Risk of adverse cardiovascular outcomes and all-cause mortality associated with concomitant use of clopidogrel and proton pump inhibitors in elderly patients

All rights reserved: reproduction in whole or part not permitted Original articleRisk of adverse cardiovascular outcomes andall-cause mortality associated with concomitantuse of clopidogrel and proton pump of concomitant use of clopidogrel and PPIs in a national sample of elderly Medicare A nested case–control design was employed. A cohort of Medicare beneficiaries who initiated clopidogrel days between clopidogrel fills between July 1, 2006 and December 31, national sample of Medicare claims data. Within this cohort, cases Address for correspondence: Yi Yang MD PhD, (beneficiaries who experienced any major cardiovascular event [MCE] [acute myocardial infarction, stroke, coronary artery bypass graft, or percutaneous coronary intervention] or all-cause mortality) and University of Mississippi, University, MS 38677, USA. 20 controls (beneficiaries who did not experience any MCE or all-cause mortality) were identified from inpatient Tel.: þ1 (662) 915-1062; Fax: þ1 (662) 915-5102; claims. Cases and controls were matched on age and the time to first clopidogrel fill.
Conditional logistic regression was performed on the matched sample to evaluate the associationbetween concomitant use of clopidogrel and PPIs and adverse health outcomes (MCEs and all-cause Clopidogrel – Drug–drug interaction – Elderly – Sale or A total of 43,159 clopidogrel users were identified. Among them, 15,415 (35.7%) received clopidogrel and Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 a PPI concomitantly at any time during the study period, 3502 (8.1%) experienced a MCE, 7306 (17.1%) died, and a total of 9908 (22.8%) experienced the primary composite outcome (any MCE or all-cause disp mortality) during follow-up. The odds ratio (OR) for the primary composite outcome was 1.26 (95% confidence interval [CI]: 1.18–1.35). Secondary analyses indicated that elderly patients using clopidogreland a PPI concomitantly were more likely to experience all-cause mortality (OR: 1.40; 95% CI: 1.29–1.53)as compared to those receiving clopidogrel only, but not MCEs (OR: 1.06; 95% CI: 0.95–1.18).
Concomitant use of clopidogrel and PPIs was associated with a slightly increased risk of all-cause mortalitybut not MCEs.
Clopidogrel belongs to the class of anti-platelet agents and is indicated for pre-vention of arterial thromboembolism in patients with peripheral arterial diseasesor patients with acute coronary syndrome (ACS) who are treated medically or Concomitant use of clopidogrel and PPIs in the elderly through coronary revascularization procedures1,2. With younger than 50 years of age28 and physicians often pre- global sales of $9.1 billion (US dollars) in 2009, clopido- scribe PPIs to these patients to provide gastrointestinal grel is the second best selling drug worldwide3.
protection29 because PPIs have been found to be the Clopidogrel is highly effective in reducing athero- most effective agent in preventing gastrointestinal bleed- thrombotic and ischemic events; however, its use is often ing related to anti-platelet therapy30. Research on the con- associated with gastrointestinal complications including comitant use of clopidogrel and PPIs focusing on the ulceration and bleeding4. Several professional organiza- elderly population has been limited. This lack of informa- tions such as the American Heart Association and the tion is concerning because the effect of concomitant use of American College of Gastroenterology have recom- clopidogrel and PPIs in the elderly cannot be simply extra- mended that a proton pump inhibitor (PPI) should be polated from studies involving younger people. A few used with anti-platelet therapy consisting of clopidogrel observational studies have evaluated the effect of clopido- alone or clopidogrel and aspirin for gastrointestinal protec- grel–PPI interaction in the elderly population and results tion5. However, evidence from mechanistic studies has from these studies are likely to be inadequate to inform indicated that the anti-platelet effect of clopidogrel is evidence-based prescribing because these studies only reduced in the presence of PPIs because PPIs inhibit included patients within restricted geographic areas31,32.
CYP2C19, an enzyme responsible for the conversion of In a randomized clinical study, Bhatt et al. examined the clopidogrel to its active metabolite6–8. Moreover, several incidence of adverse gastrointestinal events and adverse observational studies have shown that concomitant use cardiovascular events among elderly patients on dual clo- of clopidogrel and PPIs increases the risk of adverse car- pidogrel and aspirin therapy receiving either omeprazole or diovascular events9–15. In response to growing concerns placebo, and they did not find apparent cardiovascular over combined use of clopidogrel and PPIs, the US Food and Drug Administration (FDA) issued a public advisory While this randomized controlled study provides useful in 2009 advising physicians to re-evaluate the need of PPI use in patients receiving clopidogrel and subsequently among elderly patients, only the interaction between clo- a ‘black box’ warning was added to all clopidogrel pidogrel and omeprazole and not other PPIs was evaluated (Plavix*) labels in 2011 advising physicians to avoid pre- in the study. To provide further insights into the real-world scribing clopidogrel and PPIs, namely omeprazole and association between concomitant use of clopidogrel and esomeprazole, simultaneously16. Similarly, the European PPIs and adverse outcomes in the elderly population, we Medicines Agency issued a public statement in 2009 dis- conducted a nested case–control study involving a couraging the concomitant use of clopidogrel and PPIs national sample of elderly patients using the 5% sample unless absolutely necessary17. However, no consensus has of Medicare administrative claims data.
