Safety of Drug-Eluting Stents in Acute Coronary Syndromes

Transcription

1 Rotterdam, June 11 th 2012 Safety of Drug-Eluting Stents in Acute Coronary Syndromes Stephan Windecker Department of Cardiology Swiss Cardiovascular Center and Clinical Trials Unit Bern Bern University Hospital, Switzerland

2 1958 Coronary arteriography (Sones) Scientific Advancesand CardiovascularMortality Nabel and Braunwald. N Engl J Med 2012;366: Coronary angioplasty (Grüntzig) 1993 Superiority of primarypci vs. fibrinolysisin acute MI 2002 Efficacy of drug-eluting vs. baremetal stents

3 MortalityandRepeat Revascularizationwith Early Generation DES versus Bare MetalStents Stettler C et al. Lancet 2007;370: Mortality HR (95% CI) Repeat Revasc HR (95% CI) SES vs BMS 1.00 ( ) SES vs BMS 0.30 ( ) PES vs BMS 1.03 ( ) PES vs BMS 0.42 ( ) SES vs PES 0.96 ( ) SES vs PES 0.70 ( ) NNT=35 (CI 23-65) NNT NNT=7 (CI 6-8) NNT=8 (CI 7-10) 0 SES vs BMS PES vs BMS SES vs PES

4 Drug-Elutingvs. Bare MetalStentin AcuteMI Mauri L et al. N Engl J Med 2008;359: Propensity Score Matched Pair Comparison of DES and BMS in Patients Undergoing PCI for acute myocardial infarction in Massachusetts N=7,217 Patients (04/ /2004) Mortality Recurrent MI BMS 11.6% 3.1% 27% DES 8.5% BMS 8.0% 1.0% 13% DES 7.0%

5 Early Generation Drug-Eluting Stents versus Bare Metal Stents in Patients With STEMI Kalesan B et al. Eur Heart J RCTs Comparing DES and BMS in 7,843 STEMI Patients 20 RR 0.91 ( ) P=0.63 RR 1.01 ( ) P=0.90 RR 0.94 ( ) P=0.98 RR 0.51 ( ) P<0.001 RR 1.08 ( ) P= ,1 15,7 15,4 % 10 7,5 7,9 9,2 9,1 8,7 5 4,1 3,2 0 Death DES BMS Cardiac death MI TVR Definite ST

6 Vessel Size in ACS Newer Generation DES and ACS Stent Choice in ACS Thrombus Burden in ACS Discontinuation of Antiplatelet Therapy Vessel Remodelling and Inflammation in ACS

7 Impact of Vessel Diameter and Late Loss on Restenosis RVD 4.0 mm 3.5 mm 3.0 mm 2.5 mm 2.0 mm Late loss (BMS) 0.9 mm 0.9 mm 0.9 mm 0.9 mm 0.9 mm Diameter stenosis 23% 26% 30% 36% 45% Late loss (DES) 0.2 mm 0.2 mm 0.2 mm 0.2 mm 0.2 mm Diameter stenosis 5% 6% 7% 8% 10%

8 Vessel Size in Patients With Acute Myocardial Infarction Mean Reference Vessel Diameter (mm) mm 4 3 2,9 3,2 3,2 2,9 2,9 2,

9 Paclitaxel-Eluting Stents versus Bare-Metal Stents in Acute Myocardial Infarction: HORIZONS-AMI Stone G et al. N Engl J Med 2009;360: In-Stent In-Segment 1 P< P<0.001 Late Lumen Los ss (mm) 0,8 0,6 0,4 0, Late Lumen Los ss (mm) 0,8 0,6 0,4 0, PES BMS 0 DES BMS N=1081 N=332 N=1081 N=332

10 Drug-Eluting Stent Safety in Large Vessels BASKET-PROVE: DES vs BMS Kaiser C et al. N Engl J Med 2010 Death or MI Repeat Revasc 2,314 Patients 2,314 Patients

