SYNTAX - Top 30 Enrolling Centers: IAustriaCzech RepNorwayFranceGermanyHungaryItaly

CABG InvestigatorPCI InvestigatorPaul SimonDietmar GlogarJan TosovskyMichael AschermannPer Nielsen HostrupLeif ThuesenGerard FournialDidier CarrieArnaud FargeMarie-Claude MoriceJean-Paul BessouJacques BerlandPatrick SoulaJean MarcoFriedrich MohrGerhard SchulerBruno ReichartPeter BoekstegersHermann ReichenspurnerThomas MeinertzLajos PappIvan G. HorvathFerenc TarrIstvan PredaPaolo FerrazziGiulio GuagliumiAndrea dArminiEzio BramucciLucia TorraccaAntonio Colombo

SYNTAX - Top 30 Enrolling Centers: IIItalyLatviaNetherlandsPolandSwedenUKUS

CABG InvestigatorPCI InvestigatorMattia GlauberSergio BertiRomans LacisAndrejs ErglisPieter KappeteinPatrick SerruysJacques SchonbergerJacques KoolenAndrejs BochenekJanus DrzewieckiElisabeth StahleStefan JamesStephen WestabyAdrian BanningGeoff BergKeith G. OldroydSteven LiveseyKeith D. Dawkins Jatin DesaiMartyn ThomasTomasz SpytAnthony H. GershlickAndrew ForsythAdam De BelderGraham VennSimon RedwoodWilliam KillingerTift MannMichael MackDavid L. Brown

SYNTAXHeart team meeting - surgeon(s) and interventional cardiologist(s) assess each patient

Operative risk(EuroSCORE & Parsonnet score)

Coronary lesion complexity (SYNTAX score)Sianos et al, EuroIntervention 2005;1:219-227Valgimigli et al, Am J Cardiol 2007;99:1072-1081Serruys et al, EuroIntervention 2007;3:450-459BARI classification of coronary segmentsLeaman score, Circ 1981;63:285-299Lesions classification ACC/AHA , Circ 2001;103:3019-3041 Bifurcation classification, CCI 2000;49:274-283CTO classification, J Am Coll Cardiol 1997;30:649-656Dominance

Limited Exclusion CriteriaPrevious interventions (PCI or CABG)Acute MI with CPK>2xConcomitant cardiac surgerySYNTAX Trial- Eligible PatientsDe novo disease

+SYNTAX Trial Design

+SYNTAX Trial Design

+SYNTAX Trial Design

Withdrawn 47 Lost to FU 1312 mo Follow up N=1740 (96.7%)Total randomized N=1800TAXUS* 891 (98.7%)7 5TAXUS* 903 (50.2%)CABG 897 (49.8%)CABG 849 (94.6%)40 8Randomised Patient Flow (ITT)

Patient Characteristics (l)Randomised Cohort

CABG N=897TAXUS* N=903P valueAge, mean SD (y)65.0 9.865.2 9.70.55Male, %78.976.40.20BMI, mean SD27.9 4.528.1 4.80.37Diabetes, %28.528.20.89Hypertension, %77.074.00.14Hyperlipidemia, %77.278.70.44Current smoker, %22.018.50.06Prior MI, %33.831.90.39Unstable angina, %28.028.90.67Additive EuroSCORE, mean SD 3.8 2.73.8 2.60.78Total Parsonnet score , mean SD 8.4 6.88.5 7.00.76

Patient Characteristics (lI)Randomised Cohort

Patient-basedCABG N=897TAXUS* N=903P valueTotal SYNTAX Score29.1 11.428.4 11.50.19Diffuse disease or small vessels, % 10.711.30.69No. lesions, mean SD 4.4 1.84.3 1.80.443VD only, %66.365.40.70Left 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 vessel13.513.90.78Total occlusion, %22.224.20.33Bifurcation, %73.372.40.67Trifurcation, %10.610.70.92

Baseline Characteristics in DES PatientsSYNTAX Trial Versus 2 Large, Multicenter MVD Registries*Creatinine >220mol/liter for NY State, >200mol/liter for the SYNTAX trial

