Reducing the Gastrointestinal Risks of Low-Dose Aspirin
Article Outline
See “Famotidine is inferior to pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions,” by Ng F–H, Wong S–Y, Lam K–F, et al, on page 82.
Aspirin is probably the most commonly used nonsteroidal anti-inflammatory drug (NSAID) because an increasing number of adults are being encouraged to take this medication.1, 2 The use of low-dose daily aspirin, typically in the range of 75–325 mg/d, continues to rise as a result of increasing evidence of its benefits in primary and secondary prevention of cardiovascular events.3 Aspirin's effectiveness in disease prevention, however, is limited by its risks of gastrointestinal (GI) complications such as ulceration and GI bleeding. In the general population, aspirin increases the risk of major GI bleeding by about 2-fold, a consistent estimate of risk observed across several studies of patients at low to average risk for aspirin-related GI complications.4 Even at a dose as low as 75 mg/d, the risk of upper GI bleeding is 2 times higher than among nonusers5 and no clinically effective dose of aspirin is free of bleeding risk; doses as low as 10 mg cause gastric ulceration.6
Aspirin's 2-fold increase in risk in middle-aged users with no prior history of peptic ulcer and no concomitant medications substantially underestimates its actual bleeding risks in higher risk patients such as those with a prior history of peptic ulcer disease, advanced age, and concomitant use of NSAIDs, corticosteroids, clopidogrel, or anticoagulants. Among these factors, a history of prior complicated ulcer is the strongest predictor of aspirin's risks of GI complications7 because 15% of aspirin users with a prior history of bleeding ulcers have recurrent GI bleeding by 1 year.8 Thus, secondary prevention of GI bleeding in this very high-risk group of aspirin users is a worthwhile clinical goal.
Mechanisms of aspirin-induced GI injury are due to local effects within the GI mucosa that cause topical mucosal injury and to systemic effects mediated through depletion of protective GI mucosal prostaglandins through cyclo-oxygenase inhibition. As newer data become available, it is becoming increasingly apparent that local components of mucosal injury are important mechanistic contributors to the GI consequences of aspirin. Maintenance of mucosal blood flow, gastroduodenal mucus and bicarbonate secretion, inhibition, epithelial proliferation, and surface membrane phospholipids are all local mechanisms that are important contributors to aspirin-related GI injury.9
Numerous developmental programs are currently underway which target local mechanisms of gastroduodenal defense as strategies to reduce aspirin's GI risk. One of these locally focused strategies is to reduce gastric acid secretion with either a H2-receptor antagonist (H2-RA) or a proton pump inhibitor (PPI) concomitantly delivered along with aspirin, either as fixed-dose combinations of the protective strategy plus aspirin or as separately delivered medications. GI mucosal homeostasis is maintained by a balance of aggressive factors such as acid and pepsin and protective factors such as mucus, bicarbonate, and surface-active phospholipids. As mucosal surface protection is reduced or disrupted by aspirin, the gastroduodenal mucosa becomes more susceptible to injury by acid peptic activity. Therefore, a conceptually attractive strategy to counter reductions in mucosal defenses that result after aspirin challenge is to reestablish mucosal homeostasis by also reducing acid peptic activity to the level of the reduced mucosal protection.
Several experimental data have tested this hypothesis that fortification of local mucosal defenses is an effective strategy to mitigate GI mucosal injury with aspirin. Animal studies suggest that local effects, such as gastric acid secretion and disruption of the gastric barrier to acid, are important components of aspirin-induced gastropathy.9, 10, 11 In clinical trials of patients at high risk for aspirin-induced ulcers, eradication of Helicobacter pylori12 and long-term maintenance therapy with PPIs achieve statistically significant reductions in endoscopic ulcers13 and recurrent bleeding GI ulcers.8 Clinical trial data indicate also that H2-RAs effectively reduce gastroduodenal ulcers with low-dose aspirin by 80%.14 In summary, available data suggest that reduction of gastric acid secretion, with either a PPI or a H2-RA, successfully diminishes GI mucosal injury with low-dose aspirin, a viewpoint that represents a shift in conventional wisdom regarding protection against NSAID-associated injury. Most prior studies have shown that H2-RAs were insufficient therapies to protect against NSAID-induced injury, at least at usual ulcer-healing doses of H2-RAs. Apparently, by increasing the dose of H2-RA to higher than usual doses or by decreasing the NSAID dose to ranges seen with low-dose aspirin, the equilibrium for mucosal homeostasis between acid peptic activity and mucosal defense is reestablished to render acceptable levels of protection.
