1. From RITA to SYNTAX via COURAGE – 15 years on and what can we now tell patients with multi-vessel disease about their treatment options? Patrick W. Serruys Yoshinobu Onuma Thorax Center, Erasmus MC, Rotterdam, the Netherlands 10:55-11:40, 28 th January 2009 London Hilton Metropolitan Hotel Keynote Lecture

2. NO CONFLICT OF INTEREST TO DECLARE

3. Déjà vu... CABRI Trial (Sir Magdi Yacoub) - 1987, Antwerp ARTS Trial (Prof. F. Unger), 1996, Rotterdam SYNTAX Trial (Prof. F. Mohr), 2004, Frankfurt

4. Overview of the keynote lecture Meta-analysis of all the trials comparing PCI and CABG (patient-level data) Meta-analysis of the trials comparing multivessel stenting with BMS and CABG (patient-level data) Critical appraisal of COURAGE Critical appraisal of FAME Personal view on lessons learned from the Syntax

5. Overview of the keynote lecture Meta-analysis of all the trials comparing PCI and CABG (patient-level data) Meta-analysis of the trials comparing multivessel stenting with BMS and CABG (patient-level data) Critical appraisal of COURAGE Critical appraisal of FAME Personal view on lessons learned from the Syntax

6. A MEDLINE search using the keywords “coronary stenting”, “coronary artery bypass surgery”, and “multisystem/multivessel disease” was performed with the intention to select and include all randomized clinical trials comparing PCI with stenting versus CABG in patients with multivessel coronary artery disease. Finally, four trials were selected: the ARTS-trail, the SoS-trial, the ERACI-2 trial and the MASS-2 trial. Principal investigators of each study group were contacted and individual patient data was requested. The patient level based data was subsequently transferred to Dr. E. Boersma, Erasmus University Medical Center, Rotterdam, NL and two of the authors (JD, PWS) analyzed and interpreted the data.

7. PCI with stentingCABG P-value (1518 patients)(1533 patients) Age (years) Median61.6 0.37 IQR53.5 – 68.054.6 – 68.3 Range(30.2, 85.4)(31.9, 86.0) Men76.5% (1162/1518)77.1% (1182/1533)0.73 Diabetes mellitus18.1% (275/1518)17.5 (268/1533)0.67 Hyperlipidemia60.1% (910/1515)56.5% (866/1532)0.051 Hypertension50.5% (766/1518)51.7% (792/1533)0.52 Family history of CAD38.1% (498/1307)38.7% (514/1327)0.75 Current smoker28.3% (429/1516)26.5 (406/1533)0.27 Previous MI42.8% (650/1518)41.4% (635/1533)0.44 Peripheral vascular disease7.0% (107/1518)8.2% (126/1533)0.25 Aspirin93.5% (1419/1518)90.2% (1382/1533)0.001 Beta-blockers79.4% (1205/1518)81.7% (1252/1533)0.11 Calcium channel blockers37.3% (566/1518)40.2% (617/1533)0.095 Nitrates68.1% (1033/1518)69.7% (1068/1533)0.35 Statins40.9% (621/1517)39.5% (606/1533)0.44 Enrollment diagnosis* Stable angina68.2% (1036/1518)68.9% (1057/1533)0.7 Unstable Angina28.5% (432/1518)27.3 (418/1533)0.47 Silent ischemia**3.5% (48/1358)2.6% (34/1330)0.15 Ejection fraction Median60 0.91 IQR52 - 6851 - 67 Range27, 9226, 91 No. of segments with >50% stenosis Median330.92 IQR03-2 Range1, 91, 8 Complete revascularization62.0% (809/1304)89.4% (1180/1320)<0.001 Baseline and procedural characteristics and medications

8. Event rates at 5 years Total population (n=3051)Kaplan Meier estimatesHazard ratio [95% CI] VariablesPCICABGS P-value (1518 pts)(1533 pts) Death8.50%8.20%0.95 [0.73 – 1.23]0.69 Stroke3.10%3.60%1.16 [0.73 – 1.83]0.54 Myocardial infarction7.30%7.60%0.91 [0.68 – 1.23]0.54 Repeat revascularization29.00%7.90%0.23 [0.18 – 0.29]<0.001 Repeat PCI21.50%6.90%0.29 [0.22 – 0.37]<0.001 Repeat CABG10.40%1.50%0.12 [0.07 – 0.21]<0.001 Death, stroke or myocardial infarction 16.70%16.90%1.04 [0.86 – 1.27]0.69 Death, myocardial infarction or repeat revascularization 37.10%20.40%0.50 [0.43 – 0.58]<0.001 Death, stroke, myocardial infarction or repeat revascularization 39.20%23.00%0.53 [0.45 – 0.61]<0.001

