Reviewed by Professor Reid Ally;
A specialist Gastroenterologist and appointed adjunct Professor of Medicine in 2001. Currently he is the Head of Gastroenterology (Wits) and Chris Hani Baragwanath Hospital and senior lecturer and teacher of diagnostic and interventional endoscopy.
NSAID induced gastropathy can result from any dose or any frequency intake of NSAID drugs as well as long-term use. These drugs are used to decrease pain and inflammation and are often taken by those diagnosed with osteoarthritis and rheumatoid arthritis or other musculoskeletal conditions. NSAIDs are often prescribed to these individuals, as well as suggested as over the counter (OTC) types of NSAIDs. Because of the easy accessibility of these drugs, the incidence rate of NSAID induced gastropathy is high, especially among individuals who are >60 years. The small and large bowel can also be affected.
NSAID induced gastropathy can result in stomach or duodenal ulcers which may even lead to death. There are thousands of hospitalisations over each year just from symptoms resulting from NSAID use. Though these rates are high, most individuals do not know the risk of these medications and continue to take them. Also, this induced gastropathy goes on asymptomatically until it is too late and has caused further damage of the gastrointestinal tract.
NSAIDs are COX-1 inhibitors which suppress the mucous barrier in the gastrointestinal system which can lead to break down of the GI tract as well as increase in the acidity of the gastric contents.
The mechanism of action and injury of the NSAIDs is caused by interfering with the archidonic acid pathway (prostaglandins).
Gastrointestinal effects of aspirin
Aspirin is being used as an effective analgesic and anti-inflammatory agent at doses >325 mg daily. At low doses (75-325 mg daily), aspirin is the key antiplatelet drug in the pharmacological prevention of cardiovascular diseases.
However, topical and systemic effects of aspirin in the gastrointestinal mucosa are associated with mucosal damage in the upper and lower gastrointestinal tract. The risk of upper gastrointestinal bleeding with aspirin is increased with old age, male sex, ulcer history and concomitant medication with NSAIDs, cyclooxygenase 2 selective inhibitors, corticosteroids or other antithrombotic agents. In some patients, the cardiovascular benefits of low-dose aspirin might be overcome by the risk of gastrointestinal complications, but withdrawal of aspirin therapy can precipitate a cardiovascular event. These patients will need concomitant therapy with antisecretory agents, especially PPIs, to reduce the gastrointestinal risk. Eradication of Helicobacter pylori infection might be an additional option in patients with a history of ulcer. Furthermore, there is growing evidence that long-term use of aspirin decreases the risk of colorectal cancer, even at low doses. As aspirin is one of the most prescribed drugs worldwide and its clinical impact is huge, physicians need to consider the benefits and harms for each individual patient in order to maximise the benefits of aspirin.
Treatment results: RCTs
Omeprazole, the most extensively studied PPI, has a protective effect against NSAID-related mucosal injury. Not unexpectedly, because of its potent acid-inhibiting property, it prevents DU in patients taking NSAIDs. There is evidence that omeprazole also protects against GU. In a crossover, double-blind RCT, 20 normal volunteers were given aspirin 650 mg q.i.d. with either placebo or omeprazole 40 mg/day for 14 days, with endoscopy before and after each treatment period. Omeprazole significantly decreased aspirin-induced gastric mucosal injury (p < 0.01) by protecting 85% of the subjects from extensive erosions or ulcer, whereas 70% of the subjects developed severe injury (rate 3 or 4 on 0–4 scale) on aspirin and placebo. No duodenal injury was seen in any grade or any subject on omeprazole, whereas 50% on placebo developed erosions and 15% had DU (p < 0.001).
Three large RCTs have been carried out in patients with OA and RA comparing omeprazole with placebo, misoprostol, and ranitidine for the prevention of GU and DU. Overall, omeprazole significantly reduced the total number of NSAID-related ulcers when compared with placebo and ranitidine. It was more effective than misoprostol in preventing DU, and equally so in reducing GU. It should be noted that the lowest effective dose of misoprostol was used in this study, and that most of the overall prevention in NSAID-related ulcer in the placebo-controlled studies was due to a reduction in the numbers of duodenal ulcers.
Recently, esomeprazole has been used in RCTs, as it has superiority to omeprazole, in terms of acid inhibition.
PPIs for NSAID-associated symptoms and lesions
A recent review, Effective and safe proton pump inhibitor therapy in acid-related diseases – a position paper addressing benefits and potential harms of acid suppression by Carmelo Scarpignato et al, concludes that PPI therapy reduces upper GI symptoms in NSAID users.
Standard dose PPIs are indicated for patients taking non-selective NSAIDs at risk for upper GI complications (bleeding and perforation) and for those given selective cyclooxygenase (COX-2) inhibitors having had an episode of previous GI bleeding.
“In both non-selective and COX-2 selective NSAID users, PPI therapy reduces upper GI symptoms, in particular dyspepsia. However, NSAID induced adverse events in the lower GI tract are not prevented by PPIs,” the review states.
