Although the addition of clopidogrel to aspirin has reduced

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1 Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction Results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With AMI (ACCEL-AMI) Study Young-Hoon Jeong, MD, PhD; Jin-Yong Hwang, MD, PhD; In-Suk Kim, MD, PhD; Yongwhi Park, MD, PhD; Seok-Jae Hwang, MD, PhD; Seung-Whan Lee, MD, PhD; Choong Hwan Kwak, MD, PhD; Seong-Wook Park, MD, PhD, FACC Downloaded from by guest on June 28, 2018 Background Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI. Methods and Results Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (n 90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (n 30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (n 30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (n 30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 M ADP stimuli was 6.0% in the standard group, 19.1% in the high-md group, and 42.4% in the triple group (P 0.001), whereas inhibition of late aggregation with 20 M ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (P 0.001). Similar results were demonstrated when 5 M ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-md group, and 43.0% in the triple group; P 0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 M ADP-induced maximal aggregation 50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-md groups (56.7%) at 30-day follow-up (P 0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-md group except for percent changes of P2Y12 reaction unit (P 0.071). Conclusions Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-md clopidogrel or standard dual antiplatelet therapy. (Circ Cardiovasc Interv. 2010;3:17-26.) Key Words: acute myocardial infarction platelet reactivity triple antiplatelet therapy high maintenance-dose clopidogrel Although the addition of clopidogrel to aspirin has reduced the incidence of ischemic cardiovascular events related to percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI), 1,2 the risk of recurrent events remains higher than that of elective PCI. 3,4 Editorial see p 3 Clinical Perspective on p 26 Enhanced platelet reactivity may mainly underlie the increased rate of adverse cardiovascular disease in the early Received May 14, 2009; accepted November 5, From the Division of Cardiology, Department of Internal Medicine (Y.-H.J., J.-Y.H., Y.P., S.-J.H., C.H.K) and Department of Laboratory Medicine (I.-S.K), Gyeongsang National University Hospital, Jinju, Korea; and Department of Medicine (S.-W.L., S.-W.P.), Asan Medical Center University of Ulsan College of Medicine, Seoul, Korea. The online-only Data Supplement is available at Correspondence to Jin-Yong Hwang, MD, PhD, Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, 90 Chiram-Dong, Jinju , Korea. jyhwang@nongae.gsnu.ac.kr 2010 American Heart Association, Inc. Circ Cardiovasc Interv is available at DOI: /CIRCINTERVENTIONS

2 18 Circ Cardiovasc Interv February 2010 phase of AMI. 5,6 In recent studies, high-postclopidogrel platelet reactivity (HPPR) in patients with AMI has been associated with ischemic clinical events including stent thrombosis, 7 9 which together with the observation that prasugrel through its potent blockade of the P2Y12 ADP receptor reduces the occurrence of ischemic events after AMI, suggests a need to achieve adequate inhibition of ADP-induced platelet aggregation in patients with AMI. 10,11 Although compared with dual antiplatelet therapy, adjunctive cilostazol to dual antiplatelet therapy (or triple antiplatelet therapy ) reduces long-term clinical events after PCI in selected patient populations, 12,13 it has not been established whether the benefit of triple antiplatelet therapy may be derived from greater ADP-induced platelet inhibition in patients with AMI. Therefore, we conducted a prospective, randomized study to ascertain the degree of platelet inhibition by adjunctive cilostazol in patients with AMI. Methods Patient Population and Study Design Consecutive patients admitted for AMI were enrolled if they were 18 years or older and had undergone successful coronary stenting. We defined AMI as clinical symptoms compatible with acute