Percutaneous Coronary Intervention Should Be Guided by Fractional Flow Reserve Measurement

The importance of integrating coronary physiology into percutaneous coronary intervention (PCI) has been recognized since its inception. When Andreus Gruentzig first described percutaneous transluminal coronary angioplasty, he stressed the need to identify the translesional pressure gradient before and after intervention as a means of guiding a successful procedure.¹ Subsequently, other investigators examined the use of the Doppler wire to measure coronary flow velocity reserve (CFVR) before and after PCI.² Unfortunately, the lack of a low profile pressure monitoring device and the lack of appreciation of the importance of measuring hyperemic pressure gradients inhibited the full integration of coronary physiology into the PCI procedure. Additionally, with the advent of stents, the ease and safety of PCI improved dramatically. In conjunction with financial reimbursement for PCI and patient demand, these factors resulted in an inclination towards performing PCI, regardless of the functional significance of the stenosis.

While this enthusiasm over PCI was occurring, Pijls, De Bruyne and colleagues first described fractional flow reserve (FFR).^{1, 2} Like any new technique, FFR has required time to mature. Over the ensuing twenty years since its introduction, improvements in the pressure wire handling characteristics, the integration of data acquisition into the catheterization laboratory workflow, the completion of a number of multicenter, randomized studies, and the increased emphasis on appropriate use of PCI have all contributed to FFR achieving its current status as an indispensable and critical component of PCI.

Concept of FFR

Fractional flow reserve (FFR) is defined as the ratio of myocardial blood flow down a coronary artery in the presence of an epicardial stenosis as compared to the flow down the same vessel in the theoretical absence of any stenosis.³ The derivation of FFR has been described in detail and is shown in brief in Figure 1.^3,4 FFR can be calculated easily by measuring the mean distal coronary pressure with a coronary pressure wire and dividing it by the mean proximal coronary pressure, measured with a guiding catheter, during maximal hyperemia (Figure 2a and b).

Figure 1.

Derivation of fractional flow reserve. Pd represents distal coronary pressure, Pa represents proximal coronary or aortic pressure, and Pv represents venous pressure. During maximal hyperemia, resistance is minimized and assumed to be unchanged in the presence and absence of an epicardial stenosis; therefore, it is removed from the equation. Venous pressure is generally negligible in relation to coronary pressure and assumed to equal zero.

Figure 2.

a. A photograph of an angiographic image of a right coronary artery (RCA) lesion and the associated FFR tracing in a 67 year old man presenting with chest pain. The red tracing represents the mean and phasic proximal coronary pressure and the green line represents the mean and phasic distal coronary pressure. The horizontal yellow line represents the beat to beat ratio of distal pressure to proximal pressure. The vertical yellow line represents where the FFR measurement is made. On the left side of the tracing is the resting pressure gradient. On the right side of the tracing is the hyperemic pressure gradient after administration of intravenous adenosine. b. A photograph of an angiographic image of a left anterior descending (LAD) coronary artery lesion in the same patient with the associated FFR measurement. The right coronary lesion is not significant, while the LAD lesion is.

FFR was first validated in a landmark study by Pijls, De Bruyne and colleagues in which they measured FFR in 45 patients with single vessel intermediate coronary disease.⁵ Because there is no true noninvasive reference standard for diagnosing myocardial ischemia and to improve the accuracy of existing tests, every patient underwent exercise testing, dobutamine stress echocardiography and exercise thallium scintigraphy. According to Bayes' theorem and based on the individual diagnostic accuracy of each stress test, the composite accuracy of these three consecutive tests for myocardial ischemia approaches 100%. In every patient with an FFR below 0.75, myocardial ischemia was present on at least one test, and in 21 of 24 patients with FFR values of 0.75 or greater, myocardial ischemia was absent on all three tests, giving a sensitivity, specificity and diagnostic accuracy of FFR for identifying lesions capable of inducing myocardial ischemia of 88%, 100% and 93%, respectively. In the 24 patients with an FFR of 0.75 or greater, there were no ischemic events during 14 month follow-up. This small study formed the cornerstone for a number of larger studies which validated FFR in a variety of patient populations and clinical scenarios, and it demonstrated the safety of deferring revascularization of lesions which are not functionally significant (non-ischemic FFR).

