Fractional Flow Reserve and Non-Hyperaemic Pressure Ratios

Definition and pathophysiology

Fractional flow reserve (FFR) is an invasive, lesion-specific physiological index used to estimate the functional significance of an epicardial coronary stenosis. It is defined during maximal pharmacological coronary vasodilation as the ratio of mean pressure distal to the stenosis to mean aortic pressure:

FFR = Pd/Pa during maximal hyperaemia

More precisely, FFR compares the pressure driving flow distal to a stenosis with the pressure that would be available in the absence of that stenosis. The complete physiological formulation considers coronary venous pressure:

• Distal coronary driving pressure: distal coronary pressure minus coronary venous pressure

• Normal coronary driving pressure: mean aortic pressure minus coronary venous pressure

In routine clinical practice, coronary venous pressure is generally assumed to be zero, yielding the simplified ratio of mean distal coronary pressure to mean aortic pressure. FFR ranges from 0 to 1; a normal value is approximately 0.94–1.0.

The physiological basis of FFR is that, during maximal vasodilation, distal coronary pressure is proportional to maximum achievable myocardial perfusion. A pressure reduction across an epicardial stenosis therefore identifies a limitation in potential hyperaemic flow. FFR is consequently a measure of the physiological effect of an individual epicardial lesion rather than its anatomical appearance alone.

Coronary angiography provides only an imperfect estimate of functional severity. Angiographic interpretation is affected by interobserver variability, and the relationship between diameter stenosis and haemodynamic significance is weak, particularly for intermediate lesions. Even lesions with a visual diameter reduction of 50–70% may or may not produce ischaemia. Conversely, some lesions with apparently lesser narrowing are physiologically important. Lesion location also matters: stenoses in the left main stem or proximal left anterior descending artery are more likely to affect flow because they supply a larger myocardial territory.

The response of the coronary circulation reflects both epicardial stenosis and the coronary microcirculation. Microvascular dysfunction may impair maximal vasodilation even when the epicardial arteries are normal, and it may amplify the physiological consequences of an epicardial lesion. Thus, FFR is primarily an index of epicardial stenosis physiology and does not directly quantify the ability of the myocardial resistance vessels to augment flow.

Coronary flow reserve and its relationship to FFR

Coronary flow reserve (CFR) is the ratio of maximum hyperaemic coronary flow to resting coronary flow. It can be assessed invasively or with myocardial perfusion imaging using PET, SPECT or CMR. Relative flow reserve compares perfusion in a stenotic territory with that in a normal reference region under similar haemodynamic conditions.

CFR and FFR interrogate related but distinct components of coronary physiology:

• FFR is predominantly a pressure-derived index of the functional effect of an epicardial stenosis.

• CFR reflects the combined influence of epicardial stenosis, resting flow and microvascular vasodilator capacity.

The two measures may therefore be discordant. A reduced FFR with preserved CFR suggests a predominantly focal epicardial lesion that may not be strongly flow limiting. In contrast, preserved FFR with reduced CFR may indicate coronary microvascular dysfunction or diffuse epicardial disease. Concordantly normal FFR and CFR are associated with an excellent prognosis, whereas discordant measurements require interpretation in the context of the clinical presentation and other findings.

A reduced CFR may occur with angiographically insignificant epicardial disease because of abnormalities in the coronary resistance vessels. Left ventricular hypertrophy also reduces coronary flow reserve: myocardial mass increases without a proportional increase in the microcirculatory resistance network, reducing maximal flow per gram of tissue. Consequently, a moderate stenosis in a hypertrophied heart may have a physiological effect resembling a more severe lesion in a structurally normal myocardium.

Clinical applications

The principal application of FFR and non-hyperaemic pressure ratios is the assessment of angiographically intermediate coronary stenoses when the need for revascularization is uncertain. This is especially relevant in:

• Stable ischaemic heart disease or chronic coronary syndromes

• Angina or an anginal equivalent without prior definitive ischaemia testing

• Multivessel coronary artery disease with lesions of uncertain importance

• Serial, diffuse or long lesions

• Side-branch stenoses

• Intermediate left main stem disease

• Assessment of a residual lesion after PCI

FFR can change the treatment plan in approximately 30–50% of patients undergoing invasive angiography in whom it is applied to intermediate lesions. It may prevent unnecessary stenting of anatomically apparent but physiologically non-significant disease and identify lesions whose haemodynamic importance is underestimated by angiography.

