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1
Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, 2University of Portsmouth and 3University of Southampton, UK.
1354
Rheumatology Vol. 42 No. 11 ß British Society for Rheumatology 2003; all rights reserved
Thromboembolic events after taking celecoxib and meloxicam 1355
between users of these two drugs. The incidence of these three groups of events
reported in each of these two drug cohorts was low (<0.5%), therefore the
relevance of our findings need to be taken into consideration with other clinical and
pharmacoepidemiological studies.
KEY WORDS: Adverse events, Celecoxib, COX-2 selective inhibitors, Drug safety, Meloxicam,
Prescription-Event Monitoring.
Cyclooxygenase (COX)-2 isoenzyme inhibitors were studies of rofecoxib is conflicting [31, 32]. In contrast the
developed with the aim of reducing gastrointestinal CLASS (celecoxib long-term arthritis safety study) trial,
(GI) adverse reactions compared to non-selective non- which involved 8059 patients with OA or RA, and
steroidal anti-inflammatory drugs (NSAIDs) [1–6]. compared celecoxib (400 mg b.d.) with NSAIDs (ibu-
However, while emerging information suggests that use profen 800 mg t.d.s or diclofenac 75 mg b.d.), demon-
of such drugs may contribute to an increased risk of strated no excess of serious TE cardiovascular events [6].
adverse vascular events [7], this is yet to be confirmed by For both drugs, these large-scale trials were designed to
a sufficient number of studies. Furthermore, it is unclear demonstrate that gastrointestinal safety was superior to
whether the higher risk applies to all thromboembolic that of traditional NSAIDs in clinical practice, but were
(TE) events and whether it applies to all COX-2 not sufficiently powered to detect differences of TE
inhibitors at all doses, or to some products at specific events against the background cardiovascular event rates
doses or dose ranges [8]. in the placebo groups. A review of four randomized trials
The pharmacology of NSAIDs appears to be well [including the CLASS trial and VIGOR (Vioxx
described [9, 10]. However, accumulating evidence Gastrointestinal Outcomes Trial) study] that was
regarding the relationship between COX-1 mediated conducted to determine whether COX-2 inhibitors are
platelet-derived thromboxane-A2 and COX-2-mediated associated with a protective or hazardous effect on the
macrovascular endothelial-cell-derived prostacyclin risk of cardiovascular events reported a potential
[11–16] suggests that vascular haemostasis may be increase in cardiovascular event rates for users of
impaired in circumstances where blockade of COX-2- COX-2 inhibitors [31]. However, these trials were
induced prostacyclin, unopposed by COX-1-induced different in several ways and the results were not directly
platelet aggregation, may result in an increased risk of comparable.
TE events in susceptible individuals [17, 18]. Monitoring for adverse effects in the post-marketing
Celecoxib (CelebrexÕ ), launched in May 2000 was phase forms an important part of a drug’s safety profile.
the second COX-2-specific isoenzyme inhibitor to be Post-marketing data derived from spontaneous reports
marketed in the UK, and was indicated for the suggest that the risks of renal and cardiovascular ad-
symptomatic relief of osteoarthritis (OA) or rheumatoid verse events associated with the use of rofecoxib are
arthritis (RA). As reported for other COX-2 selective significantly higher than those of celecoxib and NSAIDs
agents, celecoxib (600 mg b.d. for 10 days) does not (diclofenac and ibuprofen) [33]. Prescription-Event
inhibit platelet aggregation or prolong bleeding time in Monitoring (PEM) studies of newly marketed drugs
studies in healthy volunteers [19]. However, elevated during their immediate post-marketing period in
prothrombin times and bleeding episodes have been England, provide complementary data on safety issues
observed with concomitant use of celecoxib and warfarin in addition to randomized-controlled trials and sponta-
[20], and there have been four patients with connective neous reporting schemes. PEM uses a non-interventional
tissue disorders that developed ischaemic complications observational cohort technique with a systematic
associated with thrombosis after receiving celecoxib approach to data collection; the methodology has been
[21–23]. Meloxicam (MobicÕ ), launched in the UK in described in detail elsewhere [34–38]. As part of its
December 1996, is also considered to be a COX-2 monitoring program, the Drug Safety Research Unit
selective inhibitor [24, 25], and was indicated for relief of (DSRU) has carried out individual PEM studies of
pain and inflammation in rheumatic disease, in exacer- meloxicam [39] and celecoxib [40]. This paper reports
bations of osteoarthritic pain and ankylosing spondylitis the results of a study to examine and compare the
at launch. As described previously [26], meloxicam does cardiovascular risk of these two COX-2 selective
not appear to affect COX-1-dependent platelet throm- inhibitors. An identical study was conducted using
boxane formation or platelet aggregation [27–29], and rofecoxib and meloxicam [26]. These studies, using data
reports of serious cardiovascular events have not been collected via the observational technique of PEM, did
thought attributable to treatment [30]. not require reference to an ethics committee or patient
Among the randomized, controlled trials with the consent.
