Treatment of Late stent thrombosis
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Treatment of Late stent thrombosis

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  • SVD db – 504 498 483 251 121 72MVD db – 357 347 337 186 87 53SVD db + 472 459 444 230 114 69MVD db + 334 321 312 164 91 97

Treatment of Late stent thrombosis Treatment of Late stent thrombosis Presentation Transcript

  • TREATMENT OF LATE AND VERY LATE STENT THROMBOSIS DEV PAHLAJANI MD,FACC,FSCAI CHIEF OF INTERVENTIONAL CARDIOLOGY, BREACH CANDY HOSPITAL,MUMBAI
  • DES increased thrombogenicity• According to the Euro PCR-06 Daily; a 1.2% rate of late stent thrombosis means around 30,000 people were affected, accounting for a 45% mortality rate.
  • BMS VS DES –ADVERSE EVENTS Incidences of serious adverse events (Death or MI) N=878 N=870 N=1675 N=1685
  • Study Design: BASKET LATE trial743 patients randomized in the BASKET trial and without an event during the 6 month Clopidogrel phase Drug eluting stents(DES) Bare metal (pooled paclitaxel and VISION stents (BMS) sirolimus DES groups) N=244 n=499 Followed for 1 year off clopidogrel •Primary Endpoint: Composite cardiac death or nonfatal MI •Other Endpoints: “Thrombosis-related events” Ref: Pfisterer M et al.ACC 2006
  • BASKET LATE Trial• “For every 100 patients treated with DES,3.3 cases of cardiac death or MI are induced for reduction of 5 cases of TLR”
  • BASKET-LATEn = 743, 6 – 18 months Pfisterer M. JACC 2006
  • ARC Proposed Standard DefinitionsDEFINITE (Angiographic or pathologic confirmation): Angiographic confirmation: 1. TIMI 0 with occlusion originating in or within 5 mm of stent in the presence of a thrombus 2. TIMI flow grade 1, 2, or 3 originating in or within 5 mm of stent in the presence of a thrombus 3. AND 1 of the following criteria < 48 hours: 4. New acute onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) 5. New ischemic ECG changes suggestive of acute ischemia 6. Typical rise and fall in cardiac biomarkers  Pathologic confirmation: 1. Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomyPROBABLE:1. Any unexplained death within the first 30 days2. Any MI (related to documented acute ischemia and without another obvious cause) in the territory of the stent POSSIBLE: Any unexplained death >30 days
  • ARC Definitions of Stent Thrombosis - Gaps Best Balance Includes MI with or without angio, but Too Narrow not 1.5%/year Too Broad natural history Misses people who deaths Includes natural have an MI but don’t history events (equal have an angiogram in both arms) that dilute out true ST signal* * Worse if you include post TLR events • Restenotic stent can’t really develop ST • Brachytherapy or new DES certainly canDr. Don Baim, TCT 2006. • More such events occur in the BMS arm
  • Thrombosis Can Occur Any Time Post-Stent Implantation Very Late ST Late ST SAT Acute ST
  • Time Frame Classification 365 days 90 days 30 days0 days
  • Occurrence of Stent Thrombosis EVASTENT REGISTRY ST+ (n=) 23 26 36 41 ST- (n=) 1692 1679 1669 1664Cumulative probability of stent 2.5 2.0 1.5thrombosis (%) 1.0 0.5 0.0 0 30 90 180 365 Follow-up (days) JACC 2007, 50, 501
  • Stent ThrombosisBern-Rotterdam 3.5 3.2 3Percent Stent Thrombosis Bern Cypher 2.7 Bern Taxus 2.5 2.5 Bern BMS 1.9 2 1.5 1.6 1 0.5 0 0 10 30 365 730 1095 Days Wenaweser P. et al: EHJ 2005 26 1180-1187. Wenaweser P. et al: ESC 2006. Bern-Rotterdam and HCRI CEC ST definitions both require angiographic confirmation.