GI adverse effects are the most common and include a wide clinical spectrum ranging from dyspepsia, heartburn, and abdominal discomfort to more serious events such as PU with life-threatening complications, including bleeding and perforation. Since symptoms are not a reliable indicator of mucosal damage, it is important to identify factors that predict the risk of GI events in NSAID users.
“The risk factors for upper GI bleeding (UGIB) associated with NSAID use has been well defined by several studies. Among them, the most important are prior history of complicated ulcer and age. Older age is common in NSAID users and those aged above 65 years carry a risk similar to those with a history of PU. Advancing age increases the risk by about 4% per year, probably because of the presence of other associated risk factors,” Scarpignato says.
The presence of multiple risk factors greatly increases the risk of GI complications. The role of H. pylori infection in patients taking NSAIDs and the potential benefit of eradication on upper GI risk in infected NSAID users has been controversial. However, eradication of associated H. pylori infection is beneficial when starting treatment with NSAIDs or aspirin, especially in the presence of an ulcer history.
An often forgotten risk factor for upper GI complications is represented by drug combinations with NSAIDs. While the role of steroids, antiplatelet drugs, and anticoagulants is long known, the synergistic effect of selective serotonin reuptake inhibitors (SSRIs) has until recently been overlooked.
Over the past 15 years, several epidemiologic studies, summarised by three recent meta-analyses have shown an association between SSRI use and the occurrence of UGIB, and found that this risk is further increased among patients, who concomitantly use NSAIDs and/or hold H. pylori infection while it is lowered by concomitant PPI intake.
The most plausible mechanisms underlying this detrimental effect include a marked decrease in serotonin platelet content, with consequent impairment of platelet aggregation in response to injury and prolongation of bleeding time as well as an increase in gastric acid secretion, with potential ulcerogenic activity.
“GI symptoms usually develop within the first few days of starting a NSAID therapy and can actually occur with the first dose of the drug. Although some studies have suggested that the first two months of treatment represent the period of greatest risk for complications with a relative risk of 4.5 %, available evidence (from both RCTs and observational studies) shows that the risk of GI complications is constant over time, either during short-term or long-term NSAID use,” the study states.
“Therefore, even a short course of NSAID therapy carries a risk of GI complications similar to that of long-term treatment. As a consequence, prevention strategies should be implemented regardless of the duration of therapy, especially in patients with more than one risk factor.”
PPIs effective in prevention and treatment
All RCTs have shown that PPIs are more effective than H2RAs in both preventing and treating gastroduodenal lesions. The reasons underlying the superiority of this class of antisecretory drugs have been clarified by preclinical and clinical pharmacological studies indicating that degree and duration of acid inhibition are both important factors in determining their efficacy in the prevention of NSAID injury.
“They also reduce upper GI symptoms associated with both COX-2 selective and nonselective NSAID use. Due to the long half-life and entero-hepatic circulation of several NSAIDs, a split dose PPI might be useful; there is, however, no evidence for the clinical usefulness of this regimen. COX-2 selective NSAIDs have an improved upper GI safety profile compared to traditional compounds, as extensively shown in endoscopy and clinical outcome studies,” the review suggests.
The evidence is strong, with consistent reductions in events of about 50% in large RCTs, meta-analyses of RCTs, and large observational studies in clinical practice.
“Among patients with a prior ulcer bleed, treatment with a COX-2 inhibitor or an NSAID plus PPI is still associated with a clinically important risk of recurrent ulcer bleed (some 10%). In these patients, the combination of a PPI and a COX-2 inhibitor reduces the risk of upper GI bleeding compared to that of COX-2 inhibitor alone. A very recent network meta-analysis indeed found that this drug combination represents the best strategy to prevent ulcer complications,” Scarpignato states.
In a nutshell
NSAIDs are an essential part of the therapeutic armamentarium despite their well characterised GI and CV risk profiles. Physicians should not prescribe NSAIDs before taking a careful history and doing a physical examination. When using NSAIDs, cognisance should be taken of age, comorbidities, cardiovascular risks and benefits, as well as GI risks and protection.
Finally, the appropriateness of an NSAID prescription should be emphasised, i.e., to control inflammation and pain, rather than to control pain alone; only then can we hope to limit the expanding NSAID epidemic.
- Effective and safe proton pump inhibitor therapy in acid-related diseases – A position paper addressing benefits and potential harms of acid suppression Carmelo Scarpignato, Luigi Gatta, Angelo Zullo, Corrado Blandizzi, for the SIF-AIGO-FIMMG Group and on behalf of the Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners
- American Journal of Gastroenterology, A guideline for the treatment and prevention of NSAID-induced ulcers, Frank L Lanza, Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology
- Fries, JF, Williams, CA, Bloch, DA, et al. Nonsteroidal anti-inflammatory drug-associated gastropathy: Incidence and risk factor models.
- Gabriel, SE, Jaakkimainen, L, Bombardier, C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis.
- Lanas, A, Serrano, P, Bajador, E, et al. Evidence of aspirin use in both upper and lower gastrointestinal perforation.
- Smalley, WE, Griffin, MR. The risks and costs of upper gastrointestinal disease attributable to NSAIDs.
- Smalley, WE, Griffin, MR, Fought, RL, et al. Excess costs from gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs.