Short versus Long DAPT Studies – An Academic View FDA Town Hall (NON-CME), Session V: Evaluating DES For High-Risk DAPT Patients Short versus Long DAPT Studies – An Academic View

Disclosure Statement of Financial Interest Speaker’s honoraria from Bayer, AstraZeneca and Daiichi Sankyo.

20 Years of DAPT Trials 2013 TRILOGY-ACS N=7243 2015 PEGASUS TIMI 54 N=21162 2007 TRITON TIMI 38 N=13608 2009 PLATO N=18624 2013 ACCOAST N=4033 2014 ATLANTIC N=1862 1996 2016 1996 ISAR N=517 1998 STAR N=1653 MATTIS N=350 FANTASTIC N=485 2001 CURE N=12562 PCI-CURE N=2658 2005 CLARITY TIMI 28 N=3491 COMMIT N=45852 2010 CURRENT OASIS 7 N=25086 REAL-LATE ZEST-LATE N=2701 2014 DAPT N=11648 DES-LATE N=5045 ARCTIC-I N=1259 SECURITY 2015 ISAR-SAFE N=4000 ITALIC N=2031 ISAR-TRIPLE N=614 2002 CREDO N=2116 2011 GRAVITAS N=2214 2016 I-LOVE-IT 2 N=1829 OPTIDUAL N=1799 2012 PRODIGY N=1970 EXCELLENT N=1443 RESET N=2117 2006 CHARISMA N=15603 2013 OPTIMIZE N=3119 WOEST N=573 Ticlopidine or clopidogrel trials Prasugrel trials Ticagrelor trials Piccolo R, Windecker S. Circ Cardiovasc Interv. 2016;9:e003587

Trials of DAPT Duration After PCI 15 studies, ~40,000 patients randomized Study Journal Patients Hypothesis Result Trials of short DAPT RESET JACC 2012 N=2,117 3 months noninferior to 12 months OPTIMIZE JAMA 2013 N=2,199 SECURITY JACC 2016 N=1,399 6 months noninferior to 12 months (stopped) ISAR SAFE EHJ 2015 N=4,000 I-LOVE-IT 2 CIRC CV 2016 N=1,829 6 months noninferior to 12 months OPTIMA-C TCTAP 2015 N=1,368 EXCELLENT Circulation 2015 N=1,443 IVUS XPL JACC: CI 2016 N=1,400 6 months comparable to 12 months Trials of long DAPT NIPPON ESC 2016 N=2,772 6 months noninferior to 18 months (stopped) ITALIC JACC 2015 N=1,822 6 months noninferior to 24 months (stopped) PRODIGY Circulation 2012 N=1,970 24 months more effective than 6 months ARCTIC Lancet 2014 N=1,259 ≥18 months more effective than 12 months DAPT NEJM 2014 N=9,961 30 months more effective than 12 months DES LATE Circulation 2014 N=5,045 36 months superior to 12 months OPTIDUAL N=1,385 48 months superior to 12 months (stopped) Capodanno D. Personal communication

Trials of DAPT Duration After PCI 15 studies, ~40,000 patients randomized Study Journal Patients Hypothesis Result Trials of short DAPT RESET JACC 2012 N=2,117 3 months noninferior to 12 months ✔ OPTIMIZE JAMA 2013 N=2,199 SECURITY JACC 2016 N=1,399 6 months noninferior to 12 months (stopped) ISAR SAFE EHJ 2015 N=4,000 I-LOVE-IT 2 CIRC CV 2016 N=1,829 6 months noninferior to 12 months OPTIMA-C TCTAP 2015 N=1,368 EXCELLENT Circulation 2015 N=1,443 IVUS XPL JACC: CI 2016 N=1,400 6 months comparable to 12 months Trials of long DAPT NIPPON ESC 2016 N=2,772 6 months noninferior to 18 months (stopped) ITALIC JACC 2015 N=1,822 6 months noninferior to 24 months (stopped) PRODIGY Circulation 2012 N=1,970 24 months more effective than 6 months ARCTIC Lancet 2014 N=1,259 ≥18 months more effective than 12 months DAPT NEJM 2014 N=9,961 30 months more effective than 12 months DES LATE Circulation 2014 N=5,045 36 months superior to 12 months OPTIDUAL N=1,385 48 months superior to 12 months (stopped) Capodanno D. Personal communication

