STENT THROMBISIS Insights on Outcomes and Impact of DUAL ANTIPLATELET THERAPY Permanent Discontinuation SPIRIT II, SPIRIT III, SPIRIT IV and COMPARE Elvin Kedhi Gregg. W. Stone, Dean J. Kereiakes, Patrick W. Serruys, Helen Parise, Martin Fahy, Charles A. Simonton, Krishnankutty Sudhir, Poornima Sood, Pieter C. Smits.

Background Recent studies have suggested that EES may reduce ST compared to PES, but no individual trial has been adequately powered for this endpoint The on-going propensity of the first generation DES for ST has lead towards longer DAPT regimens in current practice (Current guidelines: 1 year or more), despite the associated risks of such treatment and despite the lack of evidence that such an approach improves clinical outcomes post PCI Whether DAPT duration with newer generation DES can be shortened is unknown

Objective To investigate ST incidence with second generation EES as compared to first generation PES relation between the 2 year ST rates and permanent discontinuation of DAPT in EES and PES treated patients from a patient level pooled analysis SPIRIT II, SPIRIT III, SPIRIT IV and COMPARE trials

Design Summary of the four (EES vs PES) Trials Pooled for the Analysis (n=6789) Study Population Geography Study Design Device usage SPIRIT II 300 (3:1) Europe India New Zealand Multi-center randomized blinded active-control On-label SPIRIT III 1002 (2:1) USA SPIRIT IV 3687(2:1) COMPARE 1800(1:1) Netherlands Single-center Randomised All-comer EES : Xience V Abbott Vascular, Santa Clara (CA) USA PES : Taxus Boston Scientific, Natick (MA) USA

Methods Baseline clinical, angiographic and procedural data of the four trials were pooled to allow for a patient-level analysis Events as adjudicated in each trial were utilized To adjust for slight differences in the baseline characteristics of the study population, a propensity score matching analysis was performed The ST analyses were performed using time-to-event data and were compared with the log-rank test before and after PS adjustment

RESULTS Baseline patient demographic characteristics   EES PES p Age (years) 63.09 ± 10.61 (4247) 63.36 ± 10,68 (2541) 0.30 Gender: Male 68.5% (2911/4247) 69.5% (1766/2541) 0.42 Diabetes mellitus 28.0% (1188/4244) 26.9% (681/2536) 0.31 - Insulin-treated 7.3% (310/4244) 7.3% (184/2536) 0.96 Smoking During Past Year 25.0% (1042/4176) 25.0% (624/2493) 0.95 Hypertension 70.1% (2976/4243) 66.1% (1677/2537) <0.001 Hyperlipidemia 70.5% (2949/4184) 65.8% (1658/2518) <0.0001

RESULTS Baseline patient demographic characteristics   EES PES p Prior CABG 7.2% (306/4244) 6.0% (153/2541) 0.06 Prior myocardial infarction 20.4% (847/4157) 19.0% (476/2508) 0.17 Prior PCI 14.5% (610/4194) 13.9% (350/2516) 0.49 Stable angina 53.8% (2254/4193) 49.8% (1248/2506) 0.002 Unstable angina 22.9% (959/4193) 22.3% (559/2506) 0.61 Stable ischemic heart disease 67.2% (2854/4247) 61.1% (1551/2539) <0.0001 Acute coronary syndrome 32.8% (1393/4247) 38.9% (988/2539)

RESULTS Baseline procedural characteristics   EES PES p Vessel Location--RCA 34.2% (1865/5460) 33.8% (1132/3353) 0.71 Vessel Location--LAD 40.5% (2209/5460) 39.6% (1329/3353) 0.45 Vessel Location--LCX 25.0% (1364/5460) 25.9% (870/3353) 0.31 Vessel Location--LM 0.4% (22/5460) 0.7% (22/3353) 0.12 Vessel Location--SVG 0.5% (27/5460) 0.7% (24/3353) 0.19 Modified ACC/AHA Lesion Class A 9.0% (487/5417) 9.3% (309/3334) 0.67 Modified ACC/AHA Lesion Class B1 33.6% (1820/5417) 31.8% (1060/3334) 0.08 Modified ACC/AHA Lesion Class B2 31.7% (1716/5417) 31.0% (1034/3334) 0.52 Modified ACC/AHA Lesion Class C 25.7% (1394/5417) 27.9% (931/3334) 0.02

