Kishore J. Harjai, MD, FACC Chetan Shenoy, MD Pamela Orshaw, RN Judith Boura, MS

1. The Influence of Proton Pump Inhibitors on Clinical Outcomes After Successful Percutaneous Coronary Intervention Kishore J. Harjai, MD, FACC Chetan Shenoy, MD Pamela Orshaw, RN Judith Boura, MS Guthrie Health Care System, Sayre, PA

2. Background • Clopidogrel, a pro-drug, requires activation by cytochrome P450 isoenzymes (e.g. CYP2C19) in the liver in order to exert its inhibitory effect on platelet aggregation. • Competitive inhibition of CYP2C19 by proton pump inhibitors (PPI) can impair activation of clopidogrel. • Compared to patients who take clopidogrel alone, those who take clopidogrel with omeprazole had: • A 45% reduction in active metabolite levels • A 47% reduction in anti-platelet effect • These reductions were seen whether the drugs were given at the same time or 12 hours apart.* *http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm

3. Background • An ACC/AHA/ACG expert consensus document recommends prophylactic treatment with PPI for patients on dual anti-platelet therapy who are at risk for GI injury to reduce the risk of ulcer complications and GI bleeding • Yet, platelet aggregation studies as well as some clinical studies have demonstrated worse cardiovascular outcomes in patients using clopidogrel with PPIs. Bhatt DL, et al. JACC 2008;52:1502

4. Objective • We sought to evaluate whether the use of clopidogrel with PPIs is associated with worse clinical outcomes after PCI compared to patients using clopidogrel without PPIs in the Guthrie PCI database

5. Guthrie PCI Database • Robust single-center observational registry • All PCIs since July 2001 • Entirely funded by Guthrie Health Care System • Stable patient population • Early adoption of EMR • Committed data coordinator • Standard ACC-NCDR definitions • Patients followed for up to 5 years after PCI • Medical record review • Phone calls to patient/family • Social security death index

6. Inclusion and Exclusion Criteria • Inclusion criteria • Successful PCI between 2001-2007 • Exclusion criteria • H/o prior PCI at our institution between 2001-2007 • Presentation with cardiogenic shock • Suffered in-hospital MACE • Enrolled in RCT of anti-platelet therapy • Data on anti-platelet therapy or PPI not available • 6-month MACE data not available

7. Cardiogenic shock at presentation, N=138 Unsuccessful PCI, N=165 N = 4421 PCI (July 2001-Dec 2007) Prior PCI at our institution during study period, N=976 No prior PCI during study period N=3445 No shock N=3307 Successful PCI N=3142 Suffered death, MI, TVR, or stroke during hospitalization, N=63 Survived hospitalization without MI, TVR, or stroke N=3079 Enrolled in randomized trials of oral anti-platelet therapy*, N=27 Not enrolled in randomized trials of oral anti-platelet therapy N=3052 Discharge data on PPI use unavailable (n=7) Discharge data on dual anti-platelet therapy unavailable (n=57) Six-month MACE follow not available, n=35 Study group N=2653

8. Study End-Points • Primary end-point • Time to occurrence of MACE (death, MI, TVR, or stent thrombosis*) during the 6 months after PCI • Secondary end-point • Time to occurrence of individual components of the MACE end-point *definite or probable by ARC criteria

9. (N=751) (N=1902) Patient Classification Based on discharge prescription for PPI All patients are prescribed aspirin indefinitely and thienopyridine for 1-12 mon after PCI

10. N=439 N=1902 Subset Analysis • Clinically-significant drug-drug interactions reported to be highest for omeprazole and esomeprazole. • Separate analyses • Omep or Esomep Vs. No PPI N=312

11. Baseline Clinical Differences P<0.05 for all

12. Clinical Characteristics (Contd.) • No differences with regards to • Multivessel PCI • Final vessel diameter • LVEF • Use of IABP during PCI

13. 6.4% 6.4% MACE: Cumulative Hazard Curves PPI+ Proportion of patients with MACE PPI- Log rank p=0.97 Days since PCI Number of patients

14. 2.8% 2.5% Death: Cumulative Hazard Curves PPI- Proportion of patients with Death PPI+ Log rank p=0.63 Days since PCI Number of patients

15. 3.3% 3.0% MI: Cumulative Hazard Curves PPI+ PPI- Proportion of patients with MI Log rank p=0.72 Days since PCI Number of patients

16. 5.6% 5.1% Death or MI: Cumulative Hazard Curves PPI+ Proportion of patients with Death/MI PPI- Log rank p=0.60 Days since PCI Number of patients

17. TVR: Cumulative Hazard Curves 3.0% PPI- 2.2% Proportion of patients with TVR PPI+ Log rank p=0.29 Days since PCI Number of patients

18. Stent Thrombosis: Cumulative Hazard Curves 1.8% PPI+ 1.5% Proportion of patients with Stent thombosis PPI- Log rank p=0.62 Days since PCI Number of patients

19. Propensity-Adjusted Multivariate Impact of PPI Use on 6-Month Outcomes

20. Subset Analysis: Omeprazole or Esomeprazole Vs. No PPI Log rank p=0.09 Log rank p=0.046

21. Propensity-Adjusted Multivariate Impact of Omeprazole or Esomeprazole Vs. No PPI Use on 6-Month Outcomes • Use of omeprazole or esomeprazole compared to No PPI was independently associated with: • Significantly lower MACE rates Adjusted HR 0.51, 95% CI 0.28-0.92; p=0.026 • Marginally lower TVR rates Adjusted HR 0.32, 95% CI 0.10-1.03; p=0.056 • No significant impact on other outcomes

22. Conclusions • In patients who underwent successful PCI and received a combination of aspirin and clopidogrel, the adjunctive use of PPIs did not worsen cardiovascular outcomes. This is also true for patients who received omeprazole or esomeprazole.

23. Discussion: Possible Reasons for Lack of Impact of PPI on Outcomes • Clopidogrel use at 6 mon greater in omep or esomep Vs. no PPI groups (78 vs 70%, p=0.0078) • Predominantly caucasian population (99%) • Less likely to have CYP2C19 loss-of-function alleles • Questionable relevance of PPI-clopidogrel interaction • Possible differences in concomitant drug therapy • Our study may be underpowered to detect differences • Compliance with PPI, aspirin, or clopidogrel not assessed

24. Thank you