Rofecoxib And Meloxicam

Rheumatology 2003;42:1342–1353 doi:10.1093/rheumatology/keg379, available online at www.rheumatology.oupjournals.org Advance Access publication 27 June 2003

Comparison of the incidence rates of thromboembolic events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data D. Layton1,2, E. Heeley1, K. Hughes1 and S. A. W. Shakir1,2 Background. Rofecoxib and meloxicam are classified as cyclo-oxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit (DSRU) monitored the postmarketing 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 rofecoxib and meloxicam in general practice. Methods. Patients were identified from dispensed prescriptions written by general practitioners (GPs) for meloxicam (December 1996 to March 1997) and rofecoxib (July to November 1999). Simple questionnaires requesting details of events recorded during/after treatment, indication and potential risk factors (including age, sex 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 within each TE group were calculated; crude and age- and sex-adjusted rate ratios (RR) obtained using regression modelling. Results. During the 9 months after starting treatment, 21 (0.14%) and 19 (0.10%) patients were reported to have cardiovascular TE events, and 74 (0.48%) and 52 (0.27%) cerebrovascular TE events, and 6 (0.05%) and 20 (0.10%) were reported to have peripheral venous thrombotic events for rofecoxib and meloxicam, respectively. Regarding time to first event, there was a persistent divergence between the two drugs from the start of treatment for both the cerebrovascular TE event group (log rank test P ¼ 0.0063) and the peripheral venous thrombotic event group (log rank test P ¼ 0.0264). Indication and use of a NSAID within 3 months prior to starting treatment had no statistically significant effect on the relative risk estimates of the event groups and was excluded from subsequent analyses. Adjusting for the two identified risk factors of age (age2) and sex, for rofecoxib the adjusted cerebrovascular TE event group rate was higher than for meloxicam [RR 1.68 (95% CI 1.15, 2.46)]; lower than meloxicam for the peripheral venous thrombotic event group [RR 0.29 (95% CI 0.11, 0.78)], and not different for the cardiovascular TE event group [RR 1.38 (95% CI 0.71, 2.67)]. Conclusions. This study reports a relative increase in the rate of cerebrovascular TE events and a relative reduction in peripheral venous thrombotic events in users of rofecoxib compared with meloxicam. There was no difference in the rate of 1

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton and 2University of Portsmouth, UK. Submitted 4 October 2002; revised version accepted 26 March 2003. Correspondence to: D. Layton. E-mail: [email protected]

1342 Rheumatology Vol. 42 No. 11 ß British Society for Rheumatology 2003; all rights reserved

Thromboembolic events after taking rofecoxib and meloxicam

1343

cardiovascular thromboembolic events. The incidence of these three groups of events reported in each of these two drug cohorts was low (less than 0.5%), therefore the relevance of our findings needs to be taken into consideration with other clinical and pharmacoepidemiological studies. KEY WORDS: COX-2 selective inhibitors, Rofecoxib, Meloxicam, Adverse events, Prescriptionevent monitoring, Drug safety.

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of pain and inflammation arising from musculoskeletal and arthritic conditions, but the gastrointestinal (GI) adverse reactions that arise as a result are well known [1, 2]. Cyclo-oxygenase (COX)2 isoenzyme inhibitors were developed with the aim of reducing such GI adverse reactions compared with nonselective NSAIDs [3–7]. However emerging information suggests that use of such drugs may contribute to an increased risk of adverse vascular events [8, 9]. The pharmacology of these agents as a group has been discussed previously [10]. At therapeutic doses, traditional NSAIDs inhibit the two isoenzymes COX-1 and COX-2 to varying degrees [11, 12]. Vascular haemostasis is a balance between the activities of COX-1-mediated platelet-derived thromboxane-A2 (Tx-A2) that stimulates platelet aggregation leading to thrombus formation and vasoconstriction, and COX-2-mediated macrovascular endothelial-cell-derived prostacyclin, which acts as a vasodilator and inhibitor of platelet aggregation [1]. TxA2 biosynthesis is increased in syndromes of platelet activation, such as unstable angina, peripheral arterial obstructive disease and cerebral ischaemia [13]. Inhibition of COX-1 by traditional NSAIDs or aspirin leads to diminished Tx-A2 formation by activated platelets [14–17]. It is suggested that the clinical implication of blockade of COX-2-induced prostacyclin, unopposed by COX-1-induced platelet aggregation, is an increased risk of thromboembolic events in susceptible individuals [18, 19]. However, the physiological relationship between these two isoforms is complex, and any harmful effects difficult to predict. In June 1999 rofecoxib (Vioxx), a NSAID reported to be COX-2 selective, was launched in the United Kingdom. The licensed indication at launch was for the symptomatic relief of osteoarthritis. The results from premarketing development programme studies reported that rofecoxib did not inhibit platelet aggregation or prolong bleeding time when administered to healthy volunteers at either 7.5 or 15 mg per day for 5 days [20]. However, an additional finding from the VIGOR study (Vioxx Gastrointestinal Outcomes Trial) was a 4-fold increase in the rate of myocardial infarction (MI) in those randomized to treatment with rofecoxib (50 mg daily) compared with those treated with naproxen (500 mg twice daily), over 9 months [5]. Meloxicam (Mobic), launched in the UK in December 1996, was indicated for relief of pain and inflammation in rheumatic disease, in exacerbations of osteoarthritic pain and ankylosing spondylitis. It is also considered to

