Fractional Flow Reserve

General description of procedure, equipment, technique

Fractional flow reserve (FFR) is an invasive measurement developed in 1990s for evaluation of functional significance of stenoses in the epicardial coronary artery.

FFR is defined as a ratio of the maximal myocardial blood flow in the presence of a stenosis to the theoretical normal maximal flow in the same distribution. Because flow is proportional to pressure, if resistance is minimal and constant, pressure can be used as a surrogate of flow during maximal hyperemia. Thus, FFR is simply calculated by using the distal coronary pressure of the stenosis divided by the aortic pressure during maximal hyperemia.
The rationale for physiologic lesion assessment in the catheter laboratory is based on two simple facts:

Benefits of coronary revascularization are mainly attributable to the reduction of ischemia.

Coronary angiography frequently fails to identify the accurate hemodynamic significance of coronary stenoses, particularly those between 30% and 90% diameter stenosis.
Related Content
FFR is considered nowadays as a gold standard to assess whether any particular stenosis is responsible for inducible ischemia.
Decision making for coronary percutaneous intervention (PCI) guided by FFR is associated with favorable clinical outcomes compared with angiography-guided PCI.
FFR is easy to measure in the catheterization laboratory with an average of 7 minutes added to the case at a cost of 2.8 mSv of effective radiation dose and 35 ml of contrast medium.

Indications and patient selection

FFR was initially applied in patients with equivocal and intermediate lesions of single-vessel disease to assess hemodynamic significance. In the last decade, the validation of FFR has been established in various clinical and anatomical subsets:

Multivessel disease

Acute coronary syndrome

Left main lesions

Bifurcation and ostial branch stenoses

Sequential stenoses

Diffuse atherosclerosis

Bypass grafts
FFR is now a class 1A recommendation in European guidelines, and a class 2A recommendation in U.S. guidelines for assessment of angiographic intermediate coronary lesions (50% to 70% diameter stenosis) and for guiding revascularization decisions in patients with stable ischemic heart disease.

Is postinterventional FFR valid?

FFR values >0.9 after stent implantation are correlated with better outcomes and a reduced need for repeat revascularization. Normalization of FFR after stent placement (thereby restoring normal conductance of the artery) is accompanied by a restenosis rate of <5% at 6-month follow-up, with a strong inverse correlation between poststent FFR and event rate.
So far, no data are available to clarify what should be done in case of a suboptimal postinterventional FFR. The following solutions may be reasonable:

Intravascular ultrasound or optical coherence tomography to study stent deployment, then post dilation or not

The hyperemic pressure pull-back recording to analyze the extent and significance of residual disease proximal or distal to the stent, then stent or not

Aggressive secondary prevention

Is FFR valid for acute coronary syndrome?

In the early phase after ST segment elevated myocardial infarction (STEMI), severe microvascular impairment (no reflow, stunning, inflammation) may be present. A low FFR still indicates hemodynamic significance of the residual stenosis, but high FFR does not necessarily exclude this. Therefore, pressure-derived FFR should not be used for the culprit vessel during the acute phase (less than 5 days) of a STEMI.
After treatment of the culprit lesion, FFR analysis of other stenoses (when present) can be helpful and indicate the need for additional treatment, preventing repeated invasive procedures later on and thereby reducing costs.
In patients with prior MI (>5 days), the classical 0.75 to 0.80 threshold value could be used as usual to indicate residual ischemia of the infarct-relate or remote arteries.
In the setting of unstable angina or non-STEMI, FFR can be used if the culprit lesion is unclear or if lesions are present in multiple vessels. It has been shown that using coronary pressure measurement in unstable angina or non-STEMI, not only results in a favorable outcome, but is also cost-effective.

Contraindications

No absolute contraindications for FFR measurement itself.
Severe asthma is a contraindication for intravenous adenosine administration.

