Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors? - PowerPoint PPT Presentation

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Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors?

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  1. Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors? Tony Gershlick Leicester UK AA 2006 Advisory Board :Speakers Bureau : Meeting sponsorships Eli Lilly :The Medicines Company: BMS : Sanofi No direct financial conflicts of interest

  2. Immediate MEDIUM LONG TERM Stable / ACS: Planned /unplanned, Lesion Diabetic/Elderly Safe & Effective Outcome

  3. Pre 1996 stent thrombosis rates 10 - 15% (50% death /AMI ) Since operators improved stents improved high pressure came and went Routine IVUS came and went antiplatelet therapy introduced routine stenting became “routine” now stent thrombosis rates <1-2%

  4. Activation of platelets : stenting v PTCA * 40 * * 30 * Stent 20 % of CD62 positive platelets PTCA 10 0 1 2 3 Day after intervention

  5. Clopidogrel + ASA 1.5 0.9 MACE in patients treated with antiplatelet v anti-coagulants 11 warfarin + ASA 12 Ticlopidine + ASA 8.6 8 6.2 5.7 5.6 4 2.7 1.6 0.5 0 ISAR FANTASTIC STARS MATTIS CLASSICS (n= 517) (n=485) (n=1653) (n=350) (n=1020) 1 Hall P. et al. Circulation. 1996;93:215-222. 2 Schömig A. et al. N Engl J Med. 1996; 334:1084-1089. 3 More R. et al. Lancet. 1997;349:146-147. 4 Urban P et al. Lancet. 1997; 340:146-147 Abstract.

  6. Abciximab in PTCA 16 15.9 p<0.001 p=0.008 p=0.012 12.8 14 11.7 12 11.3 10 8.3 % 8 Placebo 5.2 6 Abciximab 4 2099 2792 1265 2 0 EPIC EPILOG CAPTURE Death or non-fatal MI at 30 days

  7. Stable ACS BMS or DES Diabetics Stent thrombosis/ enzyme rise { bumps or micro-infarcts } Clopidogrel : Is it enough? Do we still need GP IIbIIIa? {Anti-thrombins?} When start How much Which patients How long What trying to prevent

  8. Effect of Timing of Loading Dose on MACE at 30d CREDO 300 mg Events (%) Clopidogrel pre Better No-pre Better N Clopidogrel pre* No-pre* 3 to <6 hrs 7.9 7.0 893 6 to 24 hr 5.8 9.4 851 RRR -13.4 P=NS RRR 38.6 P=0.05 Overall CREDO Results RRR 18.5 P=0.23 0.4 0.6 0.8 1.0 1.2 Hazard ratio (95% CI) UTVR= urgent target vessel revascularization * Plus ASA and other standard therapies Steinhubl S, et al. JAMA. 2002;288:2411-20

  9. Clopidogrel Loading Dose and Clinical Outcome N=255 300mg/600 mg 4-8 hours pre Patti Circulation 2005;111:2099-2106

  10. Clopidogrel Loading Kastrati et al Circulation 2004;110:1916-19

  11. PCI-CURE Overall Long-Term Results Composite of CV death or MI from randomization to end of follow-up 0.15 12.6% Placebo + ASA* 8.8% 0.10 Clopidogrel + ASA* Cumulative Hazard Rate 0.05 31% RRR P = 0.002N = 2658 0.0 0 100 200 300 400 Days of follow-up

  12. What about Drug-Eluting Stents? • Credo and PCI-CURE – Bare metal stents • Ravel – 8 weeks Ticlopidine or clopidogrel • Sirius – 3 months Clopidogrel • TAXUS– 6 months Clopidogrel • After complex PCI in addition to aspirin, clopidogrel 75 mg for at least 9 to 12 months” Clopidogrel in PCI • Loading dose of 600mg - > 6 hours pre • ACS Continue maintenance dose for 12 months • Top up to 600 mg ?? • BMS – 1 month

  13. Clopidogrel Resistance in AMI Matetzky et al. Circulaion 2004;109:3171-75

  14. Clopidogrel Response is Variable Lau et al. Circulation 2004;109:166-71

  15. Clopidogrel response is variable Contribution of Hepatic P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance Lau et al. Circulation 2004;109:166-71 In contrast, rifampin, a CYP3A4 inducer, increased clopidogrel efficacy.