11 NewerGeneration GenerationDrug-ElutingStentsversus BareMetal Stentsin PatientswithSTEMI Target Lesion Revascularization EXAMINATION EES versus BMS COMFORTABLE AMI BES versus BMS

12 Vessel Size in ACS Newer Generation DES and ACS Stent Choice in ACS Thrombus Burden in ACS Discontinuation of Antiplatelet Therapy Vessel Remodelling and Inflammation in ACS

13 Acute Coronary Syndrome as Predictor of Stent Thrombosis 15 OR=12.4 ( ) OR=2.3 ( ) OR=1.8 ( ) HR=2.6 ( ) Odds/Hazard Ratio Park et al Am J Card 2006 Daemen et al Lancet 2007 Urban et al Circulation 2006 De la Torre et al JACC 2008

14 Impact of Thrombus Burden on Risk of Stent Thrombosis With DES in Patients With STEMI Sianos G et al. J Am Coll Cardiol 2007;50: Independent Predictors of ST Variable Hazard Ratio 95% CI Age Index ST Bifurcation Thrombectomy Large thrombus

15 Riskof IschemicEvents and Stent Thrombosis Stratified According totime and StentType (DES vsbms) in STEMI 15 RCTs Comparing DES and BMS in 7,843 STEMI Patients Favors SES/PES Favors BMS Kalesan, Windecker

16 Vessel Size in ACS Newer Generation DES and ACS Stent Choice in ACS Thrombus Burden in ACS Discontinuation of Antiplatelet Therapy Vessel Remodelling and Inflammation in ACS

17 ArterialHealing HealingatCulpritSites after DES Implantation in Patients withacutemi and StableAngina An AutopsyStudy Nakazawa et al. Circulation 2008; 118: Correlation between fibrous cap thickness and % uncovered struts

18 Stent Malapposition/Vessel Remodeling Cook S et al. Circulation 2007

19 ArterialHealingatCulpritSites after DES Implantation in Patients withacutemi and StableAngina An AutopsyStudy Nakazawa et al. Circulation 2008; 118: Neointimal thickness Struts with fibrin Struts with inflammation Uncovered struts 0,1 0,08 0,06 0,04 0,02 0 Acute MI culprit site P=0.008 P=0.008 P=0.003 P=0.01 mm % % % ,12 ( ) ( ) Stable Angina culprit site Acute MI culprit site 36 Stable Angina culprit site Acute MI culprit site (N=25) Acute MI culprit site 17 Stable Angina culprit site Acute MI culprit site Stable angina culprit site (N=26) 9 Stable Angina culprit site

20 Association of Eosinophilic Infiltrates of Thrombus Aspirates With Vessel Remodeling Cook S, Ladich E, Virmani R, Windecker S. Circulation 2009 Eosinophilic Infiltrates Vessel Remodeling

21 Late Acquired Stent Malapposition in HORIZONS-AMI Guo N et al. Circulation 2010;122: % P= ,8 24,2 P= ,9 P=0.02 LASM: 75% positive remodeling 25% thrombus resolution 8, Late Stent Malapposition Persistent Stent Malapposition Late Acquired Stent Malapposition BMS PES Independent predictors of LASM: -plaque/thrombus protrusion at baseline(or=5.6, 95% CI ) -PES use(or=6.3, 95% CI )

22 OCT 5 yrsafter STEMI BL Stent Thrombosis@ 5.5 yrs Courtesy Räber/Windecker, SIRTAX OCT

23 Strut Coverage, Malapposition and Protrusion in HORIZONS-AMI OCT 13 Months Guagliumi G et al. Circulation 2010;123: % 8 P= P< P< , ,1 0,9 Malapposed and Uncovered Struts BMS 1,1 1 Uncovered Struts Protruding Struts PES

24 Vessel Size in ACS Newer Generation DES and ACS Stent Choice in ACS Thrombus Burden in ACS Discontinuation of Antiplatelet Therapy Vessel Remodelling and Inflammation in ACS