been reached regarding the effect of concurrent use ofclopidogrel and PPIs, as results from two randomized con-trolled trials and several observational studies have shown no association between concomitant use of clopidogrel andPPIs and adverse cardiovascular events5,8,18–24.
Most previous research on concomitant use of clopido- The study used a nested case–control design for the grel and PPIs has focused on general patient populations.
analysis of Medicare beneficiaries with age Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 A better understanding of the effects of the potential drug– who initiated and continued to receive clopidogrel therapy drug interaction between clopidogrel and PPIs focusing with or without a PPI between July 1, 2006 and December on the elderly is important for several reasons. First, the 31, 2008. The study was approved by the University of effect of concomitant use of clopidogrel and PPIs is likely Mississippi Institutional Review Board and the data were to be different in older adults, as older adults are more accessed only after execution of a data use agreement with likely to experience cardiovascular events25 and they are the Centers for Medicare and Medicaid Services (CMS).
also more susceptible to clopidogrel–PPI interactions26.
Elderly patients might be more likely to be influenced bythe clopidogrel–PPI interaction possibly due to their reduced liver function, which reduces metabolism ofclopidogrel to its active metabolite27. When a PPI is The 2006–2008 5% national sample of Medicare admin- co-administered with clopidogrel in the elderly, clopido- istrative claims database was used for this study. Records grel’s anti-platelet effect could be further reduced. Second, for healthcare services offered to Medicare beneficiaries in elderly patients on anti-platelet drugs are more likely to various settings such as inpatient, outpatient, and skilled have gastrointestinal bleeding as compared to those nursing facilities were available through the Medicareclaims database. The database also included records for *Plavix is a registered trade name of Sanofi-Aventis, NJ, USA.
prescription drugs dispensed under Medicare Part D.
2 Concomitant use of clopidogrel and PPIs in the elderly Mahabaleshwarkar et al.
Beneficiary demographic and enrollment information was identify PCI. We identified AMI based on the approach available through the Medicare Beneficiary Summary file.
proposed by Kiyota et al. (2004)35, which has been found to All claims were linked through an encrypted unique have a high positive predictive value. For the identifica- common beneficiary identification number.
tion of stroke, we used the algorithm suggested by Rekeret al. (2001)36. Both AMI and stroke were identified usingMedicare inpatient claims. All-cause mortality was deter- mined using information from the Medicare Beneficiary The cohort used for this study consisted of Medicare ben- Summary file. For each case, we selected one control from the cohort who did not experience a MCE or all- 2006; (2) had continuous Medicare part A coverage and at cause mortality; cases and their corresponding controls least 1 month of Part B coverage from January 1, 2006 to were matched on age (Æ5 years) and time to cohort December 31, 2008 or until death, whichever occurred entry (Æ7 days). Time to cohort entry was determined as first; and (3) had initiated clopidogrel therapy and did the time between the start of the study period, July 1, 2006, not have any gap of 30 days or more between clopidogrel and the date of the first clopidogrel fill. The index date fills between July 1, 2006 and December 31, 2008, since for each control was set as the index date of the corres- previous literature suggests that a gap of 30 days or ponding case to which it was matched (i.e., the date on more between prescription fills should be considered as which a MCE or all-cause mortality occurred).
non-persistence with therapy33. Clopidogrel fills wereidentified from the Medicare Part D drug event file using the National Drug Codes for clopidogrel. Only incidentusers of clopidogrel, that is, beneficiaries who had no Information about use of clopidogrel and PPIs for each clopidogrel claims between January 1 and June 30, 2006 patient was obtained from the Medicare Part D drug (i.e., the baseline period), were included in the study.
event file. The PPIs considered in this study included ome- Beneficiaries enrolled in Medicare health maintenance prazole, esomeprazole, pantoprazole, lansoprazole, and organizations for any part of the study period were also rabeprazole. Concomitant use of clopidogrel and PPIs in excluded since no medical claims were available for cases and controls was determined based on whether or not the beneficiary possessed the two drugs simultaneouslybetween July 1, 2006 and the index date. Possession of the drugs was determined on a daily basis using the prescription fill date and the days’ supply field for each In this study, our primary end point was a composite prescription. Early fills were taken into account by carrying outcome of any major cardiovascular event (MCE) or forward the days of overlap between prescription fills.