Practical Aspects of FFR

FFR has a number of unique aspects which distinguish it from other indices of coronary physiology, such as CFVR (Table 1). FFR has an upper normal value of 1.0 in every patient and every vessel. In a study of 37 angiographically normal appearing coronary arteries in patients without signs of myocardial ischemia, the average FFR was 0.97.⁶ FFR is extremely reproducible and independent of hemodynamic perturbations. In another study, the coefficient of variation of two repeated FFR measurements was 1.6% and there was no significant difference in FFR after changing the heart rate with pacing, the blood pressure with sodium nitroprusside administration, or the left ventricular contractility with dobutamine administration.⁷

Table 1.

Unique Aspects of Fractional Flow Reserve
Normal value of 1.0 in every patient/vessel
Narrow ischemic threshold (0.75-0.80)
Highly reproducible
Independent of hemodynamic changes
Specific for epicardial artery stenosis
Independent of the microvasculature
Accounts for collateral flow

FFR has a narrow cutoff range distinguishing lesions capable of producing ischemia from non-hemodynamically significant ones. Multiple studies performed by numerous different groups in a variety of patient populations have shown that FFR values below 0.75-0.80 have a very high specificity for identifying ischemia based on a variety of noninvasive imaging studies.⁸ If the FFR value is above 0.80, it is very unlikely that the vessel or lesion interrogated is responsible for significant ischemia.

FFR has superb spatial resolution. By placing the pressure wire in the distal portion of an epicardial vessel, one can measure the FFR and determine if the disease in that vessel is responsible for ischemia. If the FFR is abnormal, and particularly if the vessel has tandem areas of narrowing, one can slowly pull the pressure wire back to the proximal vessel during maximal hyperemia and identify which lesion is responsible for the greatest portion of the gradient. It is important to note that with the pressure sensor positioned between the two narrowings, distal to the proximal one, it is not possible to determine the “FFR” of the proximal narrowing. This is because each narrowing affects flow across the other and removal of one narrowing, for example with PCI, can lead to an increase in flow down the vessel and a larger pressure gradient across the remaining lesion.

In the setting of tandem stenoses, equations have been described which allow the operator to determine the FFR of each lesion in the theoretical absence of the other lesion, however, the complexity of these equations and the requirement for measuring the coronary wedge pressure have limited their clinical utility.⁹

FFR is independent of the microvasculature, specific for epicardial coronary artery disease, and accounts for both coronary and collateral flow. In patients with remote myocardial infarction (MI), for example, FFR still correlates with the presence or absence of ischemia on noninvasive stress imaging.¹⁰ In this setting, the flow across a given stenosis subtending infarcted myocardium will be less and the pressure gradient less, leading to a higher FFR value; the higher FFR is not falsely elevated, but reflects the smaller amount of viable myocardium supplied by the vessel and still provides information about the expected gain in flow after PCI. On the other hand, if there is an intermediate lesion in a vessel supplying collaterals to viable myocardium subtended by a chronically occluded vessel, the flow down the collateral supplying vessel will be greater than in the normal setting; the pressure gradient across the intermediate stenosis will be higher than expected; and the FFR will be lower. These scenarios help to explain why FFR is more accurate than angiography or intravascular anatomic methods, such as intravascular ultrasound, at identifying lesions capable of producing myocardial ischemia.

One of the limitations of FFR is that it is not reliable in the culprit vessel of a patient with an ST segment elevation MI. This is because FFR assumes microvascular resistance will be minimized and fixed. In the culprit vessel of an ST segment elevation MI, there is a variable degree of reversible microvascular stunning resulting in a lower maximum achievable flow, a lower pressure gradient, and a higher FFR. With time, the microvasculature may recover, maximum achievable flow may increase, and a larger gradient with a lower FFR may be measured across a given stenosis. For this reason, the FFR measured in the culprit vessel in the acute setting may be higher than the FFR measured in the same vessel one month later. However, in the setting of non ST elevation acute coronary syndromes, where the degree of reversible microvascular dysfunction is likely to be low, measuring FFR in the culprit and non-culprit vessel has been shown to be safe and effective.¹¹ Moreover, in non-culprit vessels of patients with ST segment elevation MI, FFR remains accurate.¹²

