Fractional Flow Reserve (FFR) Shown to Improve Patient Outcomes and Reduce Costs. Executive Summary

(FFR) Shown to Improve Patient Outcomes and Reduce s Keywords Fractional Flow Reserve, coronary artery disease, stenosis, blood flow blockages Published: 5 October 213 Citation: RadcliffeCardiology.com, October 213 Support: The publication of this information was supported by St. Jude Medical. Executive Summary Coronary artery disease (CAD) is the most common form of heart disease and affects the health of millions of individuals worldwide. 1,2 In patients with CAD, coronary artery narrowing, or stenosis, restricts blood flow and reduces the amount of oxygen to the heart. 3 When stenosis causes insufficient oxygen supply to the heart a condition called myocardial ischemia patients with CAD may benefit from percutaneous coronary intervention (PCI), such as stenting partially occluded vessels. 4,5 In recent years, the use of PCI for CAD has been called into question. 6 Research suggests no benefit to adding stenting of partially occluded vessels to standard medical treatment. Data from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluations) trial brought into question the benefit of PCI for patients with CAD. 6 Although stenting can be helpful for many patients with stenosis, it was not beneficial when administered to all patients. Furthermore, an economic analysis of COURAGE data showed that PCI added approximately $1, to per-patient treatment costs, with no significant improvement in outcomes. 7 Fractional flow reserve (FFR) is a technique used to assess the severity of blood flow blockages in patients with CAD. 3 FFR technology can help physicians identify ischemia-inducing stenosis with greater than 9 % accuracy this facilitates treatment decision-making that improves patient outcomes, and helps to avoid unnecessary medical procedures. 3,5,8 In addition to contributing to improved patient outcomes, PressureWire FFR can also decrease costs to providers and healthcare facilities. 3,9 Fractional flow reserve technology is the key to distinguishing which patients will benefit from PCI. Two landmark studies using the St. Jude Medical PressureWire FFR technology have demonstrated that although PCI is not necessary for all patients with CAD, it is beneficial for those with ischemia-inducing stenosis. Key clinical guidelines support the use of FFR for cardiac diagnosis and treatment Guidelines and Expert Consensus Documents summarize and evaluate all available evidence with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition. Current European medical guidelines released by the European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) have designated FFR with a Class I, Level A recommendation. 11 Level of evidence A is the highest level Benefits for those with Ischemia-inducing stenosis FAME The FAME (Fractional Flow Reserve [FFR] vs. Angiography for Multivessel Evaluation) trial showed a benefit of FFR-guided PCI, with approximately 3 % reduced risk of death, myocardial infarction (MI) and revascularization compared with angiography-guided PCI. 3,5 During a 2-year follow-up, patients continued to show decreased mortality risk and MI rates. 1 FAME 2 The FAME 2 (FFR-guided Percutaneous Coronary Intervention [PCI] plus Medical Treatment vs. Medical Treatment Alone in Patients with Stable Coronary Artery Disease) trial found that use of FFR-guided PCI led to an 86 % decrease in risk of unplanned hospitalization for urgent revascularization, compared with medical treatment alone. 8 1 RADCLIFFE 213

available, requiring the most clinical evidence, and is awarded only when data has been derived from multiple randomized clinical trials or meta-analyses. Class I indicates a general agreement that a given treatment or procedure is beneficial, useful, and effective. For the treating physician, the new guidelines mean that FFR is recommended before making a decision to perform PCI or sending the patient to surgery. This assumes the patient has come to the cath lab without a prior functional test and with a stenosis of 5-9 % as shown by angiography. 12,13 FFR improves health outcomes and decreases costs. 9 ECONOMIC EVALUATION FAME An economic evaluation of data collected during the FAME clinical study showed that using PressureWire FFR versus angiography alone to assess the need for PCI in patients with multivessel CAD saved more than $2, per patient. 