Celecoxib And Meloxicam

Rheumatology 2003;42:1354–1364 doi:10.1093/rheumatology/keg401, available online at www.rheumatology.oupjournals.org Advance Access publication 16 July 2003

Comparison of the incidence rates of thromboembolic events reported for patients prescribed celecoxib and meloxicam in general practice in England using Prescription-Event Monitoring (PEM) data Deborah Layton1,2, Kerry Hughes1, Scott Harris1,3 and Saad A.W. Shakir1,2 Background. Celecoxib and meloxicam are classified as cyclooxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit monitored the post marketing safety of these drugs in England using the non-interventional observational cohort technique of Prescription-Event Monitoring (PEM). Objectives. To compare the incidence rates of selected thromboembolic (TE) (cardiovascular, cerebrovascular and peripheral venous thrombotic) events reported for patients prescribed celecoxib and meloxicam in general practice. Methods. Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996–March 1997) and celecoxib (May and December 2000). Simple questionnaires requesting details of events occurring during/after treatment, indication and potential risk factors (including age, sex and whether NSAIDs had been 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 (RRs) were obtained using Poisson regression modelling. Results. During the 9 months after starting treatment, 28 (0.16%) and 19 (0.10%) of patients were reported to have experienced cardiovascular TE events, 68 (0.39%) and 52 (0.27%) cerebrovascular TE events, and 17 (0.10%) and 20 (0.10%) experienced peripheral venous thrombotic events for celecoxib and meloxicam, respectively. Regarding time to first event, there was a persistent divergence between the two drugs from 30 days after the start of treatment for both the cardiovascular TE event group (log rank test P ¼ 0.0153) and cerebrovascular TE event group (log rank test P ¼ 0.0055). Indication and use of an NSAID within 3 months prior to starting treatment had no effect on the relative risk estimates of the event groups and was excluded in subsequent analyses. Adjusting for the two identified risk factors of age (age2) and sex, the cerebrovascular TE event group rate was higher for celecoxib than for meloxicam, RR 1.66 (95% CI 1.10–2.51), over the study period and no different for the cardiovascular TE event group, RR 1.72 (95% CI 0.87–3.40) or peripheral venous thrombotic group, RR 1.06 (95% CI 0.51–2.19). Conclusions. This study reports a relative increase in the rate of cerebrovascular TE events in users of celecoxib compared to meloxicam. There was no difference in the rate of cardiovascular TE events or peripheral venous thrombotic events 1

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, 2University of Portsmouth and 3University of Southampton, UK. Submitted 6 January 2003; revised version accepted 8 April 2003. Correspondence to: D. Layton, Drug Safety Research Unit, Southampton SO31 1AA, UK. E-mail: [email protected]

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 developed with the aim of reducing gastrointestinal (GI) adverse reactions compared to non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) [1–6]. However, while emerging information suggests that use of such drugs may contribute to an increased risk of adverse vascular events [7], this is yet to be confirmed by a sufficient number of studies. Furthermore, it is unclear whether the higher risk applies to all thromboembolic (TE) events and whether it applies to all COX-2 inhibitors at all doses, or to some products at specific doses or dose ranges [8]. The pharmacology of NSAIDs appears to be well described [9, 10]. However, accumulating evidence regarding the relationship between COX-1 mediated platelet-derived thromboxane-A2 and COX-2-mediated macrovascular endothelial-cell-derived prostacyclin [11–16] suggests that vascular haemostasis may be impaired in circumstances where blockade of COX-2induced prostacyclin, unopposed by COX-1-induced platelet aggregation, may result in an increased risk of TE events in susceptible individuals [17, 18]. Celecoxib (CelebrexÕ ), launched in May 2000 was the second COX-2-specific isoenzyme inhibitor to be marketed in the UK, and was indicated for the symptomatic relief of osteoarthritis (OA) or rheumatoid arthritis (RA). As reported for other COX-2 selective agents, celecoxib (600 mg b.d. for 10 days) does not inhibit platelet aggregation or prolong bleeding time in studies in healthy volunteers [19]. However, elevated prothrombin times and bleeding episodes have been observed with concomitant use of celecoxib and warfarin [20], and there have been four patients with connective tissue disorders that developed ischaemic complications associated with thrombosis after receiving celecoxib [21–23]. Meloxicam (MobicÕ ), launched in the UK in December 1996, is also considered to be a COX-2 selective inhibitor [24, 25], and was indicated for relief of pain and inflammation in rheumatic disease, in exacerbations of osteoarthritic pain and ankylosing spondylitis at launch. As described previously [26], meloxicam does not appear to affect COX-1-dependent platelet thromboxane formation or platelet aggregation [27–29], and reports of serious cardiovascular events have not been thought attributable to treatment [30]. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of cardiovascular thrombotic events [4]. Yet the evidence from other

