P2Y12 Antagonists Antagonists Study Year Follow-Up Comparison - PDF document

12/18/16 Optimal Duration of Dual Anti-Platelet Therapy December 18, 2016 John S. MacGregor, M.D., Ph.D. Professor of Medicine University of California San Francisco Clopidogrel v. Newer P2Y12 P2Y12 Antagonists Antagonists Study Year Follow-Up Comparison Stent P TIMI P Value Agent Route Prodrug? Reversible? Onset of Offset of Status Throm- Value Major action action bosis Bleeding Ticlopidine Oral (BID) Yes No 6 hours ~5 days Approved TRITON 2007 15 months Clopidogrel 2.4% <0.001 1.8 0.03 1991 Prasugrel 1.1 2.4 PLATO 2009 12 months Clopidogrel 2.9 0.009 7.7 0.57 Clopidogrel Oral (QD) Yes No 2 to 8 ~5 days Approved Ticagrelor 2.2 7.9 hours 1997 CHAMPION 2009 48 hours Clopidogrel 0.3 0.34 0.3 0.39 Prasugrel Oral (QD) Yes No 0.5 to 4 ~5 days Approved Cangrelor 0.2 0.4 hours 2009 CHAMPION 2009 48 hours Clopidogrel 1.4 0.01 0.1 0.99 Ticagrelor Oral (BID) No Yes 0.5 to 2 ~1 to 3 Approved PHOENIX Cangrelor 0.8 0.1 hours days 2011 OASIS-7 2010 30 days Clopidogrel 2.3 <0.001 0.7 0.074 Cangrelor IV No Yes Immediate 60 minutes Approved 2X Clopidogrel 1.6 1.0 2015 Adapted from Claessen, (2014) JACCI, 7:1081-92 1

12/18/16 P2Y12 Inhibitors: Cautions/Warnings and Considerations Clopidogrel - Consider alternative in CYP2C19 poor metabolizer - Avoid use with drugs that are moderate to strong CYP2C19 inhibitors Prasugrel - Not recommended for age >75, weight <60 Kg or prior stroke/TIA - Significantly increased fatal bleeding (0.4% v. 0.1%; p=0.002) Ticagrelor - Maintenance dose of aspirin >100mg/day reduces effectiveness - Incidence of Dyspnea (blocks reuptake of adenosine by RBCs) - BID dosing Source: The New Yorker 2016 ACC/AHA Guideline for Duration A Brief History of DAPT After PCI of DAPT in Patients with CAD • 1997 Ticlopidine for 2 weeks after BMS (STARS) • In Patients with SIHD or ACS, compare 12 • 1998 – Clopidogrel for 4 weeks after BMS months v. 3 to 6 months of DAPT(MACE, ST, • 2003 - sirolimus stent - 3 months DAPT bleeding. • 2004 – PES – 6 months of DAPT • Compare 12 months v. 18 to 48 months of • 2004 – based on PCI-CURE (2001), CREDO (2002), DAPT (mortality, MACE, ST, bleeding). and observational studies showing risk of ST • In patients post MI, does DAPT beyond one beyond 6 months – “at least” 12 months of DAPT year v. ASA monotherapy affect mortality, • Everolimus and Zotarolimus coated stents – nonfatal MI, MACE or bleeding? Optimal Duration of DAPT? JACC, 68:1082, September 2016 2

12/18/16 Factors associated with increased risk Duration of DAPT: Myocardial of ischemia or bleeding Infarction JACC. 2016;68:1080 Circulation. 2016;134:e156-e178 Duration of DAPT: Stent Thrombosis Duration of DAPT: Major Hemorrhage Circulation. 2016;134:e156-e178 Circulation. 2016;134:e156-e178 3

12/18/16 Duration of DAPT: Mortality Duration of DAPT: Primary Endpoint Circulation. 2016;134:e156-e178 Circulation. 2016;134:e156-e178 Duration of DAPT: Myocardial Duration of DAPT: Stent Thrombosis Infarction Circulation. 2016;134:e156-e178 Circulation. 2016;134:e156-e178 4

12/18/16 Duration of DAPT: Major Hemorrhage Duration of DAPT: Mortality Circulation. 2016;134:e156-e178 Circulation. 2016;134:e156-e178 Mortality rates in 11 RCTs after stent implantation Duration of DAPT: Primary Endpoint Circulation. 2016;134:e156-e178 Circulation. 2016;134:e156-e178 5

12/18/16 Safety and Efficacy of DAPT After DAPT: 18 to 36 months v. 12 months Complex PCI • Absolute reduction of ischemic events of 1 to • 9577 Patients from 6 RCTs (85% new gen. DES) 2%, with absolute increase in bleeding • Median follow up 392 days complications of about 1%. • End Point: MACE (death, MI, ST, bleeding) • Per 1000 patients treated: 6 fewer MIs, 3 • COMPLEX = having one or more of the fewer stent thromboses, 5 additional major following features: 3 vessels treated, >2 bleeds stents implanted, > 2 lesions treated, bifurcation with 2 stents, total stent length > 60 mm, or CTO Giustino et al., JACC, 68:1851 (2016) MACE: Long- versus Short-Term DAPT in Coronary Thrombotic Events: Long- versus Short- Patients With or Without Complex PCI Term DAPT in Patients With or Without Complex PCI JACC (68), 2016; 1851 JACC (68), 2016; 1851 6

12/18/16 Risk of myocardial infarction (A) and stent thrombosis (B) as a function of bleeding risk Major Bleeding: Long- versus Short-Term DAPT in Patients With or Without Complex PCI JACC (68), 2016; 1851 Circulation. 2016;134:e156-e178 Class I Recommendations for Duration DAPT Score of DAPT After PCI in Patients with SIHD • At least one month after BMS implantation • At least 6 months after DES implantation • Aspirin at a dose of 81 mg/day, indefinitely JACC , 68:1082 September 2016 JACC. 2016;68:1080 7

12/18/16 Class I Recommendations for Duration Duration of DAPT for Patients with ACS of DAPT After PCI in Patients with ACS Treated with Medical Therapy Alone • At least 12 months after BMS or DES • At least 12 months (Class I) • Aspirin at a dose of 81 mg/day, indefinitely • Aspirin, 81 mg daily, Indefinitely (Class I) JACC , 68:1082 September 2016 JACC , 68:1082 September 2016 Interruption of DAPT for Elective DAPT and OCT: WOEST Study Noncardiac Surgery Class I • Delay surgery 30 days for BMS; 6 mo. for DES MACE Any Bleeding • Continue ASA if possible Class III (Harm) • DAPT should not be discontinued for elective noncardiac surgery within 30 days of implantation of a BMS, or within 3 months of implantation of a DES JACC , 68:1082 September 2016 Dewilde W, et al. Lancet 2013; 381: 1107–15 8

12/18/16 Recommendations for OAC therapy MACE and Major Bleeding: and DAPT (Triple therapy) ISAR-TRIPLE Trial • Assess ischemic and bleeding risks • Keep triple therapy as brief as possible • Target INR of 2.0 to 2.5 • Clopidogrel is the P2Y12 inhibitor of choice • Low dose ASA (<100 mg per day) • PPI JACC , 68:1082 September 2016 Source: The New Yorker 9