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C O X I B S A N D

C A R D I O V A S C U L A R S A F E T Y4

4 . 1

C O M P A R I S O N O F T H E I N C I D E N C E R A T E S O F T H R O M B O E M B O L I C

E V E N T S R E P O R T E D F O R P A T I E N T S P R E S C R I B E D R O F E C O X I B A N D

M E L O X I C A M I N G E N E R A L P R A C T I C E I N E N G L A N D U S I N G P R E S C R I P T I O N -

E V E N T M O N I T O R I N G ( P E M ) D A T A

Deborah Layton 1,2

Emma Heeley 1

Kerry Hughes

Saad A.W. Shakir 1,2

1 Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK 2 University of Portsmouth, UK

Rheumatol 2003; 42: 1342-1353

Reproduced with kind permission from Oxford University Press

1 5 0 | C H A P T E R 4 . 1 C O X I B S A N D C A R D I O V A S C U L A R S A F E T Y | 1 5 1

I n t r o d u c t i o n

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 to non-selective 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] Tx-A2 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®), an 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 pre-marketing development

programme studies reported that rofecoxib did not inhibit platelet aggregation or

prolong bleeding time when administered to healthy volunteers at either 7.5mg or 15mg

per day for 5 days. [20] However, an additional finding from the VIGOR study (Vioxx®

in Gastrointestinal Outcomes Research) was a 4-fold increase in the rate of myocardial

infarction (MI) in those randomised to treatment with rofecoxib (50mg daily) compared

to those treated with naproxen (500mg 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

A b s t r a c t

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=0.0063) and the peripheral venous thrombotic event group (log rank test p=0.0264). Indication and use of an 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 two identified risk factors: 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 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 to meloxicam. There was no difference in the rate of 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.


(rate ratios, RR) separately for cardiovascular, thromboembolilc (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.

M e t h o d s

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

summarised 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=19 087) and for

rofecoxib between July and November 1999 (n=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 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]

inhibitor, [21] but exhibits dose-dependent COX-1 inhibition at therapeutic doses. [22]

Whilst meloxicam does not appear to affect COX-1- dependent 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 randomised controlled trials suggests that rofecoxib may be

associated with an increased incidence of cardiovascular adverse events compared to

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 postmarketing drug surveillance

scheme which monitors the safety of newly marketed drugs during their immediate

postmarketing 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 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


drug), plus confounding variables age and sex, were calculated and examined using both

univariate methods and multivariate Poisson regression modelling. For each individual

for each event group, the outcome was categorised as a binary variable (first event or

non-event). An off-set term of log (time) was fitted in the Poisson models to allow for

the different exposure times of individuals. We did not adjust for calendar period. In

addition, evidence for effect modification was investigated by first examining stratum-

specific RR with homogeneity test results for the univariate analysis, and then by the

inclusion of interaction terms within the Poisson regression model with likelihood ratio

tests of the null hypothesis of no interaction. The time to first event for each group

for each cohort was calculated and examined using the 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 maximise patient confidentiality.

R e s u l t s

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), χ2 test, p<0.0001] and be female

[68.4% (10 289/15 049) vs. 67.1% (12 590/18 763), χ2 test, p =0.013]. Osteoarthritis was

the most frequently reported indication for both rofecoxib and meloxicam respectively

[23.7% vs. 23.2%, respectively, χ2 test, p=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), χ2 test, p<0.0001]. Where

answers to the additional questions were given, significantly more rofecoxib users than

meloxicam users had been prescribed an NSAID within the 3 months prior to starting

treatment [51.3% (6194/12 076) vs. 48.0% (7978/16 634), χ2 test, p<0.0001].

Table 1. Thromboembolic (TE) event groupsa

Cardiovascular Cerebrovascular Peripheral venous thrombotic

Cardiac arrest* Amaurosis fugax Deep vein thrombosis

CVS Not specified* Aphasia Embolus pulmonary

Myocardial Infarction Cerebrovascular accident Infarction Pulmonary

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

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

Sample sizeThe 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]

AnalysisData 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


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=0.3144, Figure 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=0.0063, Figure 2]. The estimate of time to the first event

within the peripheral venous thrombotic group also differed 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=0.0264, Figure

3], with more of these events reported for meloxicam users (20 vs 6 events) during the

study period.

Figure 1. Kaplan-Meier survival estimates for cardiovascular thromboembolic events between meloxicam and rofecoxib cohorts

Figure 2. Kaplan-Meier survival estimates for cerebrovascular thromboembolic events between meloxicam and rofecoxib cohorts

Table 2. Characteristics of study cohort

Drug Meloxicam (n=19 087) Rofecoxib (n=15 268) χ2 P-value*

Age (yr)

<39 1852 (9.7) 988 (6.5) <0.0001

40-49 2297 (12.0) 1442 (9.4)

50-59 3448 (18.1) 2667 (17.5)

60-69 3947 (20.1) 3292 (21.6)

70-79 3457 (18.1) 3079 (20.2)

≥80 1876 (9.80 1468 (9.6)

Age not known 2210 (11.6) 2332 (15.2)

Sex, n(%)

Males 6173 (32.3) 4760 (31.2) 0.013

Females 12590 (67.1) 10289 (67.4)

Sex not known 324 (1.7) 219 (1.4)

Indication, n(%)

Osteoarthritis 4433 (23.2) 3624 (23.7) 0.269

Others 14654(76.8) 11644 (76.3)

NSAID prescribed within 3 months prior to starting drug, n (%)

Yes 7978 (41.8) 6194 (40.6) <0.0001

No 8656 (45.4) 5882 (38.5)

Not known 2451 (12.9) 3192 (20.9)

* Excludes values not known

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 proportion 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),

χ2 test, p=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

groups separately is presented in the form of Kaplan-Meier survival curves in Figures 1

to 3. There was no difference in the estimate of time to first event over the study period


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

Risk factorRofecoxib (n=15 268)

Cardiovascular (n=21) Cerebrovascular (n=74) Peripheral Venous (n=6)n Rate

(95% CI)Rate Ratio

(95% CI)n Rate

(95% CI)Rate Ratio

(95% CI)n Rate

(95% CI)Rate Ratio

(95% CI)Age (yr)

≤39 0 - - 0 - - 0 - -40-49 0 - - 2 3.5 (0.9,14.1) 0.1 (0.0,0.5) 0 - -50-59 3 2.6 (0.8,8.1) 0.4 (0.1,1.7) 9 7.8 (4.1,15.1) 0.3 (0.1,0.6) 2 1.7 (0.4,7.0) 1.0

(0.1,11.1)60-69 7 4.9 (2.4,10.3) 0.7 (0.2,2.4) 18 12.7 (8.0,20.2) 0.4 (0.2,0.8) 2 1.4 (0.4,5.6) 0.8 (0.1,9.0)70-79 6 4.5 (2.0,10.0) 0.7 (0.2,2.3) 18 13.5 (8.5,21.5) 0.4 (0.2,0.8) 2 1.5 (0.4,6.0) 1.0

≥80 4 6.9 (2.6,18.4) 1.0 18 31.3 (19.7,49.6) 1.0 0 - -Not known 1 - - 9 - - 0 - -

SexMale 11 5.4 (3.0,9.7) 1.0 19 9.3 (5.9,14.6) 1.0 0 - -

Female 10 2.3 (1.3,4.3) 0.4 (0.2,1.0) 55 12.9 (9.9,16.7) 1.4 (0.8,2.3) 5 1.2 (0.5,2.8) -Not known 0 - - - - 1 - -

IndicationOther 15 3.1 (1.9,5.2) 1.0 51 10.7 (8.1,14.1) 1.0 4 0.8 (0.3,2.2) 1.0

Osteoarthritis 6 3.6 (1.6,8.1) 1.2 (0.5,3.0) 23 14.0 (9.3,21.1) 1.3 (0.8, 2.1) 2 1.2 (0.3,4.9) 1.5 (0.3,7.9)NSAID*

No 5 2.2 (0.9,5.3) 1.0 29 12.8 (8.9,18.4) 1.0 3 1.3 (0.4,4.1) 1.0Yes 12 4.4 (2.5,7.7) 2.0 (0.7,5.7) 36 13.2 (9.5,18.3) 1.0 (0.6,1.7) 1 0.4 (0.1,2.6) 0.3 (0.0,2.7)

Not known 4 - - 9 - - - -

Risk factorMeloxicam (n=19 087)

Cardiovascular (n=19) Cerebrovascular (n=52) Peripheral Venous (n=20)Age (yr)

≤39 0 - - 4 6.5 (2.4,17.2) 0.5 (0.2,1.5) 0 - -40-49 0 - - 2 2.3 (0.6,9.2) 0.2 (0.0,0.8) 0 - -50-59 0 - - 2 1.5 (0.4,5.8) 0.1 (0.0,0.5) 1 0.7 (0.1,5.2) 0.2 (0.0,1.7)60-69 9 5.6 (2.9,10.9) 4.2 (0.5,32.7) 9 5.7 (2.9,10.9) 0.4 (0.2,1.0) 9 5.7 (2.9,10.9) 1.4 (0.4,5.1)70-79 6 4.4 (2.0,9.7) 3.2 (0.4,26.7) 18 13.1 (8.3,20.9) 1.0 (0.4,2.1) 6 4.4 (2.0,9.7) 1.1 (0.3,4.3)

≥80 1 1.4 (0.2,9.7) 1.0 10 13.6 (7.3,25.4) 1.0 3 4.1 (1.3,12.7) 1.0Not known 3 - - 7 - - 1 - -

SexMale 13 5.3 (3.1,9.2) 1.0 20 8.2 (5.3,12.7) 1.0 9 3.7 (1.9,7.1) 1.0

Female 6 1.2 (0.5,2.7) 0.2 (0.1,0.6) 32 6.5 (4.6,9.2) 0.8 (0.5,1.4) 11 2.2 (1.2,4.0) 0.6 (0.3,1.5)Not known 0 -- - 0 - - 0 - -

IndicationOther 16 2.8 (1.7,4.6) 1.0 39 6.9 (5.1,9.5) 1.0 12 2.1 (1.2,3.8) 1.0

Osteoarthritis 3 1.6 (0.5,5.0) 0.6 (0.2,2.0) 13 6.9 (4.0,11.9) 1.0 (0.5,1.9) 8 4.3 (2.1,8.5) 2.0 (0.8,4.9)NSAID*

No 10 3.3 (1.86.2) 1.0 22 7.3 (4.8,11.1) 1.0 8 2.7 (0.3,5.3) 1.0Yes 6 1.8 (0.8,3.9) 0.5 (0.2,1.5) 23 3.4 (6.7,4.5) 0.9 (0.511.7) 10 2.9 (1.6,5.4) 1.1 (0.4,2.8)

Not known 3 - - 7 - - 3 - -

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

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

Cross-tabulation of risk factors with event groups suggested a significant association

between age and experiencing cardiovascular (χ2 test, p<0.0001), cerebrovascular (χ2

test, p<0.0001) and peripheral venous thrombotic events (χ2 test, p=0.014); and between

sex and experiencing cardiovascular TE events (χ2 test, 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 25mg, and 7.5 or 15mg 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=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 12.5mg per day, respectively. As the reporting of dose data was low, it was not

adjusted for in the multivariate analysis.


Table 4. Crude and adjusted rate ratios of cardiovascular, cerebrovascular and peripheral venous thromboembolic events in users of rofecoxib compared to meloxicam.

