The New England Journal of Medicine January 15, 2009

Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention (FAME)

Pim A. L. Tonino, Bernard De Bruyne, Nico H. J. Pijls, Uwe Siebert, et al.

Bottom Line

In patients with multivessel coronary artery disease, routine measurement of fractional flow reserve (FFR) to guide percutaneous coronary intervention significantly reduced the composite rate of death, myocardial infarction, and repeat revascularization at 1 year compared to angiography alone.

Key Findings

1. Theprimarycompositeendpointofdeath, nonfatalmyocardialinfarction, andrepeatrevascularizationat1yearoccurredsignificantlylessfrequentlyintheFFR-guidedgroupcomparedtotheangiography-guidedgroup(13.2%vs.18.3%, P=0.02)[1.1].

2. The composite of death or nonfatal myocardial infarction was significantly reduced in the FFR-guided group (7.3% vs. 11.1%, P=0.04).

3. Patients in the FFR group received significantly fewer stents per patient than those in the angiography group (1.9 ± 1.3 vs. 2.7 ± 1.2, P<0.001).

4. Despite fewer stents being placed, there was no significant difference in the proportion of patients free from angina at 1 year (81% in the FFR group vs. 78% in the angiography group, P=0.20).

5. In the FFR group, 37% of lesions initially thought to require stenting based on visual angiographic appearance were functionally non-significant (FFR > 0.80) and were successfully deferred.

6. Procedure time was virtually identical between the two arms (71 ± 43 minutes vs. 70 ± 44 minutes, P=0.51), while contrast volume used was significantly lower in the FFR group (272 mL vs. 302 mL, P<0.001).

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

1,005

Patients

Duration

1 year

Median

Setting

Multicenter, US & Europe

Population Patients with multivessel coronary artery disease (defined as ≥50% stenosis by visual estimation in at least 2 major epicardial vessels) undergoing PCI with drug-eluting stents.

Intervention FFR-guided PCI: All indicated lesions were measured with a pressure wire, and stenting was performed only if the fractional flow reserve (FFR) was ≤0.80.

Comparator Angiography-guided PCI: Stenting of all visually indicated lesions (stenosis >50%) based on angiographic appearance alone.

Outcome Composite of death, nonfatal myocardial infarction, and repeat revascularization at 1 year.

Study Limitations

• Theopen-labeldesignmeantthatoperatorswerenotblindedtotherandomizationarm, whichcouldhaveinfluencedclinicaldecisionsregardingrepeatrevascularization[2.2].

• Lesion severity in the angiography arm was based on visual estimation rather than standardized quantitative coronary angiography (QCA), though this accurately reflected real-world clinical practice.

• The study specifically enrolled patients with multivessel disease, meaning the results may not be generalizable to patients with isolated single-vessel disease or left main disease (who were excluded).

• The trial utilized first-generation drug-eluting stents, which have different long-term event and thrombosis rates compared to contemporary ultra-thin strut drug-eluting stents.

Clinical Significance

The FAME trial was a paradigm-shifting study in interventional cardiology. It proved that physiology-guided PCI using FFR is superior to anatomy-guided PCI using conventional angiography. By objectively identifying which intermediate lesions actually cause ischemia, FFR guidance safely prevents unnecessary stenting, reduces procedural costs and contrast use, and ultimately improves patient outcomes. This cemented a Class I guideline recommendation for the use of FFR in stable ischemic heart disease.

Historical Context

Historically, interventional cardiologists relied heavily on visual assessment during coronary angiography to decide which lesions to stent—a practice sometimes critiqued as the 'oculostenotic reflex.' Prior to FAME, the DEFER trial demonstrated that deferring PCI based on an FFR > 0.75 was safe in single-vessel disease. The FAME trial expanded on this by evaluating an FFR cut-off of 0.80 in complex multivessel disease, proving that visual angiographic severity often poorly correlates with true hemodynamic significance. This paved the way for modern physiological assessment and subsequent landmark trials like FAME 2, which compared FFR-guided PCI directly against optimal medical therapy.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is maximal hyperemia with an agent like adenosine required when measuring Fractional Flow Reserve (FFR), and how does this physiological measurement explain why angiographically severe lesions might not always require stenting?

Key Response

Adenosine causes maximal microvascular vasodilation, minimizing and stabilizing microvascular resistance. This ensures that the pressure gradient across the epicardial stenosis strictly reflects the resistance of the lesion itself, independent of autoregulation. This teaches the fundamental difference between 2D anatomical stenosis (angiography) and actual physiological ischemia (FFR), explaining why visually tight lesions may not actually restrict flow during peak demand.

Resident

You are evaluating an angiogram of a patient with stable angina and multivessel CAD showing a 70% stenosis in the mid-LAD and an 80% stenosis in the RCA. Based on the FAME trial, how should FFR alter your management strategy compared to relying on angiography alone?

Key Response

The FAME trial demonstrated that visual angiographic assessment often misjudges physiological lesion severity. By utilizing an FFR threshold of <0.80 to guide intervention, you safely avoid unnecessary stenting in lesions that are not physiologically flow-limiting (often the case even for 70-80% visual stenoses). This reduces the risks of periprocedural MI, subsequent stent thrombosis, and in-stent restenosis while decreasing procedural costs and contrast use.

