Cilostazol versus Clopidogrel after Coronary Stenting Seong-Wook Park, MD, PhD, FACC Division of Cardiology, Asan Medical Center University of Ulsan College of Medicine Seoul, Korea AMC, 2004
Background Although stent thrombosis after coronary artery stenting has been reduced considerably by improving techniques and introduction of potent antiplatelet therapy, it develops in about 1% of patients. Clopidogrel has emerged as a standard antiplatelet regimen to lower the risk of stent thrombosis after coronary artery stenting.
Background Cilostazol is a potent antiplatelet agent that selectively inhibits phosphodiesterase III Previous studies suggested that cilostazol had similar antiplatelet effects with less serious adverse effects, as compared with ticlopidine Ochiai M, Am J Cardiol 1997;79:1471-74 Dawson DL, Circulation 1998;98:678-86 Park SW, Am J Cardiol 1999;84:511
Purpose To compare the effects of cilostazol with those of clopidogrel on the incidence of stent thrombosis and adverse side reactions in patients who underwent successful coronary artery stenting.
Methods Prospective randomization From June 2002 to October 2003 Patients(n=689) who underwent stenting - Cilostazol (n=344, 612 lesions) - Clopidogrel (n=345, 628 lesions) in addition to aspirin 200 mg
Study design Patients (n=689) who underwent successful stenting Randomization Loading dose: Cilostazol 200mg, Clopidogrel 300mg Cilostazol group (n=344, 612 lesions) Clopidogrel group (n=345, 628 lesions) Maintenance dose : Cilostazol 100mg BID, Clopidogrel 75mg QD Clinical follow-up at 30 days
Inclusion criteria Angiographic evidence of 50% diameter stenosis - Symptomatic coronary artery disease - Documented myocardial ischemia by treadmill exercise test or thallium SPECT Primary stenting in patients with AMI and postprocedure TIMI 2 or 3 flow
Exclusion criteria - Left main stenting - Bypass graft stenting - Radiation therapy - Drug eluting stenting - Poor LV function (EF<30%) - Hematological disease; Neutropenia (<3,000/mm 3 ) Thrombocytopenia (<100,000/mm 3 ) - Hepatic dysfunction or Renal dysfunction (Cr>3.0 mg/dl) - Administration of oral anticoagulant, GP IIb/IIIa inhibitor - Contraindication to aspirin, clopidogrel or cilostazol
Primary end point Within 30 days after stenting Subacute stent thrombosis Major adverse cardiac events -Death -Myocardial infarction -Repeat intervention
Secondary end point Any events requiring termination of study drugs during treatment period - Major bleeding - Neutropenia (<1,500/mm 3 ) - Thrombocytopenia (<100,000/mm 3 ) - Skin rash, - Liver dysfunction, and GI trouble
Baseline Characteristics Cilostazol Clopidogrel p (n=344) (n=345) Age,yrs 59 47 60 11 Sex, M/F 249/95 243/102 Diabetes 85 (24.7%) 79 (22.9%) Hypertension 160 (46.5%) 155 (44.9%) Smoking 153 (44.5%) 150 (43.5%) Hypercholesterol 108 (31.4%) 101 (29.3%)
Clinical presentation Cilostazol group Clopidogrel group AMI (27.9%) Stable angina (40.7%) AMI (25.8%) Stable angina (37.4%) Unstable angina (31.4%) Unstable angina (36.8%) Primary stenting 49 (14.2 %) P=0.787 Primary stenting 42 (13.3 %)
Angiographic Characteristics Cilostazol Clopidogrel p (n=612) (n=628) Stented site LAD LCX RCA AHA/ACC type A B1 B2 C 322 (52.6%) 101 (16.6%) 189 (30.8%) 68 (11.1%) 183 (29.9%) 139 (22.7%) 222 (36.3%) 351 (55.9%) 85 (13.6%) 192 (30.4%) 71 (11.3%) 198 (31.6%) 133 (21.2%) 226 (35.9%)
Angiographic Characteristics Cilostazol Clopidogrel p (n=612) (n=628) Small vessel (<3.0 mm) 231 (37.7%) 235 (37.5%) Long lesion ( 20 mm) 193 (31.6%) 221 (35.2%) Chronic total occlusion 27 (4.4%) 32 (5.1%) Long stent ( 30 mm) 82/634(12.9%) 74/646(11.5%) Multi-vessel stenting 180 (52.3%) 195 (56.5%)
Angiographic Characteristics Cilostazol Clopidogrel p (n=612) (n=628) Reference diameter (mm) 3.2 0.6 3.2 0.5 Lesion length (mm) 18.1 10.0 19.4 10.1 MLD(mm) Baseline 0.79 0.58 0.78 0.54 Final 3.07 0.58 3.01 0.57 Balloon artery ratio 1.12 0.22 1.11 0.23 Maximal pressure(atm) 13.5 2.6 13.5 2.7
Number of stent/patient % 50 P=0.260 Cilostazol, n=344 Clopidogrel, n=345 40 47.1 42.3 30 20 30.2 30.4 23.8 26.3 10 0 1 stent 2 stents 3 or more stents
Major Cardiac Events Cilostazol Clopidogrel p (n=344) (n=345) Acute ST 2 (0.6%) 2 (0.6%) Subacute ST 3 (0.9%) 2 (0.6%) MI 5 (1.5%) 4 (1.2%) TLR 5 (1.5%) 3 (0.9%) Death 2 (0.6%) 2 (0.6%) ST; stent thrombosis
Primary Endpoint Subacute thrombosis & MACE % 2 P=0.557 1.5 1 7 (2.0%) 5 (1.4%) 0.5 0 Cilostazol Clopidogrel
Subacute stent thrombosis (SAT) Cilostazol group 3 SAT 2 elective stenting 1 primary stenting Clopidogrel group 2 SAT 2 primary stenting IVUS study showed intrastent thrombi in 2 patients, tissue prolapse in 1 patient of 3 SAT after primary stenting
Subacute stent thrombosis (SAT) Primary vs. elective stenting % 10 8 P<0.05 6 4 2 0 3.2% (3/91) Primary stenting 0.3% (2/598) Elective stenting
Noncardiac Events Cilostazol Clopidogrel p (n=344) (n=345) Major bleeding* Vascular complication Adverse side effect Leukopenia Thrombocytopenia Elevated LFT GI trouble Skin rash 1 (0.3%) 2 (0.3%) 0 0 0 4 (1.2%) 2 (0.6%) 1 (0.3%) 1 (0.3%) 0 0 0 1 (0.3%) 6 (1.7%) * Vascular access site bleeding (n=1), Ulcer bleeding(n=1)
Secondary Endpoint Cessation of study drug (<1 Mo) % 1 All patients(n=4): skin rash P= 0.5 2(0.6%) 2(0.6%) 0 Cilostazol Clopidogrel
Summary Treatment with cilostazol after successful stenting effectively prevents stent thrombosis with few side effects in various clinical setting. Primary stenting may be associated with increased risk of stent thrombosis, requiring more potent antithrombotic therapy including GP IIb/IIIa inhibitor and/or other antiplatelet agents.
Conclusion Cilostazol is as safe and effective as clopidogrel in preventing thrombotic complications after coronary stenting in a broad spectrum of patients. This study provides the rationale for reliable use of cilostazol in patients who undergo coronary stenting, especially those with symptomatic peripheral vascular disease.