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ACC 2008 – Disclosure Slide

This study investigates the influence of a 600 mg clopidogrel reload on the outcome of percutaneous coronary intervention (PCI) in patients with chronic clopidogrel therapy. The study aims to evaluate the safety and effectiveness of the reload strategy, as well as compare outcomes in patients with acute coronary syndrome (ACS) and stable angina.

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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 600 mg 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 in patients pretreated (mean 6 hrs) with 600 mg clopidogrel loading , vs a 300 mg dose • 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 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 Angiography PCI Reload N=89 - NSTE ACS or - Stable angina NSTE ACS N=167 Placebo ‡ N=283 CABG (N=57) PCI Placebo N=78 1st blood sample 2nd, 3rd and 4th blood samples Baseline At the time of PCI 2 hrs after PCI 8 and 24 hrs after PCI • Creatine kinase-MB • Troponin-I • PRU • PRU • PRU • Creatine kinase-MB • Troponin-I • PRU ‡ On top of chronic therapy

  6. STUDY ENDPOINTS • Primary endpoint • 30-day incidence of death, MI, TVR • (MI definition: post-procedural increase of CK-MB >3 times above UNL in patients with normal baseline levels of creatine kinase-MB) • Secondary endpoints • Post-procedural increase of markers of myocardial injury above UNL (CK-MB, troponin I, myoglobin) • Occurrence of any vascular/bleeding complications • “Point of care” evaluation of platelet reactivity at different time points in the two arms

  7. ARMYDA-RELOAD Inclusion criteria Pts on chronic therapy with clopidogrel (> 10 days) with stable angina or non-STE ACS undergoing PCI(22% of PCI patient population in the recruiting centers)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 sex (%) 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 sex (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Troponin +ve (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%)

  10. ARMYDA–RELOAD Trial Procedural features Stable population N=269 600 mg Clopidogrel reload N=130 Placebo N=139 P Vessel 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)

  11. ARMYDA–RELOAD Trial Procedural features ACS population N=167 600 mg Clopidogrel reload N=89 Placebo N=78 P Vessel 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)

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

  13. 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

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

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

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

  17. ARMYDA-RELOAD Secondary endpoint Any 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

  18. ARMYDA-RELOAD Trial Secondary endpoint: Bleeding rates in the overall population 5 5 % 0 0 Placebo 600 mg Clopidogrel reload

  19. 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

  20. 20 16 P=0.035 (ACS Placebo vs ACS Reload) Death/MI/Repeat revascularization (%) 12 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

  21. 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

  22. 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±59 215±69 200 200 184±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

  23. 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 reload strategy can significantly improve outcome • Point of care aggregometry testing shows differences in platelet reactivity consistent with clopidogrel status and clinical syndrome • No major bleeding, and no increased bleeding risk are observed in the “reload” approach in either stable or ACS patients • Given the growing number of patients on clopidogrel undergoing PCI, those results may influence practice patterns in interventional pharmacology

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