FAME 2

Published

De Bruyne B, et al. "Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease". The New England Journal of Medicine. 2012. 367(11):991-1001.
PubMed • Full text • PDF

Clinical Question

Among patients with stable CAD with fractional flow reserve (FFR) ≤0.80, does PCI (including dual antiplatelet therapy) reduce the composite of all-cause mortality, non-fatal MI, or urgent revascularization when compared to optimal medical therapy (OMT) alone?

Bottom Line

Among patients with stable CAD with FFR ≤0.80, PCI reduces the composite rate of death, nonfatal MI, and urgent revascularization, compared to OMT alone, driven primarily by a reduction in urgent revascularization.

Major Points

Fractional flow reserve (FFR) identifies physiologically significant coronary stenoses by objectively measuring flow reduction caused by an atheroma rather than depending on traditional, more subjective angiographic visual inspection. The original FAME trial (2009) demonstrated that FFR-guided PCI was superior to the angiography-guided PCI of that era among patients with stable multivessel CAD.

Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) studied the role of PCI among 888 patients with stable single or multivessel CAD with physiologically significant coronary lesions. In contrast to FAME, FAME 2 focused on patients with FFR ≤0.80, comparing PCI to OMT alone. PCI yielded an 8% ARR of the primary endpoint, driven primarily by a reduction in urgent revascularizations.

Two year follow-up data published in 2014 showed an ongoing reduction in the primary endpoint, which was still driven by reduction in urgent revascularization. There was high crossover, with 41% of the OMT group receiving a stent vs. 8% in FFR receiving an additional stent. A post-hoc analysis which excluded periprocedural infarction at the index procedure in the PCI arm found a reduction in all-cause mortality or MI between 8 days and 2 years. As there was no difference between groups for this outcome between randomization and 2 years, the composite nature of the outcome, and the post-hoc design, its clinical significance is unclear.

Five year follow-up data published in 2018 (available in 19/28 centers), demonstrated a persistent 13.1% absolute reduction in the primary endpoint, although this remained driven by a reduction in urgent revascularizations. Interestingly, there was a trend toward decreased myocardial infarction in the group randomized to FFR-guided revascularization (3.9% absolute reduction), although the comparison did not reach statistical significance after correction for multiple testing. Angina severity was lower in patients randomized to FFR-guided PCI up to 3 years, but the difference was lost at 5 years; however, by this time 51% of patients randomized to medical therapy had crossed over to PCI. In summary, these findings demonstrate that FFR-guided PCI results in sustained clinical benefit over medical therapy specifically in terms of reducing the need for urgent revascularization. There is also a suggestion that FFR-guided PCI may reduce MI; however, this exploratory finding requires dedicated prospective study.

Guidelines

The 2011 ACC/AHA guidelines note that FFR may provide superior guidance for selection of physiologically significant lesions, and may in fact be better than intravascular ultrasound (IVUS) for this purpose as well. These guidelines provide a level IIa recommendation for FFR-guided PCI among patients with stable CAD.

Design

• Non-blinded, randomized, prospective, control trial
• N=888 patients with stable CAD undergoing PCI
  • FFR-guided PCI plus OMT (n=447)
  • OMT alone (n=441)
• Setting: 28 sites in Europe and North America
• Enrollment: 2010-2012 (stopped after interim analysis)
• Mean follow-up: 7 months
• Analysis: intention-to-treat
• Primary end point: composite of all-cause mortality, non-fatal MI, and unplanned hospitalization with urgent revascularization

Population

Inclusion Criteria

• Stable CAD with at least one of the following:
  • CCS angina class 1-3
  • CCS class 4 with medical stabilization for at least 7 days
  • ≥1 stenosis of ≥50% stenosis in ≥1 coronary artery with an artery diameter of ≥2.5mm with viable myocardium
• PCI candidate

Of note, patients with restenosis or previous stents were included. Those with 100% occlusion could be included if recanalization was likely and if there were another significant lesion based on FFR.

Exclusion Criteria

• Age <21 years
• CABG indicated
• Left main disease
• STEMI or NSTEMI in <7 days
• Dual antiplatelet therapy contraindicated
• LVEF <30%
• Severe LVH
• Planned valvular or aortic surgery
• Arteries not amenable to FFR measurement (i.e., tortuous or calcified)
• Life expectancy <2 years
• Current or pregnancy planned during trial duration
• Inability to consent
• Potential for non-compliance
• Enrollment (or planned enrollment in 2 years) in another cardiac clinical trial

Baseline Characteristics

Data from the PCI group, which was similar to OMT-only group except where specified.