ARTS II N=607NY State N=9963SYNTAX N=903Age, meanSD (y)63 1065.4 11.965.2 9.7Male, %7767.276.4BMI, meanSD27.5 4.1-28.1 4.8Diabetes, %2632.728.2Hypertension, %67-74.0Hyperlipidemia, %74-78.7Current smoker, %19-18.5Prior MI, %3433.731.9History of CHF, %-10.14.0Renal Failure*-1.41.1Left Main, %excludedexcluded35%3 Vessel Disease, %54%25%91%

Procedural CharacteristicsPCI Randomised Cohort

Patient-basedTAXUS* N=903Staged Procedure, %14.1Vessels treated, % LAD36.3 Circumflex32.5 RCA29.2 LM11.2Bi/trifurcation, %64.4Lesions treated/pt, mean SD 3.6 1.6No. stents implanted, mean SD 4.6 2.3Total length implanted, mm SD 86.1 47.9Range, mm8 324Long stenting (>100 mm), %33.2

Procedural CharacteristicsCABG Randomised Cohort

Procedure-related CABG N=897Off-pump surgery, %15.0Graft revascularization, % Complete arterial revascularisation18.9 At least one arterial graft97.3 Double LIMA/RIMA27.6 LIMA+venous78.1 Arterial graft to LAD95.6 Radial Artery14.1 Venous graft only2.6Grafts per patient, mean SD 2.8 0.7Distal anastomosis/pt, mean SD 3.2 0.9

Procedural CharacteristicsRandomised Cohort *Allocation to procedureFor PCI patients, includes time for staged procedurePer protocol: Complete revascularisation is defined as the treatment of any lesion with more than 50% diameter stenosis in vessels 1.5 mm diameter as estimated on the diagnostic angiogram during the local Heart Team conference. Completeness of revascularization was assessed post procedure by the operator (Surgeon or Interventional Cardiologist)

CABG N=897TAXUS* N=903P valueTime to procedure*, d, mean SD 17.4 28.06.9 13.0

ITT; Fisher Exact TestP=0.37SYNTAX - All-cause mortality to 12 Months 4.3%3.5%

SYNTAX - Cerebrovascular Events to 12 Months 0.6%2.2%P=0.003ITT; Fisher Exact Test

SYNTAX - Myocardial Infarction to 12 Months 3.2%4.8% P=0.11ITT; Fisher Exact Test

SYNTAX - Death/CVA/MI to 12 MonthsP=0.987.7% 7.6% ITT; Fisher Exact Test

SYNTAX - Symptomatic Graft Occlusion & Stent Thrombosis at 12 Months3.33.4P=0.89CABGTAXUSPatients (%)n=27n=28TAXUS* (N=903)CABG (N=897)ITT population

Chart1

3.43.3

CABG

TAXUS

Sheet1

MACCE

CABG3.4

TAXUS3.3

SYNTAX - Repeat Revascularisation to 12 Months5.9% 13.7% P

SYNTAX - MACCE to 12 MonthsP=0.001512.1% 17.8% ITT; Fisher Exact Test

SYNTAX - 12 Month Clinical Event RatesPatients (%)CABG (N=897)TAXUS* (N=903)ITT, Kaplan-Meier Rates; Fisher Exact TestAll DeathCVAMIDeath/MI/CVARevascularisationP=0.37P=0.003P=0.11P=0.98P

Primary Endpoint: 12 Month MACCE Non-inferiority analysis05%10%15%Pre-specified Margin = 6.6%Difference in MACCE20%+95% CI = 8.3%5.5%

Chart1

18.3

2

0

Sheet1

0

5.51

2

Sheet1

8.3

0

Sheet2

Sheet3

Stent Number and Length Higher in the SYNTAX TrialPatients (%)Total Number of Stents Implanted per Patient Multivessel disease: 96.2%* 3-vessel disease:90.8%Avg. stents per patient:4.6 2.3 Avg. stented length:86.1 mm*3VD+LM/3VD+LM/2VD+LM/1VD

Average Number of Stents Implanted per Patient4.62.3SYNTAXTrialSYNTAXAverage number of stents implantedin SYNTAX is higher than any othercontemporary DES versus CABG study