9 In this study, 1-year per-patient healthcare costs associated with angiography-guided PCI were $16,7, whereas costs associated with FFR-guided PCI were $14,315. 9 These cost savings were attributable to a decrease in unnecessary PCI procedures, as well as fewer rehospitalizations and adverse cardiac events. 9 This analysis found that PressureWire FFR was a dominant treatment choice meaning that it is both more effective and less expensive for patients with CAD. COST-EFFECTIVENESS FAME The cost-effectiveness of FFR has been validated in the U.S. and various other countries including Australia, Belgium, Canada, China, France, Germany, India, Italy, Japan, Korea, Switzerland and the United Kingdom. A series of 1-year European economic analyses found an expected mean savings per patient using FFR- vs. angiography-guided PCI ranging from ~ 3 in Germany to ~ 9 in France. 3 In Asia, economic evaluations found expected cost-per-patient savings ranging from USD $1,55 in Korea to $2,47 in Japan. 3 ECONOMIC EVALUATION FAME 2 Economic analysis of the FAME 2 study demonstrated that over a 3-year cost projection, use of PressureWire FFR-guided PCI was associated with a cost of increased utility of $32, per quality-adjusted life year (QALY) gained. This is well below the cost effectiveness benchmark of $5, per QALY gained. 14 FFR is recommended by major cardiovascular guidelines and appropriate use criteria to determine the need for PCI. In addition, FFR has also been identified as cost-effective and cost saving for selected patient populations across multiple geographies. FFR for patients with CAD not only improves patient outcomes, it also reduces costs. Fractional Flow Reserve (FFR) Shown to Improve Patient Outcomes and Reduce s The Role of Fractional Flow Reserve (FFR) in Coronary Artery Disease (CAD) Management Coronary artery disease (CAD) is the most common form of heart disease and affects the health of millions of individuals worldwide. 1,2 Treatment for CAD involves medical therapy, including lifestyle changes and the use of various drugs; additionally, patients with insufficient oxygen supply to the heart, or myocardial ischemia, may benefit from coronary intervention (PCI), such as stenting of partially occluded vessels. 4,5 The course of treatment for patients with CAD depends on disease severity. While coronary angiography is always performed prior to PCI, it may underestimate or overestimate the severity of specific cardiac lesions. 5 In contrast, FFR provides a quantitative ratio of the actual blood flow in a narrowed artery, compared with the normal achievable blood flow and is more accurate in diagnosing ischemic lesions than angiography alone. 5 Using this functional or morphological measurement, FFR can quantify the severity of specific stenoses, as shown in Figure 1. A measurement of 1. indicates normal, healthy blood flow. A measurement of.75 or lower indicates with 1 % specificity the lesion(s) is causing ischemia. Patients with an FFR.8 are recommended for PCI. 3 The.8 cutoff for PCI has been validated in several clinical trials these outcomes are summarized in this document. FFR Technology FFR ratio is determined using a pressure guidewire system, such as the St. Jude Medical PressureWire, to measure the pressure inside the coronary arteries. 3 Coronary interventionists insert the pressure guidewire through the stenosed artery, as seen in Figure 2. Following this, maximum blood flow is pharmacologically induced, and the FFR ratio of the lesion is calculated. 3 FFR Use in Clinical Practice Clinical research has shown that FFR is effective in patients with stable ischemic CAD who are candidates for revascularization (PCI). 3,11 FFR is particularly useful in the assessment of coronary lesions prior to PCI or CABG surgery, to identify the lesions responsible for ischemia and inform the treatment decision-making process. 3 Patients found by angiography to have obstructive CAD, or CAD of indeterminate severity, can also benefit from FFR. 12 FFR: Relevant Clinical Data The benefit of PCI for CAD treatment was recently called into question by research suggesting no benefit of stenting of partially occluded vessels compared to standard medical treatment. 6 However, this Radcliffe Cardiology 2

