DrugEluting Stents Should Not be Used as the

Drug-Eluting Stents Should Not be Used as the Default Stent for ACS Sanjay Kaul, MD, FACC, FAHA Division of Cardiology Cedars-Sinai Heart Institute Professor, Cedars-Sinai Medical Center & Geffen School of Medicine at UCLA Los Angeles, California

Disclosure Sanjay Kaul, MD Division of Cardiology Cedars-Sinai Heart Institute Cedars-Sinai Medical Center Los Angeles, California No conflicts to disclose

Gladiators

Spiderman of DES Interventions

Mediators

Thinkers/Reformers

Benefit-Risk Balance of DES vs. BMS in ST Elevation MI DES vs BMS Benefit • Reduced restenosis benefit - More thrombus, less fibroatheroma - Less prone to restenosis - Recurrent angina infrequent post-MI - Low ischemic TVR rates Risk • Excessive thrombotic risk - Prothrombogenic milieu - Proinflammatory state - Impaired reendothelialization - Slow flow, abnormal vasomotion - Malapposition, underexpansion - Noncompliance Does the benefit-risk-cost tradeoff justify DES as the default choice for PCI in STEMI?

2009 ACC/AHA Guideline Recommendations DES in STEMI Class II (Benefit >>> risk) IIa (Benefit >>risk) (Reasonably recommended) (Highly recommended) IIb (Benefit ? risk) (May be considered) Class III (Risk ? Benefit) (Not recommended) Level A (Multiple randomized clinical trials) Level B (Single randomized trial or nonrandomized studies • • • DAPT compliance • Favorable Low bleeding risk safety & efficacy No imminent surgey profile Level C (Consensus opinion, case studies, or standard of care) Kushner FG, Hand M et al. 2009 Focused Updates, JACC/Circulation 2009

DES vs. BMS in STEMI Meta-analysis Study Flow • Dates: 2000 to 2010 • FDA approved DES • Number of patients: Search of multiple data sources 35, 013 DES vs BMS in STEMI 15 RCTs (N=8, 492) DES (N=5, 119) BMS (N=3, 373) 18 Registries N=26, 521

DES vs BMS in STEMI Effect on Mortality: 15 Trials, N=8, 274 Weight (%) RR (95% CI) Year Study DES BMS 2005 Di Lorenzo 7/180 6/90 3. 00% 0. 58 (0. 20 to 1. 68) 2005 STRATEGY 10/87 12/88 5. 00% 0. 84 (0. 38 to 1. 85) 27/310 36/309 15. 00% 0. 75 (0. 47 to 1. 20) 10/251 16/250 7. 00% 0. 62 (0. 29 to 1. 35) 2006/10 PASSION 2006/09 TYPHOON 2006 BASKET-AMI 6/142 6/74 3. 00% 0. 52 (0. 17 to 1. 56) 2007 SELECTION 0/39 3/37 1. 00% 0. 14 (0. 01 to 2. 54) 5/157 8/156 3. 00% 0. 62 (0. 21 to 1. 86) 3/60 2/54 1. 00% 1. 35 (0. 23 to 7. 78) 20/313 8. 00% 1. 65 (0. 97 to 2. 81) 4/82 2. 00% 2. 00 (0. 63 to 6. 38) 2/158 4/152 2. 00% 0. 48 (0. 09 to 2. 59) 126/2257 49/749 31. 00% 0. 85 (0. 62 to 1. 17) 11/372 15/372 6. 00% 0. 73 (0. 34 to 1. 58) 2007/10 SESAMI 2007 De la Llera 2007/10 DEDICATION-STENT 33/313 HAMMU-STENT 8/82 2007 MISSION 2008/10 HORIZONS-AMI MULTISTRATEGY 2008 2009 PASSEO 15/180 12/90 7. 00% 0. 63 (0. 31 to 1. 28) 2009 DEBATER 11/424 10/446 4. 00% 1. 16 (0. 50 to 2. 70) 100% 0. 86 (0. 72 to 1. 04) P=0. 09 Overall Hetero P=0. 46; I 2=0% 274/5012 203/3262 (5. 47%) (6. 22%) D= 0. 87% Kaul et al. , AHA 2010 0. 01 0. 1 1 10 RR (log scale) Favors DES Favors BMS 100 NNT=115