Details of how the procedure is performed

Equipment

FFR is usually measured following coronary angiography in the catheterization laboratory. A guiding catheter, a pressure monitoring guidewire, and a hyperemic stimulus are required for the FFR measurement.
Although a diagnostic catheter (4 Fr or 5 Fr) is feasible, it is recommended that a normal guiding catheter should be used to perform FFR not only for easier handling but also for rapid access with balloons or stents in the rare event of vessel dissection or perforation.
Measuring intracoronary pressure requires the use of a specific solid-state sensor mounted on a floppy-tipped guidewire. Two 0.014 inch pressure monitoring guide wires are available: Pressure Wire (St. Jude Medical Inc, Minneapolis, MN, and Uppsala, Sweden) and Wave Wire (Volcano Inc, Rancho Cordova, CA). The sensor is located at the junction between the radiopaque and radiolucent part, 3 cm from the distal tip of pressure guide wire.
Administration of vasodilator is mandatory to achieve maximal hyperemia of coronary artery.
The ideal hyperemic stimulus should be easy to administer, have a short onset until maximum hyperemia is achieved, have a duration long enough to enable pressure pullback recordings (a few minutes), have few side effects, and be eliminated within a few minutes.

Practice of FFR measurement

Connect pressure wire to an interface (Analyzer Express, St. Jude Medical Inc, Uppsala, Sweden; or Combomap, Volcano Inc.) on which the pressure signals and the FFR values are displayed, and calibrate pressure wire outside of the patient.
Introduce pressure wire into guiding catheter through introducer needle. The radiopaque tip of the guide wire should be visible outside the catheter 1 or 2 mm distal to the guiding catheter tip for the equalization of pressure from the guiding catheter and pressure wire.
Then advance the pressure wire into the coronary artery beyond the stenosis and place sensor at least 2 cm beyond the stenosis. Both guide catheter and sensor wire pressures are continuously recorded.
As soon as any device is advanced into the coronary tree, heparin (40 to 60 U/kg IV) should be given. Isosorbide dinitrate (200 μg IC) or nitroglycerin (100 to 200 μg IC) is used to minimize vasomotion and measurement variability at least 30 seconds before the measurements.
Next, a pharmacologic hyperemic stimulus is administered intravenously or via an intracoronary route (through the guide catheter).
Intravenous administration of adenosine at a dose of 140 ug/kg/min is the gold standard to achieve maximum hyperemia. Different vasodilators for FFR measurement are shown in Table 1.
Aortic pressure (Pa) is taken from the guide catheter and distal pressure (Pd) from the pressure sensor. FFR is computed as the ratio Pd to Pa at maximal hyperemia.

Different vasodilators available for FFR measurement

Points for attention

The use of side-hole catheters had better be avoided not only because the intracoronary administration of medications will be unreliable, but also because the pressure recorded at the tip of the guiding catheter will be undependable.
Be careful not to damage the sensor when removing the pressure wire from the packaging coil or shaping the tip.
Use thin introducer needles and the valve of the Y-connectors should be tightly closed.
The most recent generation of these 0.014 inch pressure wires has excellent handling characteristics, although they are slightly inferior to most standard angioplasty guidewires.
Recognize and avoid hemodynamic artifact.
Seat the guiding catheter to avoid guiding-catheter obstruction of the coronary ostium, which may limit hyperemic blood flow.
To assess serial lesions or diffuse coronary artery disease (CAD), the pressure wire can be pulled back steadily from the distal to proximal vessel segments during continuous hyperemia induced by intravenous vasodilator (hyperemic pressure-pullback recording).

Interpretation of results

FFR value represents the fraction of the normal maximal myocardial flow that can be achieved despite the coronary stenosis. For example, an FFR of 0.75 means that the stenotic vessel only provides 75% of the normal expected flow in the theoretical absence of the stenosis.
The normal value of FFR is 1.0 and is not affected by changes in heart rate, blood pressure, or myocardial contractility.
FFR values <0.75: the stenosis is hemodynamically significant and revascularization should be performed.
FFR values >0.80: the stenosis has minimal hemodynamic significance, and revascularization may be safely deferred.
When FFR values are between 0.75 to 0.80, decision making for PCI should depend on clinical judgment.

If FFR and assessment of coronary angiography are contradictory, perform PCI or defer?

