Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK
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Abstract |
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Methods. Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (between December 1996 and March 1997) and rofecoxib (between July and November 1999). 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 approximately 9 months after the first prescription for each patient. Incidence rates of the first event were calculated, and crude and adjusted rate ratios were obtained using regression modelling.
Results. For rofecoxib and meloxicam respectively, 1127 (7.4%) and 1376 (7.2%) patients had symptomatic (acid/peptic) upper GI events, whereas 57 (0.4%) and 67 (0.4%) had complicated upper GI conditions (perforations/bleeding). A past medical history of upper GI problems was an important risk factor only for symptomatic (acid/peptic) upper GI events for both drugs, despite a two-fold difference in the proportion reporting previous GI problems (48.4 and 25.1% for rofecoxib and meloxicam respectively). The adjusted rate ratio of symptomatic (acid/peptic) upper GI events or complicated upper GI conditions (perforations/bleeding) for rofecoxib compared with meloxicam was 0.71 (95% confidence interval 0.65, 0.79) and 0.91 (95% confidence interval 0.59, 1.42) respectively.
Conclusions. This study reports a relative reduction (29%) in the incidence rate of symptomatic (acid/peptic) GI events, and no difference in the incidence rate of complicated upper GI conditions (perforations/bleeding) for rofecoxib compared with meloxicam.
KEY WORDS: COX-2-selective inhibitors, Rofecoxib, Meloxicam, Adverse events, Prescription event monitoring, Drug safety.
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Introduction |
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NSAIDs act by inhibiting the cyclooxygenase (COX) enzyme that mediates the conversion of arachidonic acid to prostanoids, predominantly the prostaglandins PGE2 and PGI2. In 1991 it was discovered that two isoforms exist, COX-1 and COX-2 [9]. COX-1 is important in the production of the prostaglandins mediating homeostatic functions, such as gastric mucosal protection. The COX-2 isoenzyme is involved in the production of an inflammatory response. At therapeutic doses, traditional NSAIDs inhibit both of the COX isoenzymes to varying degrees [10]. Adverse GI events that are associated with NSAIDs and are believed to be related to COX-mediated function appear to stem from two proposed mechanisms: (i) inhibition of platelet COX-1 aggregatory activity, leading to an increase in the tendency to bleed; and (ii) inhibition of gastroprotective COX-1 activity, leading to an increase in the risk of ulceration [11].
In June 1999, rofecoxib (Vioxx®), an NSAID reported to be COX-2-selective, was launched in the UK. The licensed indication at launch was for the symptomatic relief of osteoarthritis. The benefit of selectivity is seen as maximum anti-inflammatory activity by potent inhibition of the COX-2 isoenzyme [12], with minimal clinically significant effects on COX-1 isoenzyme activity, thus improving the GI adverse event profile. In clinical trials, rofecoxib was associated with an equivalent [13] or reduced incidence of GI adverse events and mucosal injury compared with other non-COX-selective NSAIDs [1420].
Meloxicam (Mobic®), launched in the UK in December 1996 and also considered to be a COX-2 inhibitor [21, 22], was indicated at launch for relief of pain and inflammation in rheumatic disease [including rheumatoid arthritis (RA)], exacerbation of osteoarthritic pain and ankylosing spondylitis. Meloxicam is reported to inhibit COX-2 up to 50 times more than COX-1, but may still inhibit COX-1 at therapeutic doses, in a dose-dependent manner [23, 24]. Its relative COX-2 specificity preserves COX-1-dependent gastric prostaglandin synthesis, resulting in favourable GI tolerability [2426].
The evidence from randomized controlled trials suggests that NSAIDs which preferentially inhibit COX-2 isoenzyme are associated with a reduced incidence of upper GI adverse events compared with non-selective NSAIDs. However, the limitations of these published trials include the exclusion of high-risk subgroups with current or recently active GI disease, and/or restrictions in those receiving concomitant gastroprotective agents, such as histamine (H)2 antagonists.
The Drug Safety Research Unit (DSRU) 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), with a systematic approach to data collection [27]. PEM collects data on patients prescribed a drug in real world clinical practice, including high-risk groups who may previously have been excluded from controlled trials, and who 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 [28] and rofecoxib [29].
The aim of this study was to investigate retrospectively, using large cohorts from the general population of England, whether there are clinically relevant differences in the type and incidence of upper GI events reported during the routine clinical use in general practice of meloxicam and rofecoxib.