DES vs BMS in STEMI Effect on MI: 15 Trials, N=8, 274 Weight (%) RR (95% CI) Year Study DES BMS 2005 Di Lorenzo 7/180 7/90 4. 00% 0. 50 (0. 18 to 1. 38) 2005 STRATEGY 7/87 8/88 4. 00% 0. 89 (0. 34 to 2. 34) 20/310 13/309 6. 00% 1. 53 (0. 78 to 3. 03) 12/251 10/250 5. 00% 1. 20 (0. 53 to 2. 72) 2006/10 PASSION 2006/09 TYPHOON 2006 BASKET-AMI 9/142 4/74 3. 00% 1. 17 (0. 37 to 3. 68) 2007 SELECTION 0/39 1/37 0. 00% 0. 47 (0. 02 to 13. 55) 3/160 2. 00% 0. 99 (0. 25 to 3. 90) 1/60 1/54 1. 00% 0. 90 (0. 06 to 14. 04) 2007/10 DEDICATION-STENT 9/313 2/82 HAMMU-STENT 2007 15/313 7. 00% 0. 60 (0. 27 to 1. 35) 5/82 2. 00% 0. 40 (0. 08 to 2. 00) 9/158 14/152 7. 00% 0. 62 (0. 28 to 1. 39) 158/2257 49/749 35. 00% 1. 07 (0. 79 to 1. 46) 17/372 12/372 6. 00% 1. 42 (0. 69 to 2. 92) 2007/10 SESAMI 2007 De la Llera MISSION 2008/10 HORIZONS-AMI MULTISTRATEGY 2008 2009 PASSEO 17/180 13/90 8. 00% 0. 65 (0. 33 to 1. 29) 2009 DEBATER 12/424 22/446 10. 00% 0. 57 (0. 29 to 1. 14) Overall 284/5012 178/3262 (5. 67%) (5. 46%) 100% 0. 92 (0. 77 to 1. 12) P=0. 42 Hetero P=0. 58; I 2=0% D= 0. 44% Kaul et al. , AHA 2010 0. 01 0. 1 1 10 RR (log scale) Favors DES Favors BMS 100 NNT=227

DES vs BMS in STEMI Effect on Stent Thrombosis: 15 Trials, N=8, 250 Year Study DES BMS Weight (%) RR (95% CI) 2005 Di Lorenzo 1/180 1/90 1. 00% 0. 50 (0. 03 to 7. 9) 2005 STRATEGY 0/87 2/88 2. 00% 0. 25 (0. 01 to 5. 5) 2006/10 PASSION 10/310 5/309 4. 00% 1. 99 (0. 69 to 5. 77) 2006/09 TYPHOON 11/251 12/250 10. 00% 0. 91 (0. 41 to 2. 03) 2006 BASKET-AMI 3/142 1/74 1. 00% 1. 56 (0. 17 to 14. 77) 2007 SELECTION 1/39 1/37 1. 00% 0. 95 (0. 06 to 14. 62) 2007/10 SESAMI 3/157 2/156 2. 00% 1. 49 (0. 25 to 8. 80) 2007 De la Llera 2/60 1/54 1. 00% 1. 80 (0. 17 to 19. 3) 2007/10 11/313 10. 00% 1. 18 (0. 54 to 2. 60) 2007 DEDICATION-STENT 13/313 HAMMU-STENT 2/82 5/82 4. 00% 0. 40 (0. 08 to 2. 00) 2007 MISSION 2/158 3/152 3. 00% 0. 64 (0. 11 to 3. 79) 2008/10 HORIZONS-AMI 107/2238 32/744 42. 00% 1. 11 (0. 76 to 1. 64) 2008 MULTISTRATEGY 15/372 10/372 9. 00% 1. 50 (0. 68 to 3. 30) 2009 PASSEO 4/180 3/90 3. 00% 0. 67 (0. 15 to 2. 92) 2009 DEBATER 13/424 9/446 8. 00% 1. 52 (0. 66 to 3. 52) Overall 187/4993 98/3257 (3. 75%) (3. 01%) 100% 1. 14 (0. 89 to 1. 45) P=0. 31 Hetero P=0. 95; I 2=0% D= -0. 42% Kaul et al. , AHA 2010 0. 01 0. 1 1 10 RR (log scale) Favors DES Favors BMS 100 NNH=238

