Session Objectives. Clopidogrel Resistance. Clopidogrel (Plavix )

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1 Session Objectives New Antithrombotics and Real Time Genetic Testing: Their Role in the Vascular Patient Margaret C. Fang, MD, MPH Associate Professor of Medicine Division of Hospital Medicine Medical Director, UCSF Anticoagulation Clinic Review evidence for testing for clopidogrel resistance Genetic testing Platelet activity testing Be familiar with new antiplatelet alternatives to clopidogrel Clopidogrel (Plavix ) Thienopyridine used by ~40 million people worldwide to treat or prevent atherothrombotic events Irreversibly blocks the P2Y12 receptor needed for platelet aggregation Effect on platelet aggregation for 7-10 days Is a prodrug: Requires hepatic biotransformation to form an active metabolite Conversion active metabolite requires two sequential oxidative steps involving several CYP450 enzymes Clopidogrel Resistance Defined by high on-treatment platelet activity during in-vitro testing Found in about 1/3 of people taking clopidogrel Associated with multiple factors Pharmacokinetics/dynamics (absorption, metabolism) Patient factors (age, BMI, smoking) Concomitant medications (e.g, PPIs) Comorbid conditions (e.g., diabetes, hyperlipidemia) Genetic variation in clopidogrel effect CYP2C19 gene accounts for ~12% of the variability 1

2 Clopidogrel Metabolism and CYP2C19 Enzyme CYP2C19 Allele Variants and Enzyme Activity Clopidogrel CYP1A2 Functional Status Alleles Clopidogrel Response CYP2C19 2-oxo-clopidogrel LIVER Wild-type / normal *1 Normal CYP2C9 CYP3A4 PON1 CYP2B6 CYP3A5 CYP2C19 Active metabolite Loss-of-function *2, *3, *4, *5, *6, *7, *8 Clopidogrel resistance (high residual platelet activity) P2RY12 Platelet Increased function *17 Clopidogrel sensitivity (high platelet ) CYP2C19 Genotype Associated with Clinical Outcomes Meta-analysis of 32 studies (n=42,016 participants) Patients with acute coronary syndrome and/or undergoing coronary stenting Patients with reduced function genotypes (*2 through *8) had increased risk of cardiovascular events (RR = 1.18) Stent thromboses (RR = 1.75) FDA Warning in 2010 Warned about reduced effectiveness in patients who are poor metabolizers of clopidogrel Informed healthcare professionals that tests are available to identify genetic differences in CYP2C19 function Advised healthcare professionals to consider use of other antiplatelet medications or alternative dosing strategies in patients already identified as poor metabolizers But did not specify when or in whom to test Holmes et al, JAMA 2011; 306 (24) 2

3 Point of Care Genetic Testing Spartan RX CYP2C19 device Results within 60 minutes after cheek swab Detects *1 and *2 alleles Nanosphere Verigene System Tests 11 CYP2C19 variants using blood 3 hours Platelet Activity and Clinical Outcomes Percutaneous coronary intervention/stents High on-treatment platelet activity (PRU > 230) associated with higher rates of myocardial infarction and stent thrombosis Medically-managed patients with coronary disease No association between platelet activity and cardiovascular outcomes Platelet may be more important during acute revascularization However, no evidence yet that tailoring treatment (e.g., by putting on high dose clopidogrel based on platelet activity) improves clinical outcomes Roberts et al, 2012 The Lancet Brar et al, JACC 2011; 58, GRAVITAS Trial, JAMA 2011; 305 (11) TRILOGY-ACS Study, JAMA 2012; 308 Platelet Function Assays Several commercial assays are available Rapid point of care testing (VerifyNow, PFA-100) Functional assays Flow cytometry Attempts to measure in vitro platelet aggregation Vary in terms of equipment, timing of blood sample, ability to detect clopidogrel response Should We Test? No prospective studies demonstrating a clinical benefit of personalizing antiplatelet therapy based on genotyping or platelet activity 2011 ACCF/AHA Guidelines and the 2012 ACCP Guidelines recommended against routine testing until there is more evidence Acknowledge that there is a potential burden and cost with testing However, availability of commercial testing increasing Alternative antiplatelet therapies now available 3