  • LATE STENT THROMBOSIS  STEMI ACUTE CORONARY SYNDROME  LEFT VENTRICULAR FAILURE  CARDIOGENIC SHOCK
  • TREATMENT OF LSTMANAGE LIKE PRIMARY PCIBALLOON DILATATIONSUPPORTIVE MEASURESIABP IF SHOCK OR LVFLIBERAL USE OF GPIIB/IIIA BLOCKERSASPIRIN AND CLOPIDOGREL IF NOT ONTHROMBUS ASPIRATIONAVOID DES PREFER BMS
  • Clinical importance of stent thrombosisAuthor/Year BMS/DES ST def Death or MI DeathCutlip 2001 BMS Angio or 70% 21% clinicalHeller 2001 BMS Angio + AMI 100% 17 %Iakovou 2005 DES Angio or 45 % clinicalOng 2005 DES Angio & 100 % 25 % clinicalKuchulakanti DES Angio 31 %2006
  • ‘Real-world’ outcomes through 1 year CYPHER (n=2067) TAXUS (n=7393) e-CYPHER ARRIVE 1& 2 Stent P value Stent P value Thrombosis Thrombosis 2.87 vs. 2.03 0.10Diabetes vs. No Diabetes 1.12 vs. 0.75 0.44 3.06 vs. 1.95 0.03 2.5 mm vs. >2.5 mm 1.02 vs. 0.73 0.47 4.49 vs. 1.96 <0.0001 >28 mm vs. 28 mm 1.90 vs. 0.76 0.22 4.20 vs. 1.43 <0.0001Multiple vs. Single stents 1.35 vs. 0.73 0.22 3.53 vs. 2.05 0.01Multiple vs. Single Vessel 1.16 vs. 0.59 0.04 3.49 vs. 2.12 0.07 Acute MI vs. Non-AMI 0.67 vs. 0.88 1.00
  • Incidence of Late stent Thrombosis >30 days meta-analysis of 14 randomized clinical trials 6675 pts Am J of Medicine 2006;119, 1056-1061
  • Bern-Rotterdam Analysis: SummaryThe data suggest that late stent thrombosis occurs at a steadyrate during follow-up up to three years, tends to be more frequentwith PES than with SES, and can unpredictably occur at any timepoint despite antiplatelet therapy.Late stent thrombosis complicating the use of DES seems to be adistinct entity with pathophysiological factors that differ fromthose of early stent thrombosis. Daemen et al. Lancet. 2007 Feb 24; 369: 667 – 78.
  • Late Stent Thrombosis— Factors to Consider
  • Incidence of Late Stent Thrombosis DES McFadden E et al. Lancet 2004;364:1519
  • Incidence of Thrombosis in 40 autopsy cases of DES
  • STENT THROMBOSIS DESPredictors of late stent thrombosis2229 consecutive patients at 3 centersIndependent predictors of late ST (>30 days < 9 mo)-premature antiplatelet therapy d/c HR=161-renal failure HR=10.1-bifurcation lesion HR=6.0-diabetes HR=5.8
  • Independent Predictors of Late ST Iakovou I et al JAMA. 2005;293:2126-2130
  • Predictors of ST after DES (SES or PES) 29/2229 pts (1.3%) at 9.3 ± 5.6 mos Iakovou et al. JAMA 2005;293:2126-2130 Multivariate predictors of stent thrombosis: Renal failure (OR=11.5), Bifurcation (7.2), Prior Brachy Rx (4.2), Diabetes(3.4), And Low LVEF(1.1) Iakovou I et al JAMA. 2005;293:2126-2130
  • Late Incomplete Apposition Drug-eluting stentDante Pazzanese Experience - 5% at 6 mths (20% had ST)
  • Impaired Re-endothelialization Pathology findings:Sirolimus-Eluting stents from different coronary arteries in the same patient (delayed healing) Cypher 16 months after deployment BMS 24 months after deployment
  • Delayed Arterial healing in DES Joner, JACC 2006
