Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2 - FAME 2

Jul 19, 2018
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
St. Jude Medical
Date Presented:
11/02/2017
Date Published:
05/22/2018
Date Updated:
07/19/2018
Original Posted Date:
07/19/2018
References

Contribution To Literature:

The FAME 2 trial showed that in patients with angiographic evidence of coronary artery disease, FFR-guided PCI in addition to OMT is superior to OMT alone in the management of patients with stable angina.

Description:

The landmark COURAGE trial demonstrated that percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) was not superior to OMT alone in the initial management of patients with stable angina. The current trial sought to study if there would be a difference in outcomes after fractional flow reserve (FFR)-guided PCI with OMT versus OMT alone in patients with stable angina.


Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Patients with either stable angina, stabilized angina pectoris, or atypical chest pain or no chest pain, but with documented silent ischemia
  • At least one stenosis is present, of at least 50% in one major native epicardial coronary artery and supplying viable myocardium
  • Eligible for PCI

    Number of screened applicants: 1,220
    Number of enrollees: 888
    Duration of follow-up: mean 214 days; 2, 3, and 5 years 
    Mean patient age: 63.7 years
    Percentage female: 22%

Exclusions:

  • Patients in whom the preferred treatment is coronary artery bypass grafting (CABG)
  • Patients with left main coronary artery disease requiring revascularization
  • Patients with a recent ST-elevation MI (STEMI) or non-STEMI
  • Prior CABG
  • Contraindication to dual antiplatelet therapy
  • Left ventricular (LV) ejection fraction <30%
  • Severe LV hypertrophy
  • Planned need for concomitant cardiac surgery
  • Extremely tortuous or calcified coronary arteries precluding FFR measurements
  • A life expectancy of less than 2 years
  • Age under 21 years

Primary Endpoints:

  • MACE (death, MI, unplanned hospitalization leading to revascularization) at 24 months

Secondary Endpoints:

  • Overall MACE at 5 years
  • Nonurgent revascularization procedures
  • Cost and cost-effectiveness
  • Functional class
  • Number of antianginal medications
  • Rate of nonurgent revascularization
  • Rate of cerebrovascular events

Drug/Procedures Used:

Stable patients who were appropriate candidates for PCI and who had angiographic evidence of coronary artery disease were included. If FFR was ≤0.80, they were randomized to either PCI or OMT. If FFR was >0.80, they were included in a registry. All patients undergoing PCI received newer generation drug-eluting stents.

Concomitant Medications:

All patients were treated with aspirin 80-325 mg daily, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, and statins. In patients randomized to PCI, loading doses of 325 mg aspirin and 600 mg clopidogrel were administered prior to PCI. All PCI patients received a minimum of 75 mg daily of clopidogrel for 12 months.

Principal Findings:

A total of 888 patients were enrolled at 28 centers. The trial was terminated early after interim analyses demonstrated a clear benefit of the PCI + OMT arm over the OMT arm. At this time, 447 patients had been randomized to PCI + OMT and 441 to OMT alone. Baseline characteristics were fairly similar between the two arms. Approximately 27% had diabetes mellitus, 10% with peripheral arterial disease, 37% with prior myocardial infarction (MI), and 17.5% with prior PCI in the target vessel. The majority of patients had Canadian Cardiovascular Society (CCS) class II angina (45%); about 7% had class IV symptoms, and 20% had class I symptoms. Approximately 57% had one-vessel disease, and 34% had two-vessel disease, with proximal/mid left anterior descending artery involvement in 65%. In the PCI arm, 1,601 stenoses were considered, of which 1,304 (76.3%) had an FFR ≤0.80.

The primary MACE endpoint of death/MI/urgent revascularization was significantly lower in the PCI + OMT arm compared with the OMT arm (4.3% vs. 12.7%, hazard ratio 0.32, 95% confidence interval [CI] 0.19-0.53, p < 0.001). This was driven predominantly by a significant reduction in the need for urgent revascularization (1.6% vs. 11.1%, p < 0.001); rates of death (0.2% vs. 0.7%, p = 0.31) and MI (3.4% vs. 3.2%, p = 0.89) were similar. Urgent revascularization was performed for unstable angina (51.8%), MI (21.4%), and unstable angina with evidence of ischemia on electrocardiography (26.8%). Nonurgent revascularizations were also lower in the FFR arm (1.6% vs. 8.6%, p < 0.001).

