J. L. Goldstein et al. the evaluation of GI toxicity in NSAID users. Presum- ably, this assumes a decrease in haemoglobin of ‡2 g ⁄ dL is reﬂective of overt or occult blood loss and represents a level of decline that is clinically meaningful and could prompt physicians to intervene with new clinical deci- sions and ⁄ or interventions. While we believe that such decreases in haemoglobin can impact clinical care, adverse outcomes potentially attributed to declines in haemoglobin are not captured in either study. Based on these considerations, this practical end point has previously been utilised as an important outcome in a number of large GI outcome trials evaluating NSAID-associated toxicity such as VIGOR (Vioxx Gastro- intestinal Outcomes Research),4 CLASS,8 TARGET (Therapeutic Arthritis Research and Gastrointestinal Event Trial)6 and MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term).5 Moreover, the direct clinical relevance of this end point and, notably the development of anaemia, are further supported in the lit- erature as being associated with a signiﬁcant increased risk of recurrent falls, hospitalisations and mortality, par- ticularly in older adults.19–22 In addition, anaemia or occult blood loss may result in diminished physical per- formance and a lesser quality of life.23–25 Low haemoglo- bin levels are now recognised as an important issue that affects a number of clinical patient outcomes – in partic- ular, the clinical impact of anaemia in the elderly popu- lation has been clearly documented.19–22 Both the CLASS (conducted from 1998–2000) and CONDOR (conducted from 2005–2009) trials were designed to assess NSAID-related damage in the GI tract in patients with undeﬁned or increased GI risk, respectively. However, there were a number of differ- ences between the two trials that potentially affected the ﬁndings (Table 1). One of the key differences was that in CLASS patients were randomised to diclofenac alone whereas, in CONDOR patients in the comparator group were randomised to diclofenac SR plus a PPI (omepra- zole 20 mg o.d.). While the addition of a PPI in the CONDOR trial would be expected to reduce the impact of diclofenac on the upper GI tract with little or no effect in the lower GI tract, the rate of deﬁned upper GI events was still higher in the diclofenac plus PPI arm than in the celecoxib arm.16 However, overall the rate of upper GI events was relatively small and thus, we believe the majority of the meaningful blood loss end points were not driven by any small differences in upper GI outcomes but instead are likely to reﬂect small bowel occult blood loss over time with continuous NSAID exposure. Presumably this differential rate might 814 be reﬂected by the differences in injury patterns in the small bowel following use of nonselective and COX-2 selective NSAIDs.12, 13, 26 In the development of this post hoc analysis, differ- ences in the design of the two clinical trials excluded the possibility for a pooled analysis. Patients in the CLASS trial were on average younger than those in the CON- DOR trial [mean age 59.1 years ( s.d. 6.9) vs. 66.4 years ( s.d. 6.9), respectively], reﬂecting an increased level of GI risk for patients in the CONDOR trial. There were also differences in the dosing of medications between the two trials; in the CLASS trial a higher dose of celecoxib 400 mg b.d. was used compared with celecoxib 200 mg b.d. in the CONDOR trial. In addition, as this was a non-US trial and diclofenac SR is one of the most popu- lar NSAIDs used outside the United States, this formula- tion was used in the CONDOR trial. However, it is theoretically possible that the diclofenac SR formulation used in the CONDOR trial may have been associated with a differing degree or location of intestinal injury as compared to the diclofenac formulation in the CLASS trial, although there is a lack of any head-to-head com- parisons between the two formulations in the literature regarding small bowel injury. Furthermore, in the CLASS trial both H. pylori positive and negative patients were included in the analy- sis, whereas in CONDOR patients who tested positive for H. pylori were excluded from the study (unless they were speciﬁcally treated for their infection and subse- quently tested negative). As seen in Figure 1, over the ﬁrst 6 months of the CLASS and CONDOR trials the frequency of scheduled laboratory evaluations differed. While CLASS subjects had three evaluations after base- line, in the CONDOR trial there were four post-baseline evaluations scheduled. As such the frequency of labora- tory evaluations might have inﬂuenced the rate of events observed in the CONDOR trial as compared with CLASS (Figure 3a,b). We made several speculations in the analysis of these data. While we believe the reported haemoglobin changes are due to GI blood loss, we have no data regarding occult blood loss to prove this is true. Moreover, there were also patients embedded in the population who had other reasons for the decrease in haemoglobin seen over time. Of those cases reaching the predeﬁned ‡2 g ⁄ dL decrease in haemoglobin component of the primary end point in the CONDOR population, 32% of patients were adjudicated as having a non-GI aetiology due to other causes (e.g. ﬂare of their underlying rheumatological disorder). Aliment Pharmacol Ther 2011; 34: 808–816 ª 2011 Blackwell Publishing Ltd