Aspirin for Barrett’s esophagus: chemoprevention potential

Aspirin is a commonly prescribed drug and its prevention of both cardiovascular and vascular events is well established. Recently, the benefits of aspirin from a chemoprevention standpoint, particularly in gastrointestinal tract cancers, have emerged. Prevention of esophageal adenocarcinomas is particularly relevant for Barrett’s esophagus patients, a premalignant condition affecting 2 percent of the adult population. Over the past 40 years there has been a trend for an increase in incidence of esophageal adenocarcinomas.1 This trend remains despite vigilant endoscopic surveillance and the five-year survival remains less than 25 percent.2 New evidence has emerged that demonstrates the chemoprevention potential of aspirin.

Role of aspirin in chemoprevention of other gastrointestinal cancers especially colon

Aspirin has been shown to reduce the incidence of colorectal adenocarcinomas by 17 percent compared to placebo4 as well as reduce the 20-year risk of death due to colorectal cancer by 40 to 50 percent.5 Aspirin has been found to have the greatest impact on proximal colon adenocarcinomas which are often flat and easily missed on colonoscopy and are often aggressive.

Role of aspirin from epidemiology studies for preventing upper gastrointestinal cancer

Aspirin has also been found to have a significant role in the prevention of upper GI cancers. Data drawn from a metanalysis of eight trials examined the long-term cancer mortality of patients taking aspirin for vascular intervention. Taking aspirin for more than five years was found to significantly reduce the risk of all GI cancers, particularly esophageal adenocarcinomas.6

Role of aspirin in preventing inflammation and surrogate markers of risk in Barrett’s esophagus

The effective anti-inflammatory and analgesic properties of aspirin in cardiovascular disease have been biologically attributed to the inhibition of cyclooxygenase (mainly COX1 and COX2) which regulates prostaglandin production. COX1 and COX2 have also been implicated in the carcinogenesis of different types of cancers including esophageal adenocarcinomas. The chemoprotective effect of aspirin as a COX inhibitor acts to down regulate the levels of prostaglandins which are responsible for resistance to apoptosis, increased angiogenesis and in Barrett’s esophagus enhanced invasion of the esophageal mucosa.7 Data from a large prospective chemoprevention trial in patients with Barrett’s esophagus, conducted in North America, found that a combination of omeprazole with short term use of high dose aspirin (325mg) significantly reduced the levels of prostaglandin concentrations in Barrett’s esophagus. Given the importance of prostaglandin levels in Barrett’s esophagus associated carcinogenesis, this evidence further supports the use of aspirin as a chemoprevention strategy.

Role of aspirin in preventing deaths and high-grade dysplasia in Barrett’s

Results from the prospective AspECT trial has provided some important insight into the efficacy of proton pump inhibitors (PPIs) and aspirin for improving outcomes in patients with Barrett’s esophagus.8  2,557 patients were recruited and were randomly assigned to different regimens of PPIs and aspirin (high dose (40 mg) or lose dose (20 mg) PPIs with or without aspirin (300 mg for UK participants and 325 mg for Canadian participants per day)). Daily high dose PPIs were found to be better than low dose PPIs at delaying oesophageal adenocarcinomas and high-grade dysplasia. This benefit was enhanced when PPIs were combined with aspirin significantly improving outcomes in patients with Barrett’s esophagus.

Safety of low dose aspirin for gastrointestinal bleeding especially when given with PPIs

One concern practitioners face when prescribing aspirin is the potential for increased adverse events linked to this drug. A large-scale study examining the effect of aspirin on bleeding in healthy elderly participants (more than 70 years old) found the use of low dose aspirin, 100 mg, significantly increased the risk of major hemorrhage compared to placebo — 8.6 years versus 6.2 events per 1,000 persons, respectively.  However, when combined with a PPI these risks are lowered. In the AspECT trial, only 1 percent of participants had a serious adverse event relating to aspirin use.8 In the study the daily dose of aspirin used (300 mg to 325 mg) is higher than the standard low dose 75 mg commonly prescribed, which could potentially increase the risk of gastrointestinal bleeding. Therefore, the 1 percent of serious events found in the AspECT study might have been less if a lower dose of aspirin was used. Lower doses of aspirin have been associated with a chemoprotective effect. There are some unknown issues such as optimal aspirin dose and optimal length of treatment.

Summary the NNT and strong benefit/risk ratio of long-term low dose aspirin

In light of the aggressive and often asymptomatic nature of esophageal adenocarcinoma, there is a strong benefit to risk ratio of taking long dose aspirin for patients with Barrett’s esophagus. The NNT, calculated in the AspECT study to prevent high grade dysplasia, adenocarcinoma or death, in Barrett’s esophagus patients was 43 in the aspirin group.8

Conclusions

Aspirin is commonly prescribed and can easily be bought over the counter but current BSG and AGA guidelines do not currently advocate the routine use of aspirin in Barrett’s esophagus. A review of these guidelines is warranted given the potential long-term chemoprevention role aspirin could play in Barrett’s esophagus patients.

Drs. Franklin and Jankowski have no conflicts to disclose.

Dr. Prasad G. Iyer, MD, MSc, AGAF, says aspirin cannot be recommended for chemoprevention in all Barrett’s esophagus patients at this time.

References

1. Edgren G., et al. A global assessment of the oesophageal adenocarcinoma epidemic. Gut. 2013;62(10):1406-1414.
2. Njei B., T.R. McCarty, J.W. Birk. Trends in esophageal cancer survival in United States adults from 1973 to 2009: A SEER database analysis. J Gastroenterol Hepatol. 2016;31(6):1141-1146.
3. Solaymani-Dodaran M., Coupland C., Logan R.F.A. Risk of oesophageal cancer in Barrett’s oesophagus and in gastro-oesophageal reflux. Gastroenterology. 2003;124(4):A33-A33.
4. Cole B.F., et al. Aspirin for the chemoprevention of colorectal adenomas: Meta-analysis of the randomized trials. J Nat Cancer Inst. 2009;101(4):256-266.
5. Rothwell P.M., et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754)1741-1750.
6. Rothwell P.M., et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31-41.
7. Falk G.W., et al. A Combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E-2 in patients with Barrett’s esophagus. Gastroenterology. 2012;143(4):917-26.e1.
8. Jankowski J.A.Z., et al. Esomeprazole and aspirin in Barrett’s oesophagus (AspECT): a randomised factorial trial. Lancet. 2018;392(10145):400-408.
9. McNeil J.J., et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509-1518.

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