  16. 35 29 30 25 20 15 8.7 10 5.5 3.5 3.2 2.6 5 1.3 0 Thrombosis Rates Accordingto Selected Patient Characteristics % Renal failure Bifurcations ULM Diabetes UA *Antiplatelet Therapy disc Prior Brachy * Premature discontinuation

  17. Outstanding Issues for Oral Antiplatelet Therapy Post PCI • How long to continue dual antiplatelet therapy post PCI with DES…….? > 12 months • Need to screen for Plavix resistance ? • Use increased maintenance doses of plavix in some cases ? • How can we maximise drug compliance ?

  18. Anfeathers.jpg “I don’t know about you, but I still take 75 mg Plavix daily whether I need it or not”

  19. ASA Resistance Important NOT ASA alone 3-6 /12 Never - NO MEDICATION – Dual till when ? AHG Website for Stent thrombosis

  20. Limitations of Clopidogrel • Variable response - Resistance • Time of onset of action • Irreversible Prasugrel (Lilly/Sankyo) Rapid onset Higher and more consistent level of platelet inhibition TRITON – TIMI 38 trial (Prasugrel vs Clopidogrel PCI in ACS) GP IIbIIIa Inhibitors

  21. GP IIb/IIIa improve outcome in PCI 16 15.9 p<0.001 p=0.008 p=0.012 12.8 14 11.7 12 11.3 10 8.3 % 8 Placebo 5.2 6 Abciximab 4 2 0 EPIC EPILOG CAPTURE 2099 2792 1265 Death or non-fatal MI at 30 days

  22. Event Rate [%] Event Rate [%] 15 15 P<0.05 P<0.001 Control n.s. P<0.05 Tirofiban RR 21% Heeschen et al., Lancet 1999 RR 19% 10 10 RR 67% Clopidogrel 5 5 CURE, ACC 2001 0 0 PRISM CURE PRISM CURE Positive Markers Negative Markers Across Study Comparism PRISM/CURE Clopidogrel is no alternative for the high risk ACS patient

  23. GP IIbIIIa in the era of Clopidogrel pre-treatment Are both necessary Is there sufficient effect with clopidogrel (upfront)

  24. Tc

  25. Stone, Circulation 2002;105:2347-54

  26. JACC 2004 Jan 21;43(2):162-8. Dalby et al , 48% inhibition Clopidogrel 80% GP IIbIIIa (p<0.0001)

  27. Clopidogrel is a potent anti-platelet agent Who doesn’t need GP IIbIIIa ?

  28. ISAR-REACTAbciximab in Low to Intermediate Risk PCI after Plavix loading Kastrati et al NEJM 2004;350:232-38.

  29. ISAR-REACT Safety P=0.37 P=0.38 P=0.002 P=0.007 % of patients Major TIMI bleed Minor TIMI bleed Thrombocytopenia Transfusions Kastrati A, et.al. NEJM 2004; 350 (3): 232-238.

  30. Diabetics 1 Year Mortality in Diabetics Following PCI with and without Abciximab Enhanced Survival Benefit of Abciximab in Diabetics EPIC, EPILOG, and EPISTENT - Meta-Analysis 6 Placebo n = 574 5 4.5 Abciximab n = 888 4  2.0% p = 0.031 Death (%) 3 2.5 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Days of Randomization JACC 2000; 35:922-28

  31. AMI *

  32. Who GP IIb/IIIa Inhibitors in setting of pre-PCI 600mg clopidogrel AMI as early as possible Inadequate stent deployment Evidence I.C thrombus COMPLEX PCI Clopidogrel resistance Diabetics ACS Stenting as perfect as possible reduces complications

  33. Ones to watch for at ACC ISAR-REACT 2Abciximab in High {ACS} Risk PCI after Clopidogrel loading Patients with ACS (Trop+ or ST-depression) undergoing PCI (STEMI excluded).Primary endpoint: composite of death, MI, urg. Revasc within 30 days.

