Randomized Comparison of Cilostazol Vs Ticlopidine for Antiplatelet Therapy After Coronary Stenting

Circ J 2005; 69: 780–785

Randomized Comparison of Cilostazol vs Ticlopidine for Antiplatelet Therapy After Coronary Stenting

Noriyuki Takeyasu, MD; Shigeyuki Watanabe, MD*; Yuichi Noguchi, MD; Kimito Ishikawa, MD; Yuko Fumikura, MD; Iwao Yamaguchi, MD*

Background Cilostazol and ticlopidine are commonly prescribed for prevention of thrombosis after coronary stenting, but few studies have compared them. Methods and Results In the present study 642 patients who underwent stenting were randomized to treatment either with cilostazol+aspirin (C group, 321 patients) or ticlopidine+aspirin (T group, 321 patients). Quantita- tive coronary angiography (QCA) was performed immediately after stenting and at the 6-month follow-up. Treatment was continued until follow-up angiography. Baseline patient characteristics did not differ significantly. With the exception of a higher rate of stenting in a venous graft in the C group, there were no differences in angiographic characteristics or stent type. Baseline QCA analysis of the reference diameter, minimal lumen diameter (MLD) showed no significant differences. Follow-up QCA analysis of the MLD showed no significant differences. There were also no differences in restenosis or target lesion revascularization rates, or in the incidence of adverse reactions. However, the rate of subacute thrombosis (SAT) was significantly higher in the C group than in the T group (2% vs 0.3%, p=0.02). Conclusion In the present study there was a similar restenosis rate with cilostazol or ticlopidine, but the rate of SAT was significantly higher with cilostazol. There was no significant difference in adverse reactions. (Circ J 2005; 69: 780–785) Key Words: Adverse drug reaction; Cilostazol; Coronary stenting; Subacute thrombosis; Ticlopidine

tent implantation reduced the rates of acute occlusion world”. and restenosis after percutaneous coronary inter- We therefore designed the present study to evaluate and S vention (PCI),1 but a new type of problem emerged, compare the clinical effects of cilostazol vs ticlopidine namely, subacute thrombosis (SAT) within the stent and it after stent implantation with respect to SAT rate, restenosis is again highlighted in the present drug-eluting-stent era. rate, cardiac events, and ADR in consecutive patients Colombo et al reported that after stent implantation, anti- undergoing emergency PCI, including acute coronary coagulants can be replaced by a combination of antiplatelet syndrome (ACS). therapy with ticlopidine and aspirin.2,3 However, serious adverse drug reactions (ADR), including hepatic dysfunction, granulocytopenia, interstitial pneumonia and throm- Methods botic thrombocytopenic purpura (TTP), have been reported Patients Selection and Drug Regimens with ticlopidine.4–6 Between August 1997 and January 2002, 642 consecu- Cilostazol, similar to ticlopidine, is used to prevent SAT tive patients with ischemic heart disease who underwent after stent implantation and is also expected to reduce the revascularization by implantation of coronary stent were incidence of restenosis,7,8 with milder adverse effects than randomized to treatment with cilostazol 200 mg/day + ticlopidine. Yoon et al reported that antiplatelet therapy aspirin (C group, 321 patients) or ticlopidine 200mg/day+ with cilostazol+aspirin was as effective as ticlopidine+ aspirin (T group, 321 patients). The randomization was aspirin in preventing stent thrombosis and there was no performed with a standard list of random numbers. The statistical difference in the incidence of ADR and compli- administration of the antiplatelet agents was open label (ie, cations.9 However, those patients had undergone elective the physicians and patients were not blinded). Treatment coronary stenting, so it remains unclear whether antiplate- was continued for at least 6 months after stent implantation let therapy with cilostazol+aspirin is equally effective as until follow-up angiography was performed. Oral aspirin ticlopidine+aspirin in emergency PCI cases in the “real was started at a dose of 81–200mg/day prior to the procedure, and oral cilostazol or ticlopidine was started 2h after (Received January 26, 2005; revised manuscript received April 13, stent implantation. Heparin was administered during the 2005; accepted May 2, 2005) PCI, but was continued for 2 or 3 days after the procedure Cardiovascular Division, Department of Internal Medicine, Tsukuba only in patients with acute myocardial infarction. Warfarin Medical Center Hospital, *Medical Science for Control of Pathologi- was not prescribed. A variety of stents were used for im- cal Processes, Graduate School of Comprehensive Human Sciences, plantation at the lesion site, with selection left to the discre- University of Tsukuba, Tsukuba, Japan Mailing address: Shigeyuki Watanabe, MD, Graduate School of tion of the treating physician. Exclusion criteria included Comprehensive Human Sciences, University of Tsukuba, 1-1-1 active hepatitis or liver cirrhosis, active internal bleeding, Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. E-mail: s-watanabe@ or an absolute contraindication to anticoagulation. The md.tsukuba.ac.jp study protocol was approved by the Institutional Review

