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Rheumatology Advance Access originally published online on July 8, 2008
Rheumatology 2008 47(9):1265-1266; doi:10.1093/rheumatology/ken229
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Safer NSAID strategies: consensus or contentious?

C. J. Hawkey

Wolfson Digestive Diseases Centre, University of Nottingham, Nottingham, UK

Correspondence to: C. J. Hawkey, Wolfson Digestive Diseases Centre, University Hospital, Nottingham, NG7 2UH, UK. E-mail: cj.hawkey{at}nottingham.ac.uk

Helicobacter pylori and NSAIDs, including increasingly aspirin, account for the vast majority of ulcers and ulcer complications of which bleeding is the most common. Whilst a simplistic view would predict that risks would be higher if both causes were present, pharmacological considerations might suggest otherwise. The principal mechanism of NSAID damage involves inhibition of the synthesis of prostaglandins that underlie protective mechanisms—mucosal blood flow, mucus and bicarbonate secretion—that adapt the stomach and duodenum to resist the harmful effects of gastric contents.

Helicobacter pylori acts differently. In the gastric mucosa and at sites of duodenal gastric metaplasia and the duodenum, it subverts host signalling mechanisms and induces a persistent ‘acute’ neutrophilic inflammatory response that may be of adaptive advantage through partial tissue digestion that releases nutrients, but may also thereby be able to cause ulcers. The inflammatory response is accompanied by an enhanced release of prostaglandins, the opposite of the effects of NSAIDs that counteract the inhibition of synthesis by NSAIDs when given to patients infected with H. pylori [1]. Helicobacter pylori still has intrinsic toxicity but the potential in whole or part to abrogate the harmful effects of NSAIDs. This would lead one to predict that results in different patients and populations might vary with outcomes ranging from enhanced to reduced toxicity when NSAIDs are given to H. pylori-positive compared with H. pylori-negative patients.

And so it has proved. The first controlled trial of H. pylori eradication in NSAID users showed no effect of eradication on endoscopic ulcer development [2]. Indeed, in that study and a number of others relating outcome to natural H. pylori status, those infected with the organism healed gastric ulcers faster than those who were H. pylori negative. This probably reflects the well-recognized fact that the potency of proton pump inhibitors (PPIs) is greater in H. pylori-positive than -negative patients [3]. Moreover many, though not all, epidemiological studies found a null effect of H. pylori or even benefit in apparent reductions in risk in positive than negative patients4. For low-dose aspirin the situation may be different. In contrast to non-selective NSAIDs, most ulcers occurring during low-dose aspirin use are H. pylori positive [4], raising the possibility that aspirin via an anti-haemostatic effect causes bleeding in ulcers due to H. pylori. It is possible, though not proven, that eradication alone might protect these patients [5]. The biggest database concerning the effect of H. pylori status on development of ulcers and ulcer complications comes from large randomized studies of NSAIDs vs COX-2 inhibitors (VIGOR [6], CLASS [7], TARGET [8], MEDAL [9]). In these studies, the rate of ulcers and ulcer complications in patients taking non-selective NSAIDs was the same for H. pylori-positive and -negative patients. Subsequent trials investigated patients starting NSAIDs for the first time and suggested that H. pylori eradication was beneficial in such individuals.

In this issue of Rheumatology, Kiltz and colleagues summarize current data and received wisdoms. Like others [10], they find that H. pylori eradication alone is of no benefit in patients already using NSAIDs. In contrast, in three studies of 5 weeks to 6 months duration in patients about to start NSAIDs for the first time, eradication reduced the incidence of endoscopic ulcers [5,11,12]. There are two possible reasons for such a discrepancy. First, there may be a honeymoon period of benefit following H. pylori eradication that is of limited duration. This possibility certainly applies to two of the studies that were of 2 months duration or less [5,11]. However, the demonstration of persistent benefit over 6 months suggests more permanent benefit [12]. If this is so it may be that patients susceptible to the combination of NSAID and H. pylori have higher initial rates of ulcer complications and then stop their treatment leaving an altered population of less susceptible patients in whom H. pylori eradication is of no benefit or possible harm. Such an analysis might explain the differing results of epidemiological studies.

Overall, one can conclude that H. pylori eradication alone is an insufficient strategy for the protection of patients taking non-selective NSAIDs. Even in NSAID-naive patients the rate of ulcer development remains significant. Indeed, in one NSAID-naive study that evaluates it, PPI was numerically the superior strategy [11]. PPI maintenance is currently the mainstay of treatment for patients at significant risk and this raises some interesting intellectual conundrums. It is clear that H. pylori eradication in such patients reduces the effectiveness of acid suppression [13]. Most would argue that H. pylori should still be eradicated on other grounds that relate principally to concerns that it is the main cause of gastric cancer. Whether that is the case in patients taking NSAIDs—which have been clearly shown to reduce gastric cancer risk and specifically in H. pylori-positive patients [14]—remains unclear.

