Clopidogrel (Plavix) and Concurrent Proton Pump Inhibitors

By Marcus M. Reidenberg, MD, FACP
Weill Cornell CERT
Summary by Kathleen Mazor, EdD
HMO Research Network CERT

Clopidogrel (Plavix ®) is a drug used to decrease platelet functioning to prevent undesired arterial blood clots. Undesired blood clots form when platelets start unwanted clots inside abnormal arteries. Proton pump inhibitors are medicines that decrease stomach acid to lower the risk of getting an ulcer. If an ulcer occurs when platelets have decreased functioning, it will bleed more than when platelets function normally. The medicines to decrease stomach acid are given to people taking clipidogrel to decrease the risk of bleeding if they should happen to develop an ulcer.

There are many studies of clopidogrel with proton pump inhibitors (PPI’s) with conflicting results about how effective it is (1-3). The issue is whether PPI’s decrease the efficacy of clopidogrel to prevent cardiovascular clotting events. The background is that clopidogrel is an inactive prodrug. It must be metabolized to an active form by enzymes in the body. People taking clopidogrel who have a mutation in the gene for this enzyme have less enzyme function and have less active metabolite. Less active drug metabolite causes less platelet inhibition, and more cardiovascular events result than in patients with two normal genes (4,5).

Summary Points

About clopidogrel (Plavix ®)

  • Clopidogrel (Plavix ®) is a medication used to prevent blood clots.
  • Arterial blood clots can cause stroke, heart attack and other serious problems.
  • Plavix ® is a type of drug called an inactive prodrug. It needs certain enzymes to make it work. These enzymes are usually present in the body so Plavix works for most people.

Why some people taking Plavix ® also take Proton pump inhibitors (PPIs)

  • An ulcer is small hole in the stomach lining caused by stomach acids. Ulcers sometimes bleed.
  • If someone taking Plavix® gets a stomach ulcer, it may bleed a lot. This is because Plavix® prevents blood from clotting. Clotting is how the body stops bleeding.
  • Proton pump inhibitors (PPIs) reduce stomach acid. Less stomach acid means less risk of an ulcer.
  • There are several different PPIs. All of them reduce stomach acid.

What is the problem with taking Plavix and PPIs?

  • Some PPIs interfere with the enzyme that activates Plavix ®. This makes Plavix ® less effective at preventing clots.
  • PPIs differ in how much they interfere with the enzyme that Plavix needs to work. Some PPIs interfere more; some interfere less.
  • Physicians need to choose the best inhibitor of stomach acid for patients taking Plavix who need acid suppression.

The question with PPI’s is, Do they inhibit the enzyme just as if the abnormal mutated enzyme were present? This question cannot be answered because different PPI’s have different degrees of enzyme inhibiting activity. This enzyme and its gene are named CYP2C19. Table 1 shows the concentration of each PPI that inhibits human recombinant CYP2C19 enzyme by 50% in a test tube assay (6). The lower the concentration, the more powerful the inhibition. It appears that omeprazole is more than seven times as potent as pantoprazole in inhibiting the activation of clipidogrel.

Thus, while one cannot answer the question, “Do PPIs inhibit this enzyme?” one can easily answer the question, “Does this particular PPI at this dose substantially inhibit the CYP2C19 enzyme?” It is likely that much of the controversy about whether PPI’s decrease clopidogrel’s effectiveness comes from studies of different PPI’s but assuming each study represents the class of PPI’s rather than the specific PPIs in the study. This is also an example of a group of drugs having the same mechanism of therapeutic benefit but different other, or “off target”, effects. While many people consider all PPIs to be therapeutically equivalent, Table 1 shows that they are not pharmacologically identical. Omeprazole and esometrazole are potent inhibitors of the enzyme that activates clopidogrel while pantoprazole and rapeprazole are weak inhibitors. The difference in the results of various studies may relate to which PPI the patients were given. Unfortunately, many of the publications of the studies fail to describe the frequency of the specific PPIs taken by the patients so they cannot be interpreted for this issue. If one wants to prescribe a PPI with clipidogrel, it seems sensible to prescribe one that is a weak inhibitor of CYP2C19 rather than one that is a strong inhibitor.

Table 1

Drug
Ki (µM)*
Dose (mg/d)
Omeprazole (Prilosec ®)
2.4
20
Esomeprazole (Nexium ®)
7.9
40
Lansoprazole (Prevacid ®)
0.7
30
Pantoprazole (Protonix ®)
15.3
40
Rabeprazole (AcipHex ®)
18.8
20

* The lower the Ki value, the more potent the inhibitor.

 

References:

  1. 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 randomized trials. The Lancet 2009; 374: 989-997.
  2. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301: 937-944.
  3. Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010;152:337-45.
  4. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 ;360:354-62.
  5. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363-75.
  6. Li XQ, Andersson TB, Ahlström M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004;32:821-7.

Posted 12/22/2010

This note can be found online at http://www.weill.cornell.edu/cert/patients/clopidogrel.html

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