COX-2 inhibitor rofecoxib, one study demonstrated a The aim of this second study was to retrospectively
significant difference between rofecoxib and its NSAID investigate, using large cohorts from the general
comparator (naproxen) in the risk of cardiovascular population of England, whether there is a difference
thrombotic events [4]. Yet the evidence from other in the type and incidence of TE cardiovascular events
1356 D. Layton et al.
reported during routine clinical use in general practice TABLE 1. Thromboembolic event groups
of meloxicam and celecoxib. As before, our objectives
Cardiovascular Cerebrovascular Peripheral venous
were: to calculate and compare rates for TE events thrombotic
occurring within the first 9 months after starting
treatment with celecoxib or meloxicam; to determine Cardiac arresta Amaurosis fugax Deep vein thrombosis
relative risks, or rate ratios (RRs) separately for CVS not specifieda Aphasia Embolus pulmonary
Myocardial Cerebrovascular Infarction pulmonary
cardiovascular and cerebrovascular TE events and infarction accident
peripheral venous thrombotic events, adjusted for the Dysarthria
possible confounders of age and sex [41–43], and Dysphagiaa
whether other oral NSAIDs had been prescribed in the Dysphasia
Embolus cerebral
3 months prior to starting the drug [15, 42, 43]; and to Embolus mesenteric
calculate and compare the time to first event within Hemianopia
each TE event group for each cohort. Hemiparesis
Hemiplegia
Hypoaesthesiaa
Methods Paralysis facial
Paralysis pseudobulbar
The PEM study conducted for celecoxib was conducted as Paralysis ocular
described previously for rofecoxib [44]. For this study, Paraesthesiaa
exposure data were obtained from green forms received for Paresisa
patients identified from NHS prescriptions written by GPs in Retinal thrombosis
England for meloxicam between December 1996 and March artery
Retinal thrombosis vein
1997 (n ¼ 19 087) and for celecoxib between May and
Slurred speach
December 2000 (n ¼ 17 458). For comparative purposes the Thrombosis cerebral
exposed are those patients prescribed celecoxib and the Transient ischaemic
unexposed are those patients prescribed meloxicam. As attack
described previously [26], the event terms for this study were Visual disturbancea
selected by medical practitioners from the DSRU dictionary
prior to the analysis and aggregated into the three TE groups During the 9 month study period, one report of embolus artery
(cardiovascular, cerebrovascular and peripheral venous was recorded for celecoxib; no reports were recorded for the
thrombotic) events (Table 1). The data were subject to the following miscellaneous TE event terms: infarction gastrointestinal,
same inclusion and exclusion criteria as specified previously, thrombosis mesenteric, thrombosis spinal, thrombosis artery, infarc-
for calculation of person-time exposed (pte) [26, 44, 45]. tion renal.
a
Non-specific terms evaluated by clinician and relevant lowest level
(doctor terms) included in the analysis.
Sample size CVS, cardiovascular system.
