Adjunctive Cilostazol Versus Double Dose Clopidogrel After PCI with Drug Eluting Stent : The HOST-ASSURE Randomized Trial Hyo-Soo Kim, MD/PhD Kyung-Woo Park, Si-Hyuck Kang, Kwang-Soo Cha, Byoung-Eun Park, Jay-Young Rhew, Hui-Kyung Jeon, In-Ho Chae On Behalf of The HOST-ASSURE Trial Investigators Seoul National University Hospital, Seoul, Korea

Background Inhibition of platelet reactivity in the first month post-PCI is critical in preventing thrombotic events. One-week duration of doubling the dose of clopidogrel was shown to improve outcome at one month compared with conventional dose in ACS patients undergoing PCI. Yet in Asia, the adjunctive use of cilostazol to dual antiplatelet therapy (triple antiplatelet therapy, TAT) is used more commonly than doubling the dose of clopidogrel (double-dose dual antiplatelet therapy, DDAT) in high-risk patients. However, there has been no large scale head-to-head comparison of TAT with DDAT to date with regard to clinical outcome.

Objectives Double-Dose Clopidogrel Dual Antiplatelet Therapy (DDAT) Triple Antiplatelet Therapy (TAT) vs. 2x2 Factorial Design PtCr-EES (Promus TM Element TM ) CoCr-ZES (Endeavor ® - Resolute) vs.

Objectives Double-Dose Clopidogrel Dual Antiplatelet Therapy (DDAT) Triple Antiplatelet Therapy (TAT) vs. 2x2 Factorial Design [Hypothesis] TAT is non-inferior to DDAT regarding net clinical outcome at 1 month vs. Triple Antiplatelet Therapy (TAT) Double-Dose Clopidogrel Dual Antiplatelet Therapy (DDAT) (DDAT)

Study Design TAT arm (N=1,875) TAT arm (N=1,875) DDAT arm (N=1,875) (N=1,875) 200 mg Cilostazol Loading No Cilostazol Loading Aspirin 100 mg QD Clopidogrel 75 mg QD Cilostazol 100mg BID Aspirin 100 mg QD Clopidogrel 75 mg QD Cilostazol 100mg BID Aspirin 100 mg QD Clopidogrel 150 mg QD Aspirin 100 mg QD Clopidogrel 150 mg QD 3,750 All Comers Receiving PCI PtCr-EES arm (N=2,500) PtCr-EES arm (N=2,500) CoCr-ZES arm (N=1,250) CoCr-ZES arm (N=1,250) Percutaneous Coronary Intervention Aspirin 300 mg + Clopidogrel mg Loading Net Clinical Outcome at 1 Month Post-PCI (Intention-To-Treat Analysis) Stent Arm 2:1 Randomization Anti-Platelet Arm 1:1 Randomization 40 Centers in Korea 2x2 Factorial Design Prospective, single-blinded, randomized multi-center trial

Enrollment Criteria General Inclusion Criteria Angiographic Inclusion Criteria Exclusion Criteria Age ≥18 years Ability to verbally confirm understandings of risks, benefits and treatment alternatives with written informed consent prior to any study-related procedure Significant lesion (>50% by visual estimate) in any of the coronary arteries, venous or arterial bypass grafts Evidence of myocardial ischemia or diameter stenosis > 70% Target lesion in coronary artery, venous or arterial bypass graft with diameter of ≥ 2.5 mm and ≤ 4.25 mm Target lesion amenable for PCI Known hypersensitivity/contraindication to heparin, aspirin, clopidogrel, cilostazol, everolimus, zotarolimus, or contrast media Systemic (intravenous) Everolimus or Zotarolimus use ≤ 12 months Female of childbearing potential History of bleeding diathesis, known coagulopathy (including HIT), abnormal CBC (Hb < 10 g/dL or PLT < 100k /μL) or refusal of blood transfusions LVEF <25% or cardiogenic shock GI or GU bleeding ≤ 3 months or major surgery ≤ 2 months Life expectancy <1 year Actively participating in another drug or device investigational study Symptomatic heart failure

Study Endpoints net clinical outcome at 1 monthPrimary Endpoint: net clinical outcome at 1 month (a composite of cardiac death, nonfatal MI, definite or probable ST, stroke and PLATO major bleeding) Secondary Endpoints –Cardiac death, all-cause death –Nonfatal MI: periprocedural/spontaneous MI –ARC-defined ST: definite or probable ST, definite ST, probable ST –Stroke –PLATO major/minor bleeding –Target vessel revascularization (TVR) –Target lesion revascularization (TLR) Platelet Function Test: VerifyNow P2Y12 Assay 1)At hours after loading of clopidogrel 2)At 1-month F/U under maintenance dose