9. 5y survival Days Logrank p-value 0.78 0365730109514601825 50 60 70 80 90 100 Overall survival (%) PCI 91.5% CABG 91.8% Group0365730109514601825 PCI151814721456144014061347 CABG153314791457143914121349 Days

10. 0.11.01010 0.52.0 Favors PCIFavors CABG HR 0.56, 95% CI 0.33 – 0.95 HR 0.95, 95% CI 0.63 - 1.43 HR 1.18, 95% CI 0.71 – 1.96 HR 1.69, 95% CI 0.91 – 3.16 HR 0.97, 95% CI 0.76 – 1.24 SoS ARTS MASS-II ERACI-II All patients Adjusted hazard ratio and 95% CI for death We found significant heterogeneity in the treatment effect for death at 5 years between SoS and the other trials (p=0.0074). In SoS, CABG was associated with a 44% reduction in 5-year mortality compared with PCI with stenting (cumulative survival: 95.5% versus 92.1% respectively; HR 0.56 and 95% CI 0.33 - 0.95), whereas no such reduction was observed in the remaining trials (91.2% versus 90.0% respectively; HR 1.15 and 95% CI 0.86 – 1.52). No heterogeneity was observed between SoS and ARTS with respect to the effects of CABG versus PCI with stenting on 5- year mortality (p=0.09).

11. Group0365730109514601825 PCI15181381913896872846 CABG15331377908891868845 5y Death/MI/Stroke PCI 83.3% CABG 83.1% Logrank p-value 0.64 50 60 70 80 90 100 Survival free of death, stroke and myocardial infarction (%) Days 0365730109514601825 Days

12. Group0365730109514601825 PCI15181204772740707665 CABG15331428927911882855 5y Revascularization PCI 71.0% CABG 92.1% Logrank p-value <0.0001 50 60 70 80 90 100 Survival free of repeat revascularizatoin (%) Days 0365730109514601825 Days

13. Group0365730109514601825 PCI15181153729691657616 CABG15331332867846812785 5y MACCE PCI 60.8% CABG 77.0% Logrank p-value <0.0001 50 60 70 80 90 100 Survival free of death, stroke, myocardial infarction and repeat revascularization (%) Days 0365730109514601825 Days

14. SoS ARTS MASS-II ERACI-II All patients 0.11.01010 0.52.0 Favors PCIFavors CABG HR 1.24, 95% CI 0.80 – 1.93 HR 0.80, 95% CI 0.60 – 1.06 HR 1.08, 95% CI 0.72 – 1.61 HR 1.74, 95% CI 1.07 – 2.83 HR 1.05, 95% CI 0.87 – 1.26 Adjusted hazard ratio and 95% CI for death, stroke or MI No significant heterogeneity for the composite endpoint of death, stroke and MI was found for any of the clinical and anatomical subgroup.

15. Hypercholesterolemia No hypercholesterolemia Diabetes No diabetes Previous MI No previous MI LVEF  60 LVEF >60 Two vessel disease Three vessel disease Peripheral vascular disease No peripheral vascular disease All patients 0.95 0.06 0.58 0.65 0.84 0.54 0.84 0.12 P for interaction 0.11.0100.52.0 Favors PCIFavors CABG Age  62 years Age >62 years Men Women Hypertension No hypertension 0.08 0.64 Adjusted hazard ratio and 95% CI for all-cause death, stroke or MI In patients with diabetes, the cumulative incidence of mortality was 12.4% in the PCI group as compared to 7.9% in the CABG group (p=0.09). The cumulative incidence of death, stroke or MI in diabetics was similar following PCI with stenting and CABG (21.4% vs. 20.9% respectively, p=0.9). However, the hazard ratio for repeat revascularization in the diabetic subgroup was 0.18 (95% CI 0.11 – 0.29) due to a three-fold higher cumulative incidence of repeat revascularization in the PCI group (29.7% vs. 9.2%; p<0.001).

