Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 3 - FAME 3

Contribution To Literature:

Highlighted text has been updated as of December 22, 2023.

The FAME 3 trial demonstrated that FFR-guided PCI using current-generation DES did not meet criteria for noninferiority compared with CABG among patients with angiographic three-vessel disease.


The goal of the trial was to demonstrate the noninferiority of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) to coronary artery bypass grafting (CABG) for patients with three-vessel disease.

Study Design

Eligible patients were randomized in a 1:1 fashion to either FFR-guided PCI (n = 757) or CABG (n = 743). In the PCI arm, all lesions with FFR value ≤0.80 were stented with current-generation drug-eluting stents (DES). All patients were preloaded with P2Y12 inhibitors and high-dose statin. Post-PCI FFR measurement was recommended. DAPT was continued for at least 6 months. In the CABG arm, FFR could be pursued during diagnostic angiography but not mandated; decision to revascularize was based on the angiogram. Left internal mammary artery was required to be used in all cases, and complete arterial revascularization was recommended.

  • Total number of enrollees: 1,500
  • Duration of follow-up: 1 year
  • Mean patient age: 65 years
  • Percentage female: 18%
  • Race: white 93%

Inclusion criteria:

  • Angiographic ≥50% stenosis in three major epicardial vessels without left main involvement
  • Amenable to revascularization by both PCI and CABG

Exclusion criteria:

  • Cardiogenic shock
  • Recent ST-segment elevation myocardial infarction (STEMI) within 5 days
  • Left ventricular ejection fraction (LVEF) <30%

Other salient features/characteristics:

  • Diabetes: 28%
  • Acute coronary syndrome presentation: 40%
  • EF ≤50%: 18%
  • SYNTAX score 26 (low 33%, intermediate 49%)
  • ≤1 chronic total occlusion 22%
  • FFR measured in 82% in PCI arm; PCI deferred in 24% of lesions

Principal Findings:

The primary endpoint, major adverse cardiovascular and cerebrovascular events (MACCE; death, MI, stroke, repeat revascularization) at 1 year for PCI vs. CABG was: 10.6% vs. 6.9% (hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.1-2.2, p = 0.35 for noninferiority).

  • Death: 1.6% vs. 0.9%
  • MI: 5.2% vs. 3.5% (spontaneous MI: 3.3% vs. 2.3%)
  • Stroke: 0.9% vs. 1.1%
  • Repeat revascularization: 5.9% vs. 3.9%

Stratified by SYNTAX score for PCI vs. CABG:

  • Low SYNTAX (0-22): 5.5% vs. 8.6%, intermediate (23-32): 13.7% vs. 6.1%, high (>32): 12.1% vs. 6.6% (p = 0.02)

Secondary outcomes for PCI vs. CABG:

  • Bleeding Academic Research Consortium (BARC) 3-5 bleeding: 1.6% vs. 3.8% (p < 0.01)
  • Acute kidney injury: 0.1% vs. 0.9% (p < 0.04)
  • Atrial fibrillation/atrial arrhythmia: 2.4% vs. 14.1% (p < 0.001)
  • Definite stent thrombosis vs. symptomatic graft occlusion: 0.8% vs. 1.3%

Quality of life assessments: The European Quality of Life–5 Dimensions (EQ-5D) and its associated visual analogue scale were completed by each subject at baseline, 1 month, and 12 months of follow-up. For PCI vs. CABG: baseline: 0.827 vs. 0.821; 1 month: 0.891 vs. 0.830; 12 months: 0.874 vs. 0.873 (p = 0.95) (p-value for trajectory < 0.001). Canadian Cardiovascular Society angina grade ≥2 at 12 months: 6.2% vs. 3.1% (p > 0.05). Return to work in patients <65 years: 68% vs. 57% (p < 0.05).

