Prepared by: Dr. Seda Kurat Güldoğuş, Dr. Kemal Göçer

Name of the study: Fractional Flow Reserve versus Angiography Guided Management in Non-ST-Segment Elevation Myocardial Infarction: Long-Term Follow-Up of A Randomized Trial

Published in: EuroPCR 2025

INTRODUCTION
Non-ST-segment elevation myocardial infarction (NSTEMI) represents a significant subset of the acute coronary syndrome (ACS) spectrum, with widespread atherosclerotic disease affecting multiple coronary arteries observed in approximately 50% of these patients. This reflects the complexity and extent of ischemic heart disease. The 2009 FAME (Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention) trial demonstrated that a percutaneous coronary intervention (PCI) strategy guided by fractional flow reserve (FFR) was both safe and effective, not only in stable coronary artery disease but also in patients presenting with ACS. These findings suggested that the benefits of FFR guidance are not significantly affected by the presence of ACS. The 2023 European Society of Cardiology (ESC) ACS guidelines recommend assessing the functional significance of non-infarct-related artery lesions using FFR or iFR, though this recommendation remains at a Class IIb level and emphasizes the need for individualized clinical decision-making. To date, the long-term clinical implications of using FFR in NSTEMI patients remain unclear.

OBJECTIVE
This study aims to evaluate the long-term clinical outcomes—including revascularization rates, major adverse cardiovascular events (MACE), and cardiovascular mortality—of a treatment strategy guided by FFR compared with conventional angiography-guided management in patients diagnosed with NSTEMI.

METHODS
The FAMOUS-NSTEMI trial is the first prospective, multicenter, randomized controlled clinical study (NCT01764334) evaluating the use of FFR in NSTEMI patients. It was conducted between 2011 and 2013 across six centers in the United Kingdom. A total of 1,297 NSTEMI patients with at least one angiographically determined coronary lesion of >30% stenosis, referred for urgent invasive management, were initially assessed. After exclusions based on informed consent and other criteria, 350 patients (27%) were randomized:

• FFR-guided group: 176 patients
• Angiography-guided group: 174 patients

For moderate lesions, the decision to perform revascularization was based on the FFR value; in cases of severe stenosis, treatment followed standard clinical practice. The primary endpoint was defined as major adverse cardiac events (MACE: cardiac death, myocardial infarction, and hospitalization due to heart failure) post-discharge.
The secondary endpoint was the rate of cardiovascular mortality. Clinical outcomes were identified through NHS electronic health records using ICD-10 codes and analyzed by an independent statistician. All patients were followed for a minimum of 10 years. The follow-up analysis included 161 patients (91.5%) from the FFR group and 163 patients (93.7%) from the angiography group.

RESULTS

• There was no statistically significant difference in revascularization-free survival between the two groups (log-rank test, p=0.091).
• No significant superiority or disadvantage in terms of MACE was observed between the FFR-guided and angiography-guided groups (p=0.343).
• However, cardiovascular mortality was significantly higher in the FFR-guided group (log-rank test, p=0.047).

Summary:
While MACE rates were similar across groups, cardiovascular mortality was significantly increased in the FFR group.

• Cardiovascular death per 1,000 person-years was higher in the FFR group (35/1337 [26.2%] vs 22/1425 [15.4%]).
• Cox regression analysis indicated a near-significant increase in cardiovascular mortality risk in the FFR group (HR: 1.70; 95% CI: 1.00–2.91; p=0.050).

DISCUSSION
The FAMOUS-NSTEMI trial showed that while FFR-guided management in NSTEMI patients may reduce revascularization rates, it does not significantly impact the incidence of major adverse cardiovascular events. Notably, a higher rate of cardiovascular mortality was observed in the FFR-guided group. This finding raises the possibility that some ischemic lesions may be inadequately assessed using FFR, or that the FFR threshold values currently in use may not be optimal for NSTEMI populations. Strengths of the study include its long follow-up duration, use of independent statistical analysis, and data derived from electronic health records. Nonetheless, limitations such as a relatively small sample size and lack of microvascular function assessment must be acknowledged. The results underscore the need for careful and individualized application of FFR in NSTEMI patients. Ongoing studies like COMPLETE-NSTEMI and COMPLETE-2 are expected to provide further evidence in this area.

CONCLUSION
This study demonstrated that FFR-guided management in NSTEMI patients may trend toward reduced revascularization rates but does not affect MACE incidence and may be associated with increased cardiovascular mortality during long-term follow-up.

Key Takeaways:

1. In NSTEMI, angiographic classification of lesions as culprit/non-culprit remains challenging, potentially influencing treatment decisions.
2. The FAMOUS-NSTEMI study stands out with its methodological rigor, including blinding, independent statistical analysis, and electronic health record usage.
3. Findings contribute meaningfully to current guidelines and clinical practice.
4. Further evidence from ongoing COMPLETE-NSTEMI (NCT05786131) and COMPLETE-2 (NCT05701358) trials will provide a more comprehensive understanding of FFR use in this setting.