A SYSTEMATIC REVIEW OF THE POTENTIAL INTERACTION BETWEEN CLOPIDOGREL AND PROTON PUMP INHIBITORS

1. A SYSTEMATIC REVIEW OF THE POTENTIAL INTERACTION BETWEEN CLOPIDOGREL AND PROTON PUMP INHIBITORS ABSTRACT Objective: To evaluate the evidence for a clinically significant drug interaction between clopidogrel and proton pump inhibitors (PPIs) Design: Systematic review Data source: Electronic literature search without language restrictions of two databases, abstracts from the major cardiology conferences and hand search of bibliographies for other relevant articles. Review methods: Inclusion criteria included all studies reporting clinical outcomes. Each study was evaluated for its risk of bias according to a prespecified quality measure scale. Results: 18 studies were identified, 10 of 13 studies judged to be of low quality reported a statistically positive interaction between clopidogrel and PPIs and each concluded there was likely a clinically meaningful effect. None of the five studies judged to be of moderate quality reported a statistically significant association. Multiple sources of heterogeneity (different populations, outcomes assessed, drug exposure methods, and study quality) prevented a formal quantitative analysis of all studies. An increased risk of bias was observed in the positive studies resulting in an inverse correlation between study quality and a reported statistically positive interaction (10/13 versus 0/5, p=0.01). There was no clinical evidence for a positive interaction according to specific PPIs. Conclusion: The observed association between clopidogrel and PPIs is found uniquely in studies judged to be of low quality with an increased risk of bias. High quality evidence supporting a clinically significant clopidogrel / PPI interaction is presently lacking. MEDLINE EMBASE N= 44 Abstracts from Cardiology Meetings N=9 53 titles identified in literature search 6 titles/abstracts excluded upon inspection 47 potentially relevant titles, retrieved as full-texts and abstracts 25 full text articles and abstracts excluded upon visual inspection (not relevant) 22potentially relevant titles: 10 retrieved as full-texts, 11 as abstracts and 1 as a conference report 4 abstracts excluded: • Impossible to interpret (despite contacting authors) (n=1) • Duplicate publications (n=3) 0 additional studies identified from references of the identified studies 18 articles included in the systematic review  Joao Paulo de Aquino Lima1 , James M. Brophy, MD, PhD2 • 1Federal University of Ceará School of Medicine, Fortaleza, Brazil • 2Division of Clinical Epidemiology, McGill University, Montreal, Canada RESULTS METHODS Study quality assessment: Well performed randomized clinical trials (RCTs) were rated as high quality Observational studies were considered of lesser quality Exact quality category determined by assessment of 1) propensity for bias (selection, confounding and misclassification) 2) methods to control biases (time dependent analyses, rigorous outcome assessment, multiple sensitivity analyses) Observational study quality was judged to be moderate if the propensity to bias was low and if specific methods to minimize bias were reported, otherwise quality considered low Assessment performed by 2 independent investigators, blinded to study outcome The quality score of unpublished studies was systematically reduced by one grade due to the absence of formal peer review Isolated abstracts were considered to be of low quality as there are insufficient details to fully evaluate these reports Whenever possible, an external quality measure that compared survival curves from the clopidogrel efficacy randomized trials to the observational hazard ratios was performed to check for consistency in the etiologically relevant time windows. Due to heterogeneity with respect to research methods, quality, study populations and health care systems, it was decided a priori that quantitative data pooling was inappropriate. Figure 1 Search strategy BACKGROUND • Clopidogrel is a widely prescribed thienopyridine antiplatelet agent • It is a prodrug requiring hepatic activation via the cytochrome P450 (CYP) system, with the CYP2C19 enzyme assuming predominance • In vitro studies have suggested that proton pump inhibitors (PPI) diminish clopidogrel’s platelet efficacy via CYP2C19 competitive inhibition. • Although the Food and Drug Administration (FDA)and the European Medicines Agency (EMA) have issued public alerts recommending the avoidance of PPIs with clopidogrel, the evidence for a clinical correlate is actually conflicting. • Most clinical studies have been non-experimental & the possibility of spurious associations due to bias needs consideration. • Therefore there a systematic review that includes a critical analysis of each study methodology is needed. OBJECTIVE Systematically review the clinical evidence for a significant drug interaction between clopidogrel and proton pump inhibitors (PPIs). • Left panel from CURE RCT, right panel from interaction observational study • Note that clopidogrel efficacy is in first 90 days, but interaction effect occurs well after 90 days • Note clopidogrel benefit is 2% but interaction study suggests PPI cause 10-20% more adverse events than clopidogrel has been shown to prevent (i.e. 5-10 times more than had been prevented) RESULTS • 18 studies identified, 10 / 13 low quality studies reported + association, 0 /5 moderate quality reported + association (p < 0.01) • Not one study reported a statistically significant association for separate PPIs (one study with an incorrect analysis did publish such a finding) • A review of efficacy RCTs showed clopidogrel to be therapeutically active in the 90 days following an ACS and + studies did not find the interaction to occur in this etiological time window, suggesting that residual confounding may be explaining the observed association METHODS Data source: Electronic literature search without language restrictions of two databases, abstracts from the major cardiology conferences and hand search of bibliographies for other relevant articles. CONCLUSIONS • The observed association between clopidogrel and PPIs is found uniquely in studies judged to be of low quality with an increased risk of bias. High quality evidence supporting a clinically significant clopidogrel / PPI interaction is presently lacking.