Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction

Abstract

Aliment Pharmacol Ther 2011; 33: 758–767 Summary Background The treatment of acute coronary syndromes involves a combination of antiplatelet therapies. Proton pump inhibitors are frequently recommended for patients receiving clopidogrel in addition to aspirin, to minimise the risk of bleeding. Several studies have shown that proton pump inhibitors can affect the platelet inhibitory effects of clopidogrel. However, the data on whether this has an effect on clinical outcomes are conflicting and a definitive answer is still awaited. Aim To provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and to discuss whether this interaction translates into adverse clinical outcomes. Despite recent developments, clear consensus is lacking. Methods A search of the published literature combined with the authors’ knowledge of the field. Results There is evidence to show that proton pump inhibitors can influence the pharmacodynamics of clopidogrel, but the data suggesting clinical effects are weak and conflicting. Supporting a clinically important interaction are four retrospective studies including over 11 000 patients prescribed both clopidogrel and a proton pump inhibitor. Evidence against a clinically important interaction is derived from over 18 000 patients from seven studies, including the only prospective trial to examine the potential interaction. Confounding variables are relevant and prospective clinical evidence is lacking. Conclusions Proton pump inhibitors offer clear protection and the concern over clinically relevant interactions with clopidogrel is biologically plausible, but not yet proven.

Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation

“…Observational studies have showed similar inconsistency regarding whether concomitant clopidogrel and PPI use is 27–31 or is not 26, 32–37 associated with adverse clinical outcomes. The only study that randomly allocated PPI treatment to clopidogrel users was the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) 38 .…”

The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway

“…62 A quite comprehensive review was provided by the cardiology and gastroenterology departments of the City Hospital of Birmingham, United Kingdom. 63 This group assumed that clopidogrel was primarily a CYP2C19 substrate and therefore expected that concomitant administration of omeprazole would have a negative effect on the performance of clopidogrel. They located 4 studies that did suggest there was an effect, but only on platelet aggregation.…”

Differences in utilisation of gastroprotective drugs between 2001 and 2005 in Australia and Nova Scotia, Canada

“…More recently, adverse effects of long‐term PPI use have been reported, including possible drug interactions, increased fracture risk (effects on bone mineralisation), rebound gastrin hypersecretion, magnesium deficiency and risk of some infections . Systematic reviews and recent meta‐analyses confirmed slight increased risk of fracture in PPI users, with no increased risk detected in H2RA users .…”