Fellow

How does the presence of diffuse atherosclerosis or serial (tandem) lesions complicate the interpretation of FFR pullbacks, and what procedural adjustments must an interventionalist make when applying the FAME trial protocol in such anatomies?

Key Response

In tandem epicardial lesions, the FFR of one lesion is influenced by the presence of the other due to complex flow interactions and blunted hyperemic flow. Fellows must understand how to perform FFR pullbacks under continuous intravenous hyperemia to identify the largest pressure 'step-ups'. Crucially, treating the most severe lesion first will increase flow and alter the FFR of the remaining lesions, necessitating a repeat FFR measurement before deciding to stent the second lesion.

Attending

The FAME trial challenged the long-standing 'oculostenotic reflex' in interventional cardiology. As an attending, how do you balance the compelling physiological data of FFR-guided deferral against the anatomical complexity often seen in multivessel disease, particularly when managing patient expectations regarding 'fixing' all their blockages?

Key Response

Attendings must navigate the cognitive bias of leaving a visually severe (e.g., 75%) angiographic lesion untreated if the FFR is >0.80. The rationale emphasizes championing the paradigm shift from anatomy to physiology, teaching trainees that optimal medical therapy is superior for non-ischemic lesions, and counseling patients pre-procedure that 'more stents do not equal better outcomes'—in fact, unnecessary stenting introduces persistent hardware-related risks without symptomatic or prognostic benefit.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The FAME trial utilized a composite primary endpoint of death, MI, and repeat revascularization, but the trial was unblinded to the operators and patients. How might this lack of blinding have differentially influenced the 'repeat revascularization' component of the endpoint, and what trial design modifications could mitigate this bias?

Key Response

Unblinded operators and patients might have lower thresholds for pursuing repeat revascularization if they know a visually significant lesion was left medically treated based on FFR. This introduces performance and detection bias. A sham-controlled design (like the later ORBITA trial) or strict blinding of the physiological FFR data to the clinical follow-up team would strengthen internal validity and ensure that subsequent revascularizations were strictly driven by objective, protocol-defined ischemic events rather than operator anxiety.

Journal Editor

Given that the FAME trial exclusively used first-generation paclitaxel-eluting stents and enrolled patients with stable multivessel disease, what are the primary threats to external validity when extrapolating these results to contemporary practice with thinner-strut, second-generation DES or acute coronary syndrome presentations?

Key Response

First-generation DES had significantly higher rates of stent thrombosis and restenosis compared to modern stents. A seasoned reviewer would note that the absolute benefit of avoiding stents via FFR might be slightly attenuated today because modern stents carry a lower baseline risk of adverse events. Additionally, applying these findings to acute coronary syndromes requires editorial scrutiny, as transient microvascular dysfunction during an ACS can artificially elevate FFR, leading to inappropriate deferral of culprit or non-culprit lesions.

Guideline Committee

Based on the robust outcomes from FAME and subsequent trials like FAME 2, how should current ACC/AHA/SCAI and ESC guidelines grade the use of FFR for assessing angiographically intermediate stenoses in stable ischemic heart disease, and what specific evidence levels support this recommendation?

Key Response

The FAME trial directly informed and solidified current guidelines, elevating physiological assessment (FFR or iFR) to a Class 1, Level of Evidence A recommendation for assessing angiographically intermediate lesions (typically 40-90% stenosis) when non-invasive functional testing is unavailable or inconclusive. It established the paradigm that deferring PCI based on an FFR >0.80 is highly safe, improves clinical outcomes compared to angiography alone, and should be the standard of care for guiding revascularization in stable CAD.

Clinical Landscape

Noteworthy Related Trials

2001

DEFER Trial

n = 325 · JACC

Tested

Deferral of PCI

Population

Patients with intermediate coronary stenosis and FFR >= 0.75

Comparator

Performance of PCI

Endpoint

Event-free survival (freedom from death, MI, CABG, or repeat PCI)

Key result: There was no significant difference in event-free survival between deferring or performing PCI in lesions with FFR >= 0.75.

2012

FAME 2 Trial

n = 1,220 · NEJM

Tested

FFR-guided PCI plus optimal medical therapy

Population

Stable CAD patients with functionally significant stenosis (FFR <= 0.80)

Comparator

Optimal medical therapy alone

Endpoint

Composite of death, MI, or urgent revascularization

Key result: FFR-guided PCI significantly reduced the primary composite endpoint, driven primarily by a lower rate of urgent revascularization compared to medical therapy alone.

2020

ISCHEMIA Trial

n = 5,179 · NEJM

Tested

Routine invasive strategy (angiography and revascularization) plus optimal medical therapy

Population

Patients with stable CAD and moderate to severe ischemia on noninvasive testing

Comparator

Initial conservative strategy (optimal medical therapy alone)

Endpoint

Composite of CV death, MI, resuscitated cardiac arrest, hospitalization for heart failure, or unstable angina

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

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