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

12/18/16 1 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

P2Y12 Antagonists

Agent Route Prodrug? Reversible? Onset of action Offset of action Status Ticlopidine Oral (BID) Yes No 6 hours ~5 days Approved 1991 Clopidogrel Oral (QD) Yes No 2 to 8 hours ~5 days Approved 1997 Prasugrel Oral (QD) Yes No 0.5 to 4 hours ~5 days Approved 2009 Ticagrelor Oral (BID) No Yes 0.5 to 2 hours ~1 to 3 days Approved 2011 Cangrelor IV No Yes Immediate 60 minutes Approved 2015

Clopidogrel v. Newer P2Y12 Antagonists

Study Year Follow-Up Comparison Stent Throm- bosis P Value TIMI Major Bleeding P Value TRITON 2007 15 months Clopidogrel Prasugrel 2.4% 1.1 <0.001 1.8 2.4 0.03 PLATO 2009 12 months Clopidogrel Ticagrelor 2.9 2.2 0.009 7.7 7.9 0.57 CHAMPION 2009 48 hours Clopidogrel Cangrelor 0.3 0.2 0.34 0.3 0.4 0.39 CHAMPION PHOENIX 2009 48 hours Clopidogrel Cangrelor 1.4 0.8 0.01 0.1 0.1 0.99 OASIS-7 2010 30 days Clopidogrel 2X Clopidogrel 2.3 1.6 <0.001 0.7 1.0 0.074 Adapted from Claessen, (2014) JACCI, 7:1081-92

12/18/16 2 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

A Brief History of DAPT After PCI

• 1997 Ticlopidine for 2 weeks after BMS (STARS)
• 1998 – Clopidogrel for 4 weeks after BMS
• 2003 - sirolimus stent - 3 months DAPT
• 2004 – PES – 6 months of DAPT
• 2004 – based on PCI-CURE (2001), CREDO (2002),

and observational studies showing risk of ST beyond 6 months – “at least” 12 months of DAPT

• Everolimus and Zotarolimus coated stents –

Optimal Duration of DAPT?

2016 ACC/AHA Guideline for Duration

• f DAPT in Patients with CAD
• In Patients with SIHD or ACS, compare 12

months v. 3 to 6 months of DAPT(MACE, ST, bleeding.

• Compare 12 months v. 18 to 48 months of

DAPT (mortality, MACE, ST, bleeding).

• In patients post MI, does DAPT beyond one

year v. ASA monotherapy affect mortality, nonfatal MI, MACE or bleeding?

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• JACC. 2016;68:1080

Factors associated with increased risk

• f ischemia or bleeding
• Circulation. 2016;134:e156-e178

Duration of DAPT: Myocardial Infarction

• Circulation. 2016;134:e156-e178

Duration of DAPT: Stent Thrombosis

• Circulation. 2016;134:e156-e178

Duration of DAPT: Major Hemorrhage

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Duration of DAPT: Mortality

• Circulation. 2016;134:e156-e178
• Circulation. 2016;134:e156-e178

Duration of DAPT: Primary Endpoint

• Circulation. 2016;134:e156-e178

Duration of DAPT: Myocardial Infarction

• Circulation. 2016;134:e156-e178

Duration of DAPT: Stent Thrombosis

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• Circulation. 2016;134:e156-e178

Duration of DAPT: Major Hemorrhage

• Circulation. 2016;134:e156-e178

Duration of DAPT: Mortality

• Circulation. 2016;134:e156-e178

Duration of DAPT: Primary Endpoint

Mortality rates in 11 RCTs after stent implantation

• Circulation. 2016;134:e156-e178

12/18/16 6 DAPT: 18 to 36 months v. 12 months

• Absolute reduction of ischemic events of 1 to

2%, with absolute increase in bleeding complications of about 1%.

• Per 1000 patients treated: 6 fewer MIs, 3

fewer stent thromboses, 5 additional major bleeds

Safety and Efficacy of DAPT After Complex PCI

• 9577 Patients from 6 RCTs (85% new gen. DES)
• Median follow up 392 days
• End Point: MACE (death, MI, ST, bleeding)
• COMPLEX = having one or more of the

following features: 3 vessels treated, >2 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 Patients With or Without Complex PCI

JACC (68), 2016; 1851

Coronary Thrombotic Events: Long- versus Short- Term DAPT in Patients With or Without Complex PCI

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Major Bleeding: Long- versus Short-Term DAPT in Patients With or Without Complex PCI

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Risk of myocardial infarction (A) and stent thrombosis (B) as a function of bleeding risk

• Circulation. 2016;134:e156-e178

DAPT Score

• JACC. 2016;68:1080

Class I Recommendations for Duration

• f 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

12/18/16 8 Class I Recommendations for Duration

• f DAPT After PCI in Patients with ACS
• At least 12 months after BMS or DES
• Aspirin at a dose of 81 mg/day, indefinitely

JACC , 68:1082 September 2016

Duration of DAPT for Patients with ACS Treated with Medical Therapy Alone

• At least 12 months (Class I)
• Aspirin, 81 mg daily, Indefinitely (Class I)

JACC , 68:1082 September 2016

Interruption of DAPT for Elective Noncardiac Surgery

Class I

• Delay surgery 30 days for BMS; 6 mo. for DES
• 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

DAPT and OCT: WOEST Study

Dewilde W, et al. Lancet 2013; 381: 1107–15

Any Bleeding MACE

12/18/16 9 MACE and Major Bleeding: ISAR-TRIPLE Trial Recommendations for OAC therapy and DAPT (Triple therapy)

• 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