Figure 1: Fractional measurement of blood flow shown in FFR 3 FFR=1. Normal Artery FFR>.75 Ischemia very unlikely, sensitivity 88 % FFR<.75 Ischemia specificity 1 % SIGNIFICANT NONSIGNIFICANT 1..95.85.75.65.55.45.35.25.15 Figure 2: Placement of PressureWire for FFR measurement 15 Catheter Stenosis Pressure guidewire with microchip Figure 3: COURAGE outcomes for patients who received PCI with medical therapy, or medical therapy alone, without any use of FFR 6 25 2 15 1 5 68 74 Death 143 128 MI 222 213 Death, MI, Stroke 135 125 Hospitalization for ACS Cumulative event rates at 4.6 years follow-up PCI with Medical Therapy (n=1,149) Medical Therapy Alone (n=1,138) DEFER Study The DEFER study was undertaken in patients with stable chest pain and a functionally nonsignificant coronary stenosis to investigate if percutaneous coronary intervention (PCI) of such stenosis is justified. Published in 21, the DEFER trial was the first prospective study that used FFR to determine the benefit of percutaneous transluminal coronary angioplasty (PTCA) among patients with an FFR score.75. 4 research did not use FFR to determine which lesions were causing ischemia. Two subsequent landmark studies used the St. Jude Medical PressureWire FFR technology to demonstrate the benefit of targeting ischemia-inducing stenoses. These studies demonstrated that utilizing FFR results in improved outcomes for patients, including reduced rates of death, myocardial infarction (MI) and in particular revascularization. 5,8 COURAGE Study In 27, evidence from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, questioned the necessity of PCI in patients with myocardial ischemia and substantial CAD. Figure 3 shows outcomes of patients in the PCI and medical therapy groups, none of which showed any significant differences. 2,287 patients with significant CAD and myocardial ischemia were randomized to receive either optimal medical therapy with PCI (n=1,149), or optimal medical therapy alone (n=1,138). 6 After a mean follow-up of 4.6 years, use of PCI in addition to optimal medical therapy was associated with no significant difference in outcomes related to death, MI, stroke or rehospitalization due to acute coronary syndrome, compared with optimal medical therapy alone. 6 Patients with a single stenosis recommended for PTCA based on angiographic results (FFR.75) were randomized to either receive or defer PTCA. All patients with an FFR <.75 received PTCA, regardless of randomization (n=144); this group was known as the reference group. Of patients with an FFR.75 (n=181), 9 received PTCA and 91 were deferred, based on randomization; these were the performance and deferral groups. 4 At 2 years follow-up, 89 % of patients in the deferral group experienced no adverse events. This outcome was statistically similar to the performance group (83 %) and significantly superior to the reference group (78 %; P=.3). 4 Patients in the deferral and performance groups had a similar incidence of MI or revascularization, while these events were more common in the reference group (P<.1 compared with deferral group and P<.5 compared with performance group). 4 There was no significant difference in mortality rates among the three groups. This study indicated that the outcomes of patients referred for PTCA without objective proof of ischemia might vary depending on the severity of coronary stenoses detected by FFR. In patients with FFR scores.75, PTCA did not appear to improve patient outcomes compared to medical treatment alone. 4 A 5-year follow-up of DEFER patients showed that these outcomes were maintained over time. Data were obtained for 98 % of patients from the original DEFER trial. 16 There was no significant difference in event-free survival between the deferral (8 %) and performance (73 %) groups; however, the reference group had significantly lower event free survival (63 %; P=.3). 3 Radcliffe Cardiology

