New England Journal of Medicine SEPTEMBER 27, 2012

Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2 (FAME 2)

Bernard De Bruyne, Nico H.J. Pijls, William F. Fearon, et al.

Bottom Line

In patients with stable coronary artery disease and functionally significant stenoses (FFR ≤0.80), FFR-guided PCI plus optimal medical therapy reduced the composite rate of death, myocardial infarction, or urgent revascularization compared to optimal medical therapy alone.

Key Findings

1. At 3 years, the primary endpoint (composite of death, MI, or urgent revascularization) was significantly lower in the PCI arm (10.1%) compared to the medical therapy alone arm (22.0%; P<0.001).

2. The benefit in the primary endpoint was primarily driven by a significant reduction in urgent revascularization rates in the PCI group (4.3% vs 17.2%; P<0.001).

3. There was no statistically significant difference between the PCI and medical therapy groups for the hard endpoints of all-cause death and myocardial infarction at 3 years (8.3% vs 10.4%; P=0.28).

4. Patients in the PCI group reported less severe angina and improved quality of life compared to the medical therapy group throughout the 3-year follow-up period.

Study Design

Design

RCT

Open-Label

Sample

888

Patients

Duration

3 yr

Median

Setting

Multicenter, international

Population Patients with stable coronary artery disease (single- or multivessel) and at least one functionally significant stenosis (FFR ≤0.80) in a major epicardial artery.

Intervention FFR-guided PCI plus best available medical therapy

Comparator Best available medical therapy alone

Outcome Composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization.

Study Limitations

• The trial was open-label, which may have introduced bias regarding the decision to perform urgent revascularization, particularly in the medical therapy arm where patients were aware of their untreated significant stenoses.

• The study focused on a composite endpoint that included non-fatal outcomes and procedures, which may not be as clinically robust as hard outcomes like cardiovascular death or myocardial infarction alone.

• The results are specific to patients with functionally significant stenosis as defined by FFR, and therefore may not be generalized to all patients with stable coronary artery disease, especially those with non-ischemic lesions.

Clinical Significance

The FAME 2 trial established that using physiological assessment (FFR) to guide revascularization in patients with stable coronary artery disease is superior to angiography-guided decision-making, as it identifies the subset of stenoses that cause ischemia, leading to better clinical outcomes and symptom relief compared to medical therapy alone.

Historical Context

Following the COURAGE trial, which failed to show that routine PCI combined with medical therapy improved outcomes over medical therapy alone in stable CAD, FAME 2 aimed to refine patient selection by using FFR to identify lesions that were truly flow-limiting, thereby providing a more precise interventional approach.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological basis of Fractional Flow Reserve (FFR), and why does it provide a more accurate assessment of a coronary stenosis than visual inspection via angiography?

Key Response

FFR represents the ratio of maximal blood flow in a stenotic artery to the maximal flow if the artery were normal, calculated by comparing distal pressure (Pd) to aortic pressure (Pa) during hypermia. Visual angiography only assesses the lumen's anatomy, which often fails to predict whether a lesion actually limits flow and causes ischemia. FAME 2 demonstrates that only those lesions that are functionally significant (FFR ≤0.80) derive a benefit from intervention.

Resident

How should the results of the FAME 2 trial influence the management of a patient with stable angina whose angiogram reveals a 70% stenosis but whose FFR is measured at 0.84?

Key Response

According to the FAME 2 registry (which tracked patients with non-ischemic FFR values), patients with an FFR >0.80 have an excellent prognosis with optimal medical therapy (OMT) alone. Performing PCI on such lesions does not improve outcomes and may expose the patient to unnecessary procedural risks. The trial reinforces the 'functional' over 'anatomical' approach to revascularization.

Fellow

Contrast the findings of FAME 2 with the COURAGE trial. What specific methodological difference in patient selection likely accounts for the divergent outcomes regarding the benefit of PCI plus OMT versus OMT alone?