Impact of post-PCI FFR and intravascular imaging: Among those randomized, 61% had a post-PCI measurement (43% one-vessel, 42% two-vessel and the remainder, three-vessel). Median post-PCI FFR was 0.89; 10% had post-PCI FFR of ≤0.8. At a cutoff value of 0.88 (vessel level) or 0.85 (patient level), post-PCI FFR was a significant predictor of target vessel failure. 11.1% had intravascular imaging post-PCI. The rate of cardiac death, all MI, or repeat revascularization was similar between patients who had intravascular imaging guidance and those who did not (p = 0.21).

Three-year outcomes for PCI vs. CABG:

  • MACCE: 12.0% vs. 9.2% (HR 1.3, 95% CI 0.98-1.83, p for superiority = 0.07)
  • All-cause mortality: 4.1% vs. 3.9% (p = 0.88)
  • Mortality from MI: 7.0% vs. 4.2% (p = 0.02)
  • Mortality from spontaneous MI: 5.2% vs. 3.0%
  • Repeat revascularization: 11.1% vs. 5.9% (p = 0.001)


The results of this trial indicate that FFR-guided PCI using current-generation DES did not meet criteria for noninferiority compared with CABG among patients with angiographic three-vessel disease. At 3 years, no difference was noted between the two arms but MI and repeat revascularization were both higher with PCI. These are important findings. Prior trials comparing PCI to CABG had used bare-metal stents or first-generation DES (SYNTAX) and did not incorporate systematic ischemic evaluation as was done here using FFR.

On subgroup analysis, there did appear to be benefit with PCI among patients with low SYNTAX scores (0-22). This is hypothesis generating and will need to be confirmed in subsequent studies. Also, the quality of life analyses suggest that patients regain functional status much sooner with PCI than with CABG, but no difference was noted at 12 months. An important limitation is the relatively short duration of follow-up (3 years) at this time; longer-term follow-up is awaited. Intravascular ultrasound/optical coherence tomography was used in only 12% of patients—this may help optimize PCI outcomes further. Patients with type 2 diabetes mellitus and low EF were also included—in these patients, CABG currently has a Class I indication as preferred mode of revascularization.


Zimmermann FM, Ding VY, Pijls NH, et al., on behalf of the FAME 3 Investigators. Fractional Flow Reserve–Guided PCI or Coronary Bypass Surgery for 3-Vessel Coronary Artery Disease: 3-Year Follow-Up of the FAME 3 Trial. Circulation 2023;148:950-8.

Piroth Z, Otsuki H, Zimmermann FM, et al., on behalf of the FAME 3 Investigators. Prognostic Value of Measuring Fractional Flow Reserve After Percutaneous Coronary Intervention in Patients With Complex Coronary Artery Disease: Insights From the FAME 3 Trial. Circ Cardiovasc Interv 2022;15:884-91.

Presented by Dr. Zsolt Piroth at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2022), Boston, MA, September 19, 2022.

Fearon WF, Zimmermann FM, Ding VY, et al., on behalf of the FAME 3 Investigators. Quality of Life After Fractional Flow Reserve-Guided PCI Compared With Coronary Bypass Surgery. Circulation 2022;145:1655-62.

Presented by Dr. William Fuller Fearon at the American College of Cardiology Annual Scientific Session (ACC 2022), Washington, DC, April 2, 2022.

Fearon WF, Zimmermann FM, De Bruyne B, et al., on behalf of the FAME 3 Investigators. Fractional Flow Reserve–Guided PCI as Compared With Coronary Bypass Surgery. N Engl J Med 2022;386:128-37.

Editorial: Welt FG. CABG versus PCI — End of the Debate? N Engl J Med 2022;386:185-7.

Presented by Dr. William F. Fearon at the Transcatheter Cardiovascular Therapeutics (TCT) Conference, Orlando, FL, November 4, 2021.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Interventions and ACS

Keywords: Acute Coronary Syndrome, Coronary Artery Bypass, Fractional Flow Reserve, Myocardial, Myocardial Infarction, Myocardial Revascularization, Percutaneous Coronary Intervention, Stroke, ACC22, TCT21, TCT22, Transcatheter Cardiovascular Therapeutics

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