An alternative and complementary strategy is to use a selective cyclo-oxygenase (COX)-2 inhibitor. There has been much irrational discussion of the hazards of these drugs, such that only celecoxib survives worldwide. This is a curious situation given that the toxicities of various, now withdrawn, COX-2 inhibitors on the heart and the liver are shared by various, still available NSAIDs [15–17]. What distinguishes COX-2 inhibitors from NSAIDs is a substantial reduction in the rate of ulcer complications that kill many thousands of patients every year. Indeed, for very high-risk patients a combination of acid suppression and a COX-2 inhibitor is undoubtedly the safest option [18]. Moreover, because they do not interfere with the pharmacodynamic effects of aspirin [19], selective COX-2 inhibitors may have advantages in patients with coronary artery disease making the advice of the European Medicines Agency against use of selective but not non-selective NSAIDs in patients with coronary artery disease capricious at best.

The impact of H. pylori in patients using COX-2 inhibitors remains under-investigated. In theory, because there is little or no NSAID-like intrinsic impact on the stomach, H. pylori eradication should be beneficial in such patients in removing the main drug-independent risks of ulcer disease and possibly obviating the need for acid suppression even in high risk patients. Observational data—for example, the higher rate of ulceration in H. pylori-positive than -negative patients taking selective COX-2 inhibitors (in contrast to NSAID users) in some outcomes studies [7,9]—suggest that this may indeed be so but this deserves further study.

Disclosure statement: C.H. has received research funding and/or honoraria from AstraZeneca, GlaxoSmithKline, Bayer, Novartis, Pfizer and Merck Serono.

References

  1. Hudson N, Balsitis M, Filipowicz B, Hawkey CJ. Effect of Helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non steroidal anti-inflammatory drugs. Gut (1993) 34:748–51.[Abstract/Free Full Text]
  2. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients taking non-steroidal, anti-inflammatory drugs: The HELP NSAIDs Study. Lancet (1998) 352:1016–21.[CrossRef][ISI][Medline]
  3. Labenz J, Tillenburg B, Peitz U, et al. Effect of curing Helicobacter pylori infection on intragastric acidity during treatment with ranitidine in patients with duodenal ulcer. Gut (1997) 41:33–6.[Abstract/Free Full Text]
  4. Stack WA, Atherton JC, Logan RF, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther (2002) 16:497–506.[CrossRef][ISI][Medline]
  5. Chan FKL, Chung SCS, Suen RN, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med (2001) 344:967–73.[Abstract/Free Full Text]
  6. Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis [comment]. Gastroenterology (2002) 123:1006–12.[CrossRef][ISI][Medline]
  7. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. J Am Med Assoc (2000) 284:1247–55.[Abstract/Free Full Text]
  8. Schnitzer TJ, Burmester GR, Mysler E, et al, On behalf of the TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research & Gastrointestinal Event Trial (TARGET), in ulcer complications: randomised controlled trial. Lancet (2004) 364:665–74.[CrossRef][ISI][Medline]
  9. Laine L, Curtis SB, Cryer B, Kaur A, Cannon CP: MEDAL Steering Committee. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet (2007) 369:465–73.[CrossRef][ISI][Medline]
  10. Vergara M, Catalan M, Gisbert JP, Calvet X. Meta-analysis: role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users. Aliment Pharmacol Ther (2005) 21:1411–18.[CrossRef][ISI][Medline]
  11. Labenz J, Blum AL, Bolten WW, et al. Primary prevention of diclofenac associated ulcers and dyspepsia by omeprazole or triple therapy in Helicobacter pylori positive patients: a randomised, double blind, placebo controlled, clinical trial. Gut (2002) 51:329–35.[Abstract/Free Full Text]
  12. Chan FK, To KF, Wu JC, et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet (2002) 359:9–13.[CrossRef][ISI][Medline]
  13. Labenz J, Tillenburg B, Peitz U, et al. Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer. Gastroenterology (1996) 110:725–32.[CrossRef][ISI][Medline]
  14. Chan FK, Wong VW, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet (2007) 369:1621–6.[CrossRef][ISI][Medline]
  15. Jiminez P, Garcia A, Santander S, Piazuelo E. Prevention of cancer in the upper gastrointestinal tract with COX-inhibition. Still an option? Curr Pharm Des (2007) 13:2261–73.[CrossRef][ISI][Medline]
  16. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet (2005) 365:475–81.[ISI][Medline]
  17. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. Br Med J (2006) 332:1302–8.[Abstract/Free Full Text]
  18. Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflamatory drugs. Aliment Pharmacol Ther (2004) 20:373–80.[CrossRef][ISI][Medline]
  19. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. New Engl J Med (2001) 345:1809–17.[Abstract/Free Full Text]
Accepted 19 May 2008


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