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1 w wz 15«1y Kor. J. Clin. Pharm., Vol. 15, No $MPQJEPHSFM y x y z e w ½ Á w w w w p q ƒ Effects of Drug Interaction with Clopidogrel on Cardiovascular Events and Side Effects Sung Hee KimG and Sukhyang Lee Graduate School of Clinical Pharmacy, Sookmyung Women s University, Seoul, Korea Clopidogrel is used to reduce the risk of cardiovascular events in patients with atherosclerosis documented by recent ischemic stroke, recent myocardial infarction (MI), or established peripheral arterial disease (secondary prevention). Clopidogrel is metabolized by CYP3A4, and the active metabolites inhibit platelet aggregation. The purpose of this study was to assess clopidogrel only versus clopidogrel + others (aspirin, CYP3A4 inhibitor, and CYP3A4 inducer) in terms of cardiovasculalr events and bleeding complications. We reviewed the charts of patients who visited between August 1, 2002 and August 31, 2003, retrospectively. Total 72 patients were included and they consisted of 5 groups; clopidogrel group (n=36), clopidogrel + aspirin group (n=11), clopidogrel + CYP3A4 inhibitor group (n=15), clopidogrel + aspirin + CYP3A4 inhibitor group (n=6), clopidogrel + CYP3A4 inducer group (n=4). The primary endpoints at 6 months, 12 months were the composite of cardiovascular (CV) events. The secondary endpoint was the incidence of bleeding events at 6months, and 12months. At 12months, the primary endpoint was not significantly different among the five groups (p=0.056). In comparison of two groups as clopidogrel only versus clopidogrel + others (aspirin, CYP3A4 inhibitor, and CYP3A4 inducer), the primary endpoint was significantly different (p=0.02). The CV events were increased in the clopidogrel + others group. The secondary end point was not significantly different among the five groups (p=0.52). However, time to bleeding events was in the clopidogrel group and 74.7 in the clopidogrel + others group (p = 0.046). In conclusion, clopidogrel interaction with aspirin, CYP3A4 inhibitor, and CYP3A4 inducer affected cardiovascular events and bleeding events. Drug interaction of clopidogrel with concurrent medications should be considered cautiously. Key words TG clopidogrel, cardiovascular events, bleeding events Clopidogrel MI(Myocardial infarction), ischemic stroke xw y y ù cardiovascular events (fatal or non-fatal ischemic stroke, myocardial infarction, other vascular deaths) w 2 š. 1,2,3) Clopidogrel thienopyridine ticlopidine w x q w. Clopidogrel y y x q w ùkü. y ADP ƒ w w platelet fibrinigen receptor(gp II b /III a ) y w. Correspondence to : w Pharm. D. w w w p q 2ƒ ( ) Tel: , Fax: slee@sdic.sookmyung.ac.kr 4,5,6) clopidogrel ticlopidine w wš ƒ w x q z w. w clopidogrel 300mg w (loading dose) n x w x x ƒ j. 3) CAPRIE clopidogrel aspirin cardiovascular events x z g. Clopidogrel 2) aspirin cardiovascular events 8.7% j x w. w n cardiovascular events z ƒ ƒ w. Aspirin cycloxygenase ww x q w, clopidogrel ADP» mw x q w wx q ƒ z ùkü. 7) PCI-CURE unstable angina non-q-wave MI y w aspirin aspirin clopidogrel w z w. Aspirin 1