Event

Rofecoxib Meloxicam

Unadjusted rate ratioa

(95% CI) n=34 355

Unadjusted rate ratiob (95% CI)

n=29 364

Adjusted rate ratioc (95% CI)

n=29 364

No. events/

1000 person-

years exposure

Rate (95% CI)

No. events/

1000 person-

years exposure

Rate (95% CI)

Cardiovascular 21/6.42 3.27 (2.13,5.01)

19/7.51 2.53(1.61,3.97)

1.29 (0.70,2.40)

1.51 (0.78,2.92)

1.38 (0.71,2.67)

Cerebrovascular 74/6.41 1.15 (9.18,14.49)

52/7.50 6.9 (0.52,0.90)

1.66 (1.17,2.37)

1.75 (1.20,2.56)

1.68 (1.15,2.46)

Peripheral Venous 6/6.43 0.93 (0.42,2.07)

20/7.51 2.66 (1.72,4.13)

0.35 (0.14,0.87)

0.32 (0.12,0.85)

0.29 (0.11,0.78)

a Poisson regression model (whole dataset); b Poisson regression model excluding age and sex not known (n=4991);cPoisson regression model adjusted for age (age2) and sex.

The crude and adjusted rate ratios are presented in Table 4. 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 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, χ2 p=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=29 364 vs n=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

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 to 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 age-specific 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 χ2 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 significant evidence of a sex-drug interaction for any of the event

groups (tests for effect modification, all χ2 p>0.063). Osteoarthritis as the indication

(compared to ‘other’ category treated as reference group) and prescription of an NSAID

within 3 months of starting treatment (compared to 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 χ2

p>0.068).


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 (Figures 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

(Figure 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 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® in Gastrointestinal Outcomes in

Research) study [5] primarily compared the efficacy and gastric safety of rofecoxib (50mg

daily) to naproxen (500mg twice daily). The unadjusted rate of all thrombotic events was

significantly lower for naproxen compared to rofecoxib (50mg - twice the recommended

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=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%) of 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 to meloxicam users [RR

1.73 (95% CI 0.99, 3.04)], a lower but non-significant 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)].

D i s c u s s i o n

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 postmarketing 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 to 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

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


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 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 non-aspirin NSAIDs

does not lend itself to such a relationship, [13] especially as 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 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

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 rofecoxib [RR

0.36 (0.17, 0.74)]. The other categories being 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

(7.5mg or 15mg per day) compared with other non-selective NSAIDs (piroxicam 20mg,

diclofenac 100mg and naproxen 750mg 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 to 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 COX-1 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 recognised 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


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.

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 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 Administration (FDA) and Joint

British Societies criteria for the use of aspirin for secondary cardiovascular prophylaxis

(history of IHD, MI, cerebrovascular, 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 a 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]

C o n c l u s i o n

The information regarding the overall safety of COX-2 inhibitors compared to 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

pulmonary embolism and arterial thrombosis in four patients with connective tissue

disorders receiving another COX-2 selective 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 postmarketing surveillance studies are not comparable

to randomised 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


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 to meloxicam is 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 to traditional non-selective 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 together with other studies seeking to determine the association

between the use of COX-2 inhibitors and thromboembolic events.

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C O M P A R I S O N O F T H E I N C I D E N C E R A T E S O F T H R O M B O E M B O L I C

E V E N T S R E P O R T E D F O R P A T I E N T S P R E S C R I B E D C E L E C O X I B A N D

M E L O X I C A M I N G E N E R A L P R A C T I C E I N E N G L A N D U S I N G P R E S C R I P T I O N -

E V E N T M O N I T O R I N G ( P E M ) D A T A

Deborah Layton 1,2

Kerry Hughes 1

Scott Harris 1,3


1 Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK2 University of Portsmouth, UK3 University of Southampton, UK

Rheumatol 2003; 42: 1354-1364

Reproduced with kind permission from Oxford University Press


I n t r o d u c t i o n

Cyclo-oxygenase (COX)-2 isoenzyme inhibitors were developed with the aim of

reducing gastrointestinal (GI) adverse reactions compared to non-selective non-steroidal

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-2-induced prostacyclin, unopposed by COX-1-

induced platelet aggregation, may result in an increased risk of TE events in susceptible

individuals. [17;18]

Celecoxib (Celebrex®), 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 (600mg, 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 (Mobic®), 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 randomised, 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

A b s t r a c t

Background: Celecoxib and meloxicam are classified as cyclo-oxygenase (COX)-2 selective inhibitors. The Drug Safety Research Unit 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 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-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=0.0153) and cerebrovascular TE event group (log rank test p=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 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 thromboembolic events, or peripheral venous thrombotic events 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.


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.

M e t h o d s

Table 1. Thromboembolic event groups

Cardiovascular Cerebrovascular Peripheral venous thrombotic

Cardiac arrest* Amaurosis fugax Deep vein thrombosis

CVS not specified* Aphasia Embolus pulmonary

Myocardial infarction Cerebrovascular accident Infarction Pulmonary

Dysarthria

Dysphagia*

Dysphasia

Embolus cerebral

Embolus mesenteric

Hemianopia

Hemiparesis

Hemiplegia

Hypoaesthesia*

Paralysis facial

Paralysis pseudobulbar

Paralysis ocular

Paraesthesia*

Paresis*

Retinal thrombosis artery

Retinal thrombosis vein

Slurred speach

Thrombosis cerebral

Transient ischaemic attack

Visual disturbance*

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.*Non specific terms evaluated by clinician and relevant lowest level (doctor terms) included in the analysis; CVS, cardiovascular system.

The PEM study conducted for celecoxib was conducted as described previously for

rofecoxib previously. [44] For this study, exposure data were obtained from Green Forms

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 (400mg b.d.) with NSAIDS (ibuprofen 800mg t.d.s or diclofenac

75mg, 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 randomised trials [including the CLASS

trial and VIGOR (Vioxx in Gastrointestinal Outcomes in Research) 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 postmarketing phase forms an important part

of a drug’s safety profile. Postmarketing 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 postmarketing period in England, provide complimentary data

on safety issues in addition to randomised-controlled trials and spontaneous reporting

schemes. PEM uses a non-interventional observational cohort technique with a systematic

approach to data collection, and 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 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


6.6% (1253/19 087), χ2 test, p=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), χ2 test, p=0.014].

Table 2. Characteristics of study cohort

Drug

Risk factor Celecoxib n=17 458 Meloxicam n=19 087 χ2 P-valuea

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)

≥80 1329 (7.6) 1876 (9.8)

Not known 6731 (38.6) 2210 (11.6)

Sex, n(%)

Males 5527 (31.7) 6173 (32.3) 0.012

Females 11928 (68.3) 12590 (67.1)

Sex not known 3 (<0.1) 324 (1.7)

Indication, n(%)

Osteoarthritis 4905 (28.1) 4434 (23.2) <0.0001

Others 12553 (71.9) 14653 (76.8)

NSAID prescribed within 3 months prior to starting drug, n(%)

Yes 7006 (40.1) 7978 (41.8) 0.014

No 7189 (41.2) 8658 (45.4)

Not known 3263 (18.7) 2451 (12.9)

All values are n (%); aExcludes values not known

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); χ2 test, p=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 Kaplan-Meier

received for patients identified from NHS prescriptions written by GPs in England for

meloxicam between December 1996 and March 1997 (n=19 087) and for celecoxib

between May and December 2000 (n=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 sizeThe 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]

AnalysisData 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 methods 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]

R e s u l t s

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), χ2 test, p<0.0001]

and be female [68.3% (11 928/17 455) vs 67.1% (12 590/18 763), χ2 test, p=0.012]. OA

was the most frequently reported indication for both celecoxib and meloxicam, although

the proportion was higher for celecoxib compared to meloxicam, respectively [28.1 vs

23.2%, χ2 test, 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


Figure 2. Kaplan-Meier survival estimates for cerebrovascular TE events between celecoxib and meloxicam cohorts.

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

Cross-tabulation of risk factors with event groups suggested a significant association

between age, and experiencing cardiovascular TE (χ2 test, p<0.0001), cerebrovascular

TE (χ2 test, p<0.0001) and peripheral venous thrombotic events (χ2 test, p=0.017);

between sex and experiencing cardiovascular TE events (χ2 test, p<0.0001) and between

indication and experiencing cerebrovascular TE events (χ2 test, p=0.017) and peripheral

venous thrombotic events (χ2 test, p=0.037). Use of a NSAID within the 3 months prior

to starting treatment was not associated with any of the event groups.

survival curve 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 celecoxib

compared to meloxicam [median pte 75.5 days (interquartile range (IQR), 39.5 to 145.5)

and 95 days (IQR, 38-108), respectively, log rank test p=0.0153; Figure 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=0.0055, Figure 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=0.7930, Figure 3], which is reflected by the survival curves,

one almost superimposed upon the other.

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


Table 3 continued

Risk factor Meloxicam (n=19 087)

Cardiovascular (n=19) Cerebrovascular (n=52) Peripheral Venous (n=20)

n Rate (95% CI)

Rate ratio (95% CI)

n Rate (95% CI)

Rate ratio (95% CI)

n Rate (95% CI)

Rate ratio (95% CI)

Age (yr)

≤39 0 - - 4 6.5 (2.4,17.2) 0.5 (0.2,1.5) 0 - -

40-49 0 - - 2 2.3 (0.6,9.2) 0.2 (0.0,0.8) 0 - -

50-59 0 - - 2 1.5 (0.4,5.8) 0.1 (0.0,0.5) 1 0.7 (0.1,5.2) 0.2 (0.0,1.7)

60-69 9 5.6 (2.9,10.9) 4.2 (0.5,32.7) 9 5.7 (2.9,10.9) 0.4 (0.2,1.0) 9 5.7 (2.9,10.9) 1.4 (0.4,5.1)

70-79 6 4.4 (2.0,9.7) 3.2 (0.4,26.7) 18 13.1 (8.3,20.9) 1.0 (0.4,2.1) 6 4.4 (2.0,9.7) 1.1 (0.3,4.3)

≥80 1 1.4 (0.2,9.7) 1.0 10 13.6 (7.3,25.4) 1.0 3 4.1 (1.3,12.7) 1.0

Not known 3 - - 7 - - 1 - -

Sex

Male 13 5.3 (3.1,9.2) 1.0 20 8.2 (5.3,12.7) 1.0 9 3.7 (1.9,7.1) 1.0

Female 6 1.2 (0.5,2.7) 0.2 (0.1,0.6) 32 6.5 (4.6,9.2) 0.8 (0.5,1.4) 11 2.2 (1.2,4.0) 0.6 (0.3,1.5)

Not known 0 -- - 0 - - 0 - -

Indication

Other 16 2.8 (1.7,4.6) 1.0 39 6.9 (5.1,9.5) 1.0 12 2.1(1.2,3.8) 1.0

Osteoarthritis 3 1.6 (0.5,5.0) 0.6 (0.2,2.0) 13 6.9 (4.0,11.9) 1.0 (0.5,1.9) 8 4.3 (2.1,8.5) 2.0 (0.8,4.9)

NSAID*

No 10 3.3 (1.86.2) 1.0 22 7.3 (4.8,11.1) 1.0 8 2.7 (0.3,5.3) 1.0

Yes 6 1.8 (0.8,3.9) 0.5 (0.2,1.5) 23 3.4 (6.7,4.5) 0.9 (0.5,1.7) 10 2.9 (1.6,5.4) 1.1 (0.4,2.8)

Not known 3 - - 7 - - 3 - -

aRates and rate ratio calculated using Poisson regression modelling; *prescribed <3 months to starting drug.

Table 3 shows crude event rates per 1000 person-years (pyrs) 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

At launch and at the time of the PEM studies, the recommended dose range of

celecoxib was 100-400mg/day, whilst meloxicam only had two doses licensed (7.5 or

15mg/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=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 200mg/day or less. As the reporting of dose data was low, it was

not adjusted for in the multivariate analysis.

