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Stent Thrombosis Following Primary PCI in STEMI: Predictors, Clinical Impact and Preventive Strategies from the Horizons

Stent Thrombosis Following Primary PCI in STEMI: Predictors, Clinical Impact and Preventive Strategies from the Horizons AMI Trial. George D. Dangas, MD Columbia University Medical Center . Disclosures. Speaker honoraria Sanofi-Aventis, Astra Zeneca and BMS Not sponsors of this study

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Stent Thrombosis Following Primary PCI in STEMI: Predictors, Clinical Impact and Preventive Strategies from the Horizons

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  1. Stent Thrombosis Following Primary PCI in STEMI:Predictors, Clinical Impact and Preventive Strategies from the Horizons AMI Trial George D. Dangas, MD Columbia University Medical Center

  2. Disclosures • Speaker honoraria Sanofi-Aventis, Astra Zeneca and BMS • Not sponsors of this study • Speaker honoraria and consulting fees • Medicines Co – modest • Boston Scientific – modest • Both provided research grant support for the Horizons Trial • Eli Lilly • Astra Zeneca

  3. Background • Stent thrombosis (ST) is a serious adverse event which occurs more frequently in pts with STEMI • Since the pathophysiologic mechanisms of ST may vary, it is conventionally categorized according to its timing after stenting: • 0-24 hours (acute ST) • 1-30 days (subacute ST) • 1-12 months (late ST) • Beyond 1 year (very late ST)

  4. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… R 3:1 R 1:1 CABG – – Primary PCI Medical Rx 3006 pts eligible for stent randomization Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years; angio FU at 13 months

  5. Primary Endpoints at 30 Days Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.005 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 0.95 1 endpoint 1 endpoint Major 2 endpoint Stone GW et al. NEJM2008;358:2218-30

  6. 1-Year Mortality (All-Cause) Bivalirudin alone (n=1800) 4.8% 5 Heparin + GPIIb/IIIa (n=1802) Δ = 1.4% 4 3.4% 3.1% 3 Mortality (%) Diff [95%CI] = -1.4% [-2.7,-0.1] HR [95%CI] = 0.70 [0.51, 0.98] P=0.036 2 2.1% Δ = 1.0% P=0.049 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Number at risk 1800 1705 1684 1669 1520 Bivalirudin alone 1802 1679 1664 1647 1487 Heparin+GPIIb/IIIa

  7. Stent Thrombosis Analysis In the current analysis we included all HORIZONS-AMI pts who received a stent, either DES (any type) or only BMS (n=3203) Stent thrombosis (n=107 [3.3%] within 1-year) was defined as Definite or Probable by the ARC criteria, as adjudicated by an independent CEC blinded to stent and pharmacology use

  8. Objectives Stent thrombosis and timing according to: Stent type (any DES vs. onlyBMS, 94% rand) Antithrombin type (UFH+GPI vs. Bival, 100% rand) GPI selection (abciximab vs. eptifibatide, stratified) Clopidogrel loading dose (300 vs. 600 mg, stratified) Pre randomization UFH (yes vs. no, stratified) Univariate and multivariable predictors of stent thrombosis (ARC Def/Prob) from 36 variables Acute, subacute, late, and 1-year

  9. Statistical Methods • Kaplan-Meier methods were used to plot landmark time-to-event curves, compared using the logrank test • Cox proportional hazards used to derive the independent predictors of ST via stepwise regression (α=0.05) • Potential covariates (36) for inclusion in the models: • CLINICAL (20): Bivalirudin (randomized v. UFH+IIb/IIIa), Any DES (v. BMS only), Age, Sex (Male), US clinical center, Clopidogrel Loading Dose, Pre-Randomization Heparin, Current Smoking, History of IDDM, History of MI, History of CHF, Killip Class 2-4, History of PVD, Anemia, Baseline Platelet Count, Renal Insufficiency (Baseline CrCl<60), Anterior MI, Direct Stenting Attempted, Post Dilation balloon used, Max Balloon Pressure • ANGIOGRAPHIC (16): Baseline RVD, Total Lesion Length, Stent to Lesion Length Ratio, Number of stents, Worst angiographic view - Thrombus, Worst angiographic view - Ulceration, Aneurysm, Baseline TIMI flow 0/1, Bifurcation lesion, Moderate/Severe Calcification, Multiple Vessels Treated, Sustained ventricular tachycardia or fibrillation on admission, Final TIMI flow 0/1, Final Lesion MLD , Final Lesion DS>50%, Final Angiography with No Reflow

  10. Two-Year Stent Thrombosis(ARC Definite or Probable) TAXUS DES (n=2257) EXPRESS BMS (n=749) 6 5 4.1% 4.1% 4 Stent Thrombosis (%) 3 HR [95%CI]= 1.00 [0.66, 1.51] 2 p= 0.99 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2238 2108 2061 1998 1661 EXPRESS BMS 744 696 681 661 547

  11. Two Year Composite Safety Endpoints* Adverse Events Between 1 and 2 Years* *Kaplan-Meier estimates

  12. 2-Year Stent Thrombosis(ARC Definite/Probable) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 6 5 4.6% 4.3% 4 Stent Thrombosis (%) 3 HR [95%CI]= 0.94 [0.67, 1.32] 2 p= 0.73 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk Bivalirudin alone 1611 1509 1475 1444 1206 Heparin+GPIIb/IIIa 1591 1482 1449 1386 1153

