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 Clinical Outcomes Following Coronary Stenting in Japanese Patients with and without Proton Pump Inhibitor * 1 Division of Cardiology, Fukuoka Tokushukai Hospital, JAPAN * 2 Department of Cardiovascular Medicine, Kumamoto University, JAPAN * 3 Division of Cardiology, Kumamoto Central Hospital, JAPAN, * 4 Cardiovascular Center, Kumamoto Saiseikai Hospital, JAPAN * 5 National Hospital Organization Kumamoto Medical Center, JAPAN * 6 Division of Pharmacology and Therapeutics, Kumamoto University, JAPAN ~One of the KICS trials~

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. Bhatt DL, et al. J Am Coll Cardiol 2008;52: Bhatt DL, et al. Circulation 2008;118: Bhatt DL, et al. Am J Gastroenterol 2008;103: 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 Test for H.pylori and treat if infected PPI More Than One Risk Factor: Age 60 years or More Corticosteroid Use Dyspepsia or GERD Symptoms Yes No

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

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: Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Sibbing D, et al. Thromb Haemost 2009;101:714-9

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

Methods Subjects 1074 individuals undergoing PCI from April 2007 to March 2009 Male810 (75%) Age69 years ( ) 2 groups aspirin 100mg+thienopyridine agent1)PPI (clopidogrel 75mg or ticlopidine 200mg daily)2)no-PPI Use of PPI was left to the discretion of the attending physician Follow up period12 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 +

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

Table 1 Baseline characteristics of patients (+)(-)p Number454(42)620(58) Male337(74)473(76)n.s Age (years) n.s BMI(kg/m 2 ) n.s Current smoker122(27)158(25) n.s Hypertension334(74)484(78) n.s Dyslipidemia254(56)372(60) n.s Diabetets165(36)262(42) n.s Previous MI82(18)165(27)n.s Previous CABG18(4)55(9)n.s PAD39(9)54(9)n.s Renal dysfunction64(14)107(17)n.s Thienopyridine derivative Ticlopidine218(48)268(43)n.s Clopidogrel236(52)352(57)n.s Statin302(67)449(72)n.s Beta-blocker146(32)324(52)n.s PPI BMI, body mass index; MI, myocardial infarction; CABG, coronary artery bypass graft surgery; PAD, peripheral arterial disease

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

Table 2 Clinical outcomes (+)(-)p Number454(42)620(58) Primary endpoint18(4.0)22(3.5)n.s CV death3(0.7)9(1.5)n.s MI 5(1.1)9(1.5)n.s Stroke10(2.2)4(0.6)n.s Non-CV death6(1.3)14(2.3)n.s All-cause death9(2.0)23(3.7)n.s Stent thromobosis2(0.4)4(0.6)n.s rePCI93(20.5)101(16.3)n.s CABG7(1.5)7(1.1)n.s GI bleeding07(1.1)n.s CV, cardiovascular; MI, myocardial infarction PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; GI, gastrointestinal PPI

Table 3 Primary endpoint and GI bleeding according to thienopyridine TiclopidineClopidogrelp Number486(45%)588(55%) Primary endpoint22(4.5)18(3.1)n.s CV death7(1.4)5(0.9)n.s MI 7(1.4)7(1.2)n.s Stroke8(1.6)6(1.0)n.s GI bleeding1(0.2)6(1.0)n.s CV, cardiovascular; MI, myocardial infarction; GI, gastrointestinal

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

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

Summary 1 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. 2.Residual platelet aggregation was higher in PPI group than in no-PPI group, although statistically not significant. 3.There was no association between PPI use and risk of cardiovascular clinical outcomes. 4.Gastrointestinal bleeding was not seen in PPI group.

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).

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

Clinical Outcomes Following Coronary Stenting in Japanese Patients with and without Proton Pump Inhibitor Presenter Disclosure Information DISCLOSURE INFORMATION There are no financial or other relations that could lead to a conflict of interest. Title