Our objectives were to calculate and compare rates for selected groups of upper GI events occurring within the first 9 months after starting treatment and to determine relative risks (rate ratios) separately for symptomatic (acid/peptic) upper GI events and for complicated upper GI conditions (perforations/bleeding), adjusted for possible confounders (age and sex) [8, 30], whether there was a history of upper GI symptoms [5], whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug, and whether gastroprotective agents [H2 antagonists, proton pump inhibitors (PPI) or misoprostol] had been prescribed during treatment [31].
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Methods |
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In PEM, the term event is defined as any new diagnosis, any reason for referral to a consultant or admission to hospital, any unexpected deterioration (or improvement) in a concurrent illness, any suspected drug reaction, any alteration of clinical importance in laboratory values, or complaint of sufficient importance to enter into the patient's notes. Reported events are coded into a computer using the DSRU event dictionary, which is a hierarchical dictionary arranged by systemorgan class with specific lower terms grouped together under broader higher terms.
Other information requested for both drugs on the green form questionnaires included the reason for stopping the drug (if any), the date of stopping and any events reported after the medication was stopped. The form for rofecoxib also asked specifically whether the drug had been stopped and the date of the last prescription. Those questionnaires returned with no information (clinical or other) provided were classified as void and excluded, as there was no means of determining whether forms not completed indicated no reported events.
Additional information on risk factors associated with the events of interest was available from the extra questions used on the green forms for both study drugs. The GP was requested to indicate whether there was a history of upper GI symptoms [5], whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug and whether gastroprotective agents (H2 antagonists, PPIs or misoprostol) had been prescribed during treatment [31]. Information on concomitant NSAIDs, aspirin, antacids and anticoagulant or antiplatelet agents during treatment had been requested for the rofecoxib study only.
For this study, exposure data were obtained from NHS prescriptions written by GPs in England for meloxicam between December 1996 and March 1997 and for rofecoxib between July 1999 and November 1999. The cohort for meloxicam consisted of 19 087 subjects and the rofecoxib cohort 15 268 patients. For comparative purposes in this study, the exposed patients were those who were prescribed rofecoxib and the unexposed patients were those prescribed meloxicam. The event terms for this study were selected by medical practitioners from the DSRU dictionary according to their clinical judgement, prior to analysis. Outcome data were those selected events associated with upper GI conditions/symptoms that were reported to have occurred whilst taking the drug (or within 7 days of stopping), during the 9 months since the start of treatment with either drug. These selected events were grouped under symptomatic (acid/peptic) upper GI events or complicated upper GI conditions (perforations/bleeding) (Table 1). Where no stopping date was given, events occurring after 30 days from the date that treatment was started were excluded. Events occurring more than 7 days after stopping the drug (allowing for five plasma elimination half-lives at steady state (tss
; meloxicam 20 h, rofecoxib 17 h [32]) were excluded. Also excluded were events for which it was not known whether they occurred during treatment, because no stop date was provided.
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Analysis
Summary statistics of the demographic characteristics of the subjects in both drug cohorts were calculated. Differences between categorical variables were tested using Pearson's 2 test, and differences between continuous variables were tested using parametric two-sample t-tests, where appropriate. Drug dose information (such as the starting dose prescribed, dose at the time of the event and whether the dose changed during the course of treatment), indication and duration of treatment were examined. The reported incidence of diagnosis of the bacterium Helicobacter pylori was also investigated.
Crude incidence rates for each event group with 95% confidence intervals (CI) were calculated from the total person-time exposure (p.t.e.). For each individual for each event group, the outcome was categorized as a binary variable (first event or non-event). For each individual for both groups, p.t.e. was calculated between the date of the first prescription dispensed (Day 0) and the date of the first event occurring specific to that event group. If no event occurred, p.t.e. was calculated either to the date of stopping or to the end of survey date, up to 270 days (9 months). Where no event date was provided, the mean p.t.e. for those who had that particular event was allocated. If the event occurred on the first day of exposure and the stop date was given as the same date, p.t.e. was taken to be 0.5 days. The unadjusted rate ratios (RR) and ratios adjusted for selected risk factors plus confounding variables (age and sex) were calculated and examined using both univariate (MantelHaenszel) methods and multivariate Poisson regression modelling. 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 Kaplan-Meier 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. All records and computer data were stored to maximize patient confidentiality.
