Review of the FAME 3 trial
PCI vs bypass surgery for coronary artery disease
Background: Patients with three-vessel coronary artery disease have better outcomes when revascularization is performed using coronary artery bypass grafting (CABG) compared to percutaneous coronary intervention (PCI), as seen in the SYNTAX and FREEDOM trials. Fractional flow reserve (FFR) was not required and was not routinely performed in these trials.
The Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) 3 trial sought to compare the outcomes of FFR-guided PCI vs CABG in patients with three-vessel coronary artery disease.
Patients: Eligible patients had three-vessel coronary artery disease defined as 50% or more stenosis, by visual estimation, in any of the three major coronary arteries or major branches. Lesions had to be amenable to revascularization by PCI and CABG as determined by the heart team.
Major exclusion criteria were left main disease, cardiogenic shock, STEMI within 5 days, active NSTEMI with cardiac troponin still rising, left ventricular ejection fraction <30%, requiring renal replacement therapy or life expectancy < 2 years.
Baseline characteristics: The trial randomized 1,500 patients – 757 randomized to PCI and 743 to CABG.
The average age of patients was 65 years and 82% were men. The average body mass index was 29 kg/m2. Approximately 73% had hypertension, 70% had hyperlipidemia, 29% had diabetes, 33% had prior myocardial infarction, and 19% were current smokers. Approximately 39% presented with NSTEMI. The left ventricular ejection fraction was 50% or less 18% of the patients.
The mean SYNTAX score was 26. SYNTAX score was low (0 - 22) in 33% of the patients, intermediate (23 - 32) in 49% and high (33 or more) in 18%. Approximately 22% of the patients had at least one vessel with chronic total occlusion.
Procedures: Patients were randomly assigned in a 1:1 ratio to undergo CABG or FFR-guided PCI. CABG was performed based on the standard practice at each site with strong emphasis on achieving complete revascularization. While using FFR to guide CABG was not mandated, surgeons were permitted to incorporate FFR data into their decision-making if it was measured during the diagnostic angiography. All patients in the PCI arm underwent FFR and revascularization was performed for lesions with an FFR of 0.80 or less. PCI was performed using Resolute Integrity or Resolute Onyx drug-eluting stents made by Medtronic.
All patients received aspirin and high-intensity statin. Patients in the PCI arm received another antiplatelet for at least 6 months.
Follow-up was performed at hospital discharge and at 1, 6, and 12 months.
Endpoints: The primary endpoint was a composite of death from any cause, myocardial infarction, stroke or repeat revascularization at 1 year. Secondary endpoints included the components of the primary endpoint as well as major bleeding.
Analysis was performed based on the intention-to-treat principle. Sample size was calculated based on non-inferiority. The sample size to provided 90% power with one-sided alpha of 0.025 was 1,424 patients. The authors aimed to enroll 1,500 patients to account for loss to follow up and withdrawing from the trial. This calculation was based on an assumed 12% event rate of the primary outcome in the CABG arm at 1-year, and an upper bound of the 95% CI of the hazard ratio of less than 1.45. During the recruitment phase and without prior knowledge of event rates, the trial steering committee increased the noninferiority margin to an upper boundary of less than 1.65. Although, this meant that less patients are needed to be enrollment to have 90% power to claim non-inferiority, the steering committee elected to complete scheduled enrollment of 1,500 patients.
Results: Among the 757 patients randomized to PCI, 98% underwent the procedure. The mean number of stents implanted per patient was 3.7. Among the 743 patients randomized to CABG, 94% underwent surgery. The mean number of distal anastomosis per patient was 3.4 and 97% received left internal mammary artery graft.
The primary composite endpoint was higher in the PCI arm at 1-year (10.6% vs 6.9%, HR: 1.5, 95% CI: 1.1 – 2.2; p for non-inferiority= 0.35). Death was numerically higher with PCI (1.6% vs 0.9%, HR: 1.7, 95% CI: 0.7 – 4.3), as well as myocardial infarction (5.2% vs 3.5%, HR: 1.5, 95% CI: 0.9 – 2.5) and repeat revascularization (5.9% vs 3.9%, HR: 1.5, 95% CI: 0.9 – 2.3). Stroke was slightly numerically higher with CABG (1.1% vs 0.9%, HR: 0.9, 95% CI: 0.3 – 2.4).
Severe bleeding (type 3-5) based on the Bleeding Academic Research Consortium (BARC) was higher with CABG (3.8% vs 1.6%; p= 0.009). Acute kidney injury was also higher with CABG (0.9% vs 0.1%; p= 0.04).
Definite stent thrombosis occurred in 0.8% of the patients in the PCI arm and definite symptomatic graft occlusion occurred in 1.3% of the patients in the CABG arm.
The authors provided figure 2 in the manuscript for subgroup analysis of the primary outcome but P value for interactions was not provided.
Conclusion: In patients with three-vessel coronary artery disease, an FFR-guide PCI strategy did not meet criteria for non-inferiority compared to CABG, for the primary composite outcome of death from any cause, myocardial infarction, stroke or repeat revascularization at 1 year. The number need to treat (NNT) with CABG to prevent one primary composite outcome is approximately 27.
The authors published a 3-year follow up study. In this study, PCI also did not meet criteria for non-inferiority for the primary outcome. At 3-years, death and stroke were not significantly different between both treatment groups but PCI was associated with more myocardial infarctions (7.0% vs 4.2%; p= 0.02) and more repeat revascularization (11.1% vs 5.9%; p= 0.001). The NNT with CABG to prevent one primary composite outcome at 3-years is approximately 16.
This trial adds to existing evidence that patients with three-vessel coronary artery disease have better outcomes when revascularization is performed using CABG as compared to PCI, taking into consideration the inclusion criteria and baseline characteristics of patients in these trials. However, as we previously discussed, it is reasonable to expect that older patients with multiple comorbidities may derive less benefit with CABG.
The primary analysis of this trial was conducted at 1 year, with the difference in events favoring CABG becoming more pronounced at 3 years. This trend of improved outcomes with CABG with longer follow-up was also observed in the FREEDOM and EXCEL trials. Therefore, we recommend that future trials comparing CABG to other revascularization strategies should ideally follow up patients for at least 4 - 5 years.
I agree that longer follow-ups are needed in order to properly compare the treatment modalities. If I am reading it correctly, the 3 year follow-up shows that the "statistical significance" for the difference in the primary end points disappears at 3 years. I don't see any indication in the original paper whether the patients were symptomatic or not. It is my understanding from prior papers that CABG had slightly better numbers with symptomatic disease but none with asymptomatic. So that is a serious omission from the table of characteristics. Another aspect worthy of mention is that the End Point Table shows that the largest differences are in the Safety End Points: arrhythmias and hospitalizations in the first 30 days. Both favor the PCI group and they show a far greater difference as well as larger incidence than the differences in the primary end points. Does this cancel out the rather tiny difference in the primary end points? The description of the statistical methods in the original paper is somewhat confusing and this always starts my BS meter flashing red. Since the incidence of events is rather small, I can see no objection to running a study with a true control group i.e. no intervention.