Interventional Cardiology

Interventional Cardiology Cost effectiveness of fractional flow reserve-guided percutaneous coronary intervention In recent years, fractional flow reserve (FFR) has become accepted as a clinically effective tool for guiding decisions about percutaneous coronary intervention (PCI). FFR poses a unique alternative to stress testing or angiography-guided PCI, in that it can interrogate the ischemic potential of an individual vessel on an impromptu basis once an angiogram is in progress, offering immediate data for decision making. With its recent greater adoption across the USA, its effectiveness has become an important consideration. There have been a few key analyses over the last decade demonstrating the effectiveness of FFR-guided PCI; we review the major effectiveness analyses, showing the economic utility of FFR-guided PCI for the modern interventionalist. Freddy Abnousi1, Celina Yong1 & William Fearon*,1 1 Division of Cardiovascular Medicine, Stanford University Medical Center, 3 Pasteur Drive, Room H213, Stanford, CA 9435, USA *Author for correspondence: Tel.: +1 65 725 2621 Fax: +1 65 725 6676 wfearon@ stanford.edu Keywords: effectiveness fractional flow reserve percutaneous coronary intervention Although angiography is the established invasive approach for assessing coronary artery disease, its ability to evaluate the functional significance of stenoses is limited. Currently, the available options for assessing the hemodynamic significance of lesions include noninvasive functional testing, such as stress echocardiography or stress perfusion scintigraphy (SPS), or invasive testing, with fractional flow reserve (FFR). FFR is defined as the ratio of the distal coronary pressure to the proximal pressure during maximum hyperemia. It has been shown to be an effective method for guiding revascularization [1 6]. As such, it has received a class IA recommendation from the European Society of Cardiology and a class IIA recommendation from the American College of Cardiology [7,8]. Its clinical effectiveness was demonstrated in the FAME trial [2], which compared angiography guided PCI with FFR-guided PCI in patients with multivessel coronary disease. This prospective, multicenter, international trial randomly assigned 15 patients with multivessel coronary disease to either PCI guided by FFR (PCI if FFR.8) or by angiography alone. Of note, this trial included 1.2217/ica.15.22 215 Future Medicine Ltd patients presenting with acute coronary syndrome, with certain limitations (any ST elevation myocardial infarction had to occur more than 5 days prior to PCI, and in the case of non-st elevation myocardial infarction, peak creatine kinase level had to be less than 1 U/l). The trial met its primary endpoint of death, myocardial infarction, and repeat revascularization at 1 year, with an event rate of 18.3% in the angiography guided PCI group and 13.2% in the FFRguided PCI group (p =.2). Subsequently, the FAME 2 clinical trial [9] was designed to test whether optimal medical therapy alone was superior to FFR-guided PCI plus optimal medical therapy in patients with stable coronary disease. Recruitment was halted early in this prospective, multi-center, international trial of 122 patients (of whom 888 underwent randomization) due to an early finding of a significant difference between the groups in the primary endpoint event (death from any cause, myocardial infarction, or unplanned hospitalization leading to urgent revascularization). The PCI group had a primary event at a rate of 4.3% as compared with the medical therapy group Interv. Cardiol. (215) 7(4), 387 392 part of ISSN 1755-532 387

Abnousi, Yong & Fearon that had an event rate of 12.7% (HR with PCI:.32; 95% CI:.19.53; p <.1). Of note, a lower rate of urgent revascularization in the PCI group drove this difference (1.6 vs 11.1%; HR:.13; 95% CI:.6.3; p <.1). Recently, the 2-year results of FAME 2 showed similar primary endpoint trajectories (8.1% event rate for the PCI group vs 19.5% event rate for the medical therapy group; HR:.39; 95% CI:.26.57; p <.1), driven by urgent revascularization (4.% in the PCI group vs 16.3% in the medical therapy group; HR:.23; 95% CI:.14.38; p <.1). Additionally, though there were no significant differences between groups in myocardial infarction or death overall; notably, if the first week of outcomes was excluded to eliminate periprocedural events, there were significantly lower rates of myocardial infarction and death at two years for the PCI group (4.6 vs 8.