2 2 Kor. J. Clin. Pharm., Vol. 15, No. 1, 2005 clopidogrel n stroke w x 1.5% w ù x aspirin n w. 8,9) Clopidogrel ticlopidine w x q z ƒ, onset time. 3,10) Clopidogrel aspirin w, ù aspirin ùkù, x aspirin ƒ. Clopidogrel n x q ùkù» ticlopidine x l «w. 11) w ticlopidine thrombotic thrombocytopenic purpura (TTP) w, clopidogrel šƒ š» w ticlopidine clopidogrel wš. 12,13) t clopidogrel atorvastatin w x q šƒ. 14,15,16,17) Clopidogrel CYP3A4 w 18), CYP3A4 w atorvastatin w clopidogrel x q w š w. w clopidogrel atorvastatin w x q z ƒ š, clopidogrel CYP3A4 n clopidogrel z cardiovascular events e w ù x w šƒ. clopidogrel CYP3A4 y aspirin n cardiovascular events bleeding e z š w. 1 ƒ cardiovascular events wš w, 2 ƒ clopidogrel ƒ j x, x wš w. clopidogrel n k n w cardiovascular events bleeding events wš w l ¾ w clopidogrel 75mg w y y,» mw zw w. Clopidogrel n, aspirin, CYP 3A4 inhibitor, CYP3A4 inhibior + aspirin, CYP3A4 inducer n ƒƒ Group I, II, III, IV, V w. 1) sw» 18 clopidogrel n y 1 ƒ w y w. 2)» 18 w, aspirin, clopidogrel wx q wx š ƒ w y w. x x q (< 150,000/mm 3 ) y ù w y(alt, AST > normal upper limit 3 ) y(serum creatinine > 2 mg/dl) y w. w clopidogrel l y x x y w. sƒü clopidogrel y,» w clopidogrel, clopidogrel + aspirin, clopidogrel + CYP3A4 inhibitor, clopidogrel + CYP3A4 inhibitor + aspirin, clopidogrel + CYP3A4 inducer (Group I, II, III, IV, V) ù š ƒ y» p w» w w w., y» p w» w ƒ y,» wš, œ y v x (Percutaneous Transluminal Coronary Angioplasty, w PTCA) x w., cardiovascular eventsƒ 6, 12 cardiovascular events, w sƒ w. cardiovascular events, x, (Q - wave non Q - wave),, x (revascularization) sww. x» chest pain(+), angina(+)» w š, creatine kinase(ck), CK-MB, LDH, AST ƒ we 2 ƒw w š, x 2,14) ù w w. x (revascularization) lp z CABG(Coronary Artery Bypass Grafting)ù PTCA(Percutaneous Transluminal Coronary Angioplasty) w. lp x (restenosis) lp wš 6 ù z wy y lp w ü 50% w. 2,3), x sƒw» w x w hemoglobin(hb), hematocrit(hct), platelet(plt), hematuria PT, aptt, INR clopidogrel 6 z, 12 z e w. x w x major bleeding minor bleeding w. Major bleeding ü x(intracranial hemorrhage), x w x, ü x, y x, x q (<100,000/mm 3 ), n x, hemoglobin eƒ baseline w 3g/dl ƒ, x

3 Clopidogrel y x y z e w 3 3 unit,» x < 90mmHg, w x ƒ 2 w w. Minor bleeding x, x, ü x major bleeding x w. 8, 9 ƒ y p t-test, ANOVA chi-square test w. ƒ cardiovascular events x y ùküš chi-square test w. m SPSS (version 11.5) t test ANOVA w š, p-value 0.05 w m w l ¾ clopidogrel 75mg w y ƒ w y 72 clopidogrel n 36, k n w 36. k clopidogrel n 36 aspirin (Group II) 11, CYP3A4 inhibitor (Group III) 15, CYP3A4 inhibitor + aspirin (Group IV) 6, CYP3A4 inducer (Group V) 4. CYP3A4 inhibitor bromocriptine, atorvastatin, paroxetine, cimetidine, verapamil, sertraline, diazepam n w š, CYP3A4 inducer primidone, carbamazepine n w. y p y» p ƒ y ù,, PT, aptt, INR, Hb, Plt, Hct» p w ƒ. Group I s³ 62.6±1.6 ƒ û š, 60. (Female/ Male-%) û, Group III û. PT, aptt, INR, Hb, Plt, Hct ù e ü m w. w, PTCA, œ y ƒ ƒ (Table 1). $BSEJPWBTDVMBS $7FWFOUT CV events clopidogrel n (Group I) clopidogrel k n (Group II, III, IV, V) ù r. Clopidogrel n 8 (22%), clopidogrel k n 17 (47%) CV eventsƒ w (p=0.02). Clopidogrel n, clopidogrel k n Table 1. Baseline characteristics of patients characteristics Group I Group II Group III Group IV Group V (n = 36) (n = 11) (n = 15) (n = 6) (n = 4) P value Age yr 62.6 ± ± ± ± ± Sex (F/M) - % 38.8/ / / / / PT - sec 14.2 ± ± ± ± ± aptt - sec 36.4 ± ± ± ± ± INR 1.09 ± ± ± ± ± Hb 13.4 ± ± ± ± ± Plt 232 ± ± ± ± ± Hct 39.8 ± ± ± ± ± Prior infarction - No. (%) 29 (80.6) 10 (90.9) 12 (80) 6 (100) 2 (50) 0.31 Prior PTCA - No. (%) 7 (19.4) 5 (45.5) 1 (6.7) 2 (33.3) 0 (0) 0.11 œ y - No Coronary Heart - Disease Congestive Heart - Failure Atrial fibrillation Hypertension Diabetes Hyperlipidemia *group I = clopidogrel group II = clopidogrel + aspirin group III = clopidogrel + CYP3A4 inhibitor group IV = clopidogrel + CYP3A4 inhibitor + aspirin group V = clopidogrel + CYP3A4 inducer