be a COX-2-selective inhibitor [21], but exhibits dosedependent COX-1 inhibition at therapeutic doses [22]. Whilst meloxicam does not appear to affect COX-1dependent platelet thromboxane formation or platelet aggregation [21, 23], reductions in blood laboratory parameters (haemoglobin, erythrocytes and haematocrit mean values) have been reported [24, 25]. Meloxicam has not been demonstrated to be cardioprotective in patients prescribed the drug, and reports of serious cardiovascular events have not been thought attributable to treatment [26]. The evidence from randomized controlled trials suggests that rofecoxib may be associated with an increased incidence of cardiovascular adverse events compared with non-selective NSAIDs. However, such trials were designed to evaluate gastrointestinal toxicity, and were not sufficiently powered to detect differences of thromboembolic events against the background cardiovascular event rates in the placebo groups. Furthermore, adequately sized trials of naproxen [9], or any NSAID, have not been performed to assess the possible cardioprotective effect of these NSAIDS. The Drug Safety Research Unit (DSRU) provides a post-marketing drug surveillance scheme which monitors the safety of newly marketed drugs during their immediate post-marketing period in England, using the non-interventional observational cohort technique of prescription event monitoring (PEM) with a systematic approach to data collection [27, 28], in accordance with international guidelines for record-based research [29–31]. Data are collected on patients prescribed a drug in ‘real world’ clinical practice, including groups at high risk of adverse events who may previously have been excluded from controlled trials, and are also likely to be exposed to the newly marketed drug because of the nature of their disease. As part of its monitoring programme, the DSRU has carried out individual PEM studies of meloxicam [32] and rofecoxib [33]. Previously we published the results of two studies which examined and compared the GI adverse event profiles of these two drugs [10], as well as celecoxib and meloxicam [34]. In view of professional and regulatory interest regarding the cardiovascular safety of these agents, we undertook a second set of studies to examine and compare the risk of cardiovascular events associated with thromboembolism between these drugs. The aim of this study on cardiovascular risk was to investigate retrospectively, using large cohorts from the general population of England, whether there is a difference in the type and incidence of thromboembolic cardiovascular events

D. Layton et al.

1344

reported during routine clinical use of meloxicam and rofecoxib in the primary care setting. Our objectives were to calculate and compare rates for thromboembolic events occurring within the first 9 months after starting treatment and to determine relative risks (rate ratios, RR) separately for cardiovascular thromboembolic (TE), cerebrovascular (TE) and peripheral venous thrombotic events adjusted for possible confounders (age, sex [35–37], and whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug [16]) and to calculate and compare the time to first event within each TE event group for each cohort.

Methods

into the three groups, cardiovascular TE, cerebrovascular TE and peripheral venous thrombotic events (Table 1). Peripheral arterial TE events were considered but there was only one report of an arterial embolus recorded during treatment with rofecoxib in the PEM study. Non-specific event terms (cardiac arrest, non-specific CV events, and dysphagia, hypoaesthesia, paraesthesia, paresis and visual disturbance) were evaluated and only included if considered to indicate a TE-related event. This was especially important since the lowest level dictionary terms (‘Doctor summary terms’) were introduced after the meloxicam study was completed. Outcome data were those selected events reported to have occurred whilst taking the drug (or within 7 days of stopping), during the 9 months since start of treatment with either drug. The data were subject to the same inclusion and exclusion criteria as specified previously for calculation of person-time exposed (pte) [10, 38].

Sample size

In PEM, patients are identified from dispensed National Health Service (NHS) prescription data supplied in confidence by the Prescription Pricing Authority (PPA) in England. The methodology of the PEM studies for both of these two drugs is summarized in the first publication [10]. 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 rofecoxib between July and November 1999 (n ¼ 15 268). For comparative purposes the exposed were those patients prescribed rofecoxib and the unexposed were those patients prescribed meloxicam. The event terms for this study were selected by DSRU clinical research fellows from the DSRU dictionary. These clinical research fellows, who were not blinded to treatment, were asked to review and select events that were associated with TE conditions prior to the analysis. The terms were aggregated

The sample size calculation for PEM studies is described previously [10]. 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 [39].