25 Discontinuation of Antiplatelet Therapy as Predictor of Stent Thrombosis HR=19.2 ( ) OR=4.8 ( ) HR=13.7 ( ) HR=13.8 ( ) HR=4.6 ( ) Odds/Hazard Rat tio

26 Premature Discontinuation of Thienopyridine Therapy After DES Implantation Spertus JA et al. Circulation 2006;113: Multicenter, prospective PREMIER registry in patients admitted with myocardial infarction -500 DES patients enrolled at 19 sites -68 (14%) patients d/c thienopyridine Factors associated with premature Thienopyridine discontinuation -older age -lower socioeconomic status -preexisting cardiovascular disease -inadequate discharge instructions -lack of referral to cardiac rehab % Mortality Between 30 Days and 1 Year HR=9.0 P< ,5 0,7 Death Off Thienopyridine HR=1.5 P= Rehosp. On Thienopyridine

27 DAPT Following DES Death, MI, or Stroke Bleeding >1 Year vs. 1 Year REAL / ZEST (N=2,701) PRODIGY (N=2,701) 1.73 ( ) 1.02 ( ) REAL / ZEST (N=2,701) PRODIGY (N=2,701) 2.93 ( ) 2.17 ( ) Overall (N=4,671) 1.25 ( ) Overall (N=4,671) 2.19 ( ) >6 Months vs. 6 Months REAL / ZEST (N=1,443) PRODIGY (N=2,701) 1.12 ( ) 1.02 ( ) REAL / ZEST (N=1,443) PRODIGY (N=2,701) 2.56 ( ) 2.17 ( ) Overall (N=4,671) 1.05 ( ) Overall (N=4,671) 2.21 ( ) Adapted from Kastrati A. ESC Congress 2011, Paris

28 Pt oriented Outcome stratified by stent From 6 up to 24 months LOG HAZARD RATIO (95% CI) 6-mo Landmark Death/MI/CVA BMS ENDEAVOR SPRINT TAXUS XIENCE V HAZARD RATIO (95% CI) 1.04 ( ) 2.55 ( ) 0.63 ( ) 1.06 ( ) P-VALUES Superiority Interaction mo Landmark Death/MI BMS ENDEAVOR SPRINT TAXUS XIENCE V 0.83 ( ) 2.07 ( ) 0.59 ( ) 1.18 ( ) mo CV Death/MI BMS ENDEAVOR SPRINT TAXUS XIENCE V 0.86 ( ) 2.33 ( ) 0.73 ( ) 0.58 ( ) month DAPT better 6-month DAPT better Courtesy: M Valgimigli

29 Vessel Size in ACS Newer Generation DES and ACS Stent Choice in ACS Thrombus Burden in ACS Discontinuation of Antiplatelet Therapy Vessel Remodelling and Inflammation in ACS

30 StrutsCoverage9 MonthsAfter Implantation of Everolimus-andSirolimus-ElutingStents Choi et al. IntJ CardiovascImaging 2011 Lesions With >10% Uncovered Struts % % EES SES 0 EES (N=40) SES (N=70)

31 Everolimus-Eluting ElutingStentversus Early Generation DES DES Safety Risk of Stent Thrombosis EES vs SES EES vs PES Trials EES SES RR (95% CI) Trials EES PES RR (95% CI) ISAR-TEST 4 SORT-OUT 4 BASKET-PROVE 4/652 2/1390 2/774 9/652 9/1384 3/ (0.14, 1.44) 0.22 (0.05, 1.02) 0.67 (0.11, 3.98) SPIRIT II SPIRIT III 1/223 6/669 2/77 2/ (0.02, 1.88) 1.49 (0.30, 7.36) RESET 5/1597 6/ (0.26, 2.73) SPIRIT IV 8/ / (0.14, 0.81) ESSENCE-DIABETES 0/149 0/151 (Excluded) COMPARE 5/897 24/ (0.08, 0.55) Burzotta et al. 0/75 0/75 (Excluded) Overall (I-squared = 0.0%, p = 0.579) 0.51 (0.26, 0.99) Overall (I-squared = 34.6%, p = 0.205) 0.35 (0.16, 0.77) Risk ratio Risk ratio Favors EES Favors SES Favors EES Favors PES N = 11,167 N = 6,789 Kalesan, Windecker

