1. Use of PPIs during Clopidogrel Therapy Andrew N. Schmelz, PharmD Post-Doctoral Teaching Fellow Dept of Pharmacy Practice Purdue University February 26, 2009

2. Objectives Describe the conversion of clopidogrel to its active metabolite Describe the conversion of clopidogrel to its active metabolite Rank PPIs in regard to 2C19 metabolism Rank PPIs in regard to 2C19 metabolism Summarize relevant literature regarding use of clopidogrel and PPIs Summarize relevant literature regarding use of clopidogrel and PPIs Develop a recommendation in response to patient-specific scenarios involving clopidogrel and PPIs Develop a recommendation in response to patient-specific scenarios involving clopidogrel and PPIs

3. Background Clopidogrel is a second-generation thienopyridine Clopidogrel is a second-generation thienopyridine –Inhibits platelet aggregation by blocking the P2Y 12 ADP receptor PPIs are commonly used in clopidogrel- treated patients PPIs are commonly used in clopidogrel- treated patients –Impaired healing of gastric ulcers AHA/ACCF Consensus Statement UA/NSTEMI Guidelines

4. Clopidogrel Metabolism Clopidogrel is a PRODRUG Clopidogrel is a PRODRUG J Clin Pharmacol. 2008; 48; 475

5. Clopidogrel Nonresponse Occurrence of thrombotic events in patients treated with clopidogrel Occurrence of thrombotic events in patients treated with clopidogrel Possible explanations: Possible explanations: –Genetic polymorphisms –Competitive drug interactions –Noncompliance –Interpatient variability of the P2Y 12 receptor Indicated by platelet aggregation tests (VASP phosphorylation analysis) Indicated by platelet aggregation tests (VASP phosphorylation analysis)

6. Enzyme Inhibition PPIs inhibit CYP450 enzymes PPIs inhibit CYP450 enzymes Competitive inhibition occurs to varying degrees Competitive inhibition occurs to varying degrees –Omeprazole –Pantoprazole –Lansoprazole –Rabeprazole Aliment Pharmacol Ther 1999;13(Suppl 3):27-36 Most 2C19 Metabolism Least 2C19 Metabolism

7. PPI Metabolism Aliment Pharmacol Ther 1999;13(Suppl 3):27-36

8. Literature OCLA Study (omeprazole) In vitro study measuring platelet reactivity index (PRI) and In vitro study measuring platelet reactivity index (PRI) and PRI on Day 7 PRI on Day 7 –Clopidogrel + PPI group: 39.8% (SD 5.6) –Clopidogrel + PBO group: 51.4% (SD 15.4) J Am Coll Cardiol. 2008 Jan 22;51(3):256-60.

9. Literature (cont.) Small et al. (lansoprazole) Lilly study; clopidogrel v. prasugrel Lilly study; clopidogrel v. prasugrel Clopidogrel inactive metabolite Clopidogrel inactive metabolite –AUC unaffected (not a good surrogate?) –IPA decreased Prasugrel active metabolite Prasugrel active metabolite –AUC insignificantly decreased (12%) –IPA insignificantly reduced J Clin Pharmacol. 2008; 48; 475

10. Clopidogrel PK and PD

11. Literature (cont.) Siller-Matula et al. (esomep & pantop) In vitro study measuring PRI In vitro study measuring PRI Esomeprazole Esomeprazole –No difference in PRI from PBO Pantoprazole Pantoprazole –No difference in PRI from PBO Am Heart J. 2009 Jan;157(1):148

12. Claims Data MEDCO Clopidogrel alone (n=9800) Clopidogrel alone (n=9800) Clopidogrel + PPI (n=6800) Clopidogrel + PPI (n=6800) RR major adverse cardiovascular events 50% higher in clopidogrel + PPI group RR major adverse cardiovascular events 50% higher in clopidogrel + PPI group –RR AMI 75% higher with PPI addition AR for CV events in 12 months 25% AR for CV events in 12 months 25% Circulation, Oct 2008; 118: S_815

13. Claims Data (cont.) AETNA AETNA J Am Coll Cardiol, 2008; 52:1038-1039

14. Observational Analysis of CREDO Circulation, Oct 2008; 118: S_815

15. Questions?

16. Patient Case 65 YOM with documented CAD (in left main and circumflex arteries) s/p drug- eluting stent placement 65 YOM with documented CAD (in left main and circumflex arteries) s/p drug- eluting stent placement PMH: DM, PUD, HTN PMH: DM, PUD, HTN SH: (+) tobacco 2PPD X 10 years SH: (+) tobacco 2PPD X 10 years

17. Recommendations Avoid routine use of PPIs in patients receiving clopidogrel therapy Avoid routine use of PPIs in patients receiving clopidogrel therapy Control other risk factors for ischemic events Control other risk factors for ischemic events Counsel patients of s/sxs bleeding Counsel patients of s/sxs bleeding Evaluate potential new therapies for CYP450 interactions Evaluate potential new therapies for CYP450 interactions