Statistical Assumption Assumption –2% in TAT group –3% in DDAT group Non-inferiority Margin: 0.75% for Primary Endpoint –Type I error (1-sided α): 2.5% –Attrition rate: 2.5% –Primary Analysis: Intention-to-treat analysis –Statistical power >90% (β<0.10)  N=3,750 Non-inferiority Design for Primary Endpoint (net clinical outcome at 1 month) Non-inferiority Design for Primary Endpoint (net clinical outcome at 1 month)

Hyo-Soo Kim Investigators at the Cardiovascular Clinical Research Center at Seoul National University Hospital Dream CIS Inc. (contract research organization) Seung-Woo Park, Young-Jin Choi, Kwangil Kim Yong-Seok Kim, Sang Min Park, Nae Hee Lee Trial Coordination Data Safety Monitoring Board Data Management Clinical Event Adjudication Committee Principal Investigator Hyo-Soo Kim, In-Ho Chae, Kwang Soo Cha, Byoung Eun Park, Jay Young Rhew, Hui-Kyung Jeon Executive Committee

Participating Centers 40 Hospitals in Republic of Korea SitePI Seoul National University HospitalKim, Hyo-Soo Seoul National University Bundang HospitalChae, In-Ho Pusan National University HospitalCha, Kwang Soo Dankook University HospitalPark, Byoung Eun Presbyterian Medical CenterRhew, Jay Young Uijeongbu St. Mary’s HospitalJeon, Hui-Kyung Ulsan University HospitalShin, Eun Seok Samsung Changwon HospitalOh, Ju Hyeon Chonnam National University HospitalJeong, Myung-Ho Chungbuk National University HospitalHwang, Kyung-Kuk Wonju Christian HospitalYoon, Jung-Han Inje University Ilsan Paik HospitalLee, Sung Yun Boramae Medical CenterKim, Sanghyun Dong-A Medical CenterPark, Tae-Ho Gangnam Severance HospitalKwon, Hyuck-Moon St. Vincent’s HospitalMoon, Keon Woong Daegu Catholic University Medical CenterRyu, Jae-Kean Keimyung University Dongsan Medical CenterHur, Seung-Ho Daegu Fatima HospitalLee, Bong-Ryul Gyeongsang National University HospitalPark, Yong-Whi SitePI Konyang University HospitalBae, Jang-Ho Hallym University Kangdong Sacred Heart HospitalHan, Kyoo-Rok Ewha Womans University Mokdong HospitalPark, Si-Hoon Korea University Guro HospitalRha, Seung-Woon Hallym University Sacred heart HospitalPark, Woo-Jung Wongwang University HospitalOh, Seok-Kyu Korea University Anam HospitalLim, Do-Sun Kwangju Christian HospitalLee, Seung-Wook Hallym University Chuncheon Sacred Heart HospitalYoon, Duck-Hyoung Kyung Hee University Hospital at GangdongKim, Chong-Jin Seoul Medical CenterKim, Seok-Yeon Gachon University Gil HospitalAhn, Taehoon Samsung Medical CenterGwon, Hyeon-Cheol Hallym University Kangnam Sacred Heart HospitalLee, Namho National Health Insurance Medical CenterJeon, Dong-Woon Soonchunhyang University HospitalHyun, Min-Soo Daejun Eulji University HospitalLee, Sang Hanyang University Guri HospitalLee, Jaewoong Kangwon National University HospitalRyu, Dong Ryeol Kosin University Gospel HospitalCha, Tae-Joon

3,755 Patients Enrolled and Randomized Allocated to TAT (N=1,879) Allocated to DDAT (N=1,876) Received TAT as Randomized (N=1,830) Received DDAT as Randomized (N=1,730) Adhered to TAT for 1 Month (N=1,721) Adhered to DDAT for 1 Month (N=1,623) 107 Did not adhere to allocated treatment 4 Lost to follow-up 17 Cardiovascular events 13 Had bleeding 8 Had side effects 9 Voluntarily withdrawn or poorly compliant 23 At physicians’ discretion 33 Other reasons 109 Did not adhere to allocated treatment 4 Lost to follow-up 9 Cardiovascular events 14 Had bleeding 34 Had side effects 11 Voluntarily withdrawn or poorly compliant 18 At physicians’ discretion 19 Other reasons 1,879 Patients Analyzed According to ITT 1,876 Patients Analyzed According to ITT 49 Did not receive allocated treatment 4 Did not receive coronary stenting 4 Did not meet inclusion criteria 14 Patient decision 27 Other reasons 146 Did not receive allocated treatment 7 Did not receive coronary stenting 11 Did not meet inclusion criteria 97 Patient decision 31 Other reasons Trial Flow