Achieving maximal hyperemia is a prerequisite to measuring FFR accurately. A potential pitfall to FFR measurement is the lack of maximal vasodilation, which will result in lower maximal flow across a stenosis, a lower pressure gradient and a falsely high FFR. In the validation studies and major clinical trials, FFR has been measured after administration of intravenous adenosine delivered via a central vein at 140 micrograms/kilogram/minute. This method has been shown to be extremely safe and reliable.⁸ Most patients do have symptoms of either chest pressure or dyspnea related to the infusion, but they are well-tolerated in the vast majority of cases and resolve as soon as the infusion is discontinued. In one respect, these symptoms are reassuring, because they inform the operator that hyperemia has occurred.

Why do we need FFR?

Myocardial ischemia is associated with symptoms and adverse cardiac outcomes. Noninvasive stress imaging identifies the presence and degree of myocardial ischemia and can predict death and MI.¹³ However, the spatial resolution (i.e. the ability to identify the culprit lesion, or even vessel) of noninvasive stress imaging is lacking, particularly in patients with multi-vessel coronary disease.¹⁴ The noninvasive test is a useful gatekeeper to decide which patients warrant invasive coronary angiography, but once in the cardiac catheterization laboratory, FFR is necessary to identify which lesion(s) is responsible for the patient's symptoms. This was recently highlighted in two studies comparing FFR and nuclear perfusion scanning in patients with multi-vessel disease, both of which demonstrated significant discordance between the two modalities and prompted the editorialists to conclude that FFR is the reference standard for identifying lesions capable of producing ischemia.^15,16,17 Not only does the inaccuracy of noninvasive imaging make FFR necessary, but the fact that noninvasive stress imaging has not been performed in the majority of patients undergoing PCI, further emphasizes the need for a cardiac catheterization laboratory-based technique for identifying lesions capable of producing ischemia.¹⁸

One might argue that the coronary angiogram is accurate enough to guide the decision regarding PCI once a patient makes it to the catheterization suite. However, in the Fractional Flow Reserve versus Angiography for Multi-vessel Evaluation (FAME) trial, FFR was measured in over 500 patients with multi-vessel coronary disease and compared to the visual interpretation of the angiogram.¹⁹ Approximately 35% of the lesions graded between 50-70% narrowed had an ischemic FFR, while roughly 20% of the lesions between 71-90% had nonischemic FFR values (Figure 3). Multiple smaller studies have asked experienced interventional cardiologists to predict which lesions will have an ischemic FFR value and which will not; in all cases, the diagnostic accuracy of the visual interpretation of the angiogram has been unacceptable for guiding decisions regarding the need for PCI.^20,21 Quantitative coronary angiography has not improved the lack of concordance between the angiographic severity of a stenosis and its ischemic potential.²²

Figure 3.

Comparison of FFR values and visual interpretation of the coronary angiogram in 509 patients randomized to FFR guided PCI in the FAME trial. Of the lesions interpreted to be narrowed between 50 and 70%, approximately 35% had an ischemic FFR. Of the lesions narrowed between 71 and 90%, roughly 20% had a non-ischemic FFR. Reprinted with permission from reference 19.

Others might argue that FFR is not necessary because intravascular imaging techniques such as intravascular ultrasound or optical coherence tomography are available and can accurately identify which lesions warrant PCI. These techniques do provide detailed visualization of coronary plaque and allow quantification of lumen area and other anatomic parameters, such as lesion length, which contribute to the ischemic potential of a stenosis. Unfortunately, they currently do not provide information regarding the viscous and separation forces or flow across a stenosis, all of which are accounted for by measuring the pressure gradient and all of which determine the functional significance of a stenosis.⁸ Most studies evaluating the accuracy of either intravascular ultrasound or optical coherence tomography for identifying lesions responsible for ischemia have compared the minimum lumen area assessed by either technique to fractional flow reserve and have found poor correlations.^23,24,25 This is because the cutoff for a significant minimum lumen area will vary depending on where the measurement is made along the vessel, the size of the vessel, and the amount of viable myocardium subtended by the vessel. One of the advantages of FFR is that the same cutoff is applied in every patient and every vessel.