myocardial ischemia within 12 hours before admission with a subsequently documented increase in cardiac troponin levels. ST-segment elevation myocardial infarction was prespecified as ST-segment elevation 1 mm in at least 2 contiguous leads in the admission ECG or left bundle-branch block, and all patients with ST-segment elevation myocardial infarction were treated with primary stenting 12 hours after the onset of pain. The remaining patients with AMI with no such ECG changes constituted the non ST-segment elevation myocardial infarction cohort, and all patients with non ST-segment elevation myocardial infarction underwent coronary stenting within 24 hours after admission. Exclusion criteria for the study were a history of active bleeding and bleeding diatheses, oral anticoagulation therapy with coumadin, left ventricular ejection fraction 30%, leukocyte count 3000/mm 3 and/or platelet count /mm 3, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 3 times the respective upper normal limits, serum creatinine level 2.5 mg/dl, or noncardiac disease with a life expectancy 1 year. The institutional review board of Gyeongsang National University Hospital approved the study protocol, and all patients signed written informed consents for participation. The adjunctive cilostazol versus high maintenance dose (MD) clopidogrel in patients with AMI (ACCEL-AMI) study is a prospective, randomized study including 90 patients with AMI undergoing coronary stenting (Figure 1). This study has no overlap in terms of enrolled patients with the adjunctive cilostazol versus high-md clopidogrel in patients with clopidogrel RESISTANCE (ACCEL-RESISTANCE) study, which enrolled patients treated with elective PCI. 14 Immediately after emergency room arrival, all patients received a 600-mg loading dose of clopidogrel followed by a MD of 75 mg daily before randomization. We also administered a 300-mg loading dose of aspirin to all patients immediately after emergency room arrival, followed by aspirin of 200 mg daily throughout the study period. Low-molecular-weight heparin (enoxaparin) or unfractionated heparin was used at the physician s discretion before PCI, and only the short half-life GPIIb/IIIa inhibitor tirofiban was administered if needed. Predischarge platelet reactivity was assessed either at least 3 days after coronary stenting in patients not treated with tirofiban or at 5 days after procedure in patients treated with tirofiban. After blood sampling, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 groups using a computer-generated randomization sequence: standard group Figure 1. Flow diagram of the study profile. LV indicates left ventricular. (n 30), clopidogrel of 75 mg daily; high-md group (n 30), clopidogrel of 150 mg daily; and triple group (n 30), adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily. At the 30-day follow-up visit, patient compliance to antiplatelet therapy was assessed by interview and tablet counting. Blood samples were obtained 2 to 4 hours after the last intake of the study medication. Platelet Function Assays Light transmittance aggregometry and the VerifyNow P2Y12 assay (Ultegra rapid platelet function assay; Accumetrics, San Diego, Calif) were performed as previously described. 14 To perform light transmittance aggregometry, blood samples were drawn into Vacutainer tubes containing 0.5 ml of sodium citrate 3.2% (Becton- Dickinson, San Jose, Calif) and processed within 2 hours. Plateletrich plasma was obtained as a supernatant fluid after centrifuging blood at 120 g for 10 minutes. The remaining blood was further centrifuged at 1200 g for 10 minutes to prepare platelet-poor plasma. Platelet-rich plasma was adjusted to a platelet count of /mm 3 by adding platelet-poor plasma as needed. Platelet reactivity was traced for 10 minutes at 37 C using an AggRAM aggregometer (Helena Laboratories Corp, Beaumont, Tex) (Figure 2). Light transmission was adjusted to 0% with platelet-rich plasma and to 100% with platelet-poor plasma for each measurement. The 5 and 20 M ADP-induced platelet aggregations were determined at maximal aggregation (Agg max ) and late aggregation at 5 minutes (Agg late ) by laboratory