16. Overview of the keynote lecture Meta-analysis of all the trials comparing PCI and CABG (patient-level data) Meta-analysis of the trials comparing multivessel stenting with BMS and CABG (patient-level data) Critical appraisal of COURAGE Critical appraisal of FAME Personal view on lessons learned from the Syntax

17. PCI vs Conservative Therapy in Nonacute CAD: a Meta-analysis 11 randomized trials (n=2950) Risk Ratio: PCI compared to medical therapy Mortality = 0.94 (0.72 to 1.24) Cardiac death = 1.17 (0.88 to 1.57) Myocardial Infarction = 1.28 (0.94 to 1.75) Katritsis DG, Ioannidis JP Circ 2005, 111:2906-12 In stable ischemic heart disease what is the evidence that revascularization reduces death or MI ?

18. Angina/QOL at 1 Year: Med Rx vs. PCI TrialQOLAnginaETT ACME PCI better ACME 2 ««« MASS PCI better ACIP PCI better RITA 2 PCI better AVERT PCI better MASS II PCI better TIME PCI better 8 prior (major) randomized trials in stable CAD Refs in: Katritsis DG et al. Circulation 2005;111:2906-12.

19. Angina/QOL at 1 Year: Med Rx vs. PCI TrialQOLAnginaETT ACME PCI better ACME 2 ««« MASS PCI better ACIP PCI better RITA 2 PCI better AVERT PCI better MASS II PCI better TIME PCI better COURAGE PCI better Refs in: Katritsis DG et al. Circulation 2005;111:2906-12. 9 prior (major) randomized trials in stable CAD

20. 1.COURAGE confirms prior studies that demonstrate that PCI is a superior approach to relieve angina, reduce medication requirements, and enhance quality of life 2.No reasonable conclusions can be drawn from COURAGE regarding prevention of death/MI Why Should COURAGE not Change our Approach to Patients with Stable Angina?

21. Patients 0 50 100 150 200 250 010203060704050 N episodes angina/week Simulated Distribution of Anginal Frequency in the COURAGE Trial Diamond, Kaul. JACC 2007 ~42% of pts had absent or minimal symptoms at baseline before Rx Of symptomatic patients, the median number of anginal episodes per week was 3 [1, 6], with a mean of 10

22. Patients 0 50 100 150 200 250 010203060704050 N episodes angina/week Simulated Distribution of Anginal Frequency in the COURAGE Trial Diamond, Kaul. JACC 2007 Who needed PCI within 1 year? ~42% of pts had absent or minimal symptoms at baseline before Rx Of symptomatic patients, the median number of anginal episodes per week was 3 [1, 6], with a mean of 6* * Recent correction by Courage investigators

23. Patients 0 50 100 150 200 250 010203060704050 N episodes angina/week Simulated Distribution of Anginal Frequency in the COURAGE Trial Diamond, Kaul. JACC 2007 Who needed PCI within 1 year? ~42% of pts had absent or minimal symptoms at baseline before Rx Of symptomatic patients, the median number of anginal episodes per week was 3 [1, 6], with a mean of 6* * Recent correction by Courage investigators

24. A North American Trial 50 Hospitals 2,287 pts enrolled between 6/99-1/04 1 pt per hospital per month 19 US Non-VA Hospitals 387 pts (0.5 pts/mo/hosp) (17% of total) 15 VA Hospitals 968 pts (1.6 pts/mo/hosp) (42% of total) 16 Canadian Hospitals 932 pts (1.5 pts/mo/hosp) (41% of total) Boden WE et al. NEJM 2007;356:1503-16

25. Does COURAGE Represent PCI in the United States? 962,732 (98.5%) 14,268 (1.5%) CanadaUS VAUS non VA Boden WE et al. NEJM 2007;356:1503-16 *US data of file, Boston Scientific

26. COURAGE :Subgroup Analyses Death from any cause and nonfatal myocardial infarction PCI Better Medical Therapy Better Baseline Characteristics Hazard Ratio (95% Cl) PCI Medical Therapy 0.25 Overall1.05 (0.87–1.27) 0.190.19 Sex Male1.15 (0.93–1.42)0.190.18 Female0.65 (0.40–1.06)0.180.26 Age > 651.10 (0.83–1.46)0.240.22 ≤ 651.00 (0.77–1.32)0.160.16 Race White1.08 (0.87–1.34)0.190.18 Not White0.87 (0.54–1.42)0.190.24 Health Care System Canadian1.27 (0.90–1.78)0.170.14 U.S. Non-VA0.71 (0.44–1.14)0.150.21 U.S. VA1.06 (0.80–1.38)0.220.22 1.752.001.000.50 1.50 Boden WE et al. NEJM 2007;356:1503-16 Health Care System Canadian 1.27 (0.90–1.78)0.170.14 Canadian 1.27 (0.90–1.78)0.170.14 U.S. non-VA 0.71 (0.80–1.38)0.150.21 U.S. non-VA 0.71 (0.80–1.38)0.150.21 U.S. VA 1.06 (0.80-1.38) 0.22 0.22 U.S. VA 1.06 (0.80-1.38) 0.22 0.22