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

Risk factor Celecoxib (n=17 358)

Cardiovascular (n=28) Cerebrovascular (n=68) Peripheral Venous (n=17)

n Rate (95% CI)

Rate ratio (95% CI)

n Rate (95% CI)

Rate ratio (95% CI)

n Rate (95% CI)

Rate ratio (95% CI)

Age (yr)

≤39 0 - - 0 - - 2 8.3 (2.1,33.2) 3.8 (0.2,223.2

40-49 0 - - 1 2.5 (0.4,18.0) 0.1 (0.0,0.5) 0 - -

50-59 1 1.3 (0.2,9.4) 0.2 (0.0,1.5) 4 5.3 (2.0,14.1) 0.1 (0.0,0.5) 2 2.6 (0.7,10.5) 1.2 (0.1,70.8)

60-69 5 5.5 (2.3,13.2) 0.6 (0.1,3.2) 8 8.8 (4.4, 17.6) 0.2 (0.1,0.6) 4 4.4 (1.6,11.7) 2.0 (0.2,98.3)

70-79 7 8.0 (3.8,16.7) 0.9 (0.2,4.2) 16 18.2 (11.2, 29.7) 0.5 (0.2,1.0) 3 3.4 (1.1,10.6) 1.5 (0.1,81.3)

≥80 4 8.8 (3.3,23.4) 1.0 16 35.3 (21.6,57.6) 1.0 1 2.2 (0.3,15.6) 1.0

Not known 11 - - 23 - - 5 -

Sex

Male 15 8.1 (4.9,13.4) 1.0 22 11.8 (7.8,18.0) 1.0 6 3.2 (1.4,7.2) 1.0

Female 13 3.2 (1.9,5.5) 0.40 (0.2,0.8) 46 11.35 (8.5,15.2) 0.9 (0.6,1.3) 11 2.7 (1.5,4.9) 0.8 (0.3,2.3)

Not known 0 - - 0 - - 0 - -

Indication

Other 17 4.2 (2.6,6.7) 1.0 39 9.6 (7.0,13.2) 1.0 10 2.5 (1.3,4.6) 1.0

Osteoarthritis 11 5.9 (3.3,10.7) 1.4 (0.7,3.0) 29 15.6 (10.9,22.5) 1.4 (1.0, 2.0) 7 3.8 (1.8,7.9) 1.5 (0.6,4.0)

NSAID*

No 11 5.0 (2.8,9.1) 1.0 28 12.8 (8.9,18.6) 1.0 4 1.8 (0.7,4.9) 1.0

Yes 14 5.2 (3.8,8.8) 1.00 (0.5,2.3) 30 11.2 (7.8,15.9) 0.9 (0.6,1.3) 11 4.1 (2.3,7.4) 2.2 (0.7,7.0)

Not known 3 - - 10 - - 2 - -

l

l


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, χ2 p=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=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=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 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%) of 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

either drug, with no systematic difference in the age-specific rates for each of the three

event groups (tests for effect modification, all χ2 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

χ2 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 χ2 p>0.2032).

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

Event

Celecoxib Meloxicam

Unadjusted RRa (95% CI)

Unadjusted RRb(95% CI)

Adjusted RRc

(95% CI)No. events/

1000 pyr exposure

Rate (95% CI)

No. events/

1000 pyr exposure

Rate (95% CI)

Cardiovascular 28/5.924.73

(3.26,6.85)19/7.50

2.53 (1.61,3.97)

1.87 (1.04,3.35)

1.89 (0.95,3.74)

1.72 (0.87,3.40)

Cerebrovascular 68/5.9111.51

(9.07,14.56) 52/7.50

0.69 (0.52,0.90)

1.66 (1.16,2.38)

1.77 (1.18,2.69)

1.66 (1.10,2.51)

Peripheral Venous

17/5.922.87

(1.79,4.62)20/7.51

2.66 (1.72,4.13)

1.08 (0.56,2.06)

1.12 (0.54,2.31)

1.06 (0.51,2.19)

a Poisson regression model (whole data set); b Poisson regression model excluding patients where age and sex not known (n= 9216 ); cPoisson regression model adjusted for age (age2) and sex.

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


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 group 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 (GI) events of the two

cohorts who may have been preferentially prescribed these drugs because of their

reported improved 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 (<325mg/day) or other antiplatelet agents. [51] Furthermore, only patients

with RA were enrolled in 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

events and peripheral venous thrombotic events were RR 1.72 (95% CI 0.95, 3.13)

and 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.

D i s c u s s i o n

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 (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 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


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.

C o n c l u s i o n

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-

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=202 916), and users of

rofecoxib (n=24 132), celecoxib (n=22 337) and other NSAIDs (n=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 (>25mg/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 (<25mg/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 non-specific cardiovascular

events) was lower than the observed rate in the study by Ray et al., [52] but this is to


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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 thromboembolic events.

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(10) Brooks P, Emery P, Evans JF, Fenner H, Hawkey CJ, Patrono C, et al. Interpreting the clinical significance of the differential inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2. Rheumatology (Oxford) 1999 Aug; 38(8):779-88.


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1 9 4 | C H A P T E R 4 . 2

4 . 3

D O S O M E I N H I B I T O R S O F C O X - 2 I N C R E A S E T H E R I S K O F

T H R O M B O E M B O L I C E V E N T S ? L I N K I N G P H A R M A C O L O G Y W I T H

P H A R M A C O E P I D E M I O L O G Y

David W.J. Clark 1

Deborah Layton 2,3


1 New Zealand Pharmacovigilance Centre, Department of Preventive and Social

Medicine, School of Medicine & Department of Pharmacology and Toxicology,

School of Medical Sciences, University of Otago, Dunedin, New Zealand2 Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK 3 University of Portsmouth, UK

Drug Safety 2004; 27 (7): 427-456

Reproduced with kind permission from Adis International


Cyclo-oxygenase (COX)-2 isoenzyme inhibitors were developed with the aim

of reducing the occurrence of gastrointestinal (GI) adverse reactions compared with

non-selective NSAIDs. However, emerging information suggests that use of such drugs

may contribute to an increased risk of adverse vascular events related to alteration

in haemostasis. [1] It is not clear whether the higher risk applies to all cardiovascular

events associated with thromboembolic (TE) events, whether it applies to all COX-2

inhibitors in all patients, [2] at all doses or only to some products at specific doses or dose

ranges. [3] Published evidence relating to the hypothesis that selective COX-2 inhibitors

are associated with a greater risk of TE events than non-selective COX-inhibitors is

reviewed.

This review aims to link the pharmacological evidence from small-scale in vitro and

in vivo investigations with pharmacoepidemiological evidence from large-scale clinical

trials, observational studies and spontaneous reporting schemes. The review will be

structured according to the following:

1. The pharmacology of cyclo-oxygenase inhibition: this section discusses evidence

from human and animal models regarding the pharmacological consequences of

COX inhibition and relates this to the plausible pharmacological mechanism for TE

events

2. Clinical trials and pharmacoepidemiological studies of COX-2 specific inhibitors,

celecoxib and rofecoxib: this section examines the published evidence from

randomised controlled trials, retrospective analyses and meta-analyses of randomized

controlled trials and observational studies relating to the hypothesis that selective

COX-2 inhibitors are associated with a greater risk of TE events than non-selective

COX-inhibitors.

3. Spontaneous Reporting Schemes of adverse drug reactions (ADRs); this section

provides a summary of published information on suspected adverse reactions reported

via postmarketing spontaneous reporting schemes worldwide.

1 . P h a r m a c o l o g y o f C y c l o - O x y g e n a s e ( C O X ) I n h i b i t i o n

At least two COX isoforms, COX-1 and COX-2, metabolise arachidonic acid to

prostaglandin (PG) H2, the intermediate step in the synthesis of prostaglandins and

related compounds (prostanoids); which include thromboxane (TX) A2, prostacyclin

A b s t r a c t

Inhibitors of the cyclo-oxygenase (COX)-2 isoenzyme were developed with the expectation that their use would be accompanied by a reduction in adverse reactions thought to be mediated though COX-1 compared with conventional non-selective NSAIDs. However, the results of some clinical studies and other evidence have led to the hypothesis that use of COX-2 inhibitors may contribute to an increased risk of adverse thromboembolic (TE) events. In this review, we have evaluated the evidence from small-scale in vitro and in vivo pharmacological studies, clinical trials and large-scale pharmacoepidemiological studies and commented on the relationship between the pharmacological characteristics related to thromboembolic events and the clinical effects in large-scale clinical trials and pharmacoepidemiological studies

Overall, the pharmacological evidence suggests that a prothrombotic effect of COX-2 selective inhibitors is plausible. To date, despite the results from the Vioxx® in Gastrointestinal Outcomes Research (VIGOR) study from which the clinical concern regarding cardiovascular TE risk arose, the published data from other randomised controlled trials (RCTs), retrospective observational studies and spontaneous reporting schemes provide a conflicting body of evidence on the TE risk with COX-2 inhibitors.

Concerns that COX-2 inhibitors may be associated with prothrombotic effects remain and these need to be addressed in large scale, RTCs designed specifically to investigate the possibility of an excess of adverse cardiovascular outcomes in users of some or all selective COX-2 inhibitors, both with and without concomitant low-dose aspirin. Consideration must also be given to other pathophysiological mechanisms for potential cardiovascular risk linked with inhibition of COX-2.

In view of the evidence reviewed, it is recommended that selective COX-2 inhibitors should be prescribed with caution, only in patients with conditions for which these drugs have proven efficacy and with careful monitoring of outcomes and adverse events. This is particularly important in the elderly, in patients with cardiovascular/renal disease and in patients with other risk factors that might predispose them to adverse events.


Figure 1. This figure summarises the prostanoid synthetic pathways and sites of inhibition of synthesis against a stylised section of a blood vessel. Platelet activation results in initiation of the process of haemostasis with an initial step involving platelet aggregation. The pro-aggregatory prostanoid thromboxane A2 (TXA2) is synthesised from arachadonic acid (AA), which in turn is produced from membrane phospholipids. Synthesis of TXA2, shown against an enlarged diagram of a platelet, is mediated by cyclo-oxygenase (COX)-1 and inhibited by NSAIDs including aspirin (acetylsalicylic acid; ASA) [which, in contrast to other NSAIDs, inhibits irreversibly]. Synthesis of the anti-aggregatory and vasodilator prostanoid, prostacyclin (PGI2) also occurs in platelets and in vascular endothelial cells where its formation is catalysed by COX-2 which is induced in response to inflammatory and other stimuli. Thus, selective COX-2 inhibition may lead to suppression of PGI2 formation without significant concomitant inhibition of TXA2 biosynthesis and platelet aggregation and haemostasis may occur unopposed.

1.1 Pharmacological Considerations of COX-2 Specific Inhibition and Haemostasis Several in vitro and in vivo studies, have attempted to model the net effect of the

interplay between the products of COX-1 and COX-2 isoenzymes. Similarities

and differences between the structure and function of these isoenzymes have been

reviewed. [8]

(PGI2) and PGE2 synthesis. The traditional view is that COX-1 is a constitutive enzyme

and is always present in high concentrations within tissues including platelets, vascular

endothelial cells, gastric epithelial cells and the renal collective tubules, whilst COX-2

is predominantly an inducible enzyme with its expression induced within inflammatory

and some other cells by inflammatory mediators such as bacterial lipopolysaccharides

(LPS) and cytokines (e.g. interleukin [IL]-1ß). Based on this traditional view, the products

of COX-1 metabolism are involved in normal regulation of physiological processes that

include stimulation of the process of haemostasis through TXA2 synthesis (which increases

platelet adhesion and aggregation), inhibition of gastric acid secretion, stimulation of

protective gastric mucus production and regulation of blood flow in various vascular

beds through the synthesis of prostanoids such as PGI2 and PGE2. This was believed to

be the dominant mechanism in a major homeostatic regulation of glomerular filtration

in the kidney, via production of vasodilator prostanoids (e.g. PGI2 and PGE2) through

COX-1 activity. Conversely, expression of COX-2 resulting in prostanoid synthesis at

sites of inflammation was traditionally seen as producing the principle unwanted effects

arising from the inflammatory process such as pain and excessive inflammation. [4]

Conventional NSAIDs (e.g. indomethacin, naproxen and diclofenac) are ‘non-

selective’ in that they inhibit both COX-1 and COX-2, but with varying degrees of

specificity for each enzyme. [5] These drugs thus show a wide spectrum of adverse

effects, including adverse renal and gastric effects traditionally thought to be largely

a result of inhibiting COX-1 and therefore the synthesis of prostanoids associated

with normal physiological control. [4] Subsequently the development and marketing

of NSAIDs, reported to be specific COX-2 inhibitors, was widely thought to herald

a major breakthrough in NSAID therapy that would greatly reduce renal, gastric and

other adverse effects without interference with physiological control.