Baseline Characteristics CharacteristicTAT(N=1,879)DDAT(N=1,876) Age62.8± ±10.9 Men1,311 (69.8)1,257 (67.0) Body mass index24.7± ±3.1 Hypertension1,256 (66.8)1,286 (68.6) Diabetes598 (31.8)588 (31.3) insulin-requiring diabetes66 (3.5)71 (3.8) Dyslipidemia1,206 (64.2)1,176 (62.7) Current smoker616 (32.8)577 (30.8) Chronic renal failure42 (2.2)50 (2.7) Peripheral artery disease44 (2.3)24 (1.3) Cerebrovascular disease120 (6.4)128 (6.8) Previous PCI188 (10.0)181 (9.6) Previous bypass surgery11 (0.6)15 (0.8) Pervious MI69 (3.7)96 (5.1) Previous CHF23 (1.2)31 (1.7)

Baseline Characteristics CharacteristicTAT(N=1,879)DDAT(N=1,876) Clinical diagnosis Slient ischemia96 (5.1)86 (4.6) Stable angina564 (30.0)549 (29.3) Unstable angina690 (36.7)688 (36.7) NSTEMI328 (17.5)332 (17.7) STEMI201 (10.7)221 (11.8) Baseline laboratory findings Left ventricular ejection fraction (%)60.3± ±10.3 Hemoglobin (g/dL)13.7± ±1.7 Platelet count (x10 3 /mm)227±63227±61 Serum creatinine (mg/dL)1.0±0.8 Total cholesterol (mg/dL)178±44177±44 Triglyceride (mg/dL)143±93136±95 HDL-cholesterol (mg/dL)44±1244±11 LDL-cholesterol (mg/dL)110±42109±38

Baseline Characteristics CharacteristicTAT(N=1,879)DDAT(N=1,876) Medications at discharge Aspirin1,867 (99.4)1,862 (99.3) Clopidogrel1,866 (99.3)1,863 (99.3) β-blocker1,277 (68.0)1,277 (68.1) Calcium channel blocker357 (19.0)407 (21.7) ACE inhibitor or ARB1,215 (64.7)1,248 (66.5) CYP3A4-metabolized statin*1,032 (54.9)1,060 (56.5) Non-CYP3A4-metabolized statin**545 (29.0)559 (29.8) Proton pump inhibitor153 (8.1)148 (7.9) *CYP3A4-metabolized statin: simvastatin, lovastatin, atorvastatin, etc **Non-CYP3A4-metabolized statin: rosuvastatin, pravastatin, pitavastatin, fluvastatin

Angiographic & Procedural Characteristics CharacteristicTAT(N=1,879)DDAT(N=1,876) P Value Angiographic disease extent vessel disease856 (45.6)877 (46.7) 2-vessel disease618 (32.9)590 (31.4) 3-vessel disease405 (21.6)409 (21.8) Number of lesions treated per patient1.5± Stent arm – intention-to-treat0.972 Promus-Element arm1,253 (66.7)1,250 (66.6) Endeavor-Resolute arm626 (33.3)626 (33.4) Type of drug-eluting stents – per protocol0.552 No stents used14 (0.7)9 (0.5) Promus-Element1,198 (63.8)1,202 (64.1) Endeavor-Resolute587 (31.2)573 (30.5) Others80 (4.3)92 (4.9) Number of stents per patient1.6± Use of IVUS or OCT737 (39.2)763 (40.7)0.365 Treatment of left main disease57 (3.0)55 (2.9)0.852 Treatment of bifurcation lesions308 (16.4)303 (16.2)0.842 Use of glycoprotein IIb/IIIa inhibitors46 (2.4)50 (2.7)0.673

