The Lancet AUGUST 13, 1988

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction (ISIS-2)

ISIS-2 (Second International Study of Infarct Survival) Collaborative Group

Bottom Line

The ISIS-2 trial demonstrated that both intravenous streptokinase and oral aspirin significantly reduce 5-week vascular mortality in patients with suspected acute myocardial infarction, with the combination providing an additive, highly significant survival benefit.

Key Findings

1. Streptokinase alone reduced 5-week vascular mortality to 9.2% compared to 12.0% in the placebo group (odds reduction 25%, 2p < 0.00001).

2. Aspirin alone reduced 5-week vascular mortality to 9.4% compared to 11.8% in the placebo group (odds reduction 23%, 2p < 0.00001).

3. The combination of streptokinase and aspirin resulted in a vascular mortality rate of 8.0% compared to 13.2% in the group receiving neither, representing a 42% reduction (95% CI 34-50%, 2p < 0.0001).

4. Streptokinase was associated with an excess of transfused bleeds (0.5% vs 0.2%) and confirmed cerebral hemorrhage (0.1% vs 0.0%), but the total stroke incidence was not significantly increased.

5. Aspirin significantly reduced non-fatal reinfarction (1.0% vs 2.0%) and non-fatal stroke (0.3% vs 0.6%) without increasing hemorrhagic complications.

Study Design

Design

RCT

Double-Blind

Sample

17,187

Patients

Duration

5 wk

Median

Setting

Multicenter, international

Population Patients within 24 hours of suspected acute myocardial infarction

Intervention 1.5 MU intravenous streptokinase over 1 hour and/or 162 mg daily oral aspirin for one month

Comparator Placebo infusion and/or placebo tablets

Outcome Vascular mortality within the first 5 weeks

Study Limitations

• The pragmatic design allowed physicians freedom in using concomitant treatments, which may introduce heterogeneity in standard-of-care practices.

• The study excluded patients deemed to be at low risk of cardiac death or those with contraindications, potentially limiting the generalizability of results to these specific groups.

• The 5-week follow-up for the primary outcome period does not capture the full spectrum of long-term mortality, although secondary reports confirmed persistence of benefit.

Clinical Significance

This trial fundamentally established the paradigm of using antiplatelet therapy (aspirin) and fibrinolytic therapy (streptokinase) as standard, additive interventions in the emergency management of acute myocardial infarction, significantly reducing morbidity and mortality.

Historical Context

ISIS-2 was a landmark 'mega-trial' that emerged during the late 1980s. Following the earlier findings of the GISSI trial regarding fibrinolytic therapy, ISIS-2 confirmed these findings while additionally proving the critical role of aspirin, thereby shifting the treatment of acute MI toward early, aggressive revascularization and antiplatelet therapy.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the distinct physiological mechanisms by which streptokinase and aspirin act to reduce mortality in acute myocardial infarction, and why their combined effect is described as 'additive' in the ISIS-2 trial.

Key Response

Streptokinase is a fibrinolytic agent that converts plasminogen to plasmin, which then degrades the fibrin mesh of an established thrombus. Aspirin irreversibly inhibits cyclooxygenase-1 (COX-1), preventing the synthesis of thromboxane A2 and subsequent platelet aggregation. Because these drugs target two different pathways of thrombus formation—the coagulation cascade/fibrin structure and platelet activation—they provide independent but complementary benefits, leading to a cumulative reduction in vascular mortality.

Resident

The ISIS-2 trial enrolled patients with 'suspected' AMI up to 24 hours from symptom onset. Based on the trial's subgroup analysis, how does the magnitude of the mortality benefit for streptokinase change over time, and how does this influence the modern 'Time is Muscle' paradigm?

Key Response

ISIS-2 showed that the mortality reduction with streptokinase was greatest (about 35%) when administered within 0-4 hours of symptom onset. While the benefit declined as the time to treatment increased, a significant benefit still persisted up to 24 hours. This established the foundational principle that earlier reperfusion saves more myocardium, but also provided a rationale for treating 'late-comers' who might still have viable myocardium at risk.

Fellow

ISIS-2 utilized a 162.5 mg dose of aspirin. In the context of modern interventional cardiology and the PLATO or TRITON-TIMI 38 trials, why has the aspirin 'loading dose' remained largely consistent with the ISIS-2 protocol despite the introduction of more potent P2Y12 inhibitors?