Analysis Data analysis was conducted in an identical manner to that described previously [10]. The unadjusted rate ratios (RR), as well as ratios adjusted for selected risk factors (whether other oral NSAIDs had been prescribed in the 3 months prior to starting the drug), plus confounding variables age and sex, were calculated and examined using both univariate and multivariate Poisson regression modelling. For each individual for each event group, the outcome was categorized as a binary variable (first event or non-event). An off-set term of log (time) was

TABLE 1. Thromboembolic event groupsa Cardiovascular b

Cardiac arrest CVS not specifiedb Myocardial infarction

a

Cerebrovascular

Peripheral venous thrombotic

Amaurosis fugax Aphasia Cerebrovascular accident Dysarthria Dysphagiab Dysphasia Embolus cerebral Embolus mesenteric Hemianopia Hemiparesis Hemiplegia Hypoaesthesiab Paralysis facial Paralysis pseudobulbar Paralysis ocular Paraesthesiab Paresisb Retinal thrombosis artery Retinal thrombosis vein Slurred speach Thrombosis cerebral Transient ischaemic attack Visual disturbanceb

Deep vein thrombosis Embolus pulmonary Infarction pulmonary

During the 9-month study period no reports were recorded for the following miscellaneous TE event terms: infarction gastrointestinal, thrombosis mesenteric, thrombosis spinal, thrombosis artery or infarction renal, for either drug. b Non-specific terms evaluated by clinician and relevant lowest level (doctor terms) included in the analysis.

Thromboembolic events after taking rofecoxib and meloxicam

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. Results are presented as incidence rates and rate ratios. A Microsoft SQL query was used to retrieve data from the DSRU PEM database, followed by analysis using STATA 7.0 (Stata Corporation, College Station, Texas, USA). All records and computer data are stored to maximize patient confidentiality.

Results The characteristics of both study cohorts are presented in Table 2. As described previously [10], rofecoxib users were more likely than meloxicam users to be aged 60 yr or more [60.6% (7839/12 936) vs 55.0% (9280/16 877), 2 P < 0.0001] and be female [68.4% (10 289/15 049) vs 67.1% (12 590/18 763), 2 P ¼ 0.013]. Osteoarthritis was the most frequently reported indication for both rofecoxib and meloxicam [23.7 vs 23.2%, respectively, 2 P ¼ 0.269], with a lower proportion of users prescribed rofecoxib for treatment of symptoms of rheumatoid arthritis (RA) than for meloxicam [4.1% (632/15 268) vs 6.5% (1253/19 087), 2 P < 0.0001]. Where answers to the additional questions were given, significantly more rofecoxib users than meloxicam users had been prescribed a NSAID within the 3 months prior to starting treatment [51.3% (6194/12 076) vs 48.0% (7978/ 16 634), 2 P < 0.0001].

1345

During the 9 months after starting treatment with rofecoxib or meloxicam, 21 (0.14%) and 19 (0.10%) patients were reported to have had cardiovascular TE events, 74 (0.48%) and 52 (0.27%) were reported to have had cerebrovascular TE events, and 6 (0.05%) and 20 (0.10%) were reported to have had peripheral venous thrombotic events, respectively. The proportions of events excluded from the study as defined in the Methods for both drugs were similar [rofecoxib 48.7% (96/197) vs meloxicam 51.0% (95/186), 2 P ¼ 0.684]. Those events excluded are additional events within each event group which were reported for each individual patient, and/or events which occurred after 270 days from start, and/or where no stopping date was given (i.e. it was not known whether the event occurred on or off treatment) and events occurred after 30 days from the start date, and/or events which occurred more than 7 days after stopping the drug. Regarding the time to first event, the crude estimate of both cohorts for each event group separately is presented in the form of Kaplen-Meier survival curves in Figs 1 to 3. There was no difference in the estimate of time to first event over the study period in the cardiovascular TE group for rofecoxib compared with meloxicam [median pte 103 days (interquartile range, IQR, 45 to 157) and 95 days (IQR 38 to 108), respectively, log rank test P ¼ 0.3144, Fig. 1]. There was a difference from the start of treatment in the time to first event curves for the first event within the cerebrovascular TE event group between the study drugs over 270 days in favour of meloxicam [median pte 106 days (IQR 25 to 190) and 100 days (IQR 23.5 to 140.5) for rofecoxib and meloxicam, respectively, log rank test P ¼ 0.0063, Fig. 2]. The estimate of time to the first event within the peripheral venous thrombotic group also differed

TABLE 2. Characteristics of study cohort Drug Age (yr) <39 40–49 50–59 60–69 70–79 80þ Age not known Sex Males Females Sex not known Indication Osteoarthritis Others NSAID prescribed within 3 months prior to starting drug Yes No Not known All values are n (%). a Excludes values not known.

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

(9.7) (12.0) (18.1) (20.1) (18.1) (9.80) (11.6)

Rofecoxib (n ¼ 15 268) 988 1442 2667 3292 3079 1468 2332

(6.5) (9.4) (17.5) (21.6) (20.2) (9.6) (15.2)

2 P value* <0.0001

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

4760 (31.2) 10 289 (67.4) 219 (1.4)

0.013

4433 (23.2) 14 654 (76.8)

3624 (23.7) 11 644 (76.3)

0.269

7978 (41.8) 8656 (45.4) 2451 (12.9)

6194 (40.6) 5882 (38.5) 3192 (20.9)

<0.0001

D. Layton et al.

1346

FIG. 1. Kaplan–Meier survival estimates for cardiovascular thromboembolic events between meloxicam and rofecoxib cohorts.