studies of rofecoxib is conflicting [31, 32]. In contrast the CLASS (celecoxib long-term arthritis safety study) trial, which involved 8059 patients with OA or RA, and compared celecoxib (400 mg b.d.) with NSAIDs (ibuprofen 800 mg t.d.s or diclofenac 75 mg b.d.), demonstrated no excess of serious TE cardiovascular events [6]. For both drugs, these large-scale trials were designed to demonstrate that gastrointestinal safety was superior to that of traditional NSAIDs in clinical practice, but were not sufficiently powered to detect differences of TE events against the background cardiovascular event rates in the placebo groups. A review of four randomized trials [including the CLASS trial and VIGOR (Vioxx Gastrointestinal Outcomes Trial) study] that was conducted to determine whether COX-2 inhibitors are associated with a protective or hazardous effect on the risk of cardiovascular events reported a potential increase in cardiovascular event rates for users of COX-2 inhibitors [31]. However, these trials were different in several ways and the results were not directly comparable. Monitoring for adverse effects in the post-marketing phase forms an important part of a drug’s safety profile. Post-marketing data derived from spontaneous reports suggest that the risks of renal and cardiovascular adverse events associated with the use of rofecoxib are significantly higher than those of celecoxib and NSAIDs (diclofenac and ibuprofen) [33]. Prescription-Event Monitoring (PEM) studies of newly marketed drugs during their immediate post-marketing period in England, provide complementary data on safety issues in addition to randomized-controlled trials and spontaneous reporting schemes. PEM uses a non-interventional observational cohort technique with a systematic approach to data collection; the methodology has been described in detail elsewhere [34–38]. As part of its monitoring program, the Drug Safety Research Unit (DSRU) has carried out individual PEM studies of meloxicam [39] and celecoxib [40]. This paper reports the results of a study to examine and compare the cardiovascular risk of these two COX-2 selective inhibitors. An identical study was conducted using rofecoxib and meloxicam [26]. These studies, using data collected via the observational technique of PEM, did not require reference to an ethics committee or patient consent. The aim of this second study was to retrospectively investigate, using large cohorts from the general population of England, whether there is a difference in the type and incidence of TE cardiovascular events

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D. Layton et al.

reported during routine clinical use in general practice of meloxicam and celecoxib. As before, our objectives were: to calculate and compare rates for TE events occurring within the first 9 months after starting treatment with celecoxib or meloxicam; to determine relative risks, or rate ratios (RRs) separately for cardiovascular and cerebrovascular TE events and peripheral venous thrombotic events, adjusted for the possible confounders of age and sex [41–43], and whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug [15, 42, 43]; and to calculate and compare the time to first event within each TE event group for each cohort.

Methods The PEM study conducted for celecoxib was conducted as described previously for rofecoxib [44]. For this study, exposure data were obtained from green forms received for patients identified from NHS prescriptions written by GPs in England for meloxicam between December 1996 and March 1997 (n ¼ 19 087) and for celecoxib between May and December 2000 (n ¼ 17 458). For comparative purposes the exposed are those patients prescribed celecoxib and the unexposed are those patients prescribed meloxicam. As described previously [26], the event terms for this study were selected by medical practitioners from the DSRU dictionary prior to the analysis and aggregated into the three TE groups (cardiovascular, cerebrovascular and peripheral venous thrombotic) events (Table 1). The data were subject to the same inclusion and exclusion criteria as specified previously, for calculation of person-time exposed (pte) [26, 44, 45].

Sample size 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% between the drugs for each event group, if such an underlying background relative difference exists [26].

Analysis Data analysis was conducted in an identical manner to that described previously [44]. The unadjusted RRs, as well as ratios adjusted for the selected risk factors were calculated and examined using both univariate and multivariate Poisson regression modelling. Evidence of effect modification by the selected risk factors on the estimates of relative risk were also investigated, and the estimate of time to first event for each group for each cohort calculated and compared as stated previously [26, 44, 46].

