Background: Fractional flow reserve (FFR) is a measure of the physiologic significance of a coronary stenosis that is defined as the ratio of maximal blood flow in a stenotic artery to normal maximal flow. It is measured during coronary angiography by calculating the ratio of distal coronary pressure measured with a coronary pressure guidewire to aortic pressure measured simultaneously with the guiding catheter. FFR in a normal coronary artery equals 1.0 whereas a value 90% and is similar to information obtained with stress imaging studies.
For patients with multivessel coronary disease, it can be a challenge in the cath lab to differentiate between blockages causing ischemia and those that are not and this may be especially challenging when patients have not undergone stress imaging prior (e.g., patients presenting with acute coronary syndromes without ST segment elevation). The FAME trial sought to test the hypothesis that revascularization guided by FFR would be superior to revascularization guided by angiography alone in a broad cohort of patients with multivessel disease in whom revascularization with PCI was indicated.
Patients: Patients with multivessel CAD of at least 50% of the vessel diameter in at least 2 of the 3 major epicardial coronary arteries in whom PCI was indicated. Patients with a STEMI could be included if the infarction occurred at least 5 days before PCI. Patients with a NSTEMI could be included earlier than 5 days. Patients who had undergone previous PCI could be included.
Patients were excluded if they had left main coronary disease, previous CABG, cardiogenic shock, extremely tortuous or calcified coronary arteries, a life expectancy less than 2 years, a contraindication to the placement of drug-eluting stents, or if patients were pregnant.
Baseline characteristics: Information is not provided on patients screened to enrolled. The average age of patients was 64.5 years and approximately three quarters were men. It is not clear from the main manuscript how many patients presented with acute MI’s. It appears that approximately one third of patients presented with unstable angina and about half of these patients had dynamic ECG changes. More than half of patients in the trial had class 2 angina or below. Approximately 25% of patients had diabetes and over 60% had hypertension. The average EF was 57%.
The mean number of lesions per patient was 2.8. About 40% of blockages were estimated to be in the 50-70% range, another 40% were in the 71-90% range, 15% were 91-99% narrowed and 3% were chronic total occlusions. The minimal luminal diameter was 1.0 mm, mean reference vessel diameter was 2.5 mm, mean lesion length was 12.5 mm and the SYNTAX score was 14.5.
Procedures: Patients were randomized after they were found to have multivessel disease, meeting the study criteria, and were thought to require PCI. Patients assigned to angiography-guided PCI underwent stenting of all indicated lesions with drug-eluting stents. Those assigned to FFR-guided PCI underwent FFR in each diseased coronary artery and drug-eluting stents were placed in lesions with FFR that was
All patients were treated with aspirin and clopidogrel for at least 1 year after PCI and if a patient underwent a repeat procedure during follow-up, the initially assigned strategy was followed in the case of stent placement. After discharge, a follow-up assessment was performed at 1 month, 6 months, and 1 year.
Endpoints: The primary endpoint was a composite of all-cause death, myocardial infarction, and any repeat revascularization at 1 year. Procedural MI’s were systematically assessed and included in the MI endpoint. Secondary endpoints included procedure time, contrast use, functional class at 1 year, health-related quality of life, the number of antianginal medications used, and individual components of the primary endpoint at 1 year as well as the rates of major adverse cardiovascular events at 30 days and 6 months. Cost effectiveness was also assessed.
A minimum sample size of 426 patients in each group was based on a two-sided chi-square test with an alpha level of 0.05 and a statistical power of 0.80, assuming 1-year rates of the primary endpoint of 14% in the angiography group and 8% in the FFR group, which equals a 6% absolute risk reduction and 43% relative risk reduction. The 14% event rate was based on outcome data in earlier studies of drug-eluting stents that were available in 2005 (RAVEL 2002, TAXUS-IV 2004).
Results: A total of 1,005 patients were enrolled in 20 centers in the United States and Europe of whom 496 were assigned to angiography-guided PCI and 509 were assigned to FFR-guided PCI. A total of 2,415 stents were placed with significantly more stents in the angiography-guided group (2.7+/-1.2 vs 1.9+/-1.3; p<0.001). In the FFR group, 874 lesions (64%) were ischemic based on FFR measurements and stents were placed, while 513 lesions (37%) were not and stents were not placed. The procedure time was similar between groups but significantly more contrast agent was used in the angiography-guided group.
Patients in the FFR-guided group were significantly less likely to experience the primary endpoint at 1-year (13.2% vs 18.3%; RR 0.72; 95% CI 0.54-0.96). This difference was based on 24 events and this translates to a Fragility Index of 4 - meaning, if 4 patients in the experimental group were converted from NOT having the primary endpoint to HAVING the primary endpoint, the study would lose statistical significance (p > 0.05). The number of patients lost to follow up in the FFR-guided group was higher than the fragility index (8 vs 4).
No statistically significant differences were noted in the rates of death, MI, repeat revascularization, functional status at 1 year, or the mean length of stay. The mean cost of materials used in the index procedure was $6,007 in the angiography-guided group and $5,332 in the FFR-guided group (p<0.001).
No subgroup information was provided in the main manuscript.
The 5-year results were published in 2016 and there was no difference in the primary endpoint (28% vs 31%, RR 0.91, 95% CI 0.75-1.10) or any major secondary endpoints.
Conclusions: In patients with multivessel CAD, in whom PCI is indicated and there is uncertainty regarding the significance of coronary lesions, an FFR-guided approach reduced coronary stent use (approximately 1 stent per patient) and reduced a composite endpoint of death, MI or repeat revascularization at 1 year compared to an angiography-guided approach with a NNT of approximately 20 patients. It should be noted that the treatment effect was associated with a fragility index of 4, which is not clinically robust and event rates in both the experimental and control groups were well above the assumed rates (it is usually the opposite). The results were not statistically significant at 5 years.
One design element of this trial, in particular, may have biased the results in favor the FFR-guided strategy and reduces confidence in the results. That was the inclusion of patients with lesions in the 50-70% range. It was NOT standard practice at the time to routinely stent such lesions as they were not felt to be ischemia-inducing. In clinical practice, such lesions may have been stented depending on the clinical circumstances, but to do it in all such cases was well beyond the standard of care. Such lesions accounted for 530 blockages (41%) in the angiography-guided group and 624 (44%) in the FFR-guided group. Ultimately, FFR-guided patients ended up with 379 less stents. A strategy of angiography guided PCI for blockages >70% vs FFR-guided strategy for blockages >50% would have been a better hypothesis test with more direct implications for patient care at the time.
The FAME trial provides evidence that PCI itself causes coronary events (at least over short-term follow-up) and the authors acknowledge this in the discussion. More stents equal more coronary events via procedural MI’s, in-stent thrombosis and in-stent restenosis. The authors believed FFR was a useful tool to determine lesions that needed revascularization or not; however, that hypothesis was not directly tested in this trial but was tested several years later in the FAME 2 trial that we have already reviewed. In FAME 2, PCI of FFR positive lesions did NOT reduce death or MI compared to up-front medical treatment alone but did reduce urgent revascularization. That particular endpoint comes with important caveats which we discussed in detail in our post.
In conclusion, the FAME trial showed that in select patients with multivessel CAD (based on blockages of >/=50% in 2 of 3 major epicardial coronary arteries) and an indication for PCI, that FFR-guidance may reduce stent use and improve outcomes over short-term follow-up. However, more data is needed to confirm this result and to distinguish patient populations most likely to benefit based on clinical indication for PCI and complexity of coronary anatomy.
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