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Results |
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When answers to the additional questions were given, significantly more rofecoxib users than meloxicam users had a past medical history of upper GI problems [62.3% (7384/11 855) vs 29.2% (4787/16 393); 2 test, P < 0.0001] and had been prescribed an NSAID within the 3 months prior to starting treatment [51.3% (6194/12 076) vs 47.9% (7978/16 634);
2 test, P < 0.0001]. The proportions reporting use of concomitant H2 antagonists/PPIs (20.5%, n=3129 and 13.4%, n=2555) or use of misoprostol (8.1%, n=1232 and 6.1%, n=1170) was higher for rofecoxib than meloxicam (both
2 test, P < 0.001). Cross-tabulation of a positive reply, or not, regarding the use of either H2-antagonists or misoprostol with a medical history of upper GI problems suggested a strong link between these two risk factors, both overall (
2 test, P < 0.0001) and when stratified by drugs (
2 test, P < 0.0001). As the response rate to this additional question was low, the use of gastroprotective drugs was not adjusted for in the multivariate analysis.
The median p.t.e. over the 9 month study period for patients in whom symptomatic (acid/peptic) upper GI events was reported was 155 days [interquartile range (IQR) 34226] for rofecoxib and 168 days (IQR 37218) for meloxicam. The corresponding median p.t.e. for complicated upper GI conditions (perforations/bleeding) was 159 days (IQR 34267) for rofecoxib and 185 days (IQR 38220) for meloxicam. There was evidence of a statistical difference in the treatment duration between the two drugs during the 270 day study period (two sample Wilcoxon rank-sum test both P<0.0001). During the 9 months after starting treatment, 1376 (7.2%) and 1127 (7.4%) patients were reported to have symptomatic (acid/peptic) upper GI events for meloxicam and rofecoxib respectively. In these patients, 50% of these events occurred early after starting treatment with either drug. There was no difference in the estimate of time to first symptomatic (acid/peptic) upper GI events between the two drugs [meloxicam, median 30 days (IQR 997); rofecoxib, median 32 days (IQR 1494.5); Log Rank test P=0.8504]. With respect to complicated upper GI conditions (perforations/bleeding), 67 (0.4%) and 57 (0.4%) patients were reported to have had such events for meloxicam and rofecoxib respectively. In these patients, 50% of these events occurred by the third month after starting treatment, and there was no difference in the estimate of time to first event in this group, between the two drugs (Log Rank test, P=0.8745).
Associations between symptomatic (acid/peptic) upper GI events and age, past medical history of upper GI problems, past prescription of NSAIDs and sex were observed (all 2 test, P<0.0001). Conversely, a significant association was evident only between experiencing complicated upper GI conditions (perforations and bleeds) and age (P<0.0001). More patients prescribed rofecoxib who experienced symptomatic (acid/peptic) upper GI events had a medical history of upper GI problems than those prescribed meloxicam [82.5% (813/986) vs 53.5% (660/1233);
2 test, P<0.0001]. Similarly, more patients prescribed rofecoxib who experienced complicated upper GI conditions (perforations/bleeding) had a past medical history of upper GI problems than those prescribed meloxicam [60.4% (29/48) vs 34.9% (22/63);
2 test, P=0.008]. There was no difference between the two cohorts, for either group of GI symptoms, in the number who had had an NSAID prescribed within 3 months prior to starting treatment (
2 test, P=0.367 and P=0.118 respectively).
Similar proportions of patients from the rofecoxib and meloxicam cohorts were reported to have been diagnosed with H. pylori infection (0.08%, n=12 and 0.09%, n=17 respectively; 2 test, P=0.74). In these patients the proportion who experienced symptomatic (acid/peptic) upper GI events (0.6%, n=15 vs 0.04%, n=14;
2 test, P<0.0001) or complicated upper GI conditions (perforations/bleeding) (0.81%, n=1 vs 0.08%, n=28,
2 test, P=0.006) was higher than in those who did not experience such symptoms.
Limited information on starting dose and dose at event was provided on the green forms. However, rofecoxib users were more likely to have a dose increase reported as an event than meloxicam users (4.0%, n=603 vs 1.8%, n=350; 2 test, P < 0.0001), but no difference was found between the cohorts in those for whom a dose reduction was reported (0.3%, n=61 and 0.4%, n=53 respectively).