Results The characteristics of both study cohorts are presented in Table 2. As described previously [26], where reported celecoxib users were more likely than meloxicam users to be aged 60 yr or more [59.7% (6378/10 727) vs 55.0% (9280/16 877), 2 P < 0.0001] and be female [68.3% (11 928/17 455) vs 67.1% (12 590/18 763), 2 P ¼ 0.012]. OA was the most frequently reported indication for both celecoxib and meloxicam, although the proportion was higher for celecoxib compared to meloxicam, respec-

TABLE 1. Thromboembolic event groups Cardiovascular

Cerebrovascular

Peripheral venous thrombotic

Amaurosis fugax Deep vein thrombosis Cardiac arresta Embolus pulmonary CVS not specifieda Aphasia Myocardial Cerebrovascular Infarction pulmonary infarction accident Dysarthria Dysphagiaa Dysphasia Embolus cerebral Embolus mesenteric Hemianopia Hemiparesis Hemiplegia Hypoaesthesiaa Paralysis facial Paralysis pseudobulbar Paralysis ocular Paraesthesiaa Paresisa Retinal thrombosis artery Retinal thrombosis vein Slurred speach Thrombosis cerebral Transient ischaemic attack Visual disturbancea During the 9 month study period, one report of embolus artery was recorded for celecoxib; no reports were recorded for the following miscellaneous TE event terms: infarction gastrointestinal, thrombosis mesenteric, thrombosis spinal, thrombosis artery, infarction renal. a Non-specific terms evaluated by clinician and relevant lowest level (doctor terms) included in the analysis. CVS, cardiovascular system.

tively [28.1 vs 23.2%, 2 P < 0.0001], with similar proportions of users prescribed either celecoxib or meloxicam for treatment of symptoms of RA, respectively [6.5% (1128/17 458) vs 6.6% (1253/19 087), 2 P ¼ 0.3520]. Where answers to the additional questions were given, significantly more celecoxib users than meloxicam users had been prescribed an NSAID within the 3 months prior to starting treatment [49.4% (7006/14 195) vs 48.0% (7978/16 634), 2 P ¼ 0.014]. During the 9 months after starting treatment with celecoxib and meloxicam, 28 (0.16%) and 19 (0.10%) of patients were reported to have had cardiovascular TE events, 68 (0.39%) and 52 (0.27%) were reported to have had cerebrovascular TE events, and 17 (0.10%) and 20 (0.10%) were reported to have had peripheral venous thrombotic events, respectively. The proportion of events excluded from the study as defined in the methods for both drugs were similar [celecoxib 56.8% (149/262) versus meloxicam 51.0% (95/186); 2 P ¼ 0.225]. Regarding the time to first event, the crude estimate of time to first event of both cohorts for each event group separately is presented in the form of Kaplen–Meier survival curves in Figures 1–3. There was a significant difference in the estimate of time to first event over the study period in the cardiovascular TE event group for

Thromboembolic events after taking celecoxib and meloxicam

1357

TABLE 2. Characteristics of study cohort Drug Risk factor

Celecoxib (N ¼ 17 458)

Age (yr)
39 871 (5.0) 40–49 1281 (7.3) 50–59 2197 (12.6) 60–69 2582 (14.8) 70–79 2467 (14.1) 80þ 1329 (7.6) Not known 6731 (38.6) Sex Male 5527 (31.7) Female 11 928 (68.3) Sex not known 3 (<0.1) Indication Osteoarthritis 4905 (28.1) Others 12 553 (71.9) NSAID prescribed within 3 months prior to starting drug Yes 7006 (40.1) No 7189 (41.2) Not known 3263 (18.7)

Meloxicam (N ¼ 19 087) 1852 2297 3448 3947 3457 1876 2210

(9.7) (12.0) (18.1) (20.1) (18.1) (9.8) (11.6)

2 P valuea <0.0001

6173 (32.3) 12 590 (67.1) 324 (1.7)

0.012

4434 (23.2) 14 653 (76.8)

<0.0001

7978 (41.8) 8658 (45.4) 2451 (12.9)

0.014

All values are n (%). a Excludes values not known.

FIG. 1. Kaplan–Meier survival estimates for cardiovascular TE events, between celecoxib and meloxicam cohorts.

FIG. 2. Kaplan–Meier survival estimates for cerebrovascular TE events between celecoxib and meloxicam cohorts.

FIG. 3. Kaplan–Meier survival estimates for peripheral venous thrombotic events, between celecoxib and meloxicam cohorts.

celecoxib compared to meloxicam [median pte 75.5 days (interquartile range (IQR), 39.5–145.5) and 95 days (IQR, 38–108), respectively, log rank test P ¼ 0.0153; Fig. 1], with the curves separating 30 days after starting treatment and no significant convergence after that time. There was also a significant difference in the time to first cerebrovascular TE event for celecoxib compared to meloxicam [median pte 105 days (IQR 40–171.5) and 100 days (IQR 23.5–140.5), log rank test P ¼ 0.0055; Fig. 2], with the survival curves separating 30 days after starting treatment and no significant convergence after that time. There was no difference observed in the time to first peripheral venous thrombotic event between the study drugs [median pte 103 days (IQR 28–186) and 118.5 days (IQR 48.5–178), log rank test P ¼ 0.7930; Fig. 3], which is

