1. 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, PharmD 1, Ronald E. Aubert, PhD 1, David A. Flockhart, MD,PhD 2, Rolf P. Kreutz, MD 2, Jianying Yao, MS 1, Jeffrey A. Breall, MD,PhD 2, Zeruesenay Desta, PhD 2, Todd C. Skaar, PhD 2, Felix W. Frueh, PhD 1, J. Russell Teagarden, DMH 1, Robert S. Epstein, MD 1 1 Medco Health Solutions, Inc., Franklin Lakes, NJ 2 Indiana University School of Medicine, Indianapolis, IN

2. © 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.

3. © 2009 Medco Health Solutions, Inc. All rights reserved. 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

4. © 2009 Medco Health Solutions, Inc. All rights reserved. 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 On PPI CREDO 16% TRITON 40%

5. © 2009 Medco Health Solutions, Inc. All rights reserved. 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.

6. © 2009 Medco Health Solutions, Inc. All rights reserved. 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

7. © 2009 Medco Health Solutions, Inc. All rights reserved. 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)

8. © 2009 Medco Health Solutions, Inc. All rights reserved. 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

9. © 2009 Medco Health Solutions, Inc. All rights reserved. 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.

10. © 2009 Medco Health Solutions, Inc. All rights reserved. Baseline characteristics Characteristic No PPI (N=9862) PPI* (N=6828) *all p<0.01 Age - yrs; mean±SD65.2±10.667.5±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)

11. © 2009 Medco Health Solutions, Inc. All rights reserved. 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)

12. © 2009 Medco Health Solutions, Inc. All rights reserved. Number at Risk No PPI 9862 9235 8952 8818 8717 8622 8546 8459 8380 8318 8253 8197 8136 PPI 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 1.39-1.64 p < 0.0001 PPIs are associated with increased risk of CV events in patients on clopidogrel

13. © 2009 Medco Health Solutions, Inc. All rights reserved. Results: Subgroup Analysis for Any PPI Use PPI effect consistent across subgroups

14. © 2009 Medco Health Solutions, Inc. All rights reserved. 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

15. © 2009 Medco Health Solutions, Inc. All rights reserved. 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±10.668.7±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 stent3124 (31.7)656 (28.4)*866 (26.6)*520 (31.5)257 (32.7) * p<0.05 vs no PPI

16. © 2009 Medco Health Solutions, Inc. All rights reserved. Individual PPI exposure and dosing PPI exposure (PPI group only): PPI daily dosing: OmeprazoleEsomeprazolePantoprazoleLansoprazole At time of stent53%54%29%46% Median days (IQ range) overlap with clopidogrel 305 (197-365)305 (193-365)287 (116-365)299 (163-365) OmeprazoleEsomeprazolePantoprazoleLansoprazole ≤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%

17. © 2009 Medco Health Solutions, Inc. All rights reserved. Number at Risk No PPI 9862 9235 8952 8818 8717 8622 8546 8459 8380 8318 8253 8197 8136 Omeprazole 2307 2117 2032 1992 1954 1915 1885 1860 1827 1803 1176 1758 1738 Esomeprazole 3257 3008 2891 2823 2782 2729 2694 2648 2596 2559 2529 2494 2460 Pantoprazole 1653 1501 1416 1378 1341 1312 1294 1276 1255 1235 1216 1194 1179 Lansoprazole 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

18. © 2009 Medco Health Solutions, Inc. All rights reserved. Hospitalization rates for upper GI bleeding were low No PPI Omeprazole Esomeprazole Pantoprazole Lansoprazole All PPIs

19. © 2009 Medco Health Solutions, Inc. All rights reserved. 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

20. © 2009 Medco Health Solutions, Inc. All rights reserved. Number at Risk No PPI 1407 1322 1284 1260 1243 1224 1212 1192 1180 1171 1154 1145 1134 PPI 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 0.84-1.70 p = 0.326 N=1641 Post-Stent Without Clopidogrel PPIs not associated with increased risk in the absence of clopidogrel

21. © 2009 Medco Health Solutions, Inc. All rights reserved. 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%

22. © 2009 Medco Health Solutions, Inc. All rights reserved. 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.

23. © 2009 Medco Health Solutions, Inc. All rights reserved. Thank you for this opportunity to share our data with you.

24. © 2009 Medco Health Solutions, Inc. All rights reserved. Additional data

25. © 2009 Medco Health Solutions, Inc. All rights reserved.

26. 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)

27. © 2009 Medco Health Solutions, Inc. All rights reserved. Individual PPIs associated with increased risk of stroke, ACS, and coronary revascularization End Point No PPI OmeprazoleEsomeprazolePantoprazoleLansoprazole %HR% % % Stroke/ TIA 1.12.2 1.54 (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/ USA 10.016.3 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/ CABG 13.316.4 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 0.20.4 1.57 (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)

28. © 2009 Medco Health Solutions, Inc. All rights reserved. Individual PPIs associated with increased secondary end point risk End Point No PPI OmeprazoleEsomeprazolePantoprazoleLansoprazole %HR% % % MI4.86.7 1.25 (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) USA6.612.5 1.75 (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) PCI12.715.8 1.24 (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) CABG0.8 0.76 (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)

29. © 2009 Medco Health Solutions, Inc. All rights reserved. No PPI Individual PPIs Patients Post-Stent on Clopidogrel All individual PPIs analyzed associated with increased risk of major CV events

30. © 2009 Medco Health Solutions, Inc. All rights reserved. H 2 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 H 2 receptor antagonist; 9390 patients without H 2 receptor antagonist Combined cardiovascular event incidence: 20.3% w/ H 2 receptor antagonist vs. 17.8% w/o H 2 receptor antagonist (chi-square p=0.1579).