However, in human and animal studies, evidence has accumulated to indicate that, whereas

TXA2 synthesis is primarily COX-1-dependant, synthesis of PGI2 is contributed to by COX-2

activity. [6;7] Thus, inhibition of the COX-2 isoenzyme may produce effects other than the

wanted reduction of pain and inflammation. One example, not covered in this review, is that

COX-2 inhibition, through inhibition of PGI2 synthesis and thus renal vasodilatation which

helps maintain glomerular filtration, leads to sodium and fluid retention and a subsequent

increase in hypertension, heart failure and other cardiovascular morbidity. Another important

issue, which is the subject of much debate and is the focus of this review, is the potential increase

in the risk of cardiovascular adverse events related to alteration in haemostasis, proposed as

occurring through unopposed platelet-derived TXA2 generation (Figure 1).


Addition of a selective COX-2 inhibitor (NS-398) largely abolished PGI2 and PGE2

synthesis but had minimal effect on TXA2 synthesis. This further strengthens evidence

that in the vascular endothelium, COX-2 inhibition reduces synthesis of prostanoids, such

as PGE2 and PG12. The authors conclude that their findings, involving the application

of an inflammatory mediator, have particular importance with regard to the potential

for cardiovascular consequences of COX-2 inhibition and support other investigations

that demonstrate that the formation of both PGI2 and TXA2 is markedly enhanced in

inflammatory conditions such as atherosclerosis where both COX-1 and COX-2 are

expressed and contribute to an increase in PGI2 as well as TXA2. [13]

In animal studies, Hennan et al. specifically addressed the possibility that selective

COX-2 inhibition suppresses the protective effects of PGI2 derived from the vascular

endothelium and that this results in an alteration of the haemostatic balance and vascular

tone. [14] These investigators induced circumflex coronary artery thrombosis in dogs by

vascular electrolytic injury. Administration of a selective COX-2 inhibitor (celecoxib)

or high-dose aspirin did not alter time to occlusive thrombus formation compared

with controls. However, high-dose aspirin produced a significant (and potentially

beneficial) increase in time to vessel occlusion, which was abolished when celecoxib was

administered. In addition, the vasodilator effect of PGI2 derived from the endothelium

of the coronary vessels was examined by monitoring coronary blood flow. In celecoxib-

treated animals, vasodilation in response to application of arachidonic acid was reduced

significantly compared with controls. Because of these results, the authors expressed

concern regarding the possibility of an increased risk of acute vascular events in patients

receiving COX-2 inhibitors, especially in individuals with underlying inflammatory

disorders, including coronary artery disease.

Further evidence that PGI2 may play a role in reducing the platelet aggregatory

effects of TXA2 came from the innovative approach of Cheng et al., [15] Using

genetically modified mice, these investigators demonstrated an enhancement of the

platelet aggregatory effects of TXA2 in mice with reduced expression of PGI2 receptors.

In parallel experiments, involving mice with reduced expression of TXA2 receptors,

they demonstrated a reduction in platelet aggregation. Their experimental evidence is

consistent with an increased risk of thromboembolism following selective inhibition of

COX-2 mediated synthesis of PGI2. The authors suggested that their work supports the

explanation for the cardiovascular outcome in the Vioxx® in Gastointestinal Outcomes

Research (VIGOR) trial (see section 2). The conclusions from these pharmacological

studies and other experimental evidence support the view that selective COX-2

In vitro studies have shown that the COX-2 inhibitor, rofecoxib, does not inhibit

platelet aggregation or prolong bleeding time (via COX-1 inhibition) when administered

to healthy volunteers at a dosage of either 12.5mg/day or 25mg/day for 5 days. [9]

Similarly, Leese et al., report that administration of celecoxib (600mg, twice daily for

10 days) does not lead to inhibition of platelet aggregation or prolong bleeding time in

healthy volunteers. [10] In a study involving healthy human volunteers, [11] McAdam

et al. compared the effects of celecoxib (100-800mg) with those of the non-selective

inhibitor ibuprofen (800mg) on indices of COX-1 activity in platelets and on systemic

biosynthesis of PGI2. Both ibuprofen and celecoxib suppressed COX-2 activity and

PGI2 synthesis, but only ibuprofen significantly inhibited both COX-1 and COX-2

activity and reduced platelet aggregation. No significant effect on models of platelet

aggregation, serum TXA2 (a marker of COX-1 activity) or urinary metabolites of

TAX2, was demonstrated following administration of celecoxib 800mg, but a modest

reduction in serum TXB2 (metabolite of TXA2) was observed. These findings support

the idea that selective COX-2 inhibition alone may reduce the production of PGI2,

which normally inhibits platelet aggregation and dilates blood vessels, while still allowing

COX-1-mediated synthesis of TXA2 to induce platelet aggregation (Figure 1).

The balance between TXA2 (platelet aggregator) and PGI2 (which counteracts

platelet aggregation) is modulated by drugs such as aspirin (acetylsalicylic acid), where

COX-1 is selectively inhibited by low dose aspirin in activated platelets by acetylation

of the hydroxyl group of a serine residue near the COX active site. The permanent

inhibitory action by aspirin on COX-1 persists for the lifetime of the platelet and

recovery is a function of platelet turnover. COX-2 activity is preserved and the

balanced is shifted to an antithrombotic state. In contrast, it is proposed that COX-

2 inhibitors suppress PGI2 formation within vascular endothelial cells and thus may

shift the balance to a prothrombotic state. Induction of COX-2 and formation of PGI2

has been demonstrated in vitro in cultured endothelial and vascular smooth muscle cells

after exposure to many different chemical and physical stimuli [6;7] and this supports

a pathophysiological role of COX-2 in the modulation of vascular response to platelet

activation and injury. [8;11]

A number of studies have investigated the effects of inhibiting COX-2 in human

endothelial cells. Caughey et al., [12] demonstrated that such cells normally expressed

only the constitutive enzyme, COX-1 resulting in synthesis of TXA2. When a cytokine

(IL-1ß) was applied, induction of COX-2 occurred and there were large increases in

the production of PGI2 and PGE2, but synthesis of TXA2 was not changed significantly.


effects on endothelial dysfunction or vascular inflammation during the 8-week treatment

period. [24]

1.2 Might Potency as a COX-2 Inhibitor Influence the Likelihood of Cardiovascular Events?The relationship between COX isoenzyme activity, prostanoid formation and cell

function in vivo is not necessarily linear. [25] There is a possible inverse relationship

between daily doses of aspirin and a relative risk reduction in vascular events largely

due to permanent irreversible inactivation of platelet COX-1, with higher aspirin doses

also reversibly inactivating endothelial COX-2. However, the incomplete and reversible

inhibition of COX-1 by non-aspirin NSAIDs does not lend itself to such a relationship,

especially in view of the large inter-individual variability in drug plasma levels with

consequential differential inhibition of COX-1 and COX-2 isoenzymes. [26]

Structurally different COX-2 inhibitors vary in their potency as inhibitors of the

COX–2 enzyme. Initial estimates of selectivity of drugs during their development are

made using in vitro tests, but this may not necessarily reflect selectivity in vivo. Because

of this, whole blood assays have been developed in order to standardize measurements

and to provide estimates of selectivity that more closely approximate the clinical

situation. [26;27] In vitro assays to more closely reflect selectivity in vivo involve a measure

of COX-2 activity, such as induced PGE2 production in whole blood or monocytes,

and of COX-1 activity such as measurement of platelet TXB2 production during blood

clotting. [11;28;29] Selectivity for the COX-2 enzyme is often expressed as a ratio of

COX-1 inhibitory concentration 50% (the concentration of COX-1 inhibitor needed

to produce 50% inhibition [IC50]) to COX-2 IC50 (i.e. the higher the ratio, the more

selective the inhibitor). Selectivity and potency of COX-2 inhibitors, including rofecoxib

and celecoxib, may differ in different tissues [27;30;31] and even in different types of

cell from the same tissue. [32] This variation may be related to differences in tissue

penetration, pharmacokinetic and other factors. However, in all tissues examined (both

human and other animal) etoricoxib and rofecoxib appear more selective and more

potent as COX-2 inhibitors than celecoxib. [27;30;31] Examples from a wide range

of NSAIDs of the COX-1/COX-2 IC50, as measured in human platelets, are given in

Table 1. [33]

A possible limitation of the above comparative data, and those from similar studies,

is that the IC50 values were derived by addition of drugs to human platelet preparations in

vitro, and not by administering the drugs to humans to achieve therapeutic concentrations

(ex vivo assays). [11;28] However, ex vivo IC50 values of rofecoxib and celecoxib from the

inhibition reduces synthesis of PGI2 and may allow COX-1 mediated synthesis of pro-

aggregatory and vasoconstrictor prostanoids to continue unchecked and increase the

risk of thrombus formation and vascular occlusion.

In contrast, other investigators advocate that there is a large reserve of PGI2 in

endothelial cells and platelets, which prevents platelet aggregation in vivo, with a

requirement of at least 90% inhibition of either system in order for clinical effects to be

seen. [16] In studies of differing experimental designs, other investigators have reached

the conclusion that therapeutic doses of the COX-2 inhibitor rofecoxib does not alter

the haemostatic balance in healthy volunteers. [17;18] Little is known regarding the

pharmacological functional consequences of COX-2 inhibition with regard to other

‘protective’ mediators involved in platelet-vessel wall interactions such as biological gases

(nitric oxide and carbon monoxide).

In several of these studies, conducted in healthy human volunteers and animal

models of vascular injury, neither rofecoxib nor celecoxib have been reported to have

significant effects on haemostasis. Nevertheless, such an effect on platelet aggregation

with possible clinical significance is suggested by observations of elevated prothrombin

times and bleeding episodes with concomitant use of celecoxib and warfarin, in a

patient with pre-existing cardiovascular disease, [19] and reports of patients with

connective tissue disorder who developed arterial thombosis after initiation of celecoxib

therapy. [20] Inflammation appears to contribute to the athersclerotic process,

and upregulation of COX-2 has been demonstrated in atherosclerotic plaques. [13]

However, it is unclear whether this upregulation plays a part in the pathogenesis of

astherosclerosis, and whether COX-2 inhibition exerts beneficial [21] or detrimental

effects [22] on this process. Elevated platelet synthesis of TXA2 has been identified

in patients with pre-existing cardiovascular disease (e.g. following acute myocardial

infarction [MI] or in unstable angina) and in diabetes mellitus. This suggests that TXA2

status is important. [2] Furthermore, an association between increasing urinary TXB2

concentrations and risk of cardiovascular events (MI and cardiovascular death) has been

reported. [23] While there a number of possible explanations such observations, including

the fact that there are a number of sources for TXA2 other than platelets, serve to fuel

the debate that patients with pre-existing cardiovascular disease may be more susceptible

to alterations in haemostatic factors with subsequently alterations in cardiovascular

risk. In a recent study in 60 patients with established coronary artery disease using

low-dose aspirin (<325mg/day) and randomised to received either rofecoxib (25mg/

day; n=30) or placebo (n=30), rofecoxib did not appear to have favourable or adverse


studies have been published that directly compare the efficacy of celecoxib with that of

rofecoxib. [36;37] However, an assumption is often made that the two drugs are more or

less therapeutically equivalent when comparing such data between studies. Whether this

means that, when used in the different dosage regimes to achieve therapeutic equivalence,

they are also equivalent in vivo in terms of blocking PGI2 formation via COX-2 and not

blocking possible COX-1-mediated prothrombotic events, requires further evaluation.