Data Supporting FFR-Guided PCI

Initially, FFR was promoted as a method for identifying which intermediate coronary lesions could be treated safely medically, without PCI. At 18 month follow-up of a retrospective cohort of 100 patients with chest pain, intermediate coronary stenoses and non-ischemic FFR values in whom PCI was deferred in favor of medical therapy, there were no cardiac deaths, one target vessel MI, and three target vessel revascularizations.²⁶ These data were reassuring, but it wasn't until the multicenter, prospective, randomized DEFER trial was published by Bech and colleagues that the safety of this approach began to gain acceptance.²⁷

The DEFER trial included 325 patients with chest pain and intermediate coronary lesions who underwent FFR assessment. The 181 patients with non-ischemic FFR values were randomized to performance of PCI or to deferral of PCI. At two year follow-up, the event-free survival rate was 89% in the deferral group and 83.3% in the perform group (p=0.27). There was a 2.2% cardiac death rate and 5.6% study lesion revascularization rate, without any MI in the deferral group. Angina relief was similar between both groups, as well. Subsequently, the 5 year death and MI rates of the two groups have been reported.²⁸ Although not statistically significant, the 3.3% rate in the deferral group was less than half the 7.9% rate in the perform group (p=0.21).

The findings from the DEFER trial established the safety of treating functionally non-significant intermediate epicardial coronary narrowings with medicine as opposed to PCI, but they did not address an important and often vexing subgroup of intermediate coronary lesions, those involving the left main coronary artery. The inadequacy of the angiogram alone for assessing the severity of moderate left main coronary disease has been appreciated for years. However, relying on a novel technique, such as FFR to make the critical decision regarding revascularization in this setting has gained acceptance more slowly. Initially, a number of small, single center studies demonstrated excellent short-term outcomes in patients with moderate left main disease in whom revascularization was deferred because the FFR was not in the ischemic range.²⁹ More recently, Hamillos and colleagues reported on 213 patients with moderate left main disease in whom FFR was measured.²¹ FFR was non-ischemic in 138 of these patients and revascularization was deferred. The 5 year survival rate was 90% in these patients, as compared to 85% in those with ischemic FFR values who underwent revascularization (p=0.48). The event-free survival was similar between the two groups as well. In this study, like in previous ones, experienced interventional cardiologists were unable to predict accurately which lesions would have a significant FFR based on their interpretation of the angiogram, further emphasizing the importance of an FFR-guided approach to PCI even when involving the left main coronary artery (Figure 4).

Figure 4.

Comparison of two expert interventional cardiologists' predictions of whether a left main coronary lesion is functionally significant, nonsignificant or unsure of the significance and the actual FFR value. Neither reviewer was able to accurately predict which lesions would have an ischemic or nonischemic FFR. Reprinted with permission from reference 21.

The DEFER trial and others like it established FFR's reputation as a method for deferring PCI, not necessarily a technique to be embraced by the interventional cardiology community. Two studies evaluating FFR after stenting did show that it could be used to determine optimal stent deployment and predict outcomes after PCI.^30,31 However, it was not until the FAME trial was performed and published by Tonino and colleagues that FFR gained traction as a method for guiding PCI.³² In the FAME trial, 1005 patients with coronary lesions of >50% diameter stenosis in two or three major epicardial vessels which were amenable to PCI with drug-eluting stents were randomized to either the standard of care, angiography-guided PCI, in which case PCI was performed based on the noninvasive clinical data and the angiographic appearance of the lesions, or to FFR-guided PCI, in which case FFR was measured across every stenosis and only if the FFR was ≤0.80 was PCI performed on the particular stenosis.

There were approximately 3 lesions identified per patient in both groups, but the angiography-guided PCI group received significantly more stents per patient, 2.7 ±1.2 versus 1.9 ±1.3, p<0.001. In addition, significantly more contrast media was administered to the angiography-guided PCI patients, 302 ±127 versus 272 ±133 milliliters, p<0.001. Importantly, the time of the procedure was identical between the two groups; although measuring FFR adds time to the procedure, avoiding unnecessary PCI saves time. Despite the fewer stents, the percentage of patients free of angina at one year was numerically higher in patients randomized to FFR guidance (81.3 versus 77.9%, p=0.20).

