1Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, 2University of Portsmouth and 3University of Southampton, UK.
Correspondence to:
D. Layton. E-mail: deborah.layton{at}dsru.org
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Abstract |
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Methods. Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996 to March 1997) and celecoxib (May to December 2000). Simple questionnaires requesting details of events occurring during/after treatment and potential risk factors (including age, sex, history of upper GI problems, and NSAIDS prescribed within 3 months of treatment) were posted to prescribing GPs at least 6 months after the first prescription for each patient. Incidence rates of the first event were calculated; crude and adjusted rate ratios (RR) obtained using regression modelling.
Results. For celecoxib and meloxicam, respectively, 1054 (6.0%) and 1376 (7.2%) patients had symptomatic (acid/peptic) upper GI events whereas 42 (0.2%) and 67 (0.4%) had complicated upper GI conditions (perforations/bleeding). A higher proportion of the celecoxib cohort had an indication for osteoarthritis (28.1 vs 23.2%), were female (68.3 vs 67.1%), were aged 60 yr or more (59.5 vs 55.0%), were prescribed NSAIDs within 3 months of starting treatment (49.4 vs 47.9%), and had a past medical history of upper GI conditions (54.7 vs 29.2%) than those prescribed meloxicam. This suggests differential channelling of groups at higher risk of such events on to celecoxib compared with meloxicam. There was no difference between the two drugs in the time to occurrence of either group of event. The RR over the 270-day study period for celecoxib compared with meloxicam were 0.77 (95% CI 0.69, 0.85) and 0.56 (95% CI 0.32, 0.96) for symptomatic (acid/peptic) upper GI events and complicated upper GI conditions (perforations/bleeding), respectively, adjusted for age, age2, sex, indication, medical history of upper GI problems and whether NSAIDs were prescribed within 3 months prior to starting treatment.
Conclusions. This study reports a relative reduction (23%) in the incidence of symptomatic (acid/peptic) GI events, and a relative reduction (44%) in the incidence rate of complicated upper GI conditions (perforations/bleeding) for celecoxib compared with meloxicam.
KEY WORDS: COX-2 selective inhibitors, Celecoxib, Meloxicam, Adverse events, Prescription-event monitoring, Drug safety.
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Introduction |
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The pharmacology of these agents as a group has been discussed previously [2]. Celecoxib (Celebrex®), a NSAID reported to be highly COX-2 selective, was launched in the UK in May 2000. The licensed indication at launch was for symptomatic relief in the treatment of OA and RA. In clinical trials, celecoxib was associated with an equivalent or reduced incidence of GI adverse events and mucosal injury compared with other non-COX selective NSAIDs [37]. Meloxicam (Mobic®), licensed in the UK in December 1996 [8], was indicated for relief of pain and inflammation in rheumatic disease (including RA), for exacerbation of osteoarthritic pain and ankylosing spondylitis at launch. Meloxicam is also considered to be a COX-2 inhibitor [9] with favourable GI tolerability [10], but exhibits dose-dependent COX-1 inhibition at therapeutic doses [11, 12].
The Drug Safety Research Unit (DSRU) provides a post-marketing drug surveillance scheme which monitors the safety of newly marketed drugs during their immediate post-marketing period in England, using the non-interventional observational cohort technique of prescription-event monitoring (PEM) [13]. PEM systematically collects data, in accordance with international guidelines for record-based research [1416], on patients prescribed a drug in real world clinical practice including high-risk groups who may previously have been excluded from controlled trials, and are also likely to be exposed to the newly marketed drug because of the nature of their disease. As part of its monitoring programme, the DSRU has carried out individual PEM studies of meloxicam [17] and celecoxib [unpublished data]. In view of professional and regulatory interest, we undertook a series of studies to examine and compare the GI adverse event profiles of these agents. The first of these studies was conducted using rofecoxib and meloxicam [2]. This paper reports the results of the second set of comparisons; this time between celecoxib and meloxicam.