Table 3 shows crude event rates per 1000 person-years for both drug cohorts over the first 9 months of treatment and rate ratios (RR) for each risk factor category. Examination of the effect of age suggests that a relationship exists; rofecoxib users who were aged 4059 yr or 6079 yr had a significantly higher rate of symptomatic (acid/peptic) upper GI events than users aged under 40 yr (the reference group) [RR 1.58 (95% CI 1.15, 2.18) and 1.52 (95% CI 1.11, 2.02) respectively]. For those aged over 80 yr, the relative rate was just below statistical significance [RR 1.40 (95% CI 0.97, 2.01)]. This trend for symptomatic (acid/peptic) upper GI events was also reported for users of meloxicam, although the RR over the age groups was not significantly different from 1. The rates for complicated upper GI conditions (perforations/bleeding) showed no difference between those aged 4059 yr and those aged 6079 yr compared with those aged 39 yr or less. However, meloxicam users aged over 80 yr had over double the rate (compared to those aged 39 yr or less) [RR 2.54 (95% CI 1.01, 6.39)]. Similarly, rofecoxib users aged over 80 yr also had a greater than two-fold relative difference in rate [RR 2.54 (95% CI 0.72, 9.00)], although this did not achieve statistical significance. Females had a significantly higher rate of experiencing symptomatic (acid/peptic) upper GI events than males, but a lower (but non-significant) rate of complicated upper GI conditions (perforations/bleeding).
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The crude and adjusted rate ratios are presented in Table 4. Adjusting for the confounders [age (also as a quadratic variable, age2) and sex] and two risk factors (a medical history of upper GI events and a prescription of an NSAID within 3 months prior to starting the study drugs) suggested that a difference existed between subjects prescribed either of the two drugs and the rate of experiencing symptomatic (acid/peptic) upper GI events. The adjusted rate for rofecoxib was lower than for meloxicam [RR 0.71 (95% CI 0.65, 0.79)]. With regard to complicated upper GI conditions (perforations/bleeding), no difference was observed [RR 0.91 (95% CI 0.59, 1.42)].
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Discussion |
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This study reports a significant reduction (29%) in the rate of symptomatic (acid/peptic) upper GI events in users of rofecoxib compared with meloxicam, and no difference in the rate of complicated upper GI conditions (perforations/bleeding) between the two cohorts, after adjustment for age (also as a quadratic variable, age2), sex, a past medical history of upper GI events and prescription of an NSAID within 3 months prior to starting the study drugs. To our knowledge, a direct comparison of upper GI adverse event rates between these two drugs has not yet been published elsewhere.
Other studies report a difference in both symptomatic and complicated GI adverse events between both drugs and non-selective NSAIDs [17, 20, 2426, 34]. Whilst our results demonstrate a relative difference in the rate of symptomatic upper GI events (acid/peptic symptoms) in line with published studies, we found no such relative difference in the rates of complicated upper GI conditions (perforations/bleeding). The differential effects of COX-1/COX-2 selectivity of the two drugs with standard clinical dosing regimes is one explanation which may contribute to the observed reduction in the rate of symptomatic (acid/peptic) upper GI events observed in this study. Meloxicam exhibits some COX-1 inhibition at therapeutic doses and it is not possible to distinguish fully the COX-2-selective effect of meloxicam in this study because the incidence rates reported reflect the entire starting dose range used and cannot provide evidence for a doseresponse relationship. Both rofecoxib and meloxicam had only two dose ranges licensed at the time of the PEM studies (12.525 and 7.515 mg/day respectively) and it could be assumed that most GPs would prescribe within the recommended dose range.
This study reports no difference in the distribution of time to symptomatic (acid/peptic) upper GI events in patients for whom such events were reported after starting treatment with either drug, and half of such events were reported to have occurred within the first 5 weeks of treatment. Conversely, complicated upper GI conditions (perforations/bleeding) were less likely to be reported early after starting either drug, and the distribution of time to events between drugs was similar in those patients for whom such events were reported.
One could argue that, due to slight differences in the licensed indication, differences in the baseline risk for patients and the treatment duration within each cohort may explain the relative difference in the time to onset of symptomatic (acid/peptic) upper GI events. For example, previous use of NSAIDs is associated with an increased risk of experiencing serious and non-serious GI events compared with non-use, which may persist after discontinuation of NSAID [35]. In our study, past prescription of an NSAID prior to starting treatment was identified as an important risk factor for symptomatic (acid/peptic) upper GI events, and when this risk factor was adjusted for the RR it was still favourable for rofecoxib. Furthermore, despite a higher proportion of patients with RA in the meloxicam cohort compared with the rofecoxib cohort, the absolute numbers were small and unlikely to explain the relative difference observed. Regarding treatment duration, the statistical differences observed for the treatment duration during the 270 day study period are also unlikely to account for those differences in that the relative reduction in favour of rofecoxib was still observed when the study period was restricted to the first 90 days after starting treatment.