The primary endpoint of the FAME trial was the one year rate of death, MI or repeat revascularization, which occurred in 18.3% of the angiography-guided PCI patients as compared to 13.2% of the FFR-guided PCI patients, p<0.02 (Figure 5). This significant reduction resulted from 30-40% relative risk reductions in each component of the composite endpoint. In addition, the rate of death and MI was reduced significantly in the FFR-guided PCI group (7.3 versus 11.1%, p=0.04). Subsequently, the two year results of FAME were reported and revealed a persistent reduction in the composite of death, MI and repeat revascularization (17.9 versus 22.4%, p=0.08).³³ Importantly, the hard endpoints of death and MI remained significantly lower in the FFR-guided PCI patients (8.4 versus 12.9%, p=0.02). The Kaplan-Meier curves at one and two years showed that the benefit attributed to FFR guidance occurred early, due to fewer procedural related events, and continued during follow-up, due to fewer late events.

Figure 5.

One year adverse events in the FAME trial. MACE represents major adverse cardiac events (death, MI, or repeat revascularization).32

The FAME trial provided further evidence regarding the safety of deferring PCI of lesions which are not functionally significant. In the FFR-guided patients, there were 513 angiographically significant appearing lesions (>50% diameter stenosis) which had FFR values > 0.80 and therefore were treated medically, without PCI. The two year rate of MI due to one of these lesions was 0.2% and the revascularization rate was 3.2%.³³ This is particularly noteworthy given that approximately one-fourth of these deferred lesions appeared >70% narrowed based on visual interpretation of the angiogram. Data like these led the European Society of Cardiology to give FFR it highest recommendation, Class IA, in favor of FFR-guided PCI when objective evidence of ischemia is lacking.³⁴ Older guidelines from the American cardiology societies give FFR a IIA recommendation for assessing the need for PCI of an intermediate lesion.³⁵

By demonstrating improved outcomes despite more judicious use of stents, the FAME trial validated the concept of “functional angioplasty”, stenting lesions responsible for ischemia and treating medically those lesions which are not hemodynamically significant. In this manner, the benefit of the stent is optimized and the risks minimized. Although this approach results in a functionally complete revascularization, it does not result in an anatomically complete one. In patients with multi-vessel coronary disease, this is particularly relevant because many of our treatment decisions regarding revascularization are made based on angiographic (or anatomic) assessment of the severity of coronary disease. For example, the SYNTAX score is an angiography-based scoring system designed to quantify the complexity of coronary disease; those patients with high SYNTAX scores tend to have better outcomes with coronary artery bypass graft surgery, while those patients with low scores appear to do equally well with PCI.³⁶

Because the SYNTAX score is based on visual interpretation of the angiogram, it is inherently limited by the inaccuracy of the angiogram. A substudy from the FAME trial asked whether incorporating FFR into the SYNTAX score and calculating a “Functional SYNTAX Score” or FSS might convert higher risk SYNTAX score patients to a lower risk and whether it might improve the risk stratification of patients with multi-vessel coronary disease undergoing PCI.³⁷

In the 497 patients in the FFR-guided arm of FAME, the SYNTAX score was calculated in the usual fashion and the patients were divided into tertiles, based on the SYNTAX score. The FSS was then determined by recalculating the SYNTAX score taking into account only those lesions with an FFR ≤ 0.80. More than 1/3 of patients moved from a higher risk group to a lower one after calculation of the FSS. In addition, the FSS was a significant predictor of death or MI, while the classic SYNTAX score was not (Figure 6). In this manner, the FSS simplifies the approach to PCI in many of these challenging multi-vessel disease patients and may make PCI a more appropriate treatment than CABG. This hypothesis is now being tested prospectively in the FAME 3 trial, comparing FFR-guided PCI to CABG in patients with three-vessel coronary disease.

Figure 6.