TAT1,8791,8551,8451,8321,7631,538DDAT1,8761,8481,8361,8201,7641,525 Cumulative Incidence of Primary Endpoint (%) TAT: 1.2% DDAT: 1.4% Primary Endpoint No. at Risk Composite of Cardiac death, nonfatal MI, stroke, definite/probable ST, and PLATO major bleeding Days after Randomization Non-inferiority P<0.001 Superiority P=0.566

TAT1,8791,8551,8451,8321,7631,538 DDAT1,8761,8481,8361,8201,7641,525 Landmark Analysis No. at Risk Cumulative Incidence of Primary Endpoint (%) Days after Randomization P=0.343 P=0.566 Overall P=0.565 Composite of Cardiac death, nonfatal MI, stroke, definite/probable ST, and PLATO major bleeding TAT DDAT

TAT (N=1,879) 23 (1.22%) DDAT (N=1,876) 27 (1.44%) Absolute Risk Difference: -0.22% (standard error: 0.37%) Upper 1-sided 97.5% CI: 0.52% Primary Endpoint Composite of Cardiac death, nonfatal MI, stroke, definite/probable ST, and PLATO major bleeding Predefined margin : 0.75% Non-inferiority P=0.005 Risk Difference with 1-sided 97.5% CI (TAT-DDAT)

Landmark Analysis Days after Randomization Cumulative Incidence (%) Overall P= P=0.563 P=0.179 Nonfatal MI DDAT TAT Days after Randomization Cumulative Incidence (%) Overall P= P=0.999 PLATO Major Bleeding DDAT TAT Days after Randomization Overall P= P=0.998 P=0.801 Cardiac Death DDAT TAT Cumulative Incidence (%) Days after Randomization Overall P= P=0.256 P=0.391 Definite/Probable ST DDAT TAT Cumulative Incidence (%) Days after Randomization P=0.343 P=0.566 Overall P=0.565 Primary Endpoint DDAT TAT Cumulative Incidence (%) Days after Randomization Overall P= P=0.157 P=0.659 StrokeStroke DDAT TAT Cumulative Incidence (%)

Clinical Outcomes End point Event Rates at D/C Event Rates at 1 Month Hazard Ratio (95% CI) PTAT(N=1,879)DDAT(N=1,876)TAT(N=1,879)DDAT(N=1,876) Primary end point16 (0.9)17 (0.9)23 (1.2)27 (1.4)0.85 ( )0.566 Secondary end points Cardiac death6 (0.3)5 (0.3)8 (0.4)7 (0.4)1.14 ( )0.798 Nonfatal MI6 (0.3)8 (0.4)7 (0.4)13 (0.7)0.54 ( )0.185 Periprocedural MI6 (0.3)8 (0.4)6 (0.3)8 (0.4)0.75 ( )0.591 Spontaneous MI0 (0.0) 1 (0.1)5 (0.3)0.20 ( )0.141 Stroke2 (0.1)3 (0.2)2 (0.1)3 (0.2)0.67 ( )0.656 Ischemic stroke2 (0.1)3 (0.2)2 (0.1)3 (0.2)0.67 ( )0.656 ST, definite or probable2 (0.1) 4 (0.2)7 (0.4)0.57 ( )0.371 ST, definite1 (0.1)0 (0.0)2 (0.1)4 (0.2)0.50 ( )0.423 ST, probable1 (0.1)2 (0.1) 3 (0.2)0.67 ( )0.656 PLATO major bleeding3 (0.2)4 (0.2)8 (0.4) 1.00 ( )0.999 Other events All-cause death6 (0.3)8 (0.4)9 (0.5)11 (0.6)0.82 ( )0.654 PLATO minor bleeding9 (0.5)1 (0.1)12 (0.6)6 (0.3)2.00 ( )0.165 TLR3 (0.2)1 (0.1)4 (0.2)5 (0.3)0.80 ( )0.739 TVR3 (0.2)1 (0.1)7 (0.4)5 (0.3)1.40 ( )0.567 *Primary endpoint : a composite of cardiac death, nonfatal MI, stent thrombosis, stroke and PLATO major bleeding at 1 month

Secondary Endpoints at 1 Month Cardiac Death p=0.798 TAT N=1,879 DDAT N=1,876TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 Nonfatal MI p=0.185 Periprocedural MI p=0.591 Spontaneous MI p= % 0.37% 0.69% 0.32% 0.43% 0.05% 0.27%

TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 Secondary Endpoints at 1 Month Definite/Probable ST p=0.371 Definite ST p=0.423 Probable ST p=0.656 ARC Stent Thrombosis 0.21% 0.37% 0.11% 0.21% 0.11% 0.16%

