1. The best strategy for the patient with multivessel coronary artery disease Claudio Moretti, MD CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette”

2. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” The debate is an anglosaxon concept. In general, debates are a waste of time and energy and are close to an exercise in futility. However, debates keep the audience entertained by artificially discussing issues which are going to be resolved spontaneously. P. Serruys PRELIMINARIES

3. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” OVERVIEW 1. Historical review of RCT on PCI vs CABG 2. Meta-analysis 1 yr of ARTS-1, SOS, ERACI-2, MASS-2 3. ARTS-1, ERACI-2 5-YRS F. up 4. Non randomized studies 6. Syntax 7. Personal view 8. Final remarks

4. 4 Trial Clinical Parameters Angiographic Endpoints Cost Assessment Mortality & MIAngina Relief Repeat Revascularizat ion GABI PCI CABGNo differencen/a EAST No differenceCABG PCI RITA No differenceCABG n/a ERACI No differenceCABG n/aPCI CABRI No differenceCABG n/a BARI No differencen/aCABGn/a MASS-2 CABG (MI)n/aCABGn/aNo difference AWESOME No difference CABGn/a ERACI-2 PCIn/aCABG No difference SoS CABG (Mortality)CABG n/a ARTSNo differencen/aCABGn/aPCI Superior Treatment Modality No stents used Stents used CABG No difference PCI

5. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Previous POBA studies Meta-analysis 3300 patients 1660 CABG, 1710 PTCA Deaths 79 PCI vs 73 CABG Revascularisation rates 33% PCI v 3% CABG Pocock SJ, et al. Lancet 1995 Unbiased estimate for patients who meet the (strict) entry criteria < 5 % pts randomized

6. One-year outcomes of CABG vs PCI in multvessel disease: Meta-analysis from randomized clinical trials ( ARTS I, SoS, ERACI II, MASS II ) PCI 1518 pts vs CABG 1533 pts (1995-2000) ( Pts with LM disease, poor LV function and diffuse disease excluded )

7. All cause mortality at one year CABGPCI Numbers at risk PCI151814841472 CABG153315011490 1476 1495 4 2 0 3 0 Cumulative event rate (%) 1 120360240 Days after randomization Adjusted HR* (95% CI) = 1.02 (0.64 – 1.60) 3.0 2.8 Mercado N, Wijns W, Serruys PW, et al. J Thorac Cardiovasc Surg 2005; 130.

8. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” CONCLUSIONS At five years there was no difference in mortality between stenting and surgery for multivessel disease. Furthermore, the incidence of stroke or myocardial infarction was not significantly different between the two groups. However, overall MACCE was higher in the stent group, driven by the increased need for repeat revascularization. (J Am Coll Cardiol 2005;46: 575–81) CONCLUSIONS At five years of follow-up, in the ERACI II study, there were no survival benefits from any revascularization procedure; however patients initially treated with CABG had better freedom from repeat revascularization procedures and from MACE. (J Am Coll Cardiol 2005;46: 582–8)

10. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette”

11. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette”

12. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality

13. Registries Broad Inclusion Stent selection by the Operator discretion Large populations > 2000 Usually multi center Less adjusted required propensity score Clinical follow-up only Reflect more “real world” experience Randomized Trials Restricted inclusion with broad exclusion criteria Small sample size < 1500 Limited centers participate Includes angio follow-up Always clinical follow up in the office More experienced centers Monitoring and adjudication of all cases Registries Versus Randomized Clinical Trials

14. ?

15. Draft of Correspondence to NEJM Letter to the editors (never submitted ! ) Letter to the editors (never submitted ! ) “This observational report attempts to equalize the two groups by using risk-adjusted survival methods. This flawed methodology attempts to adjust an unadjustable characteristic: – the judgment of the treating physician regarding the revascularization strategy that is not correctable by adjusting for clinical variables.” Ong, Serruys, Boersma (August 2005)

16. ARTS II – Study design Primary endpoint: effectiveness of coronary stent implantation using the CYPHER® Sirolimus-eluting Stent with that of surgery as observed in ARTS I measured as MACCE-free survival at 1 year. ARTS II CYPHER® Stent N=607 ARTS I CABG N= 605 Crown™ Stent N= 600 N= 600 R Same inclusion / exclusion criteria Same MACE definition. Serruys PW et al; EuroInterv 2005; 1: 147-56

17. ARTS II - MACCE up to 1 year 93.6% 80.2% 91.0% 96.9% 90.8% 93.8% Time (Days) 0 50 100 150 200 250 300 350 400 Event free Survival (%) 100 95 95 90 90 85 85 80 80 75 75 70 70 65 65 60 60 - ARTS II - ARTS I CABG - ARTS I PCI P (log rank) =0.46 between ARTS II and ARTS I-CABG 89.5% 73.7% 88.5% Serruys PW et al; EuroInterv 2005; 1: 147-56

18. “The Rosy Prophecy “

19. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Anatomy Severity Patient MVD : heterogeneous entity Euro Heart Survey on PCI