As for the first study [2], the aim of this study was to investigate retrospectively, using large cohorts from the general population of England, whether there is a clinically relevant difference in the type and incidence of upper GI events reported during routine clinical use in general practice of meloxicam and celecoxib. As before, our objectives were to calculate and compare rates for selected groups of upper GI events occurring within the first 9 months after starting treatment for meloxicam or celecoxib; to calculate rate ratios (RR) separately for symptomatic (acid/peptic) upper GI events, and complicated upper GI conditions (perforations/bleeding) adjusted for possible confounders as identified in the first study: age and sex [18, 19], whether there was a history of upper GI symptoms [20], whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug [20, 21] and whether gastroprotective agents [histamine (H)2 antagonists, proton-pump inhibitors (PPI) or misoprostol] had been prescribed during treatment [22].
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Methods |
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For this study, exposure data were obtained from green forms received for patients identified from NHS prescriptions that were written by GPs in England for meloxicam (N = 19 087) between December 1996 and March 1997 and for celecoxib (N = 17 458) between May 2000 and December 2000. For comparative purposes the exposed are those patients prescribed celecoxib and the unexposed are those patients prescribed meloxicam. As described previously [2], the event terms for this study were selected by medical practitioners from the DSRU dictionary, and aggregated into the two event groups: symptomatic (acid/peptic) upper GI events and complicated upper GI conditions (perforations/bleeding) (Table 1). The data were subject to the same inclusion and exclusion criteria as specified previously [2].
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Analysis
Data analysis was conducted in an identical manner to that described previously [2]. The unadjusted RR, as well as ratios adjusted for selected risk factors (a history of upper GI symptoms, and whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug) plus confounding variables age and sex, were calculated and examined using both univariate and multivariate Poisson regression modelling. For each individual for each event group, the outcome was categorized as a binary variable (first event or non-event). An off-set term of log (time) was fitted in the Poisson models to allow for the different exposure times of individuals. We did not adjust for calendar period. In addition, evidence for effect modification was investigated by first examining stratum-specific RR with homogeneity test results for the univariate analysis, and then by the inclusion of interaction terms within the Poisson regression model with likelihood ratio tests of the null hypothesis of no interaction. The time to first event for each group for each cohort was calculated and examined using the KaplanMeier method and the null hypothesis of no difference tested using the log rank test.
A Microsoft SQL query was used to retrieve data from the DSRU PEM database, followed by analysis using STATA 7.0 (Stata Corporation, College Station, Texas, USA). All records and computer data are stored to maximize patient confidentiality.
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Results |
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Where answers to the additional questions were given, significantly more celecoxib users than meloxicam users had a medical history of upper GI problems [54.7% (7523/13 746) vs 29.2% (4787/16 393), 2 P < 0.0001] and had been prescribed a NSAID within the 3 months prior to starting treatment [49.4% (7006/14 195) vs 48.0% (7978/16 634),
2 P = 0.014]. Cross-tabulation of these two risk factors suggested a strong link between them, overall (
2 P < 0.0001) and when stratified per drug (meloxicam
2 P < 0.0001 and celecoxib
2 P = 0.021). The proportions reporting use of concomitant H2-antagonists/PPIs of each cohort were higher for celecoxib than meloxicam (20.6%, n = 3595 vs 13.4%, n = 2555, respectively,
2 P < 0.001). Conversely, the proportion reporting use of misoprostol within the celecoxib cohort was significantly lower (0.5%, n = 95 vs 6.1%, n = 1170, respectively,
2 P < 0.0001). Since the response to the additional questions regarding concomitant use of misoprostol or H2-antagonists/PPIs was low, the use of gastroprotective drugs was not adjusted for in the multivariate analysis.
The median person-time exposed over the 9-month study period, for patients in whom symptomatic (acid/peptic) upper GI events were reported, was 74 days (interquartile range, IQR, 36 to 270) for celecoxib and 168 days (IQR 37 to 218) for meloxicam. There was a suggestion of a difference in the treatment duration between the two drugs, although not significant at the 5% level (two-sample Wilcoxon rank-sum test P = 0.0586). The corresponding median pte for complicated upper GI conditions (perforations/bleeding) was 79 days (IQR 36 to 270) and 185 days (IQR 38 to 220) for celecoxib and meloxicam, respectively (two-sample Wilcoxon rank-sum test P = 0.1828).