Both products were marketed with assertions of better GI tolerability than non-selective NSAIDs, and channelling of high-risk groups (such as patients with a history of upper GI problems) was therefore likely with both drugs [36], despite prescribing precautions in the prescribing information for both drugs. The comparison of rofecoxib with meloxicam takes account of the similar baseline risk for the two cohorts, who may have been preferentially prescribed these drugs because of their reported improved GI tolerability. In our study, over twice as many patients prescribed rofecoxib had a past medical history of upper GI problems as those prescribed meloxicam [RR 2.13 (95% CI 2.07, 2.19)], contributing to evidence of channelling of high-risk groups to rofecoxib. We also report that the use of gastroprotective drugs was associated with a past medical history of upper GI problems for both drugs, which is also likely to be related to the channelling of groups with a history of GI symptoms. Because the response to the questions regarding the use of gastroprotective drugs was variable, the use of concomitant gastroprotective drugs was not adjusted for in the analysis. We report a link between a past medical history of experiencing upper GI events and whether users are likely to experience symptomatic (acid/peptic) upper GI adverse symptoms when these two COX-2-selective inhibitors are used. However, no such association was observed for complicated upper GI events (perforations/bleeding). Other studies report an increased risk of upper GI adverse events in patients with a history of peptic ulcer and GI bleeding who are given an NSAID, in contrast to patients with no such history [31].
The issue of whether H. pylori infection is an important risk factor is complicated [37, 38]. The PEM studies of both drugs did not specifically request information on the presence of H. pylori, but recorded this event if diagnosis had been reported by the responding GP. Where reported, no difference in the proportion infected with H. pylori was detected between drugs. H. pylori infection was associated with patients reported to have either symptomatic (acid/peptic) upper GI events or complicated upper GI conditions (perforations/ bleeding) rather than those who did not experience these symptoms. The limited number of reports precluded any further investigation of this association.
Age and sex have been shown to affect the reporting of ADRs and the rates of prescribing of drugs of different therapeutic classes [30]. More importantly, older age itself is an important risk factor for GI adverse reactions with NSAIDs [1, 8]. In this study, there was a relationship between age and the rate of experiencing either type of event for both drugs, despite the meloxicam cohort being younger than the rofecoxib cohort. The highest rates of symptomatic (acid/peptic) upper GI events occurred for rofecoxib users in those aged 4059 and 6079 yr, and for meloxicam users in those aged 6079 yr, compared with those aged 39 yr or less. The effect of older age appears extremely important in determining the rate of complicated upper GI conditions (perforations/bleeding), such that elderly patients aged 80 yr or more have more than double the rate found in those aged 39 yr or less. This association between increasing age and the likelihood of experiencing complicated GI events has been reported elsewhere [35].
The strengths and limitations of PEM have been discussed elsewhere [27]. Whilst PEM collects dispensed prescription data, an assumption is made regarding compliance and drug intake. A weakness of PEM is non-response bias [39]. The individual PEM study GP response rates for rofecoxib (39%) and meloxicam (52%), while low, are nevertheless substantial compared with the proportion of suspected ADRs which are reported in spontaneous ADR reporting schemes [40] or compared with general practitioner postal surveys in general [41]. Reassuringly, only nine serious events occurred per 1000 person years with either drug. Whilst under-reporting is likely, there is no reason to assume that this would be different between the two drugs. Selection bias may be introduced via attrition, changes in clinical care patterns and cotherapies. Data collection in PEM is systematic, prospective and independent of individual studies. Therefore limited information will be available on other risk factors, for example smoking, alcohol use, and concomitant medication such as aspirin. Aspirin in low dose is frequently used for prevention of thrombotic cerebrovascular or cardiovascular disease in the same patients who may also be at increased risk of GI complications that are associated with all NSAIDs, including aspirin. The incidence of serious GI bleeding in patients taking low doses of aspirin, although low, is roughly double the incidence in those taking placebos. [42] Coprescription of aspirin with NSAIDs is known to increase the risk of such complications [43].
It should be emphasized that the relationship between GI symptoms, endoscopic ulcers and serious upper GI complications is uncertain; the presence or absence of non-specific upper GI symptoms is not a reliable predictor of subsequent serious GI complications, and this has not been investigated in this study. Therefore the event groups have been analysed separately, although they may possibly be related. Epidemiological studies indicate that the risk of serious upper GI complications is greater in certain patient groups, such as the elderly, those using high-dose NSAIDs or concomitant aspirin, and those changing from one NSAID to another [44, 45]. COX-2-specific inhibitors are often considered in such patients, although sufficient data were not available at the time of these PEM studies to support recommending their use in clinical situations associated with elevated risk.
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Conclusion |
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Conflict of interest |
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Acknowledgments |
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Notes |
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References |
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