ISIS-2

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ISIS-2 Collaborative Group. "Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither among 17187 Cases of Suspected Acute Myocardial Infarction". The Lancet. 1988. 332(8607):349-360.
PubMedFull text

Clinical Question

In patients with suspected acute MI, what is separate and combined effect of streptokinase and of aspirin in decreasing the risk of vascular mortality?

Bottom Line

Among patients with acute MI, aspirin and streptokinase reduced 5-week vascular mortality by 20% and 23%, respectively, when compared to placebo. The combination of aspirin and streptokinase reduced the same outcome by 40%.

Major Points

During the 1960s and 1970s several small trials of fibrinolytic therapy involving mainly IV streptokinase were performed. Meta-analysis suggested that fibrinolytic therapy for acute MI could reduce vascular mortality by 25%. The large GISSI trial (1986) prospectively studied this, and demonstrated that high-dose streptokinase effectively dissolves thrombi and recanalizes occluded coronary arteries.

Published in 1988, ISIS-2 was the first trial to demonstrate the clinical efficacy of the antiplatelet agent aspirin in reducing vascular mortality in acute MI. With aspirin, there was a highly significant 20% reduction in 5-week vascular mortality, which was comparable to a 23% reduction seen with streptokinase. When streptokinase and aspirin were coadministered, 5-week vascular mortality was reduced by 40%. The absolute mortality reduction was 2.4 vascular deaths prevented per 100 patients treated with aspirin, for a NNT of 42.

ISIS-2 and GISSI have been criticized for their use of thrombolytics in MI despite there being a lack of clinical equipoise. In the 1970s, 10 trials had been performed, a meta-analysis of these results found a benefit with the intervention with a P<0.01. By the time of publication of ISIS-2 and GISSI, an additional 20 trials had been performed and the P-value for the meta-analysis was reduced to <0.001.[1] Despite the solid, pre-existing evidence, ISIS-2 and GISSI were moved forward because contemporary experts were in disagreement about the efficacy of the intervention. In a time before "evidence-based medicine" had been coined, it took about a decade for the experts to catch up with the evidence.[2]

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[3]

  • Aspirin 162-325 mg without enteric coating at presentation then ASA 81-162 mg PO qday continuously, unless aspirin is contraindicated (class I, level A)
    • If aspirin is contraindicated, treat with clopidogrel with a loading dose then a maintenance dose continually (class I, level B)
  • If treated with an early invasive strategy or an ischemia-guided strategy, treat for ≤12 months with clopidogrel or ticagrelor (class I, level B)
    • In this instance, it's reasonable to use ticagrelor over clopidogrel (class IIa, level B)
  • If clinical suspicion of NSTE-ACS (examples include no ST elevation, no posterior MI, or LBBB known to be old), do not administer IV thombolytics (class III, level A)

ACCF/AHA STEMI (2013, adapted)[4]

  • Aspirin 162-325 mg without enteric coating before PCI (class I, level B) then daily (class I, level A) continuously
    • It's reasonable to use aspirin 81 mg as a daily maintenance dose (class IIa, level B)
  • Clopidogrel, prasugrel, or ticagrelor (class I, level B) as early as possible or at time of primary PCI
  • If DES or BMS stent placed during PCI, one year of therapy with clopidogrel, prasugrel, or ticagrelor (class I, level B)
  • If >120 minute delay from first medical contact until PCI, the following are indications for thrombolytics in STEMI:
    • No contraindications to the therapy, ischemic symptoms <12 hours duration (class I, level A)
    • No contraindications to the therapy, ongoing ischemia between 12-24 hours of onset of symptoms (class IIa, level C)
  • Do not administer thrombolytics if ST depression unless suspicion of a posterior/inferobasal MI or also ST-elevations in aVR (class III, level B)

