INTRODUCTION Nonsteroidal anti-inﬂammatory drugs (NSAIDs) are among the most widely prescribed class of drugs world- wide1 because of their anti-inﬂammatory, anti-pyretic and analgesic properties. However, despite their well- accepted efﬁcacy, chronic use of NSAIDs is associated with an increased risk of gastrointestinal (GI) mucosal injury and overt bleeding events.2, 3 Previous prospective, randomised outcome studies have focused primarily on GI events in the upper GI tract4–9 but recent evidence has shown that injury to the small bowel and colon during chronic NSAID use can lead to mucosal damage, ulceration, overt bleeding, obstruc- tion ⁄ perforation, protein-loss and occult blood loss (with an associated decrease in haemoglobin).2, 10–15 Extending the understanding of small bowel and colonic injury asso- ciated with NSAID use, the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheuma- toid Arthritis (RA) Patients (CONDOR) trial was a prospective randomised outcome trial of 6 months dura- tion that utilised a novel comprehensive composite pri- mary end point of both upper and lower GI events, including clinically signiﬁcant decreases in haemoglobin (‡2 g ⁄ dL).16, 17 In CONDOR the authors reported that the risk of the adjudicated composite primary end point for clinically signiﬁcant outcomes throughout the GI tract was lower in patients treated with a cyclo-oxygenase (COX)-2-selective NSAID than in those receiving a nonse- lective NSAID plus a proton pump inhibitor (PPI). Nota- bly, the difference between the two treatment arms for the primary end point of this trial appeared to be driven by one of the components of the composite end point, the number of patients reaching the predeﬁned cut-off point for a decrease in haemoglobin (‡2 g ⁄ dL) and ⁄ or haemato- crit (‡10%) over the time of exposure to drug. Like the CONDOR trial, the Celecoxib Long-Term Arthritis Safety Study (CLASS)8 was a large prospective randomised, double-blind trial with patients followed for up to 15 months evaluating GI outcomes using celecoxib and nonselective NSAIDs for the treatment of patients with arthritis. As haemoglobin values were collected sequentially over time in both trials, we identiﬁed an opportunity to evaluate changes in haemoglobin values in these two independent trials. We hypothesised that the pattern of haemoglobin decreases (presumably asso- ciated with chronic gross or occult blood loss) may be similar between the trials. Thus, in these two studies and in a non-aspirin using population, we evaluated and compared the incidence and time to event for a mean- ingful end point deﬁned by a decrease in haemoglobin of Aliment Pharmacol Ther 2011; 34: 808–816 ª 2011 Blackwell Publishing Ltd Haemoglobin decreases in NSAID users ‡2 g ⁄ dL18 after 6 months. To ensure the focus of our results would better reﬂect clinical practice we also anal- ysed patients in whom the ‡2 g ⁄ dL decrease in haemo- globin led to laboratory-deﬁned anaemia (deﬁned as a haemoglobin level £11.5 g ⁄ dL). MATERIALS AND METHODS Study designs The CLASS trial was a double-blind, prospective, rando- mised clinical trial conducted in patients with OA and RA in North America. Patients were enrolled based on the judgement of the local principal investigator regard- less of the patients’ baseline GI risk for an NSAID-associ- ated complication. A total of 8059 patients were enrolled and 7968 randomised in a 2:1:1 ratio to receive oral celec- oxib 400 mg b.d. (Pﬁzer Inc, New York, NY, USA), ibu- profen 800 mg t.d.s. (G.D. Searle & Co., Skokie, IL, USA), or diclofenac 75 mg b.d. (G.D. Searle & Co.) for up to 15 months (Figure 1a). Aspirin use for cardiovascular (CV) prophylaxis was allowed (£325 mg ⁄ day) in this trial. The primary end point was the incidence of predeﬁned adjudicated upper GI events as previously reported.8 In comparison, the CONDOR trial (NCT00141102) was a double-blind, triple-dummy, randomised, parallel-group, multicentre, international study comparing treatment with celecoxib (Pﬁzer Inc) alone versus diclofenac sus- tained release (SR) (Novartis Pharmaceuticals UK, Cam- berley, Surrey, UK) plus omeprazole (AstraZeneca LP, Wilmington, DE, USA) in patients with OA and ⁄ or RA at increased risk of GI adverse events. A total of 4484 patients were enrolled and randomised in a 1:1 ratio to receive either oral celecoxib 200 mg b.d. or diclofenac SR 75 mg b.d. plus omeprazole 20 mg o.d. for 6 months (Figure 1b). No aspirin use was allowed in this trial. The primary end point was the incidence of a predeﬁned comprehensive composite primary end point of both upper and lower GI events, including clinically signiﬁcant decreases in haemoglobin (‡2 g ⁄ dL) and ⁄ or haematocrit (‡10%), as previously reported.16, 17 Study population In the CLASS trial male or female patients aged ‡18 years were eligible for inclusion if they had been diagnosed with OA ⁄ RA for at least 3 months and were expected to require continuous treatment with an NSAID for the duration of the trial; patients who were Helicobacter pylori positive and ⁄ or using aspirin were not excluded from this trial. In the CONDOR trial, male or female patients with OA ⁄ RA who were expected to require daily 809