VA Cooperative Study

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Lewis HD, et al. "Protective Effects of Aspirin against Acute Myocardial Infarction and Death in Men with Unstable Angina -- Results of a Veterans Administration Cooperative Study". The New England Journal of Medicine. 1983. 309(7):396-403.
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Clinical Question

In men with unstable angina (UA), what is the effect of aspirin on acute MI and mortality?

Bottom Line

Aspirin reduces the risk of death or MI at 12 weeks by 50% among patients with UA.

Major Points

Unstable angina is associated with transient ischemia due, at least in part, to enhanced platelet activity, and therefore may be reversed in part by antiplatelet agents. The VA Cooperative Study sought to address the reversability of UA, demonstrating that aspirin reduced the risk of death or MI at 12 weeks by 50% with an associated NNT of 20. This provides evidence supporting the routine use of aspirin not only in patients with MI, but in all patients with acute coronary syndrome, including UA.

Guidelines

ACCF/AHA NSTE-ACS (2014, adapted)[1]

  • 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)

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=1,266
    • Aspirin 324 mg daily (n=625)
    • Placebo (n=641)
  • Setting: 12 university-affiliated VA hospitals
  • Enrollment: November 1974 to August 1981
  • Mean follow-up: 12 weeks

Population

Inclusion Criteria

  • Men with chest pain suggestive of unstable angina, defined as:
    • New onset or worsening of angina at rest or during minimal activity
    • Duration longer than 15 minutes
    • Began within previous month and still ongoing within previous week
  • Evidence of CAD, defined by one or more of following:
    • Q-wave with duration ≥0.03 sec on EKG
    • ST-segment depression, 0.1-mV horizontal or downsloping for 0.08 sec
    • ≥75% narrowing on prior angiography
    • ST-segment depression on prior exercise tests
    • History of typical angina characterized by steady chest pain produced by exertion and relieved within five minutes by rest or nitroglycerin
  • Absence of baseline EKG or cardiac enzymes abnormalities

Exclusion Criteria

  • Female sex
  • Acute MI within 6 weeks
  • CHF NYHA Class IV
  • Tachyarrhythmia (ventricular rate >150/min)
  • Anemia (Hemoglobin <10 g/dL)
  • Hypoxia (pO2<50 mmHg)
  • Fever ≥39 C
  • Hypotension (SBP ≤90 mmHg) or severe hypertension (diastolic BP >115 mmHg)
  • Thyrotoxicosis
  • Contraindications to aspirin treatment
    • Receiving Anticoagulants
    • Bleeding condition or tendency
    • PUD symptoms within 3 months
    • Allergy or intolerance to aspirin
  • Aspirin ingestion on >3 of 7 days prior to randomization
  • Other platelet-active drugs within 24 hours
  • Coronary bypass, general surgery, or cardiac catheterization within 12, 4, or 1 weeks, respectively
  • Other illness that might affect 1-year survival

Baseline Characteristics

  • Mean age: 56 years
  • Male: 100%
  • β-blocker use during week before entry: 26.5% vs. 33.7% (P=0.006)
  • Aspirin use on <4 of 7 days before entry: 19%
  • Diabetes: 18%
  • Smokers: 51%
  • Hypertension: 41%
  • History of aortocoronary bypass surgery: 9.0 vs. 11.4% (P=0.16)
  • Other cardiac surgery: 4.6% vs. 2.7% (P=0.06)
  • Mean SBP: 127.3 vs. 125.1 mmHg (P=0.04)
  • Mean DBP: 79.3 mmHg
  • Rales on exam: 14.4% vs. 11.4% (P=0.11)
  • LBBB on EKG: 1.1% vs. 3.3% (P=0.009)
  • RBBB on EKG: 1.9% vs. 5.0% (P=0.003)

Interventions

  • Of 13,666 screened, 7,312 met criteria for unstable angina, and 1,338 entered study.
  • Screening within 48 hours after presentation for men with chest pain suggestive of unstable angina.
  • EKG and serum samples drawn at time of screening, at time of random assignment (3 hours later), and 3 and 9 hours after random assignment.
  • If creatine kinase MB detected in early serum samples indicated that acute MI had occurred before random assignment, data segregated for separate analysis.
  • Randomly assigned to either:
    • Aspirin 324mg in effervescent buffered powder (Alka-Seltzer: ASA 324mg, citric acid 1000mg, and sodium bicarbonate 1904mg)
    • Placebo
  • Taken by mouth once daily for 12 weeks

Outcomes

Comparisons are aspirin vs. placebo.

Primary Outcomes

All-cause mortality or MI after 12 weeks
5.0% vs. 10.1% (P=0.0005)

Secondary Outcomes

Fatal or nonfatal MI
3.5% vs. 7.8% (P=0.001)
Nonfatal MI
3.4% vs. 6.9% (P=0.005)
All-cause mortality
1.6% vs. 3.3% (P=0.054)

Adverse Events

Epigastric burning
34.0% vs. 32.9% (P=NS)
Reduction in hemoglobin >14%
29.0% vs. 28.7% (P=NS)

Funding

Supported by the Cooperative Studies Program of the Medical Research Service, Veterans Administration Central Office, Washington, D.C.

Further Reading

  1. 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.