It is not uncommon that a clinical or angiographic situation is encountered where the measurement of FFR seems to be grossly contradictory to visual assessment by angiography. This can occur with an angiographically tight coronary lesion with an unexpectedly high value of FFR, or with a mild lesion and a surprisingly low value of FFR.
Although some pathologic factors, such as left ventricular hypertrophy, microvascular disease, or high right atrial pressure may have an influence on FFR values, it should be kept in mind that actual false-negative or false-positive FFR results are rare when measurements are performed correctly.
In the majority of cases, decision making for PCI is recommended strictly based on FFR value.
There is a small gray zone (0.75 to 0.80) where clinical, electrocardiographic, or angiographic data might be used to reach a balanced decision.

Performance characteristics of the procedure (applies only to diagnostic procedures)

FFR values <0.75 are associated with ischemia on stress testing with high sensitivity (88%), specificity (100%), positive predictive value (100%), and overall accuracy (93%).
FFR values >0.80 are associated with no ischemia with a predictive accuracy of 90%.

Advantages

FFR is simple, easy to perform in the catheterization laboratory independent of baseline flow, with low variability.
FFR can be measured successfully in 99% of the arteries, and the measurements are extremely reproducible.
Compared with other invasive physiologic assessments, FFR has unique and valuable characteristics with a normal value of 1.0 in all patients and in all coronary vessels.
FFR values are not affected by changes in heart rate, blood pressure, or myocardial contractility.
FFR may accurately identify the hemodynamic significance of stenoses in an epicardial coronary artery.
It may provide functional significance for a specific lesion, especially in the presence of multivessel coronary artery disease.
FFR takes into account the contribution of the collateral blood supply to maximal myocardial perfusion.
FFR can be useful to assess bifurcations and avoid unnecessary branch vessel stenting.

Its validation of decision making for PCI has been well demonstrated in almost all clinical and anatomic subsets with favorable clinical outcomes and markedly reduced total costs and duration of hospitalization.

Disadvantages

FFR is measured invasively.
Although simple, the measurements are also critically dependent on achieving maximal pharmacologic vasodilation.
FFR value may be influenced by some pathologic factors.

Alternative and/or additional procedures to consider

Noninvasive testing

Noninvasive stress test (exercise testing, stress echocardiography, or single photon emission computed tomography myocardial perfusion image) is recommended by current guidelines prior to diagnostic cardiac catheterization to provide functional information in stable patients.
These tests cannot provide lesion-specific information and may be of limited use in guiding selective coronary revascularization in the context of multivessel CAD due to limited spatial resolution and specificity.
Although some novel techniques applied to coronary computed tomographic angiography (CCTA) images may enable prediction of blood flow and pressure fields in coronary arteries and calculation of lesion-specific FFR, waiting for noninvasive testing in patients admitted for acute chest pain, whether or not true angina, is often time-consuming and prolongs hospital stay.

Intravascular ultrasound (IVUS)

Anatomic measurements of intermediate coronary lesions obtained by IVUS show a moderate correlation to FFR values.
IVUS minimal lumen area (MLA) may be used as an alternative to FFR when assessing the need for intervention in intermediate coronary lesions.
A study compared the FFR-guided strategy (PCI was deferred for an FFR >0.80) with the IVUS-guided strategy (PCI was deferred for a minimal lumen are >4.0 mm²). No significant difference in the rates of major acute coronary events at 1 year between the two groups was noted, but IVUS-guided PCI led to threefold higher rates of intervention compared with an FFR-guided strategy.
In the current guidelines, IVUS is a 2B recommendation for the assessment of nonleft main coronary arteries with angiographically intermediate coronary stenoses (50% to 70% diameter stenosis).

Quantitive coronary angiography (QCA)

Previous study demonstrated that QCA was correlated to FFR value.
A recent study demonstrates that accuracy of QCA in predicting functionally significant FFR is limited and is dependent on the FFR cut-off used and lesion severity.
If FFR or IVUS are not available, or are contraindicated, three-dimension QCA MLA may be particularly helpful for quantifying coronary stenoses visually assessed as being of intermediate severity.
Three-dimensional QCA should not replace FFR in the functional evaluation of coronary stenosis severity.

Other invasive measurements

There are other indexes that may reflect functional significance of the epicardial coronary artery, coronary microcirculation, or both, such as coronary flow reserve (CFR), hyperemic stenosis resistance (HSR) index, index of microvascular resistance (IMR), coronary flow velocity reserve (CFVR), and instantaneous hyperemic diastolic velocity pressure slope (IHDVPS).
So far, they are seldom used in clinical practice due to limitations and are not well established.

