Pharmacological treatment of Barrett’s Oesophagus

People often ask me what medicines they should be taking for their Barrett’s oesophagus. For the most part, the answer is the same medicines they are taking to prevent symptoms of acid reflux. Although see below for some

Proton Pump Inhibitors – PPIs

Many patients with Barrett’s oesophagus are prescribed a proton-pump inhibitor to be taken once a day. Proton pump inhibitors reduce the amount of acid produced by the stomach, which help limit the damage of the oesophageal lining, and prevent the progression of disease to oesophageal cancer.¹ They tend to work for only twelve hours, so some people will get significant extra benefit if they take the medicine twice each day. The best time to do so is half an hour before meals.

Do PPIs lead to regression of Barrett’s?

Complete regression of Barrett’s oesophagus in patients taking PPIs has been reported in approximately 7% for short-segment Barrett’s oesophagus (<3cm) ^2,3 and 2.5% for patients with long-segment Barrett’s oesophagus (>3cm) ^3,4. In other words, for the vast majority of patients, PPIs do not lead to regression of the Barrett’s.

Several studies have indicated that compared to those not treated with PPIs, PPI therapy is associated with:

• A lower incidence of dysplastic Barrett’s oesophagus disease, of any grade ⁵
• A lower incidence of oesophageal adenocarcinoma  ⁶
• A delay in the progression of metaplasia to dysplasia ^5,7

Non steroidal anti inflammatory drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin have been linked with a reduced risk of Barrett’s progression to oesophageal adenocarcinoma ^1,8. These drugs work by inhibiting the biological enzyme COX-2.

Enzymes are biological catalysts that mediate biological processes. COX-2 inhibits programmed cell death (apoptosis) and promotes the development of new blood vessels (angiogenesis). As apoptosis will cause cancerous cells to die, inhibition of apoptosis makes development of cancer more likely. Angiogenesis is needed to provide cancerous cells with oxygen and nutrients, allowing them to survive. Inhibition of COX-2 will make the development of cancer less likely.

The role of COX-2 in Barrett’s oesophagus, and its progression, is indicated by the increased expression of the enzyme in non-dysplastic, dysplastic Barrett’s oesophagus, and oesophageal adenocarcinoma ^9,10.

NSAID use is likely to be retrospectively protective, meaning individuals who have previously used NSAIDs are less likely to develop oesophageal adenocarcinoma than those who have never taken NSAIDs. In one study, there was an 80% reduction (from 14.3% to 6.6%) in the incidence of adenocarcinoma in individuals who previously used NSAIDs compared to those who have never taken such drugs ¹¹.

The Proof of the Pudding – the AspECT Trial

The best type of medical study is a randomised controlled trial. Patients are randomly offered one of two treatments and followed up over a long period of time. There is now one single trial looking at PPIs and NSAIDs in Barrett’s to see whether it reduces the risk of developing cancer. It is called the AspECT trial. It involved 2,500 patients and was published in the Lancet in 2018.

The trial is somewhat confusing. It compared high and low dose PPI (using the drug esomeprazole) and aspiring versus no aspirin in a 2 x 2 factorial design. Patients were then followed up for 10 years. They were checked for oesophageal adenocarcinoma, high grade dysplasia (the step before cancer) and also for all-cause mortality because in some studies Barrett’s has been associated with a higher risk of heart attacks and strokes.

The results suggest that if all these three endpoints are added together, both aspirin and esomprazole improve outcomes slightly. Between 34-43 people needed to be treated to prevent one event, of dysplasia, cancer or death. This is similar to the number of people with high blood pressure needed to treat to prevent a stroke or heart attack.

One of the questions is whether treating for longer would bring better outcomes. At the moment we don’t know. Cancer Research UK who funded this trial paid for follow up for 10 years. An application has been made for further funding to extend the work but given the current situation with Coronavirus, who knows whether the charity will have enough funds to take things forward. It is an important study, and one that may never be repeated.

Statins

Statins are a group of drugs that reduce the production of cholesterol by the body, and help reduce the level of cholesterol in the blood.