Average Total Stented Length86.147.9SYNTAXTrialAverage total stent length (mm)SYNTAX

Linear Increase in MACCE by Number of Stentsin the SYNTAX Trial12m MACCE in TAXUS Arm12345678+Number of Stents Implanted

SYNTAX - Outcome according to Diabetic StatusDiabetes (Medical Treatment)N=452Non-DiabeticN=1348Death/CVA/MIMACCEDeath/CVA/MIMACCEP=0.96P=0.0025P=0.08P=0.97

Diagramm1

10.310.1

14.226

Datenreihe 1

Datenreihe 2

10.3

14.2

10.1

26.0

Tabelle1

Datenreihe 1Datenreihe 2

10.310.1

14.226

Ziehen Sie zum ndern der Gre des Diagrammdatenbereichs die untere rechte Ecke des Bereichs.

Diagramm1

6.86.8

11.815.1

Datenreihe 1

Datenreihe 2

6.8

11.8

6.8

15.1

Tabelle1

Datenreihe 1Datenreihe 2

6.86.8

11.815

Ziehen Sie zum ndern der Gre des Diagrammdatenbereichs die untere rechte Ecke des Bereichs.

SYNTAX - Left Main Subgroup MACCE Ratesat 12 MonthsPatients (%)All LM N=705

Chart1

13.715.8

LM onlyLM only

LM+1VDLM+1VD

LM+2VDLM+2VD

LM+3VDLM+3VD

3VD (all)3VD (all)

CABG

PCI

Sheet1

allLM onlyLM+1VDLM+2VDLM+3VD3VD (all)

CABG13.7

PCI15.8

SYNTAX - Left Main and Three Vessel Disease Subgroup MACCE Rates at 12 MonthsCABGTAXUS*Patients (%)All LM N=705LM+1VD N=138LM Isolated N=91LM+2VD N=218LM+3VDN=2583VD ( w/o LM)N=1095

Chart1

13.715.8

8.57.1

13.27.5

14.419.8

15.419.3

11.519.2

CABG

PCI

Sheet1

allLM onlyLM+1VDLM+2VDLM+3VD3VD (all)

CABG13.78.513.214.415.411.5

PCI15.87.17.519.819.319.2

Contemporary studies of DES versus CABG1-Year Mortality in CABG ArmMultivesselLeft MainYang 2008 (n=390)ARTS I (n=602)Lee, 2007 (n=103)Javaid2008 (n=505)SYNTAXTrial(n=897)Sanmartin2007 (n=245)Palmerini2006 (n=154)Lee2006 (n=123)Chieffo2006 (n=142)Patients (%)Multivessel and/or Left Main

Contemporary studies of DES versus CABG1-Year TVR (PCI or CABG) in CABG ArmMultivesselLeft MainLee2007 (n=103)Sanmartin2007 (n=245)Palmerini2006 (n=154)Lee2006 (n=123)Chieffo2006 (n=142)Patients (%)ARTS I (n=602)Yang 2008 (n=390)SYNTAXTrial(n=897)Multivessel and/or Left Main

Contemporary studies of DES versus CABG1-Year Stroke Rates in CABG ArmMultivesselLeft MainLee2007 (n=103)Javaid2008 (n=505)Sanmartin2007 (n=245)Chieffo2006 (n=142)Patients (%)ARTS I (n=602)Yang 2008 (n=390)SYNTAXTrial(n=897)Multivessel and/or Left Main

Contemporary studies of DES versus CABG1-Year MAC(C)E* Rates in CABG ArmMultivesselLeft MainLee 2007 (n=103)Javaid2008 (n=505)*definitions varyacross studiesSanmartin2007 (n=245)Lee2006 (n=123)Patients (%)ARTS I (n=602)Yang 2008 (n=390)SYNTAXTrial(n=897)Multivessel and/or Left Main

Average Stent Number and Length in ARRIVE Registry(N=7,492 patients)Patients (%)Total Number of Stents Implanted per Patient Multivessel disease: 36.9% 3-vessel stenting:1.2%Avg. stents per patient:1.6 0.9 Avg. stented length:18.6 mm

