w wz 15«1y Kor. J. Clin. Pharm., Vol. 15, No. 1. 2005 $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 230.8 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 53-12 ( 140-742) Tel: 02-710-9579, Fax: 02-712-9725 E-mail: 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 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) 1600-5000 1 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. 2002 8 1 l 2003 8 31 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
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. 2002 8 1 l 2003 8 31 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 ± 1.6 64.5 ± 3.4 65.8 ± 1.9 63.7± 4.2 70.5 ± 3.2 0.52 Sex (F/M) - % 38.8/61.2 18.2/81.8 53.3/46.7 33.3/66.7 50/50 0.47 PT - sec 14.2 ± 1.1 13.2 ± 0.3 13.2 ± 0.2 13.2 ± 0.3 13.0 ± 0.1 0.88 aptt - sec 36.4 ± 1.9 36.6 ± 1.7 37.0 ± 1.5 34.4 ± 2.2 31.5 ± 4.3 0.73 INR 1.09 ± 0.04 1.06± 0.03 1.06± 0.02 1.06 ±0.02 1.03± 0.02 0.95 Hb 13.4 ± 0.3 13.8 ± 0.8 11.9 ±0.6 13.6 ± 0.4 13.6 ±1.0 0.13 Plt 232 ± 11 221 ± 27 270 ± 36 228 ± 20 203 ±32 0.54 Hct 39.8 ± 0.9 41.2 ± 2.0 35.2 ± 1.6 39.9 ± 1.2 39.8 ± 3.2 0.08 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. 0.16 Coronary Heart - Disease 5 7 0 2 0 Congestive Heart - Failure 1 0 1 0 0 Atrial fibrillation 0 0 1 0 1 Hypertension 18 3 6 3 2 Diabetes 9 3 7 1 0 Hyperlipidemia 2 0 0 1 0 *group I = clopidogrel group II = clopidogrel + aspirin group III = clopidogrel + CYP3A4 inhibitor group IV = clopidogrel + CYP3A4 inhibitor + aspirin group V = clopidogrel + CYP3A4 inducer
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 4 0 3 1 8 Group I 4 0 3 1 8 Clopidogrel + others 10 2 3 2 17 Group II 3 1 1 0 5 Group III 6 1 0 2 9 Group IV 1 0 2 0 3 Group V 0 0 0 0 0 Total 14 2 6 3 25 *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.
Clopidogrel y x y z e w 5 Table 3. Site of cardiovascular events at 12months of clopidogrel treatment Brain Heart Total Group I 4 4 8 Group II 2 3 5 Group III 6 3 9 Group IV 1 2 3 Group V 0 0 0 Total 13 12 25 *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 7 8 15 Group I 7 8 15 Fig. 3. Bleeding events of each group with clopidogrel treatment. Clopidogrel + others 12 7 19 Group II 2 3 5 Group III 7 2 9 Group IV 2 0 2 Group V 1 2 3 Total 19 15 34 *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 6 1.69sec, 12 7.59sec ƒw e(11-15 sec) ùkû (Fig. 7). INR clopidogrel n 6, 12
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 6 0.13, 12 0.19 ƒ w ù (0.85-1.3)ü. Plt clopidogrel n, k n 6 (7.3 10 3 /µl, 15.57 10 /µl) ƒ 3 w š, 12 (21.6 10 3 /µl, 32.6 10 3 /µl) ƒw ù (130-450 10 /µl) 3 yw (Fig. 8). š y y» wx q lp x ù x w» w v w. 2001 ACCP (American college of Chest Physicians) IV e w lp z wx aspirin 80-325 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
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 1.2-1.5% w, 28 11 1 (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 36 15 (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 6,300 1-3 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),
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