Trials of DAPT Duration After PCI 15 studies, ~40,000 patients randomized Study Journal Patients Hypothesis Result Trials of short DAPT RESET JACC 2012 N=2,117 3 months noninferior to 12 months ✔ OPTIMIZE JAMA 2013 N=2,199 SECURITY JACC 2016 N=1,399 6 months noninferior to 12 months (stopped) ISAR SAFE EHJ 2015 N=4,000 I-LOVE-IT 2 CIRC CV 2016 N=1,829 6 months noninferior to 12 months OPTIMA-C TCTAP 2015 N=1,368 EXCELLENT Circulation 2015 N=1,443 IVUS XPL JACC: CI 2016 N=1,400 6 months comparable to 12 months Trials of long DAPT NIPPON ESC 2016 N=2,772 6 months noninferior to 18 months (stopped) ITALIC JACC 2015 N=1,822 6 months noninferior to 24 months (stopped) PRODIGY Circulation 2012 N=1,970 24 months more effective than 6 months ✖ ARCTIC Lancet 2014 N=1,259 ≥18 months more effective than 12 months DAPT NEJM 2014 N=9,961 30 months more effective than 12 months DES LATE Circulation 2014 N=5,045 36 months superior to 12 months OPTIDUAL N=1,385 48 months superior to 12 months (stopped) Capodanno D. Personal communication

Meta-analysis of DAPT Duration after DES A Systematic Review for the 2016 ACC/AHA Guideline Focused Update on DAPT 12 mo vs 3-6 mo (N=12,078 pts, 5 RCTs) Mortality 1.17 (95% CI 0.85-1.63) Myocardial infarction 0.87 (95% CI 0.65-1.18) Stent thrombosis 0.87 (95% CI 0.49-1.55) Major bleeding 1.65 (95% CI 0.97-2.82) Bittl JA, et al. Circulation. 2016;134:156-78

Meta-analysis of DAPT Duration after DES A Systematic Review for the 2016 ACC/AHA Guideline Focused Update on DAPT 12 mo vs 3-6 mo (N=12,078 pts, 5 RCTs) 18-48 mo vs 6-12 mo (N=20,973 pts, 6 RCTs) Mortality 1.17 (95% CI 0.85-1.63) 1.14 (95% CI 0.92-1.42) Myocardial infarction 0.87 (95% CI 0.65-1.18) 0.67 (95% CI 0.47-0.95) Stent thrombosis 0.87 (95% CI 0.49-1.55) 0.42 (95% CI 0.24-0.74) Major bleeding 1.65 (95% CI 0.97-2.82) 1.58 (95% CI 1.20-2.09) Bittl JA, et al. Circulation. 2016;134:156-78

Short vs Long DAPT By Clinical Presentation 11,473 patients with stable CAD or ACS (low-risk) from 6 trials of 3-6 mo vs. ≥1-year DAPT Patient-level meta-analysis of SECURITY, OPTIMIZE, ITALIC, EXCELLENT, RESET and PRODIGY HR (95% CI) p value P for interaction MI or ST 0.09 Stable CAD 0.93 (0.65-1.35); 0.72 ACS 1.48 (0.98-2.22); 0.06 Major bleeding 0.52 (0.27-0.99); 0.05 0.84 0.47 (0.20-1.08); 0.08 0.1 1 10 Short DAPT better Long DAPT better Palmerini T, et al. Eur Heart J 2017 [ePub ahead of print]