The combined rates of cardiac death and acute MI were 3.3 % in the deferral group, 7.9 % in the performance group, and 15.7 % in the reference group; this difference was significant only for the reference group (p=.3). No differences in chest pain were experienced by patients in the Figure 4: 1-year outcomes of FFR-guided or angiographyguided PCI for CAD 5 12 1 113 deferral or performance groups. 16 PCI of a stenosis with an FFR score >.75 provides no benefit for the patient and should be discouraged. 16 The lesions at greatest risk of causing cardiac death or AMI are those that are functionally significant as identified by an FFR.75. 16 FAME Study The FAME study, Fractional Flow Reserve versus Angiography for Multivessel Evaluation, published in 29, was designed to demonstrate whether patients with multivessel disease had better outcomes with FFR-guided PCI compared to angiography guided PCI. 5 8 6 4 2 15 9 Death FFR (n=59) 29 MI 43 Angiography (n=496) MI = Myocardial Infarction; RV = Repeat Vascularization 67 91 Death, MI, RV 76 Total Events A total of 1,5 patients with multivessel CAD, recruited from 2 centers in Europe and the U.S., were randomized to undergo angiography-guided PCI or FFR-guided PCI. Angiography-guided PCI involved the stenting of all indicated lesions, and FFR-guided PCI involved the stenting of lesions with FFR measurements.8. 5 Patients in the angiography group had an average of 2.7 lesions per patient, which was similar to the average of 2.8 in the FFR group (P=.34). However, the number of stents used per patient was significantly different between the two groups, with 2.7 used in the angiography group and 1.9 used in the FFR group (P<.1). At 1-year after stenting, a total of 91 patients (18.3 %) in the angiography group had experienced an event (death, nonfatal MI or repeat revascularization) compared with 67 patients (13.2 %) in the FFR group; these results were statistically significant (P=.2). 5 As shown in Figure 4, the FAME study showed that the improved patient outcomes observed in the PressureWire group were likely based on targeting the specific lesions most likely to cause ischemia, rather than simply the number of stents used to treat CAD. A 2-year follow-up of FAME study participants showed that this benefit was maintained over time. 1 At 2 years: Stable Coronary Artery Disease, study was designed to investigate the outcomes of stable angina patients receiving FFR-guided PCI compared with patients who received optimal medical therapy alone. 8 The COURAGE study, which used angiography-guided PCI to study stable angina patients, showed no advantage of PCI over optimal medical therapy. FAME 2 was designed to assess whether FFR-guided PCI would result in improved outcomes for a composite endpoint of death, MI or urgent revascularization. Of 1,22 enrolled patients: - 888 (73 %) patients with 1 lesion with an FFR score of <.8 were randomly assigned to receive FFR-guided PCI plus optimal medical therapy (FFR group), or optimal medical therapy alone (medical therapy group). - 332 (27 %) patients in whom all stenoses had an FFR.8 received optimal medical therapy alone (registry group). 8 Patients in the medical therapy group showed a significantly higher need for urgent revascularization, compared to patients in the FFR group (11.1 % vs. 1.6 %, P<.1). Patients in the medical therapy group were more likely to have revascularizations triggered by MI or evidence of ischemia (P<.1). Mortality or MI in the angiography-guided group were significantly higher than in the FFR-guided group (12.9 % and 8.4 %, respectively; P=.2). No significant between-group differences were seen in the rates of PCI or coronary artery bypass surgery, or in the combined rates of death, nonfatal MI and revascularization. Patients with lesions with an FFR >.8 (for which stenting was deemed unnecessary) had a MI rate of.2 % and a revascularization rate of 3.2 %, showing very little risk associated with deferral of stenting in these specifically identified lesions. 1 These follow-up data demonstrate the benefit of FFR measurement in patients with multivessel CAD. When FFR is used prior to PCI, patient outcomes are improved and unnecessary stenting is also prevented. 1 In patients with FFR results of.8 in all lesions, only 3 % experienced a primary endpoint, indicating the safety of medical therapy alone in these patients. 8 However, in patients with lesions likely to induce ischemia, FFR-guided PCI significantly reduced patient risk for urgent revascularization, compared with medical management alone. Figure 5 shows the outcomes in patients who did have lesions with an FFR.8. Recruitment for the FAME 2 study was halted in January 212, when an independent Data and Safety Monitoring Board (DSMB) recommended early termination of the study. The preliminary results were considered so compelling that research was stopped so patients with FFR <.8 randomized to optimal medical therapy only could also receive the benefits of PCI. 8 FAME 2 Study The FAME 2, FFR-guided Percutaneous Coronary Intervention plus Medical Treatment vs. Medical Treatment Alone in Patients with These data support the idea of treating patients with Functionally Complete Revascularization. With this approach, only ischemiainducing lesions require stenting. 3 When used in patients indicated Radcliffe Cardiology 4

