1. Redulla, Rhoda DNP, RN-BC

Article Content

This article is the summary/review of the following article:


Song, H., Zhu, J., & Lu, D. (2014). Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. Cochrane Database of Systematic Reviews, (12), CD010623. doi:10.1002/14651858.CD010623.pub2



Proton pump inhibitors (PPIs) are the most widely prescribed drugs worldwide (Forgacs & Loganayagam, 2008; Heidelbaugh, Kim, Chang, & Walker, 2012) and known to be the most effective drugs to reduce gastric acid secretion (Wolfe & Sachs, 2000). However, concerns about their long-term safety have been raised. The use of PPIs can result in hypergastrinemia, which has been associated with an increased risk of gastric carcinoids, and gastric and colonic carcinomas. The tropic effect of gastrin on the gastrointestinal mucosa has been linked to the increased risk.


There has been a decline in the worldwide incidence of gastric cancer but remains to impose a significant socioeconomic burden. The issue of PPIs and their link to gastrointestinal neoplasia has been broadly investigated, but results are inconsistent. Additional insight is warranted into this issue to address the dilemma in decision making for PPI maintenance.



To compare the development or progression of gastric premalignant lesions, such as atrophic gastritis, intestinal metaplasia, enterochromaffin-like (ECL) cell hyperplasia, and dysplasia, in people taking long-term (6 months or greater) PPI maintenance therapy.



Proton pump inhibitors were developed for the treatment of gastric acid-related disorders including peptic ulcer disease, eradication of Helicobacter pylori infection, treatment and prevention of gastroduodenal cancers associated with nonsteroidal anti-inflammatory drugs, Zollinger-Ellison syndrome, and management of gastroesophageal reflux disease. This class of drugs is the most potent inhibitor of gastric acid secretion currently available and is well-tolerated, with an established safety rating (Savarino, Mario, & Scarpignato, 2009). Proton pump inhibitors block gastric H,K-ATPase, inhibiting gastric acid secretion.


The review authors included randomized controlled trials reported as full text, as abstract-only, and unpublished data. Selection criteria included adults (aged 18 years or older) who had no gastric malignant lesion at baseline, confirmed by endoscopy or biopsy sampling (or both). The type of intervention included was PPI use for 6 months or greater. Included studies had at least one intervention arm and at least one valid control arm. The authors considered only oral therapies administered at any dosage.


Primary outcomes considered were development or progression of gastric premalignant lesions after long-term PPI use. No secondary outcomes were included.


The following electronic databases were searched for identifying eligible studies: Cochrane Central Register of Controlled Trials (CENTRAL) (Isue 8, 2013); MEDLINE (1966 to August 2013); EMBASE (1988 to August 2013); and CINAHL (1982 to August 2013). The authors also hand searched the abstracts from 1995 to 2012 from the American Digestive Disease Week published in Gastroenterology and the United European Gastroenterology Week published in Gut.


Data Collection and Analysis

Two review authors independently screened titles and abstracts, assessed trial quality, and performed data extraction from the trial reports. Disagreements were resolved through discussion, or, if required, a third review author was consulted.



The review authors concluded that there was no clear evidence to support the notion that the long-term use of PPIs could promote the development of precancerous lesions. However, there was a potentially elevated risk of developing a thickening of the stomach lining (hyperplasia) among participants with long-term PPI use, which is considered as a possible precondition of gastric carcinoid, a relatively benign (noncancerous) tumor that develops within the stomach lining.


It was also pointed out by the review authors that four studies had a high risk of bias, and the risk of bias in the other three trials was unclear.



The review showed no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. A higher risk of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia exists among those receiving PPI maintenance treatment. However, further investigation is warranted. The clinical importance of this outcome is currently uncertain.


Implications for Practice

As presented in the review, no clear evidence was found to correlate long-term PPI use with an increased risk of corporal atrophic gastritis or intestinal metaplasia among people with healed erosive esophagitis. Nurses working with this patient population should advocate for patients by encouraging careful discussion with their healthcare provider. Nurses also play a key role in managing the emotional dilemma that patients undergoing long-term PPI treatment may go through. Current available evidence was of low or very low quality. Well-designed clinical trials should be performed. Follow-up research becomes even more important because PPIs are widely used.




Forgacs I., Loganayagam A. (2008). Overprescribing proton pump inhibitors. BMJ, 336, 2-3. [Context Link]


Heidelbaugh J. J., Kim A. H., Chang R., Walker P. C. (2012). Overutilization of proton-pump inhibitors: What the clinician needs to know. Therapeutic Advances in Gastroenterology, 5, 219-232. [Context Link]


Savarino V., Di Mario F., Scarpignato C. (2009). Proton pump inhibitors in GORD: An overview of their pharmacology, efficacy and safety. Pharmacological Research, 59, 135-153. [Context Link]


Wolfe M. M., Sachs G. (2000). Acid suppression: Optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology, 118(2, Suppl. 1), S9-S31. [Context Link]