%; p =.4) [1]. FFR has not only shown clinical utility, but also economic utility, with robust evidence demonstrating its effectiveness. Fearon et al. [11] first used computer modeling to compare three potential strategies for deciding whether or not to perform PCI on an intermediate lesion: 1) NUC strategy deferring the decision for PCI to obtain nuclear stress imaging; 2) FFR strategy using FFR to guide PCI at the time of; 3) STENT strategy stenting all moderate lesions without further evidence of hemodynamic signifi12 P <.1 SPS-group FFR-group P <.1 8 6 4 2 Total Cath lab Equipment Contrast RN/RT P <.5 Post-Cath Cost ($) 1 Figure 1. Costs incurred in the cath lab in patients who were randomized to stress perfusion scintigraphy versus fractional flow reserve. The itemized s include: RN/ RT, post-cath (the time that RN and RT spent per patient during and after cardiac catheterization multiplied by the hourly wages), contrast and equipment (the s of the WaveWire, guiding catheter and Tuohy steering kit). Values are means +/- SEM. Adapted with permission from Leesar et al. [12]. FFR: Fractional flow reserve; RN: Registered nurse; RT: Radiologic technologist; SPS: Stress perfusion scintigraphy. 388 Interv. Cardiol. (215) 7(4) cance. They used marginal s for both in-hospital and outpatient services to optimally estimate the of performing additional procedures. They measured the FFR as $761 (consisting of $55 for the wire, $36 for intracoronary adenosine and $175 for professional fees). Nuclear stress imaging was estimated to $193. Based on prior published data, the medical of treating angina was $1775 per year. They assumed an estimated repeat PCI rate after stenting of 11% at 1 year and 2.5% per year for the next 4 years. Based on these calculations, the FFR strategy provided a savings of $1795 per patient as compared with the NUC strategy, and $383 per patient as compared with the STENT strategy. Additionally, in terms of per quality-adjusted life-years (QALY) gained, though the NUC strategy was expensive (>$8,/QALY), both FFR and NUC strategies were superior to the STENT strategy. Conclusions from this study are limited by the general limitations of modeling work, which require a number of assumptions to arrive at the conclusions. Leesar et al. [12] provided the first clinical data by evaluating the impact of FFR compared with SPS in patients with unstable angina (UA) or non-st elevation myocardial infarction (NSTEMI) (Figure 1). Specifically, 7 patients with UA/NSTEMI (312 patients originally screened) and single vessel disease with moderate stenoses based on coronary angiography were randomized to SPS (35 patients) or FFR (35 patients). In both groups, the patients were discharged and managed medically if ischemia was not present, otherwise PCI was performed on the lesion. They found that the FFR approach significantly decreased the ($1,329 ± $44 vs $2,113 ± $12; p <.5) and duration of hospitalization (11 ± 2 h vs 49 ± 5 h; p <.1). Arguably, a limitation of this comparison study is that it does not capture the potential value of using stress testing to guide PCI if performed prior to angiogram. The approach of taking a patient off the cardiac catheterization table after the angiogram to subsequently pursue stress imaging before returning to fix a lesion is the most expensive way to use stress imaging to guide coronary interventions. However, this study reinforced the safety and effectiveness of using FFR to defer PCI of hemodynamically insignificant lesions, even in the presence of an acute coronary syndrome. In looking at the effectiveness of FFR from a large randomized clinical trial perspective, the FAME investigators conducted an analysis prospectively in the FAME trial described above [13]. This study found that QALYs showed a nonsignificant trend to be higher in the FFR-guided arm compared with the angio-guided group (.853 vs.838; p =.2) and the

Cost effectiveness of FFR-guided PCI mean overall s at 1 year were significantly less in the FFR-guided arm ($14,315 vs 16,7; p <.1). Although the use of the pressure wire and adenosine adds, the reduction in unnecessary drug-eluting stenting and the decrease in adverse events lead to lower resource utilization in the FFR-guided PCI group compared with the angio-guided PCI group. Additionally, bootstrap simulation showed that the FFR-guided strategy was unique for a new technology. Many new techniques improve outcomes, but usually more money. FFR-guided PCI was found to be -saving (improve outcomes and less) in 91% and effective at a threshold of US $5, per QALY in 99.96% (Figure 2). Additionally, sensitivity analyses showed robust results. Specifically, analyses were performed with ± 2% on prices and ± 1% on utilities, with the end results always favoring the FFR group. Note that