Figure 5: Treatment outcomes for patients with ischemiainducing CAD 8 Figure 6: Breakdown of costs in each treatment group in the COURAGE trial 7 1 9 8 7 6 5 4 3 2 1 to receive PCI, FFR is the key to determining the right treatment for each patient. 19 56 Death, MI, RV 15 17 Death or MI 14 7 Urgent Any Revascularization The economic and clinical benefits of FFR highlighted in FAME and FAME 2 studies are documented in Table 1. Clinical Guidelines and Appropriate Use Criteria Clinical Guidelines FFR is included in the U.S. guidelines recommended by the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the Society for Cardiovascular Angiography and Interventions (SCAI). The ACCF/AHA/SCAI guidelines give the use of FFR for guiding revascularization in patients with ischemic CAD a Class IIa recommendation, with Level A evidence. 11 Due to the positive results of the DEFER and FAME studies, FFR has been incorporated into recent European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) guidelines on myocardial revascularization. These guidelines acknowledge the difficulty in making accurate assessments of stenosis using visual assessments or quantitative coronary angiography, and suggest the use of FFR when functional information is lacking (i.e., when noninvasive 49 Mean follow-up duration - 214 days PCI plus Medical Therapy (n=447) Medical Therapy Alone (n=441) Table 1: Clinical and economic benefits of FFR as revealed in FAME and FAME 2 C CLINICAL BENEFIT FAME The FAME trial showed improved patient outcomes with FFR-guided PCI, compared with angiographyguided PCI. 3,5 CLINICAL BENEFIT FAME 2 The FAME 2 trial showed the benefit of adding PCI to medical therapy for patients identified by FFR to have ischemia-inducing cardiac lesions. 8 ECONOMIC BENEFIT FAME The FAME trial has shown decreased costs associated with PressureWire FFR-guided PCI, with savings of more than $2, per patient, per year. 9 The cost-effectiveness of PressureWire FFR has been validated in 13 countries worldwide, showing that targeting ischemia-inducing stenoses for PCI improves patient outcomes while saving costs. ECONOMIC BENEFIT FAME 2 The incremental cost-effectiveness ratio (ICER) for FFR-guided PCI was calculated at $32, per QALY gained based on 3-year projections, well below the commonly accepted threshold of $5, per QALY gained. 14 86 Lifetime Beyond Trial In-Trial Initial Treatment stress imaging is contraindicated, nondiagnostic or unavailable). 17 The ESC and EACTS have given the recommendation for FFR in these circumstances a Class I, Level A recommendation, which is the highest recommendation possible. The DEFER and FAME trials were cited as evidence in this decision. 17 Appropriate Use Criteria A 212 report prepared by multiple cardiology medical societies* addressed the use of FFR in appropriate use criteria for diagnostic catheterization. These appropriate use criteria recommend FFR for diagnostic evaluation of most CAD cases determined by angiography to be of intermediate, obstructive/significant or indeterminate severity. 12 In the same year, various societies including the ACCF, SCAI, STS, AATS, AHA, ASNC, HFSA and SCCT released a targeted appropriate use criteria update for coronary revascularization. The panel indicated that: Patients may be appropriately referred for coronary angiography based on symptom presentation and a high pretest probability of CAD. 13 24,718 34,843 752 12,162 65,651 64,978 9,37 99,82 $ $2, $4, $6, $8, $1, $12, Medical Therapy Alone (n=1,138) PCI plus Medical Therapy (n=1,149) However, for patients with coronary narrowing of uncertain severity, FFR is recommended as an additional invasive measurement to determine the need for PCI. 13 The FFR cutoff point of the severity of lesions for which PCI was considered necessary was set at.8, to reflect data showing patient risk. 13 *American College of Cardiology Foundation Appropriate Use Criteria Task Force (ACCF), Society for Cardiovascular Angiography and Interventions (SCAI), American Association for Thoracic Surgery (AATS), American Heart Association (AHA), American Society of Echocardiography (ASE), American Society