1.000 .999 .998 Meloxicam

.997 Proportion

.996 .995 .994 .993

Log rank test p=0.0063

Rofecoxib

.992 .991 .990 30

60

90

120 150 time(days)

180

210

240

270

FIG. 2. Kaplan–Meier survival estimates for cerebrovascular thromboembolic events between meloxicam and rofecoxib cohorts.

1.000

Rofecoxib

Proportion .9998

Log rank test p=0.0264 Meloxicam .9997 30

60

90

120 150 time (days)

180

210

240

270

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

between the study drugs, this time in favour of rofecoxib [92 days (IQR 68 to 138) days and 118.5 days (IQR 48.5 to 178) for rofecoxib and meloxicam, respectively, log rank test P ¼ 0.0264, Fig. 3], with more of these events reported for meloxicam users (20 vs 6 events) during the study period.

Cross-tabulation of risk factors with event groups suggested a significant association between age and experiencing cardiovascular TE (2 P < 0.0001), cerebrovascular (2 P < 0.0001) and peripheral venous thrombotic events (2 P ¼ 0.014); and between sex and experiencing cardiovascular TE events (2 P < 0.0001) only. Use of a NSAID within the 3 months prior to starting treatment was not associated with any of the event groups. Both rofecoxib and meloxicam had only two dose ranges licensed at the time of the PEM studies (12.5 or 25 mg, and 7.5 or 15 mg per day, respectively). Limited information on starting dose and dose at event were provided on the green forms for meloxicam, and thus had not been recorded. For rofecoxib, information on starting dose was available for 76.1% (n ¼ 11 625). Dose at event was provided for 52.4% (11/21) of patients reported to have cardiovascular TE events, 74.3% (55/74) of patients reported to have cerebrovascular TE events and all six patients reported to have peripheral venous thrombotic events. Of these, seven (63.6%), 45 (81.8%) and three (50%) patients were taking 12.5 mg per day, respectively. As the reporting of dose data was low, it was not adjusted for in the multivariate analysis. Table 3 shows crude event rates per 1000 person-years (pyr) for both drug cohorts over the first 9 months of treatment and rate ratios for each risk factor category. We reported earlier that a relationship exists between age and each of these event groups. Patients from the rofecoxib cohort aged 80 yr or more have the highest (but not statistically significantly different) rate of experiencing cardiovascular or cerebrovascular TE events compared with the younger age groups (age 80 or more years treated as the reference group). Conversely, patients from the meloxicam cohort aged 80 yr or more had the lowest rates (but not statistically significantly different) of cardiovascular TE events compared with the younger age groups. However, the 95% confidence intervals (CIs) for this event group for meloxicam were wide, thus one cannot exclude the possibility of a similar relationship to that observed for rofecoxib. The agespecific estimates of rate ratios 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 of cardiovascular TE, cerebrovascular TE or peripheral venous thrombotic events between both drugs [tests for effect modification, all 2 P > 0.080]. A between-drug comparison revealed that for cerebrovascular TE events, rofecoxib users aged 50–59 yr were more likely to have these events than meloxicam users of the same age [RR 5.37 (95% CI 1.16, 24.85)], as were rofecoxib users aged 60–69 yr [RR 2.25 (95% CI 1.01, 5.00)] and those aged 80 yr or more [RR 2.29 (1.06, 4.96)]. 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 meloxicam experiencing cardiovascular TE events. For the peripheral venous thrombotic group, all patients within the rofecoxib cohort who had these events were female. There was no

0

3

7

6

4

40–49

50–59

60–69

70–79

80þ

15

2.2 (0.9, 5.3) 12 4.4 (2.5, 7.7) 4 –

5

3.1 (1.9, 5.2) 3.6 (1.6, 8.1)

2.0 (0.7, 5.7) –

1.0

1.2 (0.5, 3.0)

1.0

0.4 (0.2, 1.0) –

1.0

–

0.4 (0.1, 1.7) 0.7 (0.2, 2.4) 0.7 (0.2, 2.3) 1.0

–

– 3.5 (0.9, 14.1) 7.8 (4.1, 15.1) 12.7 (8.0, 20.2) 13.5 (8.5, 21.5) 31.3 (19.7, 49.6) –

–

Rate (95% CI)

12.8 (8.9, 18.4) 36 13.2 (9.5, 18.3) 9 –

29

10.7 (8.1, 14.1) 23 14.0 (9.3, 21.1)

51

9.3 (5.9, 14.6) 55 12.9 (9.9, 16.7) 0 –

19

9

18

18

18

9

2

0

n

1.0 (0.6, 1.7) –

1.0

1.3 (0.8, 2.1)

