Tools for Practice

#6 PPIs and clopidogrel: Never the twain shall meet?

Do proton pump inhibitors (PPIs) interact with clopidogrel to reduce its cardiovascular (CV) benefit?

Studies are inconsistent about the impact of PPIs on clopidogrel effectiveness, though most higher-quality studies show no interaction. The association with CV risk seen with PPI use is likely due to underlying comorbidities rather than a true drug interaction.

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A systematic review1 of 33 studies encompasses the best-available evidence. Highlights: 
  • ~50% of retrospective observational studies, and ~25% of prospective observational studies found a significant association of increased CV risk with PPI + clopidogrel versus clopidogrel alone. 
    • Retrospective studies generally had higher risk of bias. 
  • One randomized controlled trial (RCT)2 of 3,761 patients receiving clopidogrel and ASA followed for a median of 3.5 months: 
    • No difference in CV events, omeprazole 4.9% versus placebo 5.7%. 
    • Limitations: Unplanned early termination, underpowered for CV comparisons. 
  • Non-randomized subgroup analyses of landmark antiplatelet trials.3,4 
    • PPI did not increase CV risk with either clopidogrel or prasugrel. 
    • PPI increased CV risk with both clopidogrel (HR 1.20) and ticagrelor (HR 1.24). 
      • Note: Ticagrelor does not require enzymatic activation and should therefore not be affected by the postulated PPI drug interaction mechanism. 
Studies that included patients not receiving clopidogrel found that PPI use was associated with increased CV risk (regardless of clopidogrel use).5-9  Context: 
  • PPIs have inconsistent effects on surrogate markers of clopidogrel efficacy.1 
  • American guidelines12 (though based on outdated evidence) reasonably recommend careful assessment of the indication for PPIs, as they are frequently prescribed without a clear indication.13 
  • There is no consistent difference in CV risk association between PPIs, including pantoprazole.14 
Reviewed: July 13, 2016 by ricky

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  • G. Michael Allan MD CCFP
  • Michael R Kolber MD CCFP MSc

1. Jaspers Focks J, Brouwer MA, van Oijen MGH, et al. Heart. 2013; 99:520-7.

2. Bhatt DL, Cryer BL, Contant CF, et al. N Engl J Med. 2010; 363:1909-17.

3. O’Donoghue ML, Braunwald E, Antmann EM, et al. Lancet. 2009; 374:989-97.

4. Goodman SG, Clare R, Pieper KS, et al. Circulation. 2012; 125:978-86.

5. Dunn SP, Macaulay TE, Brennan DM, et al. Circulation. 2008; 118:S815.

6. Charlot M, Ahlehoff O, Norgaard ML, et al. Ann Intern Med. 2010; 153:378-86.

7. Valkhoff VE, ‘t Jong GW, van Soest EM, et al. Aliment Pharmacol Ther. 2011; 33:77-88.

8. Charlot M, Grove EL, Hansen PR. BMJ. 2011; 342:d2690.

9. Schmidt M, Johansen MB, Robertson DJ, et al. Aliment Pharmacol Ther. 2012; 35:165-74.

10. Juurlink DN, Gomes T, Ko DT, et al. CMAJ. 2009; 180:713-8.

11. Ho PM, Maddox Tm, Wang Li, et al. JAMA. 2009; 301:937-44.

12. Abraham NS, Hlatky MA, Antman EM, et al. Am J Gastroenterol. 2010; 105:2533-49.

13. Forgacs I, Loganayagam A. BMJ. 2008; 336:2-3.

14. Kwok CS, Jeevanantham, Dawn B, et al. Int J Cardiol. 2012; [Epub].

Authors do not have any conflicts of interest to declare.