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Board of Tsukuba Medical Center Hospital and written Table 1 Patient Characteristics informed consent was obtained from all subjects before T group C group p value randomization. (n=321) (n=321) Definitions Lesions, n 436 428 Age, years 65.2±10.4 65.1±10.4 NS Restenosis was defined as >50% diameter stenosis at the Male, n (%) 242 (75%) 255 (79%) NS intervention site on follow-up angiography. The diagnosis Medical history, n (%) of distal embolism was based on angiographic cut-off of a Hypertension 244 (76%) 231 (72%) NS distal branch or vessel at any point during the procedure Diabetes 177 (55%) 170 (53%) NS and/or decreased flow in a distal vessel that was previously Hyperlipidemia 228 (71%) 215 (67%) NS patent in the absence of an occlusion at the site of the target Smoking 247 (77%) 238 (74%) NS Previous MI 138 (43%) 147 (46%) NS lesion. SAT was defined as angiographic documentation of CABG 12 (4%) 14 (4%) NS stent occlusion within 30 days of the procedure compared Diagnosis, n (%) with after 24h, and acute thrombosis was defined as stent ACS 112 (35%) 103 (32%) NS occlusion within 24h. The occurrence of ADR including AP 219 (65%) 218 (68%) NS rash, purpura, diarrhea, nausea, gastrointestinal bleeding, Data are the number (%) of patients or mean value ± SD. cytopenia, hepatic dysfunction and renal dysfunction were ACS, acute coronary syndrome; MI, myocardial infarction; CABG, coronary prospectively monitored. Neutropenia was defined as artery bypass grafting; AP, angina pectoris. neutrophil count <1,200/mm3 and thrombocytopenia as a reduction in the platelet count to <80,000/mm3 or a rela- tive reduction of the platelet count to <50% of baseline. analysis to compare the QCA values. The Mann-Whitney Hepatic dysfunction was defined as an increase of aspartate U test or chi-square test was used to analyze comparisons transaminase or alanine transaminase more than 2-fold the of baseline clinical and angiographic characteristics. A p- upper limit of normal and renal dysfunction as an increase value less than 0.05 was considered statistically significant. of serum creatinine >0.5 mg/dl above baseline. Hema- tologic status was evaluated every 2 or 4 weeks after the first administration of the drug. If patients had any side Results effects, the study drug was discontinued. Baseline Characteristics There were 436 target lesions in the T group and 428 tar- Angiographic Analysis and Follow-up get lesions in the C group. Baseline characteristics includ- Quantitative coronary angiography was performed ing age, gender, coronary risk factors did not significantly (QCA; Quantocor, Siemens, Erlangen, Germany) at base- differ between the 2 groups (Table 1), nor were there line (before and immediately after procedure) and at 6- significant differences in a history of myocardial infarction month follow-up to measure the reference diameter and or coronary artery bypass surgery. The number of patients minimal lumen diameter (MLD) of the lesion site, percent diagnosed as ACS at the time of procedure was not signifi- stenosis, and lesion length. In addition, the restenosis rates, cantly different between the groups. target lesion revascularization (TLR) rates, acute thrombosis and SAT rates, and incidence of ADR were compared Angiographic Characteristics, Stent Type and Stent between the 2 treatment groups. Implantation Procedure Characteristics Follow-up endpoints included restenosis, acute throm- With the exception of a higher rate of stent implantation bosis or SAT, reintervention at the stent placement site, in a venous graft in the C group (4 patients) compared with and serious ADR. the T group (0 patients), there were no other significant differences in the angiographic characteristics between the Statistical Analysis 2 groups (Table2). The lesion types at the stent placement All values are expressed as the mean±standard devia- site did not significantly differ, nor was there a significant tion. Repeated-measure ANOVA was used for statistical difference in the type of the stent implanted or the stent