  34. Patients ACS patients (N~13,800) with troponin or CPK-MB elevation or ECG changes or demographic and cardiac risk factors or history of documented coronary artery disease Aspirin, clopidogrel loading ASA + clopidogrel per local practice Main groups A: Enoxaparin B: Bivalirudin C: Bivalirudin Upstream GPIIB/IIIA Yes No Yes No No Angiography Diagnostic cath within 72 hours Definitive treatment PCI, surgical, or medical management Yes Yes Yes Yes No (bailout only) GPIIB/IIIA during PCI • Bleeding • Death/MI/Unplanned revascularization • Composite of the above 30 day endpoints ACUITY Design

  35. HORIZONS 3 400 STEMI ASA 300mg Clopidogrel 300-600mg UH Bivalirudin GP IIb/IIIa {bail-out IIbIIIa} Cath Lab TAXUS BMS CABG 3 : 1 [ 2250 : 750] 1,6 mo The independently adjudicated 30-day rates of     a. Primary - The composite of major adverse ischaemic events and major bleeding (net clinical benefit)     b. Major Secondary - Major adverse ischaemic events (death, reinfarction, stent thrombosis, disabling stroke or ischaemic target vessel revascularisation)     c. Major secondary - Major bleeding

  36. We understand better how best to administer APT –clopidogrel Concerns regarding Clopidogrel resistance BVR role unclear Prasugrel Until there is data definitively showing that standard treatment with Clopidogrel (600 mg 6 hours pre) in high risk /complex patients is equal to GP IIbIIIa IH and against a background of increased utility of Primary PCI Summary & Conclusions “Optimal Angioplasty Pharmacology in 2006 : is there a continuing need for GP IIbIIIa inhibitors?” “YES”

  37. Prasugrel Phase 3 Stent Trial Design Planned PCI for ACS Stratified Randomization: UA/NSTEMI vs STEMI Mod - Hi Risk UA/NSTEMI Antithrombin GP IIb/IIIaat MD discretion STEMI Clopidogrel Prasugrel 300 mg LD / 75 mg MD 60 mg LD/ 10 mg MD + ASA + ASA 20 EPs (30, 90 d): CVD/MI/CVA ; CVD/MI/uTVR Clopidogrel 75 mg/day + ASA Prasugrel 10 mg/day + ASA Last pt followed for 6 m (med =12m, max =15 m) 10 Endpoint(end of FU): CVD/MI/CVA 20 EP (end of FU): CVD/MI/CVA/Hosp for Rec Isch

  38. Clinical Outcomes, Comparison to CADILLAC * * 2 Strokes Post CABG

  39. 26 JUMBO -TIMI 26 Study Design Elective or Urgent PCI w stent ASA 325 mg 900patients Parallel Randomization Study Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIa Double-blind, Double Dummy Prasugrel Loading Dose 40 mg Maint. Dose 7.5 mg N=200 Prasugrel Loading Dose 60 mg Maint. Dose 10 mg N=200 Prasugrel Loading Dose 60 mg Maint. Dose 15 mg N=250 Clopidogrel Loading Dose 300 mg Maint. Dose 75 mg N=250 Maintenance Rx for 30 days 1o endpoint: Significant (non-CABG) bleeding through 30 d 2o endpoints: Major bleeding (non-CABG) through 30 d CV MACE through 30 d Component clinical endpoints

  40. 26 Clinical Target Vessel Thrombosis Target Vessel Revasc or Documented Total Occlusion RR=0.25 [0.1, 0.9] P = 0.03 P= NS Treatment Group Prasugrel LD/MD R/N 6/254 4/650 2/199 1/200 1/251

  41. 26 JUMBO -TIMI 26 Study Design Elective or Urgent PCI w stent ASA 325 mg 900patients Parallel Randomization Study Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIa Double-blind, Double Dummy Prasugrel Loading Dose 40 mg Maint. Dose 7.5 mg N=200 Prasugrel Loading Dose 60 mg Maint. Dose 10 mg N=200 Prasugrel Loading Dose 60 mg Maint. Dose 15 mg N=250 Clopidogrel Loading Dose 300 mg Maint. Dose 75 mg N=250 Maintenance Rx for 30 days 1o endpoint: Significant (non-CABG) bleeding through 30 d 2o endpoints: Major bleeding (non-CABG) through 30 d CV MACE through 30 d Component clinical endpoints

  42. 26 Clinical Target Vessel Thrombosis Target Vessel Revasc or Documented Total Occlusion RR=0.25 [0.1, 0.9] P = 0.03 P= NS Treatment Group Prasugrel LD/MD R/N 6/254 4/650 2/199 1/200 1/251

  43. How important are the enzyme leaks ? + ? represent micro infarcts unimportant < x3 adverse prognosis markers only any rise is dangerous small percent avoid at all cost surgeons are worse unpredictable interventionist knows immediacy not good select patients (?) ‘everyone’ should have GP IIb/IIIa RB only a (small) percent patients