1.3 Do COX-2 Inhibitors Antagonise the Protective Effect of Aspirin? As previously reported by McAdam et al. for celecoxib, COX-2 selective inhibitors,

in addition to inhibiting COX-2, may also have varying degrees of inhibitory effect on

COX-1 activity. [11] This has been investigated by Ouellet et al., [38] who used an in

vitro human platelet preparation to study the relative potential of the non-selective COX

inhibitor, ibuprofen and of various selective COX-2 inhibitors (celecoxib, etoricoxib,

rofecoxib, valdecoxib) to reduce the ability of aspirin to block the activity of COX-1 in

the formation of pro-aggregatory prostanoids. The main aim of their investigation was

to clarify the possible effect that various COX-2 inhibitors might have on the protection

that aspirin provides against the possibility of thrombotic effects. They showed that

blocking of COX-1 by aspirin is antagonised by ibuprofen and the COX-2 inhibitors, but

with widely different potencies. The rank order of potencies for reducing the antagonism

of COX-1 by aspirin was found to be: ibuprofen > celecoxib > valdecoxib > rofecoxib,

with the newer COX-2 inhibitor, etoricoxib requiring the highest concentration to

inhibit aspirin’s effect in blocking COX-1 (Figure 2). This study supports that, amongst

the COX-2 inhibitors, rofecoxib and etoricoxib are highly potent and selective COX-2

inhibitors with minimal effect on COX-1. In addition, the study provides evidence that

celecoxib not only inhibits COX-1 itself over most of the concentration range used in

this study, but also antagonises the COX-1 inhibition produced by aspirin (Figure 2).

The results of this study suggest that less potent selective COX-2 inhibitors, in

particular celecoxib, which also demonstrate some affinity for COX-1 in potentially

therapeutic doses, may compete with aspirin’s ability to block COX-1-mediated

synthesis of prothrombotic prostanoids, as has been reported for the non-selective

NSAID, ibuprofen. [39] On the other hand, therapeutic doses of rofecoxib, a highly

potent COX-2 inhibitor, have been demonstrated not to interfere with the antiplatelet

effect of aspirin in humans in therapeutic doses. [40]

same laboratory, enabling comparisons under similar experimental conditions, were not

identified in the literature. The data presented (Table 1) demonstrate wide differences

in IC50 values between several selective and non-selective COX inhibitors, including

celecoxib and rofecoxib in human cells and provide a guide to their relative selectivity.

The COX-2 hypothesis proposed that at comparable COX-2 inhibiting doses,

highly selective COX-2 inhibitors would be as effective as traditional NSAIDs, but

cause fewer GI adverse effects, as determined by clinical endpoints reflecting COX-1-

dependent GI toxicity. [26] Evidence suggests that both minor symptoms (e.g. dyspepsia)

and endoscopically detected lesions are not good predictors of future complicated GI

disease. It is also unclear whether serious GI complications such as perforations and

bleeding are a consequence of COX-1 inhibition in platelets or in gastric mucosa. [35]

The large-scale prospective double-blind outcome studies of celecoxib and rofecoxib

(see section 2) provided strong evidence that COX-2 specific inhibitors decrease both

endoscopically detectable ulcers and clinically important GI events compared with active

comparator drugs, thus supporting the COX-2 hypothesis. [35] However, insufficient

appreciation given to the potentially negative effects of these drugs.

Table 1. Mean IC50 (with SE) for the inhibition of cyclo-oxygenase (COX)-1 and COX-2 in human whole blood assays. Values are ranked by the order of COX-2 selectivity as shown by the ratio of IC50 COX-1/COX-2 (from Riendeau et al., [33] with permission from J Pharmacol Exp Ther).

IC50

COX-1 (mmol/L) N (donor) IC50

COX-2 (mmol/L) N (donor) COX-2 Selectivity Ratio of IC

50 COX-1/COX-2

Etoricoxib 116 ± 18 12 1.1 ± 0.1 26 106.0Rofecoxib 18.8 ± 0.9 211 0.53 ± 0.02 614 35.0Valdecoxib 26.1 ± 4.3 11 0.87 ± 0.11 14 30.0Celecoxib 6.7 ± 0.9 13 0.87 ± 0.18 18 7.6Nimesulide 4.1 ± 1.2 6 0.56 ± 0.12 6 7.3Diclofenac 0.15 ± 0.04 10 0.05 ± 0.01 16 3.0

Etodolac 9.0 ± 2.5 3 3.7 ± 0.7 6 2.4Meloxicam 1.4 ± 0.4 6 0.70 ± 0.28 5 2.0Indomethacin 0.19 ± 0.02 36 0.44 ± 0.07 34 0.4Ibuprofen 4.8 ± 3.5 5 24.3 ± 9.5 7 0.2Piroxicam 0.76 ± 0.05 6 9.0 ± 1.3.3 16 <0.1

IC50 = concentration needed to produce 50% inhibition; N (donor) = the number of individuals donating blood for each IC value.

Although, on existing comparisons, rofecoxib appears more potent and more

selective than celecoxib (Table 1), it is used in correspondingly lower doses. Two


and placebo on the effect of aspirin on platelet aggregation. [41] Whether celecoxib,

administered in lower therapeutic doses than 400mg, leads to clinically important

inhibition of aspirin’s effects on platelet aggregation needs to be determined in larger

clinical studies.

The study by Title et al., [24] supports the assertion that rofecoxib in a therapeutic

dose does not significantly alter the protective effects of aspirin in patients with

established coronary artery disease and treated with low-dose aspirin 325mg/day.

Although this study makes an important contribution to the debate on the possible

adverse cardiovascular effects of COX-2 inhibitors, [42] it does not address the question

of whether celecoxib, which is claimed to antagonise aspirin’s protective cardiovascular

effect, [38] shows a similar lack of effect on endothelium function in aspirin-treated

individuals. Furthermore, with the reports that rofecoxib does not antagonise the

protective effects of aspirin, [39] it is important to investigate COX-2 inhibitor effects

on endothelial function in patients not taking aspirin.

Overall, the pharmacological evidence supports the hypothesis that it is biologically

plausible that COX-2 inhibition might lead to potentially serious cardiovascular

problems in patients at high risk of cardiovascular adverse events. This is especially

the case in clinical syndromes associated with elevated platelet activation where TXA2

biosynthesis is increased (unstable angina, peripheral arterial obstructive disease and

cerebral ischaemia) or in situations where the risk of peripheral venous thrombosis is

high, such as immobilisation due to surgery. [43]

2. Clinical Trials and Pharmacoepidemiological Studies of COX-2 Specific InhibitorsWhen considering the evidence to support or disprove a hypothesis, one must

consider the quality of evidence available on the subject matter. Randomised controlled

trials are accepted as the gold standard for assessing efficacy of medicines. [44] However,

not all hazards can be identified or predicted from randomised controlled trials or

pharmacological studies of a drug conducted prior to marketing approval, for reasons

which have been described elsewhere. [45] The concern that increased cardiovascular risk

may be associated with use of COX-2 inhibitors arose from two sources: (i) case reports

of patients with connective tissue disease who developed arterial thrombosis after starting

celecoxib; [20] and (ii) a large-scale randomised controlled trial which investigated the

efficacy and tolerability of rofecoxib (the VIGOR trial). [46] Subsequent to this safety

signal, it has become clear that there is a gap between experimental evidence regarding

effects of COX inhibitors on haemostasis and the pharmacoepidemiological evidence

Figure 2. Figure shows the antagonism of the aspirin (acetylsalicyclic acid) inhibition of platelet cyclo-oxygenase (COX)-1 by ibuprofen and various coxibs. Platelets were treated with 0-100 µmol/L of ibuprofen (∇), celecoxib (®) , valdecoxib (X), rofecoxib (◊) and etoricoxib (-) for 5 minutes before the addition of 10 µmol/L (a) or 100 µmol/L (b) aspirin. Data points represent the average of 6-11 titrations. After a 20-minute incubation, the platelets were washed twice and challenged with calcium ionophore. After 10 minutes, the reactions were quenched, and the amount of thromoboxane B2 produced was determined by enzyme immunoassay. For celecoxib, only data between 0.005-3.7 µmol/L are plotted, as higher concentrations showed inhibition from celecoxib alone (from Ouellet et al., [38] with permission).

In contrast to the in vitro findings of Ouellet et al., [38] no significant difference

was found in a small study of healthy human volunteers comparing celecoxib 400mg

-20

0

20

40

60

80

00 A

% in

hibi

tion

% in

hibi

tion

-20

0

20

40

60

80

100

0.001 0.01 0.1 1 10 100

[Inhibitor] ( �M)

B


cardiac events were MIs (rofecoxib n=20 [0.5%] versus naproxen n=4 [0.1%]). Of the

serious vascular adverse events meeting criteria for adjudication, twice as many cases

were reported for rofecoxib than for naproxen (n=65 [1.6%] versus n=33 [0.8%]).

However, because of incomplete documentation for 33% of adverse events, the number

of adjudicated events was much lower (n=45 [1.1%] versus n=19 [0.5%], respectively).

Stratification according to aspirin indicated or not indicated and use of the standard

composite Antiplatelet Trialists’ Collaboration (APTC) endpoints, revealed a lower risk

of MI and stroke in the naproxen cohort compared with the rofecoxib cohort [(aspirin-

indicated [RR] for cardiovascular deaths, MI and stroke for naproxen versus rofecoxib

was 0.26 (95% CI 0.07, 0.91)]; and for aspirin not indicated RR 0.65 (95% CI 0.34,

1.12)]. The risk of serious thrombotic events was significantly lower for naproxen than

rofecoxib [(RR 0.42 [95% 0.25, 0.72)], especially cardiac events [RR 0.36 (95% CI

0.17, 0.74)]. Regarding time to event, there was clear divergence of the survival curves

early after starting treatment (within 2 months) which persisted during the remainder

of the study period (log rank test result not reported). Of 37 adjudicated deaths of

all causes, 22 (0.5%) were recorded within the rofecoxib cohort and 15 (0.4%) in the

naproxen cohort. There was no difference in the incidence of adjudicated cardiovascular

deaths (both 0.1%, n=6) but acute MI were less common in the naproxen group (0.1%,

n=4) compared with the rofecoxib group (0.4%, n=20) [RR 0.2 (95% CI 0.1, 0.7)].

Furthermore, a retrospective subgroup analysis based on patients meeting the criteria

for aspirin use for cardioprotection revealed that there were significant lower rates of

adjudicated events in the naproxen group compared with rofecoxib in both subgroups

[(aspirin indicated RR 0.20 (95% CI 0.06, 0.71) and aspirin not indicated RR 0.53 (95%

CI 0.29, 0.97)].

