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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
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.
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
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 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
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
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.
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
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%
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.
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)