The sample size calculation for PEM studies is described
previously [44]. This study has a 95% chance of observing a
statistically significant relative difference in rates of 10%
tively [28.1 vs 23.2%, 2 P < 0.0001], with similar
between the drugs for each event group, if such an underlying
background relative difference exists [26]. proportions of users prescribed either celecoxib or
meloxicam for treatment of symptoms of RA, respec-
Analysis tively [6.5% (1128/17 458) vs 6.6% (1253/19 087), 2
P ¼ 0.3520]. Where answers to the additional questions
Data analysis was conducted in an identical manner to that
described previously [44]. The unadjusted RRs, as well as were given, significantly more celecoxib users than
ratios adjusted for the selected risk factors were calculated meloxicam users had been prescribed an NSAID
and examined using both univariate and multivariate Poisson within the 3 months prior to starting treatment [49.4%
regression modelling. Evidence of effect modification by the (7006/14 195) vs 48.0% (7978/16 634), 2 P ¼ 0.014].
selected risk factors on the estimates of relative risk were also During the 9 months after starting treatment with
investigated, and the estimate of time to first event for each celecoxib and meloxicam, 28 (0.16%) and 19 (0.10%) of
group for each cohort calculated and compared as stated patients were reported to have had cardiovascular TE
previously [26, 44, 46]. events, 68 (0.39%) and 52 (0.27%) were reported to have
had cerebrovascular TE events, and 17 (0.10%) and 20
Results (0.10%) were reported to have had peripheral venous
thrombotic events, respectively. The proportion of events
The characteristics of both study cohorts are presented in excluded from the study as defined in the methods for
Table 2. As described previously [26], where reported both drugs were similar [celecoxib 56.8% (149/262)
celecoxib users were more likely than meloxicam users to versus meloxicam 51.0% (95/186); 2 P ¼ 0.225].
be aged 60 yr or more [59.7% (6378/10 727) vs 55.0% Regarding the time to first event, the crude estimate of
(9280/16 877), 2 P < 0.0001] and be female [68.3% time to first event of both cohorts for each event group
(11 928/17 455) vs 67.1% (12 590/18 763), 2 P ¼ 0.012]. separately is presented in the form of Kaplen–Meier
OA was the most frequently reported indication for both survival curves in Figures 1–3. There was a significant
celecoxib and meloxicam, although the proportion was difference in the estimate of time to first event over the
higher for celecoxib compared to meloxicam, respec- study period in the cardiovascular TE event group for
Thromboembolic events after taking celecoxib and meloxicam 1357
Drug
Age (yr)
39 871 (5.0) 1852 (9.7) <0.0001
40–49 1281 (7.3) 2297 (12.0)
50–59 2197 (12.6) 3448 (18.1)
60–69 2582 (14.8) 3947 (20.1)
70–79 2467 (14.1) 3457 (18.1)
80þ 1329 (7.6) 1876 (9.8)
Not known 6731 (38.6) 2210 (11.6)
Sex
Male 5527 (31.7) 6173 (32.3) 0.012
Female 11 928 (68.3) 12 590 (67.1)
Sex not known 3 (<0.1) 324 (1.7)
Indication
Osteoarthritis 4905 (28.1) 4434 (23.2) <0.0001
Others 12 553 (71.9) 14 653 (76.8)
NSAID prescribed within 3 months prior to starting drug
Yes 7006 (40.1) 7978 (41.8) 0.014
No 7189 (41.2) 8658 (45.4)
Not known 3263 (18.7) 2451 (12.9)
reflected by the survival curves, one almost superimposed reference group), although statistical significance was
upon the other. only observed for users of either drug experiencing
Cross-tabulation of risk factors with event groups cardiovascular TE events. There was no evidence of a
suggested a significant association between age and sex–drug interaction for any of the event groups (tests
experiencing cardiovascular TE (2 P < 0.0001), cere- for effect modification, all 2 P > 0.063). Examination
brovascular TE (2 P < 0.0001) and peripheral venous of drug-indication specific rates revealed no statistically
thrombotic events (2 P ¼ 0.017); between sex and significant effect on the rate of any of the event groups
experiencing cardiovascular TE events (2 P < 0.0001) within each cohort, nor did a prescription of an
and between indication and experiencing cerebrovas- NSAID within 3 months of starting treatment
cular TE events (2 P ¼ 0.017) and peripheral venous (compared to ‘none’ treated as the reference group).
thrombotic events (2 P ¼ 0.037). Use of a NSAID Furthermore, there was no evidence of a drug–risk
within the 3 months prior to starting treatment was not factor interaction (tests for effect modification, all
associated with any of the event groups. 2 P > 0.2032).