The conclusion of the adjudication for the VIGOR study was that a significant

difference was seen in the composite of stroke, MI and cardiac death that was

unfavourable for rofecoxib compared with naproxen. Consistent with this result were

the time to event tables and the adjudicated thrombotic serious cardiovascular events

(MI and cardiovascular deaths). In the same document, similar adjudicated evaluations

of two smaller efficacy randomised controlled trials of rofecoxib, named Study 085

(n=1042) and Study 090 (n=978) in which low-dose aspirin for cardioprotection was

allowed, were undertaken. [3] The number of cardiovascular events reported in either

trial was extremely small (three and nine, respectively). These two small-scale studies

could not exclude such an association on the basis of smaller sample size and the event

rate is similar to that in the VIGOR study. The overall conclusion from the report was

of increased cardiovascular risk associated with these drugs.

In the first part of this review, we summarised the pharmacological evidence to

support a biologically plausible mechanism for prothrombotic effects of celecoxib and

rofecoxib. As mentioned previously, information on other COX-2 inhibitors (etoricoxib

and valdecoxib) is limited and therefore these drugs have not been included in this review.

In the following section we will present only the evidence from randomised controlled

trials, retrospective re-analyses and meta-analyses of these randomised controlled trials,

observational studies and summary data of suspected ADRs from spontaneous reporting

schemes, which report specifically on this issue, as retrieved through literature searches

on Medline and proceedings from scientific conferences.

2.1 Randomised Controlled TrialsWhilst data from randomised controlled trials have documented that aspirin

is an effective anti-thrombotic agent for primary as well as secondary prevention of

TE events, [47;48] trials of non-selective NSAIDs, which vary in their antithrombotic

properties have been inconclusive. [9;10;49-51] In these trials of non-selective NSAIDs,

the question of whether the degree of selectivity for COX-1 in non-aspirin NSAIDs is

sufficient to translate into clinically detectable cardiovascular protection (as achieved

by irreversible inhibition of COX-1 by aspirin) was not addressed. [52;53] For

COX-2 inhibitors, as reported earlier, the pharmacological evidence suggests that the

more selective the drug, the more likely the change in haemostatic balance in favour of

platelet aggregation and occlusion.

2.1.1 Large-Scale Randomised Controlled Trials of Rofecoxib and Celecoxib Reporting on Cardiovascular Thromboembolic Outcomes

To date, the best clinically-based support for the experimental evidence discussed

earlier of an increase in cardiovascular risk for the COX-2 inhibitors stems from the

findings of the large randomized controlled trial conducted with rofecoxib: the VIGOR

study (see Table 2). [46] A separate analysis of adjudicated cardiovascular events from

the VIGOR study [3] provides overall serious adverse event data (death, hospitalisation

or extension of hospitalisation and any life-threatening events or serious disability).

The vascular events referred for adjudication included coronary events (MI, unstable

angina, cardiac thrombus, resuscitated cardiac arrest and sudden or unexplained death),

cerebrovascular events (ischaemic or hemorrhagic stroke, and transient ischaemic attack

[TIA]), venous thrombosis and pulmonary embolism. The majority of the thrombotic

2 1 0 | C H A P T E R 4 . 3 C O X I B S A N D C A R D I O V A S C U L A R S A F E T Y | 2 1 1 T

able

2.

Sum

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Out

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of R

R. K

M e

stim

ate

of

cum

ulat

ive

even

t inc

iden

ces.

SG

of ri

sk fa

ctor

s of i

nter

est (

NS)

.

Prim

ary:

inve

stig

ator

re

port

ed se

rious

CV

TE

rela

ted

even

ts. S

econ

dary

: AP

TC e

ndpo

int

Retr

o re

-ana

lysi

s of

RCTs

. [51

,56]

Tr

ials

of r

of v

s com

para

tor N

SAID

an

d/or

P a

s sel

ecte

d fro

m 2

3 ph

ase

IIb-V

tr

ials,

>4 w

k du

ratio

n, c

ompl

eted

to 1

5 Se

ptem

ber 2

000.

Stu

dy U

pdat

e: 1

033

addi

tiona

l pt-y

follo

w-u

p ad

ded

to ro

f vs

non

-nap

NSA

ID st

udie

s, an

d 96

8 pt

s w

ith 7

50 p

t-y fo

llow

-up

adde

d to

rof v

s P

stud

ies.

Rof (

>12.

5mg)

for t

reat

men

t of R

A,

OA,

AD

and

low

bac

k pa

in ( n

=19

922)

Non

-nap

com

para

tor N

SAID

co

hort

[ibu

, dic

and

nab

] (n=

2755

) N

ap c

ohor

t (n=

78 7

00)

Mod

ified

ITT.

Cox

PH

M o

f RR.

Se

nsiti

vity

ana

lysi

s of e

ffect

of

dura

tion

of st

udy

(>6

mo)

and

do

se

Com

bine

d en

dpoi

nt u

sed

by

the

APTC

. Eve

nts a

djud

icat

ed

acco

rdin

g to

CV

stan

dard

op

erat

ing

proc

edur

e

Des

ign

[Ref

eren

ce]

Sett

ing,

stud

y po

pula

tion

Inte

rven

tion

and

stud

y si

zeSt

atis

tical

ana

lyse

sSt

udy

endp

oint

s

Cele

coxi

b st

udie

s

MC,

pro

sp, D

B, p

aral

lel-

grou

p RC

T (C

LASS

) [57

]38

6 ce

ntre

s in

US

and

Cana

da; p

roje

cted

to

tal 8

00 p

ts, a

ged

18+

y w

ith R

A or

O

A (>

3 m

o) re

quiri

ng N

SAID

for s

tudy

du

ratio

n.

Cel 4

00m

g bi

d ( n

=398

7) v

s ibu

80

0mg

tid (n

=198

5) o

r dic

75m

g bi

d (n

=199

6), u

p to

6 m

o. A

SA fo

r CV

pro

phyl

axis

(<32

5 m

g /d

ay)

perm

itted

ITT.

KM

plo

ts o

f tim

e to

eve

nt o

f PU

B. P

re-s

peci

fied

SG a

naly

sis

acco

rdin

g to

pot

entia

l ris

k fa

ctor

s. In

cide

nce

of A

E.

Prim

ary:

con

firm

ed u

lcer

co

mpl

icat

ions

as p

er

algo

rithm

and

inde

pend

ent

com

mitt

ee a

djud

icat

ion

proc

ess.

Seco

ndar

y:

sym

ptom

atic

ulc

ers n

ot

mee

ting

defin

ition

of u

lcer

co

mpl

icat

ion

(as a

bove

). In

vest

igat

or d

efine

d tr

eatm

ent f

ailu

re O

ther

ad

vers

e ex

perie

nces

Des

ign

[Ref

eren

ce]

Sett

ing,

stud

y po

pula

tion

Inte

rven

tion

and

stud

y si

zeSt

atis

tical

ana

lyse

sSt

udy

endp

oint

s

Retr

o an

alys

is o

f RCT

sa

fety

Dat

a [5

8]D

ata

for c

el a

nd N

SAID

s fro

m th

e CL

ASS

tria

l (se

e ab

ove)

.As

for C

LASS

tria

l (se

e ab

ove)

ITT

(bot

h CL

ASS

stud

y pr

otoc

ols)

. Cru

de e

vent

rate

s an

d tim

e to

eve

nt a

naly

ses o

f all-

caus

e CV

eve

nts.

Pre-

spec

ified

SG

ana

lysi

s of a

ll CV

eve

nts i

n no

n-us

ers o

f ASA

. Ana

lysi

s of

inci

denc

e of

MI i

n pt

s not

taki

ng

ASA

but A

SA in

dica

ted.

Prim

ary:

Inve

stig

ator

re

port

ed se

rious

CV

TE e

vent

s: (c

ardi

ac,

cere

brov

ascu

lar a

nd

perip

hera

l vas

cula

r eve

nts)

Retr

o re

-ana

lysi

s of

RCTs

[59]

Cel v

s com

para

tor N

SAID

and

/or P

st

udie

s in

pts >

18y

with

RA

or O

A >3

mo.

Sel

ecte

d fro

m 1

5 tr

ials,

>4w

k du

ratio

n: 1

3 ne

w a

pplic

atio

n st

udie

s an

d 2

post

mar

ketin

g tr

ials,

CLA

SS a

nd

SUCC

ESS

(a M

C, p

rosp

, DB,

par

alle

l gr

oup

RCT)

ASA

(81-

325

mg/

day)

use

pe

rmitt

ed in

abo

ve tr

ials

One

LT O

L do

se

esca

latio

n sa

fety

tria

l (St

udy

024)

Cel 1

00-8

00m

g/da

y , (

n=18

942

) P

coho

rt (n

=179

4) C

ompa

rato

r NSA

ID

coho

rt: d

ic (n

=654

2), i

bu (n

=233

0),

nap

(n=2

271)

Unc

ontr

olle

d, O

L co

hort

(n=5

209)

ITT.

Sum

mar

y st

atis

tics.

KM p

lots

of

tim

e to

APT

C en

dpoi

nt in

en

tire

coho

rt a

nd S

G n

ot ta

king

AS

A. C

ox P

HM

of R

R (9

5%CI

) fo

r prim

ary

and

seco

ndar

y en

dpoi

nts f

or a

ll pt

s and

ASA

no

n-us

ers (

sum

mar

y RR

est

imat

e as

sum

ing

fixed

effe

ct a

ppro

ach)

. H

eter

ogen

eity

am

ong

stud

y ca

tego

ries t

este

d fo

r int

erac

tion.

An

alys

is o

f eve

nt ra

tes f

rom

OL

stud

y.

Prim

ary:

com

bine

d en

dpoi

nt

used

by

the

APTC

with

in 3

0d

of la

st d

rug

expo

sure

, sub

ject

to

inde

pend

ent a

djud

icat

ion.

Se

cond

ary:

CV

adve

rse

even

ts.

Cont

inue

d ov

er.


that there was an increased risk of TE events, particularly MI, in patients exposed to

rofecoxib compared with naproxen, accounting for some other cardiovascular risk factors.

However, as there was no placebo group it was difficult to assess the risk compared with

no therapy at all.

A large randomised controlled trial was also conducted with celecoxib. The Celecoxib

Long-term Arthritis Safety Study (CLASS) was constructed to replicate clinical practice

with non-restrictive inclusion and exclusion criteria (Table 2). [57] Noteworthy differences

between the VIGOR compared with the CLASS study included: (i) the exclusion of

patients using aspirin, anticoagulants or antiplatelet agents together with other cardiac-

related exclusions for the VIGOR study while aspirin use for cardiovascular prophylaxis

(<325mg/day) was permitted for the CLASS study; (ii) patients in the VIGOR study

had rheumatoid arthritis (RA) while the CLASS trial studied a combination of patients

with osteoarthritis (OA) [72%] and RA (28%); and (iii) the active comparator group for

the 2-arm VIGOR study was naproxen, while two comparator drugs (diclofenac and

ibuprofen) were chosen for the CLASS double protocol study. The possible effects of

these differences on the estimates of cardiovascular risk are discussed in further detail

later.

In order to further assess the overall safety profile of celecoxib, the US FDA

requested an additional analysis of the CLASS trial, an open-label long-term

postmarketing safety study (Study 024) and a summary of postmarketing surveillance

data collected for celecoxib during 1999. This was undertaken primarily to re-examine

and compare outcomes related to upper GI tract injury (complicated and endoscopically

evaluated symptomatic ulcers) between celecoxib and comparator NSAIDs, as well as

other potentially important drug-related toxicities, using the 12-month data from the

completed arm of the CLASS trial. [61] Because of evidence for important differences

among the treatment groups including presence of risk factors for cardiovascular disease,

sub-group analyses were performed according to patients using aspirin and for those

not taking aspirin. This was particularly important given that the published results of

the CLASS trial revealed that the beneficial GI effect of celecoxib compared with the

comparator NSAIDs was no longer so evident in aspirin users, and that the RR of

ulcer complications was significantly lower in non-aspirin users compared to aspirin

users within the celecoxib cohort. In the FDA report, this stratification according to

aspirin use was also applied to examination of selected cardiac and non-cardiac vascular

adverse events. During the entire study period, the incidence of any TE event was 4-fold

higher for aspirin users than non-aspirin users within either cohort [celecoxib RR 3.9; Tabl

e 2.