personnel blinded to the study protocol. Inhibition of platelet aggregation was defined as relative change of aggregation values between predischarge and 30-day followup: inhibition of platelet aggregation (%) ([predischarge platelet reactivity platelet reactivity at 30-day follow-up]/ [predischarge platelet reactivity]) 100. Percentage of platelet disaggregation between Agg max and Agg late was defined as follows: disaggregation (%) ([Agg max Agg late ]/[Agg max ]) The results of the VerifyNow P2Y12 assay were reported in P2Y12 reaction unit (PRU) and % platelet inhibition. Percent change of PRU was calculated as the relative change of PRU between predischarge and 30-day follow-up: percent change of PRU (%) ([predischarge PRU PRU at 30-day follow-up]/[predischarge PRU]) End Points and Definitions Primary end points were inhibitions of Agg max between predischarge and 30-day follow-up. Secondary end points were (1) inhibitions of Agg late ; (2) percent changes of PRU; (3) percentage of platelet disaggregation; and (4) the rate of HPPR. The cutoff point of HPPR was defined as 5 or 20 M ADP-induced Agg max 50% of light transmission. 15,16 In addition, we assessed the composite of death, MI, urgent target-vessel revascularization, or stent thrombosis at 30-day follow-

3 Jeong et al Adjunctive Cilostazol in Acute Myocardial Infarction 19 Figure 2. Representative tracing of light transmittance aggregometry: dual antiplatelet therapy at predischarge (A) and adjunctive cilostazol to dual antiplatelet therapy at 30-day follow-up (B) in a patient with AMI. Blue curve indicates tracing of light transmission with 5 M ADP stimuli; green curve, tracing of light transmission with 20 M ADP stimuli; red curve, tracing of light transmission with 10 g/ml collagen stimuli; LTA, indicates light transmittance aggregometry; Agg max, maximal platelet aggregation; Agg late, late platelet aggregation. up. Bleeding was defined according to the criteria used in the Thrombolysis in Myocardial Infarction trials. Sample Size Calculation and Statistical Analysis Based on previous studies, 15,17 we assumed a 22% increase in inhibition of 20 M ADP-induced Agg max by high-md clopidogrel and a 47% increase in inhibition of 20 M ADP-induced Agg max by triple antiplatelet therapy, relative to those by dual antiplatelet therapy. Thus, it was estimated that 25 patients per group would be required to provide a power of 80% to detect a statistically significant difference between the triple and high-md groups with a 2-sided -level of 0.05, assuming a SD of 30%.

4 20 Circ Cardiovasc Interv February 2010 Table 1. Baseline Clinical and Procedural Characteristics Table 1. Baseline Clinical and Procedural Characteristics Variables Standard Group (n 30) High-MD Group (n 30) Triple Group (n 30) Age, y Male 22 (73.3) 23 (76.7) 21 (70.0) BMI, kg/m Clinical presentation STEMI 17 (56.7) 17 (56.7) 14 (46.7) NSTEMI 13 (43.3) 13 (43.3) 16 (53.3) Risk factor Diabetes mellitus 4 (13.3) 6 (20.0) 9 (30.0) Hypertension 11 (36.7) 11 (36.7) 17 (56.7) Hypercholesterolemia 13 (43.3) 14 (46.7) 9 (30.0) Current smoking 21 (70.0) 22 (73.3) 16 (53.3) Chronic kidney disease 4 (13.3) 5 (16.7) 7 (23.3) History Previous MI 1 (3.3) 1 (3.3) 0 (0) Previous PCI 0 (0) 0 (0) 1 (3.3) Previous CABG 0 (0) 0 (0) 0 (0) Previous stroke 0 (0) 1 (3.3) 0 (0) Concomitant medications Statin CYP 3A4 metabolized 29 (96.7) 28 (93.3) 28 (93.3) Non-CYP 3A4 1 (3.3) 2 (6.7) 2 (6.7) metabolized -blocker 27 (90.0) 27 (90.0) 26 (86.7) ACE inhibitor 10 (33.3) 6 (20.0) 7 (23.3) ARB 20 (66.7) 24 (80.0) 21 (70.0) Nitrate 28 (93.3) 26 (86.7) 26 (86.7) Calcium channel blocker 2 (6.7) 1 (3.3) 5 (16.7) LV ejection fraction, % Hemoglobin, g/dl Platelet count, 10 3 /mm Hb A1 C,% Creatinine clearance, ml/min Total cholesterol, mg/dl Infarct-related vessel Left anterior descending 10 (33.3) 19 (63.3) 12 (40.0) artery Left circumflex artery 9 (30.0) 5 (16.7) 12 (40.0) Right coronary artery 11 (36.7) 6 (20.0) 6 (20.0) Left main artery 0 (0) 0 (0) 0 (0) Initial TIMI flow grade 0 13 (43.3) 12 (40.0) 11 (36.7) 1 9 (30.0) 8 (26.7) 4 (13.3) 2 8 (26.7) 6 (20.0) 10 (33.3) 3 0 (0) 4 (13.3) 5 (16.7) (Continued) Variables Standard Group (n 30) High-MD Group (n 30) Triple Group (n 30) Aspiration thrombectomy 8 (26.7) 6 (20.0) 4 (13.3) Administration of GPI 1 (3.3) 3 (10.0) 0 (0) Stent type Sirolimus eluting 10 (33.3) 14 (46.7) 7 (23.3) Paclitaxel eluting 17 (56.7) 15 (50.0) 20 (66.7) Zotarolimus eluting 3 (10) 1 (3.3) 3 (10.0) Stent diameter, mm Stents per patient Total stent length, mm Values are expressed as mean SD or n (%). BMI indicates body mass index; STEMI, ST-segment elevation myocardial infarction; NSTEMI, non ST-segment elevation myocardial infarction; MI, myocardial infarction; CABG, coronary artery bypass grafting; CYP 3A4, cytochrome P-450 3A4 isoenzyme; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LV, left ventricular; Hb A1 C, hemoglobin A1 C ; TIMI, thrombolysis in myocardial infarction; GPI, glycoprotein IIb/IIIa inhibitor. Continuous variables are expressed as mean SD or median (interquartile range), and their differences were tested with 1-way ANOVA. After demonstration of significant differences among groups by ANOVA, posthoc comparisons between group pairs were made with the Student-Newman-Keuls procedure for multiple comparisons. Categorical variables are expressed as frequencies and percentages, and 2 statistics or Fisher exact test was used for their comparisons. Statistical analyses were performed using SPSS version 13 (SPSS Inc, Chicago, Ill) and conducted at the 0.05 significance level. Results When baseline characteristics of patients were compared among the 3 groups, no significant differences were noted in any of the parameters (Table 1). Patients were treated with drug-eluting stent implantation only. Predischarge values of light transmittance aggregometry and the VerifyNow P2Y12 assay were similar among the groups (Tables 2 and 3). There were no significant differences between patients with non ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction among the 3 groups (supplemental Tables). Although there were 3 cases of transient headache in the triple group in the early phase after randomization, all regimens were generally well tolerated during 30 days. No patients discontinued the study regimens, and platelet function measurements at 30-day follow-up could be performed in all patients. No major cardiovascular and bleeding events were observed in any group, and the incidence of minor bleeding was similar in the 3 groups (3% in the standard group versus 0% in the high-md group versus 3% in the triple group, P 1.000). Primary End Points Agg max values at 30-day follow-up in the triple group were significantly lower as compared with those in the other 2 therapy groups (Table 2). After any of the tested concentrations of ADP stimuli, inhibitions of Agg max were consistently greater in the triple group as compared with the other groups (Figure 3). Inhibition of Agg max with 5

5 Jeong et al Adjunctive Cilostazol in Acute Myocardial Infarction 21 Table 2. Platelet Reactivity by Light Transmittance Aggregometry Variables, % Standard Group (n 30) High-MD Group (n 30) Triple Group (n 30) P Maximal platelet aggregation 20 M ADP Predischarge 60.0 (52.3 to 75.0) 62.9 (54.4 to 71.8) 62.9 (51.9 to 67.8) 30-day follow-up 60.2 (50.8 to 66.5) 54.8 (35.4 to 62.8) 33.1 (22.5 to 47.9) 0.001* 5 M ADP Predischarge 45.8 (37.5 to 64.2) 46.3 (38.7 to 55.6) 48.0 (40.8 to 60.1) 30-day follow-up 42.4 (34.3 to 51.5) 38.7 (22.8 to 47.6) 22.5 (18.8 to 28.8) Late platelet aggregation 20 M ADP Predischarge 51.0 (40.0 to 73.0) 56.0 (44.0 to 67.0) 53.0 (40.0 to 65.0) 30-day follow-up 51.5 (30.0 to 57.0) 42.0 (17.0 to 54.0) 13.0 (5.0 to 27.0) M ADP Predischarge 37.5 (25.0 to 61.0) 36.0 (28.0 to 49.0) 37.0 (27.0 to 55.0) 30-day follow-up 34.0 (18.0 to 45.0) 21.5 (10.0 to 35.0) 10.5 (5.0 to 15.0) Variables are expressed as median (interquartile range). *P for high-md versus standard group; P for triple versus standard group; P for triple versus high-md group. P for high-md versus standard group; P for triple versus standard group; P for triple versus high-md group. P for high-md versus standard group; P for triple versus standard group; P for triple versus high-md group. P for high-md versus standard group; P for triple versus standard group; P