4 4 Kor. J. Clin. Pharm., Vol. 15, No. 1, 2005 ƒƒ stroke(4, 6 ), Congestive heart failure (CHF) (1, 2 ), restenosis(3, 3 ) w š, k n unstable angina 2, cerebral infarction 4 w. Myocardial infarction (MI) ùkù.(table 2, Fig. 1) Clopidogrel n Group I, II, III, IV, V w, CV events w. Clopidogrel (Group I) 8 (22%), aspirin (Group II) 5 (45%), CYP3A4 inhibitor (Group III) 9 (60%), aspirin + CYP3A4 inhibitor (Group IV) 3 (50%) w š, CYP3A4 inducer (Group V) CV eventsƒ w.(p=0.056)(table 2, Fig. 2) CV eventsƒ clopidogrel n s³ 122.8±74, clopidogrel k n 144.5±99 ùkûš, clopidogrel n, k n clopidogrel n 16 CV eventsƒ w. CV events ù r. Group I ƒƒ (4, 4 ), Group II (2, 3 ), Group III (6, 3 ), Group IV (1, 2 ) ùkûš, Group V ùkù. CV events p=0.68 m w (Table 3). #MFFEJOHFWFOUT Bleeding event clopidogrel n (Group I) clopidogrel k n (Group II, III, IV, V) ù r. Clopidogrel Fig. 1. Cardiovascular event of clopidogrel treatment: stroke, CHD, MI, restenosis. n 15 (41%), clopidogrel k n 19 (52%) bleeding eventsƒ w (p=0.34). Minor bleeding ƒƒ(7,12 ), major bleeding (8, 7 ) w.(table 4, Fig. 4) Clopidogrel n Group I, II, III, IV, V w bleeding events w. Group I 15 (41%), Group II 5 (45%), Group III 9 (60%), Group IV 2 (33%), Group V 3 (75%) bleeding eventsƒ w (p=0.45) (Table 4, Fig. 3). Table 2. Cardiovascular events at 12months of clopidogrel treatment stroke CHD restenosis CHF total Clopidogrel only Group I Clopidogrel + others Group II Group III Group IV Group V Total *Group I / II / III / IV / V p=0.056 *Clopidogrel / clopidogrel+others p=0.02 * *CHD = coronary heart disease *group I = clopidogrel *group II = clopidogrel + aspirin *group III = clopidogrel + CYP3A4 inhibitor group IV = clopidogrel +CYP3A4 inhibitor + aspirin *group V = clopidogrel + CYP3A4 inducer Fig. 2. Cardiovascular events of each group with clopidogrel treatment : stroke, CHD, MI, restenosis.

5 Clopidogrel y x y z e w 5 Table 3. Site of cardiovascular events at 12months of clopidogrel treatment Brain Heart Total Group I Group II Group III Group IV Group V Total *group I = clopidogrel group II = clopidogrel + aspirin group III = clopidogrel + CYP3A4 inhibitor group IV = clopidogrel + CYP3A4 inhibitor + aspirin group V = clopidogrel + CYP3A4 inducer Table 4. Bleeding events at 12months of clopidogrel treatment Minor bleeding Major bleeding total Clopidogrel only Group I Fig. 3. Bleeding events of each group with clopidogrel treatment. Clopidogrel + others Group II Group III Group IV Group V Total *group I = clopidogrel group II = clopidogrel + aspirin group III = clopidogrel + CYP3A4 inhibitor group IV = clopidogrel + CYP3A4 inhibitor + aspirin group V = clopidogrel + CYP3A4 inducer ƒ minor bleeding, major bleeding Group I (7, 8 ), Group II(2, 3 ), Group III(7, 2 ), Group IV(2, 0 ), Group V(1, 2 ) w (Table 4). Minor bleeding x, x š, major bleeding GI bleeding, ICH(Intracranial hemorrhage)ƒ. Bleeding eventsƒ clopidogrel n s³ 230.8±120 ùkûš, clopidogrel k n 74.7±95 ùkû m w ùkþ (p=0.046). Clopidogrel n 14 bleeding ùkû, clopidogrel k n 10 bleeding ùkû. Bleeding event x w Hb, Hct, aptt, PT, INR, Plt y 6, 12 w. Hgb clopidogrel n clopidogrel k n 6 (0.14 g/dl, 0.48 g/dl) w š, 12 n base-line ƒ w ù clopidogrel k n 2.15 g/dl Fig. 4. Bleeding events of clopidogrel treatment. e(13-17 g/dl) û ùkû. Hct clopidogrel n k n 6 (0.6%, 3.34%) w š, 12 n base-line ƒ w ù k n 5.74% e (39-52%) û ù kû (Fig. 5). aptt clopidogrel n k n 6 (4.36sec, 8.56sec) ƒw š, 12 n base-line w ù k n 8.35sec ƒ w (Fig. 6). PT clopidogrel n 6, 12 base-line w ù k n sec, sec ƒw e(11-15 sec) ùkû (Fig. 7). INR clopidogrel n 6, 12

