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In patients positive for Helicobacter pylori (H. pylori), upper quartiles of cumulative proton pump inhibitor (PPI) doses were found to be significantly associated with precancerous gastric intestinal metaplasia (GIM) in a dose-dependent manner, a large retrospective study found.

The upper quartiles of PPI use were also associated with a five- to 10-fold increased risk for a diagnosis of GIM with low-grade dysplasia, reported Zohar Levi, MD, of Rabin Medical Center in Petah Tikva, Israel, and colleagues.

As they noted in their study, published online in the the association of cumulative PPI use with the likelihood of GIM diagnosis was dependent on H. pylori status, varying from 1.7- to 1.4-fold for patients treated for H. pylori infection compared with a non-significant association for patients who were H. pylori-negative.

"Healthcare professionals should consider evaluating patients' H. pylori infection status before initiating long-term PPI treatment," the researchers wrote.

They noted that previous has suggested that long-term PPI use is associated with a higher risk of gastric cancer development, especially in patients who underwent H. pylori eradication.

Study Details

For the new study, eligible patients had undergone upper endoscopy with gastric biopsy at Rabin Medical Center from 2005 to 2014. Covariate data included age, sex, ethnicity, smoking status, H. pylori status (based on clarithromycin/amoxicillin/PPI issued), and cumulative PPI issued within 10 years (quartiles PPI Q1 to Q4 of daily drug dose). Other variables were anti-parietal cell antibodies, body mass index, and comorbidity index.

Median age for the 14,147 patients included in the study was 63.4; 54.4% of the patients were women and 96.8% were Jewish Israeli. In addition, 29% of the patients were H. pylori-positive, and of these, 8.8% (1,244 patients) had GIM.

Increasing age, H. pylori infection, smoking, anti-parietal cell antibodies, and PPI use were all associated with a diagnosis of GIM, the researchers reported. The two upper quartiles of cumulative PPI dose (PPI Q4 and PPI Q3 vs PPI Q1) were associated with a diagnosis of GIM as follows:

• Adjusted odds ratios 1.32 (95% CI 1.11-1.57) and 1.27 (95% CI 1.07-1.52), respectively, for the whole cohort (P total 0.007, P trend 0.013)

• 1.69 (95% CI 1.23-2.33) and 1.40 (95% CI 1.04-1.89), respectively, for H. pylori-positive patients (P total 0.004, P trend 0.005)

• 1.21 (95% CI 0.98-1.49) and 1.20 (95% CI 0.96–1.49), respectively, for H. pylori-negative patients (P total 0.288, P trend 0.018)

The two upper quartiles were associated with five to 10 times the risk of low-grade dysplasia.

GIM appeared to be more frequent in patients with confirmed H. pylori eradication than in those treated but without confirmed eradication, the researchers said.

"This may be related to better compliance in this subset of patients, not only for performing a follow-up breath test to confirm eradication but also for taking the PPI prescribed," the team explained, noting, however, that this may have been due to bias stemming from the smaller sample size and false-negative eradication results related to continuous PPI use before performance of the verifying breath test.

Caveats about Clinical Relevance, Other Concerns

Asked for his perspective, Brooks Cash, MD, director of the Division of Gastroenterology, Hepatology, and Nutrition at the University of Texas Health Science Center at Houston, who was not involved with the study, urged caution in interpreting the results: "As with multiple previous studies that have evaluated PPIs and untoward outcomes, the current study has significant limitations that should raise significant concerns regarding their accuracy and their relevance," he told MedPage Today.

Specifically, he said, the study was retrospective and it was not possible to account for potential confounders between the groups of patients compared. In addition, H. pylori infection status was based on whether patients were prescribed medications for treating the infection, which itself has been proven to be associated with GIM, while PPIs have not.

Cash also noted that compliance rates with H. pylori regimens have historically been poor, and resistance to clarithromycin-based regimens, from which the authors deduced H. pylori status, has been increasing.

Moreover, comparing the lowest quartile of PPI use with the top two quartiles combined was faulty and thus insufficient to suggest any degree of causality, he said.

There is also a concern about clinical relevance in the U.S., Cash said: "The natural history and clinical importance of gastric intestinal metaplasia in Western populations such as the United States is not known, so the clinical relevance of this study is questionable. All in all, the current article implying an association with PPI use and gastric intestinal metaplasia is significantly flawed. It should be viewed with a great deal of caution and skepticism and should not affect current practice with regards to appropriate PPI use."

Study limitations cited by Levi and co-authors included that it was not possible to clarify whether the PPI-GIM association was causative and that the sample size was too small to allow stratification according to the timing of H. pylori eradication. In addition, there was no information about PPI or endoscopy indications, adherence to the operative link on the GIM assessment protocol for gastric biopsies, and use of over-the-counter PPIs.

Furthermore, the researchers said, because they inferred H. pylori infection was from dispensed drugs with clarithromycin-based triple therapy, some misclassification may have occurred, since patients allergic to penicillin received non-clarithromycin therapies and thus were incorrectly categorized as H. pylori-negative. Moreover, the team did not take into account dietary habits, which may play a role in GIM.

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