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Coronary Disease2012New England Journal of Medicine

FAME 2

Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2

Sample Size
1,220
Study Design
Multicenter, international, randomized, open-label trial (stopped early by the data safety monitoring board)
Year Published
2012
Category
Coronary Disease

Clinical Question

In patients with stable coronary artery disease and functionally significant stenoses (FFR ≤0.80), does FFR-guided PCI with drug-eluting stents plus medical therapy improve outcomes compared with medical therapy alone?

Population

Patients with stable coronary artery disease with at least one stenosis having an FFR of 0.80 or less at 28 sites in Europe and North America.

Intervention

FFR-guided PCI with second-generation drug-eluting stents plus optimal medical therapy

Control

Optimal medical therapy alone (with PCI for clinical deterioration)

Primary Endpoint

Composite of death, myocardial infarction, or urgent revascularization at 2 years (originally; modified after early stop)

Key Findings

1

The trial was stopped early due to a highly significant difference in the primary endpoint: 4.3% with PCI vs 12.7% with medical therapy (HR 0.32; 95% CI, 0.19-0.53; p<0.001).

2

The benefit was driven primarily by a reduction in urgent revascularization: 1.6% with PCI vs 11.1% with medical therapy.

3

At 5-year follow-up, PCI continued to show benefit: primary endpoint 13.9% vs 27.0% (HR 0.56; p<0.001).

4

No significant difference in death or myocardial infarction was observed between groups at any time point.

5

In the registry of FFR-negative lesions (FFR >0.80), outcomes with medical therapy alone were excellent, validating FFR as a decision-making tool.

Impact on Clinical Practice

FAME 2 established fractional flow reserve as the gold standard for guiding PCI decisions in stable coronary artery disease. By demonstrating that FFR-guided PCI dramatically reduced the need for urgent revascularization compared to medical therapy, the trial validated a physiology-first approach to coronary intervention. The trial was notable for being stopped early by the data safety monitoring board due to the large reduction in urgent revascularization with PCI. However, the lack of mortality or MI benefit generated debate about the clinical significance of preventing urgent revascularizations, which rarely result in death or permanent harm. Perhaps equally important was the FFR-negative registry, which showed that patients with hemodynamically insignificant lesions (FFR >0.80) had excellent outcomes with medical therapy alone, even when angiography suggested significant disease. This finding reinforced the principle that appearance alone should not drive intervention and that physiologic assessment is essential for appropriate patient selection.

Guideline Impact

FAME 2 is the primary evidence supporting the ACC/AHA Class I recommendation for FFR measurement in guiding PCI decisions for intermediate coronary stenoses (40-70%). ESC guidelines also give FFR-guided PCI a Class I recommendation in stable coronary disease.

Limitations

Early termination may have overestimated the treatment effect and prevented adequate assessment of hard endpoints like death and MI.

The primary endpoint was driven by urgent revascularization, a softer endpoint that can be influenced by knowledge of treatment assignment in an unblinded trial.

Open-label design may have led to lower thresholds for urgent catheterization in the medical therapy group.

Reviewed by Kunal U. Gurav, MD
Echocardiography & Nuclear Cardiology

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