In patients with acute coronary syndromes, invasive physiology is increasingly used for intermediate non-infarct-related artery lesions. PCI of the infarct-related artery should not be deferred solely on the basis of acute invasive epicardial functional assessment. The coronary microcirculation begins to recover within approximately 24 hours of primary PCI, and early assessment may underestimate the eventual haemodynamic severity of the lesion. Beyond one week after the acute event, FFR has been reported to predict abnormal nuclear perfusion imaging reliably.

Evaluation and clinical interpretation

FFR or a non-hyperaemic pressure ratio should not be interpreted in isolation. Clinical symptoms, non-invasive stress testing, lesion location, the amount of myocardium supplied and the pattern of pressure loss along the vessel all contribute to the revascularization decision.

Angiographic severity and physiological significance

Visual angiographic categories are unreliable predictors of functional importance. In registry and trial populations:

• Approximately 31% of lesions visually estimated at 40–49% stenosis were haemodynamically significant.

• Only approximately 35% of 50–70% lesions were haemodynamically significant.

• Approximately 20% of 71–90% lesions were not haemodynamically significant.

• Visual stenosis greater than 90% was the only category that predicted haemodynamic relevance with high accuracy, approximately 96%.

These observations support physiological assessment of intermediate lesions rather than routine reliance on angiographic appearance.

Pressure-wire pullback

Pressure-wire pullback can demonstrate whether pressure loss is focal or progressive:

• A focal pressure drop suggests a discrete lesion that may benefit from PCI.

• A gradual pressure decline suggests diffuse disease, for which focal stenting may provide limited physiological benefit.

Longitudinal interrogation is particularly useful in serial lesions and diffuse coronary artery disease.

Diagnostic methods

Invasive FFR

FFR requires placement of a pressure wire across the coronary stenosis. The proximal pressure is generally measured in the aorta through the guiding catheter, while the distal pressure is recorded beyond the lesion. Maximal hyperaemia is induced pharmacologically, usually with adenosine administered intravenously or intracoronarily.

The mean pressures are averaged over the cardiac cycle. The principal measurement is the ratio of distal coronary pressure to aortic pressure during maximal hyperaemia.

FFR is:

• Lesion specific

• Rapid to obtain at the time of angiography

• Reproducible

• Useful for assessing both untreated lesions and residual disease after PCI

Adequate maximal vasodilation is essential. Submaximal hyperaemia leaves distal coronary pressure higher than it would be during full vasodilation and therefore underestimates the physiological significance of the stenosis.

Non-hyperaemic pressure ratios

Non-hyperaemic indices use resting pressure measurements and avoid pharmacological vasodilation. Several indices have been developed, including:

• Instantaneous wave-free ratio (iFR)

• Resting distal coronary pressure/aortic pressure ratio

• Diastolic pressure ratio

• Relative full-cycle ratio

• Other phase-specific or whole-cycle pressure ratios

The best-established non-hyperaemic index is iFR. It is measured during the diastolic wave-free period, beginning approximately 25% into diastole and ending 5 ms before the end of diastole. During this interval, microvascular resistance is relatively stable and low, and the translesional pressure gradient can be assessed without inducing hyperaemia.

Non-invasive FFR derived from coronary CT

Coronary CT angiography can be combined with computational fluid dynamics or machine-learning analysis to estimate FFR throughout the coronary tree. FFR-CT uses a patient-specific three-dimensional coronary model derived from CT imaging and estimates coronary pressure under simulated vasodilation.

FFR-CT can complement anatomical CT angiography, improve functional characterization of coronary lesions and reduce unnecessary invasive angiography. It does not require additional pharmacological stress, contrast administration or radiation exposure beyond the CT examination. Its clinical utility depends on adequate image quality and availability.

FFR-CT has several limitations:

• It is less useful when CT angiography already demonstrates severe coronary disease.

• It cannot identify coronary microvascular dysfunction.

• Computational models generally assume a normal microcirculation and vasodilator response, which may overestimate the contribution of obstructive epicardial disease in patients with microvascular dysfunction.

• The prognostic safety of deferring intervention on the basis of FFR-CT has not been established to the same extent as for invasive measurements.