Key Response

The COURAGE trial used purely angiographic criteria (visual stenosis) to guide PCI, potentially including many patients with non-ischemic lesions who would not benefit from revascularization. FAME 2 utilized FFR to ensure that only hemodynamically significant lesions were treated. This suggests that the benefit of PCI in stable CAD is contingent upon the presence of objective, lesion-specific ischemia.

Attending

The FAME 2 trial was stopped early for efficacy due to a significant reduction in the primary composite endpoint. However, when examining the individual components (death, MI, urgent revascularization), how does the driver of the results affect your shared decision-making process with a stable CAD patient?

Key Response

The benefit in FAME 2 was almost entirely driven by a reduction in 'urgent revascularization,' with no significant difference in death or myocardial infarction at the initial 2-year follow-up. In practice, this means the attending must counsel patients that while FFR-guided PCI reduces the risk of returning to the hospital for an emergency procedure and improves symptoms, it has not yet been definitively proven to extend life or prevent heart attacks in the stable setting compared to OMT.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Discuss the potential for 'detection bias' in the FAME 2 trial design. How might the unblinded nature of the study influence the 'urgent revascularization' endpoint, and what trial design could mitigate this?

Key Response

In FAME 2, both the treating physicians and the patients knew if a functionally significant lesion was left untreated (the OMT-only group). This knowledge may have lowered the clinical threshold for admitting a patient or performing an 'urgent' procedure when they presented with chest pain. A sham-controlled, double-blinded trial (similar to ORBITA) would be the methodological gold standard to eliminate this bias, though it presents significant ethical and logistical challenges.

Journal Editor

FAME 2 was terminated early by the Data and Safety Monitoring Board (DSMB). As a reviewer, what are the primary statistical concerns regarding 'overestimation of effect' and 'low event rates' for secondary endpoints in trials that do not reach their planned duration?

Key Response

Early termination often leads to the 'Winner’s Curse,' where the treatment effect is likely exaggerated. While the primary composite reached significance, the truncated follow-up resulted in fewer total events, leaving the trial underpowered to detect differences in harder, low-frequency endpoints like cardiovascular mortality. This limits the ability to draw definitive conclusions about the long-term disease-modifying potential of the intervention.

Guideline Committee

FAME 2 supported a Class I recommendation for FFR use in stable CAD. However, how do the results of the later ISCHEMIA trial (2020) influence the current guideline-directed approach to stable patients with high-risk FFR values?

Key Response

While FAME 2 proved FFR-guided PCI is superior to OMT for reducing urgent events, the ISCHEMIA trial showed that an initial conservative strategy (OMT) is safe and results in similar rates of death and MI compared to an invasive strategy, even in patients with significant ischemia. Consequently, current ACC/AHA guidelines (2021) emphasize OMT as the first-line therapy, reserving FFR-guided PCI primarily for patients who remain symptomatic despite optimal medical management.

Clinical Landscape

Noteworthy Related Trials

2007

COURAGE Trial

n = 2287 · NEJM

Tested

PCI plus optimal medical therapy

Population

Patients with stable coronary artery disease

Comparator

Optimal medical therapy alone

Endpoint

Composite of death from any cause and nonfatal myocardial infarction

Key result: The addition of PCI to optimal medical therapy did not reduce the risk of death, myocardial infarction, or other major cardiovascular events.

2009

FAME Study

n = 1005 · NEJM

Tested

FFR-guided PCI

Population

Patients with multivessel coronary artery disease

Comparator

Angiography-guided PCI

Endpoint

Major adverse cardiac events at 12 months

Key result: FFR-guided PCI significantly reduced the rate of major adverse cardiac events compared to angiography-guided PCI alone.

2020

ISCHEMIA Trial

n = 5179 · NEJM

Tested

Invasive strategy (angiography and revascularization) plus optimal medical therapy

Population

Patients with stable coronary artery disease and moderate to severe ischemia

Comparator

Conservative strategy (optimal medical therapy alone)

Endpoint

Composite of cardiovascular death, myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure

Key result: An invasive strategy did not reduce the risk of ischemic cardiovascular events or death compared to a conservative strategy.

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