PPI Use May Not Prevent HGD and Esophageal Adenocarcinoma in Barrett's

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Proton Pump Inhibitor Use May Not Prevent High-grade Dysplasia and Oesophageal Adenocarcinoma in Barrett's Oesophagus
A Nationwide Study of 9883 Patients

F. Hvid-Jensen, L. Pedersen, P. Funch-Jensen, A. M. Drewes

Aliment Pharmacol Ther. 2014;39(9):984-991.

Abstract

Background: Proton pump inhibitors (PPI) may potentially modify and decrease the risk for development of oesophageal adenocarcinoma in Barrett's oesophagus (BO).

Aim: To investigate if the intensity and adherence of PPI use among all patients with BO in Denmark affected the risk of oesophageal adenocarcinoma.

Methods: We performed a nationwide case–control study in Denmark among 9883 patients with a new diagnosis of BO. All incident oesophageal adenocarcinomas and high-grade dysplasias were identified, and risk ratios were estimated on the basis of prior use of PPIs. Sex- and age-matched BO patients without dysplasia or malignancies in a 10:1 ratio were used for comparison. Conditional logistic regression was used for analysis, adjusting for low-grade dysplasia, gender and medication.

Results: We identified 140 cases with incident oesophageal adenocarcinomas and/or high-grade dysplasia, with a median follow-up time of 10.2 years. The relative risk of oesophageal adenocarcinoma or high-grade dysplasia was 2.2 (0.7–6.7) and 3.4 (95% CI: 1.1–10.5) in long-term low- and high-adherence PPI users respectively.

Conclusions: No cancer-protective effects from PPI's were seen. In fact, high-adherence and long-term use of PPI were associated with a significantly increased risk of adenocarcinoma or high-grade dysplasia. This could partly be due to confounding by indication or a true negative effect from PPIs. Until the results from future studies hopefully can elucidate the association further, continuous PPI therapy should be directed at symptom control and additional modalities considered as aid or replacement.

In depth Conclusion from article:

Conclusions

In patients with Barrett's oesophagus, we found no evidence of a protective effect from PPI on the development of OAC or HGD. In fact, we observed an increased risk for developing high-grade dysplasia and adenocarcinoma in the oesophagus with long-term PPI usage. This association can partly be due to bias associated to symptom driven PPI intake. Until the results from future studies can further elucidate the association, PPIs should be restricted to symptom control according to current guidelines. Hence, PPI may not protect against malignant progression in BO patients and in selected high-risk patients, clinicians may consider adding or replacing long-term medical treatment with other modalities.

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Addition

The fact that long term PPI use can possibly increase the risk of High Grade Dysplasia and Esophageal Cancer is something I did not want to hear. I think the possibility of Confounding Factors makes it a little more palatable.

Definition of Confounding Factors;

"In statistics, a confounding variable (also confounding factor, a confound, or confounder) is an extraneous variable in a statistical model that correlates (directly or inversely) with both the dependent variable and the independent variable. A perceived relationship between an independent variable and a dependent variable that has been misestimated due to the failure to account for a confounding factor is termed a spurious relationship, and the presence of misestimation for this reason is termed omitted-variable bias. In the case of risk assessments evaluating the magnitude and nature of risk to human health, it is important to control for confounding to isolate the effect of a particular hazard such as a food additive, pesticide, or new drug. For prospective studies, it is difficult to recruit and screen for volunteers with the same background (age, diet, education, geography, etc.), and in historical studies, there can be similar variability. Due to the inability to control for variability of volunteers and human studies, confounding is a particular challenge. For these reasons, experiments offer a way to avoid most forms of confounding.

As an example, suppose that there is a statistical relationship between ice-cream consumption and number of drowning deaths for a given period. These two variables have a positive correlation with each other. An evaluator might attempt to explain this correlation by inferring a causal relationship between the two variables (either that ice-cream causes drowning, or that drowning causes ice-cream consumption). However, a more likely explanation is that the relationship between ice-cream consumption and drowning is spurious and that a third, confounding, variable (the season) influences both variables: during the summer, warmer temperatures lead to increased ice-cream consumption as well as more people swimming and thus more drowning deaths."

