2012-03-26 18:52:32 UTC

Managing PPI Safety in Stent Patients

March 26, 2012


Sharlene D’Souza, MD

Clinical Lecturer, Gastroenterology, University of Michigan, Ann Arbor


James M. Scheiman, MD, AGAF

Professor, Department of Internal Medicine, University of Michigan, Ann Arbor

 Balancing GI and cardiovascular risk has been a recurring challenge in contemporary clinical practice. Understanding competing risk is a key focus of our efforts in bringing together consensus to improve patient outcomes.1 Since PPIs are widely used and cardiac stent (particularly drug-eluting) implantation has exploded in current practice, concerns have been raised regarding PPI safety in this patient population.

PPIs are of established value for a variety of disorders, including GERD, and prevention of peptic ulcer disease with associated bleeding. Due to their once-daily dosing and superiority to less effective alternatives such as H2 blockers, they are recommended to reduce the risk of ulcers and bleeding in patients at an increased risk, such as those on concomitant antiplatelet or anticoagulant medication. There are a number of antiplatelet medications used in patients with acute coronary syndrome and following placement of coronary stents to enhance stent longevity and patency. Aspirin use is universal in these patients and the inclusion of an additional agent, such a thienopyridine, improves cardiovascular outcomes. Both drugs independently double the risk of GI bleeding, which is associated with mortality.2

Thienopyridines currently in use include clopidogrel and prasurgel. These medications act by inhibiting the platelet P2Y12 receptor, which inhibits aggregation through an aspirin-independent pathway. Clopidogrel and prasurgel are pro-drugs, requiring biotransformation to active metabolites by cytochrome P450 (CYP). PPIs interact with CYP enzymes (predominantly CYP2C19); given the data that polymorphisms of this gene are associated with loss of clopidogrel activity, concerns of a drug interaction were raised. With a decreased concentration of active drug, increased risk for stent thrombosis and cardiac events may be seen. Prasugrel is much less dependent on CYP biotransformation and concerns regarding PPIs have not arisen. A new non-thienopyridine P2Y12 receptor, ticagrelor, also does not interact with PPIs.

A number of studies have investigated the potential interaction between PPIs and antiplatelet therapies, mainly clopidogrel and aspirin. Some have received great attention in the media and on the Internet, creating anxiety among patients and clinicians. With regard to aspirin, a single observational study3 noted cardiovascular outcomes in aspirin users on concomitant PPIs were worse, leading to speculation that PPIs abrogated aspirin therapy, despite a number of pharmaco-kinetic and pharmaco-dynamic studies demonstrating otherwise.

There are pharmaco-dynamic studies supporting reduced biotransformation of clopidogrel with PPIs, mainly omeprazole. This interaction has been studied by various platelet aggregation methods and may differ among the PPIs, although head-to-head comparisons are limited. A number of observational studies suggest an association between omeprazole and increased cardiovascular events in patients on clopidogrel, but less so with lansoprazole and pantoprazole. However, nested analyses of case control studies as well as a large randomized control trial, the Clopidogrel and the Optimization of Gastrointestinal Events Trial,4 cast doubt on the clinical relevance of these drug interactions, even for omeprazole, where the evidence in interaction in vitro is strongest. Recently, a pharmaco-dyamic study using dexlansoprazole, a long-acting version of lansoprazole, demonstrated no impact on clopidogrel’s action on platelets.

Which patients should we be most concerned about the potential for any impact of PPI therapy on antiplatelet action? The risk for stent thrombosis is highest after initial placement and falls significantly 30 days after implantation. Dual antiplatelet therapy after six to 12 months has modest incremental impact over aspirin alone (yet recommended by many cardiologists longer term). On the one hand, we sometimes underestimate the profound impact of low-dose aspirin alone without an additional antiplatelet medication. On the other hand, stents at critical locations such as bifurcations or in proximal key vascular fields such as a proximal left anterior descending lesion are of great concern for thrombosis to the interventional cardiologist.5

If long-term dual antiplatelet therapy is essential and the patient is at a high risk for GI bleeding, arguments can be made to use an alternative agent such as prasugrel or ticagrelor. They are more costly than clopidogrel, which is currently available as a generic in Europe and soon will be in North America. Selecting a PPI without demonstrated interaction (lansoprazole, pantoprazole) or lack of interaction (dexlansoprazole) might be another approach if stent thrombosis risk is felt to be a great concern, but cost and availability should be considered.

While there has been an argument made to change therapy to histamine H2 receptor antagonists, the efficacy of these agents, while better than no therapy, appear inferior to PPIs.6 What about separating the administration of the PPI and clopidogrel? While the studies only look at pharmaco-dynamics and not outcomes, a study in the clopidogrel label suggests that this approach is not effective.

When dealing with stent patients on antiplatelet medications and PPIs, it is most important to consider the individual’s risk of GI bleeding compared to the risk of cardiac events, and individualize therapy based on a number of factors. Patients with a high risk of bleeding (advanced age, prior GI bleeding or peptic ulcer disease, use of steroids or NSAIDs, and Helicobacter pylori infection) should be on long-term acid suppression with PPI therapy.7



1. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, Johnson DA, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2008; 52: 1502-1517.

2. Nikolsky E, Mehran R, Stone GW. Gastrointestinal bleeding in percutaneous coronary intervention and acute coronary syndromes. Am J Cardiol 2009; 104: 24-29.

3. Wurtz M, Grove EL, Kristensen SD, Hvas AM. The antiplatelet effect of aspirin is reduced by proton pump inhibitors in patients with coronary artery disease. Heart 2010;96:368-71.

4. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP. Clopidogrel with or without omeprazole in coronary artery disease. NEJM 2010; 363: 1909-1917.

5. Becker, RC, Scheiman, J, Dauerman, HL, Spencer, F, Rao, S, Sabatine, M, Johnson, DA F Chan, F, Abraham, NS, Quigley, EMM, et al. Management of Platelet-Directed Pharmacotherapy in Patients With Atherosclerotic Coronary Artery Disease Undergoing Elective Endoscopic Gastrointestinal Procedures. Am J Gastroenterol 2009, 104 (12):2903-17.

6. Ng FH, Wong SY, Lam KF, Chu WM, Chan P, Ling YH et al. Famotidine Is Inferior to Pantoprazole in Preventing Recurrence of Aspirin-Related Peptic Ulcers or Erosions Gastroenterology 2010, 138: 82-88.

7. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF. 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. JACC 2010; 56: 2051-66.



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