Con

td

Des

ign

[Ref

eren

ce]

Sett

ing,

stud

y po

pula

tion

Inte

rven

tion

and

stud

y si

zeSt

atis

tical

ana

lyse

sSt

udy

endp

oint

s

Rofe

coxi

b an

d ce

leco

xib

com

bine

d st

udie

s

Met

a-an

alys

is o

f RCT

s [6

0]St

udie

s sel

ecte

d fro

m M

EDLI

NE

sear

ch

of p

ublis

hed,

Eng

lish-

lang

uage

, RCT

fro

m Ja

n 19

98-F

eb 2

001(

VIG

OR,

CLA

SS

Stud

y 08

5 an

d St

udy

090)

. Sea

rch

of

AERS

spon

tane

ous r

epor

ting

data

base

in

US.

Cel a

nd ro

f stu

dies

: VIG

OR

(n=8

076)

CL

ASS

(n=7

968)

Stu

dy 0

85 (n

=104

2)

Stud

y 09

0 (n

=978

) Com

para

tor

coho

rt: P

gro

up fr

om a

met

a-an

alys

is o

f 4 S

tudi

es (n

=48

540,

P

n=23

407

)

KM p

lots

of e

vent

inci

denc

es.

COX

regr

essi

on m

odel

ling

of R

R An

nual

ised

MI r

ates

KM

su

rviv

al e

stim

ates

AD =

Alz

heim

er’s

dise

ase;

AE =

adv

erse e

vent

s; AE

RS

= A

dvers

e Eve

nt R

epor

ting S

ystem

; APT

C =

Ant

i Pla

telet

Tria

lists’

Col

labo

ratio

n; A

SA =

asp

irin

(ace

tylsa

licyl

ic ac

id);

bid

= tw

ice-d

aily

; cel

= c

eleco

xib;

CLA

SS =

Cele

coxi

b Lo

ng-T

erm

Arth

ritis

Safet

y St

udy;

CO

X =

cyclo

-oxy

gena

se; C

S =

cor

ticos

teroi

d; D

B=

doub

le-bl

ind;

dic

=

diclo

fenac

; GI =

gastr

oint

estin

al; i

bu =

ibup

rofen

; IT

T =

inten

tion

to tr

eat;

KM

= K

apla

n-M

eier;

LT =

long

-term

; MC

= m

ultic

entre

; MI =

Myo

card

ial i

nfar

ction

; nab

=

nab

umeto

ne; n

ap =

nap

roxe

n; N

S =

not

spec

ified

; OA

= O

steoa

rthrit

is; o

d =

onc

e dai

ly; O

L =

ope

n-la

bel;

p= p

lace

bo; P

HM

= p

ropo

rtion

al h

azar

ds m

odell

ing;

pro

sp

= p

rosp

ectiv

e; pt

(s) =

pat

ient(s

); PU

B =

Per

fora

tion,

Ulce

ratio

n an

d B

leed;

RA

= rh

eum

atoi

d ar

thrit

is; re

tro =

retro

spec

tive;

rof

= ro

fecox

ib; R

R =

rela

tive r

isk; S

G =

su

bgro

up; S

UC

CE

SS =

Suc

cess

ive C

eleco

xib

Effi

cacy

and

Saf

ety S

tudy

; tid

= th

ree-

times

dai

ly; V

IGO

R =

Vio

xx in

Gas

troin

testin

al O

utco

me R

esea

rch.


2.2 Retrospective Analysis and Meta-Analysis of Randomised Controlled Trials of Rofecoxib and Celecoxib

Meta-analysis and re-analysis are techniques used to combine results from various

studies. A meta-analysis is different to retrospective re-analysis in that there is no access to

the raw data from each individual study; only the published estimates of exposure effect

are available and are used to generate a pooled overall estimate. For both re-analyses

and meta-analyses, it is essential to ensure that all studies (published and unpublished)

are included since reliance on published studies tend to introduce a bias from over-

representation of those which showed positive findings.

2.2.1 Retrospective Analyses of Randomised Controlled Trial Data of RofecoxibThree retrospective analyses of data collected from RCTs of rofecoxib have been

published on this topic (Table 2). One study reported on the safety profile of patients

included in an open-label study that was conducted to evaluate the influence of non-

pharmacological interventions on the outcome of osteoarthritis in patients prescribed

rofecoxib (Table 2). [54] However, the authors acknowledge the select nature of the

cohort with its limited information on baseline cardiovascular risk, the absence of a

control group and the danger of comparing incidence rates between studies of different

design.

The second retrospective analysis examined the investigator-reported cardiovascular

adverse event data held within the OA safety database collected for eight premarketing

efficacy randomised controlled trials for rofecoxib (Table 2). [55] The authors

acknowledged that the combined sample size of each treatment group together with the

number of serious TE events and the numbers indicated for aspirin use was low, which

may have contributed to the study findings of no difference.

The third re-analysis also investigated this topic but assessed TE events across 23

rofecoxib randomised controlled trials in over 28 000 patients with OA, RA, Alzheimer’s

disease or chronic back pain (Table 2). [51] The researchers concluded that the risk of

a cardiovascular TE event was similar between rofecoxib and placebo cohorts and the

non-naproxen NSAID group, but significantly higher relative to the naproxen cohorts

and that these results supported the hypothesis of a cardioprotective effect of naproxen.

This study was completed in September 2000. Since that time, additional adjudicated

data for trials conducted up to May 2001 (number unknown) were published in a

paper by Weir et al., [56] where the pooled analysis was repeated. The overall results

(95% CI 2.6, 5.7) and the comparator NSAIDs combined (RR 4.6; (95% CI 3.0, 7.0)],

but no difference between aspirin users between the two treatment cohorts [(RR 1.1;

(95% CI 0.7, 1.6) and non-aspirin users (RR 1.3; (95% CI 0.8, 2.0)].

Study 024 examined exposure to celecoxib at doses of 100-400mg/day for up to

2 years and involved 5157 patients with RA or OA. [64] The types of adverse events

with an incidence of 3% or more were similar between the celecoxib arms of both the

CLASS trial and Study 024. The types and incidence of the serious adverse events

reported were also similar and considered representative of common causes of morbidity

in populations with arthritis. There was no difference in the incidence of MI between

these two cohorts [RR 1.4; (95% CI 0.9, 2.3)]. The postmarketing reporting rates of

serious renal and cardiovascular adverse events were low (<3 per 100 000 patient-years

of exposure).

The overall conclusions were that there was no difference in thromboembolic events

seen between celecoxib and the conventional NSAIDs used in the CLASS trial and that

the risk of cardiovascular events associated with celecoxib at supra-therapeutic dose is

similar to that of conventional NSAIDs.

Clear concerns were voiced about the published summaries of both the VIGOR and

the CLASS studies. Questions were raised as to why the VIGOR study was not stopped

earlier because of the higher mortality rate and higher rate of serious cardiovascular

events in the rofecoxib cohort compared with the naproxen cohort, and why information

on MI only was provided in the published paper, [62] when the FDA report clearly

showed a higher risk of serious thrombotic cardiovascular events for rofecoxib in both

aspirin indicated and non-indicated patients compared with naproxen. Interestingly,

another paper reports use of a cardiovascular adjudication standard operating procedure

by the marketing authorisation holders before the VIGOR study, which was used to

systematically collect data on all cases of CV serious adverse experiences. [51] Concerns

raised regarding the CLASS trial included the statistical analysis of pooled data from

both protocols; the selective and partial reporting of data only for 6 months when the

follow-up was longer in the two separate protocols (12 months and 16 months) and the

subgroup analysis. [63] While the authors acknowledge that an explanation was lacking

in the published paper, they alluded to the differential survival of patients between

the studies which would have confounded comparisons and that the statistical plan to

analyse the combined data from both protocols was pre-specified. [64] Whether the

methodological concerns of the CLASS trial had any effect on data collected on other

adverse events including cardiovascular-related effects is uncertain.


remained unchanged. In this same publication, Weir et al., described another pooled

analysis of placebo-controlled cardiovascular safety data from the Alzheimer’s Disease

and Mild Cognitive Impairment programme, presented at a scientific meeting 2003.

[65] Across two placebo-controlled trials and interim data from an ongoing placebo-

controlled trial comprising 2899 elderly patients, predominantly male, similar rates of

investigator-reported and -confirmed adjudicated cardiovascular events were observed

in the rofecoxib and placebo groups. Weir et al., [56] reported that the rates in these

populations were higher than that observed in the previous pooled analyses, given the

Alzheimer studies were conducted in a higher risk population, but that the RR was

still consistent with that reported previously. This publication stimulated much debate.

[66;67]

2.2.2 Retrospective Analyses of Randomised Controlled Trial Data of CelecoxibTwo retrospective re-analyses of randomised controlled trial data for celecoxib

have been published, both by White et al. (Table 2). The first examined cardiac events

in almost 4000 patients within the CLASS trial, [58] whilst the second examined the

incidence of cardiovascular events as reported across the entire controlled arthritis

clinical trial database for celecoxib. [59] The results of the re-analysis of the CLASS

study revealed no evidence for an increase in investigator-reported serious TE events,

irrespective of whether patients were treated with concomitant aspirin. The authors

also concluded that their findings further refuted the suggestion that COX-2 inhibitors,

as a class, increased cardiovascular risk. [58] In the second study, the incidences of the

primary and secondary events were not significantly different between celecoxib and

placebo, for celecoxib compared with all NSAIDs, or for celecoxib compared with

naproxen, regardless of aspirin use and NSAID type. Thus, the authors concluded that

these comparative analyses demonstrated no evidence of increased risk of cardiovascular

thrombotic events associated with celecoxib compared with conventional NSAIDs,

naproxen or placebo. The authors also acknowledge that the event rates as reported

differ from those reported elsewhere for celecoxib because of the use of the APTC

endpoint and because of independent adjudication by clinical experts rather than

regulatory definitions and investigator coded diagnosis. [59]

2.2.3 Meta-Analysis of Randomised Controlled Trials Published for COX-2 Selective Inhibitors

One meta-analysis has been published with the aim of evaluating the totality

of evidence on cardiovascular TE risk (Table 2). [60] This meta-analysis, conducted

by Mukherjee et al., aimed to determine whether COX-2 inhibitors, as a class, were

associated with a protective or hazardous effect on the risk of cardiovascular events by

comparing the adjudicated cardiovascular outcomes from major trials COX-2 inhibitors

with the annual MI rate as reported in the placebo group of a recent meta-analysis of

four aspirin primary prevention trials.

The authors reported that their findings suggested a potential increase in

cardiovascular event rates for users of COX-2 inhibitors as a ‘class-effect’, possibly due

to a prothrombotic effect, despite examining data from trials of rofecoxib and celecoxib

only. However, their conclusion was not adequately supported by their study: although

the authors acknowledged some limitations in their study, there were also several

methodological flaws. Our evaluation of this study revealed that the paper did not

display each trial’s finding in a consistent manner; it did not give an overall estimate of

the magnitude of treatment difference nor did it investigate the heterogeneity between

trials or explore the robustness of the main findings using sensitivity analysis. The

randomised controlled trials were of different design; had different study endpoints;

involved patient populations of dissimilar cardiovascular risk and they compared

inequivalent therapeutic dosages of celecoxib and rofecoxib. In addition, the sample

size of the different studies included in the meta-analysis varied and the crude estimate

was likely to be heavily influenced by the size of the VIGOR study. Furthermore, a

number of studies that were favourable to rofecoxib were excluded. There were no data

comparing the cardiovascular event rates of the comparator NSAID cohort and placebo

group and the crude incidence of MI only was compared across the different studies

rather than the rate of thromboembolic events in totality. These fell within the range

of rates reported for the four individual aspirin trials (0.36-1.33%) making it difficult

to draw any conclusions. The authors also referred to data from spontaneous reporting

schemes, but did not draw attention to the limitations of such systems or how this data

supported their findings.