all-cause mortality. MCEs considered in this study were Concomitant use of clopidogrel and PPIs was considered acute myocardial infarction (AMI), stroke, receiving cor- as a dichotomous variable. Beneficiaries who possessed onary artery bypass grafting (CABG) surgery, or receiving clopidogrel and a PPI together for one or more days percutaneous coronary intervention (PCI). For patients between July 1, 2006 and the index date were considered experiencing more than one adverse event, the first occur- as concomitant users of clopidogrel and PPIs, whereas rence of any of these events was deemed as the index those who did not possess the two drugs simultaneously Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 event. Within the cohort of clopidogrel users, we defined were considered as clopidogrel only users.
cases as patients who experienced an index event betweenthe date of the first prescription claim for clopidogrel and December 31, 2008. The date that a beneficiary experi-enced the index event was designated as the index date Covariates included in the study were baseline demo- for cases. Cases were identified using the International graphics (gender, and race), presence of end stage renal dis- ease (ESRD), dual eligibility status, presence of important Modification (ICD9-CM) diagnosis and procedure codes cardiovascular comorbidities (angina, chronic obstructive and the CMS Common Procedure Coding System pulmonary disease [COPD], congestive heart failure, (HCPCS) codes from Medicare inpatient and outpatient diabetes, hypertension, hyperlipidemia, and peripheral claims data (Appendix 1). CABG was identified based on arterial disease), previous use of dialysis, and history of the primary and secondary procedure codes associated with the inpatient records. Since PCI may be performed as an bleeding, duodenal or gastric ulcer, gastroesophageal outpatient procedure with a patient being discharged on reflux disease, and erosive esophagitis), AMI, stroke, the same day34, we used primary and secondary procedure CABG, and PCI. Race was divided into three categories: codes associated with inpatient and outpatient claims to white, black, and others. Presence of ESRD and dual Concomitant use of clopidogrel and PPIs in the elderly eligibility were both considered as dichotomous variables.
conditions (such as cancer) also contribute to all-cause Presence of cardiovascular comorbidities, history of gastro- mortality. Most of these conditions have been taken into intestinal disorders, previous use of dialysis, history of consideration in the calculation of CCI and previous AMI, stroke, CABG, and PCI were determined based research has shown that CCI is a significant predictor of on the inpatient and outpatient claims at baseline all-cause mortality38. Finally, we evaluated the association (January 1 – June 30, 2006). In addition, we adjusted for between concomitant use of clopidogrel and individual the use of classes of medications which may affect the anti- types of PPIs and the occurrence of the primary composite platelet effect of clopidogrel including other CYP2C19 outcome of any MCE or all-cause mortality. All analyses inhibitors (chloramphenicol, cimetidine, felbamate, flu- were performed using Statistical Analysis System (SAS) oxetine, fluvoxamine, ketoconazole, moedafinil, and version 9.2 (SAS Institute Inc., Cary, NC, USA). The oxcarbazepine), CYP3A4 inhibitors (amiodarone, diltia- greedy algorithm was used for matching cases and controls.
zem, verapamil, voriconazole, fluconazole, nicardipine, and nifedipine), and sulfonylureas during the study STRATA statement was used for conditional logistic period (July 1, 2006 – December 31, 2008)37. We also adjusted for the use of drugs which have the potential toreduce the likelihood of adverse cardiovascular eventssuch as angiotensin-converting-enzyme inhibitors, angio- tensin-receptor antagonists, acetylsalicylic acid, -adre-nergic antagonists, calcium-channel antagonists, digoxin, We identified 43,159 Medicare beneficiaries as incident spironolactone, statins, and diuretics during the study clopidogrel users. Of these beneficiaries, 15,415 (35.7%) used clopidogrel and a PPI concomitantly at any timeduring the study period; 3502 (8.1%) experienced aMCE, 7306 (17.1%) died, and a total of 9908 (23.0%) experienced an adverse outcome (a MCE or all-cause mor-tality) during follow-up. The majority of the beneficiaries In the bivariate analyses, the chi-square test was used for were female (61.5%) and white (84.0%). The mean age of the comparison of categorical variables whereas Student’s the cohort was 76.8 years. Detailed patient demographic t-test was used for the comparison of continuous variables and clinical characteristics are presented in Table 1.