During the 9 months after starting treatment, 1054 (6.0%) and 1376 (7.2%) of patients were reported to have symptomatic (acid/peptic) upper GI events for celecoxib and meloxicam, respectively. In this subset of patients, 50% of these events occurred early after starting treatment with either drug [median 34.5 days (IQR 15, 100) and 30 days (IQR 9, 97), respectively]. Regarding complicated upper GI conditions (perforations/bleeding), 42 (0.2%) and 67 (0.4%) patients were reported to have had such events, for celecoxib and meloxicam, respectively. In this subset of patients, 50% of these events occurred by the third month after starting treatment [median 79.5 days (IQR 16, 161) and 84 days (IQR 28, 141), respectively]. There was no difference in the estimate of time to first event in either the symptomatic (acid/peptic) upper GI event group (log rank test P = 0.6158) or the complicated upper GI conditions (perforations/bleeding) event group (log rank test, P = 0.3012).
Cross-tabulation of risk factors with event groups revealed associations between symptomatic (acid/peptic) upper GI events and age (2 P = 0.001), past medical history of upper GI problems (
2 P < 0.001) and sex (
2 P < 0.001). Conversely, there was only evidence of a significant association between experiencing complicated upper GI conditions (perforations/bleeding) and age (P < 0.0001). A higher proportion of patients who were prescribed celecoxib and who experienced symptomatic (acid/peptic) upper GI events had a medical history of upper GI problems than those prescribed meloxicam [75.1% (665/885) vs 53.5% (660/1233), respectively,
2 P < 0.0001]. Similarly a higher proportion of patients who were prescribed celecoxib, who experienced complicated upper GI conditions (perforations/bleeding), had a past medical history of upper GI problems than those prescribed meloxicam [67.7% (23/34) vs 34.9%(22/63), respectively,
2 P = 0.008]. There was no significant difference between the two cohorts, for either group of GI symptoms, in the number who had been prescribed a NSAID within 3 months prior to starting treatment (
2 P = 0.861 and 0.859, respectively).
A similar proportion of patients from the celecoxib and meloxicam cohorts were reported to have been diagnosed with Helicobacter pylori infection (0.04%, n = 7 and 0.09%, n = 17, respectively, 2 P = 0.068). Overall a higher proportion of patients diagnosed with H. pylori experienced symptomatic (acid/peptic) upper GI events (0.5%, n = 13 vs 0.03%, n = 11,
2 P < 0.0001) than those who did not experience such symptoms. However, no complicated upper GI conditions (perforations/bleeding) were reported for patients diagnosed with H. pylori.
Limited information on starting dose and dose at event were recorded from the green forms for meloxicam, and reporting was incomplete for celecoxib. Where information on dose at event was provided for celecoxib, 92.2% (671/727) of patients reported to have symptomatic (acid/peptic) conditions were taking 200 mg/day or less, and 83.9% (26/31) of patients reported to have complicated upper GI conditions (perforations/bleeding) were taking 200 mg or less. Celecoxib users were less likely to have a dose increase reported as an event than meloxicam users (1.2%, n = 207 vs 1.8%, n = 350, 2 P < 0.0001), but no evidence of a difference was found between the cohorts in those for whom a dose reduction was reported (0.3%, n = 46 and 0.3%, n = 61,
2 P = 0.321). As the reporting of dose data was low, it was not adjusted for in the multivariate analysis.
Table 3 shows crude event rates per 1000 person-years for both drug cohorts over the first 9 months of treatment and RR for each risk factor category. As indicated earlier in the results, a possible relationship exists between age and both event groups. Regarding symptomatic (acid/peptic) upper GI events, celecoxib users who are aged 4059 yr, 6079 yr and 80 yr or more had a higher (but not significant) rate of having these events than the reference group (aged under 40 yr). As reported previously, a similar relationship was also observed for users of meloxicam [2]. The age-specific estimates of RR obtained via stepwise comparison of the age-specific rates indicated that this relationship was not linear for either drug, with no systematic difference in the age-specific rates between both drugs (test for effect modification 2 P = 0.0937). Similar to that reported previously [2], the rates for complicated upper GI conditions (perforations/bleeding) also showed no significant difference (at the 5% level) between those aged 4059 yr and 6079 yr compared with those aged under 40 yr in either cohort. However, meloxicam users aged over 80 yr had over double the rate [RR 2.54 (95% CI 1.01, 6.39)] of the reference group, and over three times the rate of users aged 6079 yr [RR 3.32 (95% CI 1.78, 6.12)]. Similarly, celecoxib users aged over 80 yr also had over a 4-fold relative difference in rate [RR 4.71 (95% CI 0.59, 37.20)], although this did not achieve statistical significance, and over three times the rate of users aged 6079 yr [RR 3.55 (95% CI 1.44, 8.72)]. Furthermore, there was no evidence of a systematic difference in the age-specific rates of these events between both drugs (test for effect modification