Risk of death or MI based on low, medium or high risk SYNTAX Score tertile in the 509 patients randomized to FFR guided PCI in the FAME trial on the left and the same risk depicted for the patients once they are reclassified based on the Functional SYNTAX Score. Of note, there is a shift of higher risk patients to a lower risk score after taking into account the FFR value of each lesion being scored. The Functional SYNTAX Score was a better predictor of death or MI. Adapted with permission from reference 37.

The FAME trial also further established the safety and benefit of measuring FFR in patients with non ST elevation acute coronary syndromes. A small study of 70 patients with unstable angina and non ST segment elevation MI had suggested that measuring FFR, even in the culprit vessel, was a safe and reliable method for triaging treatment decisions.³⁸ The FAME trial, however, included a much larger cohort of 328 patients with unstable angina or non ST segment elevation MI who underwent urgent angiography and were randomized to FFR-guided or to angiography-guided PCI, including FFR assessment of both the culprit vessel and non-culprit vessel. A substudy of this cohort revealed a similar relative risk reduction from FFR-guided compared to angiography-guided PCI in the non ST segment elevation acute coronary syndrome patients as was seen in the stable patients enrolled in the FAME trial.³⁹

Although the FAME trial successfully demonstrated that decisions regarding PCI in patients with multi-vessel coronary disease should be based on FFR guidance and not the angiogram alone, one of the criticisms of the FAME trial was the use of the zotarolimus-eluting Endeavor stent in over 40% of patients, because of concern that it might be inferior to the two other drug-eluting stents available at the time of the study, the paclitaxel-eluting Taxus stent and the sirolimus-eluting Cypher stent. However, a subsequent study has demonstrated lower rates of periprocedural MI and similar rates of target lesion revascularization and target vessel failure with the Endeavor stent when compared to the Taxus stent.⁴⁰ Moreover, a longer-term comparison of the Endeavor stent to the Cypher stent revealed significantly lower rates of mortality, myocardial infarction and major adverse cardiac events.⁴¹

Another criticism that has emerged is that the results of FAME would be different if the second generation everolimus-eluting stent was used, because studies have shown that this stent is superior to first generation drug-eluting stents.⁴² However, any improved outcome seen with the everolimus-eluting stent would occur in both the angiography- and FFR-guided patients, with the FFR-guided patients still having improved outcomes compared to the angiography-guided patients. For the angiography-guided patients to achieve similar or better results than the FFR-guided patients, the event rate after everolimus-eluting stenting would need to be similar to or lower than the event rate after medical treatment of nonischemic lesions. At two year follow-up in FAME, the deferred lesions had a 0.2% MI rate and a revascularization rate of 3.2%; at two year follow-up after everolimus-eluting stenting, the MI rate was 2.5% and the target vessel revascularization rate was 6.8%.^33,43

A final criticism of FAME was the lack of a medical therapy arm in the randomization scheme, particularly in the stable coronary artery disease patients. The COURAGE trial randomized more than 2,000 patients with stable single or multi-vessel coronary disease to best medical therapy alone or to PCI in addition to best medical therapy and found no difference in the rate of death or MI at a median follow-up of 4.6 years.⁴⁴ Based on these results, some wondered what the event rate in FAME would have been if a medical therapy arm had been included in the 2/3 of stable patients in FAME not presenting with an acute coronary syndrome.

One of the goals of the FAME 2 trial was to address this concern by comparing PCI of lesions with an abnormal FFR to best medical therapy in patients with stable single or multi-vessel coronary disease.⁴⁵ One of the criticisms of the COURAGE trial is that low risk patients without significant myocardial ischemia were enrolled. The FAME 2 trial was designed specifically to ensure the inclusion of patients with a large burden of ischemia. This was achieved by randomizing only patients with at least one lesion in one of the three major epicardial vessels with >50% narrowing and an FFR ≤0.80. Those patients with narrowings of >50% but with an FFR >0.80 were not included in the randomized portion of the study but followed in a registry and treated with best medical therapy. The goal was to randomize roughly 1600 patients and follow them for two years with a primary composite endpoint of death, MI or unplanned hospitalization requiring urgent revascularization.