between cases and controls. Frequencies and percentages Baseline demographic and comorbidity characteristics were reported for categorical variables, whereas means of the matched cases and controls are also presented in and standard deviations were reported for continuous vari- Table 1. For example, cases were more likely than controls ables. In the multivariable analysis, conditional logistic to be males (39.5% vs. 33.8%, p50.001) and blacks (8.9% regression was performed on matched cases and controls vs. 7.9%, p50.001). A greater percentage of cases had to determine the association between concomitant clopi- diabetes (32.6% vs. 29.4%, p50.001), COPD (17.5% vs.
dogrel and PPI use and the occurrence of any MCE or all- 12.8%, p50.001), and congestive heart failure (20.7% vs.
cause mortality. The covariates listed earlier were adjusted 12.5%, p50.001) than controls. A greater percentage of for in the conditional logistic regression model. Odds ratios controls had hypertension (68.8% vs. 61.8%, p50.001), (OR) and 95% confidence intervals (CIs) were computed.
hyperlipidemia (52.7% vs. 40.7%, p50.001), erosive In addition, we conducted a set of secondary analyses esophagitis (3.6% vs. 2.7%, p ¼ 0.002), and gastroesopha- Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 to test the robustness of our primary findings. Firstly, geal reflux disease (13.2% vs. 11.0%, p50.001) than cases.
we evaluated the association between concomitant use of In terms of medication use, a greater percentage of cases clopidogrel and PPIs and the occurrence of each individual were users of CYP3A4 inhibitors (5.2% vs. 4.5%, adverse outcome (AMI, stroke, CABG, PCI, and all-cause p ¼ 0.037), angiotensin-converting enzyme inhibitors mortality). Secondly, we computed the odds of experien- (51.7% vs. 46.7%, p50.001), -adrenergic antagonists cing any MCE associated with concomitant use of clopi- (74.0% vs. 68.6%, p50.001), and sulfonylureas (18.3% dogrel and PPIs. For patients having more than one MCE, vs. 15.3%, p50.001) than controls. Controls were more the first occurrence of any of these events was defined as likely to be users of angiotensin receptor antagonists the index event. Thirdly, while determining the associ- (22.5% vs. 19.9%, p50.001) and statins (67.3% vs.
ation between concomitant use of clopidogrel and PPIs 60.3%, p50.001) as compared to cases.
and all-cause mortality, instead of using each individual From our primary analysis with conditional logistic cardiovascular comorbidity, the Charlson comorbidity regression performed on matched cases and controls, index (CCI, D’Hoore adaptation)38 and cardiovascular after extensive multivariable adjustment, we found that comorbidities not included in the CCI calculation – the estimated odds of experiencing the primary composite namely angina, hyperlipidemia, and hypertension – were outcome (any MCE or all-cause mortality) were 26% used as covariates, because various non-cardiovascular higher for patients with concomitant use of clopidogrel 4 Concomitant use of clopidogrel and PPIs in the elderly Mahabaleshwarkar et al.
Table 1. Baseline characteristics of incident clopidogrel users and matched cases and controls.
Medication use between July 1, 2006 and December 31, 2008Other CYP2C19 inhibitors aFor continuous variables, p values are based on t-tests for differences between means; for categorical variables, p values are based on Pearson’s chi-square testof association.
bOther races include Asian, Hispanic, and North American natives.
ESRD ¼ end stage renal disease; COPD ¼ chronic obstructive pulmonary disease; AMI ¼ acute myocardial infarction; CABG ¼ coronary artery bypass grafting; Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 PCI ¼ percutaneous coronary intervention.
and a PPI as compared to patients who were taking clopi- obtained by including individual cardiovascular comorbid- dogrel only (OR: 1.26; 95% CI: 1.18–1.34, p50.001).
ities as covariates (OR: 1.36; 95% CI: 1.25–1.47, In the secondary analyses, we found a significant effect p50.001). The results evaluating the effects of individual of concomitant use of clopidogrel and a PPI on all-cause types of PPIs were similar to the results of our primary mortality (OR: 1.40; 95% CI: 1.29–1.53, p50.001), whereas the effects on individual cardiovascular eventswere not statistically significant (Table 2). The associationbetween concomitant use of clopidogrel and PPIs and occurrence of any MCE was not statistically significant(OR: 1.06; 95% CI: 0.95–1.18, p ¼ 0.305). In terms of This study examined the risk of adverse outcomes asso- association between concomitant use of clopidogrel and ciated with concomitant use of clopidogrel and PPIs in a PPIs and all-cause mortality, the results on including national sample of elderly Medicare beneficiaries. To our CCI and cardiovascular comorbidities not included in knowledge, this is the first study evaluating the effect of the CCI calculation as covariates were similar to those clopidogrel–PPI interaction in the elderly population Concomitant use of clopidogrel and PPIs in the elderly Table 2. Association between concomitant use of clopidogrel and proton Medicare beneficiaries using clopidogrel and a PPI con- pump inhibitors and adverse health outcomes.