Other physiological and structural methods

Additional approaches include:

• CFR, measured invasively or with non-invasive imaging

• Index of microcirculatory resistance

• Hyperaemic stenosis resistance

• Microvascular resistance reserve

• Coronary flow capacity, integrating hyperaemic flow and CFR

• Intravascular ultrasound and optical coherence tomography

Intravascular ultrasound and optical coherence tomography may assist in assessing left main stem stenosis severity and prognosis. However, these structural techniques do not replace physiological assessment in all intermediate lesions.

Thresholds and practical interpretation

FFR thresholds

The commonly used thresholds are:

An FFR below 0.75 is strongly associated with ischaemia on nuclear perfusion imaging. An FFR above 0.80 rarely correlates with ischaemia. Contemporary outcome studies have generally used 0.80 as the threshold for PCI, although the historical threshold of 0.75 remains important in interpreting earlier evidence.

A value above 0.80 does not imply absence of all coronary pathology. It indicates that the particular epicardial lesion is unlikely to be the dominant flow-limiting abnormality under the conditions tested. Symptoms may persist because of diffuse disease, microvascular dysfunction or another cardiac or non-cardiac cause.

iFR thresholds

An iFR threshold of 0.89 is commonly used as analogous to an FFR threshold of 0.80. Earlier approaches used values below 0.86 as positive and above 0.94 as negative, with FFR reserved for intermediate results.

Advantages and limitations

Advantages of FFR

FFR provides a direct, lesion-specific estimate of the haemodynamic effect of an epicardial stenosis. It is particularly valuable when angiography is ambiguous, and it can be performed during the same procedure as diagnostic angiography or PCI. FFR-guided PCI reduces the number of stents used compared with angiography-guided intervention and improves clinical outcomes in selected patients with stable coronary disease.

FFR is also relatively unaffected by changes in resting flow because it compares stenotic and non-stenotic conditions during pharmacological vasodilation. It can be used immediately after PCI to assess the physiological effect of residual disease.

Limitations of FFR

FFR is invasive and requires pharmacological hyperaemia. Its accuracy depends critically on achieving maximal vasodilation. Incomplete hyperaemia produces a falsely high distal pressure and may underestimate stenosis severity.

The simplified ratio assumes negligible coronary venous pressure and a linear pressure–flow relationship during vasodilation. These assumptions are less reliable at low coronary pressures and in the presence of important collateral flow. Ignoring venous backpressure may underestimate the physiological significance of a stenosis, particularly when assessing collateral-dependent myocardium.

FFR cannot independently quantify microvascular flow limitation. Microvascular dysfunction may blunt the vasodilator response, resulting in a higher distal pressure and an apparently less severe FFR than would be obtained with a normal microcirculation. It may therefore underestimate epicardial stenosis severity in this setting.

Advancing a pressure wire across a severe lesion may itself alter flow and overestimate stenosis severity, particularly in diffuse disease and small branch vessels. Serial stenoses and diffuse atherosclerosis may also make attribution of the pressure loss to a single anatomical lesion difficult.

Advantages of iFR

iFR avoids adenosine and therefore eliminates adenosine-related symptoms and simplifies catheter-laboratory workflow. Procedures are generally shorter, and the measurement is not dependent on achieving maximal pharmacological vasodilation. Because it is performed at rest, iFR may be less affected by an attenuated adenosine response caused by coronary microvascular dysfunction.

Limitations of iFR

At resting flow, the pressure gradient across a stenosis is smaller and distal pressure is higher than during hyperaemia. iFR may therefore overestimate the functional significance of a stenosis when resting flow is abnormally elevated, such as in anaemia.

Although iFR-guided management was non-inferior to FFR-guided management at one year in two large randomized trials, longer-term pooled analyses reported a higher frequency of all-cause mortality and major adverse cardiovascular events with iFR-guided management. This was not accompanied by higher rates of myocardial infarction or unplanned revascularization. Consequently, non-hyperaemic indices should be used judiciously, and FFR remains the reference invasive strategy in situations in which uncertainty persists.

Treatment and management

Deferral of PCI

Deferral of PCI is appropriate when an intermediate lesion is not physiologically significant and the clinical findings are concordant. In stable ischaemic heart disease, lesions with FFR greater than 0.75 have shown excellent long-term outcomes when intervention was deferred. Lesions with FFR greater than 0.80 are rarely associated with ischaemia and can generally be managed medically when symptoms, stress testing and other findings do not indicate a need for revascularization.

