The Influence of Proton Pump Inhibitors on Clinical Outcomes After Successful Percutaneous Coronary ...
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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.

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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


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Background After Successful Percutaneous Coronary Intervention

  • 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


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Background After Successful Percutaneous Coronary Intervention

  • 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


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Objective After Successful Percutaneous Coronary Intervention

  • 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


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Guthrie PCI Database After Successful Percutaneous Coronary Intervention

  • 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


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Inclusion and Exclusion Criteria After Successful Percutaneous Coronary Intervention

  • 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


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Cardiogenic shock at presentation, N=138 After Successful Percutaneous Coronary Intervention

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


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Study End-Points After Successful Percutaneous Coronary Intervention

  • 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


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(N=751) After Successful Percutaneous Coronary Intervention

(N=1902)

Patient Classification

Based on discharge prescription for PPI

All patients are prescribed aspirin indefinitely and thienopyridine for 1-12 mon after PCI


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N=439 After Successful Percutaneous Coronary Intervention

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


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Baseline Clinical Differences After Successful Percutaneous Coronary Intervention

P<0.05 for all


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Clinical Characteristics (Contd.) After Successful Percutaneous Coronary Intervention

  • No differences with regards to

    • Multivessel PCI

    • Final vessel diameter

    • LVEF

    • Use of IABP during PCI


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6.4% After Successful Percutaneous Coronary Intervention

6.4%

MACE: Cumulative Hazard Curves

PPI+

Proportion of patients with MACE

PPI-

Log rank p=0.97

Days since PCI

Number of patients


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2.8% After Successful Percutaneous Coronary Intervention

2.5%

Death: Cumulative Hazard Curves

PPI-

Proportion of patients with Death

PPI+

Log rank p=0.63

Days since PCI

Number of patients


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3.3% After Successful Percutaneous Coronary Intervention

3.0%

MI: Cumulative Hazard Curves

PPI+

PPI-

Proportion of patients with MI

Log rank p=0.72

Days since PCI

Number of patients


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5.6% After Successful Percutaneous Coronary Intervention

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


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TVR: Cumulative Hazard Curves After Successful Percutaneous Coronary Intervention

3.0%

PPI-

2.2%

Proportion of patients with TVR

PPI+

Log rank p=0.29

Days since PCI

Number of patients


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Stent Thrombosis: Cumulative Hazard Curves After Successful Percutaneous Coronary Intervention

1.8%

PPI+

1.5%

Proportion of patients with Stent thombosis

PPI-

Log rank p=0.62

Days since PCI

Number of patients



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Subset Analysis: Omeprazole or Esomeprazole Vs. No PPI 6-Month Outcomes

Log rank p=0.09

Log rank p=0.046


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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


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Conclusions Esomeprazole Vs. No PPI Use on 6-Month Outcomes

  • 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.


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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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Thank you Outcomes


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