27. COURAGE Projections: 3-year death/MI 21% (OMT) vs. 16.4% (PCI + OMT) (22% ↓ ) Death/MI (%) at 4.6 years 29%↓ 27%↑   P≈0.02 Boden WE et al. NEJM 2007;356:1503-16

28. Nuclear Substudy (n=314/2,287) Hypothesis: Reduction in Ischemia will be greater for patients randomized to PCI + OMT than for those randomized to OMT Serial Rest/Stress Myocardial Perfusion SPECT (MPS) Repeat MPS at 6-18M Repeat MPS at 6-18M Shaw et al. J Nucl cardiol 2006; 13: 685-98 Pre-Rx ischemiaPre-Rx = Off Meds Pre-Rx = On Meds PCI + OMT (n=159) OMT (n=155) To compare patient management strategy for ischemia reduction

29. Myocardial Perfusion SPECT Ischemia based on Total Perfusion Defect (TPD) TPD: Quantitative Measure of defect extent & severity % Ischemic Myocardium: (Stress TPD-Rest TPD) <5%: Minimal “No Ischemia” 5.0-9.9%: Mild ≥10%: Moderate-to-Severe Significant Reduction >5% Reduction in Ischemia Shaw et al. Circulation 2008; 117: 1283-91 Slomka et al. J Nucl cardiol 2005; 12:66-77

30. P = 0.004 Ischemia Reduction ≥5% (n=159)(n=155) Primary Endpoint: % of Patients with Significant Ischemia Reduction (≥5% Myocardium, n=314) Shaw et al. Circulation 2008; 117: 1283-91

31. Rates of Death or MI by Residual Ischemia on 6-18m MPS Death or MI Rate (%) (n=23)(n=141)(n=88)(n=62) =/> 10% P=0.063 P=0.023 P=0.02 Shaw et al. Circulation 2008; 117: 1283-91

32. PCI added to OMT was more effective in reducing ischemia and improving angina than OMT, particularly in patients with moderate-to-severe pre-rx ischemia Exploratory outcomes data: - Ischemia reduction >5% associated with lower risk of death/MI - Residual ischemia >5% associated with higher risk of death / MI Randomized trials of management strategies should evaluate quantitative measures of myocardial perfusion ischemia to guide clinical decisions regarding revascularization during long-term management

33. “A substudy of the COURAGE trial, which showed that patients with the greatest relief of ischemia had the lowest rates of death or myocardial infarction, further supports the concept that PCI should be guided by physiological considerations and not solely by anatomical ones.” Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention, Tonino et al. NEJM Jan 15, 2009

34. Overview of the keynote lecture Meta-analysis of all the trials comparing PCI and CABG (patient-level data) Meta-analysis of the trials comparing multivessel stenting with BMS and CABG (patient-level data) Critical appraisal of COURAGE Critical appraisal of FAME Personal view on lessons learned from the Syntax

35. Conclusions Routine measurement of FFR in patients with multivessel coronary artery disease who are undergoing PCI with drug- eluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year.

36. Characteristic Angiography Group (N = 496) FFR Group (N = 509)P Value† Indicated lesions per patient- no. 2.7±0.92.8±1.00.34 Extent of occlusion — no. of lesions/total (%) 50–70% narrowing40.744.1 71–90% narrowing41.037.5 91–99% narrowing15.314.3 Total occlusion3.04.1 Patients with total occlusion- %7.510.6 Quantitative coronary analysis Extent of stenosis — %61.2±16.660.4±17.60.24 Minimal luminal diameter — mm1.0±0.41.0±0.50.35 Reference diameter — mm2.5±0.62.5±0.70.81 Lesion length — mm12.6±6.912.5±6.50.42 SYNTAX score14.5±8.814.5±8.60.95 EQ-5D score64.7±19.266.5±18.30.24 Patient Characteristics