for triple versus high-md group. M ADP stimuli was % in the triple group, % in the high-md group, and % in the standard group (P 0.001), whereas it was %, %, and % with 20 M ADP stimuli, respectively (P 0.001). Secondary End Points Agg late values at 30-day follow-up were also significantly reduced in the triple group as compared with the other 2 groups (Table 2). Inhibitions of Agg late in the triple group were consistently higher than those in the other groups (Figure 4A). Inhibitions of Agg late after the addition of 5 M ADP were % in the triple group, % in the high-md group, and % in the standard group (P 0.001), and inhibitions of Agg late after the addition of 20 M ADP were %, %, and %, respectively (P 0.001). At 30-day follow-up, the triple group presented trends toward lower PRU and higher % platelet inhibition as compared with the high-md group (Table 3). Percent changes of PRU significantly differed according to the regimens ( % in the standard group versus % in the high-md group versus % in the triple group, P 0.001) (Figure 4B). Triple antiplatelet therapy enhanced percent change of PRU with a greater numeric difference than that of high-md clopidogrel (P 0.071). Platelet disaggregation at predischarge was similar among the groups with 5 M ( % in the standard group versus % in the high-md group versus % in the triple group, P 0.863) and 20 M ADP stimuli ( % in the standard group versus % in the high-md group versus % in the triple group, P 0.920). Thirty days after randomization, patients enrolled to all groups experienced an increase in platelet disaggregation; however, enhanced platelet disaggregation was observed in patients assigned to the triple group versus the other 2 groups (Figure 4C). Table 3. Platelet Reactivity by the VerifyNow P2Y12 Assay Variables Standard Group (n 30) High-MD Group (n 30) Triple Group (n 30) P P2Y12 reaction unit Predischarge (204.0 to 316.0) ( to 308.0) (210.0 to 306.0) 30-day follow-up (195.0 to 299.0) (120.0 to 240.0) (95.0 to 180.0) 0.001* Percentage platelet inhibition Predischarge 13.0 (2.0 to 30.0) 15.5 (4.0 to 27.0) 17.0 (7.0 to 31.0) 30-day follow-up 26.5 (11.0 to 40.0) 42.5 (24.0 to 59.0) 55.0 (45.0 to 75.0) Variables are expressed as median (interquartile range). *P for high-md versus standard group; P for triple versus standard group; P for triple versus high-md group. P for high-md versus standard group; P for triple versus standard group; P for triple versus high-md group.

6 22 Circ Cardiovasc Interv February 2010 Figure 3. Inhibitions of maximal platelet aggregation between predischarge and 30-day follow-up. Standard group ( ) received standard clopidogrel of 75 mg daily. High-MD group ( ) received high-md clopidogrel of 150 mg daily. Triple group ( ) received adjunctive cilostazol, 100 mg twice daily, in addition to dual antiplatelet therapy. Results are expressed as mean (boxes) SD (error bars). In terms of HPPR, no between-group differences were seen at predischarge after stimuli with either of the ADP concentrations tested (Figure 5A and 5B). At 30-day follow-up, triple antiplatelet therapy significantly reduced the rate of HPPR as compared with the other antiplatelet therapies after addition of 5 M (26.7% in the standard group versus 16.7% in the high-md group versus 0% in the triple group, P 0.001) and 20 M ADP (76.7% in the standard group versus 56.7% in the high-md group versus 13.3% in the triple group, P 0.001). Discussion This study shows enhanced inhibition of ADP-induced platelet aggregation by adjunctive cilostazol to dual antiplatelet therapy in patients with AMI undergoing coronary stenting. The salient finding of this study is that triple antiplatelet therapy may result in a greater antiplatelet effect than a high-md clopidogrel of 150 mg daily in patients with AMI. Furthermore, triple antiplatelet therapy reduced significantly the rate of HPPR as compared with high-md clopidogrel, which may underlie the reduced rates of ischemic events with adjunctive cilostazol. Most cases of AMI are caused by the formation of a platelet-rich arterial thrombus at the site of atherosclerotic plaque rupture or erosion, and PCI in patients with AMI may predispose to thrombotic events because of enhanced platelet reactivity and large thrombotic burden. 