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D. Layton et al.

reflected by the survival curves, one almost superimposed upon the other. Cross-tabulation of risk factors with event groups suggested a significant association between age and experiencing cardiovascular TE (2 P < 0.0001), cerebrovascular TE (2 P < 0.0001) and peripheral venous thrombotic events (2 P ¼ 0.017); between sex and experiencing cardiovascular TE events (2 P < 0.0001) and between indication and experiencing cerebrovascular TE events (2 P ¼ 0.017) and peripheral venous thrombotic events (2 P ¼ 0.037). Use of a NSAID within the 3 months prior to starting treatment was not associated with any of the event groups. At launch and at the time of the PEM studies, the recommended dose range of celecoxib was 100–400 mg/day, whilst meloxicam only had two doses licensed (7.5 or 15 mg/day). As reported previously [26], limited information on dose was provided on the green forms for meloxicam. For celecoxib, information on starting dose was available for 84.4% (n ¼ 14 726). Dose at event was provided for 57.1% (16/28) of patients reported to have cardiovascular TE events, 75.0% (51/68) of patients reported to have cerebrovascular TE events and 90.9% (10/17) of patients reported to have peripheral venous thrombotic events. Of these, 15 (93.8%), 49 (96.1%) and seven (70.0%) patients, respectively were taking 200 mg/day or less. 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 personyears (pyr) for both drug cohorts over the first 9 months of treatment and RRs for each risk factor category. We reported earlier that age is associated with each of these event groups. Patients from the celecoxib cohort aged 80 yr or more have the highest (but not statistically significantly different) rate of experiencing cardiovascular or cerebrovascular TE events compared to the younger age groups (age 80 yr or more treated as the reference group), and the lowest (but not statistically significantly different) rate of peripheral venous thrombotic events. Conversely, patients from the meloxicam cohort aged 80 yr or more had the lowest rates (but not statistically significantly different) of cardiovascular TE events than the younger age groups. As reported previously [26], the 95% CIs for this event group for meloxicam were wide, thus one cannot exclude the possibility of a similar relationship to that observed for celecoxib. The age-specific estimates of RRs obtained via stepwise comparison of the age-specific rates indicated that these relationships were not linear for either drug, with no systematic difference in the age-specific rates for each of the three event groups (tests for effect modification, all 2 P > 0.1493). A between-drug comparison revealed that for cerebrovascular TE events, celecoxib users aged 80 yr or more were more likely to have these events than meloxicam users of the same age [RR 2.59 (95%CI 1.17–5.70)]. Females tended towards a lower rate of experiencing the selected TE events than males (treated as the

reference group), although statistical significance was only observed for users of either drug experiencing cardiovascular TE events. There was no evidence of a sex–drug interaction for any of the event groups (tests for effect modification, all 2 P > 0.063). Examination of drug-indication specific rates revealed no statistically significant effect on the rate of any of the event groups within each cohort, nor did a prescription of an NSAID within 3 months of starting treatment (compared to ‘none’ treated as the reference group). Furthermore, there was no evidence of a drug–risk factor interaction (tests for effect modification, all 2 P > 0.2032). The crude and adjusted RRs are presented in Table 4. As reported previously [26], indication and prescription of an NSAID within 3 months of starting treatment were initially regarded as important risk factors in this study; however, adjusting for these variables made no statistically significant difference to the RR estimates. Thus age and gender were the two risk factor variables included in the final Poisson regression model. Adjusting for these two risk factors of age (also as a quadratic variable age2) and sex suggests that a difference exists between subjects prescribed either of the two drugs and the rate of experiencing cerebrovascular TE events; the adjusted rate was higher for celecoxib than meloxicam [RR 1.66 (95% CI 1.10–2.51)]. With regard to cardiovascular TE events and peripheral venous thrombotic events the difference did not achieve statistical significance. Evidence of effect modification was further examined by inclusion of interaction terms within the final Poisson models for the three groups. An age–drug interaction was identified in the model predicting the estimate of peripheral venous thrombotic events (likelihood ratio test, 2 P ¼ 0.0128). The age and sex adjusted estimate for celecoxib users aged 50–59 yr was higher compared to meloxicam users of the same age, but this did not achieve statistical significance [RR 3.35 (95% CI 0.30–37.00)]. Conversely celecoxib users aged 60–69, 70–79 or 80 yr or more had a lower relative risk of these events than meloxicam users of the same age categories, but again these were not statistically different [RR 0.76 (95% CI 0.23–2.46), RR 0.79 (95% CI 0.20–3.17) and RR 0.55 (95% CI 0.06–5.26), respectively]. The effect of the 25.2% reduction in the total number of observations when fitting the final Poisson model [n ¼ 36 545 vs 27 329] was also examined, where statistically significant differences were found. The relative risk estimates for each group calculated with removal of subjects with missing values for the adjusting variables sex and age are also shown in Table 4. The unadjusted model for cardiovascular TE events fitted using the full model was of borderline statistical significance and fitting the model to the reduced dataset [n ¼ 27 329] led to a non-significant difference. However, this change was unlikely to have an impact on our findings. Furthermore, adjusting for age and sex had no statistically significant effect on