Short vs Long DAPT By PCI Complexity 9,577 patients from 6 trials of DAPT duration after PCI Patient-level meta-analysis of SECURITY, OPTIMIZE, ITALIC, EXCELLENT, RESET and PRODIGY P for interaction = 0.08 Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion Giustino G, et al. J Am Coll Cardiol. 2016;68:1851-1864

DAPT Duration in Clinical Guidelines Population ACCF/AHA/SCAI 2016 ESC Guidelines 2014 Acute Coronary Syndrome (BMS or DES) At least 12 months (Class I-BR) Shorter (Class IIb-C-LD) or longer (Class IIb-ASR) durations may be considered Maximum of 12 months (Class I-A) Shorter or longer durations may be considered (Class IIb-A) Stable Ischemia and BMS At least 1 month (Class I-A) >1 month if no HBR (Class IIb-A) At least 1 month Stable Ischemia and DES At least 6 months (Class I-B-NR) >6 months if no HBR (Class IIb-A) HBR: 3 months (Class IIb-C-LD) 6 months (Class I-B) Secondary Prevention Prior MI (1-3 yrs), no HBR: May be reasonable (Class IIb-A) Selected patients at high ischemic risk Amsterdam EA, et al. 2014 AHA/ACC Guideline for Management of NSTE-ACS. JACC 2014;64:e139-228. Montalescot G, et al. 2013 ESC Guidelines on Management of Stable CAD. EHJ 2013;34:2949-3003. Levine GN, et al. 2011 ACCF/AHA/SCAI Guidelines for PCI. JACC 2011;58:e44-122. Smith SC Jr, et al. 2011 AHA/ACCF Secondary Prevention Guidelines. JACC 2011;58:2342-46. Levine GN, et al. 2016 ACC/AHA Guidelines for DAPT. JACC AOP. Roffi M, et al. 2015 ESC Guidelines for Management of ACS. EHJ 2015 (Online Aug 29, 2015). Windecker S, et al. 2014 ESC/EACTS Guidelines on Myocardial Revascularization. EHJ 2014;35:3541-619.

DAPT duration After BVS Implantation * Simple procedures include 1 BVS implanted in ACC/AHA A/B1 lesions. # Complex procedures include 1 BVS implanted in ACC/AHA B2/C lesions, >1 BVS implanted on lesions of any ACC/AHA type, or any other unfavorable clinical, angiographic and procedural characteristics. § Considerations on the use of aspirin in combination with prasugrel or ticagrelor for the initial 30 days, followed by switch to aspirin and clopidogrel, may prevail based on the individual risks of ischemia and bleeding. Capodanno D, Angiolillo DJ. JACC: Cardiovasc Interv 2017 [In press]

Ongoing Studies Examining Abbreviated Duration of DAPT Study Size Active (month) Control (month) Population GLOBAL LEADERS 16,000 1 12 DES MASTER DAPT 4,300 6-12 HBR DES REDUCE 1,500 3 ACS PCI SMART-CHOICE 5,100 TWILIGHT 8,000 TICO 3,000 SMART DATE 6 DAPT STEMI 1,100 STEMI PCI NCT01813435; NCT03023020; NCT02118870; NCT02079194; NCT02270242; NCT02494895; NCT01701453; NCT01459627

Closing Remarks Various iterations in coronary stent technology have largely resolved stent-related adverse events with rates of definite stent thrombosis amounting to <0.5% per year with new-generation DES. Trials investigating different DAPT durations within 1 year are more sensitive to stent-related adverse events linked to the arterial healing processes. In contrast, trials investigating DAPT duration beyond 1 year are more likely to capture atherothrombotic manifestations, particularly outside the stented coronary segments. Accordingly, the optimal DAPT duration will largely be determined by the prevention of new atherothrombotic events rather than the nuisance of stent-related thrombotic complications. dcapodanno@gmail.com