The Contemporary Role of Intracoronary Physiological Assessment: Fractional Flow Reserve, Non-Hyperemic Pressure Ratios, Wireless Technologies, and Microcirculation

Background/Objectives: Angiographic stenosis severity and functional significance are discordant in up to 65% of intermediate coronary lesions. Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) has shown better clinical outcomes than standard angiography-guided PCI, therefore functional significance defines revascularization. This review evaluates the contemporary evidence for intracoronary physiology assessment tools, such as FFR, non-hyperemic pressure ratios (NHPRs), angiography-derived wire-free indices, and microvascular function testing, and proposes a framework for their implementation into clinical practice. Methods: We conducted a narrative review, synthesizing data from landmark randomized controlled trials (DEFER, FAME I–III, DANAMI-3-PRIMULTI, COMPARE-ACUTE, DEFINE-FLAIR, iFR-SWEDEHEART, iMODERN, FAVOR III China and Europe, FAST III, ALL-RISE, CorMicA), along with pooled analyses, meta-analyses, position papers, and relevant guidelines. Results: FFR-guided revascularization resulted in a 28% reduction in cardiac death or myocardial infarction in pooled analyses (HR 0.72, 95% CI 0.54–0.96). leading to a Class I, Level A indication. NHPRs, including iFR, achieved non-inferiority to the FFR at 1 year; however, a 5-year pooled meta-analysis raised concerns of increased all-cause mortality with iFR guidance compared to the FFR (HR 1.34, 95% CI 1.08–1.67). Approximately 20% of lesions show FFR–iFR discordance, driven by vessel-specific physiology and microvascular factors. Wire-free technologies yielded conflicting results: the FAVOR III China trial favored the QFR over angiography, yet FAVOR III Europe failed non-inferiority versus the FFR, while the recent FAST III and ALL-RISE trials demonstrated the non-inferiority of angiography-derived physiology at 1 year. Up to 40% of patients with angina have non-obstructed coronary arteries, and coronary vasomotor function testing can identify treatable microvascular endotypes improving symptoms and quality of life. Conclusions: Functional invasive coronary angiography is advocated to decipher vessel hemodynamics and to guide treatment. The FFR remains the gold standard for invasive physiological assessments, while NHPRs and wire-free technologies are valuable adjuncts with specific indications and limitations. A thorough microvascular evaluation is essential for differentiating between various INOCA endotypes and is gradually being adopted by the interventional community. While NHPRs and virtual technologies struggle to dethrone the king FFR, a comprehensive intracoronary physiology assessment is essential to guide treatment.