Average Stent Number and Length in OLYMPIA Registry(N=22,345 patients)Patients (%)Total Number of Stents Implanted per Patient Multivessel disease: 56.5% 3-vessel stenting:1.3%Avg. stents per patient:1.5 0.8 Avg. stented length:29.9 mm

Stent Number and Length Higher in the SYNTAX TrialPatients (%)Total Number of Stents Implanted per Patient Multivessel disease: 96.2%* 3-vessel disease:90.8%Avg. stents per patient:4.6 2.3 Avg. stented length:86.1 mm*3VD+LM/3VD+LM/2VD+LM/1VD

Average Number of Stents Implanted per Patient4.62.3SYNTAXTrialSYNTAXAverage number of stents implantedin SYNTAX is higher than any othercontemporary DES versus CABG study

Average Total Stented Length86.147.9SYNTAXTrialAverage total stent length (mm)SYNTAX

Linear Increase in MACCE by Number of Stentsin the SYNTAX Trial12m MACCE in TAXUS Arm12345678+Number of Stents Implanted

1-Year Mortality and Revascularisation Ratesin TAXUS Stent Studies Patients (%)MortalityRevascularisationTAXUSSRMetaARRIVE Simple UseARRIVE MV StentingSYNTAXTrialTAXUSSRMetaARRIVE Simple UseARRIVE MV StentingSYNTAXTrialTarget vessel onlyAny Repeat Revascularization

Contemporary studies of DES versus CABG1-Year Revascularisation in DES ArmMultivesselLeft MainYang 2008 (n=441)ARTS II (n=607)Hannan 2008 (n=9963)DELFT2008 (n=358)Sanmartin2007 (n=96)Palmerini2006 (n=157)Lee2006 (n=50)Chieffo2006 (n=107)Patients (%)42% 3VD91% 3VD54% 3VD35% LM25% 3VD(TVR)(TVR)(TLR)(TVR)All Revasc.All RevascularizationSYNTAXTrial(n=903)Multivessel and/or Left Main(All)

Contemporary studies of DES versus CABG1-Year Mortality in DES ArmMultivesselLeft MainYang 2008 (n=441)ARTS II (n=607)Lee, 2007 (n=102)Hannan2008 (n=9963)Javaid2008 (n=95)(cardiac)DELFT2008 (n=358)Sanmartin2007 (n=96)Palmerini2006 (n=157)Lee2006 (n=50)Chieffo2006 (n=107)Patients (%)SYNTAXTrial(n=903)Multivessel and/or Left Main

Contemporary studies of DES versus CABG1-Year Stroke Rates in DES ArmMultivesselLeft MainYang 2008 (n=441)ARTS II (n=607)Lee2007 (n=102)Javaid2008 (n=95)Sanmartin2007 (n=96)Chieffo2006 (n=107)Patients (%)SYNTAXTrial(n=903)Multivessel and/or Left Main

Contemporary studies of DES versus CABG1-Year MAC(C)E* Rates in DES ArmMultivesselLeft MainYang 2008 (n=441)ARTS II (n=607)Lee 2007 (n=102)Javaid2008 (n=95)DELFT2008 (n=358)*definitions varyacross studiesSanmartin2007 (n=96)Lee2006 (n=50)SYNTAX TrialPatients (%)3VDLM

Atherosclerosis: A progressive processDisease progressionPHASE I: Initiation PHASE II: ProgressionPHASE III: Complication

Atherosclerotic progression:Glagovs remodeling hypothesisNormalvesselProgressionGlagov S, et al. N Engl J Med. 1987;316:1371-1375.