5,6 P2Y12 blockade by a standard dose of clopidogrel demonstrates variable ADP-induced platelet inhibition in patients with AMI. Furthermore, a lesser inhibition of platelet reactivity by clopidogrel has been associated with a higher risk of ischemic events including stent thrombosis In patients with non-st-segment-elevation (NSTE) acute coronary syndrome, a 600-mg loading dose of clopidogrel showed greater inhibition of platelet reactivity and better clinical outcomes compared with a 300-mg loading dose of clopidogrel. 18 Prasugrel has a greater inhibitory effect on ADP-induced platelet aggregation than high-md clopidogrel. 19 Prasugrel also significantly reduces ischemic event rates by 19% as compared with a standard clopidogrel dose (hazard ratio, 0.81; 95% CI, 0.73 to 0.90; P 0.001) in patients with acute coronary syndrome. 10,11,20 These results suggest the hypothesis that a standard dose of clopidogrel may be inadequate to inhibit enhanced platelet reactivity in the case of acute coronary syndrome, and greater ADP-induced platelet inhibition in these patients may result in greater suppression of clinical ischemic events. Recent data demonstrated that triple antiplatelet therapy may be better than dual antiplatelet therapy in reducing long-term ischemic event occurrence in patients with acute coronary syndrome undergoing coronary stenting. 12,13 Cilostazol is a selective inhibitor of phosphodiesterase type III in both platelets and vascular smooth muscle cells. 21 Clinical benefit of adjunctive cilostazol to standard antiplatelet therapy in patients with AMI might be related to a myocardial protective effect against ischemiareperfusion injury, 22 restoration of endothelial dysfunction, 23,24 or reduction of in-stent restenosis However, a main impact of adjunctive cilostazol to clopidogrel in patients with AMI may come from enhanced inhibition of ADP-induced platelet aggregation. 14,17,28 This phenomenon may be elucidated by a supplementary elevation of intracellular camp through both increase of camp production by clopidogrel and inhibition of camp degradation by cilostazol. 28 Moreover, this study showed that triple antiplatelet therapy may result in greater ADPinduced platelet inhibition than a high-md clopidogrel of 150 mg daily in patients with AMI. If triple antiplatelet therapy achieves the optimal balance between adequate platelet inhibition and acceptable adverse effect rates, it could be a welcome option for patients with AMI. In this study, the standard group showed a low relative change of platelet aggregation between predischarge and 30-day follow-up. Although patients with AMI may show enhanced platelet reactivity during the early phase, the impact of increased platelet reactivity may not be much higher than those of other clinical factors. 29,30 Thus, inhibition of platelet aggregation in this study may be within the acceptable range. Enhanced platelet inhibition with high-md clopidogrel may be somewhat lower compared with those of previous studies. 15,31 We enrolled patients who presented with AMI only, contrary to previous studies including patients on chronic clopidogrel therapy ( 1 month). There might be a dynamic change of platelet reactivity in the early phase of AMI, and it could affect the postclopidogrel platelet inhibition seen in our patients. In addition, ethnic differences may be related

7 Jeong et al Adjunctive Cilostazol in Acute Myocardial Infarction 23 A 100 P < P < by ANOVA by ANOVA P < P < P < P = B P < by ANOVA P < tion (%) f late platele et aggregat In nhibition of C at 30-day follow-up (% %) Pla atelet disag ggregation P = P = ųm ADP 20 ųm ADP P = by ANOVA P = P = P = P < by ANOVA P < P = P = tion unit (% %) C hange of P2Y12 react Standard group P = High-MD group P = Triple group 0 5 ųm ADP 20 ųm ADP Figure 4. Inhibitions of late platelet aggregation (A), percent changes of P2Y12 reaction unit (B), and 5 and 20 M ADP-induced platelet disaggregation at 30-day follow-up (C). Abbreviations and results represent the same in the Figure 3. Results are expressed as mean (boxes) SD (error bars).