Several studies have indicated that regular use of statins (with or without NSAIDs) is associated with a significantly reduced risk of developing oesophageal adenocarcinoma. For example, one study (12) found that patients on long-term statins were 43% less likely to develop oesophageal cancer. Those on statins and aspirin had a 69% reduced risk of developing oesophageal cancer. 

In one study of 85 patients, the odds ratio of patients on longer-term statin use was 0.57. The use of higher doses of statins was associated with a significantly greater reduction in the OR for oesophageal adenocarcinoma. When combined with aspirin, the OR = 0.31 ¹².

A meta-analysis of 5 patient studies found that statins were associated with a 41% reduction in the risk of oesophageal adenocarcinoma after adjusting for confounding variables.

Cautionary advice

A meta-analysis published in 2015 ¹³ found that:

• Statin use was associated with a 50% risk reduction of oesophageal adenocarcinoma and high-grade dysplastic Barrett’s oesophagus in Barrett’s patients
• PPI’s do not significantly reduce the risk of high-grade dysplastic Barrett’s oesophagus or oesophageal adenocarcinoma at any dose
• Low-dose use of NSAIDs is not associated with a risk reduction for oesophageal adenocarcinoma

This meta-analysis suggests that pharmacological agents in patients with Barrett’s oesophagus should not necessarily be provided, due to the conflicting evidence for their efficacy.

1.3.         Shaheen NJ, Falk GW, Iyer PG, Gerson LB, American College of Gastroenterology. ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus. Am J Gastroenterol . 2016 Jan;111:30–50; quiz 51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26526079

2.         Weston AP, Badr AS, Hassanein RS. Prospective multivariate analysis of factors predictive of complete regression of Barrett’s esophagus. Am J Gastroenterol . 1999 Dec;94(12):3420–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10606297

3.         Konda VJ, Dalal K. Optimal management of Barrett’s esophagus: pharmacologic, endoscopic, and surgical interventions. Ther Clin Risk Manag . 2011;7:447–58. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22162921

4.         Sampliner RE. Reduction of acid exposure and regression of Barrett’s esophagus. Dig Dis . 18(4):203–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11356991

5.         El-Serag HB, Aguirre T V, Davis S, Kuebeler M, Bhattacharyya A, Sampliner RE. Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroenterol . 2004 Oct;99(10):1877–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15447744

6.         Nguyen DM, El-Serag HB, Henderson L, Stein D, Bhattacharyya A, Sampliner RE. Medication usage and the risk of neoplasia in patients with Barrett’s esophagus. Clin Gastroenterol Hepatol . 2009 Dec;7(12):1299–304. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19523538

7.         Hillman LC, Chiragakis L, Shadbolt B, Kaye GL, Clarke AC. Proton-pump inhibitor therapy and the development of dysplasia in patients with Barrett’s oesophagus. Med J Aust . 2004 Apr;180(8):387–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15089728

8.         Pophali P, Halland M. Barrett’s oesophagus: diagnosis and management. BMJ . British Medical Journal Publishing Group; 2016;353(6):i2373. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27169585

9.         Morris CD, Armstrong GR, Bigley G, Green H, Attwood SE. Cyclooxygenase-2 expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence. Am J Gastroenterol . 2001 Apr;96(4):990–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11316217

10.       Buttar NS, Wang KK, Anderson MA, Dierkhising RA, Pacifico RJ, Krishnadath KK, et al. The effect of selective cyclooxygenase-2 inhibition in Barrett’s esophagus epithelium: an in vitro study. J Natl Cancer Inst . 2002 Mar;94(6):422–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11904314

11.       Vaughan TL, Dong LM, Blount PL, Ayub K, Odze RD, Sanchez CA, et al. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett’s oesophagus: a prospective study. Lancet Oncol . 2005 Dec;6(12):945–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16321762

12.       Beales ILP, Vardi I, Dearman L. Regular statin and aspirin use in patients with Barrett’s oesophagus is associated with a reduced incidence of oesophageal adenocarcinoma. Eur J Gastroenterol {&} Hepatol . 2012 Aug;24(8):917–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22569083

13.       Masclee GMC, Coloma PM, Spaander MCW, Kuipers EJ, Sturkenboom MCJM. NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett’s oesophagus: a population-based case-control study. BMJ Open . 2015;5(1):e006640. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25633286