At launch and at the time of the PEM studies, the The crude and adjusted RRs are presented in Table
recommended dose range of celecoxib was 100–400 4. As reported previously [26], indication and prescrip-
mg/day, whilst meloxicam only had two doses licensed tion of an NSAID within 3 months of starting
(7.5 or 15 mg/day). As reported previously [26], limited treatment were initially regarded as important risk
information on dose was provided on the green forms factors in this study; however, adjusting for these
for meloxicam. For celecoxib, information on starting variables made no statistically significant difference to
dose was available for 84.4% (n ¼ 14 726). Dose at the RR estimates. Thus age and gender were the two
event was provided for 57.1% (16/28) of patients risk factor variables included in the final Poisson
reported to have cardiovascular TE events, 75.0% regression model. Adjusting for these two risk factors
(51/68) of patients reported to have cerebrovascular TE of age (also as a quadratic variable age2) and sex
events and 90.9% (10/17) of patients reported to have suggests that a difference exists between subjects
peripheral venous thrombotic events. Of these, 15 prescribed either of the two drugs and the rate of
(93.8%), 49 (96.1%) and seven (70.0%) patients, experiencing cerebrovascular TE events; the adjusted
respectively were taking 200 mg/day or less. As the rate was higher for celecoxib than meloxicam [RR 1.66
reporting of dose data was low, it was not adjusted for (95% CI 1.10–2.51)]. With regard to cardiovascular TE
in the multivariate analysis. events and peripheral venous thrombotic events the
Table 3 shows crude event rates per 1000 person- difference did not achieve statistical significance.
years (pyr) for both drug cohorts over the first 9 Evidence of effect modification was further examined
months of treatment and RRs for each risk factor by inclusion of interaction terms within the final
category. We reported earlier that age is associated Poisson models for the three groups. An age–drug
with each of these event groups. Patients from the interaction was identified in the model predicting the
celecoxib cohort aged 80 yr or more have the highest estimate of peripheral venous thrombotic events
(but not statistically significantly different) rate of (likelihood ratio test, 2 P ¼ 0.0128). The age and sex
experiencing cardiovascular or cerebrovascular TE adjusted estimate for celecoxib users aged 50–59 yr was
events compared to the younger age groups (age 80 higher compared to meloxicam users of the same age,
yr or more treated as the reference group), and the but this did not achieve statistical significance [RR 3.35
lowest (but not statistically significantly different) rate (95% CI 0.30–37.00)]. Conversely celecoxib users aged
of peripheral venous thrombotic events. Conversely, 60–69, 70–79 or 80 yr or more had a lower relative risk
patients from the meloxicam cohort aged 80 yr or more of these events than meloxicam users of the same age
had the lowest rates (but not statistically significantly categories, but again these were not statistically
different) of cardiovascular TE events than the younger different [RR 0.76 (95% CI 0.23–2.46), RR 0.79
age groups. As reported previously [26], the 95% CIs (95% CI 0.20–3.17) and RR 0.55 (95% CI 0.06–5.26),
for this event group for meloxicam were wide, thus one respectively].
cannot exclude the possibility of a similar relationship The effect of the 25.2% reduction in the total
to that observed for celecoxib. The age-specific number of observations when fitting the final Poisson
estimates of RRs obtained via stepwise comparison of model [n ¼ 36 545 vs 27 329] was also examined, where
the age-specific rates indicated that these relationships statistically significant differences were found. The
