Medco is a registered trademark of Medco Health Solutions, Inc. © 2009 Medco Health Solutions, Inc. All rights reserved. A National Study of the Effect

Medco is a registered trademark of Medco Health Solutions, Inc.© 2009 Medco Health Solutions, Inc. All rights reserved.

A National Study of the Effect of Individual Proton Pump Inhibitors on Cardiovascular Outcomes in Patients Treated with Clopidogrel Following Coronary Stenting: The Clopidogrel Medco Outcomes Study

Eric J. Stanek, PharmD1, Ronald E. Aubert, PhD1, David A. Flockhart, MD,PhD2, Rolf P. Kreutz, MD2, Jianying Yao, MS1, Jeffrey A. Breall, MD,PhD2, Zeruesenay Desta, PhD2, Todd C. Skaar, PhD2, Felix W. Frueh, PhD1, J. Russell Teagarden, DMH1, Robert S. Epstein, MD1

1 Medco Health Solutions, Inc., Franklin Lakes, NJ

2 Indiana University School of Medicine, Indianapolis, IN

© 2009 Medco Health Solutions, Inc. All rights reserved.

Disclosures

The study was supported by Medco Health Solutions, Inc., by a Clinical Pharmacology Training (DF) grant (T32GM008425), and a K24 award (DF) (K24RR020815) from the National Institutes of Health, Bethesda, MD.

Dr. Breall: speakers’ bureau of Abbott Vascular, received consulting fees from Prosolv Cardiovascular Solutions.

Dr. Flockhart: research funding for studies in breast cancer from Pfizer and Novartis; Scientific Advisory Board for Labcorp Inc,; consultant for Boehringer Ingelheim, Roche Molecular Diagnostics and Wyeth Pharmaceuticals.

Drs. Stanek, Aubert, Frueh, Teagarden, Epstein, and Ms. Yao are employees of Medco Health Solutions, Inc.

The remaining authors have no conflicts of interest to disclose.


Genetic polymorphisms and PPI use can attenuate clopidogrel effect

Hepatic cytochrome P450 2C19 (CYP2C19) is key in metabolic activation of clopidogrel

Patients with nonfunctional CYP2C19 alleles have attenuated ex vivo antiplatelet response and worse CV outcomes on clopidogrel

PPIs may interfere with CYP2C19-mediated clopidogrel metabolism and attenuate ex vivo antiplatelet effects

Effect across individual agents inconsistent

Retrospective analyses show an association of PPI use with higher risk of cardiovascular events in patients on clopidogrel

Effect across individual agents inconsistent Debate whether independent of clopidogrel


Major GI bleeding risk on clopidogrel is low – current role of PPI prophylaxis

Proton pump inhibitors (PPIs) commonly co-prescribed with clopidogrel and aspirin for GI bleeding prophylaxis

No RCTs of efficacy/safety of PPIs for GIB prophylaxis in post-PCI/stent patients on clopidogrel

– COGENT-1 trial discontinued Jan 2009 2008 AHA/ACG/ACCF consensus statement recommends PPI use Overall, serious GI bleeding in clinical trials is relatively low

1.4%

2.9%1.0%

0.01%

0%

2%

4%

6%

8%

10%

Major GI B Any GI B Treatment-emergent

GI B

Fatal GI B

GI Bleeding on Clopidogrel in Post-PCI / stent trials

CREDO TRITON

On PPICREDO 16%TRITON 40%


Study Objective

To investigate the association of PPIs (as a class, and individual agents) with major adverse cardiovascular events in patients on clopidogrel following coronary stenting.


Retrospective cohort study design

Retrospective cohort analysis of integrated medical and pharmacy claims database of 19,119,647 members (Medco Health Solutions, Inc)

Medical claims data based on ICD-9 and CPT-4 codes

Study Population: 41,063 patients who had a coronary stent procedure 10/1/05-9/30/06

Inclusion criteria: 32,786 continuously eligible 6-months prior to and 12-months following

index stent Clopidogrel-naïve prior to stent New clopidogrel prescription claim within 1 month of stent procedure Clopidogrel persisting for full 12 months post-stent and high level of

adherence (MPR >0.80) N=16,718


PPI exposure cohorts

Patients were segregated into cohorts based on PPI therapy received at any time over 12 months after date of coronary stenting (N=16,690):

