This case–control study has shown that use of selective COX‐2 inhibitors has a modest increase in the risk of UGIB due to peptic lesions, which was entirely accounted for by a twofold increase with rofecoxib, whereas no increase was observed with celecoxib. The relative risk of UGIB observed with celecoxib was similar to that observed with paracetamol or the combination of PPIs with NSAIDs. The overall relative risk of UGIB observed with coxib use was lower than estimates of relative risk associated with traditional NSAIDs and lower than that observed with cardioprotective aspirin in clinical practice. It is also important to note that NSAIDs with a long plasma half life had a greater relative risk of UGIB compared with NSAIDs with a short plasma half life, independent of daily dose.
Among traditional NSAIDs, diclofenac, aceclofenac and ibuprofen were associated with the lowest RR of UGIB. Other individual NSAIDs had a higher RR, and our results are consistent with previous reports12,13
showing that piroxicam and ketorolac were the two indivdual NSAIDs associated with the greatest risk of UGIB. It is also worth noting that meloxicam (15 mg/day was the dose used among 70% of controls) had a similar relative risk of UGIB as other common traditional NSAIDs. These observations are of interest as diclofenac and aceclofenac have either little use or are not available in some countries (eg, USA), whereas other NSAIDs such as meloxicam have been increasingly prescribed around the world since the withdrawal of rofecoxib, probably owing to the “false” perception that this drug is safer than other compounds based on a scarcity of data comparing this compound with other NSAIDs in observational studies.
Aspirin was the individual NSAID most commonly used in our study population. This is consistent with a general trend found in other recent studies14,15
and points to several important aspects in clinical practice. The first aspect is that use of “cardioprotective” aspirin is now an important gastrointestinal public health issue accounting for about 15% of all patients with UGIB in our country. The second aspect is that “analgesic” aspirin at doses of
500 mg/day (most of it being over‐the‐counter use), although representing less than one third of all aspirin use, was associated with a similar burden of UGIB as “cardioprotective” aspirin, as use of aspirin at such daily doses resulted in a very high excess risk of UGIB.16,17
This last point is an important finding not sufficiently documented in previous observational studies, suggesting that free availability of analgesic aspirin needs to be re‐evaluated from a clinical standpoint.
Outcome clinical trials have previously shown contradictory results. In Vioxx Gastrointestinal Outcome Research, rofecoxib (50 mg/day) had a reduced incidence of upper gastrointestinal complications when compared with naproxen (500 mg twice daily)3
; however, in the Celecoxib Long‐term Arthritis Safety Study4
the incidence of these events was not statistically different from that observed with standard NSAIDs. Subsequently, a few observational studies have shown that celecoxib use had a reduced risk of gastrointestinal bleeding when compared with non‐aspirin traditional NSAIDs, but there was no agreement regarding the risk of UGIB associated with rofecoxib use.18,19,20
Unlike some of these studies that used computerised databases,18,19
our study evaluated the risk of UGIB associated with the use of coxib, NSAIDs, aspirin and combinations of these drugs as reported by the patient.
Strengths of our study include the large sample size, the use of the organised national healthcare system in Spain, the well‐defined logistics of case ascertainment, the validation of all patients with the original clinical records, and the structured data collection methods of collecting data on prescription and non‐prescription drug consumption. A weakness of our study was the low prevalence of use of some drugs, which precluded a more precise evaluation of the risk of UGIB in several instances, and thus reduces the robustness of some of our findings. Information bias may also be present, especially when analysing information such as duration of treatment or past use. Indeed, our control group may have different drug use from the general population that they aim to represent, but overall our data agree with previous reports from the same country.20,21
We carried out sensitivity analyses using different subgroups of controls and found that the results and conclusions were robust between them. Finally, most previous hospital‐based studies used the day of admission as the index date among cases to ascertain the exposure status. We assigned the index date as the date of the first objective sign of UGIB among cases. As expected, the use of the hospitalisation date would have overestimated the risk associated with drugs used commonly as short‐term analgesic treatment (data not shown).