were not linear for either drug, with no systematic relative risk estimates for each group calculated with
difference in the age-specific rates for each of the removal of subjects with missing values for the
three event groups (tests for effect modification, all 2 adjusting variables sex and age are also shown in
P > 0.1493). A between-drug comparison revealed that Table 4. The unadjusted model for cardiovascular TE
for cerebrovascular TE events, celecoxib users aged 80 events fitted using the full model was of borderline
yr or more were more likely to have these events than statistical significance and fitting the model to the
meloxicam users of the same age [RR 2.59 (95%CI reduced dataset [n ¼ 27 329] led to a non-significant
1.17–5.70)]. difference. However, this change was unlikely to have
Females tended towards a lower rate of experiencing an impact on our findings. Furthermore, adjusting for
the selected TE events than males (treated as the age and sex had no statistically significant effect on
TABLE 3. Crude ratesa and RRsa of thromboembolic (cardiovascular, cerebrovascular and peripheral venous thrombotic) events, per 1000 pyr by risk factor
Cardiovascular (n ¼ 28) Cerebrovascular (n ¼ 68) Peripheral venous (n ¼ 17) Cardiovascular (n ¼ 19) Cerebrovascular (n ¼ 52) Peripheral venous (n ¼ 20)
Rate Rate ratio Rate Rate ratio Rate Rate ratio Rate Rate ratio Rate Rate ratio Rate Rate ratio
Risk factor n (95% CI) (95% CI) n (95% CI) (95% CI) n (95% CI) (95% CI) n (95% CI) (95% CI) n (95% CI) (95% CI) n (95% CI) (95% CI)
Age (yr)
39 0 – – 0 – – 2 8.3 3.8 0 – – 4 6.5 0.5 – –
(2.1, 33.2) (0.2, 223.2) (2.4, 17.2) (0.2, 1.5)
40–49 0 – – 1 2.5 0.1 0 – – 0 – – 2 2.3 0.2 – –
(0.4, 18.0) (0.0, 0.5) (0.6, 9.2) (0.0, 0.8)
50–59 1 1.3 0.2 4 5.3 0.1 2 2.8 1.2 0 – – 2 1.5 0.1 1 0.7 0.2
(0.2, 9.4) (0.0, 1.5) (2.0, 14.1) (0.0, 0.5) (0.7, 10.5) (0.1, 70.8) (0.4, 5.8) (0.0, 0.5) (0.1, 5.2) (0.0, 1.7)
60–69 5 5.5 0.6 8 8.8 0.2 4 4.4 2.0 9 5.6 4.2 9 5.7 0.4 9 5.7 1.4
(2.3, 13.2) (0.1, 3.2) (4.4, 17.6) (0.1, 0.6) (1.6, 1.17) (0.2, 98.3) (2.9, 10.9) (0.5, 32.7) (2.9, 10.9) (0.2, 1.0) (2.9, 10.9) (0.4, 5.1)
70–79 7 8.0 0.9 16 18.2 0.5 3 3.4 1.5 6 4.4 3.2 18 13.1 1.0 6 4.4 1.1
(3.8, 16.7) (0.2, 4.2) (11.2, 29.7) (0.2, 1.0) (1.1, 10.6) (0.1, 81.3) (2.0, 9.7) (0.4, 26.7) (8.3, 20.9) (0.4, 2.1) (2.0, 9.7) (0.3, 4.3)
80þ 4 8.8 1.0 16 35.3 1.0 1 2.2 1.0 1 1.4 1.0 10 13.6 1.0 3 4.1 1.0
(3.3, 23.4) (21.6, 57.6) (0.3, 15.6) (0.2, 9.7) (7.3, 25.4) (1.3, 12.7)
Not known 11 – – 23 – – 5 – – 3 – – 7 – – 1 – –
Sex
Male 15 8.1 1.0 22 11.8 1.0 6 3.2 1.0 13 5.3 1.0 20 8.2 1.0 9 3.7 1.0
(4.9, 13.4) (7.8, 18.0) (1.4, 7.2) (3.1, 9.2) (5.3, 12.7) (1.9, 7.1)
Female 13 3.2 0.4 46 11.35 0.9 11 2.7 0.8 6 1.2 0.2 32 6.5 0.8 11 2.2 0.6
(1.9, 5.5) (0.2, 0.8) (8.5, 15.2) (0.6, 1.3) (1.5, 4.9) (0.3, 2.3) (0.5, 2.7) (0.1, 0.6) (4.6, 9.2) (0.5, 1.4) (1.2, 4.0) (0.3, 1.5)
Not known 0 – – 0 – – 0 – – 0 – – 0 – – 0 – –
Indication
Other 17 4.2 1.0 39 9.6 1.0 10 2.5 1.0 16 2.8 1.0 39 6.9 1.0 12 2.1 1.0
(2.6, 6.7) (7.0, 13.2) (1.3, 4.6) (1.7, 4.6) (5.1, 9.5) (1.2, 3.8)
Osteoarthritis 11 5.9 1.4 29 15.6 1.4 7 3.8 1.5 3 1.6 0.6 13 6.9 1.0 8 4.3 2.0
(3.3, 10.7) (0.7, 3.0) (10.9, 22.5) (1.0, 2.0) (1.8, 7.9) (0.6, 4.0) (0.5, 5.0) (0.2, 2.0) (4.0, 11.9) (0.5, 1.9) (2.1, 8.5) (0.8, 4.9)
NSAIDb
No 11 5.0 1.0 28 12.8 1.0 4 1.8 1.0 10 3.3 1.0 22 7.3 1.0 8 2.7 1.0
Thromboembolic events after taking celecoxib and meloxicam
(2.8, 9.1) (8.9, 18.6) (0.7, 4.9) (1.8, 6.2) (4.8, 11.1) (0.3, 5.3)
Yes 14 5.2 1.0 30 11.2 0.9 11 4.1 2.2 6 1.8 0.5 23 3.4 0.9 10 2.9 1.1
(3.8, 8.8) (0.5, 2.3) (7.8, 15.9) (0.6, 1.3) (2.3, 7.4) (0.7, 7.0) (0.8, 3.9) (0.2, 1.5) (6.7, 4.5) (0.5, 1.7) (1.6, 5.4)
Not known 3 – – 10 – – 2 – – 3 – – 7 – – 3 – –
a
Rates and rate ratio calculated using Poisson regression modelling.