37. End Point Angiography Group (N = 496) FFR Group (N = 509) P Value† Relative Risk with FFR guidance (95%CI) Events at 1 year — % Composite of death, myocardial infarction, and repeat vascularization 18.313.20.02 0.72 (0.54–0.96) Death 3.01.80.19 0.58 (0.26–1.32) Myocardial infarction 8.75.70.07 0.66 (0.42–1.04) Repeat vascularization 9.56.50.08 0.68 (0.45–1.05) Death or myocardial infarction 11.17.30.04 0.66 (0.44–0.98) Total events — no. 11376 Events per patient — no. 0.23±0.53 0.15±0.410.02 Functional status at 1 year Patients without event and free from angina— % 67.673.00.07 Patients free from angina — % 77.981.30.2 Antianginal medications 1.23±0.741.20±0.760.48 Score on EQ-5D visual-analogue scale 73.7±16.074.5±15.70.65 One-year Outcome

38. 81.7% 86.8% 91.3% 94.3% 97.0% 98.2% 90.5% 93.5% RR = 0.72 [0.54-0.96], p=0.02 RR = 0.58 [0.26-1.32], p=0.19 RR = 0.66 [0.42-1.04], p=0.07RR = 0.68 [0.45-1.05], p=0.08

39. Conclusions Routine measurement of FFR in patients with multivessel coronary artery disease who are undergoing PCI with drug-eluting stents significantly reduces the rate of the composite end point of death, nonfatal myocardial infarction, and repeat revascularization at 1 year.

40. Overview of the keynote lecture Meta-analysis of all the trials comparing PCI and CABG (patient-level data) Meta-analysis of the trials comparing multivessel stenting with BMS and CABG (patient-level data) Critical appraisal of COURAGE Critical appraisal of FAME Personal view on lessons learned from the Syntax

41. Past Present

42. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 42 At the time of the trial design (in 2003-2004), a retrospective website survey of 104 medical centers over a period of 3 months, showed that 12,072 patients (1/3 LM, 2/3 3VD) were revascularized by surgery (2/3) or by PCI (1/3). The SYNTAX randomized trial is an attempt to provide an evidence-base to determine whether this approach, which is already currently practiced, is valid. Background Kappetein et al, Eur J Cardiothorac Surg. 2006;29:486-491

43. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 43 How does modern CABG compare to PCI in high- risk patients eligible for both techniques? Which patient group continues to be solely eligible for CABG? What characterizes complex patients not eligible for CABG? Background In an attempt to answer this paradigm we asked the following three questions:

44. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 44 Patient Profiling Local Heart team (surgeon & interventional cardiologist) assessed each patient in regards to: Patient’s operative risk (EuroSCORE & Parsonnet score) Coronary lesion complexity (newly developed SYNTAX score) Goal: SYNTAX score to provide guidance on optimal revascularization strategies for patients with high-risk lesions Sianos et al, EuroIntervention 2005;1:219-227 Valgimigli et al, Am J Cardiol 2007;99:1072-1081 Serruys et al, EuroIntervention 2007;3:450-459 BARI classification of coronary segments Leaman score, Circ 1981;63:285-299 Lesions classification ACC/AHA, Circ 2001;103:3019-3041 Bifurcation classification, CCI 2000;49:274-283 CTO classification, J Am Coll Cardiol 1997;30:649-656 Tortuosity Thrombus Bifurcation Total Occlusion 3 Vessel Left Main EuroInterv 2005;1:219-227 Dominance Calcification Number & location of lesions SYNTAX score

45. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 45 Patient 1 Patient 2 SYNTAX SCORE 21 SYNTAX SCORE 55 LCx 70-90% LAD 70-90% RCA2 70-90% RCA3 70-90% LM 99% LCx 100% LAD 99% RCA 100% There is ‘3-vessel disease’ and ‘3-vessel disease’

46. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 46 SYNTAX Score Distribution by Cohort and Treatment Group SYNTAX Score % of Patients CABG RCT PCI RCT 0 5 10 15 20 25 0612182430364248546066727884 Score Tertile Low Scores (0-22) Score (23-32) Score Tertile High Scores (  33)

47. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 47 SYNTAX Score Distribution by Cohort and Treatment Group SYNTAX Score % of Patients CABG RCT PCI RCTPCI Registry 0 5 10 15 20 25 0612182430364248546066727884 Score Tertile Low Scores (0-22) Score (23-32) Score Tertile High Scores (  33)

48. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 48 SYNTAX Score Distribution by Cohort and Treatment Group SYNTAX Score % of Patients CABG RCT PCI RCTPCI Registry Score Tertile Low Scores (0-22) Score (23-32) Score Tertile High Scores (  33) 0 5 10 15 20 25 0612182430364248546066727884

49. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 49 SYNTAX Score Distribution by Cohort and Treatment Group SYNTAX Score % of Patients CABG RCTCABG Registry PCI RCTPCI Registry Score Tertile Low Scores (0-22) Score (23-32) Score Tertile High Scores (  33)

50. 50 71% enrolled (n=3,075) All Pts with de novo 3VD and/or LM disease (n=4,337) Treatment preference (9.4%) Referring MD or pts. refused informed consent (7.0%) Inclusion/exclusion (4.7%) Withdrew before consent (4.3%) Other (1.8%) Medical treatment (1.2%) TAXUS n=903 PCI n=198 CABG n=1077 CABG n=897 no f/u n=428 5yr f/u n=649 PCI all captured w/ follow up CABG 2500 750 w/ f/u vs Total enrollment N=3075 Stratification: LM and Diabetes Two Registry Arms Randomized Arms n=1800 Two Registry Arms n= 1275 Randomized Arms n=1800 Heart Team (surgeon & interventionalist) PCI n=198 CABG n=1077 Amenable for only one treatment approach TAXUS * n=903 CABG n=897 vs Amenable for both treatment options Stratification: LM and Diabetes LM 33.7% 3VD 66.3% LM 34.6% 3VD 65.4% 23 US Sites62 EU Sites + SYNTAX Trial Design * Taxus Express

51. CABG RCT N=897 CABG Reg N=644 Age, mean±SD (y)65.0 ± 9.865.7 ± 9.4 Male, %78.980.7 SYNTAX score, mean±SD29.1 ± 11.437.8 ± 13.3 Diabetes, %28.529.7 Hypertension, %77.073.5 Hyperlipidemia, %77.276.4 Current smoker, %22.021.9 Prior MI, %33.833.5 Unstable angina, %28.021.6 Add. EuroSCORE, mean±SD3.8 ± 4.43.9 ± 2.7 Total Parsonnet score, mean±SD 8.4 ± 6.89.0 ± 7.1 Patient Characteristics Notable Differences CABG RCT + Registry * For descriptive purposes only; no statistical comparisons done

52. 012 Cumulative Event Rate (%) Event Rate ± 1.5 SE 10 20 30 0 Months Since Allocation 6 Per-protocol population Overall MACCE to 12 Months CABG RegistryOverall MACCE to 12 Months CABG Registry 8.8%

53. Patient Characteristics Notable Differences PCI RCT + Registry TAXUS RCT n=903 PCI Reg n=192 Age, mean±SD (y)65.2 ± 9.771.2 ± 10 Male, %76.470.3 SYNTAX score28.4 ± 11.531.6 ± 12.3 Diabetes, %28.235.4 Hyperlipidemia, %78.767.5 Current smoker, %18.511.2 Prior MI, %31.940.4 Unstable angina, %28.938.0 Add. EuroSCORE, mean±SD3.8 ± 2.65.8 ± 3.1 Total Parsonnet score, mean±SD 8.5 ± 7.014.4 ± 9.5 * For descriptive purposes only; no statistical comparisons done

54. 012 Cumulative Event Rate (%) Event Rate ± 1.5 SE 10 20 30 0 Months Since Allocation 6 Per-protocol population Overall MACCE to 12 Months PCI RegistryOverall MACCE to 12 Months PCI Registry 20.4%

55. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 55 Enrolled SYNTAX trial patients (N=3075) SYNTAX Trial Patient Distribution CABG registry (N=1077) Randomized (N=1800) PCI registry (N=198)

56. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 56 Patient Characteristics (II) Randomized Cohort Patient-based CABG N=897 TAXUS N=903 P value Total SYNTAX Score29.1 ± 11.4 28.4 ± 11.5 0.19 Diffuse disease or small vessels, %10.711.30.69 No. lesions, mean ± SD4.4 ± 1.8 4.3 ± 1.8 0.44 3VD only, %66.365.40.70 Left main, any, %33.734.60.70 Left Main only3.13.80.46 Left Main + 1 vessel5.15.40.78 Left Main + 2 vessel12.011.50.72 Left Main + 3 vessel13.513.90.78 Total occlusion, %22.224.20.33 Bifurcation, %73.372.40.67 Trifurcation, %10.610.70.92

57. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 57 Staged procedure, %14.1 Lesions treated/pt, mean ± SD3.6 ± 1.6 No. stents implanted, mean ± SD4.6  2.3 Total length implanted, mm ± SD86.1  47.9 Range, mm8 – 324 Long stenting (>100 mm), %33.2 Procedural Characteristics TAXUS Randomized Cohort TAXUS N=903 Patient-based

58. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 58 Death/CVA/MI to 12 Months P=0.98 * 0612 10 20 0 Months Since Allocation Cumulative Event Rate (%) ITT population 7.7% 7.6% TAXUS (N=903) CABG (N=897) Event rate ± 1.5 SE. * Fisher exact test

59. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 59 Combined Safety (Death/CVA/MI) to 12 months TAXUS CABG P=0.99 12 month MACCE, % P=0.39P=0.96P=0.29 n=897n=903n=221n=231n=348n=357n=549n=546 Medically Treated Diabetes

60. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 60 SYNTAX Score Distribution by Cohort and Treatment Group SYNTAX Score % of Patients CABG RCT PCI RCT 0 5 10 15 20 25 0612182430364248546066727884 Score Tertile Low Scores (0-22) Score (23-32) Score Tertile High Scores (  33)

61. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 61 TAXUS (N=299) CABG (N=274) 13.5% 14.4% P=0.71 * 0612 20 30 0 Months Since Allocation Cumulative Event Rate (%) 10 RCT ITT pts; site-reported data MACCE to 12 Months by SYNTAX Score Tertile Low Scores (0-22) Event Rate ±1.5 SE, * Fisher exact test; raw SYNTAX score for illustrative purposes only

62. SYNTAX: Left Main Subset SerruysTCT 14 October 2008 Slide 62 7.7% 13.0% Mean baseline SYNTAX Score CABG15.5 ± 4.3 TAXUS15.7 ± 4.4 0 6 12 20 40 0 Months Since Allocation Cumulative Event Rate (%) TAXUS (N=118) CABG (N=103) P=0.19 * Event rate ± 1.5 SE, * Fisher exact testCalculated by core laboratory; ITT population MACCE to 12 Months by SYNTAX Score Tertile Low Scores (0-22) 12 17.3% 15.2% Mean baseline SYNTAX Score CABG17.3 ± 3.7 TAXUS17.3 ± 3.8 P=0.66 * 06 20 40 0 Months Since Allocation Cumulative Event Rate (%) 12 LM subset 3VD subset TAXUS (N=181) CABG (N=171)

63. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 63 What does this mean for clinicians? Patients with low SYNTAX Scores have comparable outcomes after revascularization with PCI or CABG These patients have less complex anatomy Treatment will depend on individual patient characteristics, patient preference and physician choice

64. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 64 TAXUS (N=310) CABG (N=300) 16.6% 11.7% P=0.10 * 0612 20 30 0 Months Since Allocation Cumulative Event Rate (%) 10 MACCE to 12 Months by SYNTAX Score Tertile Intermediate Scores (23-32) RCT ITT pts; site-reported data Event Rate ±1.5 SE, * Fisher exact test; raw SYNTAX score for illustrative purposes only

65. SYNTAX: 3VD MohrTCT 14 October 2008 Slide 65 P=0.02 * Calculated by core laboratory; ITT populationEvent Rate ± 1.5 SE, * Fisher exact test Mean baseline SYNTAX Score CABG27.5 ± 2.7 TAXUS27.4 ± 2.9 0612 20 40 0 Months Since Allocation Cumulative Event Rate (%) 18.6% 10.0% 15.5% 12.6% Mean baseline SYNTAX Score CABG27.2 ± 3.0 TAXUS27.0 ± 2.7 0612 20 40 0 Months Since Allocation Cumulative Event Rate (%) LM subset 3VD subset TAXUS (N=195) CABG (N=92) TAXUS (N=207) CABG (N=208) MACCE to 12 Months by SYNTAX Score Tertile Intermediate Scores (23-32) P=0.54 *

66. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 66 MACCE is slightly, but not significantly, increased in PCI patients with intermediate SYNTAX Scores This suggests that PCI is still a valid option in patients with intermediate SYNTAX scores Treatment will depend on the patients’ characteristics and comorbidity What does this mean for clinicians?

67. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 67 TAXUS (N=290) CABG (N=316) 23.3% 10.7% P<0.001 * 0612 20 30 0 Months Since Allocation Cumulative Event Rate (%) 10 MACCE to 12 Months by SYNTAX Score Tertile High Scores (  33) RCT ITT pts; site-reported data Event Rate ±1.5 SE, * Fisher exact test; raw SYNTAX score for illustrative purposes only

68. SYNTAX: 3VD MohrTCT 14 October 2008 Slide 68 21.5% 8.8% Mean baseline SYNTAX Score CABG41.0 ± 6.6 TAXUS39.8 ± 6.0 0612 20 40 0 Months Since Allocation Cumulative Event Rate (%) P=0.002 * Calculated by core laboratory; ITT populationEvent Rate ± 1.5 SE, * Fisher exact test P=0.008 * 25.3% 12.9% Mean baseline SYNTAX Score CABG42.1 ± 7.6 TAXUS43.8 ± 9.1 0612 20 40 0 Months Since Allocation Cumulative Event Rate (%) LM subset 3VD subset TAXUS (N=155) CABG (N=166) TAXUS (N=135) CABG (N=150) MACCE to 12 Months by SYNTAX Score Tertile High Scores (  33)

69. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 69 MACCE rates in PCI patients with high SYNTAX Score were significantly higher than in CABG patients These patients have very complex anatomy This suggests that PCI is most likely not a viable option and these patients will remain surgical candidates What does this mean for clinicians?

70. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 70 SYNTAX Trial Patient Distribution CABG registry (N=1077) PCI registry (N=198) SYNTAX Scores ≥33 SYNTAX Scores 23-32 SYNTAX Scores 0-22 + - +/- All Patients

71. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 71 SYNTAX Trial Patient Distribution CABG registry (N=1077) PCI registry (N=198) SYNTAX Scores ≥33 SYNTAX Scores 23-32 SYNTAX Scores 0-22 + - +/- Left main

72. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 72 SYNTAX Trial Patient Distribution CABG registry (N=1077) PCI registry (N=198) SYNTAX Scores ≥33 SYNTAX Scores 0-22 + - - 3VD LM SYNTAX Scores 23-32 P=0.02

73. 73 71% enrolled (N=3,075) All Pts with de novo 3VD and/or LM disease (N=4,337) Treatment preference (9.4%) Referring MD or pts. refused informed consent (7.0%) Inclusion/exclusion (4.7%) Withdrew before consent (4.3%) Other (1.8%) Medical treatment (1.2%) TAXUS n=903 PCI n=198 CABG n=1077 CABG n=897 no f/u n=428 5yr f/u n=649 PCI all captured w/ follow up CABG 2500 750 w/ f/u vs Total enrollment N=3075 Stratification: LM and Diabetes Two Registry Arms Randomized Arms n=1800 Two Registry Arms N=1275 Randomized Arms N=1800 Heart Team (surgeon & interventionalist) PCI N=198 CABG N=1077 Amenable for only one treatment approach TAXUS * N=903 CABG N=897 vs Amenable for both treatment options Stratification: LM and Diabetes LM 33.7% 3VD 66.3% LM 34.6% 3VD 65.4% DM 28.5% Non DM 71.5% NonDM 71.8% DM 28.2% 23 US Sites62 EU Sites + SYNTAX Trial Design * TAXUS Express

74. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 74 Combined Safety (Death/CVA/MI) to 12 months in Diabetic Patients TAXUS CABG P=0.11 12 Mo Death/CVA/MI, % 8/604/746/708/777/74 11/74 P=0.71P=0.31

75. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 75 MACCE to 12 months in Diabetic Patients TAXUS CABG P=0.78 MACCE, % 11/6015/749/7020/779/74 24/74 P=0.046P=0.003

76. SYNTAX Primary Endpoint SerruysTCT 14 October 2008 Slide 76 SYNTAX Trial Patient Distribution CABG registry (N=1077) PCI registry (N=198) SYNTAX Scores ≥33 SYNTAX Scores 23-32 SYNTAX Scores 0-22 3VD + LM with DM LM w/o DM

77. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 77 Post SYNTAX CABG 66% PCI only CABG + PCI 28% 6% Results of the SYNTAX trial suggest that 66 % of all patients are still best treated with CABG, however, for the remaining patients PCI is an excellent alternative to surgery at least for one year

78. PCI “Best Scenario” Interpretation SerruysTCT 14 October 2008 Slide 78 Conclusions Using as criteria, a non-significant difference in MACCE, we may state: Results of the SYNTAX trial suggest that 66% of all patients are still best treated with CABG, however, for the remaining patients PCI (Syntax Score 0-22) is an excellent alternative to surgery in multivessel disease, in left main disease and in diabetic patients. Left main disease, non-diabetic with score of 23-32 could also be treated by PCI.