0

1

5

7

4

40–49

50–59

60–69

70–79

80þ

1.0 (0.5, 2.3) –

1.0

1.4 (0.7, 3.0)

1.0

0.4 (0.2, 0.8) –

1.0

–

0.2 (0.0, 1.5) 0.6 (0.1, 3.2) 0.9 (0.2, 4.2) 1.0

–

– 2.5 (0.4, 18.0) 5.3 (2.0, 14.1) 8.8 (4.4, 17.6) 18.2 (11.2, 29.7) 35.3 (21.6, 57.6) –

–

12.8 (8.9, 18.6) 30 11.2 (7.8, 15.9) 10 –

28

9.6 (7.0, 13.2) 29 15.6 (10.9, 22.5)

39

11.8 (7.8, 18.0) 46 11.35 (8.5, 15.2) 0 –

22

23

16

16

8

4

1

0

0.9 (0.6, 1.3) –

1.0

1.4 (1.0, 2.0)

1.0

0.9 (0.6, 1.3) –

1.0

–

0.1 (0.0, 0.5) 0.1 (0.0, 0.5) 0.2 (0.1, 0.6) 0.5 (0.2, 1.0) 1.0

–

Rate ratio (95% CI)

b

Rates and rate ratio calculated using Poisson regression modelling. Prescribed
3 months to starting drug.

a

17

4.2 (2.6, 6.7) Osteoarthritis 11 5.9 (3.3, 10.7) NSAIDb No 11 5.0 (2.8, 9.1) Yes 14 5.2 (3.8, 8.8) Not known 3 –

Not known Indication Other

Female

1.3 (0.2, 9.4) 5.5 (2.3, 13.2) 8.0 (3.8, 16.7) 8.8 (3.3, 23.4) –

–

–

Rate (95% CI)

Cerebrovascular (n ¼ 68)

Rate Rate ratio (95% CI) (95% CI) n

8.1 (4.9, 13.4) 13 3.2 (1.9, 5.5) 0 –

15

11

0

Age (yr)
39

Not known Sex Male

n

Risk factor

Cardiovascular (n ¼ 28)

Celecoxib (n ¼ 17 358)

2

11

4

7

10

0

11

6

5

1

3

4

2

0

2

n

1.8 (0.7, 4.9) 4.1 (2.3, 7.4) –

2.5 (1.3, 4.6) 3.8 (1.8, 7.9)

3.2 (1.4, 7.2) 2.7 (1.5, 4.9) –

2.8 (0.7, 10.5) 4.4 (1.6, 1.17) 3.4 (1.1, 10.6) 2.2 (0.3, 15.6) –

8.3 (2.1, 33.2) –

Rate (95% CI)

2.2 (0.7, 7.0) –

1.0

1.5 (0.6, 4.0)

1.0

0.8 (0.3, 2.3) –

1.0

–

1.2 (0.1, 70.8) 2.0 (0.2, 98.3) 1.5 (0.1, 81.3) 1.0

3.8 (0.2, 223.2) –

Rate ratio (95% CI)

Peripheral venous (n ¼ 17)

3

6

10

3

16

0

6

13

3

1

6

9

0

0

0

n

3.3 (1.8, 6.2) 1.8 (0.8, 3.9) –

2.8 (1.7, 4.6) 1.6 (0.5, 5.0)

5.3 (3.1, 9.2) 1.2 (0.5, 2.7) –

0.5 (0.2, 1.5) –

1.0

0.6 (0.2, 2.0)

1.0

0.2 (0.1, 0.6) –

1.0

–

7.3 (4.8, 11.1) 23 3.4 (6.7, 4.5) 7 –

22

6.9 (5.1, 9.5) 13 6.9 (4.0, 11.9)

39

0.9 (0.5, 1.7) –

1.0

1.0 (0.5, 1.9)

