What are FFR (Fractional Flow Reserve) and iFR (Instantaneous Wave-Free Ratio) measurements?

FFR and iFR: Invasive Coronary Physiological Measurements

FFR (Fractional Flow Reserve) and iFR (Instantaneous Wave-Free Ratio) are invasive, wire-based pressure measurements performed during cardiac catheterization to determine the functional significance of coronary artery stenoses, with both receiving Class I, Level A guideline recommendations for guiding revascularization decisions in intermediate coronary lesions. 1

FFR (Fractional Flow Reserve)

Definition and Measurement Technique

FFR is a pressure-derived index that measures the maximum achievable blood flow in a stenotic coronary artery as a ratio of distal coronary pressure (Pd) to aortic pressure (Pa) during pharmacologically-induced maximal hyperemia. 1, 2, 3

• The calculation is straightforward: FFR = Pd/Pa during maximal hyperemia, with a normal value of 1.0 in every patient and every coronary artery 3
• Measurement requires a 0.014-inch pressure-sensitive guide wire positioned at least 2-3 cm distal to the stenosis in the distal two-thirds of the coronary artery 1, 3
• Maximal hyperemia must be achieved using intravenous adenosine at 140 μg/kg/min for at least 2 minutes, which minimizes coronary microvascular resistance and creates a linear relationship between perfusion pressure and blood flow 1, 2, 3

Diagnostic Thresholds

The established ischemic threshold is FFR ≤0.80, which indicates hemodynamically significant stenosis requiring revascularization. 1, 3

• FFR ≤0.75 has 100% specificity for inducible ischemia 3
• FFR ≥0.80 indicates absence of inducible ischemia with 90% sensitivity 3
• A "gray zone" exists between 0.75-0.80, affecting approximately 10% of measurements, though contemporary practice uses the single cutoff of 0.80 to increase sensitivity 2, 3

Clinical Applications and Evidence

FFR-guided PCI has demonstrated superior clinical outcomes compared to angiography-guided PCI, with significantly lower rates of death, MI, and repeat revascularization. 3

• The FAME trial showed FFR-guided PCI resulted in 13.2% vs 18.3% composite event rates at 1 year compared to angiography guidance (P=0.02), while using fewer stents (1.9±1.3 vs 2.7±1.2, P=0.001) 3
• FFR is particularly valuable for assessing intermediate stenoses (40-90% diameter stenosis), left main coronary artery narrowing, and jailed side branch lesions 2, 3
• Deferring PCI for lesions with FFR >0.75 results in excellent outcomes with event rates <10% over 2-year follow-up 3

iFR (Instantaneous Wave-Free Ratio)

Definition and Measurement Technique

iFR is a resting pressure-only index that does not require adenosine administration, measured during a specific period of diastole called the "wave-free period" when microvascular resistance is naturally low and stable. 4

• iFR eliminates the need for hyperemic agents, avoiding adenosine-related adverse effects, procedural time, and cost 4
• The measurement is performed at rest without pharmacological vasodilation 5

Diagnostic Thresholds

iFR ≤0.89 indicates hemodynamically significant stenosis requiring revascularization, while iFR >0.89 supports deferral of PCI. 1, 4

Clinical Evidence and Guideline Recommendations

The 2024 ESC and 2021 ACC/AHA/SCAI guidelines provide Class I, Level A recommendations for iFR, placing it on equal footing with FFR for guiding revascularization decisions. 1, 4

• The DEFINE-FLAIR and iFR-SWEDEHEART trials demonstrated that iFR-guided PCI was noninferior to FFR-guided PCI for clinical outcomes in patients with acute coronary syndromes 4
• iFR use was associated with lower rates of procedure-related chest pain and shorter procedural time compared to FFR 4

Critical Safety Concern

A concerning finding emerged at 5-year follow-up: meta-analyses revealed a 2% absolute increase in all-cause mortality in patients managed with iFR compared to FFR, though this was not associated with increased rates of unplanned revascularization or non-fatal MI. 4

• The mechanism for this mortality difference remains unclear and requires cautious interpretation 4
• This mortality signal was not accompanied by increased procedural complications or ischemic events 4

Comparison and Controversy

Diagnostic Agreement

There is significant scientific debate about the diagnostic concordance between iFR and FFR. 5

• One multicenter study (VERIFY) found that iFR showed only 60% diagnostic accuracy compared to FFR ≤0.80, with accuracy dropping to 51% for FFR values in the 0.60-0.90 range 6
• The VERIFY study demonstrated that iFR was significantly influenced by hyperemia induction (mean iFR 0.82±0.16 at rest vs 0.64±0.18 with hyperemia, P<0.001), contradicting the premise that iFR is independent of hyperemia 6
• Conversely, other studies (CLARIFY, JUSTIFY-CFR) suggested iFR showed stronger correlation with coronary flow reserve than FFR and had equivalent diagnostic classification 7, 8

Hybrid Approach

A sequential hybrid strategy using iFR first, followed by FFR only when iFR falls in an intermediate range, can provide excellent diagnostic accuracy while reducing adenosine use. 9

• Using an iFR threshold of 0.91 for initial screening, followed by high-dose intracoronary adenosine FFR only for iFR <0.91, yielded 96.7% diagnostic accuracy with 100% sensitivity and 94.7% specificity 9
• The previously described iFR gray zone (0.85-0.94) approach also provided 95% diagnostic accuracy 9

Current Guideline Recommendations

The 2024 ESC guidelines recommend selective (not routine) assessment of functional severity of intermediate diameter stenoses during invasive coronary angiography using: 1

• FFR/iFR (significant ≤0.8 or ≤0.89) - Class I, Level A recommendation 1
• QFR (quantitative flow ratio) ≤0.8 - Class I, Level B recommendation 1
• CFR/HSR/CFC as complementary investigations - Class IIa, Level B recommendation 1
• Systematic and routine wire-based coronary pressure assessment of all coronary vessels is NOT recommended (Class III, Level A) 1

Technical Pitfalls and Quality Assurance

Common Artifacts to Avoid

Catheter ventricularization/damping can impair coronary flow during hyperemia; solution requires disengaging the guiding catheter from the ostium during measurement 3

Pressure signal drift can be detected by parallel pressure signals with similar morphology; solution involves pulling back the sensor to equalize pressures and repeating measurements 3

Pseudostenosis can occur in tortuous vessels where the wire itself creates artifacts, rendering FFR measurements uninterpretable 3

Standardization Requirements

• Guiding catheters without distal side holes are required for accurate research measurements 1
• Proper pressure equalization between the guiding catheter and pressure wire must be performed before wire advancement 3
• Intracoronary nitrates should be administered before measurements 1

Limitations

FFR data in patients with acute or recent myocardial infarction are limited, and established criteria should not be extended to this specific patient subgroup. 2

• In diffuse coronary disease with continuous pressure fall along arterial length, interpretation requires careful consideration 2
• While right atrial pressure should theoretically be included in FFR calculation, it is often omitted in clinical practice as it has minimal influence on FFR values or revascularization decisions 2