one of this study s limitations was that it applied US s to the analysis, while the majority of patients were from outside the USA. The FAME investigators also demonstrated the economic attractiveness of FFR-guided PCI in comparison to optimal medical therapy in the analysis of the FAME 2 clinical trial data [14]. Of note, the direct effectiveness of FFR itself is difficult to assume from this analysis, as all patients underwent FFR for this trial. As expected, initial s were significantly higher for the FFR-guided PCI group ($9927 vs 39; p <.1) because of the of the drug-e luting Incremental [$] 5 4 ICER of 5, $ / QALY 3 2 1 -.75 -.5 -.25. -1 FFR guidance improves outcomes.25.5.75 Incremental QALY -2-3 FFR guidance saves resources -4-5 Figure 2. Bootstrap simulation of incremental s and effects. Numbers on axes represent differences between FFRguided and angiography-guided strategies. Positive incremental QALYs indicate higher effectiveness for FFR-guided treatment. Negative incremental s indicate lower s for FFR-guided treatment compared with angiographyguided strategy. Data are from 5 bootstrap replications. Adapted with permission from Fearon et al. [13]. FFR: Fractional flow reserve; QALY: Quality-adjusted life-years. www.futuremedicine.com 389

Abnousi, Yong & Fearon Cumulative ($) 14, 12, $2,883 1, 8, $6,27 6, 4, 2, FFR-guided PCI Medical therapy 1 2 3 4 5 6 7 8 9 1 11 12 Follow-up (months) Figure 3. Cumulative medical s (vertical axis) of a strategy of PCI in the setting of an abnormal FFR (solid line) and a medical therapy strategy (dashed line) over 12 months of follow-up (horizontal axis). Adapted with permission from Fearon et al. [14]. FFR: Fractional flow reserve; PCI: Percutaneous coronary intervention. stenting. However, during the first year, this margin narrowed from $627 to $2883 (p <.1) driven primarily by the of subsequent revascularization in the medical therapy arm (Figure 3). In terms of patient utility, the FFR group had significant benefits at 1 month (.54 vs.1 units; p <.1). Overall, this led to a effectiveness ratio of FFR-guided PCI compared with optimal medical therapy to be $36,/QALY (Figure 4). This study was mainly limited by the early halt in recruitment secondary to the recommendation by the Data Safety Monitoring Board. This led to the need for a number of assumptions with regards to s and PCI durability (the benefit of PCI would diminish to zero over 3 years) in order to be able to forecast results. The effectiveness of FFR has also been evaluated outside the USA. Sengottuvelu et al. performed an analysis of a small Indian population, comparing FFR-guided decision making to what an independent reviewing cardiologist would have decided based on angiography alone [15]. They found a net benefit in favor of FFR-based management of $15,6. A prospective economic evaluation comparing FFR versus angiography in patients with multivessel disease evaluated the effectiveness and budget impact for Australia [16]. Using Australian utilities and s, they showed that FFR was -saving and reduces s by 1776 AD per patient per year. Over 2 years, the public health impact ranged from 7.8 to 73.9 QALYs gained with a budget impact from 1.8 to 14.5 million AUD total savings. Further studies are necessary to evaluate whether these findings are generalizable to 39 Interv. Cardiol. (215) 7(4) different national medical systems that reimburse and finance medical care in different ways. In comparing FFR to other non-invasive modalities, computed tomography based FFR (FFRCT ) has been studied through modeling. FFRCT applies computational fluid dynamics to images from computed tomography angiography (ccta) to noninvasively quantify FFR of coronary arteries [17]. Hlatky et al. [17] simulated a number of scenarios that evaluated the novel strategy of FFRCT from Heartflow Inc. Specifically, clinical data from 96 patients in the DISCOVER-FLOW [18] trial and literature-based outcomes data were combined to forecast initial management s and 1 year death/mi rates associated with five strategies: 1) invasive angiography-guided PCI; 2) invasive coronary angiography and invasive FFR-guided PCI; 3) ccta-guided PCI; 4) ccta followed by invasive FFR-guided PCI; and, 5) ccta and FFRCT-guided PCI. The approaches that did not evaluate hemodynamic significance of lesions had the most expensive initial (invasive angiography guided PCI at $1,72, and ccta guided PCI at $9635). Additionally, these approaches had the greatest rate of death and MI at 1 year (invasive angiography guided PCI 2.63%, and ccta guided PCI at 2.56%). On the other hand, invasive angiography and invasive FFR-guided PCI had an initial of $8499 