of Nuclear Cardiology (ASNC), Heart Failure Society of America (HFSA), Heart Rhythm Society (HRS), Society of Critical Care Medicine (SCCM), Society of Cardiovascular Computed Tomography (SCCT), Society for Cardiovascular Magnetic Resonance (SCMR, and the Society of Thoracic Surgeons (STS). Economic Impact of FFR In addition to improving patient outcomes, data show that the use of FFR technology is an economically viable and in many cases, preferred option for patients with multivessel coronary disease. The COURAGE trial called into question the effectiveness of PCI; an economic evaluation of these same data showed a lack of cost-effectiveness using PCI without FFR. Figure 6 shows the costs of initial treatment, costs within and beyond the trial, and lifetime costs for each group. The COURAGE trial did not show any benefit of PCI compared to medical therapy alone; cost-effectiveness data also did not show a benefit to 5 Radcliffe Cardiology

Table 2: The medical and economic impact of using FFR-guided PCI for patients with multivessel CAD 15 Health Impact Budget Impact Overall Number of Outcomes in 2 Years Time ($ USD) QALYs Deaths MI MACE PCI CABG Savings per Gained Avoided Avoided Avoided Avoided Avoided Patient Australia* 27 36 84 85 49 41 $1,812 Australia** 23 29 7 7 42 35 $1,812 China 94 7 164 286 97 8 $951 India 98 73 172 298 12 83 $1,437 Japan 42 297 73 1,226 416 342 $2,47 Korea 18 81 19 33 113 92 $1,55 QALY = quality-adjusted life years; MI = myocardial infarction; MACE = major adverse cardiovascular events; PCI = percutaneous coronary intervention; CABG = coronary angiography bypass graft. *Public sector of Australia health care **Private sector of Australia health care PCI. These data were expressed as the ratio of the cost of PCI to the lifeyears gained and quality-adjusted life years (QALYs) gained. 7 The total in-trial cost for the PCI group was $1,125 higher than the medical therapy group ($34,843 and $24,718, respectively). - This was primarily driven by the cost of revascularization for the PCI group, which was $1,533 higher than the medical therapy group ($14,91 versus $4,368). 7 The PCI group had a $9,45 higher lifetime cost than the medical therapy group ($99,82 versus $9,37). 7 Due to these high costs, nearly all estimates of QALYs gained totaled >$5, per QALY gained; with an incremental cost-effectiveness ratio (ICER) point estimate of $168,19 per QALY gained. 7 These cutoffs are generally accepted benchmarks of cost effectiveness; therefore, PCI was not found to be a cost effective treatment. 7 However, as discussed, the COURAGE study likely included the use of PCI in patients with an FFR.8. The use of PCI only for patients with more severe stenoses could likely change this cost-effectiveness analysis. 18 Coronary interventionists can use FFR measurements to determine the patients who will benefit most from PCI. Treating the right patient, at the right time, can improve patient outcomes while maintaining cost-effectiveness. FAME Study: U.S. Economic Data The FAME study used FFR to determine the patients who would benefit most from PCI, and found PCI to improve health outcomes for patients with ischemia-inducing stenoses. An economic analysis of FAME data, performed in the context of the U.S. healthcare system, demonstrated the cost-effectiveness of using FFR to guide treatment decisions for the use of PCI in patients with multivessel CAD. 9 A cost-utility analysis compared costs and QALYs using FAME data, with a 1 year timespan, including medical costs associated with treatment, PCI and follow-up. At 1 year, average overall costs were significantly less in patients who received FFR ($14,315 vs. $16,7, P<.1). FFR-guided PCI was found to be cost saving in 91 % of patients, and was cost-effective at a threshold of U.S. $5, per QALY in nearly 1 % of patients. 9 As shown in Figure 7, this economic evaluation of FAME data demonstrated that, in addition to improving health outcomes, FFR-guided PCI in patients with multivessel CAD also reduces treatment costs. 