On landmark analysis, results were more pronounced after 7 days following randomization compared with before. Results were similar in various subgroups tested. In particular, patients with FFR lesion values <0.65 appeared to derive an even greater benefit (p for interaction = 0.01). There was a significant improvement in CCS angina class from baseline in the PCI + OMT arm, as compared with the OMT arm at 30 days and 6 months.

The overall event rate in the registry patients was 3%, which was similar to the event rate in the PCI + OMT arm (p = 0.61), but lower than that in the OMT arm (p < 0.001).

Two-year results: Results for the primary endpoint were sustained at 2 years of follow-up for PCI + OMT vs. OMT (8.1% vs. 19.5%, HR 0.39, 95% CI 0.26-0.57, p < 0.001). Death (1.3% vs. 1.8%, p = 0.58), MI (5.8% vs. 6.8%, p = 0.56), and death/MI (6.5% vs. 8.2%, p = 0.35) were similar between the two arms. Revascularization rates were significantly lower in the PCI arm (8.1% vs. 40.6%, p < 0.001). On landmark analysis at 7 days, the primary endpoint was still significantly lower in the PCI + OMT arm (HR 0.29, 95% CI 0.18-0.45, p for interaction < 0.001). Death or MI were also lower on landmark analysis at 7 days (HR 0.56, 95% CI 0.32-0.97, p for interaction = 0.002).

Patients in whom revascularization was not performed (n = 607) were divided into four groups based on FFR ≤/>0.8 and degree of stenosis (DS) </≥50%. The rate of VOCE (vessel-oriented clinical endpoint, i.e. cardiac death/vessel-related MI, vessel-related revascularization) was highest in the group with FFR ≤0.8 and DS ≥50%, and lowest in the group with FFR >0.8 and DS <50%. Having an FFR ≤0.8 had a greater impact on 2-year outcomes than DS.

Cost-effectiveness analysis: Direct medical costs were higher in the PCI arm at baseline ($9,927 vs. $3,900). This decreased over the duration of follow-up; final costs were $12,646 vs. $9,763 between the two arms. This corresponded to a 3-year (extrapolated) cost-effectiveness of $36,000/quality-adjusted life-year (QALY), an amount consistent with current benchmarks for cost-effectiveness.

FFR immediately post-PCI (residual FFR burden) was measured in approximately two-thirds of the patients (median 0.9). At 2 years, the risk of vessel-related death, MI, or revascularization was lowest in patients with a post-PCI FFR of 0.92 or higher, primarily driven by a reduction in the need for revascularization.

Three-year results: Results for the primary endpoint were sustained at 2 years of follow-up for PCI + OMT vs. OMT (10.1% vs. 22.0%, p < 0.001). Death (2.7% vs. 3.6%, p = 0.43), MI (6.3% vs. 7.7%, p = 0.41), and death/MI (8.3% vs. 10.4%, p = 0.28) were similar between the two arms. Revascularization rates were significantly lower in the PCI arm (10.3% vs. 44.2%, p < 0.001), mainly due to nonurgent revascularization (6.3% vs. 30.2%, p < 0.001). Three-year total costs were similar ($16,792 vs. $16,737, p = 0.94). At 3-year follow-up, the incremental cost-effectiveness ratio (ICER) for PCI compared with medical therapy was $1,600/QALY.

Five-year results: Results for the primary endpoint were sustained at 5 years of follow-up for PCI + OMT vs. OMT (13.9% vs. 27.0%, p < 0.001). Death (5.1% vs. 5.2%, HR 0.98, 95% CI 0.55-1.75) and MI (8.1% vs. 12.0%, HR 0.66, 95% CI 0.43-1.0) were similar. Urgent revascularization rates were significantly lower in the PCI arm (6.3% vs. 21.1%, HR 0.27, 95% CI 0.18-0.41).

