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

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Anti-platelet Therapy for Vascular Surgery Patients

What’s new and what is coming soon

4/14/2016

Christopher D. Owens Associate Professor, Department of Surgery Division of Vascular and Endovascular Surgery University of California San Francisco

Disclosure

None relevant to this talk

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Outline

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On-clopidogrel platelet response and its relevance in patients with PAD Guidelines for DAPT duration for surgery following PCI Fairly new ADP receptor inhibitors, prasugrel and ticagrelor TRITON TIMI 38 PEGASUS TIMI 54 & PAD Introduce EUCLID

Clopidogrel ADME and DDIs

• It is a prodrug
• Absorbed in the Duodenum
• 15% of the prodrug is

converted to active drug

• Several P450 enzymes are

involved in the converting pro- active drug

• CYP1A2, CYP2B6,

CYP2C19, CYP2C9, CYP3A4

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CYP 2C19 enzyme activity

Poor Metabolizer Increased risk for restenosis or MACE 3 out of 100 Intermediate Metabolizer Possible increased risk for restenosis or MACE 20 out of 100 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

Enzyme more active

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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)

High on-treatment platelet reactivity does not predict adverse events nor restenosis in PAD as it does in PCI (VASA 45 (2016) 155-161)

2016 DAPT Duration Guidelines for Patients having Surgery following PCI

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Clopidogrel v. Ticagrelor receptor binding

(Allosteric)

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PEGASUS TIMI 54

Hypothesis: The addition of Ticagrelor to standard therapy including low dose 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

Ticagrelor 60 mg or 90 mg plus standard therapy was found to be superior to placebo plus standard therapy

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Efficacy and Safety of Ticagrelor as long-term Secondary Prevention in Patients with PAD & MI

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• 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

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Efficacy and Safety of Ticagrelor as long-term Secondary Prevention in Patients with PAD & MI

JACC 2016

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Conclusion

Like most biomarkers, Platelet reactivity is higher in PAD vs CAD – even those

• n 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

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Thank You For Your Attention