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* 1 Division of Cardiology, Fukuoka Tokushukai Hospital, JAPAN

Clinical Outcomes Following Coronary Stenting in Japanese Patients with and without Proton Pump Inhibitor. ~One of the KICS trials~.

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* 1 Division of Cardiology, Fukuoka Tokushukai Hospital, JAPAN

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  1. Clinical Outcomes Following Coronary Stenting in Japanese Patients with and without Proton Pump Inhibitor ~One of the KICS trials~ Hideki Shimomura, MD*1; Seiji Hokimoto, MD*2; Shuichi Oshima, MD*3; Koichi Nakao, MD*4; Yuji Miyao, MD*5; Kazuko Nakagawa, MD*6; Hisao Ogawa, MD*2; for the Kumamoto Intervention Conference Study (KICS) investigators *1Division of Cardiology, Fukuoka Tokushukai Hospital, JAPAN *2Department of Cardiovascular Medicine, Kumamoto University, JAPAN *3Division of Cardiology, Kumamoto Central Hospital, JAPAN, *4Cardiovascular Center, Kumamoto Saiseikai Hospital, JAPAN *5National Hospital Organization Kumamoto Medical Center, JAPAN *6Division of Pharmacology and Therapeutics, Kumamoto University, JAPAN

  2. Background 1 1)AHA, ACC, ACG recommended in 2008 conference that PPI should be used in patients with dual antiplatelet therapy for prophylaxis of gastrointestinal bleeding. Need for Antiplatelet Therapy Assess GI Risk Factors History of Ulcer complication History of Ulcer Disease(non-bleeding) GI Bleeding Dual Antiplatelet Therapy Concomitant Anticoagulant Therapy Yes Test for H.pylori and treat if infected Yes No PPI More Than One Risk Factor: Age 60 years or More Corticosteroid Use Dyspepsia or GERD Symptoms Bhatt DL, et al. J Am Coll Cardiol 2008;52:1502-17 Bhatt DL, et al. Circulation 2008;118:1894-909 Bhatt DL, et al. Am J Gastroenterol 2008;103:2890-90 PPI

  3. Background 2 2)Several studies have indicated that concomitant use of clopidogrel and PPI is associated with reduced antiplatelet efficacy of clopidogrel, and increased adverse clinical outcomes after stent placement in patients with acute coronary syndrome (ACS). A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. Juurlink DN, et al. CMAJ 2009;180:713-8 Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome Ho PM, et al. JAMA 2009:301;937-44

  4. Background 3 3)However, recent studies show that concomitant use of clopidogrel and PPI was not related with the increased risk of clinical outcomes after coronary stenting. 4)Moreover, drug interaction between PPI and clopidogrel may be related with CYP2C19 gene polymorphism. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. O’Donoghue ML, et al. Lancet 2009; 6736:61525-7 Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Sibbing D, et al. Thromb Haemost 2009;101:714-9

  5. Purpose To examine the association between PPI use, measures of platelet aggregation, CYP2C19 polymorphism, and clinical outcomes in Japanese patients treated with coronary stenting

  6. Methods Subjects 1074 individuals undergoing PCI from April 2007 to March 2009 Male 810 (75%) Age 69 years (33 - 93) 2 groups aspirin 100mg+thienopyridine agent 1)PPI (clopidogrel 75mg or ticlopidine 200mg daily) 2)no-PPI Use of PPI was left to the discretion of the attending physician Follow up period 12 months Primary endpoint Cardiovascular death Myocardial infarction Stroke Measurement in some patients (Data in Kumamoto University) Platelet aggregation induced by 20μM adenosine diphosphate (ADP) CYP2C19 polymorphism +

  7. Measurement of platelet aggregation Light transmission aggregometer Optical density method Platelet aggregation MCM Hema Tracer 313 % (PAM12C, LMS Inc, Japan) Area=value time 10 min