9 Figure 7: s associated with FFR-guided or angiographyguided PCI in the FAME trial 9 Overall of Events During Follow-up of Initial Hospitalization Initial Treatment 1,821 1,134 6,7 5,332 16,7 14,315 14,878 13,182 $ $2, $4, $6, $8, $1, $12, $14, $16, $18, Angiography-guided PCI (n=496) FFR-guided PCI (n=59) Figure 8: The health impact of using FFR-guided PCI in selected European markets 15 MIs and Deaths Avoided 2,5 2, 1,5 1, 5 Germany France Italy UK Belgium MIs and Deaths Avoided 2-Year Health Impact Number of PCIs 4, 3, 2, 1, FAME: Global Economic Data -effectiveness analyses of the FAME study are currently available for 12 countries worldwide: Australia, Belgium, Canada, China, France, Germany, India, Italy, Japan, Korea, Switzerland and United Kingdom. 3 Data evaluated include patient outcomes (cardiac events), quality of life and resources used, within the context of various markets. 15 The use of FFR to determine PCI in patients with multivessel CAD makes both medical and financial sense. Based on data from the FAME clinical study, FFR-guided PCI has been shown to be cost-effective in every market in which they have been analyzed. 15 In the European markets, FFR-guided PCI has been shown to improve health outcomes over a 2-year timeframe (Figure 8). Additionally, Figure 9 shows the expected total 2-year cost savings associated with the improved health outcomes that result from using FFR-guided PCI. Number of PCIs per year Radcliffe Cardiology 6

Figure 9: The budget impact of using FFR-guided PCI in selected European markets 15 Expected total savings (in million ) 2 15 1 5 2-Year Budget Impact Germany France Italy UK Belgium Expected total savings 4, 3, 2, 1, Number of PCIs Number of PCIs per year FAME 2 Study: U.S. Economic Data An economic analysis of FAME 2 data was presented at the 212 Transcatheter Cardiovascular Therapeutics (TCT) conference on October 24, 212, and concluded that 14 : The incremental cost-effectiveness ratio (ICER) for FFR guided PCI was calculated at $32, per QALY gained based on 3-year projections, well below the commonly accepted threshold of $5, per QALY gained. Angina and quality of life are significantly improved by FFR-guided PCI compared to medical therapy. FFR-guided PCI has higher initial cost than medical therapy, but the cost gap narrows >5 % by 1 year. Figure 1: Cumulative cost over 12 months: FFR-guided PCI vs. medical therapy Mean Cumulative $1, $8, $6, $4, $2, $5,485 % of study population 1 % 2 4 6 8 1 12 FFR-Guided PCI $2,58 56 % 11 % Month Medical Therapy Figure 11: -effectiveness of COURAGE, FAME and FAME 2 outcomes Study COURAGE FAME FAME 2 Comparators Angio-guided PCI vs. Medical Therapy Angio-guided PCI vs. FFR-Guided PCI FFR-Guided PCI vs Medical Therapy Very Effective $5,/QALY -effectiveness Ratio >$168,/QALY FFR-Guided PCI is dominant ( $ / QALY) $32,/QALY Result >$15,/ QALY <$5,/QALY <$5,/QALY At baseline, patients in the FFR-guided PCI group had higher costs than patients who received optimal medical therapy. This was due to the initial procedure and hospitalization. However, at 1 year, cost estimates of follow-up expenditures for the FFR guided PCI group were statistically significantly lower compared with the medical therapy group, primarily due to the increased revascularization costs in the medical therapy group as shown in Table 3. differences between the two groups over 1 year are shown in Figure 1. Table 3: estimates, baseline and follow-up FFR-Guided PCI Medical Therapy P-value Baseline $8,79 $3,35 <.1 Drug-eluting Stent(s) $4,34 $48 <.1 1-Year Follow-Up $2,584 $5,561 <.1 Revascularization $442 $3,928 <.1 Total $11,374 $8,866 <.1 In addition, study results showed that FFR-guided PCI improved angina and quality of life. Patients in the FFR group also experienced an increase in utility* of.54, compared with.3 in the medical therapy group (p<.1). In-trial results showed $53, per QALY gained. This is in line with the common QALY threshold of $5,. In addition, because the FAME 2 study was stopped early, a 3-year projection was completed to determine a more realistic QALY calculation. The results of this analysis showed $32, per QALY gained, well below the $5, QALY threshold. *A utility is a numeric way of expressing a patient s preference for a particular state of health; a higher value equals improved health (typically,.=dead; 1.