1.0

1.4 (0.8, 2.3) –

1.0

–

0.1 (0.0, 0.5) 0.3 (0.1, 0.6) 0.4 (0.2, 0.8) 0.4 (0.2, 0.8) 1.0

–

1

3

2

4

1

5

0

0

0

2

2

2

0

0

1.3 (0.4, 4.1) 0.4 (0.1, 2.6) –

0.8 (0.3, 2.2) 1.2 (0.3, 4.9)

1.2 (0.5, 2.8) –

–

–

1.7 (0.4, 7.0) 1.4 (0.4, 5.6) 1.5 (0.4, 6.0) –

–

–

Rate (95% CI)

0.3 (0.0, 2.7) –

1.0

1.5 (0.3, 7.9)

1.0

–

–

–

–

–

1.0 (0.1,11.1) 0.8 (0.1, 9.0) 1.0

–

–

Rate ratio (95% CI)

Peripheral venous (n ¼ 6)

Rate ratio (95% CI) n

Cerebrovascular (n ¼ 74)

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

b

a

Not known

Yes

NSAID No

b

Osteoarthritis 6

Not known Indication Other

Female

2.6 (0.8, 8.1) 4.9 (2.4, 10.3) 4.5 (2.0, 10.0) 6.9 (2.6, 18.4) –

–

–

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

5.4 (3.0, 9.7) 10 2.3 (1.3, 4.3) 0 –

11

1

0

Age (yr)
39

Not known Sex Male

n

Risk factor

Cardiovascular (n ¼ 21)

Rofecoxib (n ¼ 15 268)

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

–

Rate (95% CI)

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 ratio (95% CI)

7.3 1.0 (4.8, 11.1) 23 3.4 0.9 (6.7, 4.5) (0.5, 11.7) 7 – –

22

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

39

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)

3

10

8

8

12

0

11

9

1

3

6

9

1

0

0

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 (0.4, 2.8) –

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)

TABLE 3. Crude rates and rate ratiosa of thromboembolic (cardiovascular, cerebrovascular and peripheral venous thrombotic) events, per 1000 person-years by risk factor

Thromboembolic events after taking rofecoxib and meloxicam 1347

D. Layton et al.

1348

significant evidence of a sex–drug interaction for any of the event groups (tests for effect modification, all 2 P > 0.063). Osteoarthritis as the indication (compared with ‘other’ category treated as reference group) and prescription of a NSAID within 3 months of starting treatment (compared with none treated as the reference group) had no significant effect on rate of any of the event groups within each cohort, nor any significant evidence of a drug–risk factor interaction (tests for effect modification, all 2 P > 0.068). The crude and adjusted rate ratios are presented in Table 4. Indication and prescription of a 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 rate ratio estimates. Thus age and sex were the two risk factor variables included in the final Poisson regression model. Adjusting for these two risk factors: 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, and peripheral venous thrombotic events. The adjusted rate of cerebrovascular TE events for rofecoxib was higher than for meloxicam [RR 1.68 (95% CI 1.15, 2.46)]. With regard to peripheral venous thrombotic events the adjusted rate for rofecoxib was lower than meloxicam [RR 0.29 (95% CI 0.11, 0.78)]. Evidence of effect modification was further examined by inclusion of interaction terms within the final Poisson model for all three groups. A drug–sex interaction was identified in the model predicting the estimate of relative risk of peripheral venous thrombotic events (likelihood ratio test, 2 P ¼ 0.0291), but this may be explained by the absence of male rofecoxib users who had these events. An analysis was undertaken to assess whether the 14.5% reduction in the total number of observations included in the final model (n ¼ 29 364 vs n ¼ 34 355) may have contributed in some way to the observed relative difference in rates, where 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 models, fitted to the reduced dataset (n ¼ 29 364), show that the cases with no missing

values for age or sex are not drastically different from the full dataset. The effect of treatment duration was examined by restricting the study period to 90 days after starting treatment with either drug for each event group. During this period, 8 (0.05%) and 9 (0.05%) patients were reported to have cardiovascular TE events, 34 (0.22%) and 22 (0.12%) were reported to have cerebrovascular TE events, and 3 (0.02%) and 9 (0.05%) were reported to have peripheral venous thrombotic events for rofecoxib and meloxicam, respectively. There was a higher but non-significant risk of cerebrovascular events for rofecoxib users compared with meloxicam users [RR 1.73 (95% CI 0.99, 3.04)], a lower but nonsignificant reduction in risk of peripheral venous thrombotic events, in favour of rofecoxib [RR 0.26 (95% CI 0.06, 1.21)] and no difference for the cardiovascular TE event group [RR 1.04 (95% CI 0.40, 2.70)].

