A Prospective Randomized Multi-center Study of Antiplatelet using versus 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 , ADP inhibitor and GP IIb/IIIa antagonist. Cilostazol Newly developed aggregation inhibitor Increases the intracellular concentration of cAMP by inhibiting III Decrease neointimal proliferation Decrease MACE and restenosis rate after PCI. Antiplatelet Agent Overview

' TXA2 antagonists: Aspirin

' ADP antagonists: -Ticlopidine and

' Phosphodiesterase inhibitors: Cilostazol and

' Glycoprotein (GP) IIb/IIIa receptor antagonists: , and .

' Other: 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 = 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 ®  Known allergies to aspirin, clopidogrel , ticlopidine, , 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, , 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

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 -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.