From the AGA Journals

PPIs lower progression risk in Barrett's esophagus

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Best data yet in support of PPIs
Nicholas J. Shaheen, M.D., MPH

Dr. Nicholas J. Shaheen
Everyone taking care of Barrett’s patients has heard the question. “Really? I have to take these acid pills forever? Forever is a long time!” Given the popular media barrage associated with every putative side effect of proton pump inhibitors (PPIs), it is to be expected that patients might be uneasy.

Kastelein and colleagues provide the best data yet in support of this approach. PPI use in their observational study was associated with a substantial risk reduction in cancer and high-grade dysplasia, both at study enrollment and in follow-up.

This is far-from-perfect evidence of a protective effect of PPIs in Barrett’s. As the authors recognize, there are several substantial issues limiting the study’s generalizability. The few patients who were not on a PPI may differ substantially from the rest in multiple unmeasurable ways. Also, to the credit of the Dutch health care system, 99% of Barrett’s patients were on PPIs for at least part of the follow-up, and 97% of total follow-up time was spent on PPIs. Therefore, the investigators had few non-PPI years to assess. In fact, the entire study really hinges on 12 years of non-PPI follow-up in subjects destined to go on to high-grade dysplasia/cancer.

Despite these limitations, this prospective study is the best to date, and may be the best we see on this topic. Given the weight of the observational data supporting PPI use in Barrett’s, a randomized controlled trial of PPIs versus placebo as an antineoplastic measure in Barrett’s will not likely be undertaken. Given the risk-benefit ratio, we should continue to promote PPI use in our Barrett’s patients, while acknowledging the less-than-perfect evidence underpinning this recommendation.

Nicholas J. Shaheen, M.D., MPH, AGAF, is professor of medicine and epidemiology, director of the Center for Esophageal Diseases and Swallowing, at the University of North Carolina School of Medicine, Chapel Hill. He receives or has received research funding from Takeda Pharmaceuticals, AstraZeneca, and Shire.


Proton pump inhibitor use was associated with a greater than 75% reduction in the risk of neoplastic progression in Barrett’s esophagus.

Indeed, despite the "considerable costs" of these drugs, "prolonged PPI use is ... justified and feasible in Barrett’s patients and should be strongly recommended, in particular in guidelines," concluded Dr. Florine Kastelein in the April 1 issue of Clinical Gastroenterology and Hepatology (doi:10.1016/j.cgh.2012.11.014).

In what they called "the first methodological[ly] sound prospective study which shows that PPIs strongly reduce the risk of neoplastic progression in BE," Dr. Kastelein of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues looked at 540 patients with known or newly diagnosed endoscopic Barrett’s esophagus (BE) confirmed by intestinal metaplasia.

Patients had a median age of 60.5 years at inclusion and were followed for a median of 5.2 years; 71% were male.

All patients were recruited from multiple academic and regional hospitals across the Netherlands, and patients were excluded if they had Barrett’s esophagus shorter than 2 cm, prior antireflux surgery, or a history of high-grade dysplasia or esophageal adenocarcinoma.

Patients with neoplastic progression found within the first 9 months after study inclusion also were ultimately excluded "since high-grade dysplasia or esophageal adenocarcinoma may be missed at index endoscopy in these patients," the investigators said.

Surveillance was performed according to the guidelines of the American College of Gastroenterology, such that patients without dysplasia underwent gastroscopy with biopsy sampling every 3 years and patients with low-grade dysplasia underwent it every year.

Overall, at inclusion in the study, 462 (85%) patients had used a PPI for a median duration of 4.0 years.

Dr. Kastelien and her associates found that, during follow-up, 28 patients developed high-grade dysplasia and another 12 developed esophageal adenocarcinoma, for a combined annual incidence of 1.6%.

"PPI use at inclusion was associated with a reduced risk of neoplastic progression (hazard ratio, 0.43; 95% confidence interval: 0.21-0.88) and remained associated with a trend toward a protective effect after adjusting for age, gender, time of BE diagnosis, BE length, esophagitis histology, and use of other medications (HR, 0.47; 95% CI: 0.19-1.18)," the researchers wrote.

Moreover, among the 99% of patients who used a PPI at any time during follow-up (median, 5.1 years), time-dependent analysis revealed that PPI use was associated with a reduced risk of neoplastic progression (HR, 0.15; 95% CI: 0.06-0.40) and remained so after adjusting for age, gender, BE length, histology, baseline PPI use, and use of other medications (HR, 0.21; 95% CI: 0.07-0.66).

The authors found no significant difference between neoplastic progression and the various PPIs assessed in this study (including esomeprazole and pantoprazole as well as omeprazole, rabeprazole, and lansoprazole).

According to Dr. Kastelein and her associates, the study is actually limited by the incredibly high rate of compliance among its population.

"Despite the large sample size, only eight (2%) patients never used a PPI and 18 (3%) patients used a PPI during [only] a part of their follow-up period," they wrote.

"Although this reflects clinical practice in Western countries and is representative for a disease in which patients seek to avoid reflux symptoms, it limits the options for investigating the effect of PPIs," they added.

However, "because not all patients used PPIs throughout their entire follow-up period, we were able to perform time-dependent analyses."

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