Long Term Low-Dose Aspirin Associated With Gastro-Duodenal Damage, Term Paper Example

Aspirin has many benefits such as reducing fever, pain, and inflammation. It prolongs bleeding and when taken in small doses, aspirin can help to prevent cardiovascular and cerebrovascular problems. Low-dose aspirin (LDA) therapy has been shown to protect against myocardial infarctions, stroke, and death. Aspirin has the advantages of both a low cost and a long duration of anti-platelet action (Yeomans et al., 2005). It may even prove to be beneficial in preventing and treating certain cancers, including breast, ovarian, esophageal, and colorectal cancer (Flower, 2003).

Yet even when taken at a low dose, the prophylactic use of aspirin has been shown to be associated with significant gastroduodenal mucosal injury (Chowdhury, Ganguly, Debashis, Santra, Das Gupta, & Roy, 2001). When taking just 10 mg of aspirin a day, the gastric mucosal prostaglandin levels are significantly reduced, creating gastric mucosal damage (Iwamoto, Saito, Honda, & Matsuzaki, 2013). The mucosal damage of the gastrointestinal tract creates an erosive lesion, otherwise known as an ulcer.

The gastrointestinal damage affiliated with LDA treatments has been shown increase the risk of gastroduodenal ulcers and their potentially fatal complications, such as gastrointestinal bleeding and perforation. The mortality attributable to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or LDA treatment is approximately 20?to?25 cases per million people, and one-third of these cases are attributable to LDA treatment (Kawamura et al., 2013).

Even though there is a significant risk when chronically taking LDA treatment, not all patients taking LDA treatment develop gastrointestinal ulcers. Yeomans et al. (2005) found that gastrointestinal ulcers develop in only 10% of patients taking LDA treatment.

The fact that patients are affected in different ways by LDA therapy and gastroduodenal ulcers raises certain questions. What causes some patients taking LDA therapy to develop gastroduodenal ulcers while others do not? Why are some patients with gastroduodenal ulcers asymptomatic, while others prevent with severe dyspeptic problems? If found, should patients with gastroduodenal ulcers discontinue LDA therapy? The purpose of this paper is to analyze the relationship between gastroduodenal ulcers and LDA treatment. Even though adverse gastrointestinal effects of LDA have been shown to impact a limited number of individuals, it is important to understand the etiology, pathogenesis, risk factors, the signs and symptoms, and the methods to prevent and treat ulcers and their complications.

Etiology and pathogenesis

The American Society for Gastrointestinal Endoscopy (2010) defines a peptic ulcer as “a defect in the gastric or duodenal wall that extends through the muscularis mucosa (the lowermost limit of the mucosa) into the deeper layers of the wall (submucosa or the muscularis propria).” An ulcer occurs when direct epithelial damage in the gastrointestinal tract stimulates acid-back diffusion and impairs platelet aggregation. Prostaglandins would normally heal the ulcer; however, aspirin inhibits the chemical that forms prostaglandins when taken. When aspirin is taken at the low dose of 10 mg per day, the gastric mucosal prostaglandin levels decrease and causes significant gastric mucosal damage (Iwamoto, Saito, Honda, & Matsuzaki, 2013).

Iwamoto, Saito, Honda, and Matsuzaki (2013) report that the LDA therapy mechanism of action can be divided into local and systemic action. Cyclooxygenase (COX) is an inflammatory chemical that forms prostaglandin. Prostaglandins cause inflammation, fever, and pain; however, they do have gastrointestinal cytoprotective actions and are implicated in platelet aggregation (Flower, 2003). Despite the potentially harmful qualities of prostaglandins, their inflammatory nature provides them with the ability to heal an ulcer or erosion in the gastrointestinal tract.

The half-life of aspirin in plasma is short; esterases remove the acetyl group leaving free salicylate, which may have a secondary pharmacological effect  through cyclooxygenase inhibition or other mechanism, adding to the complexity of aspirin’s action (Flower, 2003).

