“We could fractional flow reserve it…” This is a common refrain heard in many catheterization laboratories and, unfortunately, it has often been followed by either “Well, let’s just stent it…” or by “Let’s try another angle and maybe we will see it better…” There are a number of potential reasons why fractional flow reserve (FFR) has been underutilized in the catheterization laboratory, including a lack of understanding of the technique and/or of the data supporting its role in decision-making, the perception that it adds significant time and complexity to the procedure, and operator volume and financial considerations.
Lack of familiarity with the FFR technique & data
There is little excuse for today’s interventional cardiologist to be unfamiliar with the concept of FFR. For example, in the USA, FFR has been featured on the Interventional Cardiology American Board of Internal Medicine examination for the past number of years. There have been countless reviews published in prominent international medical journals. Every major cardiology and interventional cardiology meeting dedicates symposia to the assessment of physiologic lesions. New data continue to become available supporting the role of FFR in guiding percutaneous coronary intervention (PCI).
There are now more than 10 years of data published regarding the role of FFR in various settings. A published landmark study in the New England Journal of Medicine by Pijls, De Bruyne and colleagues demonstrated the accuracy of FFR for identifying ischemia-producing lesions in patients with chest pain and angiographically intermediate coronary stenoses Citation[1]. Subsequently, these same investigators and others demonstrated the safety of deferring PCI in patients with an FFR above the ischemic threshold Citation[2]. In the Deferral versus Performace of PCI of Non-Ischemia-Producing Stenoses (DEFER) study, patients with an indeterminate stenosis and an FFR of 0.75 or greater were randomized to either PCI with a bare-metal stent or to medical therapy. The rate of adverse events at 2 years was similar between the two groups. At 5 years, the death and myocardial infarction rate in the medical therapy arm was less than half of what it was in the stent arm Citation[3]. One might argue that these results would be different with drug-eluting stents. However, in a pooled analysis of four randomized studies evaluating drug-eluting stents, the death and myocardial infarction rates at 1 year in patients with intermediate lesions treated with drug-eluting stents was similar to the 5-year event rate in the deferred arm of the DEFER study Citation[4].
More recently, the results of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study were published in the New England Journal of MedicineCitation[5]. The goal of this study was to compare the current standard method of using the coronary angiogram to guide PCI in patients with multivessel disease to a strategy employing the routine measurement of FFR to guide PCI. The hypothesis was that FFR guidance would improve patient outcomes and decrease costs. The inclusion criteria for this large, 1000-patient, multicenter, international, randomized study were broad. Essentially, any patient with lesions of 50% or greater in at least two major epicardial vessels and that the investigator believed warranted PCI, based on the angiographic appearance and clinical data, could be enrolled, unless the patient presented with an ST-segment elevation myocardial infarction or large non-ST-segment elevation myocardial infarction within the past 5 days, significant left main disease, a previous CABG surgery, severe left ventricular dysfunction, cardiogenic shock or extremely calcified and tortuous coronary arteries.
After a baseline angiogram was performed and demonstrated multivessel disease, the investigator declared which lesions, based on the angiogram and noninvasive clinical data, warranted PCI. The patient was then randomized. If randomized to angiographic guidance, then the investigator performed PCI on the previously declared lesions with drug-eluting stents. If the patient was randomized to FFR guidance, then FFR was first measured across each lesion with intravenous adenosine to induce maximal hyperemia. If the FFR was below 0.80, then PCI was performed; otherwise, PCI was deferred on that lesion. The primary end point of the study was the difference in the rate of death, myocardial infarction or the need for revascularization between the two groups at 1 year. There were a number of important secondary end points, including procedure time, the amount of contrast agent administered, the quality of life and the cost of the procedure.
The FAME study showed that, with FFR guidance, 30% fewer stents were necessary, significantly less contrast was used, there was no difference in procedure time, the cost of the procedure was significantly reduced and angina was equally well relieved. Most importantly, the rate of death, myocardial infarction or the need for revascularization were significantly lower in the FFR-guided arm compared with the angio-guided arm (13.2 vs 18.4%; p = 0.02). Moreover, the death or myocardial infarction rate was also significantly lower in the FFR-guided arm (7.3 vs 11.1%; p = 0.04). Based on the results of these studies and many others, it is difficult to argue that there is a lack of data supporting the utility of measuring FFR to guide PCI.
Measuring FFR adds significant time & complexity
The FAME study demonstrated that the routine measurement of FFR in all lesions, even angiographically severe lesions, when performing PCI in patients with multivessel disease, does not prolong the procedure. Granted this study was performed by investigators familiar with measuring FFR; however, it was a multicenter, international study involving six US centers and 14 European sites. Measuring FFR does add a short amount of time for preparation of the adenosine, calibration of the wire and infusion of the adenosine. However, because it identifies angiographically significant lesions that are not functionally significant and do not require PCI, measuring FFR also saves significant time, contrast and money.
With respect to increasing the complexity of the procedure, measuring FFR does not involve learning any new interventional techniques. The coronary pressure wire behaves in a similar fashion to a ‘workhorse’ coronary guidewire. By performing some simple preparatory steps, the process of measuring FFR can take less than 5 mins. At many centers where FFR is commonly measured, the analyzer remains mounted to the catheterization laboratory table and plugged in at all times. Adenosine is often mixed before the case and ready for administration. In this way, if the operator decides to measure FFR, all that is necessary is to open, calibrate and advance a wire to the ostium of the guide catheter to equalize pressures and then cross the lesion in question and start infusing the adenosine. A pullback of the wire can then be performed to localize the area responsible for the gradient and to confirm that there has been no ‘drift’ in the pressure recording. As with any other adjunctive technology employed in the catheterization laboratory, such as intravascular ultrasound, if only used once a month, it will seem complex and time-consuming. Future advances in wire technology, as well as incorporation of the coronary pressure monitor into the catheterization laboratory’s primary hemodynamic system, will further simplify the routine measurement of FFR.
