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

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.* *

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

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

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

Inclusion and Exclusion Criteria  Inclusion criteria  Successful PCI between  Exclusion criteria  H/o prior PCI at our institution between  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

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

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

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

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

Baseline Clinical Differences CharacteristicPPI Group (N=751) No PPI Group (N=1902) Age, years (median)6764 Female, %3828 Serum creatinine, mg/dL Cerebrovascular disease, %117.5 Peripheral arterial disease, %1611 Hypertension, %7365 Dyslipidemia, %7970 Prior CABG, %2216 MI at presentation, %3242 Stent used during PCI, %9396 Aspirin dose, mg/day P<0.05 for all

Clinical Characteristics (Contd.) nNo differences with regards to  Multivessel PCI  Final vessel diameter  LVEF  Use of IABP during PCI

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

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

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

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

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

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

Propensity-Adjusted Multivariate Impact of PPI Use on 6-Month Outcomes Study OutcomeAdjusted Hazard Ratio (95% CI)P MACE0.89 ( )0.40 Death0.95 ( )0.86 Myocardial Infarction1.04 ( )0.89 Death or myocardial infarction0.99 ( )0.94 Target vessel revascularization0.74 ( )0.28 Stent thrombosis1.32 ( )0.42

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

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 ; p=0.026  Marginally lower TVR rates Adjusted HR 0.32, 95% CI ; p=0.056  No significant impact on other outcomes

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.

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

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