discrepancy, and how does it influence modern reperfusion triage?
Key Response
Fibrin-rich thrombi become more highly cross-linked and resistant to lysis over time, making delayed thrombolytic therapy less effective and increasing bleeding risks without commensurate benefit. Conversely, aspirin's inhibition of ongoing platelet activation and prevention of secondary re-infarction is beneficial regardless of the age of the primary thrombus, dictating why early aspirin is universal while lytics have a strict time window.
ISIS-2 enrolled patients based on 'suspected' acute MI without requiring ECG confirmation of ST elevation. How did this pragmatic inclusion criterion influence the trial's impact, and what critical lesson does the trial's famous 'astrological sign' subgroup analysis teach us about interpreting clinical data?
Key Response
The pragmatic design maximized enrollment and real-world generalizability. To demonstrate the dangers of over-analyzing subgroups, Richard Peto famously showed that streptokinase appeared ineffective or harmful in patients born under the astrological signs of Gemini and Libra. This teaches a vital lesson for attending physicians evaluating literature: overall trial results powered for primary endpoints should override biologically implausible, underpowered subgroup findings.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The ISIS-2 trial utilized a 2x2 factorial design to evaluate streptokinase and aspirin. What are the statistical assumptions required to validly assess main effects in such a design, and how did the investigators establish that the effects were independently additive?
Key Response
A 2x2 factorial design assumes no significant biological or statistical interaction between the interventions if main effects are to be interpreted independently. The investigators formally tested for interaction and found the reduction in the odds of death for the combination was approximately the product of the individual odds reductions, statistically confirming independent, additive mechanisms rather than a super-additive synergistic or antagonistic effect.
Given that streptokinase causes profound hypotension and systemic effects, fully blinding the treating clinicians in ISIS-2 was practically impossible. As an editor, how would you evaluate the risk of performance bias, and how does the choice of the primary endpoint mitigate this threat?
Key Response
The physiological effects of streptokinase likely unblinded clinicians, risking co-intervention bias. However, using all-cause 5-week vascular mortality as the primary endpoint is highly robust against detection and performance biases, as death is a completely objective, non-adjudicated outcome immune to subjective clinical interpretation, preserving internal validity despite the unblinding.
ISIS-2 provides foundational Level 1A evidence for universal aspirin administration in acute coronary syndromes. How do current ACC/AHA STEMI guidelines adapt the dosing and delivery method from the original ISIS-2 protocol to optimize patient outcomes?
Key Response
ISIS-2 used 162.5 mg of enteric-coated oral aspirin daily. Current ACC/AHA guidelines provide a Class I recommendation for the immediate administration of non-enteric-coated, chewable aspirin (162 to 325 mg) at presentation. This guideline adaptation is based on pharmacokinetic data showing that chewed, non-enteric formulations achieve much faster buccal absorption and rapid platelet inhibition, optimizing the early survival benefit demonstrated in ISIS-2.
Clinical Landscape
Noteworthy Related Trials
GISSI-1
Tested
Intravenous streptokinase 1.5 million U
Population
Patients with acute myocardial infarction admitted within 12 hours of symptom onset
Comparator
Standard medical care
Endpoint
In-hospital mortality at 21 days
GUSTO-I
Tested
Accelerated tissue plasminogen activator (t-PA) with intravenous heparin
Population
Patients with acute myocardial infarction presenting within 6 hours
Comparator
Streptokinase with subcutaneous or intravenous heparin
Endpoint
30-day mortality
COMMIT
Tested
Clopidogrel 75mg daily plus aspirin
Population
Patients with suspected acute myocardial infarction
Comparator
Placebo plus aspirin
Endpoint
Composite of death, reinfarction, or stroke, and all-cause mortality at 28 days
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