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12 -month clinical and 13 -month angiographic outcomes from a randomized trial evaluating the 12 -month clinical and 13 -month angiographic outcomes from a randomized trial evaluating the Absorb Bioresorbable Vascular Scaffold vs. metallic drug-eluting stent in de novo native coronary artery lesions ABSORB JAPAN Takeshi Kimura M. D. and Gregg W. Stone M. D. on behalf of the ABSORB Japan Investigators

ABSORB Japan Study Backgrounds Theoretically, bioresorbable vascular scaffolds (BVS) may overcome the shortcomings of ABSORB Japan Study Backgrounds Theoretically, bioresorbable vascular scaffolds (BVS) may overcome the shortcomings of permanent metallic prosthesis. However, whether BVS are as safe and effective as metallic DES prior to complete bioresorption is currently unknown. Therefore, a randomized, controlled trial comparing the clinical and angiographic outcomes of BVS with those of Xience cobalt-chromium everolimus-eluting stents (Co. Cr-EES) was designed to support regulatory approval of the Absorb BVS in Japan.

ABSORB Japan Prospective, randomized, active control, single-blind, non-inferiority, multi-center Japanese study Inclusion: Patients with ABSORB Japan Prospective, randomized, active control, single-blind, non-inferiority, multi-center Japanese study Inclusion: Patients with up to 2 de novo target lesions in separate native coronary arteries Lesion length ≤ 24 mm, Dmax ≥ 2. 5 mm to ≤ 3. 75 mm, %DS ≥ 50% to <100% Exclusion: AMI, EF <30%, e. GFR <30 m. L/min/1. 73 m 2, LMCA, Ostial lesion, Excessive vessel tortuosity, Heavy calcification, Myocardial bridge, Bifurcation with side branch ≥ 2 mm Randomized 2: 1 BVS Co. Cr-EES Tx. with single study device Diameter: 2. 5, 3. 0. 3. 5 mm Length: 8, 12, 18, 28 mm Primary Clinical Endpoint: Target Lesion Failure (TLF): Cardiac death, TV-MI, ID-TLR at 12 months Major Secondary Angiographic Endpoint: In-segment Late Lumen Loss at 13 months

ABSORB Japan • • Sample Size Calculation 12 -Month TLF Randomization ratio: 2 to ABSORB Japan • • Sample Size Calculation 12 -Month TLF Randomization ratio: 2 to 1 Non-inferiority study design Significance level: 5% (one tail) Assumed event rate of 12 -month TLF in the Co. Cr-EES arm: 9% Non-inferiority Margin: 8. 6% Power: 90% Required Sample Size: 390 patients (BVS: 260, Co. Cr-EES: 130) Total Sample Size: 400 patients assuming dropouts If the non-inferiority P-value from the one-sided Farrington-Manning test is <0. 05, BVS is regarded as non-inferior to Co. Cr-EES for the primary endpoint. True rate was based on results from SPIRIT III RCT and SPIRIT III Japan, and 95% UCI was applied. Non-inferiority margin was ½ of treatment effect of Co. Cr-EES over BMS, i. e. (1 st Gen DES – BMS) + (Co. Cr-EES – 1 st Gen DES)

ABSORB Japan Imaging Follow-up Clinical FU Imaging FU The ABSORB Japan had an extensive ABSORB Japan Imaging Follow-up Clinical FU Imaging FU The ABSORB Japan had an extensive imaging follow-up protocol including angiography, IVUS, OCT, and MSCT. Post-procedure intracoronary imaging evaluation was mandatory in the IVUS and OCT-1 groups, while it was not allowed in the OCT-2 group.

ABSORB Japan Study Organization Study Protocol Committee: Takeshi Kimura (Principal Investigator), Ken Kozuma, and ABSORB Japan Study Organization Study Protocol Committee: Takeshi Kimura (Principal Investigator), Ken Kozuma, and Kengo Tanabe Data management: Abbott Vascular Safety Oversight Committee: Harvard Clinical Research Institute (HCRI) Clinical Events Committee: Harvard Clinical Research Institute (HCRI) Angiographic Core laboratory: Beth Israel Deaconess Medical Center, Inc. , Angiographic Core Lab, IVUS Core laboratory: Cardiovascular Core Analysis Laboratory (CCAL), Stanford University OCT Core laboratory: Cardialysis BV, Rotterdam, the Netherlands MSCT Core laboratory: Cardiocore Japan

