masthead


Frequently Asked Questions

What does the ACC/ACG/AHA 2010 Expert Consensus Document recommend regarding the concomitant use of PPIs and thienopyridines?

Introduction

In November 2010, the American College of Cardiology (ACC), the American College of Gastroenterology (ACG), and the American Heart Association (AHA) issued a 2010 Expert Consensus Document focused on the concomitant use of proton pump inhibitors and thienopyridines (clopidogrel and prasugrel). 1 The document is an update of the 2008 consensus statement, which recommended the use of proton pump inhibitors (PPIs) to reduce gastrointestinal (GI) bleeding in patients taking clopidogrel and aspirin.2 Recent data suggest an interaction between PPIs and thienopyridines (see FAQ October 2009 - Interaction between PPIs and thienopyridines). An overview of the consensus statement is summarized below. Clinicians are encouraged to review the full update at http://circ.ahajournals.org/cgi/reprint/CIR.0b013e318202f701.

Risk of GI bleeding

There are several risk factors for GI bleeding with antiplatelet therapy.1 There is a strong correlation with an upper GI bleed and a history of bleeding or peptic ulcer disease. Additional risk factors include older age, use of medications including steroids, anticoagulants, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as Helicobacter pylori infection. Several observational studies have evaluated the risk of GI bleeding with thienopyridines and randomized controlled trials have assessed bleeding as an endpoint. In head-to-head trials, the risk of GI bleeding was higher with aspirin compared to clopidogrel. Dual therapy with clopidogrel and aspirin was associated with an increased risk of GI bleed. The CURE and ACTIVE trials assessed the risk of GI bleed with dual therapy with clopidogrel and aspirin.3,4 The relative risk (RR) of GI bleeding in the CURE trial was 1.78 (95% confidence interval (CI) 1.25 to 2.54).3 Similar results were shown in the ACTIVE trial [RR 1.96 (95% CI 1.46 to 2.63)].4

PPIs and clopidogrel/prasugrel efficacy

Several observational studies have been conducted which assessed the effect of PPIs on clinical cardiovascular (CV) outcomes in patients prescribed clopidogrel.1 Of the 10 published studies, 5 showed a small but significant association between PPI use and CV events, while the remaining 5 showed no significant association. O'Donoghue and colleagues analyzed 2 randomized controlled trials to determine the clinical efficacy of clopidogrel or prasugrel with or without a PPI.5 Over 13,600 patients were randomized to either clopidogrel or prasugrel after percutaneous coronary intervention (PCI). The composite outcome of CV death, myocardial infarction (MI), or stroke was not affected by the use of PPIs in either the clopidogrel group [adjusted hazard ratio (HR) 0.94 (95% CI 0.8 to 1.11)] or the prasugrel group [HR 1 (95% 0.84 to 1.2)]. There was no difference in the PPI used, which included omeprazole, lansoprazole, esomeprazole, and pantoprazole. In addition, the CREDO trial showed that PPIs were associated with an increase in CV events with or without clopidogrel.6

Gilard and colleagues conducted a randomized controlled trial to determine if the concomitant use of omeprazole reduces pharmacological action of clopidogrel.7 In this study, 3,761 patients undergoing elective coronary stent implantation and receiving standardized, dual antiplatelet therapy with aspirin and clopidogrel were randomized to omeprazole or placebo. There was no significant difference between the groups in the composite outcome of MI, stroke, coronary artery bypass graft, PCI, and CV death. Fewer GI adverse effects were seen in the patients that received omeprazole (see FAQ May 2008 - Drug interaction between omeprazole and clopidogrel ).

Pharmacokinetic and pharmcodynamic studies, which used platelet assays as surrogate endpoints, suggest that the available PPIs inhibit cytochrome P450 2C19 to differing extents.1 However, published observational studies have not shown a difference in CV events among the various PPIs.

Recommendations

The Expert Consensus Document provides the following 11 recommendations.1

  1. Clopidogrel reduces major CV events compared with placebo or aspirin.
  2. Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease and reduces coronary artery stent thrombosis, but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding.
  3. Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding.
  4. Patients with prior GI bleeding are at highest risk of recurrent bleeding on antiplatelet therapy. Additional risk factors include advanced age, concomitant use of steroids, anticoagulants, and NSAIDs (including aspirin), and H. pylori infection. The risk of GI bleeding increases as the number of risk factors increase.
  5. A PPI or histamine H2 receptor antagonist (H2RA) reduces the risk of upper GI bleeding compared to no therapy; PPIs reduce GI bleeding to a greater extent.
  6. PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.
  7. Routine use of either a PPI or H2RA is not recommended for patients at lower risk for upper GI bleeding.
  8. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.
  9. Pharmacokinetic and pharmacodynamic studies suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel. The strongest evidence is for omeprazole and clopidogrel. It is not established that changes in surrogate endpoints translate into clinically meaningful differences.
  10. Observational studies and a single randomized clinical trial have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel.
  11. The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.

Conclusion

The ACC/ACG/AHA 2010 Expert Consensus Document provides clinicians with guidance on the use of concomitant PPIs and thienopyridines. It is appropriate to use PPIs to reduce GI bleeding among patients with a history of upper GI bleeding; however, use of either a PPI or H2RA is not recommended for patients at lower risk for upper GI bleeding. The document is silent on the definition of high- and low-risk patients, as well as if 1 PPI is preferred over another. Healthcare providers must use clinical judgment and weigh the benefits and risks, both CV events and GI bleeding, when placing a patient on concurrent PPI and thienopyridine therapy.

References

  1. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation. 2010; doi: 10.1161/CIR.0b013e318202f701.
  2. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118(18):1894-1909.
  3. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
  4. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066-2078.
  5. O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374(9694):989-997.
  6. Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ, CREDO Investigators. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2009;157(2):369-374.
  7. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin (OCLA). J Am Coll Cardiol. 2008;51(3):256-260.