1. 4 th European Bifurcation Club 26-27 September 2008 - PRAGUE A comprehensive meta- analysis on drug-eluting stenting for unprotected left main disease

2. Background Cardiac surgery is the gold standard revascularization means for unprotected left main disease (ULM). Percutaneous drug-eluting stent (DES) implantation has been recently reported in patients with ULM, but with unclear results. Moreover, predictors of adverse events after DES implantation in ULM are still under investigation.

3. Aims To perform a systematic review of the outcomes of DES implantation in patients with ULM coronary disease. To pool major outcomes with meta- analytic techniques. To identify predictors of adverse events by means of meta-regression analysis.

4. Methods Several databases (BioMedCentral, clinicaltrials.gov, Google Scholar, and PubMed) were systematically searched for pertinent clinical studies Major selection criteria were: enrolment of at least 20 patients, follow-up for at least 6 months, and full text publication (thus excluding abstracts) Pre-specified subgroup analyses were performed according to ostial ULM, and non-high-risk features (defined by means of Parsonnet or EuroSCORE systems) Generic-inverse-variance random-effect methods were used to pool incidence rates and adjusted risk estimates (odds ratios [OR], with 95% confidence intervals) of death, myocardial infarction (MI), target vessel revascularization (TVR), or their composite, ie major adverse cardiovascular events (MACE)

5. Methods Several databases (BioMedCentral, clinicaltrials.gov, Google Scholar, and PubMed) were systematically searched Major selection criteria were: enrolment of at least 20 patients, follow-up for at least 6 months, and full text publication (thus excluding abstracts) Pre-specified subgroup analyses were performed according to ostial ULM, and non-high-risk features (defined by means of Parsonnet or EuroSCORE systems) Generic-inverse-variance random-effect methods were used to pool incidence rates and adjusted risk estimates (odds ratios [OR], with 95% confidence intervals) of death, myocardial infarction (MI), target vessel revascularization (TVR), or their composite, ie major adverse cardiovascular events (MACE) Meta-regression was performed to identify regression coefficients (with 95% confidence intervals) for event predictors

6. Review profile 17 studies (16 original cohorts) included in the review 774 titles/abstracts excluded because non-relevant 32 articles excluded according to selection criteria 7 duplicate publications 4 enrolling <20 patients 9 ongoing 7 unpublished 5 using BMS only 823 hits retrieved from extensive database search 49 articles assessed according to inclusion/exclusion criteria

7. Included studies Study design and IDCountryPatients treated with DES Observational cohorts on DES Agostoni et al (2005)Netherlands58 de Lezo et al (2004)Spain52 Dudek et al (2006)Poland28 KOMATE (2005)Korea54 Lozano et al (2005)Spain42 Migliorini et al (2006)Italy156 Price et al (2006)USA50 Wood et al (2005)USA100 Non-randomized studies of DES vs BMS Carrié et al (2006)France120 Chieffo et al (2005)Italy85 Christiansen et al (2006)Denmark46 Han et al (2006)China138 Park et al (2005)Korea102 Sheiban et al (2006)Italy85 Non-randomized studies of PCI vs CABG Chieffo et al (2006)Italy107 Lee et al (2006)USA50 Palmerini et al (2006)Italy94