8 24 Circ Cardiovasc Interv February 2010 Figure 5. Rate of HPPR at predischarge and 30-day follow-up (A and B). HPPR indicates high-postclopidogrel platelet reactivity (5 or 20 M ADP-induced maximal platelet aggregation 50%). Abbreviations and results represent the same in the Figure 3. with the reduced response to high-md clopidogrel. Carriers with the cytochrome P450 (CYP) 2C19 mutant allele have shown reduced platelet inhibition with clopidogrel and a higher rate of major adverse cardiovascular events, than did noncarriers. 32,33 Because the common polymorphism of the CYP2C19 gene is more prominent among East Asians than whites ( 60% versus 30%), additive platelet inhibition with high-md clopidogrel would be much diminished in East Asians. Furthermore, cilostazol is mainly converted into active metabolites by the CYP3A system, 35 which translates into less impact of the CYP2C19 mutant allele for additive platelet inhibition with cilostazol. Further large-scale studies assessing whether intensified antiplatelet therapy in patients with AMI provides similar efficacy of ADP-induced platelet inhibition according to ethnicity are needed. Limitations The small number of patients studied and the short follow-up period are limitations of this study. Patients with AMI show enhanced platelet reactivity during the early phase, and their platelet reactivity can be decreased thereafter. Measurements of the standard group may provide a reference for decreasing platelet reactivity after AMI. Because this study enrolled East Asians only, results cannot be generalized to a global scale. One major limitation of this study may be the time point of platelet function measurements. Matetzky et al 7 showed that there may be no significant changes of postclopidogrel platelet reactivity from days 3 to 5 after coronary stenting in patients with AMI. Because we assessed platelet reactivity mostly from 3 to 5 days after coronary stenting, the results from our patients may principally reflect predischarge residual platelet reactivity. Conclusions Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect than a high-md clopidogrel of 150 mg daily. The use of triple antiplatelet therapy in patients with AMI may achieve adequate inhibition of ADP-induced platelet aggregation to suppress the occurrence of major adverse cardiovascular events. Sources of Funding This study was partly supported by grants from the Research Foundation of Gyeongsang National University Hospital. Disclosures Dr Jeong has received honoraria for lectures for Sanofi-Aventis, Daiichi Sankyo Inc, and Otsuka. Dr Lee has received honoraria for lectures for Otsuka. Dr Park has received honoraria for lectures for Otsuka. References 1. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. 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: Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI- CLARITY study. JAMA. 2005;294: Gurm HS, Smith DE, Collins JS, Share D, Riba A, Carter AJ, LaLonde T, Kline-Rogers E, O Donnell M, Changezi H, Zughaib M, Safian R, Moscucci M; Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). The relative safety and efficacy of abciximab and eptifibatide in patients undergoing primary percutaneous coronary intervention: insights from a large regional registry of contemporary percutaneous coronary intervention. J Am Coll Cardiol. 2008;51:

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10 26 Circ Cardiovasc Interv February Kim IS, Choi BR, Jeong YH, Kwak CH, Kim S. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost. 2009;7: Hiratsuka M, Hinai Y, Sasaki T, Konno Y, Imagawa K, Ishikawa M, Mizugaki M. Characterization of human cytochrome p450 enzymes involved in the metabolism of cilostazol. Drug Metab Dispos. 2007;35: CLINICAL PERSPECTIVE Because patients with acute myocardial infarction (AMI) have shown enhanced platelet reactivity during the early phase, the standard doses of clopidogrel and aspirin might not achieve adequate platelet inhibition. Furthermore, recent studies have identified that high-postclopidogrel platelet reactivity in these patients has been associated with ischemic clinical events. Based on the premise that intensified antiplatelet therapy in patients with AMI may lead to better ADP-stimulated platelet inhibition and a reduced risk for adverse cardiovascular events, adjunctive cilostazol to dual antiplatelet therapy (or triple antiplatelet therapy ) can be an attractive alternative in patients with AMI. Triple antiplatelet therapy has shown more beneficial effects on platelet inhibition and endothelial senescence than has dual antiplatelet therapy in selected subsets. In this study, we assessed the degree of platelet inhibition by adjunctive cilostazol in patients with AMI. We enrolled patients with AMI treated with drug-eluting stents only, and we assessed platelet reactivity at predischarge and 30-day follow-up. Among these patients, triple antiplatelet therapy resulted in a greater antiplatelet effect than high maintenance dose clopidogrel of 150 mg daily, as demonstrated by various parameters of conventional aggregometry and the VerifyNow P2Y12 assay. Because a common polymorphism of cytochrome P450 (CYP) 2C19 gene is more prominent among East Asians than whites ( 60% versus 30%), high maintenance dose clopidogrel can exhibit much diminished platelet inhibition in East Asians than in whites. Furthermore, cilostazol is mainly converted into active metabolites by CYP3A system, and adjunctive cilostazol can inhibit platelet aggregation consistently irrespective of the carriage of CYP2C19 mutant allele.