  • Lack of Re-Endothelialization at sites of Thrombosis in DES
  • Percentage of Endothelialization in Drug-eluting Stents (DES) VERSUS Bare-metal Stents (BMS) as a function of Time J Am Coll Cardiol 2006
  • Granulomatous reaction seen in 12.5 and 35% ofCYPHER stents implanted for 28 & 90 days in Pig Coronary Arteries
  • Case presented in EURO PCR-05• A 38 year old female died suddenly, 6 months following Taxus stent placement for AMI No healing or inflammation observed over the 6 months stent implantation time
  • DES failed to cross a heavily calcified lesion!!Undamaged Severe polymerpolymer damage Columbia University Medical Centre Cardiovascular Research Foundation
  • Mechanisms leading to incomplete stent apposition Cook, S. et al. Circulation 2007;115:2426-2434
  • The protocol sequence of IVUS imaging in very late ST patients is depicted in A, as follows: (1) After administration of nitroglycerin (0.2 mg), an angiogram with the use of a 6F guiding catheter was performed to define the site of thrombotic stent occlusion Cook, S. et al. Circulation 2007;115:2426-2434
  • Clinical outcomes and Stent Thrombosisfollowing off-label use of drug eluting stents
  • Antiplatelets  4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response  5% to 45% of patients treated with conventional doses of aspirin do not display adequate antiplatelet response (Nguyen TA et al.JACC 2005;45:1157-1164. Gum PA Stone et al.JACC 2003;41:961-965) Premature DiscontinuationStudy Yes No RR (95% CI) PARIakovou et 5/17 (29%) 24/2,212 27 (12, 63) 17%al.,2005 (7) (1.0%)Kuchulakanti et 14/310 (4.5%) 24/2,658 5 (3,10) 29%al.,2006 (8) (0.9%) PAR= Pr * [(RR-1)/Pr * (RR-1)+1] CI= confidence interval; DES= drug eluting stent; PAR= population attributable risk; Pr=prevalence of clopidogrel discontinuation; RR= relative risk
  • Clopidogrel and DESLate clinical events after clopidogrel discontinuation may limitthe benefit of drug-eluting stents.An observational study of DES versus BMS –BASKET-Late study
  • Timing of late thrombotic events after clopidogrel discontinuation Pfisterer, M. et al. J Am Coll Cardiol 2006;48:2584-2591Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.
  • JACC 2007, 50, 501 SES Thrombosis in Diabetic And Non DiabeticEVASTENT REGISTRY Patients 1.00 SVD db - MVD db - MACE free Survival 0.95 SVD db + MVD db + Log Rank P <= 0.001 0.90 0.85 0 100 200 300 400 500 600 Follow-up (days) SVD db – 504 498 483 251 121 72 MVD db – 357 347 337 186 87 53 SVD db + 472 459 444 230 114 69 MVD + 334 321 312 164 91 97
  • EVASTENT REGISTRY – SES Diabetic Vs Non Diabetic Patients 1.00 0.95 1.00 Stent Thrombosis Free SurvivalSurvival 0.90 Non-diabetic 0.95 Diabetic 0.90 Non-diabetic 0.85 Diabetic Logrank p = 0.0001 0.80 0.85 Log rank p = 0.003 0 200 400 600 0.80 Follow-up (days) 0 200 400 600 Follow-up (days) Db - 870 861 835 448 216 129 pts Db + 818 799 774 401 212 144 pts Db - 859 847 823 437 210 125 pts Db + 800 776 755 394 202 135 pts JACC 2007, 50, 501