b
Prescribed 3 months to starting drug.
1359
1360 D. Layton et al.
(95% CI)
cerebrovascular TE event was inflated slightly after
fitting the model using the reduced dataset, but would
not be sufficient to account for the relative rate
increase observed for cerebrovascular TE events with
TABLE 4. Crude and adjusted RRs of thromboembolic cardiovascular, cerebrovascular and peripheral venous thrombotic events in users of celecoxib compared to meloxicam
effect.
Rate
Discussion
Meloxicam
20/7.51
68/5.91
28/5.92
17/5.92
of any of the event groups. We acknowledge that the VIGOR study, whereas in the CLASS trial the
information on co-morbidity, such as past medical proportions of RA and OA patients were 28 and 72%,
history of cardiovascular disease, recent surgery and respectively, leading to differences in baseline risk of
lifestyle factors (e.g. smoking) is important. However, patients. Data from CLASS suggested no evidence of
the effect of these and other risk factors for TE events signals of any increased risk of cardiovascular events,
were not controlled for in this study. As reported including myocardial infarction (MI) and angina for
previously [26], age and sex are known to be strong celecoxib users. Separate analyses were performed for all
confounders [41, 43, 47]. Both of these studies support patients and those not taking aspirin. The incidence rate
this relationship, and again reports that older patients of serious cardiovascular TE events out of 3987 patients
are at greater risk of cerebrovascular TE events. taking celecoxib was reported as: MI (0.8 per 100 pyr),
Regarding peripheral venous thrombotic events, there cerebrovascular accident (CVA) (0.2 per 100 pyr). There
was evidence of an age–drug interaction on the relative was evidence of important differences among this group
risk estimate, in that women aged 50–59 yr were at and the other treatment groups. The relative risks for any
higher but non-significant risk of these events if serious cardiovascular TE event were 1.1 (95% CI
prescribed celecoxib rather than meloxicam, but a 0.7–1.6) for all patients and 1.1 (95% CI 0.6–1.9) for the
lower (non-significant) risk if aged 60 yr or more. We subgroup not taking aspirin, for celecoxib versus
discussed previously [26] that the risk factors for NSAID comparator drugs. Furthermore, no difference
peripheral venous thrombotic events are different to was observed when the TE events were aggregated into
those for cardiovascular or cerebrovascular events, but cardiac (fatal/non-fatal) or peripheral vascular events
because the number of events recorded for each groups (fatal/non-fatal), but celecoxib was associated with fewer
is small it is possible that this finding may have CVA than diclofenac/ibuprofen (0.2 vs 0.5%, respec-
occurred by chance. tively, P < 0.05). No difference was reported in the
A strength of this study is that the comparison of subgroups not taking aspirin. Thus, these analyses
celecoxib with meloxicam takes account of the similar demonstrated no increased risk of serious cardiovascular
baseline risk of adverse gastrointestinal events of TE events associated with celecoxib compared to
the two cohorts who may have been preferentially conventional NSAIDs.
prescribed these drugs because of their reported Our justification for choice of event terms for this
improved gastrointestinal (GI) tolerability [44, 48]. As comparative study has been presented previously [26].
