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.*

*http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm

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 2001-2007 Exclusion criteria

H/o prior PCI at our institution between 2001-2007Presentation with cardiogenic shockSuffered in-hospital MACEEnrolled in RCT of anti-platelet therapyData on anti-platelet therapy or PPI not available6-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 shockN=3307

Unsuccessful PCI, N=165

Not enrolled in randomized trials of oral anti-platelet therapy N=3052

Study groupN=2653

No prior PCI during study periodN=3445

Successful PCIN=3142

Survived hospitalization without MI, TVR, or strokeN=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-pointTime to occurrence of MACE (death, MI,

TVR, or stent thrombosis*) during the 6 months after PCI

Secondary end-pointTime to occurrence of individual

components of the MACE end-point

*definite or probable by ARC criteria

Patient Classification

PPI Group28%

No PPI Group72%

(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

Omep or Esomep

12%

Other PPI17%

No PPI Group71%

N=439

N=1902

N=312

Baseline Clinical Differences

Characteristic PPI Group (N=751)

No PPI Group (N=1902)

Age, years (median) 67 64

Female, % 38 28

Serum creatinine, mg/dL 1.1 1.0

Cerebrovascular disease, % 11 7.5

Peripheral arterial disease, % 16 11

Hypertension, % 73 65

Dyslipidemia, % 79 70

Prior CABG, % 22 16

MI at presentation, % 32 42

Stent used during PCI, % 93 96

Aspirin dose, mg/day 288 298

P<0.05 for all

Clinical Characteristics (Contd.)

No differences with regards to Multivessel PCIFinal vessel diameterLVEFUse of IABP during PCI

Prop

orti

on o

f pa

tien

ts w

ith

MA

CE

Days since PCI

PPI+ 751 726 715 703

PPI- 1902 1853 1815 1780

Number of patients

Log rank p=0.97

PPI+

PPI-

MACE: Cumulative Hazard Curves

0

.01

.02

.03

.04

.05

.06

.07

0 25 50 75 100 125 150 175 200

6.4%

6.4%

Prop

orti

on o

f pa

tien

ts w

ith

Dea

th

Days since PCI

PPI+ 751 743 737 730

PPI- 1902 1883 1871 1853

Number of patients

Log rank p=0.63

PPI+

PPI-

Death: Cumulative Hazard Curves

0

.005

.01

.015

.02

.025

.03

0 25 50 75 100 125 150 175 200

2.8%

2.5%

Prop

orti

on o

f pa

tien

ts w

ith

MI

Days since PCI

PPI+ 751 726 711 701

PPI- 1902 1852 1819 1795

Number of patients

Log rank p=0.72

PPI+PPI-

MI: Cumulative Hazard Curves

0

.005

.01

.015

.02

.025

.03

.035

0 25 50 75 100 125 150 175 200

3.3%

3.0%

Prop

orti

on o

f pa

tien

ts w

ith

Dea

th/M

I

Days since PCI

PPI+ 751 728 719 709

PPI- 1902 1858 1831 1804

Number of patients

Log rank p=0.60

PPI+

PPI-

Death or MI: Cumulative Hazard Curves

0

.01

.02

.03

.04

.05

.06

0 25 50 75 100 125 150 175 200

5.6%

5.1%

Prop

orti

on o

f pa

tien

ts w

ith

TV

R

Days since PCI

PPI+ 751 734 717 706

PPI- 1902 1863 1822 1791

Number of patients

Log rank p=0.29

PPI+

PPI-

0

.005

.01

.015

.02

.025

.03

.035

0 25 50 75 100 125 150 175 200

TVR: Cumulative Hazard Curves

2.2%

3.0%

Prop

orti

on o

f pa

tien

ts w

ith

Sten

t tho

mbo

sis

Days since PCI

PPI+ 751 735 720 713

PPI- 1902 1862 1840 1820

Number of patients

Log rank p=0.62

PPI+

PPI-

0

.002

.004

.006

.008

.01

.012

.014

.016

.018

0 25 50 75 100 125 150 175 200

Stent Thrombosis: Cumulative Hazard Curves

1.8%

1.5%

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

Study Outcome Adjusted Hazard Ratio (95% CI) P

MACE 0.89 (0.63-1.27) 0.40

Death 0.95 (0.56-1.63) 0.86

Myocardial Infarction 1.04 (0.64-1.69) 0.89

Death or myocardial infarction 0.99 (0.68-1.44) 0.94

Target vessel revascularization 0.74 (0.42-1.29) 0.28

Stent thrombosis 1.32 (0.67-2.58) 0.42

3.9

6.4

1.6

2.52.2

33.2

5.1

1

3

1

1.5

0

1

2

3

4

5

6

7

MACE Death MI Death/MI TVR ST

Omeprazole or esomeprazole PPI-

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 0.28-0.92; p=0.026Marginally lower TVR rates

Adjusted HR 0.32, 95% CI 0.10-1.03; p=0.056No 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

Thank you