Aspirin is able to reduce inflammation due to its ability to act as both an irreversible COX-1 and COX-2 inhibitor; however, it has a greater capacity to inhibit COX-1 over COX-2. As a COX-1 inhibitor, aspirin reduces gastrointestinal mucosal flow, reduces mucus and bicarbonate secretion, and impairs platelet aggregation in the gastrointestinal tract. As a COX-2 inhibitor, aspirin reduces angiogenesis and increases leukocyte adherence in the gastrointestinal tract. Iwamoto, Saito, Honda, and Matsuzaki (2013) confirm that both the direct effect of aspirin on the gastrointestinal mucosa and the systemic effect related to reduction of prostaglandin level contribute in the pathogenesis of LDA-induced GI mucosal damage. Truly selective COX-2 inhibitors have been shown to have no effect on gastric mucosal prostaglandin synthesis, to cause no acute injury, and no chronic ulceration compared to placebo (Hawkey, 2003).

Aspirin alters prostaglandin metabolism, therefore altering the regulation of gastrointestinal motility. According to Hoffman, Gschossmann, Buenger, Gerken, and Talley (2002), these factors can create changes in gastric emptying also may be relevant in the pathogenesis of aspirin-induced dyspepsia. In addition to alterations of visceral sensory function, disturbances of gastric emptying also may play a role in the development of symptoms in functional dyspepsia. (Hoffman, Gschossmann, Buenger, Gerken, & Talley, 2002).

There has been some speculation that aspirin coated with cellulose, silicon, or other inactive ingredients is likely to prevent its dissolution and absorption from the stomach. Manufacturers would advertise that an enteric coat would potentially function as a barrier and not cause aggravation to the gastrointestinal tract. However, Chowdhury, Ganguly, Debashis, Santra, Das Gupta, and Roy (2001) found that enteric-coated aspirin did not offer any advantages over uncoated aspirin in terms of frequency or severity of damage to the gastrointestinal tract. The authors suggest that gastroduodenal damage due to LDA treatments may be due to aspirin’s systemic effect when it is absorbed.

Risk factors

Individuals taking LDA therapy may be predisposed to developing gastroduodenal ulcers if they are over 70-years old, have history of ulcers or upper gastrointestinal bleeding, simultaneously use non-aspirin NSAIDs including COX-2-selective NSAIDs, or have ever had a Helicobacter pylori (H. pylori) infection. However, the risks associated with LDA treatments and developing gastroduodenal ulcers are significantly less the risks associated with patients taking NSAIDS (Iwamoto, Saito, Honda, & Matsuzaki 2013). In addition to advanced age and H. pylori infection, the risk factors associated with NSAIDS and developing gastrointestinal ulcer, simultaneous use of corticosteroids, higher dose of NSAID including the use of more than one NSAID, simultaneous administration of anticoagulants, diabetes, kidney failure, cigarette smoking, and alcohol consumption (Iwamoto, Saito, Honda, & Matsuzaki, 2013).

Signs and symptoms

The main symptoms of a gastroduodenal ulcer are nausea, acid regurgitation, heartburn, and abdominal bloating (Iwamoto, Saito, Honda, & Matsuzaki, 2013). However, many patients with gastroduodenal ulcers exhibit no symptoms whatsoever. According to Yeomans et al. (2005), the prevalence of gastrointestinal ulcers was 10.7% in 187 patients taking long-term LDA, yet only 20% of those with a gastrointestinal ulcer had dyspeptic symptoms. Hoffman, Gschossmann, Buenger, Gerken, and Talley (2002) suggested that asymptomatic patients characteristically have a higher gastric sensory threshold. There may be “a failure of visceral sensory thresholds to appropriately respond to a noxious stimulus in a subset of patients with functional gastrointestinal disease.” The authors (2002) estimate that the presence of mucosal ulcers stimulates increased amounts of visceral afferents. The ulcers do no result in dyspeptic symptoms if endogenous pain control systems, such as mechanosensory thresholds, are activated. Dyspeptic symptoms are more likely to occur if there is no increase of visceral sensory thresholds, such as sensory thresholds remain unchanged.

The 2002 study by Hoffman, Gschossmann, Buenger, Gerken, and Talley confirmed that subjects reporting dyspepsia during treatment with LDA do not have more severe mucosal ulcers compared with subjects without symptoms.x2Collins, AJ, Davies, J, and Dixon, SA. Contrasting presentation and findings between patients with rheumatic complaints taking nonsteroidal anti-inflammatory drugs and a general population referred for endoscopy. Br J Rheumatol. 1986; 25: 50–52