20. Multivessel disease …. Focal lesions

21. Multivessel disease ….

22. Tortuosity Thrombus Bifurcation Total Occlusion 3 Vessel Left Main Lesion location Calcification Scoring system

23. SYNTAX (SYNergy between PCI with TAXUS and cardiac surgery) Post – ESC, Munich 2008

24. Limited Exclusion Criteria Previous interventions (PCI or CABG) Acute MI with CPK>2x Concomitant valve surgery

25. SYNTAX Score Anatomic Scoring For Each Lesion Segment –Location –Length –Calcification –Tortuosity –Bifurcation –Diffuse Disease –Occlusion –Thrombus SYNTAX Score SYNTAX Score = 18 SYNTAX Score = 41

26. Primary Endpoint: Randomized trial The primary clinical endpoint is the 12-Month binary MACCE rate. MACCE* is defined as: All cause Death Cerebrovascular Event (Stroke) Documented Myocardial Infarction Repeat Revascularization (PCI and/or CABG) The primary endpoint (12-month MACCE) will be analyzed for all patients as well as the subgroups of patients with 3VD only and patients with LM disease. SYNTAX *ARC MACCE definition Circulation 2007; 115:2344-2351

27. Final Enrollment Data Enrollment Completed April 2007 Total Enrollment N=3075 Greater Lesion Complexity Chronic total occlusions Diffuse coronary disease More Comorbities Compassionate use 23 North American 62 European Sites Randomized N=1800 CABG N=1077 PCI N=198 Presented by P. Serruys, MD - EuroPCR 2007

46. What can we conclude from SYNTAX Trial ? In patients with MVD ( including patients with LM disease):  Equivalence in safety overall outcomes (Death, MI, CVA) in PCI and CABG patients ( 7.7% vs 7.6 %)  Significant higher rates of TLR / TVR in PCI patients (13.7 % vs 5.9% )  Significant higher rates in CVA in CABG patients (2.2% vs 0.6%)  Similar symptomatic gratf occlusion and stent thrombosis at 12 months

47. What can we conclude from SYNTAX Trial ?  Only 65% of patients with MVD are amenable for PCI  Surgery is not the only option for unprotected LMCA disease  Need for patients’ startification for the appropriate revacularization option ( SYNTAX Score ? )  Need for a longer follow up data

48. How will the results of the SYNTAX study impact your practice on patients with multivessel disease and unprotected LM? More CABG 22 % More PCI with DES 39 % Will not change 39 % From: www.CRTonline.orgwww.CRTonline.org September 2008

49. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Multivessel PCI...my personal opinion

50. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” MVD : focal lesions DES!

51. Safe and effective treatment..... Two days later….. 24 h post multivessel PCI

52. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” MVD : diffuse disease ….

54. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette”

55. Surgery Has Changed !!

56. Adverse events from CAGs… in contemporary practice

57. Graft occlusion in 2007….

58. Multivessel PCI in 2008 :  For unselected patients, MV PCI with DES is a safe option but remains associated with an increased need for repeat procedures compared to surgery  Appropriate patient selection (risk scoring, medication compliance, co-morbidities) and revascularization strategy (single session vs staging, complete vs partial revascularization, etc) continue to play a critical role  To compete effectively with surgical revascularisation where SYNTAX has shown equvalnce we must ensure: - complete revascularisation - optimal stent expansion - minimise myocardial injury

59. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality

60. Angiography-guided PCI FFR-guided PCI Measure FFR in all indicated stenoses Stent all indicated stenoses Stent only those stenoses with FFR ≤ 0.80 Randomization Indicate all stenoses ≥ 50% considered for stenting Patient with stenoses ≥ 50% in at least 2 of the 3 major epicardial vessels 1-year follow-up FLOW CHART

61. FFR-guided 30 days 2.9% 90 days 3.8% 180 days 4.9% 360 days 5.3% Angio-guided absolute difference in MACE-free survival FAME study: Event-free Survival

62. FAME study: CONCLUSIONS (1) Routine measurement of FFR during PCI with DES in patients with multivessel disease, when compared to current angiography guided strategy reduces the rate of the composite endpoint of reduces the rate of the composite endpoint of death, myocardial infarction, re-PCI and CABG death, myocardial infarction, re-PCI and CABG at 1 year by ~ 30% at 1 year by ~ 30% reduces mortality and myocardial infarction at reduces mortality and myocardial infarction at 1 year by ~ 35 % 1 year by ~ 35 %

63. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality THANKS … for Your attention !