Operator volume & financial considerations
A final potential reason why it has been taking a longer time than expected for FFR to be more widely applied is the perception that measuring FFR will decrease an operator’s PCI volume and have negative financial implications for both the operator and the hospital. It is true that if one’s practice is to stent all intermediate coronary lesions, then measuring FFR and abiding by its result will decrease one’s PCI volume, as usually only 40% of intermediate lesions are ischemia-producing and require PCI. However, many operators do not routinely perform PCI for all intermediate lesions but rely on the clinical data and their interpretation of the angiogram to guide them. Numerous studies, including FAME, have demonstrated that relying on the angiogram and one’s clinical judgment can result in misclassification of lesion significance even by the most experienced operators. It is important to remember that the severity of proximal lesions, particularly in the left anterior descending artery, is typically underestimated. By measuring FFR more routinely, operators will identify these lesions that are causing ischemia and may lead to adverse events but which may have otherwise gone unrecognized if the physician relied solely on the angiogram and clinical data. For this reason, incorporating the pressure wire more routinely into one’s interventional practice may also help identify opportunities for PCI.
Another area where FFR may increase PCI volume is in patients with multivessel disease who may have otherwise been referred for CABG. The FAME study showed that on average, 30% fewer stents can be used when FFR is routinely assessed. Furthermore, many cases of apparent three-vessel disease are downgraded to two- or one-vessel disease, which can be approached more easily with PCI. In another interesting study, 150 patients with three-vessel coronary disease who were initially referred for CABG underwent FFR measurement; based on the FFR result, 63 cases could be converted to two-vessel disease or less and were successfully treated with PCI, with equivalent results to historical bypass patients Citation[6].
Some may counter that the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial, which compared, in a randomized fashion, PCI with drug-eluting stents to CABG in patients with multivessel coronary disease, demonstrated superiority of CABG over PCI Citation[7]. However, in the SYNTAX trial, PCI was guided by angiography alone. Since the clinical characteristics of the patients studied in SYNTAX were similar to the FAME study, it is of no surprise that the PCI arm in SYNTAX had a similar outcome to the angio-guided arm in FAME. If one extrapolates the FAME data to the SYNTAX trial, PCI that is guided by FFR could have very similar outcomes to CABG, if compared in a randomized trial. Thus, one can argue that measurement of FFR in multivessel disease will allow operators to perform PCI in patients they may otherwise send to CABG, and achieve equivalent outcomes.
A final potential manner in which FFR may increase an operator’s PCI volume relates to the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial Citation[8]. According to the COURAGE study, which compared optimal medical therapy to PCI plus optimal medical therapy and showed no significant difference in the rate of death and myocardial infarction in patients with stable coronary disease, many physicians are electing to treat their coronary-disease patients medically. An important substudy of COURAGE revealed that patients who had a more complete resolution of their ischemia had better outcomes than those who did not Citation[9]. Again, similar to SYNTAX, PCI in COURAGE was guided by angiography alone. One can argue that if PCI had been guided by FFR, there would have been better relief of ischemia and fewer instances of death and myocardial infarction, as was seen in the FAME study. This may have led to a more favorable comparison between PCI and medical therapy in these patients. If one could demonstrate that FFR-guided PCI actually improves outcomes compared with medical therapy, a significant number of patients, who otherwise may be treated medically, may instead be referred for PCI.
In conclusion, with continued physician education and generation of data, such as the FAME study, appreciation of the clinical value of measuring FFR to guide PCI will continue to grow, as will its everyday application. Furthermore, if and when expert guidelines, healthcare institutions and/or insurers mandate the documentation of ischemia before performing PCI, the importance of FFR in the cardiac-catheterization laboratory will increase further. Instead of hearing, “We could FFR it…”, we will start hearing, “We did FFR it…”
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
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- Bech GJ, De Bruyne B, Pijls NH et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation103, 2928–2934 (2001).
- Pijls NH, van Schaardenburgh P, Manoharan G et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J. Am. Coll. Cardiol.49, 2105–2111 (2007).
- Moses JW, Stone GW, Nikolsky E et al. Drug-eluting stents in the treatment of intermediate lesions: pooled analysis from four randomized trials. J. Am. Coll. Cardiol.47, 2164–2171 (2006).
- Tonino PA, De Bruyne B, Pijls NH et al.; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N. Engl. J. Med.360, 213–224 (2009).
- Botman KJ, Pijls NH, Bech JW et al. Percutaneous coronary intervention or bypass surgery in multivessel disease? A tailored approach based on coronary pressure measurement. Catheter Cardiovasc. Interv.63, 184–191 (2004).
- Serruys PW, Morice MC, Kappetein AP et al.; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N. Engl. J. Med.360, 961–972 (2009).
- Boden WE, O’Rourke RA, Teo KK et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med.356, 1503–1516 (2007).
- Shaw LJ, Berman DS, Maron DJ et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation117, 1283–1291 (2008).