FFR vs Angiography for Multivessel Evaluation FAME Study FFR vs Angiography for Multivessel Evaluation

Does measuring FFR really make a difference? FAME is a large, randomized, controlled, multicenter trial comparing stent treatment guided by FFR versus angiographic guidance alone The FAME study was designed to reflect the daily practice of performing PCI in patients with multivessel disease The purpose of this study was to investigate the relationship between angiographic and functional severity of coronary artery stenoses in the FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation) study. It can be difficult to determine on the coronary angiogram which lesions cause ischemia. Revascularization of coronary stenoses that induce ischemia improves a patient’s functional status and outcome. For stenoses that do not induce ischemia, however, the benefit of revascularization is less clear.

Study Design In 20 medical centers in the United States and Europe, we randomly assigned 1005 patients with multivessel coronary artery disease to undergo PCI with implantation of drug-eluting stents guided by angiography alone or guided by FFR measurements in addition to angiography. Before randomization, lesions requiring PCI were identified on the basis of their angiographic appearance. Patients assigned to angiography guided PCI underwent stenting of all indicated lesions, whereas those assigned to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was 0.80 or less. The primary end point was the rate of death, nonfatal myocardial infarction, and repeat revascularization at one-year.

Key Inclusion and Exclusion criteria Inclusion criteria: - Patients with multivessel disease - At least 2 stenoses greater than or equal to 50% in 2 or 3 major epicardial coronary artery vessels, amenable to stenting Exclusion criteria: - Left main disease or previous bypass surgery - ST-elevation MI with CK greater then 1000 U/l within last 5 days - Extremely tortuous or calcified coronary arteries Note: patients with previous PCI were not excluded Patients were included in the study if they had multivessel coronary artery disease, which was defined as coronary artery stenoses of at least 50% of the vessel diameter in at least two of the three major epicardial coronary arteries, and if PCI was indicated. Patients who had a myocardial infarction with ST-segment elevation could be included if the infarction had occurred at least 5 days before PCI. Patients who had a myocardial infarction without ST-segment elevation could be included earlier than 5 days after the infarction if the peak creatine kinase level was less than 1000 U per liter. Patients who had undergone previous PCI could be included in the study. Patients who had angiographically significant left main coronary artery disease, previous coronary-artery bypass surgery, cardiogenic shock, extremely tortuous or calcified coronary arteries, a life expectancy of less than 2 years, or a contraindication to the placement of drug-eluting stents and patients who were pregnant were excluded.

Endpoints Primary Endpoint Composite of death, myocardial infarction, or repeat revascularization (“MACE”) at 1-year Secondary Endpoints - individual components of MACE at 1-year - functional class - use of anti-anginal drugs - health-related quality of life (EuroQOL-5D) - procedure time - amount of contrast agent used during procedure - cost of the procedure The primary endpoint was the rate of major adverse cardiac events at 1- year. Major adverse cardiac events were defined as a composite of death, myocardial infarction, and any repeat revascularization. Secondary end points included the procedure time, the amount of contrast agent used, functional class at 1-year as assessed using the Canadian Cardiovascular Society classification system, health-related quality of life (as measured by the score on the European Quality of Life–5 Dimensions [EQ-5D] scale), the number of anti-anginal medications used, and the individual components of the primary endpoint at 1-year, as well as the rates of major adverse cardiac events at 30 days and 6 months. Cost-effectiveness was a secondary endpoint as well. Death was defined as death from all causes. Myocardial infarction was defined as an elevation of the creatine kinase MB fraction by a factor of 3 or more or new Q waves in 2 or more contiguous leads of the electrocardiogram (ECG).

Participating Sites Fourteen European centers and six United States centers enrolled more than 1,000 patients in the FAME Study From January 2006 through September 2007, a total of 1005 patients were enrolled at 20 centers in the United States and Europe. Of the 1005 patients, 496 were randomly assigned to angiography-guided PCI and 509 to FFR-guided PCI. Baseline characteristics of the two groups were similar, as were the number of indicated lesions, vessel and lesion dimensions as assessed by quantitative coronary angiography, and extent and severity of coronary artery disease as indicated by the SYNTAX score.