ABSORB Japan Patient Flow Chart Randomized (N=400) Enrollment from 38 Japanese centers Between April ABSORB Japan Patient Flow Chart Randomized (N=400) Enrollment from 38 Japanese centers Between April 27, 2013 and December 27, 2013 BVS (N=266) Co. Cr-EES (N=134) Withdraw consent without POCE: 1 BES (N=1617) BVS (N=265) BVS BES (N=263) Withdraw consent without POCE: 1 Intention-to-treat Population (N=398) EES (N=1618) Co. Cr-EES (N=133) (N=266) 12 -Month Clinical FU Complete (N=397: ) 99. 7%) Co. Cr-EES BVS (N=133) (N=264) (N=1601) 13 -Month Angiographic FU Qualified (N=378: 95. 0%) BVS (N=252) Co. Cr-EES (N=126)

ABSORB Japan Baseline Patient Characteristics BVS (266 Patients) Co. Cr-EES (134 Patients) P-value 67. ABSORB Japan Baseline Patient Characteristics BVS (266 Patients) Co. Cr-EES (134 Patients) P-value 67. 1 ± 9. 4 67. 3 ± 9. 6 0. 90 79% 74% 0. 25 24. 0 ± 3. 0 24. 3 ± 3. 0 0. 41 Current Tobacco Use 20% 22% 0. 69 Stable CAD 90% 84% 0. 054 Diabetes 36% 0. 96 Prior PCI/CABG 36% 38% 0. 70 Prior MI 16% 24% 0. 06 e. GFR <60 (m. L/min) 32% 28% 0. 37 Age (years) Male BMI (kg/m 2)

ABSORB Japan Lesion Location and Morphology BVS (275 Lesions) Co. Cr-EES (137 Lesions) P-Value ABSORB Japan Lesion Location and Morphology BVS (275 Lesions) Co. Cr-EES (137 Lesions) P-Value LAD 46% 42% 0. 46 LCX/Ramus 23% 26% 0. 45 RCA 31% 0. 92 Calcification (Mod. /Severe) 28% 33% 0. 28 Tortuosity (Mod. /Severe) 8. 4% 8. 0% 0. 90 Eccentric 82% 83% 0. 84 Bifurcation 37% 42% 0. 32 Type A 4. 0% 3. 6% 0. 86 Type B 1 20% 0. 92 Type B 2 56% 50% 0. 22 Type C 20% 26% 0. 15

ABSORB Japan Baseline QCA BVS (275 Lesions) Co. Cr-EES (137 Lesions) P-value Lesion Length ABSORB Japan Baseline QCA BVS (275 Lesions) Co. Cr-EES (137 Lesions) P-value Lesion Length (mm) 13. 4 ± 5. 3 13. 3 ± 5. 5 0. 87 Pre RVD (mm) 2. 71 ± 0. 45 2. 79 ± 0. 46 0. 10 Pre MLD (mm) 0. 96 ± 0. 33 0. 99 ± 0. 36 0. 40 Pre %DS (%) 64. 5 ± 11. 1 64. 7 ± 10. 91

ABSORB Japan Procedural Information BVS (266 Patients) (275 Lesions) Co. Cr-EES (134 Patients) (137 ABSORB Japan Procedural Information BVS (266 Patients) (275 Lesions) Co. Cr-EES (134 Patients) (137 Lesions) P-value Single Target Lesion 97% 98% 0. 76 Non-study Lesion Treated 7. 5% 1. 00 % Pre-Dilatation 100% 1. 00 % Post Dilatation 82% 77% 0. 25 Bailout Procedure 1. 8% (5/275) 0. 7% (1/137) 0. 67 - By BVS 4 0 0. 31 - By Co. Cr-EES 1 1 1. 00 20. 2 ± 5. 8 19. 5 ± 5. 8 0. 22 Total Device Length (mm)

ABSORB Japan Acute Success and Procedure Duration Devise Success Procedure Duration Acute Success P=1. ABSORB Japan Acute Success and Procedure Duration Devise Success Procedure Duration Acute Success P=1. 00 100% 98. 9% 99. 3% P=0. 72 60 Procedure Duration P=0. 04 97. 7% 98. 5% 50 Procedure Duration (min. ) 90% 80% 70% 60% 49. 8± 24. 8 min 44. 9± 21. 7 min 40 BVS 30 Co. Cr-EES 50% 40% 20 30% 20% 10 10% 0% Device Success BVS Co. Cr-EES Procedural Success BVS Co. Cr-EES 0 BVS Co. Cr-EES Device success: Successful deployment of the assigned device at the target lesion with <30% residual stenosis Procedure success: Device success without TLF during the hospital stay (maximum of 7 days)

ABSORB Japan Balloon Diameters and Inflation Pressure Nominal Expected Pre-dilatation Inflation Pressure Deployment Post-dilatation ABSORB Japan Balloon Diameters and Inflation Pressure Nominal Expected Pre-dilatation Inflation Pressure Deployment Post-dilatation Final Balloon Pre-dilatation 11. 6 ± 3. 8 atm. 11. 9 ± 3. 7 atm. P=0. 52 Deployment 10. 4 ± 3. 0 atm. 11. 2 ± 2. 7 atm. P=0. 003 Post-dilatation 15. 5 ± 4. 2 atm. Final ± 4. 1 atm. 14. 7 16. 0 ± 3. 9 atm. P=0. 24 15. 1 ± 4. 1 atm. P=0. 36 Expected diameter was calculated based on the compliance chart of the device