Discussion This comparative study between a highly selective and a partially selective COX-2 inhibitor type of NSAID was performed on data collected under general practice conditions. The study population for each of the two drugs is over 15 000 patients and therefore provides a huge database of post-marketing events. Meloxicam was chosen as the comparator drug because it was from the same therapeutic class (which helps to control for events that are characteristic of the conditions for which the drug is prescribed) and because the licensed indications were generally similar. Furthermore, meloxicam was the only other NSAID accredited with COX-2 selectivity that had been monitored recently using the technique of PEM. In this study patients prescribed and dispensed rofecoxib have an age- and sex- adjusted relative rate of 1.68 (95% CI 1.15, 2.46) of cerebrovascular TE events and 0.29 (95% CI 0.11, 0.78) of peripheral venous thrombotic events, compared with patients prescribed meloxicam. With regard to cardiovascular TE events, the observed rate ratio between the two drugs did not achieve statistical significance [RR 1.38 (95% CI 0.71, 2.67)]. Examination of the effect of missing variables revealed that the reduction in the sample size (occurring as a result of fitting the statistical model) made no significant

TABLE 4. Crude and adjusted rate ratios of thromboembolic (cardiovascular, cerebrovascular and peripheral venous thrombotic) events in users of rofecoxib compared with meloxicam Rofecoxib

Event Cardiovascular Cerebrovascular Peripheral venous a

Meloxicam

No. events/1000 person-years exposure

Rate (95% CI)

No. events/1000 person-years exposure

21/6.42 74/6.41 6/6.43

3.27 (2.13, 5.01) 1.15 (9.18, 14.49) 0.93 (0.42, 2.07)

19/7.51 52/7.50 20/7.51

Rate (95% CI)

Unadjusted rate ratiob (95% CI) n ¼ 29 364

Adjusted rate ratioc (95% CI) n ¼ 29 364

2.53 (1.61, 3.97) 1.29 (0.70, 2.40) 1.51 (0.78,2.92) 1.38 (0.71,2.67) 6.9 (0.52, 0.90) 1.66 (1.17, 2.37) 1.75 (1.20,2.56) 1.68 (1.15,2.46) 2.66 (1.72, 4.13) 0.35 (0.14, 0.87) 0.32 (0.12,0.85) 0.29 (0.11,0.78)

Poisson regression model (whole dataset). Poisson regression model excluding age and sex not known (n ¼ 4991). c Poisson regression model adjusted for age (age2) and sex. b

Unadjusted rate ratioa (95% CI) n ¼ 34 355

Thromboembolic events after taking rofecoxib and meloxicam

changes to the estimates of relative risk for each of the event groups. The incidence of these three groups of events reported in each of these two cohorts was low (less than 0.5%). Such absolute measures are important when considering whether a particular drug is the cause of the event(s) under study. The relevance of our findings needs to be taken into context with other clinical studies. Regarding the time to first event from the start of treatment, there is a clear divergence between the two drugs at the start of treatment that persists throughout the study period for both the cerebrovascular TE event group and the peripheral venous thrombotic event group (Figs 2 and 3). Conversely, the time to first event for the cardiovascular TE group is similar over the first 4 months and then diverges thereafter (Fig. 1). Restriction of the study period to the first 90 days after starting treatment revealed no statistically significant differences in the relative risk estimates of each event group, between these two drugs. Clearly the temporal relationship needs to be examined further. It is plausible that difference in licensed indication may contribute to difference in cohort characteristics. Whilst more patients were prescribed rofecoxib for osteoarthritis than meloxicam, indication demonstrated no statistically significant effect on the estimate of relative risk of any of the event groups and thus was not considered a confounding factor. Regarding recent use of NSAIDs, rofecoxib users were more likely than meloxicam users to have use NSAIDs within 3 months of starting treatment, but again this risk factor had no statistically significant effect on the estimate of relative risk of any of the three events groups and was not adjusted for. Age and sex have been shown to affect the reporting of adverse drug reactions and the rates of prescribing of drugs of different therapeutic class [35]. More importantly, age and sex are important risk factors for MI and stroke [37, 40]. Our study supports this and reports that patients aged 80 yr or more tended towards a greater relative risk of cardiovascular TE events, with women experiencing a lower relative risk of cardiovascular TE events than men. Regarding cerebrovascular TE events, we identified that rofecoxib users aged 50 yr or more were significantly more likely to experience these events than meloxicam users of the same age. Whilst we did not reveal any statistical evidence of a sex–drug interaction for cerebrovascular TE events, female rofecoxib users were more likely to experience these events than male rofecoxib users, but less likely than female meloxicam users. To our knowledge a direct comparison of TE adverse event rates between these two drugs has not yet been published. The VIGOR (Vioxx Gastrointestinal Outcomes Trial) study [5] primarily compared the efficacy and gastric safety of rofecoxib (50 mg daily) with naproxen (500 mg twice daily). The unadjusted rate of all thrombotic events was significantly lower for naproxen compared with rofecoxib (50 mg—twice the recommended daily dose) [RR 0.42 (95% CI 0.25, 0.72)]. Of the breakdown of thrombotic events, the rate of cardiac events was significantly lower for naproxen than

