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Stent Thrombosis Response to Antiplatelet Therapy

Stent Thrombosis Response to Antiplatelet Therapy. Keith G Oldroyd Department of Cardiology Western Infirmary Glasgow. Cangrelor – baseline (PRP). Cangrelor - 30 mins (PRP). Cangrelor - 30 mins post infusion (PRP). Variability in Response to Aspirin. 326 patients on ASA 325mg daily

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Stent Thrombosis Response to Antiplatelet Therapy

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  1. Stent ThrombosisResponse to Antiplatelet Therapy Keith G Oldroyd Department of Cardiology Western Infirmary Glasgow

  2. Cangrelor – baseline (PRP)

  3. Cangrelor - 30 mins (PRP)

  4. Cangrelor - 30 mins post infusion (PRP)

  5. Variability in Response to Aspirin • 326 patients on ASA 325mg daily • ASA resistance: Persistent aggregation in response to AA of  20% AND aggregation in response to ADP  70%. Gum et al. JACC 2003; 41: 961-65

  6. Variability in Response to AspirinHOPE sub-study; 976 patients on ASA 75-325mg Ekelboom et al. Circ 2002; 105: 1650-55.

  7. Variability in Response to Aspirin(Accumetrics – AA)

  8. Variability in Response to Aspirin(Accumetrics - CPG) CK-MB and TnI elevation in ASA-resistant (19.2%, black) and ASA-sensitive (white) patients after elective PCI. Chen et al. JACC 2004; 43(6): 1122-1126.

  9. ACS post ASA withdrawalFerrari et al. JACC 2005; 45: 456-9 (Pasteur Hospital, Nice, France) *: Mean delay from ASA withdrawal – 10 (1.9) days Mean time since implant – 15.6 (6.5) months

  10. Variability in Response to Clopidogrel Gurbel et al. JACC 2005; 45: 1392-6. (Optical aggregometry, Chronolog; n = 190)

  11. Variability in Response to Clopidogrel

  12. Quartiles by degree of inhibition of platelet aggregation on clopidogrel.(a) changes in ADP-induced aggregation as % of baseline(b) % reduction in aggregate size at day 6 compared with baseline(c) incidence of recurrent MACE during 6-month follow-up Matetzky: Circulation, Volume 109(25).June 29, 2004.3171-3175 Variability in Response to Clopidogrel Primary PCI for STEMI

  13. CRESTClopidogrel Effect on Platelet Reactivity in Patients with Stent Thrombosis • 20 patients with bare metal stent thrombosis • 100 controls • (A) 5 μmol ADP-induced platelet aggregation • Dashed line = 75th %ile in non-SAT group. • (B) 20 μmol ADP-induced platelet aggregation • Dashed line = 75th %ile in non-SAT group Gurbel et al. JACC 2005; 46: 1827-32.

  14. Bare Metal Stent Thrombosis (Berne) • Nov 95 – Mar 03 • n = 6058 • Angiographically confirmed stent thrombosis • 95 (1.6%) • 71 (75%) early (0-30 days) • 24 (25%) late (> 30 days) • 70 (74%) initially underwent PCI for ACS • 22/95 had discontinued thienopyridine • 5/95 had discontinued both APT

  15. Bare Metal Stent Thrombosis (Berne)

  16. Bare Metal Stent Thrombosis (Berne) • 95 patients with ST • 12 (13%) died • 60 (63%) refused or had C/I • 23 (24%) agreed • Control group • 50 patients stented + dual APT for 1-12/12 • Reference group • 9 healthy volunteers • Top: 5 μmol ADP • Middle: 20 μmol ADP • Bottom: 0.5 mg/ml AA on ASA • Black = ASA 100 mg qid • White = ASA + clop 75 mg qid JACC 2005; 45(11): 1748-1752

  17. Bare Metal Stent Thrombosis (Berne) • ASA Resistance • ≥ 20% platelet aggregation in response to AA 0.5 mg/ml • Clopidogrel resistance • relative change between aggregation on ASA and ASA + clopidogrel in response to 5 μM ADP of < 10%. • JACC 2005; 45(11): 1748-1752

  18. Conclusions • Most methods of testing show that the pharmacological response to both ASA and clopidogrel is highly variable • Dichotomous definitions of “resistance” make no biological sense and are unhelpful • There is some retrospective observational data which suggests that a sub-optimal response to antiplatelet therapy may be a risk factor for stent thrombosis and other MACE • There are a variety of laboratory based and POC tests of platelet function which could be used in a large prospective study to test this hypothesis

  19. Logical Reasoning • There is a very small excess incidence of very late stent thrombosis with DES • Some of these events are temporally related to discontinuation of dual APT • There are major downsides to lifelong dual APT • At the point of going from dual APT to a single drug there would be value in knowing the relative efficacy of each agent in each patient“Doctor, when will it be safe to stop my Plavix?”

  20. Variability in Response to ClopidogrelWhat to do? • Give more • Wait longer • Repeat loading dose • Measure effect • Triple antiplatelet therapy • New thienopyridine P2Y12 antagonists

  21. Variability in Response to Clopidogrel VASP-Phosphorylation in response to PGE and PGE + ADP with different concentrations of AR-C69931MX on board (competitive P2Y12 antagonist) More inhibition = less VASP-Phosphorylation in response to ADP. Aleil B et al. J Thromb Haemostasis 2005; 3: 85–92.

  22. Variability in Response to Clopidogrel Aleil B et al. J Thromb Haemostasis 2005; 3: 85–92.

  23. Variability in Response to Clopidogrel Serebruany V et al. JACC 2005; 45: 246–51. Optical aggregometry; Chronolog. n=544 (405 PCI, 94 IHD, 25 CHF, 20 post-CVA) Majority on ASA 325mg/day.

  24. Variability in Response to Aspirin Platelet activation after TIA/stroke on ASA 75mg. PFA100 vs VerifyNow ASA (CPG) vs AA 1mg/ml Harrison P et al. Stroke 2005; 36:1001-1005. (Oxford Group)

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