An important issue not addressed by previously available clinical studies is whether cotherapy with an H2-RA is as effective of a strategy as PPIs to reduce aspirin's GI injury. Although at first glance this question may seem to have been a foregone conclusion, the answer is not as straight forward as it may seem on the surface. When extrapolating from other clinical targets such as in the treatment of esophagitis, many would assume that use of a PPI would be a more effective strategy than use of a H2-RA.15 However, in the management of NSAID-induced GI injury, larger doses of PPIs have paradoxically not been more effective than lower PPI doses in prevention or healing of NSAID-induced GI injury as observed across a number of trials.16, 17, 18 In fact, the incidence NSAID-induced ulcers is paradoxically numerically increased in patients administered the higher PPI doses.16, 17 NSAID-induced GI injury is dose related, with higher doses of NSAIDs rendering greater amounts of GI damage. For the prevention of ulcers with high-dose NSAIDS, a PPI is more effective than regular doses of H2-RAs.18 However, with lower doses of NSAIDs, such as with aspirin in the 75–325 mg/d range, effective mucosal protection might be easily achieved with lesser degrees of gastric acid inhibition. In fact, the FAMOUS trial demonstrated that 20 mg twice daily of the H2-RA, famotidine, when compared with placebo, significantly reduces endoscopic ulcers after 3 months of low-dose daily aspirin in an average-risk population that was not enriched with patients at high risk for GI complications with aspirin.14 Thus, low daily dosages of aspirin may not require the greatest achievable degree of gastric acid inhibition to reduce GI ulcers to a desirable range.
Given that >1 acid inhibitory strategy might be reasonably employed, an important but yet unanswered question is how a H2-RA might compare with a PPI for prevention of gastroduodenal ulcers with low-dose daily aspirin in a patient population at higher risk of GI complications. In this issue of Gastroenterology, Ng et al19 compare the efficacy of high-dose famotidine and a PPI in the prevention of gastroduodenal ulcers in patients at relatively high risk for development of aspirin-related ulcers. This study evaluated higher GI risk patients by recruiting 160 patients who presented with dyspepsia or upper GI bleeding and in whom a baseline endoscopy revealed either a gastric or duodenal ulcer or greater than five erosions. After mucosal healing and eradication of H pylori, if present, patients were randomized to either high-dose famotidine (40 mg twice daily) or pantoprazole (20 mg daily) while receiving aspirin at a dose of 80 mg/d and were followed for 48 weeks with a primary study end point of recurrent dyspeptic or bleeding ulcers/erosions. Among low-dose aspirin patients treated with high-dose famotidine, recurrent symptomatic or bleeding ulcers/erosions were observed in 20% and were not seen in any pantoprazole-treated patient, a highly significant difference. Although this study was not designed as an outcomes trial, GI bleeding was significantly more common in those receiving high-dose famotidine (7.7%), but did not occur in any PPI-treated patient.
Considering that PPI treatment was so much more effective than high-dose H2-RA in the prevention of recurrent ulcers in this current study, it seems reasonable to conclude that in high GI risk patients taking aspirin, such as those with a history of peptic ulcers, PPI cotherapy seems to be the preferred strategy. However, it is not known whether the superiority of the PPI strategy extends to average GI risk patients taking aspirin, a patient population in which H2-RAs have been shown recently to be an acceptable approach.14 An important observation from Ng et al's study19 is that all patients who presented with recurrent GI bleeding were asymptomatic before their bleed. GI bleeding not preceded by symptoms is a key clinical characteristic of aspirin and NSAIDS use, which has been consistently observed across previous trials. Another interesting finding in this trial is that 60% of the events characterized as GI bleeds were defined by a fall in hemoglobin of >2 g/dL. GI bleeding characterized by asymptomatic falls in blood counts is an increasingly prevalent characteristic of patients defined to have a GI bleeding event in recent NSAID trials and represents a major shift in the study end point from trials in the not too distant past in which GI events were largely defined by clinically apparent GI bleeding and perforations.