Deferral should not be based on pressure thresholds alone. Symptoms, non-invasive ischaemia testing, lesion location, myocardial territory, diffuse disease and possible microvascular dysfunction must be considered.

FFR-guided PCI

When FFR is ≤0.80, PCI in addition to optimal medical therapy can reduce major adverse cardiovascular events compared with medical therapy alone in stable coronary lesions. The principal early benefit is a reduction in urgent revascularization, while a later reduction in myocardial infarction has also been reported. FFR-guided intervention reduces the number of stents required compared with angiography-guided PCI and is associated with fewer composite cardiac events at one year.

In multivessel disease, routine physiological interrogation of every epicardial vessel has not consistently improved outcomes compared with angiography alone. Physiological assessment should therefore generally focus on intermediate lesions rather than systematically measuring vessels that are clearly severe or clearly mild by clinical and angiographic assessment.

Medical therapy

The source material identifies optimal medical therapy as the comparator and an essential component of management but does not specify drug classes, doses or detailed secondary-prevention regimens. No medication dosing recommendations are provided.

Assessment after PCI

FFR can be measured after PCI to determine the physiological effect of a residual lesion. A persistently abnormal post-PCI value may reflect residual focal stenosis, diffuse disease or other physiological abnormalities. Pressure-wire pullback can help distinguish a focal residual pressure drop, potentially amenable to further intervention, from diffuse pressure loss, for which additional focal stenting may not be beneficial.

Guideline recommendations

Current European guidance supports wire-based physiological assessment when invasive angiography identifies an intermediate epicardial stenosis and non-invasive stress testing is inconclusive or has not been performed. FFR during maximal hyperaemia or iFR at rest is recommended to improve risk assessment and guide revascularization decisions.

The relevant practical thresholds are:

• FFR ≤0.80: haemodynamically relevant stenosis; supports consideration of PCI in the appropriate clinical setting.

• iFR ≤0.89: haemodynamically relevant stenosis; supports consideration of PCI in the appropriate clinical setting.

• FFR or iFR above the relevant threshold: revascularization can often be deferred, provided that the patient’s symptoms, stress-test findings and overall clinical context are consistent.

Physiological assessment is particularly important for intermediate lesions, typically visually estimated at approximately 40–90% stenosis in non-left-main vessels and 40–70% in the left main stem. In multivessel disease, pressure measurement should generally be reserved for intermediate lesions.

The use of FFR is endorsed as a class I recommendation in patients with angina or an anginal equivalent, no prior evaluation for ischaemia and angiographically intermediate stenoses in the cited American coronary revascularization and chronic coronary disease guidelines.

Prognosis and follow-up

Physiological classification provides prognostic information beyond angiography. Patients with functionally non-significant lesions in whom PCI is deferred have excellent long-term outcomes, including substantially lower myocardial infarction rates than patients undergoing prophylactic intervention despite a non-ischaemic FFR.

In stable coronary disease, FFR-guided PCI compared with angiography-guided PCI has been associated with:

• Fewer stented lesions

• Lower one-year major adverse cardiac event rates

• Fewer myocardial infarctions

• Fewer repeat revascularizations

• No demonstrated mortality difference in the principal one-year comparison

In patients with FFR <0.80, PCI plus optimal medical therapy reduces major adverse cardiovascular events compared with medical therapy alone, primarily through fewer urgent revascularizations and with a later reduction in myocardial infarction. A meta-analysis of individual patient data also suggested a reduction in the combined endpoint of cardiac death or myocardial infarction.

iFR-guided treatment has outcomes comparable to FFR-guided treatment at one year and provides practical procedural advantages. However, pooled five-year analyses have raised concern regarding a possible excess in all-cause mortality and major adverse cardiovascular events with iFR-guided management, despite no increase in myocardial infarction or unplanned revascularization. These findings support continued clinical caution and careful integration of iFR with symptoms, non-invasive testing and, where appropriate, confirmatory FFR.

Follow-up should therefore be guided by the patient’s symptoms, functional status, ventricular function, the extent of coronary disease and the physiological findings at the index procedure. Persistent symptoms after deferral of a non-significant epicardial lesion should prompt consideration of microvascular dysfunction, diffuse disease or another diagnosis rather than automatic repeat PCI.