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ACC 2008 – Disclosure Slide

Name of the speaker: Germano DiSciascio I have the following potential conflicts of interest to report:  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest.

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ACC 2008 – Disclosure Slide

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  1. Name of the speaker: Germano DiSciascio I have the following potential conflicts of interest to report:  Consulting  Employment in industry  Stockholder of ahealthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest ACC 2008 – Disclosure Slide

  2. ARMYDA (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study group Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional clopidogrel load in patients on chronic therapy - “ARMYDA-Reload” Chairman: Germano Di Sciascio Principal Investigators:Giuseppe Patti, Vincenzo Pasceri, Giuseppe Colonna Investigators:Antonio Montinaro, Leonardo Lassandro Pepe, Antonio Tondo, Laura Gatto, Fabio Mangiacapra, Francesco Ciccirillo, Andrea D’Ambrosio, Annunziata Nusca, Giordano Dicuonzo, Gennaro Sardella, Bibi NGuyen

  3. Antiplatet effects of a 600 mg load in pts with or without chronic clopidogrel Rx No prior clopidogrel N=20 Chronic clopidogrel N=20 P<0.001 100 P<0.001 80 P<0.001 ADP (5 mol/L)-induced aggregation, % 60 40 20 0 After load Before load After load Before load 600 mg clopidogrel Kastrati et al. Circulation 2004

  4. ARMYDA - Reload: BACKGROUND • The ARMYDA-2 trial confirmed improved PCI outcome with 600 mg clopidogrel loading vs a 300 mg dose in clopidogrel naïve patients • In patients already receiving clopidogrel, concerns about bleeding (with reloading), and/or adequacy of antiplatelet effect (without additional loading) GOAL OF THE STUDY • To evaluate safety and effectiveness of a strategy of 600 mg clopidogrel reload in patients undergoing PCI while on chronic clopidogrel therapy, and to evaluate difference in outcome in patients with ACS vs stable angina

  5. ARMYDA-Reload: Study design 30 days 4 - 8 hrs PCI Reload N=130 Medical Rx (N=75) Stable angina N=269 Clopidogrel 600 mg reload ‡ N= 285 568 Patients on chronic Clopidogrel therapy (>10 days) with PCI Placebo N=139 • Primary • endpoint: • Death • MI • TVR Randomization 219 Reload 217 Placebo PCI = 436 Angiography PCI Reload N=89 - NSTE-ACS or Stable angina NSTE-ACS N=167 Placebo ‡ N=283 CABG (N=57) PCI Placebo N=78 Baseline blood sample PCI 2 hrs 8 and 24 hrs • CK-MB • Troponin-I • PRU • PRU • PRU • CK-MB • Troponin-I • PRU ‡ On top of chronic therapy

  6. ARMYDA-ReloadSTUDY ENDPOINTS • Primary endpoint • 30-day incidence of death, MI, TVR • MI definition: Consensus statement of the Joint ESC/ACCF/AHA/WHF Task Force, as a post procedural increases of cardiac biomarkers (troponin or CK-MB) greater than 3 x 99th percentile of the upper reference limit in patients with normal baseline levels of CK-MB, and as a subsequent elevation of more than three-fold in CK-MB from baseline value in patients with raised baseline levels of CK-MB • Secondary endpoints • Post-procedural increase of markers of myocardial injury above UNL (CK-MB, troponin I) • Occurrence of any vascular/bleeding complications • “Point of care” testing of platelet reactivity (PRU) at different time points in the reload and placebo arms

  7. ARMYDA-Reload Inclusion criteria Patients on chronic (> 10 days) therapy with clopidogrel (22% of PCI pts population in the recruiting centers) with stable angina or non-STE ACS undergoing PCI Exclusion criteria- Primary PCI- Platelet count <70x103/ml- Pts with high risk of bleeding- Coronary by-pass surgery in the previous 3 months