6 6 Kor. J. Clin. Pharm., Vol. 15, No. 1, 2005 Fig. 5. Hematocrit(Hct) of clopidogrel treatment. Fig. 8. Platelet of clopidogrel treatment. Fig. 6. aptt of clopidogrel treatment. Fig. 7. INR of clopidogrel treatment. base-line w ù, k n , ƒ w ù ( )ü. Plt clopidogrel n, k n 6 ( /µl, /µl) ƒ 3 w š, 12 ( /µl, /µl) ƒw ù ( /µl) 3 yw (Fig. 8). š y y» wx q lp x ù x w» w v w ACCP (American college of Chest Physicians) IV e w lp z wx aspirin mg ticlopidine w 500mg n z 250 mg 1 2z n w ù clopidogrel w 300mg n z 75 mg n w wš. 19) Ticlopidine w, x q, l w «šwš» ticlopidine w w w t š clopidogrel ƒw š. 3) Clopidogrel ticlopidine w CLASSICS 3), Pache ƒ w 20) clopidogrel ticlopidine w z š w. Clopidogrel aspirin w PCI-CURE 8) CAPRIE ƒ 2). PCI-CURE unstable angina y ù non-q-wave MI y ww aspirin clopidogrel z w š, clopidogrel w y w. aspirin n sww» CAPRIE w. CAPRIE clopidogrel aspirin n CV events z ƒ w, clopidogrel n (Group I) clopidogrel + aspirin n (Group II) w ƒ ù. Group I 36 8 (22.2%) CV

7 Clopidogrel y x y z e w 7 eventsƒ w ù Group II 11 5 (45.4%) w clopidogrel aspirin n CV events w ùkù. ù Group I II Group III IV w, clopidogrel aspirin n CV events û ùkû. Group IV 6 3 (50%) CV events ƒ Group III 15 9 (60%) CV events û ùkû. ƒ Group III IV aspirin clopidogrel n ƒ CV events û CAPRIE ew ùkü. CAPRIE w y ƒ» ƒ. w CLASSICS clopidogrel + aspirin 28 CV eventsƒ % w, (9%) w. Lau WC, Waskell LA 14,15) Clarke TA 16), Victor L, Serebruany 17) atorvastatin clopidogrel n CYP 3A4 inhibitor atorvastatin w clopidogrel y x ƒ û x q û š w. ù x q sƒw š x q w» CV events x q t. CYP 3A4 inhibitor (Group III) 15 9 (60%) CV eventsƒ w ù, CYP3A4 inducer (Group V) CV eventsƒ w w clopidogrel x CYP3A4 w š. Group I II, III, IV, V j ù clopidogrel n CV events 22.2% clopidogrel k n CV events 47.2% û ùkû. CREDO 21) clopidogrel + aspirin bleeding eventsƒ 4.8% w ù Group II 11 5 (45.4%) ùkù ƒ. CURE 8) clopidogrel aspirin n aspirin n w x x š w. aspirin n w, clopidogrel n (Group I) clopidogrel + aspirin (Group II) w (41.6 %) 11 5 (45.4%) aspirin ƒ n w bleeding eventsƒ w. CURE e w. ù Group III 60% bleeding eventsƒ w, Group IV 33% ùkù aspirin n x w. CURE w. w Group III 60% bleeding eventsƒ w š, Group V 75% w. CYP3A4 clopidogrel w bleeding events w š. Bleeding events Group I II, III, IV, V j ù clopidogrel n 41.6%, clopidogrel k n 52.7% ùkû. w bleeding eventsƒ w, clopidogrel k n n w s³ 160 x w. clopidogrel w x ƒ k š ƒ. CAPRIE ƒ 6, w w 72 y ƒ. Clopidogrel n y 300 ƒ¾ ù clopidogrel warfarin y w ù k», CYP3A4 inhibitor inducer ƒ k. w 1» ww» CAPRIE w ƒ ƒ. w platelet aggregation ratio sƒ w w ù ùkü w, platelet aggregation ratio ƒ x šƒ š, clopidogrel warfarin j x x» platelet aggregation ratio ww y ƒ ƒ 1 m w» sƒ w w. zw» mw sƒw y ƒ wš, tw» y ƒ š ƒ. Clopidogrel y w yw w» w wz y sw g w ƒ v w. y y š x ù šg l x œ y. š x ù šg l x atorvastatin š, z w. w d diazepam ù, stroke convulsion» ù d m carbamazepine, primidone CYP3A4 clopidogrel y w š v w. Clopidogrel aspirin, CYP3A4 n w, clopidogrel z e w sƒw. Clopidogrel CYP3A4 inhibitor n CV events m w ƒw š(p=0.02),

