The document discusses the background and design of the SYNTAX trial, which compared coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) using drug-eluting stents in patients with complex, multi-vessel coronary artery disease. It found that at 12 months, the primary endpoint of major adverse cardiovascular and cerebrovascular events was significantly lower in the CABG group compared to the PCI group. However, rates of death, myocardial infarction, and stroke were similar between groups. The higher revascularization rate in the PCI group accounted for most of the difference in the primary endpoint. Subset analyses found comparable safety outcomes for CABG and PCI in patients with isolated left main coronary artery disease.

1. Per Hostrup Århus Universitetshospital, Skejby DCS/DTS Odense 8. jan. 2009

4. Baggrund I 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.

5. Baggrund II Ultimo 2007: 23 RCTs included 9963 patients and span 4 decades; however, in 2005 alone, more than 900 000 revascularization procedures were performed in the United States. How many of these procedures were performed on patients like those in the trials is unknown, but the modest number of patients in RCTs is disturbing.

6. SYNTAX Trial Design + * TAXUS Express 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 ad Diabetes LM 33.7% 3VD 66.3% LM 34.6% 3VD 65.4% 23 US Sites 62 EU Sites

7. SYNTAX Primary Endpoint Randomized trial The primary clinical endpoint is the 12-month Major Cardiovascular or Cerebrovascular Event rate (MACCE * ) MACCE is defined as: All-cause Death Cerebrovascular Accident (CVA/Stroke) Documented Myocardial Infarction Any Repeat Revascularization (PCI and/or CABG) All events CEC Adjudicated * ARTS I: Serruys et al, NEJM 2001; 344: 1117-1124

8. Primary Endpoint: 12-month MACCE Non-inferiority analysis 0 5% 10% 15% Pre-specified Margin = 6.6% Difference in MACCE 20% +95% CI = 8.3% 5.5% The criteria for non-inferiority comparison was not met for the primary endpoint, further comparisons for the LM and 3VD subgroups are observational only and hypothesis generating

9. Main Results 12 months End Point CABG (%) DES (%) p MACCE 12.1 17.8 0.0015 Death/MI/stroke 7.7 7.6 0.98 Revascularization 5.9 13.7 <0.0001 Stroke 2.2 0.6 0.003 MI 3.2 4.8 0.11 All-cause death 3.5 4.3 0.37

10. CVA (Stroke) to 12 Months 0.6% 2.2% ITT population P =0.003 * Event rate ± 1.5 SE. * Fisher exact test 0,3% 1 % 0,9 % 0 6 12 10 20 0 Months Since Allocation Cumulative Event Rate (%) TAXUS (N=903) CABG (N=897)

11. 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, C irc 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

12. There is ‘3-vessel disease’ and ‘3-vessel disease’ Patient 1 Patient 1 Patient 2 Patient 2 LCx 70-90% RCA3 70-90% LCx 100% LAD 99% RCA 100% SYNTAX SCORE 21 SYNTAX SCORE 52 LAD 70-90% RCA2 70-90% LM 99%

13.  33 MACCE to 12 Months vs SYNTAX Score TAXUS (N=903) CABG (N=897) ≤ 22 23-32  33 ≤ 22 23-32 P =0.38 P =0.007 P =0.29 P =0.002 P =0.04 12-month MACCE, % SYNTAX Score RCT ITT pts; site-reported data

14. MACCE Rates to 12 Months CABG Registry (n=644) 2.5 2.2 2.5 6.6 3.0 Per-protocol population All Death CVA MI Death/CVA/MI Revascularization Total MACCE 8.8 0 5 15 20 10 25 Patients (%) 3.5 % 2.2 % 12.1 % 7.7 % PCI 17.4 % 3.2 % CABG RCT 5.9 % In-Hospital MACCE

15. MACCE at 12 Months by SYNTAX Score Tercile All Terciles PCI Registry Cumulative Event Rate (%) Months Since Allocation 0 12 10 20 30 0 6 40 5.9% Low (0-22) Intermediate (23-32) 5.6% High (  33) 10.5%

16. Overall MACCE at 12 Months Left Main Subset ITT population (n=705) (n=91) (n=138) (n=218) (n=258) P =0.44 P =1.0 P =0.27 P =0.29 P =0.42 Patients (%) TAXUS CABG

17. Summary Left Main Subset Overall MACCE in the PCI group was comparable with CABG (13.7% CABG vs 15.8% TAXUS) Similar overall safety outcomes (Death/CVA/MI) between CABG and PCI at 12 months (9.2% CABG vs 7.0% TAXUS) There was a higher rate of revascularization in the PCI group (6.5% CABG vs 11.8% TAXUS), and a higher rate of CVA in the CABG group (2.7% CABG vs 0.3% TAXUS) PCI outcomes are excellent relative to CABG in LM isolated and LM+1VD Per protocol rates of symptomatic graft occlusion and stent thrombosis were similar

18. Konklusioner: Alle komplekse ptt. – LM/3VD – vurderes ved konferencen + Syntax-score Inddrage patienten CABG: Stroke må minimeres 1/3 af LM/3VD ptt. kan ikke tilbydes PCI. - CABG med fremragende resultater Udvalgte LM ptt. kan tilsyneladende tilbydes PCI Flere RCT – LM-Projektet

19. TAK for opmærksomheden