Interpretation:

The results of this trial indicate that, in patients with angiographic evidence of coronary artery disease, FFR-guided PCI in addition to OMT is superior to OMT alone in the management of patients with stable angina. This difference is driven by a significant reduction in the need for urgent revascularization for acute coronary syndrome symptoms. There is also a significant improvement in angina symptoms up to 5 years of follow-up. Based on the registry results, it also appears that in patients with evidence of angiographically significant disease, but negative FFR, OMT alone is associated with low event rates.

The FAME 2 results thus indicate that the presence of significant demonstrable ischemia (as noted by a positive FFR test) is important to risk-stratify patients before pursuing PCI. Results of the landmark analysis at 7 days demonstrate a significant reduction in not just the composite endpoint, but also death/MI at 2 years. These results are very interesting and hypothesis generating.

These are very important results and are likely to significantly impact the management of patients with stable angina. Following the results of the COURAGE trial, there was a significant decline in the number of patients undergoing PCI for stable angina. One reason for the discrepancy between this trial and COURAGE is that the current trial only included truly ischemic lesions, not just those that were angiographically significant as in the COURAGE trial. Earlier trials such as FAME and DEFER have demonstrated the pitfalls of relying on angiographic severity alone to judge hemodynamic significance.

A couple of limitations warrant mention. The mandated mean follow-up was very short—approximately 7 months. Thus, it was too short to study meaningful differences in hard endpoints such as death or MI, and also for assessing the impact of restenosis in the PCI arm. Thus, it will remain a point of discussion that the Data Safety Monitoring Board terminated this trial early based on differences in unplanned revascularization between the two arms, since rates of death and MI were similar. The practicality and cost-effectiveness of FFR-guided PCI for every stable angina lesion will need to be further studied.

The cost-effectiveness analysis suggests that an FFR-guided PCI strategy is cost-effective at 3 years. Various model assumptions and extrapolations were made, which will need to be validated in future studies.

References:

Xaplanteris P, Fournier S, Pijls NH, et al., on behalf of the FAME 2 Investigators. Five-Year Outcomes With PCI Guided by Fractional Flow Reserve. N Engl J Med 2018;379:250-9.

Ciccarelli G, Barbato E, Toth GG, et al. Angiography versus Hemodynamics to Predict the Natural History of Coronary Stenoses: A FAME 2-Substudy. Circulation 2017;Nov 21:[Epub ahead of print].

Fearon W, Nishi T, De Bruyne B, et al. Clinical Outcomes and Cost-Effectiveness of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease: Three-Year Follow-Up of the FAME 2 Trial. Circulation 2017;Nov 2:[Epub ahead of print].

Presented by Dr. William F. Fearon at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2017), Denver, CO, November 2, 2017.

Presented by Dr. Zsolt Piroth at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2016), Washington, DC, October 29, 2016.

De Bruyne B, Fearon WF, Pijls NH, et al., on behalf of the FAME 2 Trial Investigators. Fractional Flow Reserve-Guided PCI for Stable Coronary Artery Disease. N Engl J Med 2014;371:1208-17.

Presented by Dr. Bernard de Bruyne at the European Society of Cardiology Congress, Barcelona, Spain, September 1, 2014.

De Bruyne B, Pijls NH, Kalesan B, et al., on behalf of the FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991-1001.

Fearon WF, Shilane D, Pijls NH, et al., on behalf of the FAME 2 Investigators. Cost-Effectiveness of Percutaneous Coronary Intervention in Patients with Stable Coronary Disease and Abnormal Fractional Flow Reserve. Circulation 2013;Aug 14:[Epub ahead of print].

Presented by Dr. Bernard De Bruyne at the European Society of Cardiology Congress, Munich, Germany, August 28, 2012.

Presented by Dr. William Fearon at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2012), Miami, FL, October 24, 2012.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Cardiac Surgery and SIHD, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Chronic Angina

Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Follow-Up Studies, Angina, Stable, Drug-Eluting Stents, Clinical Trials Data Monitoring Committees, Peripheral Arterial Disease, Constriction, Pathologic, Electrocardiography, Myocardium, Hemodynamics, Percutaneous Coronary Intervention, Registries, Chest Pain, Myocardial Revascularization, Confidence Intervals, Diabetes Mellitus, Quality-Adjusted Life Years, ESC Congress, TCT17, Transcatheter Cardiovascular Therapeutics, Angina, Stable


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