ABSORB Japan Post Procedural QCA BVS (275 Lesions) Co. Cr-EES (137 Lesions) P-value RVD ABSORB Japan Post Procedural QCA BVS (275 Lesions) Co. Cr-EES (137 Lesions) P-value RVD Post (mm) 2. 75 ± 0. 42 2. 85 ± 0. 43 0. 03 In-Device MLD Post (mm) 2. 43 ± 0. 37 2. 64 ± 0. 40 <0. 0001 In-Device %DS Post (%) 11. 6 ± 7. 5 7. 3 ± 8. 1 <0. 0001 In-Segment MLD Post (mm) 2. 20 ± 0. 39 2. 27 ± 0. 43 0. 15 In-Segment %DS Post (%) 20. 0 ± 6. 7 20. 6 ± 8. 80 0. 49 In-Device Acute Gain (mm) 1. 47 ± 0. 40 1. 65 ± 0. 40 <0. 0001 In-Segment Acute Gain (%) 1. 25 ± 0. 41 1. 28 ± 0. 45 0. 49

ABSORB Japan Primary Endpoint: 12 -Month TLF (through 393 days) 8. 0% 12 -Month ABSORB Japan Primary Endpoint: 12 -Month TLF (through 393 days) 8. 0% 12 -Month TLF Upper 95% Confidence Limit of the Difference P=0. 85 4. 2% 4. 0% Difference (BVS - Co. Cr EES) 6. 0% 3. 8% 2. 0% 0. 0% BVS Co. Cr-EES -2% NI Margin = 8. 6% Non-inferiority P < 0. 0001 0. 39% ● 3. 95% 0% 2% 4% 6% 8% 10% The one-sided upper 95% confidence limit for the 0. 39% observed difference in event rates was 3. 95%, suggesting that any absolute difference between the 2 devices is likely to be small. Likelihood score method by Farrington and Manning

ABSORB Japan Primary Endpoint: 12 -Month TLF (through 393 days) 0 days 37 days ABSORB Japan Primary Endpoint: 12 -Month TLF (through 393 days) 0 days 37 days 208 days 393 days BVS at Risk 266 259 256 251 Co. Cr-EES at Risk 134 131 130 128

ABSORB Japan 12 -Month Clinical Outcomes (~393 -Day ) BVS (N=266) Co. Cr-EES (N=134) ABSORB Japan 12 -Month Clinical Outcomes (~393 -Day ) BVS (N=266) Co. Cr-EES (N=134) P-value 4. 2% (11/265) 3. 8% (5/133) 0. 85 - Cardiac Death 0. 0% (0/265) 0. 0% (0/133) 1. 00 - Target Vessel MI 3. 4% (9/265) 2. 3% (3/133) 0. 76 - Ischemia driven-TLR 2. 6% (7/265) 2. 3% (3/133) 1. 00 TLF (CD/TV-MI/ID-TLR)

ABSORB Japan 12 -Month Definite/Probable ST 0 days 37 days 208 days 393 days ABSORB Japan 12 -Month Definite/Probable ST 0 days 37 days 208 days 393 days BVS at Risk 266 262 260 257 Co. Cr-EES at Risk 134 132 131

ABSORB Japan Characteristics of ST Cases The 6 patients with ST (BVS: 1. 5%/4 ABSORB Japan Characteristics of ST Cases The 6 patients with ST (BVS: 1. 5%/4 cases, Co. Cr-EES: 1. 5%/2 cases) appear to have a cluster of risk factors for ST including – Small residual in-segment MLD post-procedure (4 BVS, 2 Co. Cr-EES) – DAPT discontinuation (1 BVS, 1 Co. Cr-EES) – Diabetes (2 BVS, 1 Co. Cr-EES) – No post-dilatation or under-expansion (2 BVS, 0 Co. Cr-EES)

ABSORB Japan Major Secondary Angiographic Endpoint: 13 -Month In-Segment LLL 13 -Month In-segment LLL ABSORB Japan Major Secondary Angiographic Endpoint: 13 -Month In-Segment LLL 13 -Month In-segment LLL Upper 95% Confidence Limit of the Difference Differnce and 95% UCL 0. 30 P=0. 74 0. 20 0. 13 mm 0. 12 mm 0. 10 Difference (BVS - Co. Cr EES) NI Margin = 0. 195 mm Non-inferiority P < 0. 0001 0. 01 mm ● 0. 07 mm 0. 00 BVS Co. Cr-EES -0. 05 0. 15 0. 2 Asymptotic test statistic based on Z test