66. FAME study: BACKGROUND (1) Stenting of non-ischemic stenoses has no benefit Stenting of non-ischemic stenoses has no benefit compared to medical treatment only compared to medical treatment only Stenting of ischemia-related stenoses improves Stenting of ischemia-related stenoses improves symptoms and outcome symptoms and outcome In multivessel coronary disease (MVD), identifying In multivessel coronary disease (MVD), identifying which stenoses cause ischemia is difficult: which stenoses cause ischemia is difficult: Non-invasive tests are often unreliable in MVD and Non-invasive tests are often unreliable in MVD and coronary angiography often results in both under- coronary angiography often results in both under- or overestimation of functional stenosis severity or overestimation of functional stenosis severity

67. 0.0729 (5.7)43 (8.7) All myocardial infarctions 1727 Other infarctions (“late or large”) Events at 1 year, No (%) 1216 Small periprocedural CK-MB 3-5 x N Myocardial infarction, specified 0.0276113 Total no. of MACE 0.0833 (6.5)47 (9.5) CABG or repeat PCI 0.0437 (7.3)55 (11.1) Death or myocardial infarction 0.199 (1.8)15 (3.0)Death 0.0267 (13.2)91 (18.4) Death, MI, CABG, or repeat-PCI P-value FFR-group N=509 ANGIO-group N=496 FAME study: Adverse Events at 1 year

68. 0.07360 (73)326 (68) Patients without event and free from angina 0.20399 (81)374 (78) Patients free from angina, No. (%) 0.481.2 ± 0.81.2 ± 0.7 Number of anti-anginal meds, No. 0.6575 ± 1674 ± 16 EQ-5D visual analogue scale P-value FFR-group N=509 ANGIO-group N=496 FAME study: Functional Class at 1 Year

69. FAME study: CONCLUSIONS (2) Routine measurement of FFR during PCI with DES in patients with multivessel disease, when compared to current angiography guided strategy, furthermore: is cost-saving and does not prolong the procedure is cost-saving and does not prolong the procedure reduces the number of stents used reduces the number of stents used decreases the amount of contrast agent used decreases the amount of contrast agent used results in a similar, if not better, functional status results in a similar, if not better, functional status

70. Routine measurement of FFR during DES-stenting in patients with multivessel disease is superior in patients with multivessel disease is superior to current angiography guided treatment. to current angiography guided treatment. It improves outcome of PCI significantly It improves outcome of PCI significantly It supports the evolving paradigm of It supports the evolving paradigm of “Functionally Complete Revascularization”, “Functionally Complete Revascularization”, i.e. stenting of ischemic lesions and i.e. stenting of ischemic lesions and medical treatment of non-ischemic ones. medical treatment of non-ischemic ones. FAME study: CONCLUSIONS (3)

72. Multivessel stenting is off label……. but…….

73. 68 yrs old Stable angina Not diabetic Normal LV 3 vessel disease SYNTAX score 15 Can we do it ?

74. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality

75. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality

76. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality

77. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Superior Treatment Modality

78. FREEDOM Trial Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease

79. Multivessel PCI - Conclusions  For selected patients, MVPCI with BMS is a safe option but remains associated with an increased need for repeat procedures compared to surgery  The use of DES appears to be associated with MACCE rates similar to those of surgery, despite a stent thrombosis rate per patient that is probably higher than for single vessel procedures  The pivotal RCT’s of DES vs CABG are still ongoing  Appropriate patient selection (risk scoring, medication compliance, co-morbidities) and revascularization strategy (single session vs staging, complete vs partial revascularization, etc) continue to play a critical role

80. Conclusion Our preliminary results provide evidence that the Syntax score may become a suitable tool to risk-stratify early and late outcome in patients with 3VD. Patients with the Syntax score greater than 26 (31?) may be better treated with surgical revascularization. The Syntax study will confirm whether the Syntax score of 26 is a discriminating criteria to select patients who should be treated by either surgery or DES. So far, two third (score < 26) of the ARTS II patients with 3VD have an excellent outcome.

81. CONCLUSIONS  CABG will remain the Gold Standard until PCI has long term data that is better  Despite sicker patients, CABG results have uniformly improved – STS  Resource utilization for CABG has dramatically decreased  Off pump surgery can provide complete revascularization at lower risk and cost  Aggressive use of statins and life style changes will improve results of both therapies  Aggressive treatment for LDL and soon HDL will diminish both surgical and catheter interventions

83. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Length is no longer important or is it?

84. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette” Incomplete expansion remains a major cause of stent thrombosis Incomplete expansion remains a major cause of stent thrombosis Incomplete expansion of DES is a major cause of stenosis and therefore re-stenosis Incomplete expansion of DES is a major cause of stenosis and therefore re-stenosis Issues in MVD (3) Calcification - limiting stent expansion

85. Not all MVD patients are born equal ……..

89. Complete revascularization Complete revascularization Long stents - Procedural MI Long stents - Procedural MI Calcification – limiting stent expansion Calcification – limiting stent expansion Key issues in MVD PCI

91. CARDIOLOGIA INTERVENTISTICA - UNIVERSITA’ DI TORINO OSPEDALE S.G.BATTISTA “Molinette”

92. 24 h post multivessel PCI 24 h post CABG Slide Acknowledgements K Dawkins P Urban L Testa & team at JR

95. There is ‘3-vessel disease’ and ‘3-vessel disease’. Patient 1 Patient 2