8. Major excluded studies StudyCountryPatientsDesignReason for exclusion Arampatzis et al(2003)Netherlands31Observational cohortDuplicate publication Arampatzis et al(2004)Netherlands16Observational cohortDuplicate publication Berenguer et al(2005)Spain7Observational cohortDuplicate publication CARDIA(2006)UK600RCT of PCI vs CABGOngoing COMBATWorldwide1800RCT of PCI vs CABGOn hold eCYPHER(2006)Worldwide171Observational cohortUnpublished Erglis et alEurope103RCT of DES vs BMSUnpublished European RegistryEurope224Observational cohortUnpublished French Multicenter Taxus StudyFrance150Observational cohortOngoing Herz et al(2005)Israel4Non-RCT of PCI vs CABG<20 patients included Kim et al(2006)Korea116Observational cohortDuplicate publication Korean Randomized StudyKorea124RCT of PCI vs CABGOngoing LE MANS(2005)Poland37Observational cohortUnpublished Lefevre et alFrance146Observational cohortUnpublished Leipzig StudyGermany200RCT of PCI vs CABGOngoing Lopez-Palop et al(2004)Spain10Observational cohort<20 patients included Munich StudyGermany340RCT of Cypher vs TaxusOngoing Palmerini et al(2005)Italy42Observational cohortDuplicate publication Peszek-Przybyla et al(2006)Poland62Observational cohort<20 patients included Pohl et al(2004)Germany23RCT of PCI vs CABGBMS use only REVASCULARIZEUSANARCT of PCI vs CABGOngoing SECUREUSA20Observational cohortUnpublished SYNTAXWorldwide1500RCT of PCI vs CABGOngoing Teplitsky et al(2004)Israel11Observational cohort<20 patients included TRUEEurope115Observational cohortUnpublished Valgimigli et al(2005)Netherlands80Before-after studyDuplicate publication Valgimigli et al(2006)Netherlands110Observational cohortDuplicate publication

9. Characteristics of included studies Study Age (years) Males (%) DM (%) ACS (%) Non- bifurcation al ULM (%) Surgical high risk features (%) LVEF (%) COPD (%) RF (%) Angio follow-up (%) Oral antiplatelet regimen SES vs PES use (%) Agostoni et al(2005)63±1369333245NA48±1 2 NA A+C, 6 mNA Carrié et al(2006)66±127529630NA59±1 1 NA 100A+C, 6m0/100 Chieffo et al(2005)63±12842131194551±1 1 NA 85A+C, ≥6 mNA Chieffo et al(2006)64±10NA1932193252±1 0 NA685NA51/49 Christiansen et al(2006) NA 4643NA A+C, ≥3 mNA de Lezo et al(2004)63±1142358358NA57±1 3 NA 67A+C, 12 m100/0 Dudek et al(2006)NA A+C, 6-12 m46/54 Han et al(2006)*62±11NA294529NA 36A+C, 6-9 mNA KOMATE (2005)59±968276567NA60±1 8 NA444A+C, 6 m65/35 Lee et al(2006)72±15503666406451±1 5 NA1642A+C, 6 m84/16 Lozano et al(2005)70±116033173110037*NA 57A+C, 3-6 m71/19 Migliorini et al(2006)70±10803269156127 † NA2784A+C, 6 m26/74 Palmerini et al(2006)73±11702663206452±1 4 162066NA68/32 Park et al(2005)60±1175286029NA60±8NA 84A+C, 6 m100/0 Price et al(2006)69±1364263465824 ‡ NA1698A+C, indefinitely 100/0 Sheiban et al(2006)68±10772267404655±1 0 NA461A+C or A+T, 6 m 100/0 Wood et al(2005)68±136430NA31NA47±1 3 NA A+C, ≥6 mNA

10. Unadjusted clinical outcomes StudyN In-hospital death (%) In- hospital MI (%) Follow-up (months) Follow-up completion (%) MACE (%) MACCE (%) Death (%) MI (%) Stroke (%) TVR (%) ST (%) Agostoni et al (2005)58231410016NA53 7 Carrié et al (2006)–BMS arm*57051010066NA75 260 Carrié et al (2006)–DES arm*49431010013 103021 Chieffo et al (2005)–BMS arm64081210042NA14NA 300 Chieffo et al (2005)–DES arm85061210025NA4 191 Chieffo et al (2006)–CABG arm14222612100424482726NA Chieffo et al (2006)–DES arm 107091210033343101201 Christiansen et al (2006)–BMS arm* 39313610044 31508NA Christiansen et al (2006)–DES arm* 422061007752052 de Lezo et al (2004)5204121006NA04 20 Dudek et al (2006)36NA 9 14NA 0 Han et al (2006)–BMS arm34NA 12NA27NA93 15NA Han et al (2006)–DES arm138NA 12NA11NA71 10NA KOMATE (2005)54206815NA20 20 Lee et al (2006)–CABG arm123526NA141711281NA Lee et al (2006)–DES arm50206NA11 44070 Lozano et al (2005)42100 10026NA204NA21 Migliorini et al (2006)*15671610024 1110120 Palmerini et al (2006)–CABG arm 154NA 6 14NA1113NA Palmerini et al (2006)–DES arm94NA 6 22NA913NA Park et al (2005)–BMS arm121081210025NA08 170 Park et al (2005)–DES arm10207121009NA07 20 Price et al (2006)5008810054NA10 NA444 Sheiban et al (2006)–BMS arm*69103 9936 2030130 Sheiban et al (2006)–DES arm*77331010091033140 Wood et al (2005)*100231910019NA63 71