1.0

0.8 (0.5, 1.4) –

1.0

–

0.5 (0.2, 1.5) 0.2 (0.0, 0.8) 0.1 (0.0, 0.5) 0.4 (0.2, 1.0) 1.0 (0.4, 2.1) 1.0

Rate Rate ratio (95% CI) (95% CI)

8.2 (5.3, 12.7) 32 6.5 (4.6, 9.2) 0 –

20

4

n

Cerebrovascular (n ¼ 52)

6.5 (2.4, 17.2) – – 2 2.3 (0.6, 9.2) – – 2 1.5 (0.4, 5.8) 5.6 4.2 9 5.7 (2.9, 10.9) (0.5, 32.7) (2.9, 10.9) 4.4 3.2 18 13.1 (2.0, 9.7) (0.4, 26.7) (8.3, 20.9) 1.4 1.0 10 13.6 (0.2, 9.7) (7.3, 25.4) – – 7 –

–

Rate Rate ratio (95% CI) (95% CI)

Cardiovascular (n ¼ 19)

Meloxicam (n ¼ 19 087)

TABLE 3. Crude ratesa and RRsa of thromboembolic (cardiovascular, cerebrovascular and peripheral venous thrombotic) events, per 1000 pyr by risk factor

3

10

8

8

12

0

11

9

1

3

6

9

1

–

–

n

2.7 (0.3, 5.3) 2.9 (1.6, 5.4) –

2.1 (1.2, 3.8) 4.3 (2.1, 8.5)

3.7 (1.9, 7.1) 2.2 (1.2, 4.0) –

0.7 (0.1, 5.2) 5.7 (2.9, 10.9) 4.4 (2.0, 9.7) 4.1 (1.3, 12.7) –

–

–

Rate (95% CI)

–

1.1

1.0

2.0 (0.8, 4.9)

1.0

0.6 (0.3, 1.5) –

1.0

–

0.2 (0.0, 1.7) 1.4 (0.4, 5.1) 1.1 (0.3, 4.3) 1.0

Rate ratio (95% CI)

Peripheral venous (n ¼ 20)

Thromboembolic events after taking celecoxib and meloxicam 1359

D. Layton et al.

1.72 (0.87, 3.40) 1.66 (1.10, 2.51) 1.06 (0.51, 2.19)

cardiovascular risk in this study. The estimate for 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 celecoxib compared to meloxicam. The effect of treatment duration was also examined by restricting the study period to the first 90 days after starting either drug for each event group. During this period, 15 (0.09%) and nine (0.05%) patients were reported to have cardiovascular TE events, 31 (0.18%) and 22 (0.12%) were reported to have cerebrovascular TE events and seven (0.04%) and nine (0.0.05%) were reported to have peripheral venous thrombotic events for celecoxib and meloxicam, respectively. For cardiovascular TE events, the final adjusted estimate to 90 days was RR 1.60 (95% CI 0.64–4.10), respectively, for celecoxib compared to meloxicam. The corresponding estimates for cerebrovascular TE events and peripheral venous thrombotic events were RR 1.72 (95% CI 0.95–3.13) and RR 1.11 (95% CI 0.38–3.11), respectively. For these two groups the 95% CI reported for the adjusted RR did not change to such a degree that might indicate that time may contribute a confounding effect.

c

b

Poisson regression model (whole data set). Poisson regression model excluding patients where age and sex not known (n ¼ 9216). Poisson regression model adjusted for age (age2) and sex.

Discussion

a

1.87 (1.04, 3.35) 1.66 (1.16, 2.38) 1.08 (0.56, 2.06) Cardiovascular Cerebrovascular Peripheral venous

28/5.92 68/5.91 17/5.92

4.73 (3.26, 6.85) 11.51 (9.07, 14.59) 2.87 (1.79, 4.62)

19/7.50 52/7.50 20/7.51

2.53 (1.61, 3.97) 0.69 (0.52, 0.90) 2.66 (1.72, 4.13)

1.89 (0.95, 3.74) 1.77 (1.18, 2.69) 1.12 (0.54, 2.31)

Adjusted RRc (95% CI) Unadjusted RRb (95% CI) Unadjusted RRa (95% CI) Rate (95% CI) No events 1000 pyr exposure Event

No events/ 1000 pyr exposure

Rate (95% CI)

Meloxicam Celecoxib

TABLE 4. Crude and adjusted RRs of thromboembolic cardiovascular, cerebrovascular and peripheral venous thrombotic events in users of celecoxib compared to meloxicam