  8. ARMYDA-Reload Trial Clinical Characteristics Stable population: N=269 600 mg Clopidogrel reload N=130 Placebo N=139 P 66±10 90 (69) 39 (30) 92 (71) 104 (80) 26 (20) 40 (31) 66 (51) 14 (11) 45 (35) 53±7 130 (100) 127 (98) 67±11 94 (68) 41 (30) 98 (71) 105 (76) 28 (20) 43 (31) 61 (44) 10 (7) 44 (32) 54±8 139 (100) 130 (94) 0.44 0.88 0.97 0.93 0.46 0.90 0.92 0.31 0.42 0.70 0.28 - 0.17 Age (yrs) Male gender (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%)

  9. ARMYDA-Reload Trial Clinical Characteristics ACS population: N=167 600 mg Clopidogrel reload N=89 Placebo N=78 P 64±10 80 (90) 31 (35) 77 (87) 70 (79) 15 (17) 40 (45) 24 (27) 43 (48) 9 (10) 26 (29) 53±7 89 (100) 82 (92) 65±10 70 (90) 30 (39) 75 (96) 67 (86) 17 (22) 36 (46) 26 (33) 30 (39) 6 (8) 26 (33) 54±8 78 (100) 70 (90) 0.52 0.82 0.75 0.06 0.31 0.54 0.99 0.47 0.26 0.78 0.69 0.39 - 0.79 Age (yrs) Male gender (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Troponin +ve (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%)

  10. ARMYDA-Reload Trial Composite primary endpoint (30-day death, MI, TVR) Overall population N=436 P=0.70 9 % 7

  11. ARMYDA-Reload Trial Composite primary endpoint (30-day death, MI, TVR) Stable ACS 18 P=0.23 P=0.035 % % 8 7 4 Placebo 600 mg Clopidogrel reload

  12. ARMYDA-Reload Trial Individual components of primary endpoint Stable ACS 18 % % 7 7 4 1 600 mg Clopidogrel reload Placebo

  13. ARMYDA-Reload Secondary endpoints Post-procedural elevation of markers of myocardial injury above UNL Stable ACS P=0.31 P=0.41 55 P=0.016 50 46 45 41 P=0.48 25 23 21 % of patients % of patients 600 mg Clopidogrelreload Placebo

  14. ARMYDA-Reload Trial Secondary endpoints Bleeding rates in the overall population 5 5 % 0 0 Placebo 600 mg Clopidogrel reload

  15. ARMYDA-Reload Trial Secondary endpoint Bleeding rates Stable ACS 10 10 % % 2 2 0 0 0 0 N=3 N=3 N=8 N=9 Placebo 600 mg Clopidogrel reload * P=0.03

  16. ARMYDA-Reload: Platelet aggregometry* Stable ACS P=0.046 P=0.12 240 240 227±85 218±62 210±57 203±62 220 220 Clopidogrel 600 mg Clopidogrel 600 mg 192±63 193±59 200 200 215±69 184±63 186±61 201±67 205±55 200±61 176±71 180 180 189±65 Platelet reaction units (PRU) Platelet reaction units (PRU) 162±71 159±63 180±79 160 160 171±61 168±71 172±83 156±62 132±51 140 140 148±66 Placebo 120 120 Placebo 126±61 100 100 Estimated Study PCI 2 hrs 8 hrs 24 hrs baseline ** Drug Estimated Study PCI 2 hrs 8 hrs 24 hrs baseline ** Drug Placebo Reload ** Using baseline TRAP channel * By VerifyNow TM

  17. ARMYDA-Reload Odds Ratios for 30-day MACE 1 2 0 3 5 4 ACS 0.36 (0.29-0.92) No ACS 1.2 (0.95-1.4) Diabetes mellitus 0.75 (0.18-4.7) No diabetes 0.90 (0.38-2.2) MV intervention 1.2 (0.22-7.8) No MV intervention 0.80 (0.35-1.9)