=complete health). Effective <$5,-15,/QALY Not Effective >$15,/QALY Similar economic outcomes were found in the context of multiple Asian countries (i.e., Japan, China, Korea, India) and Australia. effectiveness and budget impact analyses were performed for these five countries (Table 2). These analyses used FAME data to identify the overall per-person costs of using angiography- vs. FFR-led PCI, as well as expected overall outcomes after 2 years of follow-up. Figure 11 shows how FFR-guided PCI is cost-effective compared with angio-guided PCI or medical therapy, based on multiple study outcomes. Summary Fractional flow reserve has contributed to physician decision-making and improved patient and economic outcomes. FFR remains one of the most validated and accurate lesion assessment tools and is supported by an unprecedented legacy of randomized outcome trials, including DEFER, FAME and FAME 2. n 1. Centers for Disease Control and Prevention. Heart Disease Facts. America s Heart Disease Burden. 212; Available at: http://www.cdc.gov/heartdisease/facts.htm. 2. World Health Organization. Cardiovascular Disease Atlas. Types of Cardiovascular Disease. 24; Available at: http:// www.who.int/cardiovascular_ diseases/en/cvd_atlas_1_ types.pdf. 3. St. Jude Medical. Data on File. 4. 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. Circulation. 21;13(24):2928-34. 5. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 29;36(3):213-24. 6. Boden WE, O Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 27;356(15):153-16. 7. Weintraub WS, Boden WE, Zhang Z, et al. -effectiveness of percutaneous coronary intervention in optimally treated stable coronary patients. Circ Cardiovasc Qual Outcomes. 7 Radcliffe Cardiology

28;1(1):12-2. 8. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 212;367(11):991-11. 9. Fearon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation. 21;122(24):2545-5. 1. Pijls NH, Fearon WF, Tonino PA, et al. 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. 21;56(3):177-84. 11. Levine GN, Bates ER, Blankenship JC et al. 211 ACCF/AHA/ SCAI Guideline For Percutaneous Coronary Intervention: Executive Summary. JACC. 211;58(24):255-83. 12. Patel MR, Bailey SR, Bonow RO, et al. ACCF / SCAI / AATS / AHA / ASE /ASNC /HFSA / HRS / SCCM / SCCT / SCMR / STS 212 appropriate use criteria for diagnostic catheterization. J Thoracic Cardiovasc Surg. 212;144(1):39-71. 13. Patel MR, Smith PK, Spertus JA, et al. ACCF / SCAI / STS / AATS / AHA / ASNC / HFSA/ SCCT 212 appropriate use criteria for coronary revascularization focused update. JACC. 212;59(9):78-83. 14. Fearon WF. FAME 2 -effectiveness: A Prospective, Randomized Trial Evaluating the -effectiveness of FFR- Guided PCI in Patients with Stable Coronary Artery Disease. Presented at Late Breaking Clinical Trials 1 at TCT 212, Miami, Florida, October 24, 212. 15. Siebert U. -Effectiveness and Public Health and Budget- Impact of FFR-Guided PCI in Patients with Multivessel Disease in Germany (Europe). Toronto. Annual ihea Meeting; 211. 16. 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. 27;49(21):215-11. 17. Wijns W, Kolh P, Danchin N et al. Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur H Journal. 21;31:251-55. 18. Kirtane AJ, Cohen DJ. When is better not good enough? Insights from the COURAGE economic study. Circ Cardiovasc Qual Outcomes. 28;1(1):4-6. This document and the information contained herein is for general information purposes only and is not intended, and does not constitute, legal, reimbursement, business, or other advice. Furthermore, it does not constitute a representation or guarantee of cost-effectiveness, and it is not intended to increase or maximize payment by any payer. Nothing in this document should be construed as a guarantee by St. Jude Medical regarding cost-effectiveness, expenditure reduction, reimbursement or payment amounts, or that reimbursement or other payment will be received. The ultimate responsibility for determining cost-effectiveness and obtaining payment/reimbursement remains with the customer. This includes the responsibility for accuracy and veracity of all claims submitted to third-party payers. Also note that actual costs for products and services and any related expenditures vary, and that the information presented herein represents only one of many potential scenarios, based on the assumptions, variables, and data presented. In addition, the customer should note that laws, regulations, and coverage policies are complex and are updated frequently, and, therefore, the customer should check with its local carriers or intermediaries often and should consult with legal counsel or a financial or reimbursement specialist for any questions related to cost-effectiveness, expenditure reduction, billing, reimbursement or any related issue. C-34 (1) Global EN 1/13 Radcliffe Cardiology 8