8 8 Kor. J. Clin. Pharm., Vol. 15, No. 1, 2005 CYP3A4 inducer n bleeding events ƒw. m w ù Clopidgrel n k n ù w clopidogrel n x w g, x w g. w CV events clopidogrel n, k n w m w (p=0.02) CV events ƒ g. š x 1. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation. 1999; 100: CAPRIE steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk for ischemic events (CAPRIE). Lancet. 1996; 348: Bertrand ME, Repprecht HJ, Urban p, et al. Double blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) Circulation 2000; 102: Savi P, Herbert JM, pflieger AM, et al. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol. 1992; 44: Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Disp. 2002; 30: Gerger J, Brich J, Honig-Liedl P, et al. Specific impairment of human platelet P2Yac ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol. 1999; 19: Armin J, Grau, Sven Reiners et al. Platelet function under aspirin, clopidogrel, and both after ischemic stroke. Stroke 2003; 34: Shamir R Mehta, Salim Yusuf, Ron J G Peters, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention : the PCI-CURE Study. Lancet 2001; 358: Gregory W. Albers, Pierre Amarenco. Combination therapy with clopidogrel and aspirin. Stroke 2001; 32: Herbert JM, Frehel D, Vallee E, et al. Clopidogrel, a novel antiplatelet and antithrombotic agent. Cardiovasc Drug Rev. 1993; 11: Gregory W, albers, chair. Supplements to the Guidelines for the management of transient ischemic attacks. Stroke 1999; 30: Steinhubl SR, Tan WA, foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic due to ticlopidine following coronary stenting. JAMA 1999; 281: Charles L, Bennett, Jean M, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. New England J. Medicine 2000; 342: Lau WC, Waskell LA, Watkins PB, et al. Atrovastatin reduces the ability of clopidogrel to inhibit platelet aggregation. A New drug-drug intervention. Circulation 2003; 107: Lau WC, Waskell LA, Neer CJ, et al. The antiplatelet activity of clopidogrel is inhibited by atorvastatin but not pravastatin. Circulation 2000; 102(suppl II): Clarke TA, Waskell LA. The metabolism of clopidogrel is catalysed by human cytochrome P 450 3A and is inhibited by atorvastatin. Drug Metab Dispos 2003; 31: Victor L, Serebruany, et al. Are antiplatelet effects of clopidogrel inhibited by atorvastatin? Circulation 2003; 107: Sugidachi A, Asai F, Yoneda K, et al. Antiplatelet action of R-99224, an active metabolite of a novel thiopyridine type G1-linked P2T antagonist, CS-747. Br J Pharmacol. 2001; 132: Popma JJ, Ohman EM, Weitz J, et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention Chest 2001; 119(suppl): 321s-336s. 20. Pache J, Kastrati A, Mehilli J, et al. Clopidogrel therapy in patients undergoing coronary stenting: value of a high loading dose regimen. Cathet Cardiovasc Intervent 2002; 55: Steinhubl SR, berger PB, Topol EJ, et al. Early and sustained dual antiplatelet therapy following percutaneous coronary intervention. JAMA 2002; 288:

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15(2)-7.fm w wz 15«2y Kor. J. Clin. Pharm., Vol. 15, No. 2. 25 lp z$mpqjephsfm $JMPTUB[PM E BCÁ»CDÁ B w w w C s w D s w w E w w w w Comparison of Clopidogrel versus Cilostazol in Coronary Artery Stenting In Sook