with a projected 1-year death and MI rate at 1.96%, as compared with the ccta and FFRCT-guided PCI strategy that had an initial of $7674 with an accompanied one year death and MI rate of 2.31%. Finally, the ccta followed by invasive FFR-guided PCI strategy had a of $835 and 1-year death and MI rate of 2.6%. Although FFRCT holds promise and may eventually become widely applicable, larger trials are needed to assess its validity. Additionally, since coronary analysis by CT is limited in the setting of calcification (which is common in our elderly patient population), this may limit how widely we can use the FFRCT modality. Finally, as is inherently a limitation to all modeling studies, this study relies on numerous assumptions for their effectiveness outcomes. Conclusion FFR is a -effective tool to determine the hemodynamic significance of coronary lesions, and can be used to guide appropriate PCI in the -conscious setting. However, its adoption is still relatively low in the USA and remains to be fully evaluated in different medical systems and among diverse patient groups. Future perspective Current use of FFR is still limited; a nationwide survey of 189 interventionalists reported that they use FFR measurement in less than one third of cases and 15%

Cost effectiveness of FFR-guided PCI Financial & competing interests disclosure The authors have 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. 8 6 Difference in s ($) never use it [19]. However, in the coming decade, further developments in the pharmacology and technology of FFR-guided PCI may push adoption of its use even further. For example, it will be interesting to see the role that FFRCT-guided PCI will play once more widely adapted. While FFRCT may become a powerful noninvasive tool for predicting hemodynamically significant coronary lesions, we anticipate a continued role for traditional FFR for a large p roportion of patients who may not receive ccta imaging before angiogram or have calcified vessels that preclude accurate CT imaging. With continued innovation, a host of FFR modalities will offer options for the modern interventionalist s toolkit; and in the setting of skyrocketing healthcare s, it will be important to continue to focus on the effectiveness of each of these options..3.47 $15, $1, $5,.1928.7999 4 2.23-2 -.5..5.1.15 Difference in QALYS Figure 4. Bootstrap replications of the incremental effectiveness of the strategy of percutaneous coronary intervention in the setting of an abnormal fractional flow reserve compared with best medical therapy. Each of the 1, points represents the results of one bootstrap replication. The difference in cumulative s is displayed in the vertical axis, and the difference in QALYs is displayed on the horizontal axis. Willingnessto-pay thresholds of $5, per QALY added (solid line), $1, per QALY added (dashed line), and $15, per QALY added (dotted line) are indicated in the plane. The fractions of replications in each sector of the plane are indicated (e.g.,.23 of the replications had a difference < and QALY difference >). Adapted with permission from Fearon et al. [14 QALY: Quality-adjusted life-years. Executive summary There is strong evidence to support the use of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) of moderate coronary lesions. Economic modeling as well as clinical data from large trials show savings. FAME I compared FFR-guided PCI to angiography and showed that FFR-guided PCI was -effective at a threshold of US $5,/quality-adjusted life-years (QALY). FAME II compared FFR-guided PCI to optimal medical therapy and showed that FFR-guided PCI had a effectiveness ratio of $36,/QALY. Newer, less invasive FFR technologies have the potential to expand interventionalists options for effective hemodynamic assessment of moderate coronary lesions in the near future. References Landmark clinical trial. Papers of special note have been highlighted as: of interest; of considerable interest 3 Pijls NHJ, De Bruyne B, Peels K et al. Measurement of fractional flow reserve to assess the functional severity of coronary artery stenoses. N. Engl. J. Med. 334, 173 178 (1996). 1 2 Bech GJ, De Bruyne B, Pijls NHJ et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 13, 2928 2934 (21). 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. 36, 213 224 (29). Provides a historical perspective. 4 Hamilos M, Muller O, Cuisset T et al. Long-term clinical outcome after fractional flow reserve guided treatment in patients with angiographically equivocal left main coronary artery stenosis. Circulation 12, 155 1512 (29). www.futuremedicine.com 391

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