4 Alternatives to Clopidogrel Alternatives to Standard Clopidogrel Therapy Prasugrel (Effient ) Ticagrelor (Brilinta ) Approved for unstable angina/nstemi only Prasugrel (Effient ) Thienopyridine with faster onset of action, more potent antiplatelet effects Does not depend on CYP2C19 for activation Loading dose of 60mg followed by 10mg maintenance dose Clopidogrel vs. Prasugrel in Patients with ACS Undergoing PCI (TRITON-TIMI 38) Randomized 13,608 patients with acute coronary syndrome undergoing scheduled PCI to clopidogrel vs. prasugrel (+ASA) Prasugrel more effective than clopidogrel, but caused more hemorrhages Primary endpoint (CVD death, MI, stroke) Prasugrel Clopidogrel HR 9.9% 12.1% 0.81 [ ] Major hemorrhage 2.4% 1.8% 1.32 [ ] Wiviott et al, NEJM 2007; 357 4

5 Clopidogrel vs. Prasugrel for Medically Managed ACS (TRILOGY ACS) Randomized 9326 medically managed ACS patients to clopidogrel vs. prasugrel (+ ASA) Prasugrel associated with greater platelet (median PRU at 30 days: 64 vs. 200 for clopidogrel) No significant difference in primary outcome at 30 months Primary endpoint (CVD death, MI, stroke) Prasugrel Clopidogrel HR 18.7% 20.3% 0.96 [ ] Major hemorrhage 2.5% 1.8% 1.23 [ ] Summary: Prasugrel Can consider for patients with ACS undergoing revascularization More effective than clopidogrel, but higher risk of bleeding No advantage over clopidogrel in medically managed patients Cautions: No net benefit in patients > 75 years or weighing < 60kg AVOID in patients with prior stroke or TIA Higher rates of intracranial hemorrhage (2.3% in prasugrel group vs. 0% in clopidogrel, p = 0.02) and no difference in efficacy Roe et al, NEJM 2012; 367 Ticagrelor (Brilinta ) Direct acting, reversible P2Y12 inhibitor, faster onset of action and stronger platelet 180mg/90mg q12h more effective than clopidogrel Patients with acute coronary syndrome randomized to clopidogrel vs. ticagrelor Primary endpoint (CVD death, MI, stroke) Major hemorrhage (non CABG related) Ticagrelor Clopidogrel HR 9.8% 11.7% 0.84 [ ] 4.5% 3.8% 1.19 [ ] Summary: Ticagrelor Can consider for patients with acute coronary syndrome More effective than clopidogrel, but may have a higher risk of bleeding Caution: possible decreased efficacy when given concomitantly with 100mg of aspirin PLATO Trial, Wallentin et al, NEJM 2009; 361 5

6 Take Home Points Clopidogrel resistance might be associated with worse cardiovascular outcomes in patients undergoing coronary stenting There are tests that can assess for clopidogrel resistance (genetic and platelet activity tests) Unclear whether tailoring therapy based on test results improves clinical outcomes, and routine testing is not currently recommended Take Home Points May consider selective testing for high-risk patients undergoing coronary revascularization Undergoing PCI for extensive/complex lesions, history of stent thromboses Suggested Treatment by Genotype Take Home Points Genotype Normal wildtype (*1/*1) Ultrarapid metabolizers (*1/*17, *17/*17) Intermediate metabolizer (*1/*2) Poor metabolizers (*2/*2, *2/*3, *3/*3) Clopidogrel Response Normal platelet Increased platelet Reduced platelet Significantly reduced platelet Recommendation Clopidogrel labelrecommended dosage and administration Clopidogrel labelrecommended dosage and administration Alternative therapy (if no contraindication) Alternative therapy (if no contraindication) Strength of Recommendation Strong Strong Moderate Strong Consider alternative antiplatelet regimens for high-risk patients Prasugrel and Ticagrelor are more effective than clopidogrel, but associated with higher bleeding risk Approved only for coronary artery disease Ongoing efforts to determine whether there are advantages in patients with peripheral arterial disease 2011 Clinical Pharmacogenetics Implementation Consortium Guidelines 6