Introduction
The management of stable coronary artery disease (CAD) has been a subject of intense debate within the cardiology community for decades. While medical therapy remains the cornerstone of treatment, the role of revascularization—specifically percutaneous coronary intervention (PCI)—has faced scrutiny regarding its long-term impact on hard clinical endpoints. The landmark Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial was designed to address whether a physiology-guided approach to PCI could offer superior outcomes compared to optimal medical therapy (OMT) alone in patients with hemodynamically significant stenoses. Now, with long-term data reaching a median follow-up of 11.2 years, the results provide a definitive perspective on the enduring benefits of FFR-guided intervention.
Highlights
The long-term analysis of the FAME 2 trial yields several critical insights for clinical practice:
Superiority in Composite Outcomes
FFR-guided PCI significantly reduced the primary composite outcome of death, myocardial infarction (MI), or urgent revascularization over an 11-year period compared to medical therapy alone.
The Win Ratio Advantage
Utilizing a hierarchical win ratio analysis, PCI demonstrated a clear statistical advantage (Win Ratio 1.25), prioritizing the most severe clinical outcomes such as mortality.
Reduction in Urgent Revascularization
The primary driver of the benefit remained a profound reduction in the need for urgent revascularization, highlighting the stability afforded by physiology-guided stenting.
Long-term Safety and Efficacy
The results reaffirm that identifying ischemia-producing lesions via FFR is a durable strategy for selecting patients who will benefit most from invasive intervention.
Background: The Shift from Anatomy to Physiology
Historically, the decision to perform PCI was based on visual estimates of stenosis severity during coronary angiography. However, anatomical narrowing does not always correlate with functional ischemia. The introduction of Fractional Flow Reserve (FFR) allowed clinicians to measure the pressure drop across a stenosis, identifying lesions that actually restrict blood flow (typically defined as FFR ≤ 0.80). The original FAME 2 trial sought to determine if treating only these hemodynamically significant lesions with PCI plus OMT was superior to OMT alone. The trial was famously halted early by the Data Safety Monitoring Board due to a highly significant reduction in urgent revascularizations in the PCI group, raising questions about the long-term durability of this early benefit.
Study Design and Methodology
The FAME 2 trial was a multicenter, randomized controlled trial involving 16 hospitals across Europe and North America. The study included patients with stable CAD in whom at least one stenotic lesion was found to be hemodynamically significant (FFR ≤ 0.80). Patients were randomized in a 1:1 ratio to receive FFR-guided PCI plus OMT (n = 447) or OMT alone (n = 441).
Long-Term Follow-Up
The long-term follow-up study involved 748 of the original randomized patients, with a median follow-up duration of 11.2 years. This extended timeframe is crucial for evaluating late-term catch-up phenomena or potential late complications associated with drug-eluting stents.
Statistical Innovation: The Win Ratio
To address the complexities of long-term data, including missing non-fatal data in patients who died, the investigators employed the unstratified win ratio. This hierarchical approach prioritizes the most clinically significant events (death > MI > urgent revascularization). In this model, every patient in the PCI group is compared to every patient in the OMT group. A ‘win’ occurs if a patient in one group experiences a primary event later than the patient in the comparison group or not at all.
Key Findings: A Decade of Evidence
At the 11.2-year mark, the primary composite endpoint occurred in 33.6% of the PCI group compared to 41.3% in the medical therapy group.
The Win Ratio Analysis
The hierarchical win ratio was 1.25 (95% CI 1.01-1.56, P = 0.043), favoring the PCI group. This indicates that for any given patient pair, the one receiving FFR-guided PCI was 25% more likely to have a better clinical outcome than the one receiving OMT alone. The win difference was calculated at 5.9%, and the number needed to treat (NNT) to prevent one composite event was 17.
Component Analysis
Breaking down the composite endpoint provided more granular detail:
All-Cause Mortality
The win ratio for death was 0.88 (95% CI 0.66-1.17), showing no statistically significant difference between the two groups. While PCI did not lower the risk of death, it also did not increase it, confirming the long-term safety of the procedure.
Myocardial Infarction
The win ratio for MI was 1.50 (95% CI 0.98-2.31). While showing a trend toward fewer MIs in the PCI group, it did not reach the threshold for statistical significance at this long-term interval.
Urgent Revascularization
The most dramatic difference was seen here, with a win ratio of 4.57 (95% CI 2.53-8.24). This underscores that patients treated with OMT alone were more than four times as likely to require an emergency or urgent return to the catheterization lab due to unstable symptoms or acute coronary syndromes.
Expert Commentary and Clinical Context
The long-term results of FAME 2 must be interpreted alongside other major trials like ISCHEMIA. While the ISCHEMIA trial did not show a reduction in the primary composite endpoint with an initial invasive strategy, FAME 2 differs in its inclusion criteria—specifically, it required documented hemodynamic significance via FFR before randomization. This suggests that the precision of physiological assessment is key to identifying the subset of stable CAD patients who truly benefit from revascularization.
The Significance of Urgent Revascularization
Some critics argue that urgent revascularization is a ‘softer’ endpoint than death or MI. However, from a patient-centered and healthcare-system perspective, preventing an urgent, unplanned hospitalization for unstable angina or worsening ischemia is a major clinical victory. The FAME 2 data suggests that by ‘pre-emptively’ treating flow-restricting lesions, clinicians can prevent these acute deteriorations.
Limitations
The trial’s early termination for benefit may have affected the power to detect differences in mortality. Additionally, as with any long-term study, the technology of PCI (stent platforms and pharmacology) has evolved since the trial’s inception, meaning modern outcomes might be even more favorable.
Conclusion
The 11-year results of the FAME 2 trial provide robust, long-term evidence that FFR-guided PCI is superior to medical therapy alone in patients with stable CAD and hemodynamically significant stenoses. While the benefit is primarily driven by a reduction in urgent revascularization, the use of the win ratio demonstrates a consistent hierarchical advantage for the invasive strategy. These findings reinforce the clinical value of physiological lesion assessment and support the continued use of FFR-guided PCI to improve the long-term stability and outcomes of patients with symptomatic CAD.
Funding and ClinicalTrials.gov
The FAME 2 trial was supported by St. Jude Medical (now Abbott). ClinicalTrials.gov registration: NCT06159231.
References
1. Collet C, Mahendiran T, Fearon WF, et al. Fractional flow reserve-guided percutaneous coronary intervention versus medical therapy for stable coronary artery disease: long-term results of the FAME 2 trial. Nat Med. 2026;32(1):318-324. doi:10.1038/s41591-025-04132-5. 2. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991-1001. 3. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-Year Outcomes with PCI Guided by Fractional Flow Reserve. N Engl J Med. 2018;379(3):250-259.