ABSORB Japan Cumulative Distribution Function Curves for In-segment MLD Pre 0. 96± 0. 33 ABSORB Japan Cumulative Distribution Function Curves for In-segment MLD Pre 0. 96± 0. 33 mm 0. 99± 0. 36 mm P=0. 42 Follow-up 2. 08± 0. 45 mm 2. 15± 0. 50 mm P=0. 18 Post 2. 21± 0. 39 mm 2. 26± 0. 43 mm P=0. 19

ABSORB Japan Impact of Post-procedure Intracoronary Imaging In-device MLD BVS 3. 00 In-device MLD ABSORB Japan Impact of Post-procedure Intracoronary Imaging In-device MLD BVS 3. 00 In-device MLD (mm) 2. 50 Co. Cr-EES P=0. 90 P=0. 16 2. 40 P=0. 44 2. 47 2. 22 2. 64 2. 63 P=0. 72 2. 49 2. 46 2. 27 Post-imaging Imaging 2. 00 No post-imaging No imaging 1. 50 1. 00 0. 50 0. 00 Post Procedure 13 M F/U No complications were noted by the post-procedure intracoronary imaging after BVS implantation. However, in both BVS and EES groups, post-procedure intracoronary imaging did not affect the in-device MLD at post-procedure and at 13 -month follow-up.

ABSORB Japan Study Limitations 1. Large non-inferiority margin for the primary clinical endpoint, particularly ABSORB Japan Study Limitations 1. Large non-inferiority margin for the primary clinical endpoint, particularly with event rate lower than anticipated • ABSORB Japan was designed to support regulatory approval of the Absorb BVS in Japan. The Japanese Regulatory Agency requested a clinical primary endpoint and agreed to a relatively large non-inferiority margin to keep the • study sample size reasonable. Although TLF rates of both BVS and Co. Cr-EES were lower than the anticipated rate of 9%, the 0. 39% observed difference (P=0. 85) suggest that the 2 devices are similar. 2. Underpowered to evaluate the low frequency events such as ST 3. Inclusion of a highly selected patient population • The study provides data for a patient population typical of pivotal studies for approval. • Data in broader patient populations will be studied in subsequent trials.

ABSORB Japan Conclusions In the ABSORB Japan trial, BVS demonstrated a similar mid-term (12 ABSORB Japan Conclusions In the ABSORB Japan trial, BVS demonstrated a similar mid-term (12 -month) clinical safety and efficacy profile as Co. Cr-EES, with comparable 13 -month angiographic outcomes. These positive results lay a solid foundation for continued evaluation of long term outcomes in patients undergoing percutaneous coronary intervention with Absorb BVS.

ABSORB Japan Investigational Sites (38) • • • • • Shin-Tokyo Hospital, Chiba Saitama ABSORB Japan Investigational Sites (38) • • • • • Shin-Tokyo Hospital, Chiba Saitama Sekishinkai Hospital, Saitama Saiseikai Yokohamashi Tobu Hospital, Kanagawa Shonan Kamakura General Hospital, Kanagawa The Cardiovascular Institute, Tokyo Women's Medical University Hospital, Tokyo Kurashiki Central Hospital, Okayama Kansai Rosai Hospital, Hyogo Shinkoga Hospital, Fukuoka Iwate Medical University Hospital, Iwate Sakakibara Heart Institute, Tokyo Kyoto University Hospital, Kyoto Saiseikai Kumamoto Hospital, Kumamoto Osaka University Hospital, Osaka Tokushima Red Cross Hospital, Tokushima Miyazaki Medical Association Hospital, Miyazaki Teikyo University Hospital, Tokyo Fujita Health University Hospital, Aichi Kanto Rosai Hospital, Kanagawa • • • • • National Cerebral and Cardiovascular Center, Osaka Kurume University Hospital, Fukuoka Kokura Memorial Hospital, Fukuoka Hokkaido Social Insurance Hospital, Hokkaido Showa University Hospital, Tokyo Sakurabashi Watanabe Hospital, Osaka Yamaguchi University Hospital, Yamaguchi Mitsui Memorial Hospital, Tokyo The University of Tokyo Hospital, Tokyo Tokai University Hospital, Kanagawa Japanese Red Cross Nagoya Daini Hospital, Aichi Tenri Hospital, Nara Toho University Ohashi Medical Center, Tokyo Kobe University Hospital, Hyogo Saitama Medical Center Jichi Medical University, Saitama Dokkyo Medical University Hospital, Tochigi Juntendo University Hospital, Tokyo Wakayama Medical University Hospital, Wakayama Tsukuba Medical Center Hospital, Ibaraki

doi: 10. 1093/eurheartj/ehv 435 eurheartj. oxfordjournals. org doi: 10. 1093/eurheartj/ehv 435 eurheartj. oxfordjournals. org