Our findings suggest a lower risk of upper gastrointestinal haemorrhage associated with use of selective COX 2 inhibitors than with conventional, non-selective NSAIDs. The rate of haemorrhage with celecoxib was similar to that among the control group not using NSAIDs. While the risk of haemorrhage with rofecoxib was significantly lower than that with non-selective NSAIDs, it was significantly higher than that with celecoxib.
Although we attempted to control for many important confounders, we were unable to account for some potentially important factors such as smoking and alcohol consumption. The distribution of such factors among the different groups studied and the consequent influences on our findings is unknown. However, despite a potentially heavier disease burden among the patients using rofecoxib and celecoxib (as a result of the limited use of selective COX 2 inhibitors licensed in Ontario), they had lower risk ratios than the patients using non-selective NSAIDs. Our population based incidence estimates for upper gastrointestinal haemorrhage (table ) among the controls and non-selective NSAID group are also consistent with those of other studies,8,20
as are our relative risks.7–10
In addition, when we analysed results among both users and non-users of gastroprotective agents, we still found lower adjusted relative risks for upper gastrointestinal haemorrhage for users of selective COX 2 inhibitors than among non-selective NSAID users. Users of gastroprotective agents had a higher incidence of upper gastrointestinal haemorrhage than subjects in their respective groups not dispensed gastroprotective agents. This implies that these agents were selectively prescribed to those at higher risk of upper gastrointestinal haemorrhage and were a marker for underlying gastrointestinal disease associated with a higher risk of upper gastrointestinal haemorrhage.
A second limitation is that we used administrative databases to identify and define exposure to study drugs and clinical outcomes. We have no direct measure of adherence or appropriateness of use. Since NSAIDs may be used in varying doses over time for symptom control, dose equivalence of the various drugs could not be adequately examined with these data. Instead, the NSAIDs were examined as they are commonly used in this population.
We were unable to identify use of non-prescription NSAIDs. However, ibuprofen and aspirin are the only non-prescription non-selective NSAIDs available in Canada, and subjects in our study have a strong financial incentive to obtain these drugs by prescription, especially with regular use. Over a quarter of the elderly subjects were given a NSAID during the observation period, consistent with previous studies examining the use of prescription and non-prescription NSAIDs among elderly people.2,3
This implies that the vast majority of NSAID use in our population is probably captured by our databases. The use of non-prescription aspirin is perhaps the biggest problem, but since the distribution of prescription aspirin use was similar in the study drug groups, the use of non-prescription aspirin is also likely to be equally distributed.
We identified outcomes using diagnostic codes that have been validated previously, but we were unable to capture other important information such as the severity of the gastrointestinal haemorrhage and more subtle outcomes such as non-bleeding ulcers. Also, it is possible that upper gastrointestinal haemorrhage is more readily diagnosed or reported among users of traditional NSAIDs than among users of specific COX 2 inhibitors. However, the diagnosis is not generally difficult to make, its coding has been validated, and the impact of this potential bias is likely minimal.
The low absolute number of events in the study groups precluded reliable subgroup analyses such as comparisons among users of anticoagulants or individual NSAIDs, and the generalisability of our findings to younger patients or settings with different drug policies over longer periods of follow up is uncertain.
Relative gastrointestinal safety of rofecoxib and celecoxib
Currently, comparisons between rofecoxib and celecoxib are based largely on data from clinical trials and studies of whole blood assays. Two large randomised trials separately comparing rofecoxib12
with non-selective NSAIDs provided similar relative risk reductions of 40-60% in the incidence of clinical upper gastrointestinal haemorrhage events (that is, upper gastrointestinal haemorrhage ulcer complications plus symptomatic ulcers). However, valid comparisons of upper gastrointestinal haemorrhage event rates between rofecoxib and celecoxib cannot be made from such data for several reasons. Firstly, in the absence of a direct comparison, conclusions about the relative gastrointestinal safety of these drugs are largely speculative. Secondly, the primary endpoints of the two trials were slightly different. Thirdly, the comparator groups, using non-selective NSAIDs, in the two trials were different: the non-selective NSAIDs assessed in the celecoxib trial were either ibuprofen or diclofenac, whereas naproxen was assessed in the rofecoxib study. Since naproxen is probably more gastrotoxic than ibuprofen or diclofenac,11
it is difficult to assess the relative gastrointestinal safety of rofecoxib and celecoxib from these two trials. Fourthly, the interpretation of the celecoxib trial is complicated by the nature of its reporting.21
The findings were based on a combined analysis of the first six months of two separate and longer trials whose protocols differed substantially from the published paper in design, outcomes, duration of follow up, and analysis. Although 12 month data revealed no significant differences between celecoxib and its non-selective NSAID comparators with respect to complicated ulcer outcomes (the primary endpoint of the trials), the incidence of clinical upper gastrointestinal haemorrhage events remained significantly different.22
Our understanding of the cellular effects of the COX 2 inhibitors is also evolving, and conclusions about the relative safety of these agents based on in vitro data may be premature. For example, although whole blood assay studies suggest that rofecoxib is more COX 2 selective than celecoxib,23
such assays have been criticised for having limited clinical relevance.24
Furthermore, recent studies of cancer cell lines have shown what may be COX independent differences in antiproliferative activity between celecoxib and rofecoxib.25–27
The clinical implications of such differences for the gastrointestinal safety of these two drugs are not known.
Our evaluation represents the first direct comparison of rofecoxib and celecoxib for a clinically meaningful gastrointestinal outcome using common comparator groups over the same period, with data reflecting clinical practice. The demographic characteristics of rofecoxib and celecoxib users were strikingly similar in our study, implying that selection of one COX 2 inhibitor over another is probably arbitrary in clinical practice. Therefore, the differences in unobserved covariates between the rofecoxib and celecoxib groups are probably minimal and would not explain the difference in upper gastrointestinal haemorrhage observed between the two drugs.
Our study found lower rates of upper gastrointestinal haemorrhage with selective COX 2 inhibitors than with non-selective NSAIDs. The significantly higher rate of upper gastrointestinal haemorrhage among users of rofecoxib than users of celecoxib was unexpected. Although the absolute difference in rates of upper gastrointestinal haemorrhage was small, the difference, if true, is clinically important given the large numbers of patients prescribed selective COX 2 inhibitors. Large randomised controlled trials directly comparing the drugs are urgently needed to better examine these differences.