2 P = 0.9143).
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Examination of drug-indication specific rates demonstrated a significantly lower relative rate of symptomatic (acid/peptic) upper GI events for patients prescribed celecoxib for osteoarthritis compared with those where other indications were reported. This was not observed for meloxicam users. Furthermore, a between drug comparison revealed evidence of an indicationdrug interaction (test for effect modification 2 P = 0.0171); patients prescribed celecoxib for osteoarthritis were less likely to experience such events than patients prescribed meloxicam for the same indication [RR 0.84 (95% CI 0.92, 1.08)], whilst those celecoxib users with other indications had a higher (but non-significant) relative risk of these events than meloxicam users with other indications [RR 1.05 (95% CI 0.96, 1.16)]. Again there was no such interaction observed for complicated upper GI conditions (perforations/bleeding) (test for effect modification
2 P = 0.1120).
Similar to that reported previously [2], patients who had a medical history of upper GI problems had a 2.4-fold increase in rate of experiencing symptomatic (acid/peptic) upper GI events compared with those who did not [RR 2.40 (95% CI 2.06, 2.80) and RR 2.73 (95% CI 2.44, 3.06) for celecoxib and meloxicam, respectively]. There was no significant difference observed in the relative rate of complicated upper GI conditions (perforations/bleeding) in those who reported a medical history of upper GI problems compared with those who did not for either drug (Table 3). Furthermore, there was no evidence of differences in the drug stratum-specific rates for either event (test for effect modification 2 P = 0.1780 and 0.5156, respectively).
Patients who had been prescribed a NSAID within 3 months prior to starting the drug had a significantly lower rate of experiencing symptomatic (acid/peptic) upper GI events than those who had not [RR 0.76 (95% CI 0.66, 0.86) and 0.83 (95% CI 0.74, 0.92) for celecoxib and meloxicam, respectively], similar to that reported previously [2]. Celecoxib users who had been prescribed NSAIDs within 3 months prior to starting the drug tended towards a lower rate of experiencing complicated upper GI conditions (perforations/bleeding) than those who had not [RR 0.55 (95% CI 0.29, 1.06)], but this did not achieve statistical significance. Again, there was no significant difference between drug stratum-specific rates for either event (test for effect modification 2 P = 0.1780 and 0.1122, respectively).
The crude and adjusted RR are presented in Table 4. The crude RR indicated that there was no significant difference in the rates of either event groups between these two drugs. Age (also as a quadratic variable age2), sex and indication together had little confounding effect on the overall estimate of relative risk of symptomatic (acid/peptic) upper GI events, but strongly confounded the estimate of relative risk of complicated upper GI conditions (perforations/bleeding). Adjusting for medical history of upper GI events and a prescription of a NSAID within 3 months prior to starting the study drugs indicated that a difference does exist between subjects prescribed either of the two drugs and the rate of experiencing symptomatic (acid/peptic) upper GI events and complicated upper GI conditions (perforations/bleeding). The rates over the 270-day study period, adjusted for all the identified risk factors (age, age2, sex, indication, medical history of upper GI problems and NSAIDs within 3 months prior to starting treatment), were in favour of celecoxib [RR 0.77 (95% CI 0.69, 0.85) and 0.56 (95% CI 0.32, 0.96), respectively].
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A sensitivity analysis was undertaken to ascertain whether the reduction in sample size may have contributed in some way to the observed relative difference in rates, where significant differences were found. For symptomatic (acid/peptic) upper GI conditions, the estimate removing subjects with missing values for the adjusting variables past medical history of upper GI conditions and NSAID prescribed within 3 months of starting treatment was 0.96 (95% CI 0.88, 1.05). The estimate removing subjects with missing values for any of the adjusting variables was 0.99 (95% CI 0.89, 1.09). For complicated upper GI conditions (perforations/bleeding) the corresponding estimates removing subjects with missing values for any of the adjusting variables was 0.62 (95% CI 0.37, 1.06). Therefore the significance of the drug in the final adjusted model is not purely down to a reduction in the data set, as none of these models (that are based on the same cases) without fitting the terms show any significant differences.