comitantly as compared to beneficiaries using clopidogrelonly. Results from our secondary analyses indicate that concomitant use of clopidogrel and PPIs is associated with significantly increased risk for all-cause mortality, but not for MCEs. The significant association between concomitant clopidogrel and PPI use and occurrence of all-cause mortality held even after controlling for CCI in the secondary analysis. These results suggest that all-cause mortality was the major contributor to our primary finding of statistically significant association between concomi- tant use of clopidogrel and PPI and adverse health out- comes. These results are somewhat consistent with the aObtained from conditional logistic regressions performed on cases and findings from two previous studies focusing on the elderly controls matched on age (Æ5 years) and time to cohort entry (Æ7 days).
bAdjusted for all patient characteristics (covariates) in Table 1 except for population. Rassen et al. (2009) evaluated the clopidogrel– age, time to cohort entry, and Charlson comorbidity index.
PPI interaction in low-income patients enrolled in three PPI ¼ proton pump inhibitor; MCE ¼ major cardiovascular event (AMI, health insurance programs in British Columbia, New CABG ¼ coronary artery bypass grafting; PCI ¼ percutaneous coronary Jersey, and Pennsylvania32. They studied patients aged !65 years who were hospitalized for ACS or PCI between2001 and 2005. They found that concomitant use of clo-pidogrel and PPIs was associated with an increased but not Table 3. Association between concomitant use of clopidogrel and statistically significant risk of myocardial infarction or individual types of proton pump inhibitors and major adverse cardiovascularevents or all-cause mortalitya.
death (OR: 1.22; 95% CI: 0.99–1.51). The associationsbetween concurrent clopidogrel and PPI use and occur- rence of individual outcomes of death (OR: 1.20; 95% CI: 0.84–1.70) and revascularization (OR: 0.97; 95% CI: 0.79–1.21) were also found to be non-significant in this study. In a Canadian study, Juurlink et al. (2009) studied elderly AMI patients who were prescribed clopidogrel within 3 days of discharge from a local hospital. Theyfound a significant association between readmission for aAdjusted for all patient characteristics (covariates) in Table 1 except for AMI and current use of a PPI (most recent prescription age, time to cohort entry, and Charlson comorbidity index.
bObtained from conditional logistic regressions performed on cases and fill for a PPI within 30 days before readmission for AMI or controls matched on age (Æ5 years) and time to cohort entry (Æ7 days).
death) (OR: 1.27; 95% CI: 1.03–1.57). However, a signifi- Major cardiovascular event ¼ AMI, stroke, CABG, or PCI.
cant association between readmission for AMI and PPI use AMI ¼ acute myocardial infarction; CABG ¼ coronary artery bypass grafting;PCI ¼ percutaneous coronary intervention.
was not observed by the authors in previous users of clopi-dogrel, who had their most recent prescription fill for a PPI31–90 days before readmission for AMI or death, and in using a national sample. Elderly patients on clopidogrel remote users of clopidogrel, who had their most recent Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 therapy have an increased tendency to gastrointestinal prescription fill for a PPI 91–180 days before readmission bleeding and hence need effective medications such as for AMI or death31. As far as the effect of the clopidogrel– PPIs for gastrointestinal protection. On the other hand, PPI interaction in the general population is concerned, they may be more prone to be affected by a potential clo- some observational studies have found an increased risk pidogrel–PPI interaction. Although a previous randomized of cardiovascular events9–15, whereas others have found controlled study has examined the potential interaction no statistically significant effect19–24. Since these studies between clopidogrel and omeprazole in an elderly popula- consisted of patient populations that included younger tion18, this study adds to the literature by determining individuals, direct comparison of findings from our study the real-world effect of clopidogrel–PPI interaction in with these studies was not possible.
