The Case for Routine CYP2C19 ( Plavix® ) Genetic Testing 1998 Plavix® FDA Approved 115 million prescriptions written The ACC/AHA considers Plavix® the gold standard in Antiplatelet therapy March 2010 FDA Black Box Warning

Plavix® Clinical Indications taken from Plavix® website Acute Coronary Syndrome ( ACS ) Recent MI, Recent Stroke, or Established Peripheral Arterial Disease PLAVIX has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. For patients with ST-elevation myocardial infarction (STEMI), PLAVIX has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo PLAVIX has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death

Plavix® Dosing taken from Plavix® website DOSAGE AND ADMINISTRATION Acute Coronary Syndrome ( ACS ) Non-ST-segment elevation ACS (UA/NSTEMI): 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75–325 mg once daily) STEMI: 75 mg once daily, in combination with aspirin (75–325 mg once daily), with or without a loading dose and with or without thrombolytics Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily

Plavix® The FDA issued this Black Boxed Warning March 2010 WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1) Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5) Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5) Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1) copied from Plavix® website

Recommendations for Convalescent and Long-Term Antiplatelet Therapy Focused Update of 2011 ACCF/AHA the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline) J Am Coll Cardiol, 2011; 57:1920-1959, doi:10.1016/j.jacc.2011.02.009 (Published online 28 March 2011 Recommendations for Convalescent and Long-Term Antiplatelet Therapy 1 For UA/NSTEMI patients treated medically without stenting, ASA - clopidogrel (75 mg per day) should be prescribed for at least 1 month (13) and ideally up to 1 year 2 For UA/NSTEMI patients treated with a BMS, ASA* 162 to 325 mg per day should be prescribed for at least 1 month, then continued indefinitely at a dose of 75 to 162 mg per day. (Level of Evidence: A) The duration and maintenance dose of thienopyridine therapy should be as follows:a Clopidogrel 75 mg daily (17) or prasugrel 10 mg daily (22) should be given for at least 12 months (13,17). (Level of Evidence: B) b If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by thienopyridine therapy, earlier discontinuation should be considered. (Level of Evidence: C)

Recommendations for Convalescent and Long-Term Antiplatelet Therapy Focused Update of 2011 ACCF/AHA the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline) Recommendations for Convalescent and Long-Term Antiplatelet Therapy 3 For UA/NSTEMI patients treated with a DES, ASA* 162 to 325 mg per day should be prescribed for at least 3 months after sirolimus-eluting stent implantation and 6 months after paclitaxel-eluting stent implantation (Level of Evidence: B), then continued indefinitely at a dose of 75 to 162 mg per day. (Level of Evidence: A). The duration and maintenance dose of thienopyridine therapy should be as follows: a Clopidogrel 75 mg daily (17) or prasugrel 10 mg daily (22) should be given for at least 12 months (13,17). (Level of Evidence: B) b If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by thienopyridine therapy, earlier discontinuation should be considered. (Level of Evidence: C) 4 Clopidogrel 75 mg daily (preferred) or ticlopidine (in the absence of contraindications) should be given to patients recovering from UA/NSTEMI when ASA is contraindicated or not tolerated because of hypersensitivity or GI intolerance (despite use of gastroprotective agents such as PPIs) (11,61,108). (Level of Evidence: A)

ONLINE FIRST JAMA. Published online November 16, 2011. doi: 10 ONLINE FIRST JAMA. Published online November 16, 2011.doi: 10.1001/jama.2011.1703 Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease ELEVATE TIMI 56 Conclusion Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes ( Intermediate Metabolizers ) achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes ( Poor Metabolizers ) , doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition. http://jama.ama-assn.org/content/early/2011/11/09/jama.2011.1703.abstract