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The PEM observational studies of celecoxib and meloxicam enable a retrospective comparison between a highly selective and a partially selective COX-2 inhibitor type of NSAID to be performed under general practice conditions. Data was collected for over 36 000 patients prescribed meloxicam and/or celecoxib under routine clinical practice conditions. In this study, a statistically significant relative rate increase was observed for cerebrovascular TE events 1.66 (95% CI 1.10–2.51) for celecoxib compared to meloxicam, after adjustment for age (also as a quadratic variable age2) and sex. This relative difference (of the same magnitude) was also observed in the previous study [26]. A reduction in the sample size (occurring as a result of including variables with missing values in the statistical model) is unlikely to account for this relative rate increase alone. As observed in the previous study [26], restriction of the study period to the first 90 days after starting treatment revealed no statistically significant difference in the relative risk estimates for each of the three event groups. Examination of the effect of time suggested that differences between celecoxib and meloxicam for cardiovascular or cerebrovascular TE events became apparent after 30 days of starting treatment, which persisted for the subsequent study period. Unlike the previous study there was no difference in the time to first peripheral venous thrombotic event between celecoxib and meloxicam, and no difference in relative risk difference was observed [RR 1.06 (95% CI 0.51–2.19)]. Clearly the temporal relationships need to be examined further. In both of these studies, indication and recent use of NSAIDs had no important effect on the relative rates

Thromboembolic events after taking celecoxib and meloxicam

of any of the event groups. We acknowledge that information on co-morbidity, such as past medical history of cardiovascular disease, recent surgery and lifestyle factors (e.g. smoking) is important. However, the effect of these and other risk factors for TE events were not controlled for in this study. As reported previously [26], age and sex are known to be strong confounders [41, 43, 47]. Both of these studies support this relationship, and again reports that older patients are at greater risk of cerebrovascular TE events. Regarding peripheral venous thrombotic events, there was evidence of an age–drug interaction on the relative risk estimate, in that women aged 50–59 yr were at higher but non-significant risk of these events if prescribed celecoxib rather than meloxicam, but a lower (non-significant) risk if aged 60 yr or more. We discussed previously [26] that the risk factors for peripheral venous thrombotic events are different to those for cardiovascular or cerebrovascular events, but because the number of events recorded for each groups is small it is possible that this finding may have occurred by chance. A strength of this study is that the comparison of celecoxib with meloxicam takes account of the similar baseline risk of adverse gastrointestinal events of the two cohorts who may have been preferentially prescribed these drugs because of their reported improved gastrointestinal (GI) tolerability [44, 48]. As for the first study [26], a channelling effect of past users of NSAIDs onto celecoxib exists, in that more patients within this cohort had been prescribed an NSAID within the 3 months prior to starting treatment. Such channelling effects of groups at high risk of GI adverse events have been reported previously for both these agents [48, 49]. We stated in the comparison between rofecoxib and meloxicam examining TE cardiovascular risk [26] that we did not examine the effect of this phenomenon, but we acknowledge that there may also be channelling of patients at high-risk of cardiovascular events. In PEM, incomplete information on risk factors predisposing patients to these types of events, such as past history of cardiovascular disease or lifestyle factors, is available and thus the confounding effect of these and other risk factors could not be controlled for. It is important to stress that the quality of the data in PEM is dependent on the precision and completeness of the form-filling by GPs. We highlighted many of the limitations of PEM in the previous paper [26]. While the collection of data in PEM is of a systematic and prospective nature, it often results in incomplete information on concomitant medication that may later prove to be important risk factors for selected events [26, 44]. In our studies, information on concomitant aspirin use was incomplete and thus the confounding effect of aspirin could not be controlled for. The VIGOR study [4] and CLASS trial [6] differed in several aspects [50]; importantly, in the CLASS trial patients were permitted to take prophylactic low dose aspirin (<325 mg/day) or other antiplatelet agents [51]. Furthermore, only patients with RA were enrolled in