  • 1.00TLR Free Survival 0.95 0.90 Non-diabetic Diabetic 1.00 0.85 Log rank p = 0.032 0.95 TVF Free Survival 0.80 0.90 Non-diabetic Diabetic 0 200 400 600 Follow-up (days) 0.85 Logrank p = 0.0001 Db - 867 848 821 436 210 126 pts 0.80 Db + 814 775 747 388 200 134 pts 0 200 400 600 Follow-up (days) Db - 858 835 805 426 203 123 pts Db + 797 753 722 368 195 128 pts JACC 2007, 50, 501
  • AMI Stent THROMB. vs DENOVO (table 1) Baseline clinical characteristics STEMI STEMI with ST P Value (n=98) (n= 86)Age (yrs) 62.9 _+ 10.3 66.0 _+11.9 0.06Male 81 (82.7%) 68 (79.1%) 0.5Cardiac risk factorsHypertension 45 (45.9%) 44 (51.8%) 0.4Diabetes Mellitus 14 (14.3%) 21 (25.3%) 0.06Hypercholesterolemia 34 (34.7%) 37 (43.4%) 0.2Current smoker 47 (48.0%) 23 (26.5%) 0.003Family history of CAD 35 (35.7%) 23 (26.5%) 0.2Creatine >= 1.5mg/dl 4 (4.1%) 13 (15.7%) 0.008COPD 3 (3.1%) 8 (9.5%) 0.07Prior MI 11 (11.2%) 59 (68.2%) < 0.0001Prior stroke 0 (0%) 6 (7.1%) 0.007
  • AMI Stent THROMB. vs DENOVO (table 2) ST characteristics (n=92)Definite ST (ARC definition) 92 (100%)Thrombosis timing (ARC definition)Early (< 30 days) 59 (64.1%)Late (30-360 days) 14 (15.2%)Very Late (> 360 days) 19 (20.7%)Clinical presentation at the Index procedure 43 (46.5%)MI (acute or sub acute) 38 (41.9%)UA/ NSTEMI stable angina or silent ischemia 11 (11.6%)Double antiplatelet therapy at the moment of stent thrombosis 62 (67.4%)Early discontinuation of double antiplatelet therapy 6 (6.9%)StentBMS 22 (23.9%)DES 70 (76.1%)Stent Length 25.2_+ 12.7Stent diameter 2.8_+ 0,3 ARC= Academic Reasearch Consortium; BMS= abre-metal stent; DES=drug eluting stent; MI=myocardial infarction; ST=stent thrombosis; UA/NSTEMI= unstable angina/non- ST-segment elevation myocardial infarction
  • AMI Stent THROMB. vs DENOVO (table 3) Angiographic Analysis STEMI STEMI with ST p Value (n=98) (n= 92)Pre-procedural TIMI flow <=1 77 (78.6%) 69 (80%) 0.8Post-procedural TIMI flow =3 95 (96.9%) 74 (80.4%) < 0.0001Pre-procedural TG >= 3 92 (93.9%) 92 (100%) 0.01Post-procedural myocardial 1(1.0%) 12 (13.0%) 0.001blush <=1Post-procedural cTFC* 24.2 _+ 12.6 21.2 _+ 9.4 0.1Successful reperfusion 95 (96.9%) 74 (80.4%) <0.0001Distal Embolization 0(0%) 6 (6.5%) 0.01Residual dissection 1(1.0%) 15 (16.3%) <0.0001Post-procedural QCA analysisRVD (mm) 3.2 _+ 0.4 2.9 _+ 0.3 <0.0001Lesion length (mm) 2.9 _+ 2.6 7.0 _+ 4.7 < 0.0001MLD (mm) 2.9 _+ 0.4 2.0 _+ 0.7 < 0.0001Diameter stenosis (%) 8.1 _+ 6.6 31.8 _+ 24.9 < 0.0001
  • Successful Reperfusion Chechi, T. et al. J Am Coll Cardiol 2008;51:2396-2402
  • All-Cause Mortality and Cumulative MACCE Rate Chechi, T. et al. J Am Coll Cardiol 2008;51:2396-2402