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rofecoxib [RR 0.36 (0.17, 0.74)]. The other categories, cerebrovascular and peripheral vascular events, also favoured naproxen, but had smaller numbers of events and did not achieve statistical significance [RR 0.73 (95% CI 0.29, 1.80) and 0.17 (95% CI 0.0, 1.37), respectively]. A separate analysis across 23 pre-marketing rofecoxib studies involving over 28 000 patients demonstrated that rofecoxib was not associated with excess CV thrombotic events compared with placebo or non-naproxen NSAIDs [41]. With regard to meloxicam, large-scale studies investigating cardiovascular risk are limited. One review of pre-marketing clinical studies of 4175 patients prescribed meloxicam (7.5 mg or 15 mg per day) compared with other non-selective NSAIDs (piroxicam 20 mg, diclofenac 100 mg and naproxen 750 mg per day) and placebo did not report any serious cardiovascular event attributable to treatment [26]. The event terms for this comparative study were selected on the basis of an association with thromboembolic conditions, and aggregated into the three groups (Table 1), generally similar to those reported in other studies of rofecoxib investigating such events [5, 6, 9, 42–46]. Most of these studies investigated the relative cardiovascular risk of rofecoxib to naproxen (which is known to inhibit platelet aggregation [20]), or of a combination of non-selective NSAIDs. The results of our study reflect the findings from these studies with the exception of the reduced relative risk of peripheral venous thrombotic events for rofecoxib compared with meloxicam. One explanation for the reduction in the rate of cerebrovascular TE events in favour of rofecoxib could be related to the differential effects in COX-1/ COX-2 selectivity of the two drugs at the clinical dosing regimes used. Meloxicam exhibits dose-dependent COX1 inhibition at therapeutic doses and it is not possible to distinguish fully the COX-2-selective effect of meloxicam in this study. Given the lack of clinically recognized effects on platelet aggregation for both drugs, this variation may have other indirect influences on the rates of TE events. The incidence rates reported in this study reflect the entire starting dose range used and cannot provide evidence for a dose–response relationship. The comparison of rofecoxib 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 GI tolerability, as reported previously and in other studies [10, 47]. This study also reports a channelling effect of past users of NSAIDs on to rofecoxib in that more patients within this cohort had been prescribed a 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 meloxicam [47]. In this study we could not examine this effect on cardiovascular risk. However, we acknowledge that there may also be channelling of patients at high risk of cardiovascular events, such as patients with a greater probability of being exposed to aspirin, and are more likely to have experienced a perforation ulcer or bleed, resulting in subsequent

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treatment with a COX-2- selective NSAID, if such treatment is required. This issue requires further investigation. With regard to the relative reduction in peripheral venous thrombotic events, this observation may reflect a chance finding, a relative reduction in peripheral venous thrombotic events for rofecoxib or a relative increase in these events for meloxicam. The risk factors for peripheral venous thrombosis such as immobility, surgery and recent traumas are different from the risk factors for cardiovascular and cerebrovascular TE events [48]. Because of the small numbers reported in the other published studies, these cannot confirm or refute our findings. Hence it is plausible that different mechanisms are responsible for different thromboembolic events, especially since both COX isoenzymes appear to have diverse roles in different tissues. However, the functional consequences of COX-2 inhibition are still unclear; the nature and duration of consequential platelet activation and counter-regulatory mechanisms evoked may vary between sites of platelet–vessel wall interaction. The relationship between COX isoenzyme activity, prostanoid formation and cell function in vivo is not necessarily linear [49]. Although there is a possible inverse relationship between daily doses of aspirin and a relative risk reduction in vascular events (i.e. dose dependent) largely due to permanent inactivation of platelet COX-1, the incomplete and irreversible inhibition of COX-1 by nonaspirin NSAIDs does not lend itself to such a relationship [13], especially as there is inter-individual variability in drug plasma levels with consequential differential inhibition of COX-1 and COX-2 isoenzymes [21]. By July 2000, 17 reports of peripheral vascular disorders, including one report of arterial occlusion non-specific (NOS) and four reports of deep vein thrombosis (DVT), had been reported for rofecoxib to the Medicines Control Agency in the UK via the spontaneous reporting system of suspected adverse drug reactions (ADRs). No reports had been received for pulmonary embolism (PE). No reports of peripheral vascular disorders associated with TE were reported for meloxicam up to December 1999. By October 2000, 19 spontaneous reports of pulmonary or venous embolus and 14 reports of miscellaneous occlusions had been submitted to the adverse events reporting system in the US for rofecoxib. Interestingly, there are published reports of venous thrombosis, possible pulmonary embolism and arterial thrombosis in four patients with connective tissue disorders receiving another COX-2selective inhibitor, celecoxib, which suggests that patients with diseases that predispose to thrombosis may be at greater risk of peripheral vascular events [50]. This highlights another explanation for the observed difference in that there are limitations in the types of data received in PEM, for example incomplete information on risk factors predisposing patients to these types of events, such as past medical history of cardiovascular disease, use of hormone replacement therapy, recent surgery and lifestyle factors such as smoking. The effect of these and other risk factors for thromboembolic events were not

