A Prospective Randomized Multi-center Study of Antiplatelet using Cilostazol versus Ticlopidine Undergoing Coronary Artery Stenting
Junbo Ge, MD, FACC, FESC Shanghai institute 2005-1-25of Cardiovascular Diseases Zhongshan Hospital, Fudan University On behalf of RACTS investigators Background
Antiplatelet therapy is essential in PCI both in preventing thrombosis and restenosis. The currently used antiplatelet agents include aspirin, ADP inhibitor and GP IIb/IIIa antagonist. Cilostazol Newly developed platelet aggregation inhibitor Increases the intracellular concentration of cAMP by inhibiting phosphodiesterase III Decrease neointimal proliferation Decrease MACE and restenosis rate after PCI. Antiplatelet Agent Overview
' TXA2 antagonists: Aspirin
' ADP receptor antagonists: Thienopyridine-Ticlopidine and Clopidogrel
' Phosphodiesterase inhibitors: Cilostazol and Dipyridamole
' Glycoprotein (GP) IIb/IIIa receptor antagonists: Eptifibatide, tirofiban and abciximab.
' Other: Thromboxane A2 receptor antagonists; Omega-3 fatty acids; thromboxane synthase inhibitors; Monoclonal antibodies; .. etc MechanismMechanism ofof AntiplateletAntiplatelet ActionAction ofof TiclopidineTiclopidine inin ComparisonComparison toto CilostazolCilostazol
Ticlopidine ADP receptor
ATP ADP ADP Cilostazol
ADP Activation cAMP ADP TXA2 Phosphodiesterase Fibrinogen Receptor 5’AMP
ADP = adenosine diphosphate, TXA2 = thromboxane A2 RACTS-Purpose
To assess the safety and efficacy of cilostazol plus aspirin compared with conventional regimen using ticlopidine plus aspirin in patients undergoing coronary artery stenting. RACTS – Inclusion Criteria
The patient is 18 75 years old ; Symptomatic ischemic heart disease and/or evidence of myocardial ischemia ; Target lesion is 30mm in length ; Target lesion is 2.75mm and 4.0mm in diameter (QCA); The target lesions located in a native coronary artery which can be covered preferably by 1 stent (lesion 30 mm); two lesions in a vessel is allowed; Target lesion stenosis is >50% and <99%; No significant (>50%) stenosis proximal or distal to the target lesion that need to be treated during the procedure; RACTS – Exclusion Criteria
MI within 120 hours ˗ Unprotected left main coronary disease with 50% stenosis; Unstable angina Braunwald Class III B and C In-stent restenosis Target lesion involves bifurcation LVEF 30%; Totally occluded vessel (TIMI 0) Prior stent within 5mm of the target lesion; Current treatment with Warfarin® Known allergies to aspirin, clopidogrel , ticlopidine, heparin, or stainless steel; RACTS -Endpoints
Primary Endpoint : Restenosis rate and MLD after 6 months of procedure.
Secondary Endpoint: Death, myocardial infarction, cerebrovascular event, stent thrombosis, target vessel revascularization (TVR), and bleeding complication at 9 months.
Drug related events: Neutropenia, thrombocytopenia, liver dysfunction, etc., and early discontinuation of the study drug. RACTS –Study Design
Study Design Prospective, Randomized , Multi-center
Number of Patients 397
Patient Included Patients undergoing coronary stenting for coronary stenosis Study Drugs Cilostazol 100mg twice daily for 6 months Ticlopidine 250mg twice daily for 1 month Concomitant Drugs Aspirin 100mg once daily
Investigational Centers 7 Medical Centers in P.R.China RACTS -FLOW
AllAll RandomizedRandomized PatientsPatients N=397N=397
TiclopidineTiclopidineControl Control GroupGroup CilostazolCilostazolGroup Group N=196N=196 N=201N=201
AngioAngio followfollow upup atat 66 monthmonth˖˖83.683.6ˁˁ AngioAngiofollow follow upup atat 66 monthmonth ˖˖81.181.1ˁˁ ClinicalClinical followfollow upatupat9 9 monthmonth˖˖98.998.9ˁˁ ClinicalClinical followfollow upatupat9 9 monthmonth ˖˖99.599.5ˁˁ RACTS - Baseline Demographic Characteristics