  13. Stent Thrombosis 1-Day Landmark Analysis: Impact of Antithrombin Bivalirudin monotherapy Heparin + GPIIb/IIIa inhibitor 3.5 HR [95%CI] = 5.93 [2.06-17.04] P = 0.0002 3.0% 3.0 2.5 2.2% 2.0 Def/Prob Stent Thrombosis (%) 1.5% 1.5 HR [95%CI] = 1.73 [0.47-1.13] P = 0.06 1.0 0.3% 0.5 0.0 0 1 30 90 180 270 365 Time in Days Number at risk Bivalirudin 1611 1600 1562 1525 1506 1485 1355 UFH+GPIIb/IIIa 1591 1587 1521 1495 1476 1457 1315

  14. Acute Stent Thrombosis: Impact of Pre-Randomization Heparin 3.5 No Pre-Randomization Heparin Pre-Randomization Heparin 3.0 2.6% Bivalirudin 2.5 HR [95%CI] = 3.07 [1.33,7.09] P = 0.006 2.0 Def/Prob Stent Thrombosis (%) 1.5 0.9% Bivalirudin 1.0 0.8% UFH+GPI HR [95%CI] = 9.64 [1.00,92.70] P = 0.02 0.5 0.1% UFH+GPI 0.0 0 6 12 18 24 Time in Hours Number at risk P-R Heparin 1066 1052 1051 1050 1049 No P-R Heparin 545 531 529 528 528 P-R Heparin 1211 1208 1207 1207 1207 No P-R Heparin 378 377 375 374 374 Pint antithrombin x pre-rand hep = 0.39

  15. Independent Predictors of Acute ST (Cox Model)

  16. 1-Year Stent Thrombosis: Impact of GPI in the UFH Group Eptifibatide Abciximab 4 3.6% 2.8% 3 Def/Prob Stent Thrombosis (%) 2 HR [95%CI] = 0.78 [0.44-1.37] P = 0.38 1 0 0 30 60 90 120 150 180 210 240 270 300 330 365 Time in days Number at risk Eptifibatide 727 693 685 678 668 592 Abciximab 829 793 778 768 759 698

  17. 1-Year Stent Thrombosis: Impact of Clopidogrel Loading Dose (all pts) 600mg Clopidogrel 300mg Clopidogrel 5 3.8% 4 3.0% 3 Def/Prob Stent Thrombosis (%) 2 HR [95%CI] = 1.30 [0.86-1.95] P = 0.10 1 0 0 30 60 90 120 150 180 210 240 270 300 330 365 Time in days Number at risk 600 mg 1983 1906 1881 1858 1832 1653 300 mg 1034 983 974 965 952 871

  18. Stent Thrombosis 1-Day Landmark Analysis: Impact of Clopidogrel Loading 600mg Clopidogrel 300mg Clopidogrel 5 HR [95%CI] = 1.47 [0.93,2.33] P = 0.18 4 HR [95%CI] = 0.96 [0.41-2.23] P = 0.92 3.2% 3 Def/Prob Stent Thrombosis (%) 2.2% 2 0.8% 1 0.8% 0 0 1 30 90 180 270 365 Time in Days Number at risk 600 mg 1983 1978 1920 1881 1858 1832 1653 300 mg 1034 1027 990 974 965 952 871

  19. Independent Predictors of Subacute ST (Cox Model)

  20. Independent Predictors of Late ST (Cox Model)

  21. Independent Predictors of 1-Year ST (Cox Model)

  22. Overall Conclusions Following stent implantation in STEMI, ST occurs frequently within the first 24 hours (0.9%), between 1 and 30 days (1.6%), and between 1 month and 1 year (1.0%) – 3.3% in total by 1 year 4.1% by 2 years Acute, subacute and late ST appear to be related to different factors Pharmacological therapy, vessel flow, lesion characteristics and number and length of stents are the most important predictors of acute and subacute ST events Patient related factors including cigarette smoking and prior MI are most important for late ST events

  23. Implications The type of stent implanted (DES vs. BMS) was not related to ST during any time interval up to 2-years ST within 1-year occurred with similar frequency in patients treated with UFH+GPI and bivalirudin alone However, acute ST was more common with bivalirudin, especially within the 1st 5 hours, whereas ST tended to be less common with bivalirudin than with UFH+GPI beyond 24 hours

  24. In the primary results of the HORIZONS-AMI trial, bivalirudin monotherapy resulted in less major bleeding, comparable rates of ischemia and improved survival compared to UFH+GPI Taking under account the present analysis we may be able to optimize adjunct pharmacology with bivalirudin during primary PCI may further improve outcomes: Pre-randomization UFH attenuated the risk of acute ST This is especially meaningful if bivalirudin is not stored at point of first medical contact (ED, ambulance etc) A 600 mg clopidogrel LD attenuated the risk of subacute ST Should be the dosage of choice in STEMI Other means of intense antiplatelet therapy should be important as well including prasugrel, ticagrelor and extended double dose regimen of clopidogrel Whether a prolonged bivalirudin infusion (4-6 hrs) post-PCI warrants further study as well Practical Points

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