• Demographics: Age 63.5 years, male 79.6%
• Baseline health data: BMI 28.29 kg/m², LVEF <50% 19.6% PCI+OMT vs. 13.7% OMT (P=0.04)
• Family history of CAD: 48.3%
• PMH: Smokers 19.9%, HTN 77.6%, HLD 73.8%, DM 27.5% (8.7% insulin dependent), renal insufficiency 1.8%, PVD 9.6%, CVA or TIA 7.4%, MI 37.1%
• PSH: PCI in involved vessel 17.9%
• Angina:
  • Asymptomatic: 11.9%
  • CCS class I: 18.3%
  • CCS class II: 45.6%
  • CCS class III: 17.9%
  • CCS class IV (stabilized): 6.3%
• "Silent ischemia": 16.3%
• Angiography:
  • Significant lesions: 1.87/patient
  • Amount of vessels with ≥1 significant lesion:
    • 1: 56.2%
    • 2: 34.9%
    • 3: 8.9%
  • ≥1 proximal or middle LAD lesion: 65.1%
  • Lesion-specific:
    • Degree of stenosis:
      • <50%: 6%
      • 50-69%: 35.6%
      • 70-90%: 43.0%
      • >90%: 11.3%
      • 100%: 4.0%
• FFR:
  • "Functionally significant lesions": 1.52/patient
  • Amount of vessels with ≥1 significant lesion:
    • 1: 74.0%
    • 2: 22.8%
    • 3: 3.1%
  • ≥1 proximal or middle LAD lesion: 62.4%
  • FFR ≤0.80: 76.3% (of these, mean FFR was 0.68)

Interventions

General strategy:

• All patients had coronary disease assessed angiographically, with assessment of FFR in diseased vessels
• Patients with physiologically significant lesions in ≥1 vessel (ie, FFR ≤0.80) were randomized to either PCI plus OMT or OMT alone
• Patients with FFR >0.8 were not part of the randomized element of the study; they were treated with OMT alone

Optimal medical therapy:

• Aspirin (80-325mg daily)
• Beta-1 selective blocker (eg, metoprolol 50 to 200mg daily) ± CCB
• ACE inhibitor (eg, lisinopril ≥5mg daily) or ARB
• Statin (eg, atorvastatin 20 to 80mg daily) ± ezetimibe titrated to LDL <70 mg/dL
• Smoking cessation counseling for smokers
• Diabetic specialist referral for diabetics

In addition, the PCI group received:

• Clopidogrel loading dose (600mg orally once) and aspirin before procedure
• Clopidogrel 75mg daily for ≥1 year

Follow-up:

• Baseline EKG, cardiac enzymes
• Visits at month 1, month 6, and then annually for 5 years
  • Evaluation of angina, work status, medication reconciliation, resting EKG, lipid panel
  • Completion of European Quality of Life-5 Dimensions tool
  • Assessment of patient's utilization of medical resources

Outcomes

Comparisons are FFR-guided PCI vs. OMT alone.

Primary Outcomes

All-cause mortality, non-fatal MI, or unplanned hospitalization with urgent revascularization

4.3% vs. 12.7% (HR 0.32; 95% CI 0.19-0.53; P<0.001)

Secondary Outcomes

All-cause mortality

0.2% vs. 0.7% (HR 0.33; 95% CI 0.03-3.17; P=0.31)

Non-fatal MI

3.4% vs. 3.2% (HR 1.05; 95% CI 0.51-2.19; P=0.89)

Urgent revascularization

1.6% vs. 11.1% (HR 0.13; 95% CI 0.06-0.30; P<0.001)

Death or MI

3.4% vs. 3.9% (HR 0.61; 95% CI 0.28-1.35; P=0.22)

CV death

0.2% vs. 0.2% (HR 0.96; 95% CI 0.06-15.17; P=0.98)

Any revascularization

3.1% vs. 19.5% (HR 0.14; 95% CI 0.08-0.26; P<0.001)

Non-urgent revascularization

1.6% vs. 8.6% (HR 0.17; 95% CI 0.08-0.39; P=0.56)

Angina class II to IV

12 months - 2.4% vs. 16.2% (HR 0.15; 95% CI 0.02-1.19; P=0.07)

Adverse Events

Stroke

0.2% vs. 0.5% (HR 0.49; 95% CI 0.04-5.50; P=0.56)

Stent thrombosis, definite or probable

1.1% vs. 0.2% (HR 4.98; 95% CI 0.59-42.25; P=0.10)

Subgroup Analysis

Primary endpoint by FFR - interaction P-value = 0.01

FFR <0.65 - 3.1% vs. 17.1% (HR 0.08; 95% CI 0.03-0.26; P not given)

FFR ≥0.65 - 5.4% vs. 8.9% (HR 0.46; 95% CI 0.21-1.01; P not given)

Criticisms

• Patients were not blinded to the presence of a lesion believed to be hemodynamically significant. The great majority of events were revascularisations performed based on symptoms, and they occurred mainly in the early half of the trial.
• The PCI arm received not only stents but dual antiplatelet therapy. The OMT arm received neither. This might have artificially reduced the event rate in the PCI arm. Bleeding events were not counted, and therefore any potential benefit in the OMT arm of not having dual antiplatelet therapy could not be assessed.
• Enrollment was prematurely closed, limiting the length of the follow-up
• OMT did not include lifestyle changes directed by nurse care managers like in COURAGE

Funding

St. Jude Medical

Further Reading

• NEJM Letters to the Editor