Cilostazol Ticlopidine N=201 N=196 Mean age(years) 59.2f10.0 60.4f 9.9 Male sex(%) 83.6 79.1 Diabetes Mellitus(%) 11.4 12.2 Hyperlipidemia(%) 23.4 29.6 Hypertension(%) 55.7 60.2 Prior MI(%) 39.3 34.7 Ever smoked/Current smoker(%) 47.3 40.8 Family history (%) 13.9 10.2 ALL P>0.05 RACTS - Concomitant Medications
Cilostazol(%) Ticlopidine(%) N=201 N=196 Nitrate 85.5 81.6 ACE inhibitor 60.0 62.2 Beta-blocker 64.0 65.8 Lipid-lowering agent(HMG-CoA) 70.7 78.1 Calcium-channel blocker 34.7 38.4
ALL P>0.05 RACTS - Stent Procedural Details
Cilostazol(%) Ticlopidine(%) N=201 N=196 Target Lesion Calcified 24(9.6) 21(9.1) Diffuse target Lesion 49(19.7) 42(18.1) Number of Stent Implant 159(79.1) 161(82.1) 1 2 36(17.9) 34(17.3) 3 6(3.0) 1(0.5)
ALL P>0.05 RACTS - Baseline Angiographic Characteristics
3 3 11.9% 9.7% 2 2 1 No. of diseased vessels, P=0.150 19.9% 26.9% 61.2% 1 70.4%
RCA RCA 26.9% LAD Target Vessel 27.2% LAD location,P=0.301 51.8% 56.9% LCX LCX 21.3% 15.9%
Cilostazol+Aspirin Ticlopidine +Aspirin RACTS - Baseline Angiographic Characteristics
3.75- 7.2% 2.25- 10.0% 3.75- 2.6% 2.25-13.8% 3.25- 3.25- Reference diameter 24.5% 2.75- P=0.076 26.7% 2.75- 58.2% 56.9%
<10mm <10mm 9.5% >20mm 9.27% >20mm 17.7% 17.2% Lesion length 10-20mm P=0.990 10-20mm 73.1% 73.3%
Ticlopidine +Aspirin Cilostazol+Aspirin RACTS - Angiographic Results at 6 months
Cilostazol Ticlopidine P N=163 N=164 Minimal lumen diameter (mm)
Before 0.42f0.35 0.38f0.33 0.324 After 3.11f0.35 3.06f0.35 0.168 Follow-up 2.31f1.06 2.10f1.16 0.057 Stenosis (%) Before 76 f11 77f11 0.342 After 5.6 f6.4 4.9f7.2 0.142 Follow-up 34 f25 38f30 0.190 RACTS - Angiographic Results at 6 months
Cilostazol Ticlopidine P N=163 N=164 Acute lumen gain (mm) 2.69f0.45 2.67f0.43 0.727 Late lumen loss (mm) 0.80f1.00 0.96f1.08 0.120 Net lumen gain (mm) 1.89f1.07 1.71f1.14 0.107 Loss index 0.30f0.39 0.36f0.41 0.125 (late loss/acute gain) RACTS – QCA analysis
3.5 3.0 Cilostazol Late loss 1.89f1.07 2.5 Ticlopidine 2.0 1.71 1.5 Acute gain f1.14 Net gain P=0.107 1.0 0.5 0.0 PRE POST FOLLOW-UP (6 MONTHS)
ALLALL P>0.05P>0.05 RACTS - Angiographic Restenosis at 6 months
P=0.086 36.6% % 29.1% 35
30
25
20
15
10
5
0 Cilostazol+Aspirin Ticlopidine +Aspirin RACTS -Cumulative Frequency Distribution Curves
100 90 80 Pre- Follow-up Post- 70 Cilostazol Pre Ticlopidine Pre 60 Cilostazol Post
of stenosis 50 Ticlopidine post Cilostazol FU ˁ 40 Ticlopidine FU 30 20 10 0 Minimal Luminal Diameter (mm) 01234 RACTS -Stent Thrombosis
Cilostazol Ticlopidine N=201 N=196
Acute(<24hour) 0.5%(1) 0
Subacute(1~30days) 0.5%(1) 0.5%(1)
Late (>30days) 0 0.5%(1)
Total 1.0%(2) 1.0%(2) RACTS - Clinical Events During 9 Months
Cilostazol Ticlopidine N=201 N=196
Death 0(0.0) 2(1.0) Myocardial infraction 2 (1.0) 1(0.5) Cerebrovascular thrombosis 1(0.5) 1(0.5) Cerebrovascular Hemorrhage 0 (0.0) 1(0.5) Coronary bypass surgery 0 (0.0) 0 (0.0) TVR per patient* 46˄22.9˅ 64˄32.7˅ TVR per vessel* 50(25.3) 67 (34.5)
*P<0.05 RACTS-Cumulative curve for TVR per patients during 9 months follow-up
0.5
0.4 Ticlopidine Cilostazol 34.5% 0.3 36.4%
P=0.0151 0.2 25.3%
0.1 Patients requiring TVR(%) Patients requiring 0.0
0 0 0 0 0 0 0 0 0 2 4 60 80 60 80 10 12 14 1 1 200 22 24 26
Days after procedure RACTS- Safety
Cilostazol Ticlopidine (%)N=201 (%)N=196 Composite any of the below 10(5.0) 19(9.7) Neutropenia 0(0.0) 2(1.0) Thrombocytopenia 0(0.0) 0(0.0) Skin rash 4(2.0) 6(3.1) Minor bleeding complication Hematuria 0(0.0) 1(0.5) Gingival bleeding 0(0.0) 1(0.5) Liver dysfunction 2(1.0) 5(2.6) Headache(discontinuing drug) 2(1.0) 0(0.0) Nausea 2(1.0) 4(2.0)
ALL P>0.05 RACTS-Conclusion Cilostazol has equivalent beneficial effects to ticlopidine in 6 month restenosis rate and the frequency of short-term MACE. Cilostazol significantly reduced the long-term TVR rates compared to ticlopidine(time course?). Cilostazol tended to have less side effect rate but more headache compared to ticlopidine. Cilostazol may be used as a complementary drug for antiplatelet therapy when patient is allergic to ADP inhibitors.