Secondary Endpoints at 1 Month TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 Stroke p=0.656 PLATO Major Bleeding p= % 0.16% 0.43%

Other Events at 1 Month All-Cause Death p=0.654 TAT N=1,879 DDAT N=1,876TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 TAT N=1,879 DDAT N=1,876 PLATO Minor Bleeding p=0.165 Target Lesion Revascularization p=0.739 Target Vessel Revascularization p= % 0.59% 0.64% 0.32% 0.21% 0.27% 0.37% 0.27%

Per-Protocol Analysis End point TAT(N=1,773)DDAT(N=1,637) Hazard Ratio (95% CI) P Primary end point21 (1.2)27 (1.6)0.73 ( )0.287 Secondary end points Cardiac death7 (0.4) 0.92 ( )0.918 Nonfatal MI6 (0.3)13 (0.8)0.44 ( )0.092 Periprocedural MI6 (0.3)8 (0.5)0.71 ( )0.522 Spontaneous MI0 (0.0)5 (0.3) Stroke1 (0.1)3 (0.2)0.32 ( )0.317 Ischemic stroke1 (0.1)3 (0.2)0.32 ( )0.317 ST, definite or probable3 (0.2)7 (0.4)0.41 ( )0.191 ST, definite1 (0.1)4 (0.2)0.24 ( )0.198 ST, probable2 (0.1)3 (0.2)0.63 ( )0.614 PLATO major bleeding8 (0.5) 0.95 ( )0.912 *Primary endpoint : a composite of cardiac death, nonfatal MI, stent thrombosis, stroke and PLATO major bleeding at 1 month

TAT1,7331,7141,7081,6971,6371,427DDAT1,6371,6181,6071,5981,5481,337 Cumulative Incidence of Primary Endpoint (%) TAT: 1.2% DDAT: 1.6% No. at Risk Days after Randomization Primary Endpoint – Per Protocol Composite of Cardiac death, nonfatal MI, stroke, definite/probable ST, and PLATO major bleeding HR: 0.73 ( ) P=0.287

Subgroup Analysis Subgroups Pt No. Δ Absolute Risk at 1 Month (95% CI) P Int P Age≥ 65 years1, < 65 years1, SexMen2, Women1, Acute coronary syndromeYes2, No1, Diabetes mellitusYes1, No2, Presence of renal dysfunctionYes No3, Concomittant use of statinYes3, No Concomittant use of CCBsYes No2, Allocated stent armPromus-Element2, Endeavor-Resolute1, Multivessel stentingYes2, No1, Total3, Favors TAT Favors DDAT

On-Clopidogrel Platelet Reactivity At Baseline (12-24 hours after the loading dose) At Baseline (12-24 hours after the loading dose) TATDDAT 173±97213±93 P<0.001 P2Y12 Reaction Units

On-Clopidogrel Platelet Reactivity At 1 Month (after maintenance dose) At 1 Month (after maintenance dose) TATDDAT P2Y12 Reaction Units 169±80192±80 P<0.001

Limitations 1.Event rates were lower than expected -Expected rate of primary endpoint in DDAT group: 3.0% -Actual event rate: 1.4%  Possibility of being underpowered 2.Chance of under-reporting -Dedicated periodic on-site monitoring was performed -Event rates after PCI are known to be lower in Asian population 3.Low rates of peri-procedural MI -Cardiac enzyme measurement was not mandated 4.Non-adherence to allocated treatment may have affected outcomes - Non-adherence rate: 91.6% (TAT group) and 86.5% (DDAT group) - However, PP analysis yielded consistent results

The adjunctive use of cilostazol in addition to conventional dual antiplatelet therapy was noninferior to doubling the maintenance dose of clopidogrel in this all-comer PCI population receiving exclusively drug-eluting stents with regard to net clinical outcome at 1 month. There were no differences between the two treatment regimens regarding the individual components of the primary outcome.

Adjunctive Cilostazol Versus Double Dose Clopidogrel After PCI with Drug Eluting Stent : The HOST-ASSURE Randomized Trial Hyo-Soo Kim, MD/PhD Kyung-Woo Park, Si-Hyuck Kang, Kwang-Soo Cha, Byoung-Eun Park, Jay-Young Rhew, Hui-Kyung Jeon, In-Ho Chae On Behalf of The HOST-ASSURE Trial Investigators Seoul National University Hospital, Seoul, Korea