11. Results After excluding 806 non-pertinent citations, we finally included 16 original studies (1274 patients, median follow-up 9 months [range 6- 24]) There were 8 uncontrolled reports on DES, 5 non-randomized comparison between DES and bare-metal stents (BMS), and 3 between DES and CABG Overall, 31% of patients had non-bifurcational ULM and 59.5% had high-risk features at EuroSCORE or Parsonnet

12. Results Mid-term MACE occurred in 18.2%, mid-term death in 4.4%, and repeat revascularization in 7.4% Meta-regression showed that location of disease was the most significant predictor of mid-term MACE (p=0.001) as well as of TVR (p=0.050) On the other hand, high-risk features at EuroSCORE or Parsonnet were the most significant predictor of mid-term death (p=0.027) Stenting technique was also significantly associated with MACE rate (p=0.050)

13. Risk of in-hospital death 2,3 (1,1-3,4) 2,0 2,8 0,0 7,1 9,5 2,0 1,9 0,0 2,4 0,0 4,2 1,7 03691215 Overall estimate (95%CI) Wood et al (2006, 100 pts) Sheiban et al (2006, 85 pts) Price et al (2006, 50 pts) Park et al (2005, 102 pts) Migliorini et al (2006, 156 pts) Lozano et al (2005, 42 pts) Lee et al (2006, 50 pts) KOMATE (2005, 54 pts) de Lezo et al (2004, 52 pts) Christiansen et al (2006, 42 pts) Chieffo et al (2005, 85 pts) Carriè et al (2006, 120 pts) Agostoni et al (2005, 58 pts) Study Rate of in-hospital death (%)

14. Risk of in-hospital MI 3,0 2,6 8,0 6,9 0,6 0,0 3,9 0,0 5,9 2,5 3,5 03691215 Wood et al (2006, 100 pts) Sheiban et al (2006, 85 pts) Price et al (2006, 50 pts) Park et al (2005, 102 pts) Migliorini et al (2006, 156 pts) Lozano et al (2005, 42 pts) Lee et al (2006, 50 pts) KOMATE (2005, 54 pts) de Lezo et al (2004, 52 pts) Christiansen et al (2006, 42 pts) Chieffo et al (2005, 85 pts) Carriè et al (2006, 120 pts) Agostoni et al (2005, 58 pts) Study 2,5 (1,2-3,8) Overall estimate (95%CI) Rate of in-hospital myocardial infarction (%)

15. Risk of MACE at follow-up 19,0 9,1 54,0 8,8 25,5 23,7 26,2 10,6 4,6 10,9 14,3 5,8 7,1 32,7 12.5 15,5 015304560 Wood et al (2006, 100 pts) Sheiban et al (2006, 85 pts) Price et al (2006, 50 pts) Park et al (2005, 102 pts) Palmerini et al (2006, 94 pts) Migliorini et al (2006, 156 pts) Lozano et al (2005, 42 pts) Lee et al (2006, 50 pts) KOMATE (2005, 54 pts) Han et al (2006, 138 pts) Dudek et al (2006, 28 pts) de Lezo et al (2004, 52 pts) Christiansen et al (2006, 42 pts) Chieffo et al (2005, 85 pts) Carriè et al (2006, 120 pts) Agostoni et al (2005, 58 pts) Study Rate of mid-term MACE (%) 16,5 (11,7-21,3) Overall estimate (95%CI)