No PPI Therapy N=9862 patients with no prescription claim for a PPI

PPI therapy N=6828 on a PPI (pooled) Individual PPI agents

– Esomeprazole (N=3257) – Omeprazole (N=2307)– Pantoprazole (N=1653)– Lansoprazole (N=785)– Rabeprazole (N=298)


End point definitions

Primary end point: Combined hospitalization for a major adverse cardiovascular event

over 12 months (determined by ICD-9 and CPT-4 codes)– Cerebrovascular event (Stroke or TIA)– Acute coronary syndrome (MI or unstable angina)– Cardiovascular death (resuscitated; resulting in hospitalization)– Coronary revascularization (CABG and PCI)

Secondary end points: Individual components of primary end point

– MI– Unstable angina– CABG– PCI


Analysis plan

Patient demographics and clinical characteristics

12-month incidence of primary and secondary endpoints– No PPI vs Any PPI– No PPI vs individual PPIs

Event-free survival (Kaplan-Meier survival analysis)

Univariate and multivariate Cox proportional hazards regression to calculate end point hazard ratio (HR) and 95% confidence interval (CI); No PPI group as reference cohort

All statistical analyses were conducted using SAS version 9.1 (SAS Institute, Cary, NC), and significance was determined at p<0.05 for all comparisons.


Baseline characteristics

CharacteristicNo PPI

(N=9862)

PPI*(N=6828)

*all p<0.01

Age - yrs; mean±SD 65.2±10.6 67.5±10.4

Age ≥65 years - no. (%) 4903 (49.7) 4076 (59.7)

Female - no. (%) 2572 (26.1) 2596 (38.0)

Prior cardiovascular event - no. (%) 2226 (22.6) 1845 (27.0)

Congestive heart failure - no. (%) 1831 (18.6) 1719 (25.2)

Diabetes mellitus - no. (%) 2238 (22.7) 1767 (25.9)

Hypertension - no. (%) 4581 (46.5) 3454 (50.6)

Dyslipidemia treatment - no. (%) 5190 (52.6) 3991 (58.5)

Dyslipidemia diagnosis or treatment - no. (%) 6254 (63.4) 4630 (67.8)

Chronic kidney disease - no. (%) 265 (2.7) 312 (4.6)

Any upper gastrointestinal disease - no. (%) 474 (4.8) 1649 (24.2)

Prior upper gastrointestinal bleeding - no. (%) 13 (0.1) 122 (1.8)

Any prior or active PPI use - no. (%) 396 (4.0) 4103 (60.1)

Drug-eluting stent – no. (%) 3124 (31.7) 1964 (28.9)


Clopidogrel dosing and PPI exposure

Clopidogrel 75 mg/day in 99.5% of patients

PPI:

Median duration of clopidogrel-PPI overlap: 293 days (IQ range 160-365)

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Number at RiskNo PPI 9862 9235 8952 8818 8717 8622 8546 8459 8380 8318 8253 8197 8136PPI 6828 6286 6036 5901 5793 5693 5617 5532 5438 5359 5286 5217 5135

No proton pump inhibitor

Proton pump inhibitor

No PPI 17.9%; PPI 25.1%Hazard Ratio 1.51, 95% CI 1.39-1.64p < 0.0001

PPIs are associated with increased risk of CV events in patients on clopidogrel


Results: Subgroup Analysis for Any PPI Use

PPI effect consistent across subgroups


Individual PPI analysis plan

At least 674 subjects per arm needed to detect a ≥25% increase in 1-year incidence of MACE vs. no PPI (17.9% incidence) with 80% power (α=0.05)

Adequate sample size and power for: Omeprazole (N=2307) Esomeprazole (N=3257) Pantoprazole (N=1653) Lansoprazole (N=785)

These four agents represented 96% of all PPI use

Rabeprazole (n=298); inadequate sample size and power for stable statistical comparison


Individual PPI Baseline Characteristics

Characteristic

No PPI

N=9862

Omeprazole

N=2307

Esomeprazole

N=3257

Pantoprazole

N=1653

Lansoprazole

N=785

Age - yrs; mean±SD 65.2±10.6 68.7±10.14* 67.3±10.2* 67.0±11.0* 67.1±10.3*

Age ≥65 years 4903 (49.7) 1496 (64.9)* 1921 (59.0)* 950 (57.5)* 452 (57.6)*

Female 2572 (26.1) 857 (37.2)* 1312 (40.3)* 616 (37.3)* 304 (38.7)*

Prior CV event 2226 (22.6) 638 (27.7)* 865 (26.6)* 504 (30.5)* 192 (24.5)

