Risk of Adverse Outcomes Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome

Background:  Recent studies have suggested that proton pump inhibitors (PPI’s) may reduce the effectiveness of clopidogrel.  Since these two drugs are commonly prescribed together after an acute coronary syndrome (ACS), research is needed to evaluate the adverse events associated with the concomitant use of clopidogrel and PPIs.

Objective:  To assess the adverse outcomes of concomitant use of clopidogrel and PPIs verses clopidogrel alone.

Methods:  This was a retrospective cohort study.  Patient were enrolled based on Veterans Health Administration (VHA) medical center records if they had been discharged due to an ACS and prescribed clopidogrel with or without a PPI.  A total of 8205 patients were enrolled from October 1, 2003 to January 31, 2006.  Median follow-up after hospital discharge was 521 days.  The primary outcome measured the combined end point of all-cause mortality or rehospitalization for ACS following discharge.  Secondary outcomes included (1) rehospitalization for ACS; (2) revascularization procedures including percutaneous coronary intervention or coronary artery bypass graft surgery; and (3) all-cause mortality following index ACS hospitalization.  Multivariable logistic regression was used to analyze the primary outcomes.  Based on the sample size of 8205, the minimum detectable odds ratio (OR) with 80% power in a 2-sided test and an α level of .05 was 1.17.

Results:  Of the 8205 patients hospitalized due to an ACS and prescribed clopidogrel at discharge, 63.9% were prescribed a proton pump inhibitor concomitantly and 36.1% were not.  Primary outcomes were seen in 29.8% of patients taking clopidogrel and PPI compared to 20.8% of patients using clopidogrel alone; OR 1.62 (95% CI 1.45-1.80); AOR 1.25 (05% CI 1.11-1.41).  The rate of secondary outcomes were higher in patients on clopoidogrel and PPI  compared to those on clopidogrel alone; rehsoptialization:14.6% vs 6.9% P≤0.001, OR 2.29 (95% CI 1.95-2.69), AOR 1.86 (95% CI 1.57-2.20), revascularization procedures: 15.5% vs 11.9% P≤0.001, OR 1.36 (95% CI 1.19-1.55), AOR 1.49 (95% CI 1.30-1.71), all cause mortality: 19.9% vs 16.6% P≤0.001, OR 1.24 (95% CI 1.10-1.40), AOR 0.91 (95% CI 0.80-1.05).

Strengths:  The rationale of this study was good since the use of clopidogrel and PPIs are very common.  The study was adequately powered with an acceptable alpha level.  Authors performed various secondary analyses which accounted for a multitude of variables, something needed for this type of study design.

Weaknesses:  The use of a retrospective cohort study design makes it difficult to draw significant conclusions based on this data.  This type of design prevents authors from controlling variables before the study begins and requires them to adjust for these variables during analyses.  This study’s subjects were not equal at baseline.  Patients on clopidogrel and a PPI had more serious comorbidities compared to those not on a PPI.  This could have significantly affected outcomes because patients with more serious diseases often have an indication for both drugs and are more likely to experience adverse outcomes compared to patients with milder diseases.  Also, the data used in this study was collected from medical records, which may not be accurate or complete. Additionally, follow-up time was not consistent on a patient-to-patient basis.  Also, this study did not account for over-the-counter PPI use.  This study would have benefitted if the mortality outcome could have been limited to cardiovascular causes alone.  Although the use of secondary analyses was beneficial, the descriptions of these analyses and their results were confusing and difficult to follow. 

Conclusion:  The authors of this study concluded that concomitant use of clopidogrel and a PPI is associated with an increased risk of an ACS compared to clopidogrel alone.  Based on the results of this study and given the study’s limitations, PPIs should be limited to those cases where it’s indicated, rather than for prophylactic purposes.  Randomized, double-blinded, controlled trials are needed to confirm that the use of clopidogrel concomitantly with a PPI is associated with unfavorable outcomes.  These future experimental studies should reduce baseline characteristic differences, use various doses of PPIs, and limit mortality results to those specifically related to cardiovascular events.

Ho MP, Maddox TM, Wang W, et al.  Risk of Adverse Outcomes Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome.  JAMA.  2009; 301(9): 937-44.

Lindsey P. Koliscak, PharmD Candidate