16. Risk of death at follow-up 8,0 2,6 10,0 0,0 13,8 10,9 19,1 4,0 1,9 5,1 0,0 4,8 2,8 5,2 015304560 Wood et al (2006, 100 pts) Sheiban et al (2006, 85 pts) Price et al (2006, 50 pts) Park et al (2005, 102 pts) Palmerini et al (2006, 94 pts) Migliorini et al (2006, 156 pts) Lozano et al (2005, 42 pts) Lee et al (2006, 50 pts) KOMATE (2005, 54 pts) Han et al (2006, 138 pts) de Lezo et al (2004, 52 pts) Christiansen et al (2006, 42 pts) Chieffo et al (2005, 85 pts) Carriè et al (2006, 120 pts) Agostoni et al (2005, 58 pts) Study Rate of mid-term death (%) 5,5 (3,4-7,7)Overall estimate (95%CI) 10,0

17. Risk of TVR at follow-up 8,0 3,9 44,0 2,0 12,1 2,4 6,3 2,3 7,3 0,0 1,9 4,8 18,8 1,7 6,9 015304560 Wood et al (2006, 100 pts) Sheiban et al (2006, 85 pts) Price et al (2006, 50 pts) Park et al (2005, 102 pts) Migliorini et al (2006, 156 pts) Lozano et al (2005, 42 pts) Lee et al (2006, 50 pts) KOMATE (2005, 54 pts) Han et al (2006, 138 pts) Dudek et al (2006, 28 pts) de Lezo et al (2004, 52 pts) Christiansen et al (2006, 42 pts) Chieffo et al (2005, 85 pts) Carriè et al (2006, 120 pts) Agostoni et al (2005, 58 pts) Study Rate of mid-term TVR (%) 6,5 (3,7-9,2)Overall estimate (95%CI)

18. Surgical risk and death rate Prevalence of high-risk clinical features (%) 10090807060504030 Risk of death at follow-up (Log10 of the actual rate) -,6 -,8 -1,0 -1,2 -1,4 -1,6 Christiansen Lee Sheiban Lozano Palmerini Chieffo Migliorini Price P=0.027 ←Lower risk Higher risk → Patients at high surgical risk are significantly more likely to die during follow-up

19. Stenosis location and MACE rate Prevalence of non-bifurcational disease (%) 706050403020100 -,2 -,4 -,6 -,8 -1,0 -1,2 -1,4 Komate De Lezo Christiansen Agostoni Lee Sheiban Lozano Wood Park Han Carrié Palmerini Chieffo Migliorini Price P=0.001 Risk of MACE at follow-up (Log10 of the actual rate) ←Lower risk Higher risk → Patients with high distal ULM are significantly more likely to have MACE

20. Stenting technique and MACE rate Rate of complex stenting technique (%) 10080604020 0 -,2 -,4 -,6 -,8 -1,0 -1,2 -1,4 De Lezo Christiansen Agostoni Lee Sheiban Park Han Carrié Palmerini Chieffo Migliorini Price Dudek P=0.050 Risk of MACE at follow-up (Log10 of the actual rate) ←Lower risk Higher risk → Patients treated with 2 stents are significantly more likely to have MACE

21. Stenosis location and TVR rate Prevalence of non-bifurcational disease (%) 706050403020100 -,2 -,4 -,6 -,8 -1,0 -1,2 -1,4 -1,6 -1,8 Komate De Lezo Christiansen Agostoni Lee Sheiban Lozano Wood Park Han Carrié Chieffo Migliorini Price P=0.050 Risk of TVR at follow-up (Log10 of the actual rate) ←Lower risk Higher risk → Patients with high distal ULM are significantly more likely to have TVR

22. Conclusions The largest cohort reported to date of patients with ULM treated with DES provides encouraging mid-term follow-up data, at least in selected patients Analysis of the largest cohort to date of patients treated with DES for ULM shows that risk-stratification should be based in these patients on location of disease and overall risk features Event-free survival is excellent in low-risk patients with non-bifurcational ULM, while a high case fatality can be expected in high-risk subjects, irrespective of disease location

23. For further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html For further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html