Design

  • Multicenter, double-blinded, two-by-two factorial, randomized, placebo-controlled trial
  • N=17,187
    • Streptokinase (n=8,592) vs. placebo (n=8,595)
    • Aspirin (n=8,587) vs. placebo (n=8,600)
  • Four treatment groups:
    1. Streptokinase (n=4,300)
    2. Aspirin (n=4,295)
    3. Aspirin and streptokinase (n=4,292)
    4. Placebo (n=4,300)
  • Setting: 417 centers in 16 countries
  • Median time to discharge: 10 days
  • Median follow-up: 15 months

Population

Inclusion Criteria

  • Suspected acute MI within 24 hours of symptom onset
  • No clear indication for, or contraindication to, streptokinase or aspirin

Exclusion Criteria

  • History of stroke
  • History of GI bleed or PUD
  • Recent arterial puncture
  • Recent severe trauma
  • Severe persistent hypertension
  • Allergy to streptokinase or aspirin

Interventions

  • Randomized by 2x2 factorial design
    • Streptokinase (1.5 million units of Streptase vs. placebo (hepatitis-B-antigen-free albumin); infused over 1 hour
    • Aspirin (162.5 mg enteric-coated tablets) vs. placebo (enteric-coated starch tablets); given daily for 1 month, with first tablet crushed, sucked, or chewed for rapid effect
  • Four treatment groups: streptokinase alone, aspirin alone, both, or neither

Outcomes

Primary Outcome

Vascular mortality at 5 weeks
Streptokinase vs. placebo:
9.2% vs 12.0% (RR 0.77, 2P<0.00001, NNT=35)
Aspirin vs. placebo
9.4% vs 11.8%, (RR 0.80, 2P<0.00001, NNT=42)
Aspirin and streptokinase vs. placebo:
8.0% vs 13.2% (RR 0.60, 2P<0.0001, NNT=19)

Secondary Outcomes

Nonfatal reinfarction
Streptokinase vs. placebo: 1.8% vs. 1.1%
Aspirin vs. placebo: 1.0% vs. 2.0%
Streptokinase and aspirin vs. placebo: 1.1% vs. 1.6%
Bleeds requiring transfusion
Streptokinase vs. placebo: 0.5% vs. 0.2% (2P <0.001)
Aspirin vs. placebo: 0.4% vs. 0.4% (P=NS)
Streptokinase and aspirin vs. placebo: 0.6% vs. 0.3%
Nonfatal strokes
Streptokinase vs. placebo: 0.4% vs. 0.5% (P=NS)
Aspirin vs. placebo: 0.3% vs. 0.6%
Streptokinase and aspirin vs. placebo: 0.3% vs. 0.6% (2P=0.02)
Cerebral hemorrhage
Streptokinase vs. placebo: 0.1% vs. 0.0% (2P <0.02)
Aspirin vs. placebo: (P=NS)
Streptokinase and aspirin vs. placebo: 0.1% vs. 0%

Adverse Events

Comparisons are streptokinase vs. placebo infusion.

Hypotension and/or bradycardia
10% vs. 2%
Allergic reactions (shivering, pyrexia, rashes)
4.4% vs. 0.9%
Any bleed
4.0% vs. 1.2% (2P<0.0001)
GI symptoms
1.2% vs. 0.2%
Arrhythmias
1.3% vs. 0.3%

Funding

Supported by the British Heart Foundation, Sterling Drugs, Behringwerke, and the manufacturers of Streptase.

Criticisms

  • Lack of clinical equipoise for thrombolytics[1]

Further Reading

  1. 1.0 1.1 Antman EM, et al. "A comparison of results of meta-analyses of randomized controlled trials and recommendations of clinical experts. Treatments for myocardial infarction." JAMA. 1992;268(2):240-248.
  2. Guyatt G, et al. "Users' guides to the medical literature: A manual for evidence-based clinical practice." 3rd ed. JAMA Evidence. McGraw-Hill Education. Published 2015. pp8-10.
  3. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  4. O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.