Complications and their management

The clinical practice of using sensor-wire measurements with pharmacologically induced hyperemia has been applied in the past decade and is generally considered safe.
Complications with the procedure are rare, including transient bradycardia (1.7%), coronary spasm (2%), and ventricular fibrillation (0.2%).
Occasionally, guiding catheter or wire may cause vessel trauma (not different from regular angioplasty wires) and thrombus and vasospasm are possible.

What’s the evidence?

Pijls, NH, De Bruyne, B, Peels, K. “Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses”. N Engl J Med. vol. 334. 1996. pp. 1703-8. (This paper demonstrated that FFR appears to be a useful index of the functional severity of the stenoses as compared with standard noninvasive tests.)

Bech, GJ, De Bruyne, B, Pijls, NH. “Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial”. Circulation. vol. 103. 2001. pp. 2928-34.

Pijls, NH, van Schaardenburgh, P, Manoharan, G. “Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study”. J Am Coll Cardiol. vol. 49. 2007. pp. 2105-11. (The DEFER study is a landmark publication which demonstrated stable patients with FFR >0.75 do not benefit from PCI.)

Tonino, PA, De Bruyne, B, Pijls, NH. “Fractional flow reserve versus angiography for guiding percutaneous coronary intervention”. N Engl J Med. vol. 360. 2009. pp. 213-24.

Pijls, NH, Fearon, WF, Tonino, PA. “Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study”. J Am Coll Cardiol. vol. 56. 2010. pp. 177-84. (In another landmark publication, the FAME study, routine measurement of FFR in patients with multivessel coronary artery disease significantly reduces the rate of the outcome events and in-hospital cost.)

Puymirat, E, Peace, A, Mangiacapra, F. “Long-term clinical outcome after fractional flow reserve-guided percutaneous coronary revascularization in patients with small-vessel disease”. Circ Cardiovasc Interv. vol. 5. 2012. pp. 62-8.

Hamilos, M, Muller, O, Cuisset, T. “Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis”. Circulation. vol. 120. 2009. pp. 1505-12.

Muller, O, Mangiacapra, F, Ntalianis, A. “Long-term follow-up after fractional flow reserve-guided treatment strategy in patients with an isolated proximal left anterior descending coronary artery stenosis”. JACC: Cardiovascular Interventions. vol. 4. 2011. pp. 1175-82.

Samady, H, McDaniel, M, Veledar, E. “Baseline fractional flow reserve and stent diameter predict optimal post-stent fractional flow reserve and major adverse cardiac events after bare-metal stent deployment”. JACC. Cardiovascular interventions. vol. 2. 2009. pp. 357-63.

Sels, JW, Tonino, PA, Siebert, U. “Fractional flow reserve in unstable angina and non-ST segment elevation myocardial infarction experience from the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study”. JACC: Cardiovascular Interventions. vol. 4. 2011. pp. 1183-9.

Koo, BK, Part, KW, Kang, HJ. “Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve”. Eur Heart J. vol. 29. 2008. pp. 726-32.

Aqel, R, Zoghbi, GJ, Hage, F. “Hemodynamic evaluation of coronary artery bypass graft lesions using fractional flow reserve”. Catheter Cardiovasc Interv. vol. 72. 2008. pp. 479-85. (In these papers, the validation of FFR has been demonstrated in various clinical and anatomic subsets.)

Pijls, NH, Sels, JW. “Functional measurement of coronary stenosis”. J Am Coll Cardiol. vol. 59. 2012. pp. 1045-57. (In this state-of-the-art paper, the basic concept of FFR and its application, characteristics, and use in several subsets of patients are discussed from a practical point of view.)

Levine, GN, Bates, ER, Blankenship, JC. “ACCF/AHA/SCAI guideline for percutaneous coronary intervention a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines and the Society for Cardiovascular Angiography and Interventions”. J Am Coll Cardiol. vol. 58. 2011. pp. e44-e122.

Wijns, W, Kolh, P, Danchin, N. “Guideline on myocardial revascularization”. Eur Heart J. vol. 31. 2010. pp. 2501-55. (Recommendation of FFR measurement in the US and Europe guidelines.)

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