Do proton pump inhibitors reduce the clinical efficacy of clopidogrel?

Tim Meadows, Medicines Information Pharmacist, Midlands and East Medicines Advice Service (East Anglia site)Published

This updated Medicines Q&A evaluates the available evidence for an interaction between clopidogrel and proton pump inhibitors


  • Clopidogrel is converted into its active metabolite by the liver cytochrome P450 isoenzymes, mainly CYP2C19 and CYP3A4. All PPIs are also metabolised via the cytochrome P450 system, particularly CYP2C19 and CYP3A4.
  • All PPIs inhibit these isoenzymes to different degrees and therefore could affect the clinical efficacy of clopidogrel.
  • There have been no RCTs to date to specifically assess the effect of PPIs on clinical outcomes in patients taking clopidogrel.
  • Secondary analyses of the COGENT, TRITON-TIMI 38 and PLATO trials have not shown an increased risk of major adverse cardiovascular events in patients taking PPIs and clopidogrel together.
  • Most of the meta-analyses and systematic reviews published suggest an increased risk of MACE when PPIs are administered with clopidogrel but no increase in long-term mortality
  • Treatment decisions regarding concomitant use of clopidogrel and PPIs must balance the overall risks and benefits and consider the risk of cardiovascular and gastrointestinal complications in individual patients. In some patients the benefits of a PPI may outweigh the risk of reduced clopidogrel efficacy.
  • The FDA, MHRA and EMA discourage use of omeprazole and esomeprazole in patients taking clopidogrel.
  • There is insufficient evidence regarding which PPI is least likely to interact. Based on data from pharmacokinetic and pharmacodynamic studies and the COGENT study, pantoprazole is the least likely to interact and lansoprazole and rabeprazole are also suitable alternatives.