Study Enrollment and Randomization Were not eligible N=900 Left main stenosis N=157 Extreme coronary tortuosity or calcification N=217 Did not provide informed consent N=86 Participation in other study N=94 Logistic reason N=210 Other reason N=31 Assessed for eligibility N=1905 Angiography guided PCI N=496 FFR guided PCI N=509 Lost to follow-up N=11 N=8 Analyzed Randomized N=1005 Complete one-year follow-up data were obtained for 98.1% of the patients (11 were lost to follow-up in the angiography group and 8 were lost to follow-up in the FFR group [P = 0.45]).

Baseline Characteristics Similar characteristics in the two groups Baseline characteristics of the two groups were similar, as were the number of indicated lesions, vessel and lesion dimensions as assessed by quantitative coronary angiography, and extent and severity of coronary artery disease as indicated by the SYNTAX score. A total of 26.5% of the patients in the angiography group had a left ventricular ejection fraction of 50.0% or less, as compared with 28.6% in the FFR group (P = 0.47). Explanation symbols for baseline characteristics: * Plus–minus values are means ―SD. ACE denotes angiotensin-converting enzyme, ARB angiotensin II–receptor blocker, ECG electrocardiogram, FFR fractional flow reserve, and PCI percutaneous coronary intervention. † All categorical variables were compared with the use of the chi-square test; all continuous variables were compared with the use of the Mann–Whitney U test. ‡ Angina was assessed according to the Canadian Cardiovascular Society Functional Classification of Angina Pectoris. § Before randomization, the physician who performed the procedure indicated all lesions to be included in the study and classified them according to severity by visual estimation, on the basis of the angiogram. ¶ The SYNTAX score is the scoring system used in the SYNTAX study to assess the extent and severity of coronary artery disease. A score of 0 indicates no angiographically significant coronary disease. There is no designated highest score. A score of 14.5 indicates rather extensive disease. ‖ The European Quality of Life–5 Dimensions (EQ-5D) scale is a visual-analogue scale that measures health-related quality of life. Scores range from 0 to 100, with higher scores indicating higher health-related quality of life.

Baseline Characteristics (cont’d) Explanation symbols for baseline characteristics: * Plus–minus values are means ―SD. ACE denotes angiotensin-converting enzyme, ARB angiotensin II–receptor blocker, ECG electrocardiogram, FFR fractional flow reserve, and PCI percutaneous coronary intervention. † All categorical variables were compared with the use of the chi-square test; all continuous variables were compared with the use of the Mann–Whitney U test. ‡ Angina was assessed according to the Canadian Cardiovascular Society Functional Classification of Angina Pectoris. § Before randomization, the physician who performed the procedure indicated all lesions to be included in the study and classified them according to severity by visual estimation, on the basis of the angiogram. ¶ The SYNTAX score is the scoring system used in the SYNTAX study to assess the extent and severity of coronary artery disease. A score of 0 indicates no angiographically significant coronary disease. There is no designated highest score. A score of 14.5 indicates rather extensive disease. ‖ The European Quality of Life–5 Dimensions (EQ-5D) scale is a visual-analogue scale that measures health-related quality of life. Scores range from 0 to 100, with higher scores indicating higher health-related quality of life.

