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Antiplatelets. Clopidogrel vs. aspirin. Overview . When should clopidogrel be prescribed instead of aspirin? What is meant by ‘intolerance to aspirin’? Does clopidogrel cause fewer GI adverse effects than aspirin? How can the risk of GI adverse effects of aspirin or clopidogrel be reduced?

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Clopidogrel vs. aspirin

  • When should clopidogrel be prescribed instead of aspirin?
  • What is meant by ‘intolerance to aspirin’?
  • Does clopidogrel cause fewer GI adverse effects than aspirin?
  • How can the risk of GI adverse effects of aspirin or clopidogrel be reduced?
  • Which is preferable – aspirin plus PPI or clopidogrel?
  • What is the significance of the interaction between clopidogrel and PPIs?
what does nice say about clopidogrel nice vascular disease clopidogrel dipyridamole ta90 may 2005
What does NICE say about clopidogrel?NICE. Vascular disease – clopidogrel & dipyridamole. TA90. May 2005

“….the Committee concluded that clopidogrel was likely to be at least as effective as aspirin. Therefore, for people with recent MI or symptomatic PAD who are intolerant of aspirin, clopidogrel was an appropriate alternative.

….Genuine aspirin intolerance, defined by hypersensitivity reactions or severe dyspepsia, should be differentiated from mild dyspeptic symptoms, which are common.”

Does clopidogrel cause fewer GI adverse effects than aspirin?CAPRIE. Lancet 1996;348:1329–39; MeReC Bulletin 2005;15(2)
  • There is no robust evidence to support the view that clopidogrel is a safer alternative to low-dose aspirin and that its use is associated with a lower risk of GI side effects
  • In the CAPRIE study, clopidogrel was associated with an approximate one-third reduction in the incidence of GI bleeding compared with aspirin. However, this study used a ‘high’ 325mg dose of aspirin, known to significantly increase the risk of bleeding (possibly three-fold) relative to standard low-dose aspirin (i.e. 75mg)
    • GI haemorrhage: clopidogrel 1.99% vs. aspirin 2.66% (P<0.05, NNT 149)
  • Although clopidogrel alone is an option recommended by guidelines for patients with severe dyspepsia caused by low-dose aspirin, clopidogrel also causes GI adverse events in a significant number of patients
    • Any indigestion/nausea/vomiting: clopidogrel 15.0% vs. aspirin 17.6% (P<0.05)
    • Severe indigestion/nausea/vomiting: clopidogrel 0.97% vs. aspirin 1.23% (NS).


Evidence to support adding a PPI rather than switching to clopidogrel?Chan FKL, et al. New Engl J Med 2005;352:238–44
  • Double blind randomised controlled trial
  • 320 patients on aspirin with ulcer bleeding
  • After healing, if negative to H pylori: clopidogrel 75mg/day, or aspirin 80mg/day plus esomeprazole 20mg bd
  • Recurrent ulcer bleeding 12 months:
    • Aspirin plus esomeprazole

0.7% (95%CI 0.0 to 2.0%)

    • Clopidogrel

8.6% (95%CI 4.1 to 13.1%)

    • NNH = 13 (95%CI 8 to 29)
  • Lower GI bleeding:
    • 4.6% both groups (P=0.98).
reducing gi risk www cks nhs uk antiplatelet treatment revised july 2009
Reducing GI Revised July 2009
  • When prescribing aspirin:
    • Prescribe 75mg daily unless a higher dose is indicated
    • Do not prescribe enteric coated formulations
    • Advise the person to take aspirin after food
    • If high-risk, co-prescribe a PPI for gastroprotection, rather than switching to clopidogrel
  • When prescribing clopidogrel alone or in combination with low-dose aspirin:
    • If gastroprotection is necessary e.g. in high-risk patients, consider prescribing a H2-receptor antagonist (but not cimetidine)
    • Co-prescribing of a PPI with clopidogrel should be avoided unless considered essential (but see updated MHRA advice)
  • In high-risk patients, consider testing for and treating Helicobacter pylori if there is a history of ulcer disease or upper GI bleeding, unless this has previously been done
  • Review current medications
  • Advise sensible alcohol intake
  • Advise smokers to quit or reduce their smoking.

Do clopidogrel and PPIs interact?MHRA/CHM. Drug Safety Update. Volume 2, issue 12. July;

do clopidogrel and ppis interact mhra chm drug safety update volume 3 issue 9 april 2010
Do clopidogrel and PPIs interact?MHRA/CHM. Drug Safety Update. Volume 3, issue 9. April 2010

Update on clopidogrel and Monthly No.27. June 2010


  • This provides an excellent opportunity to review patients taking clopidogrel and a PPI to see if both are still appropriate.
  • Options to consider may include stopping either the clopidogrel, if it is being used outside NICE guidance or beyond the recommended period, or reviewing the PPI, or both.
  • If the original reason for using clopidogrel was due to GI intolerance on aspirin alone, switching to aspirin plus a PPI would seem a reasonable approach.
Doubts about the clinical relevance of the interactionO’Donoghue ML, et al. Lancet 2009;374;989–
  • Analysis of two studies
  • PPIs attenuated the in-vitro antiplatelet effects of clopidogrel
  • Combination of clopidogrel plus PPI was not associated with an increased risk of CV death, MI or stroke
    • HR 0.94, 95%CI 0.80 to 1.11
    • TRITON-TIMI 38
  • Findings were consistent regardless of which PPI was used, or whether an H2-receptor antagonist was used.
More data from a large observational studyRassen JA, et al. Circulation 2009;120:2322–
  • Three large cohorts (one in Canada, two in the US)
  • 18,565 users of clopidogrel aged 65 years or older
  • Looked at the risk of CV outcomes and mortality associated with the prescribing of clopidogrel and a PPI to elderly patients after percutaneous coronary intervention or hospitalisation for acute coronary syndrome
  • The difference in the primary endpoint of MI or death was not statistically significantly different between PPI users and non-users
    • Adjusted rate-ratio RR 1.22, 95%CI 0.99 to 1.51
  • No conclusive evidence for a clinically relevant drug interaction between clopidogrel and PPIs in this group of elderly patients.
  • Low-dose aspirin is generally the first choice antiplatelet drug
    • Clopidogrel 75mg daily should only be prescribed as an alternative to aspirin in people who have genuine aspirin intolerance
    • Consider gastroprotection (e.g. a PPI) for patients at increased risk of GI bleeding, including those taking other drugs which increase the risk
    • Gastroprotection with a PPI should generally be used before switching to clopidogrel
  • As the clinical significance of the interaction is uncertain, the combination of clopidogrel and certain PPIs (omeprazole and esomeprazole) should be avoided unless considered essential