Drug Eluting Stents Sometimes Fail ESC Stockholm 29 Set 2010 Stent Thrombosis 11.45-12.07 Alaide Chieffo San Raffaele Scientific Institute, Milan, Italy
Historical Perspective 25 20 15 10 5 0 Serruys 1991 24 Roubin 1992 7.6 ASA and Oral Anticoagulation Schatz 1991 6 Fishman 3.5 Colombo 1995 ASA and Ticlopidine 1.4 0.5 Leon 1998 Moussa 1999 ASA and Clopidogrel 1.5 0.9 1.6 1 Cutlip 2001 Wenaweser 2005 Moreno 2006 DES? Prasugrel
Stent Thrombosis Rate (%) 5.0 4.0 BMS are not immune from Thrombosis Stent Thrombosis (Bare Metal Stents) 1.7% n=28,821 3.0 2.0 1.8 1.5 2.3 1.9 1.9 2.8 1.6 1.0 0.9 0.4 0.0 Study: Patients: Era: Karillon De Servi Schuller Cutlip Moussa Werner Cheneau ARTS I Wenaweser 2900 939 2833 6186 1001 215 7484 1205 605 92-95 95-96 92-97 95-99 93-95 95-96 93-02 93-02 95-03
Multifactorial Nature of DES Thrombosis Device factors -Surface -Drugs -Polymer Procedural factors -Dissection -Incomplete stent apposition -Stent expansion Lesion factors -Vessel size/length -Thrombus -Plaque characteristics -Bifurcation -Calcification -Total occlusions STENT THROMBOSIS Patient factors -Drug response/interactions -Gene polymorphism -LV function -Acute coronary syndrome -Renal failure -Diabetes Platelet and Coagulation factors -Coagulation activity -Inhibition of platelet aggregation -inadequate response to anti-platelet therapy -premature antiplatelet therapy discontinuation Windecker and Meier. Circulation 2007;116:1952-65
Early Stent Thrombosis Meta-analysis SES vs BMS Bavry A et al. Am J Card 2005 Meta-analysis PES vs BMS Stone G et al. NEJM 2007 % RR=0.76 95% CI =0.30-1.80 P=0.55 % RR=0.80 95% CI =0.32-2.03 P=0.79
Late Definite ST (1 Month - 1 Year) Drug-Eluting vs Bare Metal Stents 63 late ST cases (0.4%) of 18,023 patients % Stettler C et al. Lancet 2007;370:937-48
Cumulative incidence, % Definite Stent Thrombosis With DES: Bern-Rotterdam Cohort Study @ 4 Years 192 ST cases in a cohort of 8,146 patients 5 4 3 3.3% 2 1 0 Incidence density 1.0 / 100 pt years 0 1 2 3 3.5 4 Time since PCI in years Wenaweser et al. J Am Coll Cardiol 2008;52:1134-40
Cumulative incidence, % Definite Stent Thrombosis With DES: Bern - Rotterdam Cohort Study 20 15 10 Death or MI 14.6% Death 10.6% 5 MI 4.9% 0 ST Mortality 0.4% 0 1 2 3 4 Time since PCI in years
Myocardial Infarction (%) Target-Lesion Revascularization (%) Stent Thrombosis (%) Death (%) 2.0 Pooled Analysis of Data Comparing SES With BMS Estimated 4-year cumulative incidence of stent thrombosis, death, MI, and TLR 10 1.5 1.0 0.5 0.0 0 1 2 3 4 Years Since Procedure 10 8 6 4 2 0 Sirolimus stent (1.2%) Bare-metal stent (0.6%)) Bare-metal stent (6.2%) P=.20 Sirolimus stent (6.4%) P=.86 0 1 2 3 4 Years Since Procedure 8 6 Sirolimus stent (6.7%) 4 P=.23 2 Bare-metal stent (5.3%) 0 0 1 2 3 4 Years Since Procedure 30 25 20 15 10 5 0 Bare-metal stent (23.6%) P<.001 Sirolimus stent (7.8%) 0 1 2 3 4 Years Since Procedure Stone et al. N Engl J Med. 2007;356:998-1008.