Significant difference between the two groups Results Significant difference between the two groups Significantly more stents per patient were placed in the angiography group than in the FFR group (2.7±1.2 vs. 1.9±1.3, P<0.001). In the FFR group, FFR was successfully measured in 94.0% of all lesions. In 874 lesions (63.0%), the FFR was 0.80 or less, and stents were placed in these lesions, per protocol. In 513 lesions (37.0%), the FFR was greater than 0.80, and stents were not placed in these lesions. The procedure time was similar in the two groups (70±44 minutes in the angiography group and 71±43 minutes in the FFR group, P = 0.51). Significantly more contrast agent was used in the angiography group than in the FFR group (302±127 ml vs. 272±133 ml, P<0.001). The mean cost of materials used in the index procedure was $6,007±2,819 in the angiography group, as compared with $5,332±3,261 in the FFR group (P<0.001). Explanation symbols for results: * Plus–minus values are means ―SD. FFR denotes fractional flow reserve, and PCI percutaneous coronary intervention. † All categorical variables were compared with the use of the chi-square test; all continuous variables and the number of drug-eluting stents per patient were compared with the use of the Mann–Whitney U test. ‡ Procedure time was defined as the time from the introduction of the first guiding catheter until the removal of the last guiding catheter. § For the angiography group, the data shown are the number and percentage of lesions indicated at baseline; for the FFR group, the data are the number and percentage of lesions with an FFR of 0.80 or less. ¶ The data shown are the number and percentage of all indicated lesions. A total of 85 lesions were not measured for FFR: 58 (4.1%) that were in totally occluded arteries, for which a default FFR value of 0.50 was assigned, and 27 (1.9%) that could not be measured for FFR because of technical reasons. ‖ The materials used during PCI (e.g., guiding catheters, guidewires, balloons, stents, and, if applicable, pressure wires and vials of adenosine) were recorded, and their costs were calculated according to the actual local price and translated into U.S. dollars.

Endpoints The primary endpoint (a composite of death, myocardial infarction, and repeat revascularization) occurred in 91 patients (18.3%) in the angiography group and in 67 (13.2%) in the FFR group (P = 0.02). The one-year rate of death or myocardial infarction, which was not a prespecified secondary end point but is an important clinical variable, was 11.1% (55 patients) in the angiography group and 7.3% (37 patients) in the FFR group (P = 0.04). At one year, 77.9% of the patients in the angiography group were free from angina, as compared with 81.3% in the FFR group (P = 0.20). A total of 67.6% of patients in the angiography group and 73.0% in the FFR group did not have an event and were free from angina at 1 year (P = 0.07). Explanation symbols for endpoints: * Plus–minus values are means ―SD. FFR denotes fractional flow reserve. † All categorical variables were compared with the use of the chi-square test; all continuous variables and the number of events per patient were compared with the use of the Mann–Whitney U test. ‡ This was the primary end point of the study. § Antianginal medications included beta-blockers, calcium antagonists, and nitrates. ¶ The European Quality of Life–5 Dimensions (EQ-5D) scale is a visual-analogue scale that measures health-related quality of life. Scores range from 0 to 100, with higher scores indicating higher health-related quality of life.

Results One-year Follow-up FAME: - proof that measuring FFR during the stenting procedure really does make a difference...

Results One-year Follow-up ...there is a reduction in MACE: 28% less risk of dying, having a heart attack or having to come back for more stents or a bypass operation ...there is a reduction in death or MI: 34% less risk of dying or having a heart attack Summary: Better outcomes... AND it significantly SAVES on costs AND it doesn’t prolong the procedure.

Sub-analysis – Angiographic vs Functional Severity 65% 20% 4% 35 % Pim Tonino et al. performed a sub-analysis where the objective was to investigate the relationship between angiographic and functional severity of coronary artery stenoses in the FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation) study. Before FFR measurement, these lesions were categorized into 50% to 70% (47% of all lesions), 71% to 90% (39% of all lesions), and 91% to 99% (15% of all lesions) diameter stenosis by visual assessment. In the category 50% to 70% stenosis, 35% were functionally significant (FFR 0.80) and 65% were not (FFR 0.80). In the category 71% to 90% stenosis, 80% were functionally significant and 20% were not. In the category of subtotal stenoses, 96% were functionally significant. Of all 509 patients with angiographically defined multivessel disease, only 235 (46%) had functional multivessel disease (2 coronary arteries with an FFR 0.80). The conclusion is that angiography is inaccurate in assessing the functional significance of a coronary stenosis when compared with the FFR, not only in the 50% to 70% category but also in the 70% to 90% angiographic severity category. Tonino P. A. L et al; J. Am. Coll. Cardiol. 2010;55;2816-2821