  • Stent thrombosis in DM NDMRisk factors for stent thrombosis after implantation of Sirolimus- eluting stents in Diabetic and Nondiabetic patients. The EVASTENT Matched-Cohort RegistryIndependent predictors of stent thrombosis Parameter QR (95% CI) p Value Overall population Previous stroke 3.2 (0.99-1.0) 0.052 Renal failure 3.6 (1.6-7.7) 0.001 Insulin-requiring diabetes 2.7 (1.4-5.2) 0.004 Calcified lesion 3.7 (1.8-7.7) 0.001 Lower EF (per U) 0.95 (0.93-0.97) <= 0.001 Length stented (per mm) 1.01(1.0-1.03) 0.045
  • Very Late DES Thrombosis On-Label Use >1 Year Post Implant Pooled RCTs
  • Aalen-Nelson Estimate Curves of Cumulative Hazard Function for Stent Thrombosis Park, D.-W. et al. J Am Coll Cardiol Intv 2008;1:494-503
  • Kaplan-Meier Curves of Cumulative Incidence of Stent Thrombosis Park, D.-W. et al. J Am Coll Cardiol Intv 2008;1:494-503
  • Rates of Stent Thrombosis in Meta-analysisReference Year Patients Stents FU ST RateMoreno 2005 5,030 BMS 48% 6–12 mn SAT: 0.35% (BMS = DES) SES 17% LST: 0.23% (BMS = DES) PES 34%Bavry 2005 3,817 BMS 48% 6–12 mn SAT + LST: 0.76% (PES = BMS) PES 52%Morice 2006 1,386 SES 51% 12 mn SAT: SES 0.4%, PES 1.0%(REALITY) PES 49% LST: SES 0%, PES 0.3%Kastrati 2005 3,669 SES 50% 6–13 mn SAT + LST: 1.0% (PES = SES) PES 50%Spalding 2007 1,748 BMS 50% 48 mn SAT: SES 0.5%, BMS 0.5% SES 50% LST: SES 0.3%, BMS 1.3% VLST: SES 2.8%, PES 1.7Mauri 2007 4,545 SES 19% 48 mn SAT: SES 0.5%, BMS 0.3% PES 31% LST: SES 0.1%, BMS 1.0% BMS 50% VLST: SES 0.9%, BMS 0.4% SAT: PES 0.5%, BMS 0.5% LST: PES 0.4%, BMS 0.3% VLST: PES 0.9%, BMS 0.6%
  • Preventive Strategies Optimizing stent implantation  Selection of the appropriate diameter and length of stent.  Placement of excessively long DES (overstenting) should be avoided.  Residual stent marginal dissections or significant stenoses should be treated.  Suboptimal under- or overdeployment of stent diameter should be avoided.  IVUS may be useful in optimizing deployment results.  Some specific techniques may be associated with higher rates of ST. Adjunctive therapy  Dual antiplatelet therapy after DES implantation is crucial.  Recently, the recommendation has been to extend this therapy for up to 12 months in patients at low risk for bleeding events.  Preliminary data suggest that “triple” antiplatelet therapy may be associated with a reduction in MACE, including ST, and may be a therapeutic option for patients at high risk for ST.
  • Triple Versus Dual Antiplatelet Therapy Dual Triple p Value (n=1597) (n= 1415)Stent thrombosis 9 (0.596) 1 (0.196) 0.024Acute stent occlusion 3(0.296) 0 0.252Sub acute stent 6(0.396) 1(0.196) 0.223thrombosis Major cardiac eventsMyocardial infarction 11(0.796) 3(0.296) 0.063Target lesion 9(0.596) 1(0.196) 0.024revascularizationRepeat intervention 8(0.697) 1(0.196)Emergency bypass 1(0.02) 0Death 5(0.396) 3(0.296) 0.730Primary end point 13(0.896) 4(0.396) 0.085 J. Am. Coll. Cardiol. 2005;46;1833-1837
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