Stent Thrombosis (%) Myocardial Infarction (%) Stone et al. N Engl J Med. 2007;356:998-1008. Target-Lesion Revascularization (%) Death (%) 2.0 Pooled Analysis of Data Comparing PES With BMS Estimated 4-year cumulative incidence of stent thrombosis, death, MI, and target lesion revasc. 10 1.5 1.0 0.5 Paclitaxel stent (1.3%) Bare-metal stent (0.9%) 0.0 0 1 2 3 P=.30 4 Years Since Procedure 10 8 6 4 Paclitaxel stent (7.0%) Bare-metal stent (6.3%) 2 P=.66 0 0 1 2 3 4 Years Since Procedure 8 6 4 Bare-metal stent (6.6%) 2 0 Paclitaxel stent (6.1%) P=.68 0 1 2 3 4 Years Since Procedure 30 25 20 15 10 5 Bare-metal stent (20.0%) P<.001 Paclitaxel stent (10.1%) 0 0 1 2 3 4 Years Since Procedure
Predictors of Thrombosis After Successful Implantation of DES Diabetes Unprotected LMCA Bifurcation lesion Bifurcation with 2 stents Renal failure Prior brachytherapy Premature Antiplatelet Therapy Discontinuation Incidence of Stent Thrombosis (%) Iakovou I et al. JAMA. 2005;293:2126-2130.
Discontinuation of Thienopyridine and Risk of Stent Thrombosis: Milan-Siegburg Cohort Study 3,021 patients with 5,389 lesions treated with DES (2002-2004) HR=13.7 4.0-47 P<0.001 HR=0.94 0.30-3.0 P=0.92 Airoldi et al. Circulation 2007;116:745-54
REAL-LATE N=1,625 Broader population of patients who had received any DES ZEST-LATE N=1,357 Patients who had participated in ZEST trial Pooled Analysis of REAL LATE and ZEST LATE N=2,701 Patients who were free of MACCE with dual antiplatelet therapy for at least a 12 month after DES implantation From July 2007 through September 2008 R N=1,357 Clopidogrel + Aspirin N=1,344 Aspirin Alone 1 2 year Clinical follow-up every 6 months Composite of MI or Death from cardiac causes Park et al NEJM 2010; 362
Primary End Point: Cardiac Death or Myocardial Infarction Aspirin Alone Aspirin Alone Clopidogrel + Aspirin 1.8 Clopidogrel + Aspirin 0.7 1.2 0.5 Log-rank, P=0.17 No. at Risk Continuation group 1357 1122 299 Discontinuation group 1344 1100 301
Definite Stent Thrombosis Aspirin Clopidogrel + Alone Aspirin 0.2 0.4 0.1 0.4 Log-rank, P=0.76 No. at Risk Continuation group 1357 1124 301 Discontinuation group 1344 1102 303
On March 12, 2010, the FDA approved a new label for clopidogrel with a boxed warning about the diminished effectiveness of the drug in patients with impaired ability to convert the drug into its active form
Genetic Variability and Clopidogrel Response * * CYP2C19*1 corresponds to normal function. CYP2C19*2 and CYP2C19*3 are loss-of-function alleles and explain most of the reduced function in those who are poor metabolizers
Number of patients Patient-to-Patient Variability in Antiplatelet Responsiveness This retrospective analysis demonstrates a marked variability in subject s response after standard dosing of the anti-platelet agent clopidogrel (N=544) 110 100 90 80 70 60 50 40 30 20 10 0 Distribution of Changes in ADP-Induced Platelet Aggregation Clopidogrel Hyporesponders (-2 SD) 4.2% (23/544) -20 [-10, 0] [11, 20] [31, 40] [51, 60] [71, 80] [91, 100] Delta 5 µm ADP Clopidogrel Hyperresponders (+2 SD) 4.8% (26/544) ADP = adenosine diphosphate; SD = standard deviation. Serebruany et al. J Am Coll Cardiol. 2005;45:246.