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Comparison to Previous Studies

Comparison to Previous Studies

"Patients with BO have an increased risk of developing pre-malignant or malignant transformation of the metaplastic epithelium, although the risk is lower than previously believed.[8,9] As BO is the main risk factor for developing OAC, studies regarding cancer prevention in this group of patients are of great clinical importance. Previously reflux symptoms have been described as an independent risk factor for OAC,[17] and oesophageal acid exposure as the prominent factor in the malignant transformation from BO into OAC. This assumption has justified widespread routine prescription of PPI to BO patients, despite present international guidelines recommend PPI's as symptomatic treatment only.[24,25]

In a case–control study from the UK using the general practitioners database, the use of PPI was associated with significantly increased risks of developing OAC. However, when adjusting for reflux symptoms as reported by the doctors, the association was attenuated (although still significant for long-term usage). Even though this is a very solid study, it is important to note that estimates were made using regular population controls and contained no information about BO status.[17]

A study in a large cohort of veterans with BO found no significant association between the use of PPIs and of OAC.[16] However, the study used a selected patient group, and a follow-up of less than 2 years. A follow-up time of more than 5 years, as in our study, might also be considered as a minimum to obtain a plausible evaluation of the OAC risk during PPI therapy.

In another veterans study of 236 BO patients, the incidence of dysplasia was reduced in PPI users and there was an inverse correlation with duration of use. However, the number of cases was rather small and PPI treatment length after BO diagnosis was less than 2 years. Calculating risk estimates for OAC was not possible due to few cases (N = 2).[13] Similarly two studies from Australia have shown that absence or delay of PPI therapy before and after BO diagnosis increased the risk of dysplastic progression among BO patients.[14,18]

A recent Dutch prospective study containing 540 BO patients found a significant preventive effect from PPIs on the risk of both HGD and OAC associated to increasing treatment duration and adherence.[19] The authors suggest that this neoplastic prevention may obviate the need for future expensive endoscopic treatment procedures (EMR, resection). Irrespective of the strong study design, however, the conclusions may be premature due to the relatively small cohort diluted into several stratified groups and a small control group of non-PPI users.

Our results extend the current knowledge in several important ways. The finding of an increased risk of OAC or HGD combined, among high-adherence patients is problematic, and several possible explanations should be taken into account. First, it should be stressed that there is more to reflux than just acid. Gastro-oesophageal reflux is often a mixture of gastric and duodenal contents.[26] Bile has been shown to induce inflammation and cell proliferation in the oesophageal mucosa, and recent in vitro studies have shown a possible increased mutagenic effect associated with alkalisation of refluxed bile.[27–29] Hence – although further studies are necessary – PPI use may facilitate the formation of carcinogenic bile acids, explaining some of our findings.

Second, increased gastrin production may also influence the scenario. Gastrin is secreted from the gastric antrum and duodenum and has a stimulating effect on cells throughout the gastrointestinal system. The gastrin level may increase 5–10 fold during PPI therapy, and may have anti-apoptotic and proliferative effects that contribute to neoplasia.[30] This may increase the risk of gastrointestinal tumours.[31,32] Previous studies have been conflicting. A recent study investigating colorectal cancer risk found no such association.[23] In BO, a recent in vivo and vitro study found no association between length of oesophageal metaplasia and gastrin level,[33] whereas two other studies found a significant correlation between gastrin and the risk of dysplasia and OAC.[34,35]

Third, confounding by indication, as discussed below, can play an important role in the observed associations."




To summarize....This is what I found to be possible causes of their increased risk findings;
1) PPI use may facilitate the formation of carcinogenic bile acids.
2) Increased gastrin production may also influence the scenario
3) confounding by indication,