After 888 patients had been randomized, recruitment into FAME 2 was stopped prematurely by the data and safety monitoring board because of a highly significant difference in the primary endpoint between the two groups. After a mean follow-up of only 7 months, the primary endpoint occurred in 12.7% of patients in the best medical therapy arm compared to 4.3% in the PCI plus best medical therapy arm. There was no significant difference in death (0.7 vs. 0.2%, p=0.31) or MI (3.2 vs. 3.4%, p=0.89), but a highly significant difference in the rate of unplanned hospitalization requiring urgent revascularization (11.1 versus 1.6%, p<0.001) between the best medical therapy arm and PCI arm, respectively. The rate of any revascularization was also significantly higher in the best medical therapy arm (19.5 vs. 3.1%, p<0.001).

Both groups in FAME 2 received excellent medical therapy, with the vast majority prescribed aspirin, a statin, a beta blocker and an angiotensin converting enzyme inhibitor, in similar rates to what was seen in the COURAGE trial. The majority of the best medical therapy arm also received a calcium channel blocker and/or nitrate for refractory angina. Despite this, the hospitalization rate for an acute coronary syndrome requiring urgent revascularization in the best medical therapy arm was 11.1% at just 7 months. In comparison, in the COURAGE trial, the rate of an acute coronary syndrome at a median follow-up of 4.6 years was only 11.8%.⁴⁴ This difference is likely because in the FAME 2 trial, by measuring FFR first, patients with a larger burden of ischemia were randomized.

The concept of more severe ischemia resulting in worse outcomes is supported further by the fact that stratifying outcomes in FAME 2 based on an FFR value of 0.65 demonstrated a significant interaction, meaning that those patients with more severe ischemia at baseline had even greater benefit with PCI as compared to medical therapy alone.⁴⁵

Importantly, there were 332 patients in the FAME 2 trial with angiographic coronary disease which was not significant based on FFR assessment and 166 of these were randomly assigned follow-up in a registry receiving best medical therapy alone. The primary endpoint occurred in only 3.0% of these registry patients with a 2.4% rate of urgent revascularization. This finding further emphasizes the importance of not only identifying angiographic evidence of coronary disease, but further characterizing whether the disease is responsible for ischemia; patients with these types of lesions benefit from PCI, while patients with angiographic disease which is not functionally significant based on FFR respond well to medical therapy alone.

The FAME 2 trial has been criticized because it was stopped early, because there was no significant difference in the rate of death or MI, and because the primary endpoint included unplanned hospitalization requiring urgent revascularization, which some consider a subjective or “soft” endpoint. The data and safety monitoring board concluded that from a scientific standpoint the difference in the rate of the composite endpoint between the two groups was so statistically significant, it was extremely unlikely that completing enrollment would alter the results. Even though there was no difference in death and MI, they considered unplanned hospitalization requiring urgent revascularization as an important safety outcome. Although this is a subjective endpoint in comparison to death and MI, it was adjudicated by an independent clinical events committee. Approximately one half of the unplanned hospitalizations requiring urgent revascularization were associated with biomarker elevation or electrocardiographic changes consistent with ischemia; using this stricter and more objective definition for acute coronary syndrome, there was still a highly significant difference in the rate of unplanned hospitalization requiring urgent revascularization between the two groups (0.9 vs. 5.2%, p<0.001, unpublished data).

The FAME 2 trial was not powered to detect a significant difference between the two randomized groups with respect to death and MI; however, a landmark analysis showed that during the first 7 days after enrollment there was a higher rate in the PCI arm (1.8 vs. 0.2%, p=0.04) primarily because of periprocedural MI in the PCI patients, while after 7 days there was a higher rate of death and MI in the best medical therapy arm (1.6 vs. 3.7%, p=0.05) primarily due to spontaneous MI.⁴⁵ Other studies have found that late spontaneous MI is a much stronger predictor of long-term mortality as compared to peri-PCI MI.⁴⁶ Longer term follow-up of the FAME 2 trial will be important to evaluate this further.

Many accepted therapies which we provide our patients, for example, orthopedic procedures, do not reduce death or MI, but improve quality of life and decrease the need for hospitalization. The fact that PCI guided by FFR has not yet been shown to decrease death or MI rates in comparison to medical therapy, should not diminish its value.