Regarding the effect of concomitant use of clopidogrel Through a nested case–control design, we studied the and individual types of PPIs on adverse health outcomes, association between concomitant use of clopidogrel and the results were statistically significant across all types of PPIs and the risk of experiencing a MCE or all-cause mor- PPIs. The significant interaction between clopidogrel and tality using the 5% national sample of Medicare benefici- pantoprazole was a little unexpected, given that previous aries. We found that the risk of experiencing this mechanistic studies and observational studies evaluating composite outcome was 26% higher among elderly the potency of PPIs in CYP2C19 inhibition showed that 6 Concomitant use of clopidogrel and PPIs in the elderly Mahabaleshwarkar et al.
pantoprazole had the least inhibitory potency39–44.
gastrointestinal disorders or a physician’s impression that Significant interaction between clopidogrel and pantopra- a given patient is at an increased risk for gastrointestinal zole was also observed in studies by Kreutz et al.11 and problems. Furthermore, in our analyses, we could not Stockl et al.45, suggesting that a different mechanism account for unmeasured factors such as smoking, blood may be associated with the interaction between clopido- pressure level, serum cholesterol level, and family history grel and PPIs. Results concerning the clopidogrel–panto- of cardiovascular disease, which are likely to affect cardio- prazole interaction in studies focusing on elderly adults vascular outcomes. We used Medicare beneficiaries’ pre- have been inconsistent. While Rassen et al.32 observed scription drug filling data to identify medication uses.
no difference in rate ratios for adverse outcomes in panto- Though the beneficiaries possessed the medications, we prazole and other PPI users, Juurlink et al.31 found that were not able to verify whether they actually took them.
current pantoprazole users were less likely to experience Nonetheless, previous research has shown that filling a adverse outcomes compared to other PPI users. Future prescription is usually consistent with taking the drug46.
efforts are needed to further explore the mechanism under- Finally, causes of death were not available from our data lying the interaction between clopidogrel and PPIs.
therefore all-cause mortality, and not cardiovascular mor- Our study has a number of strengths. To our knowledge, tality, was used as an outcome measure in our study.
this is the only study evaluating the effect of concomitantuse of clopidogrel and PPIs in older adults using a nationalsample. Second, we have included all clopidogrel users inthe study unlike other studies which have concentrated on a specific set of users such as individuals hospitalized for We found a slightly increased risk of experiencing any ACS or PCI32 or AMI31. We believe this broad-based MCE or all-cause mortality in elderly adults using clopido- patient inclusion makes findings from our study more gen- grel and PPIs concomitantly. These results were consistent eralizable. Furthermore, we have taken utmost care to across all PPIs. The associations between concomitant clo- eliminate many sources of confounding in our study.
pidogrel and PPI use and occurrence of MCEs, considered For example, we have adjusted for the presence of major individually or as a group, were not statistically significant, cardiovascular comorbidities such as hypertension, dia- while the odds of all-cause mortality were higher in elderly betes, and congestive heart failure, which usually lead to concomitant users of clopidogrel and PPIs. Since the adverse cardiovascular events. We also adjusted for the use reasons of death were unidentifiable from our data, of medications which may potentially affect clopidogrel’s considering the fact that all-cause mortality can occur anti-platelet effect. Additionally, we included CCI as a due to non-cardiovascular reasons, the results for the asso- covariate in our analysis to determine the effect of clopi- ciation between concomitant clopidogrel and PPI use and dogrel–PPI interaction on all-cause mortality.
all-cause mortality might have been biased away from Several limitations of our study need to be addressed.
the null in spite of controlling for CCI in the secondary Due to limitations of the data source, we could not identify analyses. Therefore, findings from this study do not present from our cohort, beneficiaries who were poor metabolizers conclusive evidence to suggest avoiding PPIs in elderly of clopidogrel due to genetic polymorphisms of the cyto- patients on anti-platelet therapy with clopidogrel.
chrome P450 enzyme CYP2C19. Poor clopidogrel metab-olizers may be more likely to experience adverse Conservatively, other gastrointestinal protecting agents cardiovascular outcomes or mortality. Using Medicare such as histamine-2-receptor antagonists could be Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 administrative claims data, we were also unable to identify over-the-counter use of PPI medications (omeprazole andlansoprazole). It is possible that clopidogrel only userswould be more likely to have purchased over-the-counter PPIs than those who have received prescription PPIs.
Similarly, we were unable to account for the over- the-counter use of aspirin, which is generally used with This study was sponsored by the Centers for Medicare and clopidogrel to treat peripheral arterial diseases or ACS because aspirin is often available over the counter. In add- Declaration of financial/other relationships ition, although we have tried to minimize confounding by R.K.M., Y.Y., M.V.D., J.P.B., M.W.S., B.F.B., and K.D.N. have indication through controlling for history of gastrointes- disclosed that they have no significant relationships with or tinal disorders (including gastrointestinal bleeding, duo- financial interests in any commercial companies related to this denal or gastric ulcer, gastroesophageal reflux disease, and erosive esophagitis) in our analyses, there may be CMRO peer reviewers may have received honoraria for other sources of confounding by indication which are their review work. The peer reviewers on this manuscript have not captured by our data such as uncoded diagnoses of disclosed that they have no relevant financial relationships.