  8. Table 1 Baseline characteristics of patients PPI (+) (-) p Number 454(42) 620(58) Male 337(74) 473(76) n.s Age (years) 70.1 68.9 n.s BMI(kg/m2) 23.6 24.1 n.s Current smoker 122(27) 158(25) n.s Hypertension 334(74) 484(78) n.s Dyslipidemia 254(56) 372(60) n.s Diabetets 165(36) 262(42) n.s Previous MI 82(18) 165(27) n.s Previous CABG 18(4) 55(9) n.s PAD 39(9) 54(9) n.s Renal dysfunction 64(14) 107(17) n.s Thienopyridine derivative Ticlopidine 218(48) 268(43) n.s Clopidogrel 236(52) 352(57) n.s Statin 302(67) 449(72) n.s Beta-blocker 146(32) 324(52) n.s BMI, body mass index; MI, myocardial infarction; CABG, coronary artery bypass graft surgery; PAD, peripheral arterial disease

  9. Fig. 1 Comparison of platelet aggregation between patients with or without PPI n.s AU*min 6000 Platelet aggregation 4000 2000 No-PPI PPI n=150

  10. Table 2 Clinical outcomes PPI (+) (-) p Number 454(42) 620(58) Primary endpoint 18(4.0) 22(3.5) n.s CV death 3(0.7) 9(1.5) n.s MI 5(1.1) 9(1.5) n.s Stroke 10(2.2) 4(0.6) n.s Non-CV death 6(1.3) 14(2.3) n.s All-cause death 9(2.0) 23(3.7) n.s Stent thromobosis 2(0.4) 4(0.6) n.s rePCI 93(20.5) 101(16.3) n.s CABG 7(1.5) 7(1.1) n.s GI bleeding 0 7(1.1) n.s CV, cardiovascular; MI, myocardial infarction PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; GI, gastrointestinal

  11. Table 3 Primary endpoint and GI bleeding according to thienopyridine Ticlopidine Clopidogrel p Number 486(45%) 588(55%) Primary endpoint 22(4.5) 18(3.1) n.s CV death 7(1.4) 5(0.9) n.s MI 7(1.4) 7(1.2) n.s Stroke 8(1.6) 6(1.0) n.s GI bleeding 1(0.2) 6(1.0) n.s CV, cardiovascular; MI, myocardial infarction; GI, gastrointestinal

  12. Fig. 2 Distribution of CYP2C19 genotype (right) and phenotype (left) in patients undergoing coronary intervention n=121 EM, extensive metabolizer (*1/*1) IM, intermediate metabolize (*1/*2, *1/*3) PM, poor metabolizer (*2/*2, *2/*3, *3/*3)

  13. AU*min EM IM Fig.3 Comparison of residual platelet aggregation according to CYP2C19 genotype during dual antiplatelet therapy p<0.05 8000 p<0.05 6000 Platelet aggregation 4000 2000 n=121 PM (*1/*1) (*2/*2, *2/*3, *3/*3) (*1/*2, *1/*3)

  14. Summary 1 The ratio of clopidogrel use following PCI was very different from that of Western countries due to delay of adoption or permission of medical insurance system. Residual platelet aggregation was higher in PPI group than in no-PPI group, although statistically not significant. There was no association between PPI use and risk of cardiovascular clinical outcomes. Gastrointestinal bleeding was not seen in PPI group.

  15. Summary 2 5. CYP2C19 polymorphism is involved with metabolism of both PPI and thienopyridine agent, and there was a huge gap in the distribution of CYP2C19 genotype between Japanese and Caucasian. 6. Residual platelet aggregation during dual antiplatelet therapy was lower in extensive metabolizers (EM) than in intermediate (IM) and poor metabolizers (PM). 7. Irrespective of PPI use, there was no difference in residual platelet aggregation in each CYP2C19 genotype (Data not shown).

  16. Conclusions Concomitant use of PPI and thienopyridine derivative (clopidogrel or ticlopidine) has no impact on cardiovascular events.

  17. Presenter Disclosure Information < Hideki Shimomura, Seiji Hokimoto, Hisao Ogawa > Title Clinical Outcomes Following Coronary Stenting in Japanese Patients with and without Proton Pump Inhibitor DISCLOSURE INFORMATION There are no financial or other relations that could lead to a conflict of interest.

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