Another important consideration in evaluating the value of a new approach is the economic and quality of life implications of the approach in comparison to the standard of care. An early analysis using computer modeling and a randomized, single center study both suggested that measuring FFR was cost-effective in patients with intermediate single vessel coronary disease when compared to a noninvasive stress imaging strategy.^47,38 In the FAME trial, comparing FFR-guided PCI to angiography-guided PCI in patients with multi-vessel coronary disease, the FFR-guided approach significantly reduced costs both at the time of the procedure and during follow-up.⁴⁸ Although the coronary pressure wire and adenosine cost approximately $800, by decreasing the number of drug-eluting stents necessary for revascularization, the FFR-guided approach resulted in roughly $700 savings in procedural costs. Because of the lower rate of adverse events in the FFR-guide group, the one year costs were reduced significantly by $2,400.

Quality of life in the FAME trial was assessed by using the EuroQual 5 dimension (EQ-5D) health survey at baseline, one month and one year. The quality adjusted life years (QALY) were numerically higher in the FFR-guided patients, although not statistically different at one year (0.853 vs. 0.838, p=0.20). Bootstrap simulation revealed that the FFR-guided strategy was cost-saving in over 90% of cases and cost-effective (at a threshold of $50,000 per QALY gained) in 99.96% of cases (Figure 7a). Thus, compared to an angiography-guided approach, an FFR-guided strategy is a dominant one.

Figure 7.

a. Bootstrap simulation of the incremental cost effectiveness of FFR-guided PCI as compared to angiography-guided PCI. Data are from 5,000 bootstrap replications. Willingness to pay threshold of $50,000 per QALY is added (solid line). Reprinted with permission from reference 44. b. Bootstrap replications of the incremental cost effectiveness of the PCI in the setting of an abnormal FFR strategy compared with best medical therapy. Each of the 10,000 points represents the results of one bootstrap replication. The difference in cumulative costs is displayed in the vertical axis, and the difference in quality-adjusted life-years (QALY) is displayed on the horizontal axis. Willingness to pay thresholds of $50,000 per QALY added (solid line), $100,000 per QALY added (dashed line), and $150,000 per QALY added (dotted line) are indicated in the plane. The fractions of replications in each sector of the plane are indicated (e.g., 0.088 of the replications had a cost difference <0 and QALY difference >0). Reprinted with permission from reference 45.

More recently, the cost-effectiveness of an FFR-guided strategy to PCI has been compared to medical therapy in patients with stable coronary disease. In the FAME 2 trial, performance of PCI on lesions with an abnormal FFR resulted in a roughly $6,000 initial cost increase as compared to best medical therapy.⁴⁹ However, during the course of one year, this difference narrowed to just under $3,000 because of increased revascularization costs in the best medical therapy arm. Quality of life improved significantly in the PCI group of patients, while there was no change in the best medical therapy arm. It was assumed, based on previous data from the COURAGE trial and other studies that this difference in quality of life would gradually dissipate over three years, but that the cost difference between the two strategies would not narrow any further. Based on these assumptions, the cost-effectiveness of performing PCI on lesions with an abnormal FFR was $36,000 per QALY gained, when compared to best medical therapy. Bootstrap simulation revealed that for 80% of cases the cost effectiveness ratio was <$50,000 per QALY gained and for 99.5% of cases it was <$100,000 per QALY gained (Figure 7b).

Conclusion

Should FFR be measured in all cases of PCI? If a patient has typical angina and single vessel coronary disease with a significant appearing lesion in a vessel subtending myocardium which is ischemic on a noninvasive stress imaging study, then FFR measurement is not necessary. If a patient is having an acute MI with significant single vessel coronary disease, FFR is not necessary. However, these two scenarios represent the minority of cases seen in the cardiac catheterization laboratory. The vast majority of cases involve patients with multi-vessel disease, lesions of indeterminate severity, and/or discordant or absent stress imaging data. In these scenarios, there is now a wealth of data supporting the routine measurement of FFR to guide PCI. Our primary goal in the catheterization laboratory should be to relieve the symptoms and improve the prognosis of our patients. This is best accomplished by identifying and relieving stenoses responsible for myocardial ischemia. Measuring FFR is currently the most cost-effective and accurate method for achieving this goal.