The effect of treatment duration was also examined by restricting the study period to 90 days after starting treatment. For symptomatic (acid/peptic) upper GI conditions, the crude and final adjusted estimate to 90 days was observed to be 1.00 (95% CI 0.91, 1.09) and 0.79 (95% CI 0.70, 0.89), respectively, for celecoxib compared with meloxicam. The corresponding estimates for complicated upper GI conditions (perforations/bleeding) were 0.97 (95% CI 0.58, 1.63) and 0.38 (95% CI 0.17, 0.84), respectively, also in favour of celecoxib. Thus the reduction in risk was still significant during the first 90 days of treatment for both event groups, in favour of celecoxib.
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Discussion |
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After adjustment for age (and age2), sex, medical history of upper GI events and a prescription of a NSAID within 3 months prior to starting the study drugs, significant relative rate reductions were observed for symptomatic (acid/peptic) upper GI events and complicated upper GI conditions (perforations/bleeding), 0.77 (95% CI 0.69, 0.85) and 0.56 (95% CI 0.32, 0.96), respectively, for celecoxib compared with meloxicam. Differences in treatment duration and reduction in the sample size (occurring as a result of fitting the statistical model) are unlikely to account for this relative rate reduction in favour of celecoxib. Increasing age is an important risk factor for GI adverse events with NSAIDs [19], and as described in the previous study [2], older age was important in determining risk of experiencing complicated upper GI events (perforations/bleeding) and this did not differ between the two drugs. There is evidence of differential effects of sex and indication on the relative rate estimate of symptomatic (acid/peptic) upper GI events. The reduction in risk is more significant for those with OA, and those who are female. One explanation is that patients with OA have different characteristics than those with other indications. This effect was not observed for complicated upper GI conditions (perforations/bleeding).
Other studies which have examined the groups of patients prescribed COX-2-specific inhibitors report that patients at high risk of GI events may be preferentially prescribed these agents [17, 23, 24]. Our comparison enables this channelling of high-risk patients to be taken into account, in that both products were likely to have been prescribed because of better GI tolerability. In this study, a higher proportion of celecoxib users had an indication for osteoarthritis, were female, were aged over 60 yr, had been prescribed NSAIDs within 3 months of starting treatment and nearly double the proportion of patients prescribed celecoxib had a medical history of upper GI conditions compared with those prescribed meloxicam [risk ratio 1.87 (95% CI 1.82, 1.93)], all of which may contribute to differences in baseline risk of patients experiencing such events. This suggests differential channelling of groups at higher risk of such events on to celecoxib compared with meloxicam. One explanation may be the introduction of the NICE guidelines during the celecoxib study, which were proactive in encouraging the use of COX-2 inhibitors in patients at greater risk of NSAID-induced gastrotoxicity. We acknowledge that prescribing decisions are also dependent on other issues such as concurrent drugs, disease or anticipated side-effects and all these factors may contribute to differences in baseline risk between these cohorts. We have reported previously that limited information is available on other risk factors [2], for example smoking, concomitant medication such as aspirin or gastroprotective agents [6] and infection with H. pylori, which are all known to be associated with an elevated risk of GI events. We were unable to adjust for these risk factors because such data were sparse, thus we cannot exclude the fact that differences observed in our study could be due to the confounding effect of these variables. Nevertheless, this study supports the importance of the risk factors that we have identified in this report (age, sex, medical history of upper GI events and previous use of NSAIDs) with increasing risk of adverse GI events. Furthermore we can report that, after adjusting for these risk factors, celecoxib has a reduced risk of either type of GI event compared with meloxicam.