CHF 1831 (18.6) 584 (25.3)* 800 (24.6)* 517 (31.3)* 201 (25.6)*

Diabetes mellitus 2238 (22.7) 630 (27.3)* 845 (25.9)* 390 (23.6) 209 (26.6)*

Hypertension 4581 (46.5) 1159 (50.2)* 1661 (51.1)* 813 (49.2)* 396 (50.5)*

Dyslipidemia Rx 5190 (52.6) 1406 (60.9)* 1958 (60.1)* 828 (50.1) 435 (55.4)

CKD 265 (2.7) 107 (4.6)* 131 (4.0)* 90 (5.4)* 37 (4.7)*

Upper GI disease 474 (4.8) 561 (24.3)* 863 (26.5)* 367 (22.2)* 215 (27.4)*

Upper GI bleeding 13 (0.1) 31 ( 1.3)* 51 (1.6)* 61 (3.7)* 12 (1.5)*

PPI use 396 (4.0) 1489 (64.5)* 2183 (67.0)* 603 (36.5)* 465 (59.2)*

Drug-eluting stent 3124 (31.7) 656 (28.4)* 866 (26.6)* 520 (31.5) 257 (32.7)

* p<0.05 vs no PPI


Individual PPI exposure and dosing

PPI exposure (PPI group only):

PPI daily dosing:

Omeprazole Esomeprazole Pantoprazole Lansoprazole

At time of stent 53% 54% 29% 46%

Median days (IQ range) overlap with clopidogrel

305 (197-365) 305 (193-365) 287 (116-365) 299 (163-365)


≤20 mg 80.8%

21-40 mg 18.5%

>40 mg 0.7%

≤20 mg 4.9%

21-40 mg 89.3%

>40 mg 5.8%

≤40 mg 92.3%

>40 mg 7.7%

≤15 mg 4.3%

16-30 mg 83.1%

>30 mg 12.6%


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Number at RiskNo PPI 9862 9235 8952 8818 8717 8622 8546 8459 8380 8318 8253 8197 8136Omeprazole 2307 2117 2032 1992 1954 1915 1885 1860 1827 1803 1176 1758 1738Esomeprazole 3257 3008 2891 2823 2782 2729 2694 2648 2596 2559 2529 2494 2460Pantoprazole 1653 1501 1416 1378 1341 1312 1294 1276 1255 1235 1216 1194 1179Lansoprazole 785 719 692 673 660 650 644 637 626 620 613 608 598

HR 1.61 (1.44-1.81 ), p<0.000129.2%Pantoprazole

HR 1.39 (1.16-1.67 ), p=0.000424.3%Lansoprazole

HR 1.57 (1.40-1.76 ), p<0.000124.9%Esomeprazole

HR 1.39 ( 1.22-1.57), p<0.000125.1%Omeprazole

Ref17.9%No PPI

Lansoprazole

Esomeprazole

Omeprazole

Pantoprazole

Individual PPIs are associated with increased risk of major CV events


Hospitalization rates for upper GI bleeding were low

1.11%

0.08%

0.82%

2.54%

0.76%

1.10%

0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0%

12-month Incidence

No PPI

Omeprazole

Esomeprazole

Pantoprazole

Lansoprazole

All PPIs


Individual PPI effects consistent across multiple subgroups

Individual PPI association with increased CV event risk was consistent across these subgroups:

Exceptions: Omeprazole – risk in patients with CV event in 6 months pre-stent Esomeprazole - risk in patients with no prior PPI therapy Lansoprazole - risk in patients w/o dyslipidemia diagnosis or therapy

Significant effect observed for each PPI in patients without prior PPI use and without prior upper GI bleeding

▪ Gender ▪ Age ▪ Diabetes mellitus ▪ Hypertension

▪ Stent type ▪ Prior upper GI bleeding ▪ Chronic kidney disease ▪ Heart failure


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Follow-up Days

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Number at RiskNo PPI 1407 1322 1284 1260 1243 1224 1212 1192 1180 1171 1154 1145 1134PPI 234 224 214 211 206 202 197 194 191 189 184 182 181

No PPI; N=1407

Any PPI; N=234

Hazard Ratio 1.19, 95% CI 0.84-1.70p = 0.326

N=1641 Post-Stent Without Clopidogrel

PPIs not associated with increased risk in the absence of clopidogrel


Summary

In a nationally representative, claims-based, observational study of 16,690 patients adherent and persistent to clopidogrel therapy following coronary stenting over 12 months:

Concomitant use of PPIs as a class was associated with a 51% greater risk of a CV event vs clopidogrel alone

Omeprazole, esomeprazole, pantoprazole, and lansoprazole (96% of patients on PPI) were each associated with a 39%-61% greater risk of a CV event vs clopidogrel alone

PPI use in the absence of clopidogrel was not associated with increased CV event risk

Overall risk of hospitalization for upper GI bleeding was <1%


Conclusion

Concomitant use of clopidogrel with PPIs as a class, and omeprazole, esomeprazole, pantoprazole, or lansoprazole individually after coronary stenting was associated with a significantly increased risk of hospitalization for major adverse cardiovascular events compared to clopidogrel alone.

These results provide further support for the hypothesis that PPIs attenuate the effects of clopidogrel.

More data are needed to establish if newer PPIs (rabeprazole, dexlansoprazole) have similar effects.

Considering all available evidence, PPI use should be limited to situations where clearly indicated in patients on clopidogrel after coronary stenting.


Thank you for this opportunity to share our

data with you.


Additional data



Cardiovascular and GI comorbidity adjustment Baseline variables included in multivariate Cox models:

– Age (<65; ≥65)– Gender– Hospitalization for any component of the primary endpoint within 6

months (in addition to index stent)– Type of stent deployed – bare metal vs drug eluting– Diabetes mellitus– Hypertension– Congestive heart failure– Chronic kidney disease– Dyslipidemia diagnosis or active/prior therapy with a statin, bile acid

sequestrant, cholesterol absorption inhibitor, fibrate, or niacin– Hospitalization for upper gastrointestinal bleeding within 6 months– Prior/active PPI use

Very highly correlated with diagnosis of any upper gastrointestinal disease (ICD-9 codes 530-535)


Individual PPIs associated with increased risk of stroke, ACS, and coronary revascularization

EndPoint

No PPI


% % HR % HR % HR % HR

Stroke/TIA

1.1 2.21.54

(0.99-2.39)2.0

1.48

(0.98-2.24)2.7

1.79

(1.21-2.66)1.9

1.74

(0.92-2.33)

MI/

USA10.0 16.3

1.50

(1.27-1.76)16.6

1.76

(1.54-2.03)19.3

1.74

(1.50-2.01)16.6

1.48

(1.18-1.85)

PCI/

CABG13.3 16.4

1.22

(1.05-1.42)15.9

1.41

(1.23-1.62)18.4

1.42

(1.24-1.64)16.4

1.27

(1.02-1.58)

CV death

0.2 0.41.57

(0.56-4.42)0.3

0.88

(0.29-2.70)0.4

1.00

(0.34-2.93)0.3

1.22

(0.22-6.72)


Individual PPIs associated with increased secondary end point risk

End

Point

No PPI


% % HR % HR % HR % HR

MI 4.8 6.71.25

(0.97-1.59)6.4

1.56

(1.26-1.94)9.4

1.74

(1.42-2.13)7.1

1.24

(0.88-1.73)

USA 6.6 12.51.75

(1.44-2.11)12.8

2.00

(1.70-2.37)14.1

1.93

(1.62-2.29)12.2

1.68

(1.29-2.22)

PCI 12.7 15.81.24

(1.06-1.45)15.1

1.42

(1.23-1.63)17.1

1.39

(1.20-1.61)15.3

1.24

(0.99-1.55)

CABG 0.8 0.80.76

(0.38-1.50)1.2

1.30

(0.75-2.24)1.8

1.74

(1.06-2.86)1.4

1.53

(0.70-3.36)


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No PPI

Individual PPIs

Patients Post-Stent on Clopidogrel

All individual PPIs analyzed associated with increased risk of major CV events


H2 receptor antagonist therapy had no effect on cardiovascular event incidence

Analysis in 9862 patients on clopidogrel but no PPI therapy over follow-up

472 patients receiving H2 receptor antagonist; 9390 patients without H2 receptor antagonist

Combined cardiovascular event incidence: 20.3% w/ H2 receptor antagonist vs. 17.8% w/o H2 receptor antagonist (chi-square p=0.1579).

Documents

Medco is a registered trademark of Medco Health Solutions, Inc. © 2009 Medco Health Solutions, Inc. All rights reserved. A National Study of the Effect