for the first study [26], a channelling effect of past users Our study reflects the findings from CLASS, with the
of NSAIDs onto celecoxib exists, in that more patients exception of the increased relative risk of cerebrovascular
within this cohort had been prescribed an NSAID events for celecoxib compared to meloxicam. However, it
within the 3 months prior to starting treatment. Such is noteworthy that while the adjusted RR for cerebro-
channelling effects of groups at high risk of GI adverse vascular TE events in our study was 1.66, the lower end
events have been reported previously for both these of the 95% CI was 1.10, marginally greater than the null
agents [48, 49]. We stated in the comparison between estimate which could have resulted from bias or chance.
rofecoxib and meloxicam examining TE cardiovascular One cannot exclude the possibility that the variation in
risk [26] that we did not examine the effect of this COX-1/COX-2 selectivity of the two drugs at the clinical
phenomenon, but we acknowledge that there may also dosing regimes used may have undetermined effects on
be channelling of patients at high-risk of cardiovas- vascular haemostasis, however this is beyond the scope of
cular events. In PEM, incomplete information on risk this study.
factors predisposing patients to these types of events, The restrospective, observational cohort study by Ray
such as past history of cardiovascular disease or et al. [52], used data collected from the expanded
lifestyle factors, is available and thus the confounding Tennesse Medicaid programme, TennCare, to investi-
effect of these and other risk factors could not be gate the occurrence of serious coronary heart disease in
controlled for. It is important to stress that the quality non-users (n ¼ 202 916) and users of rofecoxib
of the data in PEM is dependent on the precision and (n ¼ 24 132), celecoxib (n ¼ 22 337) and other NSAIDs
completeness of the form-filling by GPs. (n ¼ 129 391), aged 50–84 yr, who lived in the community
We highlighted many of the limitations of PEM in the and had no life-threatening non-cardiovascular illness.
previous paper [26]. While the collection of data in PEM New users of high-dose rofecoxib (>25 mg/day) had a
is of a systematic and prospective nature, it often results rate of serious coronary heart disease (CHD) events
in incomplete information on concomitant medication (hospital admission for acute MI or death from CHD) of
that may later prove to be important risk factors for 24.0 per 1000 pyr, new users of low-dose rofecoxib
selected events [26, 44]. In our studies, information on (25 mg/day) had a rate of 13.7, new users of celecoxib
concomitant aspirin use was incomplete and thus the had a rate of 12.2, and non-users had a rate of 13.0. The
confounding effect of aspirin could not be controlled for. adjusted incidence RR for high-dose rofecoxib was 2.20
The VIGOR study [4] and CLASS trial [6] differed in (95% CI 1.17–4.10) compared to celecoxib, 1.93 (95% CI
several aspects [50]; importantly, in the CLASS trial 1.09–3.43) compared to non-users. The corresponding
patients were permitted to take prophylactic low dose adjusted estimate for celecoxib compared to non-users
aspirin (<325 mg/day) or other antiplatelet agents [51]. was 0.88 (95% CI 0.67–1.16). In our study the rate of
Furthermore, only patients with RA were enrolled in cardiovascular events (MI, cardiac arrest and relevant
1362 D. Layton et al.
non-specific cardiovascular events) was lower than the when considered together with other studies seeking to
observed rate in the study by Ray et al. [52], but this is to determine the association between the use of COX-2
be expected since this study uses event data reported by inhibitors and TE events.
GPs. While a large number of events had been followed
up requesting further information, it is possible that
some events may either not have been reported or been Conflict of interest
reported incorrectly. Nevertheless, we have no reason to
believe that there was differential under-reporting The DSRU is an independent charity, which works in
between the two products. We acknowledge that the association with the University of Portsmouth. It
two PEM studies were conducted during different receives unconditional donations from pharmaceutical
calendar periods, and the study for celecoxib was companies. The companies have no control on the
initiated at the same time as the results of the VIGOR conduct or the publication of the studies conducted by
study were published. It is possible that publication bias the DSRU. The DSRU has received such funds from
might have influenced the reporting of such events the manufacturers of celecoxib and meloxicam. S. A.
between the two drugs, and this issue requires further W. Shakir has received support from Pfizer to attend
investigation. scientific meetings.
By May 2002, four reports of MI (one fatal), one
report of pulmonary embolism (PE) (fatal) and two
reports of CVA had been reported for celecoxib to the References
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