Highlight
Long-Term Clinical Benefit
At a median follow-up of 11.2 years, FFR-guided PCI plus medical therapy demonstrated a significant clinical advantage over medical therapy alone in patients with stable coronary artery disease (CAD) and hemodynamically significant stenoses.
Hierarchical Success
Using the unstratified win ratio to prioritize mortality, PCI was superior in 29.2% of comparisons, resulting in a win ratio of 1.25 (P = 0.043) in favor of the invasive strategy.
Reduction in Urgent Revascularization
The primary driver of the composite endpoint benefit remained the significant reduction in urgent revascularizations, with a specific win ratio of 4.57 for this component.
Number Needed to Treat
To prevent one primary composite outcome event over 11 years, the calculated Number Needed to Treat (NNT) was 17, reflecting a robust long-term clinical impact.
Background: The Evolution of Physiological Assessment
For decades, the management of stable coronary artery disease (CAD) has been the subject of intense debate. Early trials like COURAGE and more recently ISCHEMIA suggested that an initial conservative strategy of optimal medical therapy (OMT) was comparable to an invasive strategy regarding the risk of death or myocardial infarction. However, a critical limitation of many earlier studies was the reliance on visual, anatomical assessment of coronary stenoses rather than physiological significance.
Fractional Flow Reserve (FFR) emerged as a transformative tool, allowing clinicians to objectively identify which stenoses actually impede blood flow and cause ischemia. The original FAME 2 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2) trial was designed to test whether PCI, when specifically targeted at these functionally significant lesions (FFR <= 0.80), would provide superior outcomes compared to OMT alone. While the 5-year results established a clear benefit in reducing urgent revascularizations, the long-term durability of this effect—extending beyond a decade—remained an open question until now.
Study Design and Methodology
Patient Population and Randomization
FAME 2 was a multicenter, international trial involving patients with stable CAD. All patients underwent FFR assessment. Those with at least one stenosis with an FFR value of 0.80 or less were randomized to either FFR-guided PCI plus medical therapy (n = 447) or medical therapy alone (n = 441). Patients with FFR values > 0.80 were entered into a separate registry. This specific analysis focuses on the 11.2-year follow-up of the randomized cohort, involving 16 hospitals and 748 participants.
The Win Ratio: A Modern Statistical Approach
To address the complexities of long-term follow-up, particularly the differential missingness of data and the varying clinical weight of composite endpoints, the investigators utilized the unstratified win ratio. This hierarchical method prioritizes the most severe outcomes (death), followed by myocardial infarction and urgent revascularization. This approach ensures that the clinical benefit is not masked by non-fatal events occurring in patients who have already died, providing a more nuanced view of the treatment effect.
Key Findings: A Longitudinal Advantage for PCI
Primary Composite Outcome
Over the 11.2-year median follow-up period, the primary composite endpoint—death, myocardial infarction, or urgent revascularization—occurred in 33.6% of the PCI group compared to 41.3% in the medical therapy group. The win ratio analysis favored PCI at 1.25 (95% CI 1.01-1.56, P = 0.043). The win difference was 5.9%, emphasizing a clear, persistent benefit for the invasive strategy.
Component Breakdown
When examining the individual components of the composite outcome, the results provide critical insights into how PCI improves patient trajectories:
Urgent Revascularization
This was the most significantly impacted component. The win ratio for urgent revascularization was 4.57 (95% CI 2.53-8.24). This indicates that patients managed with medical therapy alone were more than four times more likely to experience an unstable clinical presentation requiring emergency intervention compared to those who received upfront FFR-guided PCI.
Death and Myocardial Infarction
For all-cause death, the win ratio was 0.88 (95% CI 0.66-1.17), showing no statistically significant difference between the groups. For myocardial infarction, the win ratio was 1.50 (95% CI 0.98-2.31), trending toward a benefit for PCI but not reaching statistical significance at the 11-year mark.
Expert Commentary and Clinical Implications
Contextualizing Revascularization Benefits
Critics of revascularization in stable CAD often point to the lack of a mortality benefit as a reason to favor medical therapy. However, the FAME 2 results suggest that preventing urgent revascularization is a major clinical success. Urgent revascularizations are often associated with acute coronary syndromes, significant patient distress, and higher healthcare costs. By identifying and treating hemodynamically significant lesions early, FFR-guided PCI effectively stabilizes the patient’s clinical course over the long term.
The Role of Physiological Guidance
These findings reinforce the necessity of FFR (or equivalent physiological indices) in the catheterization lab. Revascularizing a lesion based solely on its appearance on an angiogram (the “oculostenotic reflex”) is no longer sufficient. FAME 2 demonstrates that when we are precise about which lesions we treat, the benefits of PCI are durable and statistically superior to medical therapy alone.
Study Limitations
It is important to acknowledge that FAME 2 was an unblinded trial, which can introduce bias, particularly in the decision to perform urgent revascularization. Furthermore, the advancements in medical therapy and second-generation drug-eluting stents (DES) since the trial’s inception may alter the absolute risk reductions seen today. However, the physiological principle established—that ischemia-causing lesions benefit from mechanical intervention—remains robust.
Conclusion
The 11-year follow-up of the FAME 2 trial provides definitive evidence that for patients with stable CAD and FFR-confirmed ischemia, an initial strategy of FFR-guided PCI is superior to medical therapy alone. The reduction in the primary composite endpoint, driven by a dramatic decrease in the need for urgent revascularization, highlights the long-term value of targeted invasive intervention. These results support a management strategy that prioritizes physiological assessment to guide revascularization decisions, ensuring that the right patients receive the right intervention at the right time.
Funding and clinicaltrials.gov
This study was supported by various institutional grants and research funds. 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.