Table 2 Angiographic Characteristics

T group C group p value (n=436 lesions), n (%) (n=427 lesions), n (%) Artery stented LAD 215 (49%) 203 (48%) NS LCX 76 (17%) 61 (14%) NS RCA 139 (32%) 155 (36%) NS LMT 5 (1%) 3 (1%) NS SVG 0 (0%) 4 (1%) 0.04 LITA or RITA 1 (0.2%) 1 (0.2%) NS Lesion type A 118 (27%) 103 (24%) NS B1 101 (23%) 111 (26%) NS B2 108 (25%) 115 (27%) NS C 109 (25%) 98 (23%) NS Data are the number (%) of lesions. LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; LMT, left main coronary trunk; SVG, saphenous vein graft; LITA, left internal thoracic artery; RITA, right internal thoracic artery.

Circulation Journal Vol.69, July 2005 782 TAKEYASU N et al.

T group (436 lesions) C group (427 lesions)

Cordis Ter umo Cordis 2 (0.5%) 1 (0.2%) 1 (0.2%)

PS PS GFX 50 (13%) GFX 58 (14%) 57 (13%) 58 (14%)

Wiktor Wiktor 30 (7%) 30 (7%)

ML ML 89 (20%) 91 (21%)

NIR NIR 193 (44%) 204 (48%)

Fig1. Stent type. Data are the number (%) of lesions. PS, Palmaz-Schatz; ML, Multilink.

Table 3 Stent Implantation Procedure Characteristics

T group C group p value (n=436 lesions), n (%) (n=427 lesions), n (%) Bail out stenting, n (%) 15 (3%) 14 (3%) NS Chronic total occlusion, n (%) 19 (4%) 12 (3%) NS Restenosis lesion, n (%) 24 (6%) 19 (4%) NS Presence of dissection at stent edge, n (%) 42 (10%) 39 (9%) NS No. of stents per lesion, n (%) 1 404 (93%) 396 (93%) NS 2 27 (6%) 27 (6%) NS 3 5 (1%) 4 (1%) NS Average no. of stents per lesion, n 1.1±0.3 1.1±0.3 NS Average no. of stents per patient, n 1.3±0.6 1.4±0.6 NS Average stent size, mm 3.1±0.4 3.1±0.4 NS Average stent length, mm 15.9±5.3 16.1±5.5 NS Stent dilatation pressure, atm 18.0±3.8 17.8±3.4 NS

Data are the number (%) of lesions or mean value ± SD.

Table 4 Quantitative Angiographic Results or TLR rate (T group, 23.5%; C group, 22.4%). T group C group p value (n=436 lesions) (n=427 lesions) Clinical and Angiographic Events Angiographic events within the 6 months included a sig- Reference diameter, mm 2.98±0.62 3.06±0.60 NS nificantly higher rate of distal embolism during the proce- MLD, mm NS dure in the C group (10 patients, 3%) compared with the T Baseline 1.01±0.53 1.02±0.56 NS Final 2.77±0.69 2.71±0.48 NS group (3 patients, 1%), and a significantly higher rate of Lesion length, mm 13.93±7.84 13.26±7.22 NS stent SAT in the C group (8 patients, 2% vs 1 patient, 0.3% Restenosis rate (%) 29.3 27.8 NS in T group) (Table5, Fig3). Acute stent thrombosis did not TLR (%) 23.5 22.4 NS occur in either group. Clinical events within 1 month MLD, minimal lumen diameter; TLR, target lesion revascularization included a significantly higher rate of repeat intervention (revascularization) in the C group (9 patients, 3%) compared with the T group (1 patient, 0.3%); however, there implantation procedure characteristics (Fig1, Table3). were no significant differences in the rates of emergency coronary artery bypass grafting, myocardial infarction, or QCA Data death (Table5). In a comparison of patient characteristics, QCA analysis at the time of stent implantation showed angiographic characteristics and procedural characteristics no significant differences in reference diameter, MLD between patients with SAT (n=9) and those without SAT before or immediately after the procedure, or lesion length (n=633), the only significant difference was the drug (Table4). On 6-month follow-up QCA, the MLD at the regimen (p=0.0188). stent implantation site did not significantly differ between the T group (2.00±0.65 mm) and the C group (2.04± ADR 0.64mm) (Fig2). There were also no significant differ- The incidence of ADR did not significantly differ ences in restenosis rate (T group, 29.3%; C group, 27.8%) between the T group (22 patients, 7%) and C group (12

