When It Comes to PPIs, Why All the 'Mayhem'?

David A. Johnson, MD


May 26, 2017

Hello. I am Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.

It would be an understatement to say that proton pump inhibitor (PPI) noise has created mayhem for patients and healthcare providers. Two papers have just come out that will help us put some sanity around these concerns. The first paper is an evidence-based Delphi international consensus[1] that addressed over-the-counter (OTC) use of PPIs, and the second is the most recent expert consensus from the American Gastroenterological Association (AGA)[2] for prescription use of PPIs. These papers give very strong re-edification that evidence of harm is very weak.

Let's go through the different concerns and talk about best practice recommendations.

Dementia Risk

The AGA[2] recognizes that the science on the [association of dementia with PPI use] is lacking. For the two studies that alleged harm, the odds ratios (ORs) were extremely low, [and the studies were] very subject to stratification bias. There was no recommendation for concern.

Bone Fracture Risk

The very insidious concern about bone fracture [risk associated with PPIs] goes back to a University of Pennsylvania study published in JAMA.[3] Long-term, evidence-based studies, such as that from Laura Targownik[4] in Canada, have shown us that there is not a concern for bone density loss. For both the Delphi consensus[1] and the AGA[2] documents, there is no specific recommendation that people on OTC or long-term PPIs should be monitored any differently for bone density. Patients do not need baseline or serial sequential studies, and they do not need supplemental calcium.

Vitamin and Mineral Changes

Along those same lines, [possible changes] in iron and magnesium [levels associated with PPI use] are recognized in the literature. These changes may be idiosyncratic and rare. Both the Delphi consensus[1] and the AGA expert guidance[2] do not recommend routine monitoring of any element, including calcium, magnesium, and iron. In addition, vitamins, such as B12, do not need to be monitored in people on long-term or short-term PPIs.

Renal Insufficiency

How about renal insufficiency?

The renal issue has made a lot of noise, and people are fearful about acute or chronic renal insufficiency. Both the Delphi and the AGA documents recognize that there is a risk for renal insufficiency due to acute interstitial nephritis. We think that this is idiopathic. Both documents recommend that people do not need to be monitored or screened routinely for renal toxicity [associated with PPI use]. Only symptom-directed testing, if applicable, is recommended.

Infection Risk

How about infection?

There are randomized controlled trial (RCT) data finding that pneumonia is not increased with PPIs and actually may be a little bit decreased.

The bigger concern has been for infection with Clostridium difficile. The ORs are very low, in the 1.5 to 1.6 range, and there are stratification biases across the C difficile study populations. [For patients on PPIs,] we are talking about relatively nominal acid suppression rather than true achlorhydria, which you would see in a vagotomy patient or gastric surgery patient. The consensus in the Delphi document[1] does not recommend that PPIs be stopped in concern for C difficile. The researchers also recommend that there is no rationale for probiotic use in patients on PPIs. Other types of infection have been of concern.

One that is a bit contrarian is spontaneous bacterial peritonitis (SBP). There are nominal ORs in the population of patients with cirrhosis with ascites [for this infection risk]. Whether or not this is going to bear out, the recommendation is that if you need a PPI, you should take it; and if you do not, you should not. Routine monitoring or avoidance of a PPI in a patient with cirrhosis specifically because of SBP concern is not recommended at this point. These patients have lots of other complexities that may put them at risk for SBP.

Interaction With Clopidogrel

Another area of concern is the interaction with Plavix® (clopidogrel). I think that has been laid to rest. Hopefully you do not have any more problems getting PPIs approved in patients who are taking long-term Plavix. The AGA document[2] says that there is really no discriminant analysis that one agent should be selected over another because of concern about adverse events. Across the class of PPIs, they are equal as far as the relative risk, and there is no selection bias that would say that one should be more safe than another or that one would be more harmful than the other.

Barrett Esophagus

Any medication has a potential for harm. We always need to use the lowest dose to control symptoms. The AGA document[2] does speak to continuation of PPIs where appropriate. Benefits outweigh the potential harms [for PPI use] in patients with Barrett esophagus and continued use in symptomatic patients with strictures. Long-term use in Barrett esophagus is probably appropriate, particularly for symptomatic Barrett esophagus. In asymptomatic Barrett esophagus, there is some, albeit relatively weak, evidence that suggests that you may decrease some of the neoplastic progression risk. It is something that should be considered; certainly, the concerns for harm that we are weighing here really are not of issue.

Stroke Risk

A new study from Taiwan[5] speaks to [risk for] stroke associated with PPIs. Again, the ORs were incredibly low. I would even question the scientific basis of why this was published. The stratification risk takes this paper way down on my scope of concern. Because this study was just released, it was not addressed in either the Delphi consensus or the AGA document.

Risks of Withdrawing PPI Therapy

For the final area, Kurlander and colleagues[6] from Michigan surveyed providers using clinical vignettes of low-, moderate-, and high-risk populations at risk for gastrointestinal bleeding associated with nonsteroidal anti-inflammatory drug use. They found that prescribers were taking people off of PPIs because of concern for bone fracture and were more likely to take the highest-risk patients off than the lower-risk patients. Harm incurred by PPI withdrawal can be the real deal.


Hopefully this will give you some insight for the next time you have a conversation with your patients. I would proactively bring it up every time you see a patient with a PPI in their medication list. It gives you that teaching moment to discuss use of PPIs. Can it be taken away or taken down to a lower dose? If they need it, then keep it. Put into perspective some of these implications of harm so that they do not stop it on their own account. We have great data. The AGA document and the Delphi consensus document put some science around this mayhem.

I am Dr David Johnson. Thank you again for listening.


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