CYP2C19*2 Polymorphisms and Cardiovascular Outcomes
Pharmacodynamic Studies of Platelet Responsiveness to Different Clopidogrel Dosing Protocols
Effect of Different Clopidogrel Dosing Protocols on Patient Outcomes
Ongoing Trials Evaluating Antiplatelet Therapy Tailored by Genotyping and/or Phenotype Assessment
Trials Evaluating Antiplatelet Therapy Tailored by Pharmacodynamic Assessment
New Antiplatelet Drugs: Clopidogrel vs Prasugrel Cardiac death, MI, stroke Major bleeding non CABG related TRITON-TIMI 38 ACS patients
PLATO study
Stent thrombosis (%) ARC Definite or Probable SPIRIT IV: Stent Thrombosis XIENCE V (n=2458) TAXUS Express (n=1229) HR [95%CI] = 0.27 [0.11, 0.67] p=0.003 1.06% Δ 0.77% 0.29% Number at risk Months XIENCE V 2458 2426 2412 2388 2376 TAXUS 1229 1195 1184 1174 1166 Stone GW. NEJM 2010;362:1663-74.
Stent thrombosis (%) COMPARE 2 Endpoint Result Stent Thrombosis (ARC definite or probable) 5 4 Taxus Liberté (n=903) Xience V (n=897) P = 0.002 (log-rank test) 3 RR = 0.26 (0.11-0.64) 2.6 % 2 1 0.7 % 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Days Since Index Procedure Kedhi et al. Lancet 2010 on-line
Cumulative Incidence of Events (%) Stent Thrombosis in RESOLUTE All-Comers (ARC Def/Prob) 2.0 1.5 Definite Stent Thrombosis Cardiac death MI (according to ARC definition) Target-lesion revascularization Probable Stent Thrombosis Cardiac death MI (according to ARC definition) Zotarolimus 1.0 P=0.05 0.5 Everolimus 0.0 0 10 20 30 270 360 Days since Initial Procedure Serruys PW et al. NEJM 2010; on-line.
% Effect of DAPT Discontinuation Overall Population Patient who d/c DAPT P = 0.73* N=0/154 N=2/163 N=3/479 N=0/484 *P values for superiority
LEADERS OCT Substudy 10 8 6 4 2 0 Uncovered Struts -2.0 (-5.7 to 0.1) P=0.04 0,7 2,7 Lesions With At Least 5% Uncovered Struts Biolimus Stent Sirolimus Stent Biolimus Stent Sirolimus Stent 4,592 Struts 6,476 Struts 29 Lesions 35 Lesions Sensitivity Analysis: adjusted for lesion length, RVD, N of implanted stents, stent overlap 60 50 40 30 20 10 0-45.5 (-76.9 to 14.3) P<0.01 3,5 50,5 Barlis et al Eur Heart Journal (2010) 31, 165 176
OCT Analysis in HORIZONS and ODESSA Stents analyzed every 0.3 mm - 7,748 cross-sections or 43,884 struts in 117 pts in HORIZONS and 6,968 cross-sections or 53.047 struts in 77 pts in ODESSA (PES, SES, ZES, BMS) Guagliumi et al JACC Cardiovascular Intrv 2010; 3 (5):531-9
Heterogeneity of neointimal healing after DES placement and the impact on late stent thrombosis DES Thrombosis (n=28) No DES Thrombosis (n=34) Fibrin score 2.4±1.3 1.2±1.1 0.002 p Endothelialization, % Uncovered strut per section, # Stent length w/o neointima, mm Ratio of uncovered struts per total struts per section* 40.5±29.8 80.8±25.2 <0.0001 5.0±2.7 2.0±2.7 <0.0001 20.1±11.5 9.9±10.1 0.0004 0.50±0.23 0.19±0.25 <0.0001 *The most powerful morphometric predictor of endothelialization was RUTSS. The odds ratio for LST in lesions having an RUTSS >30% is 9.0 (95% CI, 3.5 to 22.0) with a sensitivity and specificity of 75% and 76%, respectively. Finn et al Circulation. 2007;115:2435-2441
CONCLUSIONS -Lesion and Patient characteristics are clearly correlated to ST -It has not been established yet which is the optimal duration of DAPT after DES but a more tailored approach (dose adjustment, more effective antiplatelet therapy, new drugs etc) is warranted. -2 and 3 generation DES have been reported to have higher efficacy and safety as compared to 1 gen DES.