  18. 20 16 P=0.035 (ACS Placebo vs ACS Reload) 12 Death/MI/Repeat revascularization (%) 8 4 0 5 10 15 20 25 30 Days after randomization ARMYDA-Reload EVENT CURVES 30-day MACE and Benefit with Reload ACS Placebo ACS Reload Stable Angina Placebo Stable Angina Reload

  19. CONCLUSIONS • The ARMYDA-Reload trial indicates that a significant proportion of patients undergoing PCI are on chronic clopidogrel therapy • Patients with stable angina who are already taking clopidogrel can safely undergo PCI without need of further reload • In patients with ACS, a 600 mg reloading strategy can significantly improve outcome (64% RR of MACE) • Serial point of care aggregometry studies show platelet reactivity curves consistent with clopidogrel status and clinical syndrome, and may correlate with outcome • No major bleeding, and no increased bleeding risk are observed in the “reload” approach vs placebo in either stable or ACS patients • Given the growing number of patients undergoing PCI while on clopidogrel, those results may influence practice patterns in interventional pharmacology

  20. ARMYDA-Reload Trial Individual events at 30 days 9 % 6.8 0.5 600 mg Clopidogrel reload Placebo

  21. 20 16 P=0.035 (ACS Placebo vs ACS Reload) 12 Death/MI/Repeat revascularization (%) 8 4 0 5 10 15 20 25 30 Days after randomization ARMYDA-RELOAD 30-day MACE and Benefit with Reload (600 mg Clopidogrel) ACS Placebo Stable Angina Reload ACS Reload Stable Angina Placebo

  22. ARMYDA–Reload Trial Procedural features Stable population : N=269 600 mg Clopidogrel reload N=130 Placebo N=139 P Vessels treated (%) Left main LAD LCx RCA SVG Chronic total occl. (>3 mo.)(%) Restenotic lesions (%) Lesion type B2/C (%) Multivessel intervention (%) Type of intervention (%) Balloon only Stent DES (%) IIb/IIIa inhibitors (%) 4 (2) 63 (39) 38 (24) 54 (34) 2 (1) 18 (14) 18 (14) 70 (54) 30 (23) 15 (12) 115 (88) 70 (54) 7 (5) 0.79 0.28 0.77 0.47 0.66 0.25 0.25 0.74 0.99 0.42 0.42 0.30 0.90 4 (2) 78 (46) 37 (22) 50 (29) 2 (1) 12 (9) 12 (9) 71 (51) 31 (22) 11 (8) 128 (92) 65 (47) 6 (4)

  23. ARMYDA–Reload Trial Procedural features ACS population : N=167 600 mg Clopidogrel reload N=89 Placebo N=78 P Vessels treated (%) Left main LAD LCx RCA SVG Chronic total occl. (>3 mo.)(%) Restenotic lesions (%) Lesion type B2/C (%) Multivessel intervention (%) Type of intervention (%) Balloon only Stent DES (%) IIb/IIIa inhibitors (%) 2 (2) 41 (42) 20 (20) 29 (29) 7 (7) - 4 (5) 51 (57) 10 (11) 5 (6) 84 (94) 20 (22) 18 (20) 0.69 0.90 0.99 0.98 0.83 0.86 0.46 0.75 0.91 0.91 0.77 0.88 2 (2) 37 (42) 17 (19) 25 (28) 8 (9) - 3 (4) 50 (64) 11 (14) 5 (6) 73 (94) 20 (26) 16 (21)

  24. Placebo Reload ARMYDA-Reload: Platelet aggregometry* Overall population P=0.01 240 215±65 211±66 220 Clopidogrel 600 mg 200 190±66 208±68 178±69 199±58 170±70 180 185±65 Platelet reaction units (PRU) 148±65 160 172±61 162±58 140 142±61 Placebo 120 100 Estimated Study PCI 2 hrs 8 hrs 24 hrs baseline ** Drug ** Using baseline TRAP channel * By VerifyNow TM

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