What types of lesions cause MI?Falk E, et al. Circulation. 1995;92:657-671.10080604020014%18%68%All 4 studies50%-70%70%1006040200Ambrose 1988Little 1988Nobuyoshi 1991Giroud 1992Coronary stenosis (%)Coronary stenosis severity prior to MI80

Atherosclerosis: The first sign of CHD is often sudden death or MI062% (552/895 men)Men45% (305/674 women)Women

Patients who experienced an MI (%)Murabito JM, et al. Circulation. 1993;88:2548-2555.20304050607010

Breakdown of Current CAD TreatmentCDC MMWR 2007;56:113-118Eur Heart J 2005;26:1011-1022 J Am Coll Cardiol 2002;39:1096-1103 USEuropeCABG is the current gold-standard of care in patients with left main & multivessel disease

Isolated LM includes portion of ostial LAD and CX. A lesion would have to be 3x RVD away from another lesion to count as a separate lesion. So if lesion originates in LM and extends to both LAD and CX that would be a LM isolated. Only when the RVD criteria is met further down vessel, or obviously RCA, does it count as +1/2/3.

******In this trial the Local Heart team (surgeon & interventional cardiologist) assessed each patient in regards to:

Patients operative risk ( the EuroSCORE & Parsonnet score) and Coronary lesion complexity ( a newly developed SYNTAX score)

The goal of the SYNTAX score is provide a tool to assist physicians in their revascularization strategies for patients with high risk lesions**********Exhibit 6**Exhibit 6*NY State:3 Diseased Vessels, with or without proximal LAD = 7683 total / out of 17400 patients = 44% 3VD overallStent: 2481 / 9963 patients = 25%CABG: 5202 / 7437 = 69.9%**Exhibits 10, 12**Exhibits 18, 19**Exhibit 9**All cause death to 12 months was 4.3 for TAXUS patients and 3.5 for CABG patients (p=0.37)**Cerebrovascular Events to 12 months was 0.6 for TAXUS patients and 2.2 for CABG patients (p=0.003)**Myocardial Infarction to 12 months was 4.8 for TAXUS patients and 3.2 for CABG patients (p=0.11)**The composite of Death, Cerebrovascular events and myocardial infarction to 12 months was 7.6 for TAXUS patients and 7.7 for CABG patients (p=0.98)**Symptomatic Graft Occlusion and Stent Thromobosis was not statistically different between CABG and TAXUS at 12 months**Repeat Revascularization to 12 months was 13.7 for TAXUS patients and 5.9 for CABG patients (p=0.0001).**MACCE to 12 months was 17.8 for TAXUS patients and 12.1 for CABG patients (p=0.0015). This was primarily driven by the higher rates of repeat revascularization in the PCR cohort.*No 95% CI around a binary rate**Non-inferiority comparison was not met for the primary endpoint, further comparisons for the LM and 3VD subgroups are observational only and hypothesis generating

*Source: BSC Internal Data on File (SYNTAX_CSR_Randomized_Unblinded_2008Aug07.doc, Exhibit 7 & 12)

3 vessel disease = 3VD, LM+3VD, LM+2VD = 90.8%Multivessel disease = everything but LM isolated = 96.2%*******The LM and 3VD subgroup MACE rates were analyzed by number of vessels treated as depicted on this slide.**The LM and 3VD subgroup MACE rates were analyzed by number of vessels treated as depicted on this slide.*Multivessel: - Yang 2008: J. H. Yang et al., The Annals of Thoracic Surgery 85, 65 (2008). - ARTS I: P. W. Serruys et al., EuroIntervention 1, 147 (2005). - Lee, 2007: M. S. Lee et al., Int J Cardiol 123, 34 (2007). - Javaid, 2008: A. Javaid et al., Circulation 116, I200 (2007). - rates are for 3VD. Paper also lists rates in 2VD

Left main- Sanmartin, 2007: M. Sanmartin et al., Am J Cardiol 100, 970 (2007)- Palmerini, 2006: T. Palmerini et al., Am J Cardiol 98, 54 (2006).- 430 days median follow-up- Lee, 2006: M. S. Lee et al., J Am Coll Cardiol 47, 864 (2006).- Chieffo, 2006: A. Chieffo et al., Circulation 113, 2542 (2006).