Key Response

ISIS-2 proved that a medium dose of aspirin (160mg range) was sufficient to achieve near-total inhibition of platelet thromboxane production rapidly. Higher doses (e.g., 325mg+) increase gastrointestinal toxicity and potentially inhibit prostacyclin without providing additional survival benefit. Modern trials of P2Y12 inhibitors (like ticagrelor or prasugrel) were designed as 'add-on' therapies to the foundational aspirin regimen established by ISIS-2, confirming that aspirin's mortality benefit is a baseline requirement in ACS management.

Attending

ISIS-2 was one of the first 'mega-trials' in cardiology. How did the decision to use a simple, pragmatic trial design with 17,000+ patients—rather than a highly controlled, small-scale mechanistic study—fundamentally shift the standard of care for MI management globally?

Key Response

Before ISIS-2, aspirin use was inconsistent and streptokinase was controversial due to small, underpowered studies. By enrolling over 17,000 patients, ISIS-2 provided the statistical power necessary to demonstrate a 25-42% reduction in mortality that smaller trials missed. This pragmatic approach proved that widely available, inexpensive treatments could have a massive public health impact, shifting cardiology toward large-scale randomized evidence to drive international guidelines.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Evaluate the 2x2 factorial design used in ISIS-2. What are the statistical risks associated with assuming a lack of interaction between the two treatments (aspirin and streptokinase), and how does the trial's large sample size mitigate the concerns of a 'multiplicity' effect in subgroup analyses?

Key Response

The 2x2 design is efficient if there is no interaction, but if treatments are synergistic (as suggested here), the main effects might actually be overestimated if analyzed separately. However, ISIS-2 was powered such that the combined group's benefit was so robust that even a formal test for interaction would not negate the individual findings. Regarding multiplicity, the trial investigators used 'large-scale' evidence to discourage over-interpreting small subgroups (like the famous 'astrological sign' analysis) to prove that only the aggregate data should drive clinical conclusions.

Journal Editor

As a reviewer, if a trial today used 'suspected MI' as an entry criterion without mandatory troponin or ST-segment elevation confirmation, what concerns would you raise regarding internal validity, and how does ISIS-2's result counter those concerns?

Key Response

A modern reviewer would flag 'misclassification bias,' as including patients without true MI would theoretically dilute the treatment effect toward the null. However, ISIS-2 demonstrates that despite this 'noise,' the treatment effect was so powerful that it reached high statistical significance. This pragmatic inclusion actually increases external validity (generalizability) by showing the treatment works in the real-world setting where definitive diagnosis is often delayed.

Guideline Committee

ISIS-2 is a foundational study for Class I, Level A recommendations for aspirin in STEMI guidelines (e.g., ACC/AHA and ESC). How does the committee reconcile the historical mortality benefit of fibrinolysis in ISIS-2 with the current preference for Primary PCI, and in what scenarios does the ISIS-2 data still dictate the primary treatment path?

Key Response

While Primary PCI is now preferred (Class I) due to superior patency rates compared to thrombolytics (as seen in later trials like DANAMI-2), ISIS-2 remains the primary evidence for STEMI management in 'non-PCI capable' centers or systems with long transport delays (>120 mins). Current guidelines (ACC/AHA 2013 STEMI) still recommend fibrinolysis when PCI is not timely, with the ISIS-2 aspirin+lytic regimen remaining the standard for those patients to reduce 35-day mortality.

Clinical Landscape

Noteworthy Related Trials

1986

GISSI-1 Trial

n = 11,806 · Lancet

Tested

Intravenous streptokinase

Population

Patients with acute myocardial infarction within 12 hours of symptom onset

Comparator

Standard care without thrombolytic therapy

Endpoint

In-hospital mortality

Key result: Intravenous streptokinase significantly reduced in-hospital mortality compared to standard care, establishing the role of thrombolysis in MI treatment.

1986

ISIS-1 Trial

n = 16,027 · Lancet

Tested

Intravenous atenolol followed by oral atenolol

Population

Patients with suspected acute myocardial infarction

Comparator

Standard care without beta-blocker therapy

Endpoint

Vascular mortality

Key result: Early intravenous atenolol treatment resulted in a modest reduction in vascular mortality and a significant reduction in the rate of cardiac rupture and non-fatal reinfarction.

1988

ASSET Trial

n = 5,011 · NEJM

Tested

Recombinant tissue-type plasminogen activator (rt-PA)

Population

Patients with acute myocardial infarction within 5 hours of symptom onset

Comparator

Placebo

Endpoint

Mortality at 1 month

Key result: Treatment with rt-PA significantly reduced 1-month mortality in patients with acute myocardial infarction compared to placebo.

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