32 Cumulative inc cidence (%) Bern-Rotterdam CohortStudy Very Late Definite ST (1-4 yrs) Räber et al. Circulation 2012; 125: EESvs. SESHR* = 0.33, 95% CI , P=0.006 EESvs. PESHR* = 0.24, 95% CI , P< Paclitaxel Stent 2.4% Sirolimus Stent 1.6% 0 Everolimus Stent 0.6% Months after index PCI *from Cox proportional hazards model

33 BiolimusElutedfromBiodegradablePolymer versus SirolimusElutedfromDurable Polymer BarlisP et al. Eur Heart J2010 Lesions With At Least 5% Uncovered Struts (-76.9 to 14.3) P< ,5 (%) ,5 Biolimus Stent Sirolimus Stent Biolimus N=29 Sirolimus N=35 29 Lesions 35 Lesions

34 BiodegradablePolymer DES versus Durable Polymer SirolimusElutingStents Stefanini G et al. Lancet 2011 DES Safety Risk of Stent Thrombosis Definite ST Meta-Analysis Definite ST LEADERS 4 years BP-DES DP-SES RR (95% CI) ISAR-TEST 3 ISAR-TEST 4 1/202 9/1299 2/202 9/ (0 05, 5 47) 0 50 (0 20, 1 26) 0 to1 year* RR 0.99 (95% CI ) p= to4 year* RR 0.20 (95% CI ) p=0.004 LEADERS 20/857 32/ (0 36, 1 08) Overall (I-squared = 0 0%, p=0 92) 0 58 (0 37, 0 93) Risk ratio Favours biodegradable polymer DES Favours durable polymer SES * RR 0-1 vsrr 1-4 p forinteraction=0.017

35 Biodegradable Polymer BES vs Durable Polymer SES Association of Cardiac Events With Definite ST NOT ASSOCIATED with ST Stefanini G et al. Lancet 2011 BES SES RR (95% CI) P P-inter Cardiac death, MI, or ci-tvr year 78/857 87/ ( ) to 4 years 67/749 79/ ( ) 0 21 Cardiac death or MI year 48/857 47/ ( ) to 4 years 43/779 52/ ( ) 0 30 Clinically-indicated TVR year 37/857 45/ ( ) to 4 years 39/776 40/ ( ) 0 77 ASSOCIATED with ST Cardiac death, MI, or ci-tvr year 13/857 15/ ( ) to 4 years 2/749 11/ ( ) Cardiac death or MI year 11/857 11/ ( ) to 4 years 3/779 11/ ( ) Clinically-indicated TVR year 13/857 15/ ( ) to 4 years 2/776 10/ ( ) year 1 to 4 years Favours BES Favours SES

36 DES Thrombosisin Perspective Very Late Definite ST in All-Comers 3 Years 2,5 Early Generation DES Newer Generation DES % 2,0 1,5 2,0 1,6 1,4 1,0 0,9 0,7 0,5 0,4 0,3 0,2 0,0 PES SIRTAX PES COMPARE SES SIRTAX SES LEADERS EES COMPARE EES RESOLUTE R-ZES RESOLUTE BES LEADERS

37 Definite Stent Thrombosis among Patients with Stable Coronary Artery Disease and Acute Coronary 4 Years Bern-Rotterdam Cohort Study Stable CAD % % 5 5 P= , , , PES SES EES N=5,138 ACS P= ,7 3,2 1,4 PES SES EES N=7,201