Concomitant use of clopidogrel and PPIs in the elderly This study was conducted as part of a project titled ‘Using Medicare/Medicaid Claims Data to Support Medication Outcomes and Pharmacovigilance Research’, which was sup- Public statement on possible interaction between clopidogrel and proton ported by grant award 1COCMS330731/01 from the Office of pump inhibitors. London: European Medicines Agency, 2009. Available at: Research, Development and Information, CMS.
Previous presentation: This work was presented at the Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole International Society for Pharmacoeconomics and Outcomes in coronary artery disease. N Engl J Med 2010;363:1909-17 Research 17th Annual International Meeting, 2–6 June 2012, Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors. Ann Intern Med 2010;152:337-45 Schmidt M, Johansen MB, Robertson DJ, et al. Concomitant use of clopido-grel and proton pump inhibitors is not associated with major adverse cardio-vascular events following coronary stent implantation. Aliment Pharmacol Hsiao FY, Mullins CD, Wen YW, et al. Relationship between cardiovascular Aschenbrenner DS. Drug watch. Am J Nurs 2006;106:29-31 outcomes and proton pump inhibitor use in patients receiving dual antiplatelet Joseph JJ, Pillai A, Bramley D. Clopidogrel in orthopaedic patients: a review of therapy after acute coronary syndrome. Pharmacoepidemiol Drug Saf current practice in Scotland. Thromb J 2007;5:6 Top 15 Global Products, 2009, Total Audited Markets. IMS Heath Reports.
Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are asso- New Jersey, US: IMS Health, 2009. Available at: ciated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med 2010;153:378-86 Tentzeris I, Jarai R, Farhan S, et al. Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after Gurbel PA, Tantry US, Kereiakes DJ. Interaction between clopidogrel and coronary stent implantation. Thromb Haemost 2010;104:1211-18 proton-pump inhibitors and management strategies in patients with cardio- Rossini R, Capodanno D, Musumeci G, et al. Safety of clopidogrel and proton vascular diseases. Drug Healthc Patient Saf 2010;2:233-40 pump inhibitors in patients undergoing drug-eluting stent implantation. Coron Harjai KJ, Shenoy C, Orshaw P, et al. Clinical outcomes in patients with the concomitant use of clopidogrel and proton pump inhibitors after percutaneous Cardiovascular disease risk factors. Geneva: World Heart Federation.
coronary intervention. Circ Cardiovasc Interv 2011;4:162-70 Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the anti- platelet action of clopidogrel associated with aspirin: the randomized, double- Delafuente JC. Understanding and preventing drug interactions in elderly blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol2008;51:256-60 patients. Crit Rev Oncol Hematol 2003;48:133-43 Li XQ, Andersson TB, Ahlstro¨m M, et al. Comparison of inhibitory effects of Wynne HA, James OFW. The ageing liver. Age Ageing 1990;19:1-3 Nikolsky E, Stone GW, Kirtane AJ, et al. Gastrointestinal bleeding in patients the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole,pantoprazole, and rabeprazole on human cytochrome P450 activities.
with acute coronary syndromes: incidence, predictors, and clinical implica- tions: analysis from the ACUITY (Acute Catheterization and Urgent Intervention O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic Triage Strategy) trial. J Am Coll Cardiol 2009;54:1293-302 effect and clinical efficacy of clopidogrel and prasugrel with or without Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the anti- a proton-pump inhibitor: an analysis of two randomized trials. Lancet fracture efficacy of alendronate. Arch Intern Med 2011;171:998-1004 Ng FH, Tunggal P, Chu WM. Esomeprazole compared with famotidine in Gupta E, Bansal D, Sotos J, et al. Risk of adverse clinical outcomes with the prevention of upper gastrointestinal bleeding in patients with acute concomitant use of clopidogrel and proton pump inhibitors following percu- coronary syndrome or myocardial infarction. Am J Gastroenterol 2012;107: taneous coronary intervention. Dig Dis Sci 2010;55:1964-8 Ho PM, Maddox TM, Wing L, et al. Risk of adverse outcomes associated with Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug Curr Med Res Opin Downloaded from informahealthcare.com by 207.68.251.244 on 02/27/13 concomitant use of clopidogrel and proton pump inhibitors following acute interaction between proton pump inhibitors and clopidogrel. CMAJ 2009; Kreutz RP, Stanek EJ, Aubert R, et al. Impact of proton pump inhibitors on the Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes effectiveness of clopidogrel after coronary