CrossRef | PubMedSee all References2 However, the authors found that in treatment with aspirin, there appears to be distinct changes of visceral mechanosensory thresholds. Patients who did not develop dyspepsia during aspirin treatment were characterized by a significant increase of sensory thresholds. Conversely, sensory thresholds remained unchanged or reduced in patients who developed dyspeptic symptoms. Altered visceral mechanosensory function, or hyperalgesia, is a driving force in the development of dyspeptic symptoms. In conjunction with visceral hypersensitivity, sensitization by mucosal inflammation, impaired central down-regulation of visceral afferents may be important (Hoffman, Gschossmann, Buenger, Gerken, & Talley, 2002). A high-risk patient taking LDA therapy must be careful because they may develop an ulcer, but show no symptoms that would indicate necessary treatment. There is also reason to believe that because aspirin and NSAIDS are pain-relievers, their analgesic effects may mask any dyspeptic symptoms (Hoffman, Gschossmann, Buenger, Gerken, & Talley, 2002).

Tests and diagnosis

When patients do exhibit dyspeptic symptoms, ulcers may be identified using radiographic imaging. More aggressive ulcers may require a biopsy or endoscopy for further evaluation. Endoscopy is an effective tool in the diagnosis, prognostication, and therapy of bleeding ulcers. In addition to lowering the mortality rate, endoscopies reduce the need for blood transfusions, shortens intensive care unit and hospital stays. However, endoscopies and biopsies are invasive procedures and are not always necessary. According to the American Society for Gastrointestinal Endoscopy (2010), routine biopsy of a duodenal ulcer is usually not recommended. If an ulcer is found in the duodenum, it is highly unlikely that it will be malignant. Endoscopies are also not recommended to evaluate benign and uncomplicated duodenal ulcers identified on radiologic imaging.

Preventative measures and treatment

The effects of gastroduodenal ulcers can be severe when left untreated, and lead to internal bleeding, perforation, or even death. However, even though untreated ulcers can create many health problems, stopping LDA treatment altogether can cause even more damage. In patients with LDA-induced upper gastrointestinal bleeding, the risk involved in stopping the LDA treatment usually proves higher than the risk of continuing LDA treatments (Iwamoto, Saito, Honda, & Matsuzaki, 2013). Continuous aspirin therapy in the case of gastrointestinal bleeding may increase the risk for recurrent bleeding, but has a greater potential to reduce mortality rates.

It is also important to treat any underlying conditions that may exacerbate gastrointestinal bleeding. Any food sensitivities or triggers should be eliminated and any infections should be treated. If the ulcer coexists with an H. pylori infection, then the infection should be treated to prevent recurrent bleeding (Iwamoto, Saito, Honda, & Matsuzaki, 2013). Infection with H. pylori can predispose patients to developing an ulcer, even if the infection has been resolved.

Proton pump inhibitors are the most effective in preventing the development of LDA-induced gastrointestinal ulcers (Iwamoto, Saito, Honda, & Matsuzaki, 2013). More than 90% of duodenal ulcers heal with four weeks of implementing proton pump inhibitor therapy (American Society for Gastrointestinal Endoscopy, 2010). Proton pump inhibitor therapy reduces the risk of developing gastric or duodenal ulcers in patients without pre-existing gastroduodenal ulcers. Proton pump inhibitors are used to decrease LDA-associated gastroduodenal mucosal and NSAID-induced injuries (Kawamura et al., 2013). Since 2011, in Japan, treatment with half-dose of the proton pump inhibitor lansoprazole at 15 mg per day, has been permitted as a medical service covered by health insurance for the prevention of NSAID- or LDA-induced peptic ulcers for high-risk patients who have a history of peptic ulcers (Kawamura et al., 2013). Yeomans et al. (2005) report that the use of esomeprazole 20 mg per day reduces the risk of developing LDA-associated gastric and/or duodenal ulcers in elderly patients without pre-existing gastroduodenal ulcers. However, even with proton pump inhibitors, the risk of developing a gastrointestinal ulcer increases in patients who are taking anticoagulants and in patients with diabetes (Kawamura et al., 2013). If proton pump inhibitors are not appropriate for some patients, there are other options available, such as histamine-2 receptor antagonists. Even though they are not as powerful as proton pump inhibitors, histamine-2 receptor antagonists serve as an effective alternative in treating and preventing the development of LDA-induced gastrointestinal ulcers. While both proton pump inhibitors and histamine-2 receptor agonists prevent gastroduodenal ulcers attributable to the use of LDA therapy and NSAIDs by targeting the inhibition of gastric acid secretion, histamine-2 receptor antagonists are usually not tolerated well. Histamine-2 receptor antagonists, such as high-dose misoprostol, create diarrhea and abdominal discomfort (Vonkeman, Fernandes, van der Palen, van Roon, & van de Laar, 2007).

The American Society for Gastrointestinal Endoscopy (2010) reports that surveillance endoscopy has a low yield in healing if an ulcer is detected with radiographic imaging or endoscopy. Constant endoscopic surveillance is unnecessary if dyspeptic symptoms resolve after a course of acid suppression, eradication therapy for H. pylori if present, and discontinuation of NSAIDs. LDA treatments may be continued in conjunction with proton pump inhibition therapy, as the benefits outweigh the risks. Surveillance endoscopy should only be considered in patients who experience persistent symptoms despite an appropriate course of therapy, specifically to rule out a more severe or life-threatening cause.

Conclusion

LDA therapy provides many benefits to patients who are at risk for myocardial infarction, stroke, or other cardiovascular or cerebrovascular pathologies. Aspirin is both anti-inflammatory and promotes bleeding. An unfortunate side effect of LDA therapy is the potential for an ulcer to form in the gastrointestinal tract. However, the benefits of LDA therapy are numerous, and it is not recommended that its usage automatically cease simply because of the development of an ulcer. Proton pump inhibitors have found to be most effective in both treating and preventing ulcers in the gastrointestinal tract. While patients with gastroduodenal ulcers should be monitored, if they are responsive to proton pump inhibitors, then no further invasive procedures, such as endoscopies or biopsies are required. If high-risk patients prophylactically take proton pump inhibitors, then there is no reason to discontinue the administration of LDA treatments, which could potentially save their lives.

References

American Society for Gastrointestinal Endoscopy. (2010). The role of endoscopy in the management of patients with peptic ulcer disease. Gastrointestinal Endoscopy 71 (4), 663-668. http://dx.doi.org/ 10.1016/j.gie.2009.11.026

Chowdhury, A., Ganguly, G., Debashis, C., Santra, A., Das Gupta, J. & Roy, T. (2001). Gastro- duodenal mucosal changes associated with low-dose aspirin therapy: A prospective, endoscopic study. Indian Journal of Gastroenterology 20. Retrieved from http://indianjgastro.com/IJG_pdf/nov2001/227-229.pdf

Flower, R. (2003). What are all the things that aspirin does? British Medical Journal 327(527-573), http://dx.doi.org/ 10.1136/bmj.327.7415.572

Hawkey, C.J. (2001). COX-1 and COX-2 inhibitors. Best Practices in Residential Clinical Gastroenterology 15(5), 801-820. http://dx.doi.org/10.1053/bega.2001.0236

Hoffman, G., Gschossmann, J., Buenger, L. Gerken, G., &Talley, N.J. (2002). Do changes in visceral sensory function determine the development of dyspepsia during treatment with aspirin?. Gastroenterology 123(5), 1451-1458. http://dx.doi.org/10.1053/gast.2002.36556

Iwamoto, J., Saito, Y., Honda, A., & Matsuzaki, Y. (2013). Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy. World Journal of Gastroenterology 19(11), 1673-1682. http://dx.doi.org/ 10.3748/wjg.v19.i11.1673

Kawamura, N., Ito, Y., Sasaki, M., Iida, A., Mizuno, M., Ogasawara, N., Funaki, Y., & Kasugai, K. (2013). Low-dose aspirin-associated upper gastric and duodenal ulcers in Japanese patients with no previous history of peptic ulcers. BMC Research Notes 6. http://dx.doi.org/ 10.1186/1756-0500-6-455

Vonkeman, H.E., Fernandes, R.W., van der Palen, J., van Roon, E.N., & van de Laar, M.A.F.J. (2007). Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: A nested case-control study. Arthritis Residential Therapy 9(3). http://dx.doi.org/ 10.1186/ar2207

Yeomans, N.D., Lanas, A.I., Talley, N.J., Thompson, A.B.R., Daneshjoo, R., Eriksson, B., Appelman-Eszczuk, S., Langstrom, G., Naesdal, J., Serrano, P., Singh, M., & Hawkey, C.J. (2005). Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Alimentary Pharmacology and Therapeutics. 22(9), 795-801. http://dx.doi.org/ 10.1111/j.1365-2036.2005.02649.x