RESULTS Baseline procedural characteristics   ESS PES p Number treated lesions 1.29 ± 0.53 (4246) 1.32 ± 0.57 (2540) 0.02 Number treated vessels 1.20 ± 0.43 (4246) 1.22 ± 0.44 (2541) 0.04 Pre-procedure LL (mm) 15.96 ± 9.50 (4963) 16.78 ± 11.60 (2867) 0.001 Pre-procedure RVD (mm) 2.68 ± 0.51 (5077) 2.68 ± 0.54 (2958) 0.88 Pre-procedure MLD (mm) 0.80 ± 0.42 (5103) 0.83 ± 0.44 (2986) 0.01 Pre-procedure %DS 70.3 ± 14.7 (5147) 69.5 ± 15.5 (3007) 0.03 Total stent length (mm) 32.2 ± 21.6 (4227) 34.0 ± 25.8 (2530) 0.004 Total number stents 1.7 ± 1.0 (4238) 1.7 ± 1.1 (2538) 0.05

DAPT compliance during 2y FU   EES PES p Discharge Aspirin 97.3% (4123/4238) 96.9% (2454/2533) 0.33 Any thienopyridine 99.3% (4208/4238) 99.4% (2517/2533) 0.76 Aspirin + any thienopyridine 96.9% (4106/4238) 96.7% (2449/2533) 0.67 6-Months 95.9% (4047/4220) 94.5% (2379/2517) 0.01 Any Thienopyridine 96.8% (4085/4220) 96.9% (2439/2517) 0.89 93.6% (3964/4233) 92.5% (2338/2528) 0.07 1-Year 93.7% (3929/4194) 92.7% (2318/2501) 0.12 81.7% (3428/4194) 81.3% (2033/2501) 0.65 78.3% (3310/4230) 77.0% (1941/2522) 0.23 2-Year 91.0% (3772/4144) 91.1% (2243/2461) 53.3% (2209/4144) 47.8% (1177/2461) <0.0001 50.0% (2107/4215) 44.5% (1117/2508)

Unadjusted def/prob (ARC) ST at 2y <0.0001 2·3% EES PES HR 0·30 [95% CI: 0·19 to 0·47] p = <0·0001 Unadjusted ARC Definite/Probable (%) Unadjustzd ARC Definite/Probable (%) 1 2 3 Time in Months 4247 4177 4082 3998 3479 2542 2463 2408 2350 2110 Number at risk p= <.001 HR: 0.30 [95% CI: 0.19, 0.47] 0.7% 2.3% 6 9 12 15 18 21 24 HR:0.21 95%CI:[0.10,0.46] p<0.0001

Unadjusted and PS adjusted definite/probable ST (ARC) <0.0001 2·3% EES PES HR 0·30 [95% CI: 0·19 to 0·47] p = <0·0001 Unadjusted ARC Definite/Probable (%) Unadjustzd ARC Definite/Probable (%) 1 2 3 Time in Months 4247 4177 4082 3998 3479 2542 2463 2408 2350 2110 Number at risk p= <.001 HR: 0.30 [95% CI: 0.19, 0.47] 0.7% 2.3% 6 9 12 15 18 21 24 2.2% 0.9% EES PES HR 0·37 [95% CI: 0·22 to 0·63] p = <0·001 Adjusted ARC Definite/Probable (%) Adjusted ARC Definite/Probable (%) 1 2 3 Time in Months 2348 2310 2263 2218 1959 2283 2236 2186 1968 Number at risk p= <.001 HR: 0.37 [95% CI: 0.22, 0.63] 6 9 12 15 18 21 24

Unadjusted definite ST (ARC) at 2y 1·6% 0·5% HR 0·30 [95% CI: 0·18 to 0·52] p = <0·001 Unadjusted ARC Definite (%) Unadjusted ARC Definite (%) 1 2 3 Time in Months 4247 4178 4084 4001 3483 2542 2466 2413 2358 2121 Number at risk EES PES p= <.001 HR: 0.30 [95% CI: 0.18, 0.52] 0.5% 1.6% 6 9 12 15 18 21 24

Unadjusted and PS adjusted definite ST at 2 years (ARC) EES EES PES 3 PES EES PES 3 HR 0·30 [95% CI: 0·18 to 0·52] p = <0·001 HR: 0.30 [95% CI: 0.18, 0.52] HR: 0.37 [95% CI: 0.19, 0.70] HR 0·37 [95% CI: 0·19 to 0·70] p = 0·001 p= <.001 p= 0.001 2 2 Unadjusted ARC Definite (%) Adjusted ARC Definite (%) Unadjusted ARC Definite (%) 1·6% 1.5% 1.5% 1.6% Adjusted ARC Definite/Probable (%) 1 1 0·5% 0.5% 0.6% 0.6% 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24 Time in Months Time in Months Number at risk Number at risk EES 4247 4178 4084 4001 3483 EES 2348 2311 2265 2221 1962 PES 2542 2466 2413 2358 2121 PES 2348 2286 2240 2193 1978