controlled for in this study, because of the incomplete data available, and thus any differences observed may be due to the confounding effect of these risk factors. The limitations of PEM have been discussed elsewhere [10, 28, 34]. Safety monitoring and data collection in post-marketing surveillance studies are not comparable with randomized clinical trials (RCTs), therefore reporting rates are an estimate of incidence rate. PEM cannot be used to identify changes in the background prevalence of events of interest or risk factors in the general population of England, but to identify differences in the incidences of selected events between patients prescribed different agents under primary care conditions. As for other observational studies, an assumption is made regarding compliance and drug intake. Data are limited solely to experience in general practice and do not include information on patients initially prescribed either drug in secondary care, and selection bias may be introduced via attrition, changes in clinical care patterns and co-therapies. We acknowledge that these PEM studies were conducted during different calendar periods, but feel that it is unlikely that medical practice in primary care and diagnosis of these events had changed sufficiently during this short period of time. A weakness of PEM is non-response bias [51]. The effect of such bias on the results of both PEM studies was not assessed, because the population of patients whose doctors did return the green forms was not compared with the population of patients whose doctors did not return these questionnaires. It is also important to state that in PEM the events are those reported by GPs and there may be under-reporting for one or more of the event groups that may have introduced bias in our findings. While a large number of events had been followed up requesting further information, it is possible that some events may not have been reported, or were reported incorrectly. This may give one explanation regarding our findings of no relative difference for cardiovascular TE events, in that the failure to identify a difference may merely represent the low occurrence rate of cardiovascular events. However, we have no reason to believe that there was differential under-reporting between the two products within each event group. In PEM, incomplete information is available on concomitant medication such as aspirin. Aspirin in low dose is frequently indicated for the secondary prevention of thrombotic events in cerebrovascular or cardiovascular disease [52] and may be prescribed to the same patients receiving treatment for arthritis. These patients are also likely to have been prescribed non-selective NSAIDs previously, which may have conferred cardioprotective effect, although the effect may be transient and is dependent on clearance of the drug and has not been confirmed by epidemiological studies (unlike aspirin, which binds irreversibly to the enzyme) [53]. In our study, indication and a NSAID prescribed within 3 months of starting treatment had no important effect on event rates. However, as mentioned earlier, the confounding effect of aspirin or other unidentified risk factors cannot be excluded.

Thromboembolic events after taking rofecoxib and meloxicam

Information available from the 74 case histories of thromboembolic events in the PEM study for rofecoxib [33] showed that 54 (73%) of the patients were 65 yr, 58 (80%) had risk factors for ischaemic heart disease (IHD) or thromboembolism and 34 (46%) were on concomitant aspirin or other anticoagulant or antiplatelet agents. Among those not taking such medication, 20% (8/40) satisfied the US Food and Drug Administation and Joint British Societies criteria for the use of aspirin for secondary cardiovascular prophylaxis (history of IHD, MI, cerebrovascular accident, transient ischaemic attack, angioplasty or coronary artery bypass graft) [54]. With regard to the VIGOR trial of rofecoxib, use of low-dose aspirin was not permitted, yet 4% of patients met the clinical criteria for use of low-dose aspirin, and 38% of those who had an MI were in this subgroup [5]. The lack of evidence for an association between celecoxib and MI in the major trial for celecoxib (CLASS) may have resulted from the use of low-dose aspirin (approximately 20% of patients), which may have protected against thrombotic events [55].

Conclusion The information regarding the overall safety of COX-2 inhibitors compared with the traditional ‘non-selective’ NSAIDs is incomplete at present. It is also unclear whether there are differences between the individual COX-2 inhibitors with regard to the association with thromboembolic events and whether such events are dose related. It is yet to be established whether the differential risk between COX-2 inhibitors and conventional NSAIDs is due to the detrimental effect of one group, or the beneficial effect of the other. Furthermore, the role of concomitant use of low-dose aspirin and the risk factors for thrombotic events in users are yet to be fully understood. Our observational study has demonstrated that the age- and sex-adjusted relative rate of cerebrovascular TE events for rofecoxib compared with meloxicam was 1.68 (95% CI 1.15, 2.46) and that for peripheral venous thrombotic events was 0.29 (95% CI 0.11, 0.78). There was no difference in the rate of cardiovascular TE events. While the incidence of gastrointestinal events is less with COX-2 inhibitors compared with traditional nonselective NSAIDs considering the initial safety profile, it has not been established that the COX-2 inhibitors are safer in general than traditional NSAIDs. Clinical experience with these drugs is at present insufficient to predict less common complications, such as thromboembolic vascular events. The recent change in the Vioxx label in the United States to include new warnings of higher cardiovascular risks than standard arthritis treatment is cautionary following the adjudicated review by the FDA [56]. There is ongoing debate as to whether the association between an increased risk of thrombosis and rofecoxib extends to other COX-2 inhibitors, i.e. is a class effect. With regard to the clinical implication, the results of our study are only useful when considered

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

Conflict of interest The Drug Safety Research Unit is an independent charity, which is associated 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 rofecoxib and meloxicam.

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