11 Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition than High Maintenance Dose Clopidogrel in Patients With Acute Myocardial Infarction: Results of the Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With AMI (ACCEL-AMI) Study Young-Hoon Jeong, Jin-Yong Hwang, In-Suk Kim, Yongwhi Park, Seok-Jae Hwang, Seung-Whan Lee, Choong Hwan Kwak and Seong-Wook Park Circ Cardiovasc Interv. 2010;3:17-26; originally published online January 26, 2010; doi: /CIRCINTERVENTIONS Circulation: Cardiovascular Interventions is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2010 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Interventions can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation: Cardiovascular Interventions is online at:

12 SUPPLEMENTAL MATERIAL

13 Supplemental Table 1. Platelet Reactivity in Patients with Non-ST-segment Elevation Myocardial Infarction Standard group Maximal platelet aggregation 20 ųm ADP (n = 13) High-MD group (n = 13) Triple group (n = 16) P Pre-discharge 62.8 ± ± ± day follow-up 58.9 ± ± ± 14.8 < Inhibition (%) 4.4 ± ± ± 19.3 < ųm ADP Pre-discharge 50.5 ± ± ± day follow-up 46.6 ± ± ± 10.4 < Inhibition (%) 3.9 ± ± ± 14.0 < Late platelet aggregation 20 ųm ADP Pre-discharge 55.0 ± ± ± day follow-up 47.7 ± ± ± Inhibition (%) 4.5 ± ± ± 28.0 < ųm ADP Pre-discharge 44.3 ± ± ± day follow-up 35.0 ± ± ± Inhibition (%) 12.2 ± ± ± VerifyNow P2Y12 assay P2Y12 reaction unit Pre-discharge ± ± ± day follow-up ± ± ± Percent change 4.1 ± ± ± % platelet inhibition Pre-discharge 16.7 ± ± ± day follow-up 25.3 ± ± ± MD, maintenance dose; and ADP, adenosine diphosphate.

14 Supplemental Table 2. Platelet Reactivity in Patients with ST-segment Elevation Myocardial Infarction Standard group (n = 17) High-MD group (n = 17) Triple group (n = 14) P Maximal platelet aggregation 20 ųm ADP Pre-discharge 60.2 ± ± ± day follow-up 55.7 ± ± ± Inhibition (%) 7.3 ± ± ± 23.4 < ųm ADP Pre-discharge 46.2 ± ± ± day follow-up 41.3 ± ± ± Inhibition (%) 9.2 ± ± ± 25.2 < Late platelet aggregation 20 ųm ADP Pre-discharge 50.6 ± ± ± day follow-up 43.4 ± ± ± Inhibition (%) 15.5 ± ± ± ųm ADP Pre-discharge 35.9 ± ± ± day follow-up 28.6 ± ± ± Inhibition (%) 19.9 ± ± ± 35.1 < VerifyNow P2Y12 assay P2Y12 reaction unit Pre-discharge ± ± ± day follow-up ± ± ± Percent change 15.6 ± ± ± % platelet inhibition Pre-discharge 21.2 ± ± ± day follow-up 32.8 ± ± ± MD, maintenance dose; and ADP, adenosine diphosphate.