ST Incidence Rate 1 year EES PES HR [95% C.I.] p Early ST (0-30 Days)   EES PES HR [95% C.I.] p Early ST (0-30 Days) ARC Definite 0.2% (9) 0.8% (19) 0.28 [0.13,0.63] 0.0009 ARC Definite/Probable 1.0% (25) 0.21 [0.10,0.46] <0.0001 Late ST (31-365 Days) 0.1% (5) 0.4% (10) 0.30 [0.10,0.87] 0.02 0.6% (14) 0.38 [0.17,0.88] ST (0-365 Days) 0.3% (14) 1.2% (29) 0.29 [0.15,0.54] 0.4% (18) 1.5% (38) 0.28 [0.16,0.49] Cardiac Death or MI (0-30 Days) 1.6% (68) 2.8% (70) 0.58 [0.41,0.81] 0.001 (0-365 Days) 2.7% (113) 4.5% (114) 0.59 [0.45,0.76]

ST (ARC) Incidence Rate at 2 years   EES PES HR [95% C.I.] p Very Late ST (366-730 Days) ARC Definite 0.2% (6) 0.5% (11) 0.32 [0.12,0.87] 0.02 ARC Definite/Probable 0.3% (10) 0.8% (19) 0.31 [0.14,0.67] 0.001 ST (0-730 Days) 0.5% (20) 1.6% (39) 0.30 [0.18,0.52] <0.0001 0.7% (28) 2.3% (56) 0.30 [0.19,0.47] Cardiac Death or MI (0-730 Days) 4.0% (166) 6.6% (163) 0.60 [0.48,0.74] Does EES improved safety profile have an impact on DAPT duration?

DAPT permanent discontinuation analysis (either aspirin and/or a thienopyridine) DAPT status at 0,1,6, 12 and 24 months as well as at event time was known in all studies 1-6 m NO DAPT ST 2y DAPT 6-12 m NO DAPT DAPT 12-24m PCI 1 month 6 months 12 months 24 months DAPT Patients in whom a ST occurred while not on DAPT were included in the respective DAPT interruption group based on their DAPT status at the time of the event, regardless of DAPT usage afterwards

ST at 2 years according DAPT discontinuation timing DAPT interruption 1-6 m 6-12m 12-24m No DAPT interruption >24m p EES 75.0% (75/100) 92.3% (562/609) 97.8% (1168/1194) 97.5% (1969/2019) <0.0001 ARC Definite 1.1% (1) 0.2% (1) 0.3% (4) 0.6% (11) 0.43 ARC Probable 0.0% (0) 0.3% (2) 0.2% (2) 0.2% (4) 0.86 ARC Def/Prob 0.5% (3) 0.5% (6) 0.8% (15) 0.75 PES 74.3% (55/74) 94.6% (336/355) 98.2% (808/823) 97.1% (1023/1054) 6.2% (4) 1.1% (4) 1.4% (11) 1.3% (14) 0.01 1.2% (4) 1.0% (8) 0.3% (3) 0.16 2.3% (8) 2.3% (19) 1.5% (16) 0.05

Two-year Cumulative Def/Prob ST (ARC) according to DAPT Permanent Discontinuation p for trend= 0.75 p for trend = 0.05 discontinuation at 24 m No DAPT DAPT discontinuation 1-6 m DAPT discontinuation 6-12 m DAPT discontinuation 12-24 m

DAPT permanent discontinuation LANDMARK ANALYSIS 6m ST 2y DAPT Events of first 6m excluded Group 1 6-12m NO DAPT DAPT Group 1 12-24 m NO DAPT DAPT Group 3 >24m 1 month 6 months 12 months 24 months PCI DAPT permanent discontinuation

Two-year Cumulative Definite/Probable Stent Thrombosis (ARC) Landmark Analysis Beyond 6 Months 2.5 EES PES p for trend = 0·97 p for trend = 0·04 2 1·7 1.5 p = 0·82 p = 0·51 1·2 Stent Thrombosis Definite/Probable ARC (%) p = 0·86 p = 0·17 1 p = 0·89 p = 0·01 0·5 1.5 0·4 0·4 0·3 discontinuation at 24 m No DAPT DAPT discontinuation 6-12 m DAPT discontinuation 12-24 m discontinuation at 24 m No DAPT DAPT discontinuation 6-12 m DAPT discontinuation 12-24 m

Conclusions Second generation EES (Xience V) was associated with a significant reduction in definite and definite/probable ST at 2 years as compared to first generation PES (Taxus) This reduction was already present in early phase and increased in magnitude during the first and second year of FU The reduction in ST rates with EES was paralleled by a significant reduction in the rate of the composite safety endpoint of Death and Myocardial Infarction

Conclusions Permanent DAPT discontinuation at any time beyond one month did not impact ST rates at 2 years in EES (Xience V) treated patients, while DAPT treatments longer that 2 years may be safer for PES (Taxus) treated patients The hypothesis that DAPT could be safely permanently discontinued starting from 6 months after EES implantation is supported from findings of the landmark analysis These results should be regarded as hypothesis generating and need to be confirmed by larger dedicated randomised studies