Outline It is a prodrug On-clopidogrel platelet response and its - PowerPoint PPT Presentation

Disclosure None relevant to this talk Anti-platelet Therapy for Vascular Surgery Patients What’s new and what is coming soon Christopher D. Owens Associate Professor, Department of Surgery Division of Vascular and Endovascular Surgery University of California San Francisco 4/14/2016 2 Anti-platelet therapy 4/14/2016 Clopidogrel ADME and DDIs Outline • It is a prodrug � On-clopidogrel platelet response and its relevance in patients with PAD • Absorbed in the Duodenum � Guidelines for DAPT duration for surgery following PCI • 15% of the prodrug is � Fairly new ADP receptor inhibitors, prasugrel and ticagrelor converted to active drug � TRITON TIMI 38 • Several P450 enzymes are involved in the converting pro- � PEGASUS TIMI 54 & PAD active drug • CYP1A2, CYP2B6, � Introduce EUCLID CYP2C19, CYP2C9, CYP3A4 3 Anti-platelet therapy 4/14/2016 1 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

CYP 2C19 enzyme activity 1 2 � Poor Metabolizer � Increased risk for restenosis or MACE � 3 out of 100 Enzyme more active � Intermediate Metabolizer � Possible increased risk for restenosis or MACE � 20 out of 100 3 � Extensive metabolizer � Expected to benefit from standard dose � 38 out of 100 � Ultra-rapid metabolizer � Possibly increased benefit but possible increased bleeding � 32 out of 100 2016 DAPT Duration Guidelines for Patients having Surgery following PCI � Platelet reactivity is higher following peripheral intervention than it is following coronary intervention in patients on DAPT! All PAD patients have on-therapy decreased responsiveness � (Atherosclerosis 232(2014) 119-124) Title Garamond – 30pt font Subtitle Garamond Italic – 30pt font � High on-treatment platelet reactivity does not predict adverse events nor restenosis in PAD as it does in Presenter’s Name PCI (VASA 45 (2016) 155-161) Office or Department Name 4/14/2016 8 Anti-platelet Therapy 4/14/2016 2 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

(Allosteric) Clopidogrel v. Ticagrelor receptor binding Title Garamond – 30pt font Subtitle Garamond Italic – 30pt font Presenter’s Name Office or Department Name 4/14/2016 Title Garamond – 30pt font Title Garamond – 30pt font Subtitle Garamond Italic – 30pt font Subtitle Garamond Italic – 30pt font Presenter’s Name Presenter’s Name Office or Department Name Office or Department Name 4/14/2016 4/14/2016 3 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

PEGASUS TIMI 54 Ticagrelor 60 mg or 90 mg plus standard therapy was found to � Hypothesis: The addition of Ticagrelor to standard therapy including low dose be superior to placebo plus standard therapy aspirin woud reduce the incidence of major adverse cardiovascular events during long term follow up after MI • CHARISMA (CLOPIDOGREL) did not show benefit of prolonged therapy following MI • Post-hoc MI subgroup analysis did show benefit 14 Anti-platelet Therapy 4/14/2016 Efficacy and Safety of Ticagrelor as long-term Efficacy and Safety of Ticagrelor as long-term Secondary Prevention in Patients with PAD & MI Secondary Prevention in Patients with PAD & MI � 1,143 patients had PAD of the 21,162 enrolled in PEGASUS TIMI 54 � At 3-years, the endpoint of CV death, MI, or Stroke, was seen in 19.3% in patients randomized to placebo vs 8.4% for those assigned to Ticagrelor JACC 2016 JACC 2016 15 Anti-platelet Therapy 16 Anti-platelet Therapy 4/14/2016 4/14/2016 4 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

Conclusion � Like most biomarkers, Platelet reactivity is higher in PAD vs CAD – even those on DAPT indicating a relative resistance to therapy • May explain the negative recent aspirin trials � Data does not support testing for clopidogrel responder type in PAD � But other platelet reactivity tests may be warranted � Be mindful of DDI � Newer ADP receptor inhibitors, prasugrel and ticagrelor, have the advantage of not requiring metabolism to an active entity and are available now but not indicated for PAD per se � PEGASUS Trial is intriguing but confirmatory EUCLID could be impactful if it is shown to be superior to clopidogrel. Data would represent level A evidence for secondary prevention in PAD � 2016 antiplatelet guidelines are published in Circulation and worth checking out 18 Anti-platelet Therapy 4/14/2016 Thank You For Your Attention 5 4/14/2016 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]