Randomised controlled studies4,5
have shown that high‐dose coxib treatment combined with low‐dose aspirin had a similar incidence of upper gastrointestinal complications as that observed with a high dose of traditional NSAIDs and low‐dose aspirin. We have now documented that combining cardioprotective aspirin, either with traditional standard doses of NSAIDs or with coxibs, potentiates the risk of UGIB beyond that expected from a simple additive effect of these agents. This observation supports the hypothesis that some of the benefits of coxibs in the gastrointestinal tract are due to their lack of any clinical antiplatelet effect, and that when combined with antiplatelet agents, coxibs lose their safety advantage over traditional NSAIDs. However, the magnitude of interaction between cardioprotective aspirin and NSAIDs may be different with different NSAIDs.22
Here, we reported that concurrent use of diclofenac with low‐dose aspirin presented the lowest RR of UGIB among patients taking low‐dose aspirin and traditional NSAIDs. Therefore, it is possible that a similar finding could be observed with individual COX‐2 selective inhibitors (celecoxib v
rofecoxib), but the limited exposure of our study population to concurrent cardioprotective aspirin and individual coxibs prevented this analysis.
We also found that use of non‐aspirin antiplatelet agents did not have a lower risk of UGIB than low‐dose cardioprotective aspirin. Furthermore, concurrent use of non‐aspirin antiplatelet agents with traditional NSAIDs also potentiated the risk of UGIB, supporting the hypothesis that the antiplatelet effect of low‐dose aspirin is the main mechanism associated with its increased risk of UGIB. It also agrees with our finding that there were more patients with bleeding duodenal than gastric ulcers, suggesting that H pylori
‐induced duodenal ulcers may be pre‐existing lesions in many patients who bled with the addition of antiplatelet agents.23
These data complement recent reports from a small study that found that in high‐risk patients, clopidogrel treatment had a higher incidence of UGIB than the combination of low‐dose aspirin with esomeprazole.24
It is also important to note that the increasingly used combination of clopidogrel and low‐dose aspirin25
presented a greatly increased risk of UGIB in our study. Finally, we have found that the use of oral anticoagulants was an independent risk factor for UGIB and that in combination with NSAIDs the risk is further potentiated.
Finally, our study found that the RR associated with NSAID use varied according to whether peptic ulcer history was present or not, which was the main independent risk factor of UGIB. The presence of this major risk factor reduces the effect of other risk factors (eg, negative interaction with NSAID use) and explains why the estimate of RR of UGIB for NSAID use in patients with ulcer history was lower than that observed in patients without ulcer history as already found in previous studies.26
Notwithstanding, it should be remembered that the baseline incidence of ulcer bleeding is much higher in patients with ulcer history than among patients without peptic ulcer antecedents1,24
and consequently patients with ulcer history have a greater excess risk due to NSAIDs despite a relatively smaller RR associated with its use.
In summary, our data provide an additional basis to assess the relative gastrointestinal safety of various anti‐inflammatory drugs. Now that use of coxibs and some traditional NSAIDs has been shown to have an increased risk of serious cardiovascular events,6,7,8,9
all risks and benefits with the use of traditional NSAIDs and coxibs need to be thoroughly re‐evaluated. The small increased risk of developing UGIB either with coxib use or with a combination of PPI with traditional NSAIDs found in this study suggests that they may be used preferentially when the main objective is to reduce the risk of gastrointestinal complications. On the other hand, a large proportion of patients with cardiovascular risk factors will be taking low‐dose aspirin and our study indicates that the gastrointestinal advantage of coxibs tend to disappear in these patients. Together with the modest increase in cardiovascular events6,7,8,9
observed with coxibs and some traditional NSAIDs, special caution would be desirable when using these agents in such a population until more data are available. Our data also suggest that non‐aspirin antiplatelet drug use alone or combined with traditional NSAIDs should not be considered a safer alternative to low‐dose cardioprotective aspirin alone or in combination with NSAIDs, respectively.