A review of the gastrointestinal safety data--a gastroenterologist's perspective

Abstract

Although NSAIDs have a well-established place for certain indications in the management of OA and RA, they are associated with significant gastrointestinal (GI) toxicity. The risk of NSAID-related upper GI events, such as dyspepsia or peptic ulcer and complications such as perforation or bleeding, is well characterized. Non-selective NSAIDs increase the risk of peptic ulcer disease approximately 5-fold, and that of upper GI bleeding 4-fold, whereas selective cyclo-oxygenase-2 (COX) inhibitors are associated with a significantly lower GI toxicity than non-selective agents. There is evidence that, while the incidence of NSAID-related upper GI complications has decreased in recent years, that of lower GI complications is increasing. Observational studies and analyses from studies, primarily designed to investigate upper GI events, suggest that lower GI complications are relatively common in NSAID users and that COX-2 selective inhibitors are associated with a lower risk of these events. Such events have been poorly characterized, but are associated with significant mortality; indeed, they may have even more serious consequences than the better characterized upper GI events. There is thus a strong case for evaluating the impact of such complications in prospective outcome studies. To facilitate such studies a new endpoint, Clinically Significant Upper or Lower GI Events, has been introduced that captures both upper and lower GI events.

Fig. 1

Total number of GI complications per year (a) and estimated incidence of GI complications (per 100 000 person-years) (b) in Spain, 1996–2005 [12]. Reproduced from Lanas et al. [11].

Fig. 2

Risk factors for upper GI bleeding associated with NSAID use [13–15]. Adapted from Pérez Gutthann et al. [13], Huang et al. [14] and Lanas et al. [15].

Fig. 3

Kaplan–Meier plot showing the risk of recurrent ulcer bleeding in 287 arthritis patients treated for 6 months with either diclofenac, 75 mg twice daily, plus omeprazole, 20 mg twice daily, or celecoxib, 200 mg twice daily [23]. Reproduced with permission from Chan et al. [23]. Copyright © 2002 Massachusetts Medical Soceity. All rights reserved.

Fig. 4

Incidence of small bowel mucosal breaks, assessed by video capsule endoscopy, in two randomized, placebo-controlled studies comparing celecoxib, 200 mg twice daily, with the combination of a non-selective NSAID and omeprazole in healthy volunteers [32, 33]. Reproduced from Goldstein et al. [32] with permission from the American Gastroenterological Association and Goldstein et al. [33] with permission from Wiley-Blackwell.

Fig. 5

Unadjusted mortality over 11.2 years, according to haemoglobin concentration quintiles, in the Cardiovascular Health Study [43]. Reproduced with permission from Zakai et al. [43]. Copyright © 2005 American Medical Association. All rights reserved.