A potential limitation of the current study is that endoscopic ulceration rather than clinical events such as GI bleeding mostly characterized its primary end point. Whether endoscopically assessed ulcers are appropriate end points to assess strategies designed to reduce GI risks with NSAIDs is under active debate.20, 21, 22, 23 Many prior studies evaluating prevention of NSAID-induced ulcers have used endoscopic ulcers as surrogates for clinical GI events. It has been argued that there is a biological progression from lesser to more severe disease with NSAID adverse events, from endoscopic erosions and asymptomatic ulcers, to symptomatic ulcers, to ulcer complications.22, 23 Endoscopic ulcers may represent an early step in the biological progression from mucosal injury to symptomatic ulcer and ulcer complications. Furthermore, substantial evidence from meta-analyses of clinical trials, outcomes trials, and observational studies indicate consistent and reproducible effects that parallel endoscopic observations, which strongly argues that endoscopic ulcers predict clinical consequences with NSAIDs.21 In addition to aspirin's ulcer-inducing properties, it has antiplatelet effects, which might aggravate the bleeding potential of underlying asymptomatic GI mucosal lesions. Therefore, in the context of low-dose aspirin, the argument that endoscopic ulcers predict outcomes is not as strong as with nonaspirin NSAIDS, but is nevertheless the current standard for the evaluation of NSAID and aspirin ulcer prevention used in the US by the Food and Drug Administration. This study's finding that PPIs are more effective than H2-RAs for prevention of aspirin-induced GI injury is consistent with recent data from an observational study comparing rates of GI bleeding with various protective strategies (Figure 1).24 The consistency of observations with endoscopic ulcers in the current study by Ng et al19 and GI bleeding in the observational study strengthens further the argument that endoscopic ulceration predicts clinically important GI events with low-dose aspirin.
Figure 1.
Comparison of strategies for prevention of upper gastrointestinal (GI) bleeding with aspirin. The adjusted relative risks (and 95% confidence intervals) of hospitalizations for upper GI bleeding in Spain are presented in this case-control study of 2777 cases of patients with upper GI bleeding and 5532 controls without bleeding. The relative-risks of upper GI bleeding with nitrates, H2-receptor antagonists, and proton pump inhibitors are shown compared with bleeding rates associated with aspirin without cotherapy. (Figure constructed using data presented in Lanas et al.24)
There are several strategies in the pharmaceutical pipeline which are currently being developed to reduce NSAID-associated GI injury. In our evaluation of these strategies, important questions to be decided by clinicians in the near future will be issues such as the preferred agent to reduce aspirin's GI risks based on the clinical scenario and the target patient population in which risk reduction might be used. Lessons learned from prior observations indicate that the answers to these questions are likely to vary based on the clinical context and by our patients' GI and cardiovascular risks.3 Although the answers to many of these issues with nonaspirin NSAIDS continue to remain unsettled, when considering GI risk reduction with low-dose aspirin, the current trial by Ng et al19 makes an important step toward informing our management decisions, at least when the comparison is conducted using endoscopic ulcers as the end point. However, because aspirin has the unique characteristic of being an antiplatelet agent as well as an ulcerogenic agent, prevention of endoscopic ulceration after aspirin therapy may not necessarily predict reductions in clinically apparent GI bleeding. Therefore, before we seal the conclusion that a PPI is a better strategy for prevention of GI events with low-dose aspirin, comparative data of PPI and other developmental strategies as well as outcomes data from trials evaluating clinically important events such as GI bleeding and symptomatic ulcers would be desirable.
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Conflicts of interest The author discloses the following: he has current consulting relationships with AstraZeneca, Inc, Horizon Therapeutics, McNeil Consumer Products, NiCox Inc, PLx Pharma, Pfizer Inc. and POZEN, Inc. and that he has received current research grants from PLx Pharma and Pfizer Inc.
PII: S0016-5085(09)02049-6
doi:10.1053/j.gastro.2009.11.032
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Refers to article:
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Famotidine Is Inferior to Pantoprazole in Preventing Recurrence of Aspirin-Related Peptic Ulcers or Erosions
, 19 October 2009
