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Tonino PAL, et al. "Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention". The New England Journal of Medicine. 2009. 360(3):213-224.
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Clinical Question

In patients with multivessel CAD, does a fractional flow reserve (FFR)-guided PCI reduce death, nonfatal MI, and repeat revascularization compared to PCI alone?

Bottom Line

In patients with multivessel CAD, an FFR-guided approach reduces the composite of death, nonfatal MI, and repeat revascularization at one year compared to PCI alone.

Major Points

The role of coronary revascularization in reducing symptoms, MI and death has been amply studied in ACS, but its role in stable CAD has remained elusive. One problem is that conventional PCI has traditionally relied upon angiographic analysis of lesions. For example, COURAGE (2007) and SYNTAX (2009) respectively studied PCI and CABG for stable CAD, and failed to demonstrate a benefit with routine revascularization of unselected coronary lesions when compared to optimal medical therapy (OMT) alone. This led some investigators to speculate that the null results came about from PCI to vessels not inducing ischemia. What followed were studies of targeted revascularization of physiologically significant lesions. Fractional flow reserve (FFR), the mean distal pressure of the diseased coronary artery divided by mean aortic pressure, was developed in the early 1990s as a means of selecting physiologically significant lesions. DEFER (2001) demonstrated that coronary revascularization could be safely deferred when lesions had an FFR greater than 0.75.[1] The Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) investigators hypothesized that FFR-guided revascularization of physiologically significant lesions could improve outcomes in stable CAD when compared to conventional angiography-guided PCI.

FAME randomized 1,005 patients undergoing routine PCI for stable multivessel CAD to either FFR-guided or angiography-guided PCI, with both groups receiving OMT. FFR-guided PCI was performed only on lesions with FFR ≤0.80. At 1 year, FFR-guided PCI reduced the primary composite end point of death, MI, or repeat revascularization compared to angiography-guided PCI (13.2% vs. 18.3%). FFR-guided PCI was also associated with a trend towards reductions in each of the individual end points of mortality (1.8% vs. 3.0%), MI (5.7% vs. 8.7%), and repeat revascularization (6.5% vs. 9.5%). The follow-up study, FAME 2 (2012), served to challenge COURAGE by using FFR and demonstrated reduction in urgent revascularization when compared to medical therapy alone.


  • Multicenter, adjudicator-blinded, parallel-group, randomized, controlled trial
  • N=1,005
    • FFR-guided PCI (n=509)
    • Angiography-guided PCI (n=496)
  • Setting: 20 centers in Europe and the US
  • Enrollment: 2006-2007
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary endpoint: Death, MI and repeat revascularization at 1 year


Inclusion Criteria

  • Age ≥18 years
  • Multivessel CAD, defined as ≥2 major coronary arteries with stenoses ≥50%, with an investigator-determined indication for PCI

Exclusion Criteria

  • STEMI ≤5 days prior
  • NSTEMI ≤5 days prior if CK >1000 U/L
  • Significant left main disease
  • Previous CABG
  • Cardiogenic shock
  • Extremely tortuous or calcified coronary arteries
  • Life expectancy ≤2 years
  • Contraindication to DES
  • Pregnancy

Baseline Characteristics


  • Age: 64.4 years
  • Female: 26%


  • Angina class:
    • I: 24.6%
    • II: 33.4%
    • III: 24.9%
    • IV: 17.2%
  • Previous MI: 36.5%
  • Previous PCI: 27.4%
  • DM: 24.7%
  • HTN: 63.6%
  • HLD: 72.4%
  • Family history of CAD: 39.3%
  • Current smoker: 29.3%
  • Unstable angina with dynamic EKG changes: 16.3%
  • Unstable angina without dynamic EKG changes: 16.3%
  • LVEF: 57.2%
  • EQ-5D score: 64.7 (0=low, 100=perfect)


  • ASA: 91.4%
  • Statin: 81.0%
  • ß-blocker: 76.8%
  • Clopidogrel: 59.9%
  • ACE-inhibitor/ARB: 52.0%
  • CCB: 21.6%
  • Nitrate: 34.4%

Angiographic Findings:

  • Lesions per patient: 2.8
  • 50-70% narrowing: 42.4% of lesions
  • 71-90% narrowing: 39.2% of lesions
  • 91-99% narrowing: 14.8% of lesions
  • Total occlusion (FFR=0.50): 3.6% of lesions
  • Average narrowing: 60.8%
  • Minimal luminal diameter: 1.0 mm
  • Diameter of reference lumen: 2.5 mm
  • Lesion length: 12.5 mm
  • SYNTAX score: 14.5 (0=no angiographic evidence of narrowing, 14.5=extensive disease)


  • Assessment of baseline angina, European Quality of Life-5 Dimension (EQ-5D) score, EKG
  • Randomized to:
    • FFR-guided PCI: DES stents in indicated lesions only if FFR ≤0.80
    • Angiography-guided PCI: DES stents of all indicated lesions
  • Cardiac enzymes measured at 12 and 24 hrs following PCI; EKG within 24 hrs and at 1 yr
  • Follow up at 1 month, 6 months, and 1 year
  • All patients treated with aspirin and clopidogrel for ≥1 year
  • If repeat angiography during followup, same strategy of FFR-guided vs. angiography-guided was repeated for stenting


Comparisons are FFR vs. angiography group at one year.

Primary Outcomes

Composite of death, MI, or repeat vascularization
13.2% vs. 18.3% (RR 0.72; 95% CI 0.54-0.96; P=0.02; NNT=20)

Secondary Outcomes

1.8% vs. 3.0% (RR 0.58; 95% CI 0.26-1.32; P=0.58)
5.7% vs. 8.7% (RR 0.66; 95% CI 0.42-1.04; P=0.07)
Repeat vascularization
6.5% vs. 9.5% (RR 0.68; 95% CI 0.45-1.05; P=0.08)
Death or MI (post-hoc)
7.3% vs. 11.1% (RR 0.66; 95% CI 0.44-0.98, P=0.04)
Patients without event and free from angina
73.0% vs. 67.6% (P=0.07)
Patients free from angina
81.3% vs. 77.9% (P=0.20)
Antianginal medications
1.20 vs. 1.23 (P=0.48)
Score on EQ-5D visual-analogue scale
74.5 vs. 73.7 (P=0.65)

Results of PCI

Comparisons are FFR vs. angiography group.

Procedure time
71 vs. 70 mins (P=0.51)
Volume of contrast agent used
272 vs. 302 cc (P<0.001)
Stents per patient
1.9 vs. 2.7 (P<0.001)
Total length stented per patient
37.9 vs. 51.9 mm (P<0.001)
Cost of materials
$5,332 vs. $6,007 (P<0.001)
Mean LOS
3.4 vs. 3.7 days (P=0.05)


  • Did not adequately describe method of selecting vessels appropriate for PCI.[2]
  • Authors note that the threshold FFR of ≤0.80 was used, rather than a range of 0.75-0.80 as in prior studies, to signify physiologically significant stenoses.
  • Between-group differences may be related to stenting of inappropriate lesions rather than to FFR-guided PCI.[3]


  • Radi Medical Systems
  • Stichting Vrienden van het Hart Zuidoost Brabant
  • Medtronic matched the price of Endeavour stents to local reimbursements at some sites
  • Authors with multiple conflicts of interest

Further Reading

  1. Bech GJW, et al. "Fractional Flow Reserve to Determine the Appropriateness of Angioplasty in Moderate Coronary Stenosis." Circulation. 2001;103: 2928-2934.
  2. Ellis SG. "Refining the art and science of coronary stenting." NEJM. 2009;360(3):292-4.
  3. Letters to the editor regarding FAME