Lee, 2006, 1 year- Seung 2008, MAIN COMPARE (396 DES, 3906 CABG wave 2), 3 years. (give 1 year interim)*Multivessel: - Yang 2008: J. H. Yang et al., The Annals of Thoracic Surgery 85, 65 (2008). - ARTS I: P. W. Serruys et al., EuroIntervention 1, 147 (2005). - Lee, 2007: M. S. Lee et al., Int J Cardiol 123, 34 (2007). - not sure if rate is all revascularization (any vessel) or TVR; paper doesnt specify. - Javaid, 2008: A. Javaid et al., Circulation 116, I200 (2007). - does not list revasc (TVF only) not in table

Left main- Sanmartin, 2007: M. Sanmartin et al., Am J Cardiol 100, 970 (2007)- Palmerini, 2006: T. Palmerini et al., Am J Cardiol 98, 54 (2006).- rate of 25.5% is TLR.- 430 days median follow-up- Lee, 2006: M. S. Lee et al., J Am Coll Cardiol 47, 864 (2006).- Chieffo, 2006: A. Chieffo et al., Circulation 113, 2542 (2006).

*Multivessel: - Yang 2008: J. H. Yang et al., The Annals of Thoracic Surgery 85, 65 (2008). - ARTS I: P. W. Serruys et al., EuroIntervention 1, 147 (2005). - Lee, 2007: M. S. Lee et al., Int J Cardiol 123, 34 (2007). - Javaid, 2008: A. Javaid et al., Circulation 116, I200 (2007). - rates are for 3VD. Paper also lists rates in 2VD

Left main- Sanmartin, 2007: M. Sanmartin et al., Am J Cardiol 100, 970 (2007)- Palmerini, 2006: T. Palmerini et al., Am J Cardiol 98, 54 (2006).- stroke rates not given; 430 days median follow-up- Lee, 2006: M. S. Lee et al., J Am Coll Cardiol 47, 864 (2006).- stroke rates not given- Chieffo, 2006: A. Chieffo et al., Circulation 113, 2542 (2006).

*Multivessel: - Yang 2008: J. H. Yang et al., The Annals of Thoracic Surgery 85, 65 (2008).- MACCE = all cause death, AMI, CVA, revasc. by PCI or CABG - ARTS I: P. W. Serruys et al., EuroIntervention 1, 147 (2005). - Lee, 2007, 1 year- MACCE = all cause death, nonfatal MI, CVA, revasc. by PCI or CABG - Lee, 2007: M. S. Lee et al., Int J Cardiol 123, 34 (2007).- MACE = death, MI, repeat revasc. - Javaid, 2008: A. Javaid et al., Circulation 116, I200 (2007). - rates are for 3VD. Paper also lists rates in 2VD- MACCE = MACE + cerebrovascular event (paper does not define MACE)

Left main- Sanmartin, 2007: M. Sanmartin et al., Am J Cardiol 100, 970 (2007)- MACCE = death, Q-MI, stroke, repeat revascularization- Lee, 2006: M. S. Lee et al., J Am Coll Cardiol 47, 864 (2006).- MACCE = death, MI, CVA, TVR***Source: BSC Internal Data on File (SYNTAX_CSR_Randomized_Unblinded_2008Aug07.doc, Exhibit 7 & 12)

3 vessel disease = 3VD, LM+3VD, LM+2VD = 90.8%Multivessel disease = everything but LM isolated = 96.2%*********Atherosclerosis, the process underlying most CVD, has 3 distinct stages: Initiation - during which lipids are deposited on the vessel wall Progression - during which inflammation increases, plaque formation builds up in the intima, and fibrous caps are formed, increasing the potential for atheroma Clinical disease - when complications result from stenosis or unstable plaque rupture, leading to myocardial infarction (MI), stroke, or death.1

1. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365-372.

*The new model of atherosclerosis was based on histological analysis of coronary artery sections reported by Glagov et al in 1987.1 The work they described showed that the early stages of disease were marked by plaque accumulation in the vessel wall, with subsequent enlargement of the EEM but no change in lumen size. In Glagovs original hypothesis, plaque development is extraluminal until the lesion occupies 40% of the area within the EEM. Only then does the lumen begin to shrink.

1. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316; 22:1371-1375.

*Several investigators have examined the question of which types of lesions cause MI. This slide shows collated data from a number of studies.1 The proportion of patients with MI caused by either >70%, 50%-70%, or