In PEM, data for evidence of a doseevent relationship are sparse; data for dose at event are requested but are not always provided on green form questionnaires. We acknowledge that the therapeutic dose for either drug may vary according to an individual's characteristics or needs, but in this study the incidence rate reflects the entire dose range used in general practice. Whilst there is evidence of a doseevent relationship for non-aspirin NSAIDs for serious GI complications [11, 25], there is limited information on this issue regarding the COX-2-specific agents [26, 27]. The debate around classification of these agents, the degree of COX-2 selectivity and the existence of between-patient pharmacodynamic and pharmacokinetic variation adds to the complex nature of identifying such a relationship [28, 29] and is beyond the scope of this observational study. In addition, it must be emphasized that symptomatic events do not always precede or predict complicated events [30]. Therefore, in this study the event groups have been analysed separately, although they may possibly be related, to provide a comparison of common and rare GI events in patients prescribed one or other of these drugs.
Other strengths and limitations of PEM are discussed in detail elsewhere [31], and in the first study in this series [2]. In summary, limitations of the reporting system include non-response bias, underreporting, misclassification, concomitant non-prescription drug use and compliance. In addition, PEM only relates to general practice (exposure does not include hospital prescriptions) and we have no measure of patient compliance. Another important source of bias is that the studies were completed approximately 4 yr apart. We acknowledge the limitations of comparing cohorts over different calendar periods and that temporal changes in the background risk of GI adverse events in the general population may exist. In our study, we did not adjust for calendar period since both cohorts were regarded as new users of these agents, and there was evidence of channelling of patients at high risk of GI events for both drugs. The NICE prescribing guidelines were introduced in July 2001, after the prescription data were collected for celecoxib and towards the end of the follow-up observational period and thus were unlikely to have contributed to reporting bias for celecoxib users. Furthermore, guidelines for the use of gastroprotective agents to protect chronic users of NSAIDs against NSAID-associated gastric and duodenal ulcers, and for eradication of H. pylori were available when the meloxicam PEM study was undertaken [32, 33]. Nevertheless, other comparative PEM studies report no evidence to suggest differential reporting of events between the first and latest drug in other therapeutic groups [34]. Furthermore, PEM cannot be used to identify changes in the background prevalence of events of interest or risk factors in the general population of England, but to identify differences in the incidences of selected events between patients prescribed different agents under primary care conditions.
A strength of PEM is that GPs are requested to supply event data without making any assumptions regarding causality, which can then be analysed to identify potential signals of drugevent relationships not previously listed in prescribing information. Clearly PEM is dependent on reporting by a third party, who may or may not provide laboratory confirmation of disease or a diagnostic test such as endoscopic evaluation. Whilst such endpoints provide stronger evidence of efficacy or safety in controlled trials, in this study conducted in general practice it is likely that many of the clinical decisions were made on presenting clinical parameters. Indeed the incidence of endoscopy/gastroscopy reported for celecoxib and meloxicam was low and did not differ (0.21%, n = 40 and 0.25%, n = 43, respectively, P = 0.4610).
To our knowledge, a direct comparison of upper GI event rates between these two drugs has not been published elsewhere. Other studies report improved tolerability in terms of GI adverse events for COX-2-specific inhibitors compared with non-selective traditional NSAIDs or placebo [6, 35, 36]. An observational cohort study using linked records from the administrative healthcare databases in Ontario, Canada compared rates of upper GI haemorrhage resulting in admission to hospital in patients aged over 66 yr who started treatment with either rofecoxib, celecoxib, non-selective NSAIDs or diclofenac plus misoprostol, with each other and with a large control group. They reported that the risk of upper GI haemorrhage resulting in admission was significantly higher for non-selective NSAIDs [RR 4.4 (95% CI 2.3, 8.5] and for rofecoxib [RR 1.9 (95% CI 1.2, 2.8] compared with celecoxib [37]. The meta-analysis by Deeks et al. [36] was restricted to 6 months follow-up and therefore was not able to examine long-term effects, and the study by Mamdani et al. [37] excluded high-risk patients who used NSAIDs in the previous year to starting treatment, patients 65 yr or less, and only examined the issue of upper GI haemorrhage leading to hospital admission.
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Conclusion |
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Acknowledgments |
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Conflict of interest
The Drug Safety Research Unit is an independent charity, which works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. The DSRU has received such funds from the manufacturers of celecoxib and meloxicam. SAWS has received support from Pfizer to attend scientific conferences.
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References |
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