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the VIGOR study, whereas in the CLASS trial the proportions of RA and OA patients were 28 and 72%, respectively, leading to differences in baseline risk of patients. Data from CLASS suggested no evidence of signals of any increased risk of cardiovascular events, including myocardial infarction (MI) and angina for celecoxib users. Separate analyses were performed for all patients and those not taking aspirin. The incidence rate of serious cardiovascular TE events out of 3987 patients taking celecoxib was reported as: MI (0.8 per 100 pyr), cerebrovascular accident (CVA) (0.2 per 100 pyr). There was evidence of important differences among this group and the other treatment groups. The relative risks for any serious cardiovascular TE event were 1.1 (95% CI 0.7–1.6) for all patients and 1.1 (95% CI 0.6–1.9) for the subgroup not taking aspirin, for celecoxib versus NSAID comparator drugs. Furthermore, no difference was observed when the TE events were aggregated into cardiac (fatal/non-fatal) or peripheral vascular events (fatal/non-fatal), but celecoxib was associated with fewer CVA than diclofenac/ibuprofen (0.2 vs 0.5%, respectively, P < 0.05). No difference was reported in the subgroups not taking aspirin. Thus, these analyses demonstrated no increased risk of serious cardiovascular TE events associated with celecoxib compared to conventional NSAIDs. Our justification for choice of event terms for this comparative study has been presented previously [26]. Our study reflects the findings from CLASS, with the exception of the increased relative risk of cerebrovascular events for celecoxib compared to meloxicam. However, it is noteworthy that while the adjusted RR for cerebrovascular TE events in our study was 1.66, the lower end of the 95% CI was 1.10, marginally greater than the null estimate which could have resulted from bias or chance. One cannot exclude the possibility that the variation in COX-1/COX-2 selectivity of the two drugs at the clinical dosing regimes used may have undetermined effects on vascular haemostasis, however this is beyond the scope of this study. The restrospective, observational cohort study by Ray et al. [52], used data collected from the expanded Tennesse Medicaid programme, TennCare, to investigate the occurrence of serious coronary heart disease in non-users (n ¼ 202 916) and users of rofecoxib (n ¼ 24 132), celecoxib (n ¼ 22 337) and other NSAIDs (n ¼ 129 391), aged 50–84 yr, who lived in the community and had no life-threatening non-cardiovascular illness. New users of high-dose rofecoxib (>25 mg/day) had a rate of serious coronary heart disease (CHD) events (hospital admission for acute MI or death from CHD) of 24.0 per 1000 pyr, new users of low-dose rofecoxib (
25 mg/day) had a rate of 13.7, new users of celecoxib had a rate of 12.2, and non-users had a rate of 13.0. The adjusted incidence RR for high-dose rofecoxib was 2.20 (95% CI 1.17–4.10) compared to celecoxib, 1.93 (95% CI 1.09–3.43) compared to non-users. The corresponding adjusted estimate for celecoxib compared to non-users was 0.88 (95% CI 0.67–1.16). In our study the rate of cardiovascular events (MI, cardiac arrest and relevant

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non-specific cardiovascular events) was lower than the observed rate in the study by Ray et al. [52], but this is to be expected since this study uses event data reported by 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 reported incorrectly. Nevertheless, we have no reason to believe that there was differential under-reporting between the two products. We acknowledge that the two PEM studies were conducted during different calendar periods, and the study for celecoxib was initiated at the same time as the results of the VIGOR study were published. It is possible that publication bias might have influenced the reporting of such events between the two drugs, and this issue requires further investigation. 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 Medicines Control Agency in the UK via the spontaneous reporting system of suspected adverse drug reactions. No reports had been received for deep vein thrombosis (DVT) by that time. Information available from 51 case histories of TE events (CVA, MI, DVT and PE) reported in the celecoxib PEM study [40], showed that 76.1% (35/46 where age was specified) were >65 yr, 86.6% (39/45) had risk factors for thromboembolism/ CHD and 43.5% (20/46) were on concomitant aspirin or other anticoagulant/antiplatelet agents. There is no evidence from the PEM data currently available to suggest that any cardiovascular deaths were attributable to celecoxib. Interestingly, there are published reports of venous thrombosis, possible PE and arterial thrombosis in four patients with connective tissue disorders receiving celecoxib, which suggests that patients with diseases that predispose to thrombosis may be at greater risk of peripheral vascular events [21]. As mentioned previously, in PEM there is incomplete information available on risk factors predisposing patients to these types of events.

Conclusion Our understanding of the clinical effects of COX-2 inhibitors is still evolving. Our observational study has demonstrated that the age- and sex-adjusted relative rate of cerebrovascular TE events for celecoxib compared to meloxicam in this cohort was 1.66 (95% CI 1.10–2.51) over the study period of 270 days. There was no significant difference in the rate of cardiovascular TE events or peripheral venous thrombotic events. The debate as to whether the association between an increased risk of thrombosis and the use of COX-2 inhibitors is a ‘class effect’, continues. It is possible that COX-2 inhibitors may possess different pharmacological characteristics and some of these differences may be dose related, however, the implications of these differences remain unclear. With regard to the clinical implications of our findings, the results of our study are only useful

when considered together with other studies seeking to determine the association between the use of COX-2 inhibitors and TE events.

Conflict of interest The DSRU 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. S. A. W. Shakir has received support from Pfizer to attend scientific meetings.

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