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Table 5 Primary Angiographic and Clinical Events in 6-Month Clinical Follow-up

T group C group p value (n=321), n (%) (n=321), n (%) Angiographic events Distal embolism 3 (1%) 10 (3%) 0.049 Acute stent thrombosis 0 (0%) 0 (0%) NS Subacute stent thrombosis 1 (0.3%) 8 (2%) 0.02 Clinical events MI 5 (2%) 10 (3%) NS Repeat intervention 1 (0.3%) 9 (3%) 0.01 Emegency CABG 1 (0.3%) 0 (0%) NS Death 5 (2%) 4 (1%) NS

Data are the number (%) of patients. MI, myocardial infarction; CABG, coronary artery bypass grafting

Fig2. Minimal lumen diameter (MLD) in the baseline and follow- up quantitative angiography.

Fig3. Number of days of subacute thrombosis after stent implantation. patients, 4%), although there was a significantly higher Table 6 Adverse Drug Reactions incidence of “purpura” in the T group (4 patients, 1% vs 0 T group C group p value patients, 0% in the C group). No life-threatening ADR, (n=321), n (%) (n=321), n (%) such as TTP or severe hepatic dysfunction, occurred in either group (Table6). Adverse reactions 22 (7%) 12 (4%) NS Liver injury 9 (3%) 5 (2%) NS Cytopenia 3 (1%) 1 (0.3%) NS Discussion Rash 3 (1%) 6 (2%) NS Purpura 4 (1%) 0 (0%) 0.045 This prospective randomized study found no significant Gastrointestinal bleeding 1 (0.3%) 1 (0.3%) NS difference in stent restenosis, TLR or composite frequency Renal dysfuncrtion 1 (0.3%) 0 (0%) NS of ADR between the use of cilostazol+aspirin or ticlopi- Others 2 (1%) 0 (0%) NS dine+aspirin. However, the incidence of stent thrombosis Data are presented as the number (%) of patients. during the 6 months after coronary stenting was significantly higher with cilostazol than with ticlopidine. It is considered that cilostazol will reduce the incidence stenting than ticlipidine. However, this is still controver- of cardiac events and restenosis after coronary artery inter- sial. vention by virtue of its antiplatelet effects and inhibition In our study, which included patients with ACS, there of vascular smooth muscle cell proliferation. The drug’s was no significant difference between cilostazol and ticlo- effects on prevention of restenosis after plain old balloon pidine in preventing restenosis after stent implantation. angioplasty without a stent have been reported,10 and the Similarly, in a randomized trial of “cilostazol+aspirin” vs primary mechanism of action is considered to be inhibition “ticlopidine+aspirin” in 409 patients who underwent elec- of intimal hyperplasia.11–13 Cilostazol has also been re- tive stenting, Park et al also reported no significant differ- ported to prevent restenosis after stent implantation by ences in restenosis rate.14 Kozuma et al13 who thought it might be more beneficial in The antiplatelet effects of cilostazol are pharmacologi- preventing both angiographic and clinical restenosis after cally potent, in addition to those of aspirin and ticlopi-

Circulation Journal Vol.69, July 2005 784 TAKEYASU N et al. dine,15,16 but the time to onset of the inhibitory effect on References platelet aggregation in vivo of cilostazol is shorter than that 17 1. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, of ticlopidine. “Ticlopidine+aspirin” became established Heyndrickx G, et al. A comparison of balloon-expandable-stent as a post-stent treatment regimen after reports by Colombo implantation with balloon angioplasty in patients with coronary et al,2,3 but ticlopidine is associated with potentially life- artery disease: Benestent Study Group. N Engl J Med 1994; 331: threatening ADR, including severe hepatic dysfunction, 489–495. 4,5 2. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G, granulocytopenia, interstitial pneumonia and TTP. Thus, et al. Intracoronary stenting without anticoagulation accomplished the alternative regimen of “cilostazol+aspirin” has been with intravascular ultrasound guidance. 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