Results 2-year Follow-up Significant difference in MI and MI/death between the two groups FAME 2-year Follow-up results, affirm the advantages of using FFR to guide multivessel intervention. FFR-guided PCI significantly improves patient outcomes and results in reduced procedural and healthcare costs, without prolonging the cath lab procedure, compared to angiography alone. Tonino P. A. L et al; J. Am. Coll. Cardiol. 2010;55;2816-2821

2-year Survival from Death and MI Tonino P. A. L et al; J. Am. Coll. Cardiol. 2010;55;2816-2821

Results Two-year Follow-up Significant difference in MI and MI/death between the two groups FAME two-year Follow-up results, affirm the advantages of using FFR to guide multivessel intervention. FFR-guided PCI significantly improves patient outcomes (combined death or MI and MI alone) and results in reduced procedural and healthcare costs, without prolonging the cath lab procedure, compared to angiography alone.

2-year Survival from Death and MI Tonino P. A. L et al; J. Am. Coll. Cardiol. 2010;55;2816-2821

Outcome of Deferred Lesions 513 Deferred Lesions in 509 FFR-Guided Patients 2-years 37 in a New or Restenotic Lesion 53 Repeat Revascularizations 16 Originally Deferred Lesions 6 Without FFR or Despite an FFR > 0.80 Only 10/513 or 1.9% of deferred lesions clearly progressed requiring repeat revascularization. Only 10/513 or 1.9% of deferred lesions clearly progressed requiring repeat revascularization 10 Originally Deferred Lesions with Clear Progression William F. Fearon et al, on behalf of the FAME Study Investigators. Presented at TCT “==)

Outcome of Deferred Lesions 513 Deferred Lesions in 509 FFR-Guided Patients 2-years 22 Peri-procedural 31 Myocardial Infarctions 9 Late Myocardial Infarctions 8 Due to a New Lesion or Stent-Related Only 1/513 or 0.2% of deferred lesions resulted in a late myocardial infarction. Only 1/513 or 0.2% of deferred lesions resulted in a late myocardial infarction 1 Myocardial Infarction due to an Originally Deferred Lesion William F. Fearon et al, on behalf of the FAME Study Investigators. Presented at TCT “==)

2-year follow-up: Better Outcomes at Lower Costs This bootstrap simulation shows that the FFR strategy is cost-saving and cost-effective! Tonino P. A. L et al; J. Am. Coll. Cardiol. 2010;55;2816-2821

Measuring FFR using St Jude Medical’s PressureWire improves patient outcomes up to 2-years post procedure and reduces procedural and healthcare costs without prolonging procedure time.

Results Two-year Follow-up At 2-years a significant decrease in the rate of MI in the FFR-guided arm is demonstrated. There continues to be a significant decrease in death and MI favoring the FFR-guided approach. There is a strong trend toward a lower rate of death, MI or the need for repeat revascularization in the FFR-guided arm. There is no sign suggesting that deferred lesions are likely to be responsible for late myocardial infarctions or to progress and require repeat revascularizations.

Rx Only Please review the Instructions for Use prior to using these devices for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use. Product referenced is approved for CE Mark. PressureWire is designed, developed and manufactured by St. Jude Medical Systems AB. PressureWire, RADI, ST. JUDE MEDICAL, the nine‐squares symbol and MORE CONTROL. LESS RISK. are registered and unregistered trademarks and service marks of St. Jude Medical, Inc. and its related companies. ©2011 St. Jude Medical, Inc. All rights reserved.