stent placement: the Clopidogrel and mortality in patients using clopidogrel with proton pump inhibitors after Medco Outcomes Study. Pharmacotherapy 2010;30:787-96 percutaneous coronary intervention or acute coronary syndrome. Circulation Tsai Y, Wen Y, Huang W, et al. Cardiovascular and gastrointestinal events of three antiplatelet therapies: clopidogrel, clopidogrel plus proton-pump inhibi- Sørensen R, Gislason GH, Fosbøl EL, et al. Initiation and persistence with tors, and aspirin plus proton-pump inhibitors in patients with previous gastro- clopidogrel treatment after acute myocardial infarction: a nationwide study. Br intestinal bleeding. J Gastroenterol 2011;46:39-45 Van Boxel OS, Van Oijen MGH, Hagenaars MP, et al. Cardiovascular and Rao SV, Kaltenbach LA, Weintraub WS, et al. Prevalence and outcomes of gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: same-day discharge after elective percutaneous coronary intervention among results of a large Dutch cohort study. Am J Gastroenterol 2010;105:2430-6 Yasuda H, Yamada M, Sawada S, et al. Upper gastrointestinal bleeding in Kiyota Y, Schneeweiss S, Glynn RJ, et al. The accuracy of Medicare claims- patients receiving dual antiplatelet therapy after coronary stenting. Intern Med based diagnosis of acute myocardial infarction: estimating positive predictive value based on review of hospital records. Am Heart J 2004;148:99-104 Bhurke SM, Martin BC, Li C, et al. Effect of the clopidogrel-proton pump Reker DM, Hamilton BB, Duncan PW, et al. Stroke: Who’s counting what? J inhibitor drug interaction on adverse cardiovascular events in patients with acute coronary syndrome. Pharmacotherapy 2012;32:809-18 Harmsze AM, van Werkum JW, Moral F, et al. Sulfonylureas and on-clopido- Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) – grel platelet reactivity in type 2 diabetes mellitus patients. Platelets 2011;22: drug interaction. FDA Safety Information. Washingon, DC: US Food and Drug 8 Concomitant use of clopidogrel and PPIs in the elderly Mahabaleshwarkar et al.
D’Hoore W, Sicotte C, Tilquin C. Risk adjustment in outcome assessment: the Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantopraole and esome- Charlson comorbidity index. Method Inform Med 1993;32:382-7 prazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1-5 Li XQ, Andersson TB, Ahlstrom M, et al. Comparison of inhibitory effects of the Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pan- and pantoprazole on the pharmacodynamics and pharmacokinetics of clopi- toprazole, and rabeprazole on human cytochrome P450 activities. Drug dogrel in healthy subjects: randomized, placebo-controlled, crossover com- parison studies. Clin Pharmacol Ther 2011;89:65-74 Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantopra- Stockl KM, Le L, Zakharyan A, et al. Risk of rehospitalization for patients zole influence on a high 150-mg clopidogrel maintenance dose. The PACA using clopidogrel with a proton pump inhibitor. Arch Intern Med 2010;170: (Proton Pump Inhibitors and clopidogrel Association) prospective randomized Steiner JF, Prochazka AV. The assessment of refill compliance using phar- Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the macy records: methods, validity, and applications. J Clin Epidemiol 1997;50: antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:714-19 Neubauer H, Engelhardt A, Kruger JC, et al. Pantoprazole does not influence Tran M, Tafreshi J, Pai RG. Combination of clopidogrel and proton pump the antiplatelet effect of clopiodgrel: a whole blood aggregometry study after inhibitors: implications for clinicians. J Cardiovasc Pharmacol Ther coronary stenting. J Cardiovasc Pharmacol 2010;56:91-7 Appendix 1. ICD9-CM and HCPCS codes used to identify cardiovascular outcomes.
primary diagnosis code of 430.xx–434.xx, 436.xx, 433.01, 433.11, 433.21, 433.31, 433.81, or 433.91 or primary diag-nosis code of V57.xx and any secondary diagnosis code of342.xx, 430.xx, 431.xx, 432.xx, 433.xx, 434.xx, 435.xx,436.xx, 437.xx or 438.xx or primary diagnosis code of 433.xxor 435.xx and any secondary diagnosis code of 342.xx, 430.xx,431.xx, 432.xx, 434.xx, or 436.xxa 33510–33514, 33516, 33533–33536, 33517–33519 33521–33523, 36.01, 36.02, 36.05, 00.66, 36.06, 36.07b 92982, 92984, 92995, 92996, 92980, 92981, 92973–92975, 92978, aICD9-CM diagnosis codes.
bICD9-CM procedure codes.
CABG ¼ coronary artery bypass graft; PCI ¼ percutaneous coronary intervention; AMI ¼ acute myocardial infarction; ICD9-CM ¼ International Classification forDiseases version 9 Clinical Modification; HCPCS ¼ Centers for Medicare and Medicaid Services Common Procedure Coding System.
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