38 Clinical OutcomesWithEverolimus-and Paclitaxel-ElutingStentsin PatientsWithACS Planer D et al. J Am Coll Cardiol Intv 2011;4: A Pooled Analysis of SPIRIT II, III, IV, and COMPARE 2 Years % 12 P=0.04 P=0.01 P=0.38 P=0.01 P= ,7 7, ,2 4 6,2 6,2 4,7 2 1,4 1,9 0 Cardiac death, MI, TLR Cardiac death or MI EES (N=1393) Cardiac death MI TLR PES (N=988)

39 StentThrombosis ThrombosisWithEverolimus-and Paclitaxel-ElutingStentsin PatientsWithACS Planer D et al. J Am Coll Cardiol Intv 2011;4: A Pooled Analysis of SPIRIT II, III, IV, and COMPARE 2 Years % 5 4 P=0.01 P= ,2 2, ,4 Definite ST EES (N=1393) 0,7 Definite or Probable ST PES (N=988)

40 EXAMINATION Trial -Everolimus-ElutingStents vsbare MetalStentsin 12 Months Sabaté M. Presented at ESC Congress 2011 P=0.16 P=0.003 P=0.01 P=0.01 % , Death, MI, any Revasc 5,1 2,2 2,6 1,9 0,5 0,9 TLR Definite ST Definite/Probable EES - Xience BMS - Vision ST (N=751) (N=747)

41 EXAMINATION trial Definite/Probable StentThrombosis p = 0.01 Sabaté M. ESC Congress 2011

42 COMFORTABLE AMI Trial Biolimus-Eluting Stent vs Bare Metal Stent in STEMI Primary Endpoint MACE MACE (%) yrhr 0.49 ( ) 1 Year BMS 8.7 % BES 4.3 % 0 No at risk BMS BES Days since index procedure MACE= Cardiac death, TV-MI, ci-tlr Clinical outcomes were adjudicated by an independent and blinded CEC

43 COMFORTABLE AMI Trial -Biolimus-ElutingStents vsbare MetalStentsin 12 Months Räber L Presented at EuroPCR 2012 % P= ,2 8,7 Cardiac Death, TV-MI, TLR P=0.53 P=0.01 P<0.001 P=0.10 5,7 3,5 2,9 2,7 2,1 1,6 0,9 0,5 Cardiac Death TV-MI TLR Definite ST BES-BioMatrix (N=575) BMS - Gazelle (N=582)

44 Target vessel MI up to 30 days Restenosis Stent thrombosis Number of events BES BMS BES BMS Target vessel MI between 30 days and 1 year Restenosis Stent thrombosis Number of events BES BMS BES BMS

45 StentThrombosisWithEverolimus-ElutingEluting Stentsand andbare MetalStents A Network Meta-Analysis Palmerini T. et al. Lancet 2012

46 Short and Long-Term Outcomes with Drug Eluting and Bare Metal Stents A Mixed Treatment Comparison of 77 RCTs and 117,762 Patient-Years Fup Bangalore S et al. Circulation 2012, in press Death 0 to 1 Year MI Long Term

47 Short and Long-Term Outcomes with Drug Eluting and Bare Metal Stents A Mixed Treatment Comparison of 77 RCTs and 117,762 Patient-Years Fup Bangalore S et al. Circulation 2012, in press Definite or Probable ST Target Lesion Revasc 0 to 1 Year Long Term

48 Eur Heart J 2010

49 No safety concerns Use of Drug-Eluting Stents Consistent reduction in repeat revascularization with the use of DES Eur Heart J 2011

50 NewerGeneration Drug-Eluting Stents WhatHaveWeAchieved? Improved safety in all-comers Reduced risk of stent thrombosis Reduced risk of cardiac death or MI associated with ST Improved efficacy in all-comers Reduced risk of TLR Improved efficacy and safety in STEMI compared with BMS Reduced risks of TLR and ST, translating into a lower risk of MI at 1 year

51 QuestionsforTomorrow Are newer generation DES safer than BMS during long-term follow-up? Are biodegradable polymer based DES superior to newer generation durable polymer based DES? Will BVS outperform newer generation DES?