DES vs BMS in STEMI Effect on TVR: 15 Trials, N=8, 274 Year DES BMS Weight (%) RR (95% CI) 2005 Di Lorenzo 7/180 14/90 3. 00% 0. 25 (0. 10 to 0. 60) 2005 STRATEGY 8/87 21/88 4. 00% 0. 39 (0. 18 to 0. 82) 2006/10 PASSION 23/310 32/309 6. 00% 0. 69 (0. 41 to 1. 16) 2006/09 TYPHOON 24/251 43/250 8. 00% 0. 56 (0. 35 to 0. 89) 2006 BASKET-AMI 10/142 9/74 2. 00% 0. 58 (0. 25 to 1. 36) 2007 SELECTION 2/39 13/37 2. 00% 0. 15 (0. 04 to 0. 60) 2007/10 SESAMI 13/157 25/156 5. 00% 0. 52 (0. 27 to 0. 97) 2007 De la Llera 0/60 3/54 1. 00% 0. 15 (0. 01 to 2. 90) 2007/10 DEDICATION-STENT 28/313 62/313 12. 00% 0. 45 (0. 30 to 0. 69) 2007 HAMMU-STENT 3/82 9/82 2. 00% 0. 33 (0. 09 to 1. 19) 2007 MISSION 8/158 20/152 4. 00% 0. 38 (0. 17 to 0. 85) 2008/10 HORIZONS-AMI 212/2257 113/749 32. 00% 0. 62 (0. 50 to 0. 77) 2008 MULTISTRATEGY 12/372 38/372 7. 00% 0. 32 (0. 17 to 0. 59) 2009 PASSEO 13/180 21/90 5. 00% 0. 31 (0. 16 to 0. 59) 2009 DEBATER 26/424 42/446 8. 00% 0. 65 (0. 41 to 1. 04) Overall 389/5012 465/3262 (7. 75%) (14. 27%) 100% 0. 51 (0. 45 to 0. 58) P<0. 001 Hetero P=0. 18; I 2=24% D= 7. 0% Kaul et al. , AHA 2010 0. 01 0. 1 1 10 RR (log scale) Favors DES Favors BMS 100 NNT=14

DES vs. BMS in STEMI Meta-analysis Summary Endpoint DES BMS RR (95% CI) P ARD NNT/NNH Death (N=477) 5. 5% 6. 2% 0. 86 (0. 72, 1. 04) 0. 09 0. 87% 115 MI (N=462) 5. 7% 5. 5% 0. 92 (0. 77, 1. 12) 0. 42 0. 44% 227 Stent thrombosis (N=285) 3. 8% 3. 0% 1. 14 (0. 89, 1. 45) 0. 31 -0. 42% -238 TVR (N=854) 7. 8% 14. 3% 0. 51 (0. 45, 0. 58) <0. 001 7% 14 DES significantly reduced TVR without increasing death, MI, or stent thrombosis

DES vs. BMS in STEMI Meta-analysis Summary Endpoint 2009 Meta-analysis (Brar) 2010 Meta-analysis (Kaul) (13 trials, N=7352, F/U<24 m) (15 trials, N=8492, F/U <60 m) DES BMS RR (95% CI) Death 3. 7% 4. 3% 0. 89 (0. 70, 1. 14) 5. 5% 6. 2% 0. 86 (0. 72, 1. 04) MI 3. 4% 3. 8% 0. 82 (0. 64, 1. 5) 5. 7% 5. 5% 0. 92 (0. 77, 1. 12) Stent thrombosis 2. 6% 2. 7% 0. 97 (0. 73, 1. 28) 3. 8% 3. 0% 1. 14 (0. 89, 1. 45) TVR 5. 3% 11. 5% 0. 44 (0. 35, 0. 45) 7. 8% 14. 3% 0. 51 (0. 45, 0. 58) Comparable results that DES significantly reduced TVR without increasing death, MI, or stent thrombosis

DES in AMI: The TYPHOON Trial Primary Endpoint (TVF*) Through 360 Days D= 2. 0% D= 7. 0% * Defined as target vessel-related cardiac death, Re. MI or ischemia driven TVR Spaulding C et al. NEJM 2006; 355: 1093 -104

Secondary Efficacy Endpoint: Ischemic TLR HORIZONS-AMI Stent (3 Year Follow-Up) Ischemic TLR (%) 15 14. 2% TAXUS DES (n=2257) EXPRESS BMS (n=749) 12 8. 3% D= 5. 7% 8. 7% 9 NNT=36 6 D=5. 8% 2. 8% 13 mo angio FU 0. 61 (0. 44, 0. 84) D= 2. 9%; P=0. 003 13 m NNT=34 angio f/u 3 NNT=18 0 0 Number at risk TAXUS DES EXPRESS BMS 3 6 9 12 15 18 21 24 Months 2257 749 2085 671 2016 646 Stone GW, TCT 2010 1912 600 1587 498

Multivariate Predictors of 1 -Year TLR HORIZONS-AMI (BMS Express Stent, N=749) Variable Weighted Score HR (95% CI) P value Insulin-treated diabetes 1 3. 12 (1. 23, 7. 87) 0. 02 Baseline RVD <3. 0 mm 1 2. 89 (1. 56, 5. 34) 0. 0007 Total lesion length >30 mm 1 2. 49 (1. 33, 4. 68) 0. 004 DES likely to be effective in patients with longer, smaller diameter lesions, and high-risk patients such as diabetics Stone GW, JACC 2010; 56

1 -Year TLR According to BMS Risk Score Ischemic TLR at 1 Yr (%) HORIZONS-AMI (N=2939) HR 0. 39 (0. 21. 0. 74) P=0. 003 Express BMS Taxus DES HR 0. 99 (0. 43. 2. 17) P=0. 93 HR 0. 58 (0. 37. 0. 92) P=0. 02 N=947 (32. 2%) N=1583 (53. 9%) N=409 (13. 9%) Low (0) Intermediate (1) High (>2) Express BMS TLR Risk Score DES more effective in patients with higher risk scores; however the prevalence of high-risk score is low (~14%) Stone GW, JACC 2010; 56

Events at 1 Yr (%) 1 -Year Outcomes According to High Risk Score HORIZONS-AMI Express BMS Taxus DES P=0. 08 P=0. 93 P=0. 29 Cardiac death MI Stent thrombosis High Risk Score for Restenosis (>2) Risk score is not predictive of cardiac death, reinfarction or stent thrombosis Stone GW, JACC 2010; 56

DES: Cost-Effectiveness TVR reduction with DES (%) 80% BMS TVR rate (%) 20% 15% 10% 5% $20 K ($15 K) $23 K ($17 K) $27 K ($20 K) $30 K ($23 K) $36 K ($27 K) $40 K ($30 K) $46 K ($34 K) $53 K ($40 K) $80 K ($60 K) $92 K ($69 K) $107 K ($80 K) 50% $32 K ($24 K) $43 K ($32 K) $64 K ($48 K) $128 K ($96 K) 40% $40 K ($30 K) $53 K ($40 K) $80 K ($60 K) $160 K ($120 K) 30% $53 K ($40 K) $71 K ($53 K) $107 K ($80 K) $214 K ($160 K) 70% 60% DES/case 2. 0 (1. 5) Cost per TVR avoided $$ Cost-effective threshold $30 K per TVR avoided

DES vs. BMS in STEMI Conclusions • The use of DES appears safe and efficacious in randomized trials of patients with STEMI. • Although, these results allay the early concerns of stent thrombosis in the STEMI setting, the modest, albeit statistically significant, benefit in TVR coupled with the increased cost of DES and the attendant prolonged dual antiplatelet therapy argues against DES being the default choice for PCI in all patients with STEMI. • A DES may be considered for clinical and anatomic settings in which the efficacy/safety/cost profile appears favorable.

Balancing Risk and Benefit Mitigate Risk and Accentuate Benefit • Mitigate risk at “acceptable” benefit - Avoid DES in patients unable or unlikely to take dual antiplatelet therapy or in need of non-cardiac procedures - ? Extend antiplatelet therapy beyond 6 -12 month (perhaps indefinitely in patients at low bleeding risk) • Accentuate benefit at “acceptable” risk - Judicious, selective, evidence-based use ideally reserved for patients at highest risk for restenosis (longer lesions >30 mm, smaller vessels <3. 0 mm)

Balancing Risk and Benefit “Optimal” DES Utilization 0% use 100% use Evidence-based threshold The evidence (and common sense) support selective, thoughtful application!

DES: Balancing Risk and Benefit Gartner’s Hype Cycle Don’t join in just ? Bioabsorbable because it is “in” stents nd rd 2 /3 2011 Generation DES 2012 Visibility 2005 2006 2007 2008 2009 2010 Don’t miss out just because it is “out” Time Technology Peak of Inflated Trough of Slope of Plateau of Trigger Expectations Disillusionment Enlightenment Productivity “A sequence of events experienced by an overly-hyped product or technology, including a peak of unrealistic expectations followed by a valley of disappointment when those expectations aren't met”