Despite accumulating published evidence on this topic, it is still difficult to draw any

conclusions from the results of all these randomised controlled trials, retrospective re-

analyses and the meta-analysis on differences of cardiovascular TE risk between celecoxib

and rofecoxib. For the randomised controlled trials described earlier, the heterogeneity

of study design (efficacy versus safety), the variability in the recording and the reporting

of outcomes (based on both subjective and objective measures) especially adverse events,

make comparisons of cardiovascular risk difficult. Furthermore, the sample size and


primary outcomes of these randomised controlled trials were based on the assessment

of upper GI risk, not cardiovascular risk. Thus, the randomised controlled trials were

unlikely to have sufficient power to detect small clinically significant differences in rare

cardiovascular outcomes, morbidity or mortality. In addition, with the exception of the

VIGOR and CLASS trials, the length of follow-up of the trials was relatively short

resulting in paucity of adverse effect data associated with long-term drug use.

In many of the studies reviewed, the choice of active comparator was either

naproxen or a combination of non-selective NSAIDs, each with different COX-1/

COX-2 selectivity. As mentioned earlier, the comparison with naproxen is important

since three case-control studies support a potential cardioprotective effect of naproxen,

[68-70] but not with other non-aspirin NSAIDs. What is clear is that there is still very

little information on patients unexposed to NSAIDs, so that the excess risk to patients

using COX-2 inhibitors still cannot be determined. To date, the second retrospective

analysis by White et al., [59] provides the best information on this subgroup, in that this

study reports cardiovascular TE outcomes for a large pooled placebo cohort of over

1700 subjects.

Focusing on the characteristics of patients enrolled in these trials, as mentioned

earlier, there was evidence of differential exclusion of patients with cardiac risk factors,

i.e. a preferential selection of patients with low cardiovascular risk. In the VIGOR study,

patients using aspirin were excluded, although 221 patients (4%) had a clear indication

for aspirin, whereas aspirin use was permitted in the CLASS trial. Some authors

advocate that a difference in TE rates in the CLASS trial was not revealed because

of the use of aspirin by some patients. [26] As mentioned previously, it is possible that

high-dose celecoxib competes with aspirin for COX-1 and thus abolishes any aspirin-

mediated cardioprotective effect. [38] Modification by non-selective NSAIDs of the

clinical benefits conferred by aspirin has been observed elsewhere. [71] The majority of

serious TE events in the CLASS trial occurred in the population that were not receiving

aspirin prophylaxis (78%, n=3105). Strand and Hochberg [72] suggested that the best

population to compare with the study population from the VIGOR study were those

not taking aspirin in the CLASS study. The relative risk of serious TE events was 1.1

(95% CI 0.6, 1.9) for non-aspirin celecoxib users (0.8%, n=25) versus non-aspirin users

of NSAID-treated patients (0.7%, n=23). The second retrospective analysis by White et

al., [59] also suggests that the findings of no difference in cardiovascular risk in users of

celecoxib compared with NSAIDs is not attributable to the associated use of aspirin for

cardioprotection in patients with cardiovascular risk factors.

Further complication in making comparisons between celecoxib and rofecoxib arise

from differences in cardiovascular risk between patients who have RA compared with

OA. Several investigations have reported that RA is associated with an increased risk for

cardiovascular disease (MI, congestive heart failure and stroke), compared with those

with OA, or no arthritis. [73;74] The indications of the study populations within each

trial were clearly different. As yet, trials aimed to specifically compare the cardiovascular

safety between the different COX-2 inhibitors in patients with equivalent cardiovascular

risk, have not been undertaken.

Another important issue is that of the dose of each COX-2 inhibitor and active

NSAID comparator used. In the VIGOR study, the dose of rofecoxib was intentionally

high (50mg), whereas the dose for naproxen (1000mg) was within standard prescribing

regimens. This prescribing bias (in favour of higher doses for the study drug of interest)

is also reflected in the CLASS study, with supra-therapeutic daily doses of celecoxib

(800mg) compared with standard daily doses of either ibuprofen (2400mg) or diclofenac

(150mg). As discussed previously (Figure 2), in vitro COX-1/COX-2 selectivity and

potency differs between different non-selective NSAIDs and the COX-2 selectivity of

celecoxib is lost at high doses (>800mg), [11] whereas the COX-2 selectivity of rofecoxib

(25-1000mg) remains constant. [75] Such loss of selectivity of celecoxib at the dose

used in the CLASS study, as well as the abolishment of the cardioprotective effect of

aspirin, may have contributed to the observed overall lack of effect on cardiovascular

risk compared to the non-selective NSAIDs. A more appropriate efficacy trial would

be to compare therapeutically equivalent doses of each NSAID of interest. None

of the aforementioned trials specifically addressed the issue of inequivalence of

COX-2 inhibition. While we acknowledge that there is no consensus on methods for

determining selectivity, one cannot yet draw conclusions regarding possible differences

in cardiovascular risk between the COX-2 inhibitors being attributable to differences in

COX-1/COX-2 selectivity. This hypothesis requires testing in large scale randomised

controlled trials.

In summary, only one meta-analysis has been published on this topic and, albeit

methodologically flawed, this study was a comprehensive attempt to pool data between

the COX-2 inhibitors. The retrospective re-analyses of randomized controlled trials were

undertaken for each COX-2 inhibitor independently, [51;56;59] and examined patient

derived data from all eligible randomised controlled trials for rofecoxib and celecoxib

separately. They were well conducted and used endpoints accepted to be of world-wide

clinical significance. While these re-analyses reported no evidence of increased risk of


cardiovascular reactions according to these endpoints for either drug, these studies were

still unable to answer the question of whether there is a difference between rofecoxib

and celecoxib in terms of cardiovascular safety.

2.3 Observational StudiesPopulation-based pharmacoepidemiological studies aim to identify and quantify

adverse events from the treatment experiences of the population from which the adverse

events arose and examine that population for characteristic features in order to learn

and inform from these experiences. Such studies usually include far more patients

than randomized controlled trials, but suffer from likelihood of bias and confounding.

Another important difference is that observational studies are often non-interventional

in that they do not interfere in the prescribing decisions of the medical practitioners, nor

do they require the strict inclusion criteria that are essential for randomized controlled

trials. Therefore, findings in observational studies are more generalisable. Observational

studies are often used to test a hypothesis at a population level and thus may contribute

information on a possible relationship between any NSAID use and the risk of TE events

in patients with concurrent medical problems and/or using concomitant medication.

As mentioned previously, one of the possible explanations for the observed

difference in cardiovascular risk between rofecoxib and naproxen in the VIGOR study

is that naproxen may be cardioprotective, yet the epidemiological evidence to support

this assertion appears contradictory. A review of four epidemiological studies with

different study designs and populations suggest no overall effect of traditional non-

selective NSAIDs, including naproxen on the risk of coronary heart disease (CHD),

regardless of chemical class or plasma half-life on the risk of CHD. [53] The results of

this review included prepublication material from a large-scale observational study using

a retrospective cohort design by Ray et al., which was later published in full. [76] The

authors concluded that none of the NSAIDs included in this study should be used for

cardioprotection, including naproxen, contrary to the VIGOR study, the retrospective

analysis by Konstam et al., [51] and other observational studies. [68-70] However, the

authors commented that consideration should be given to the higher cardiovascular risk

in this study population compared with those patients involved in the VIGOR study.

There have been eight pharmacoepidemiological observational studies published

that have reported on cardiovascular adverse events associated with either rofecoxib

and/or celecoxib (Table 3). Of these, three studies were individual postmarketing studies

(Table 3) whilst five studies were retrospective analyses of postmarketing data (Table 3).

2.3.1 Postmarketing Surveillance Studies of Rofecoxib and Celecoxib.One prospective postmarketing cohort study assessed the efficacy and tolerability

of rofecoxib in general practice conditions in Germany. [77] Two other postmarketing

studies were conducted in England using the non-interventional observational cohort

technique of Prescription-Event Monitoring (PEM) (Table 3), [78;79] where all events

reported by patients to English National Health Service general practitioners (GPs) are

collected prospectively in a systematic manner. [86] The authors’ conclusions from these

three postmarketing studies were that the tolerability of either drug was consistent with

previous experience in controlled trials.

The issue regarding excess risk of cardiovascular TE events arose after the

completion of the PEM study for rofecoxib [78] and during the PEM study for

celecoxib. [79] In the two PEM studies, the incidence of cardiovascular TE events

was low (0.6%). The strengths and limitation of such observational studies have been

discussed in detail elsewhere. [87] These postmarketing studies can provide information

on the incidences and rates of common adverse events in cohorts, but the sample sizes

(whilst large compared with most randomised controlled trials) are insufficient to detect

rare adverse events with an incidence lower than 1 in 3000. [88]

2.3.2 Retrospective Analyses of Postmarketing DatabasesThere have been four retrospective pharmacoepidemiological observational studies

published that were specifically designed to investigate the issue regarding the risk of

cardiovascular TE adverse events following use of COX-2 inhibitors, with information

for a fifth available in abstract form only (Table 3). [80-82;84]

The strongest evidence from observational studies to support the hypothesis to

date regarding an increase in cardiovascular TE events between the COX-2 inhibitors,

other NSAIDs and non-NSAID users comes from a second retrospective observational

study by Ray et al., which was conducted using the multipurpose Medicaid database in

the US (Table 3). [80] The authors concluded that high-dose rofecoxib (>25mg/day)

could be associated with a raised risk of serious CHD, whereas rofecoxib <25mg/day,

celecoxib, naproxen and ibuprofen were not. In contrast to the randomised controlled

trials presented earlier, this study did not examine all serious cardiovascular TE events

or report on the proportion of prescribed aspirin use, although this appears to have

been adjusted for in the analysis. Unlike for the investigators’ first retrospective study of

CHD for non-selective NSAIDs described earlier, [76] it is not clear whether there was a

difference in baseline risk of NSAID users compared with the controls, how information


Des

ign

[Ref

eren

ce]

Sett

ing,

stud

y po

pula

tion

Dru

g ex

posu

re, f

ollo

w-u

p du

ratio

n,

stud

y si

zeSt

atis

tical

ana

lysi

sSt

udy

endp

oint

s

Retr

o ob

s co

hort

des

ign

[81]

Link

ed a

dmin

istr

ativ

e he

alth

care

da

taba

ses,

Ont

ario

, Can

ada.

All

resi

dent

s (1.

44 m

illio

n), a

ged

66+y

, re

gist

ered

as r

ecei

ving

hea

lthca

re

betw

een

Apr 1

998

and

Mar

200

1.

Thre

e ex

posu

re c

ateg

orie

s: N

SAID

use

r, ne

w N

SAID

use

r, (n

=66

964)

, con

trol

s [N

o N

SAID

use

] (n=

100

000)

P-T

from

in

dex

date

to m

axim

um 1

y, to

end

el

igib

ility

, die

d, st

udy

end

or e

ndpo

int.

Crud

e an

d ag

e/se

x ad

just

ed ti

me

to

even

t ana

lysi

s usi

ng C

ox P

HM

with

se

nsiti

vity

ana

lysi

s.

Prim

ary:

hos

pita

l adm

issi

on fo

r ac

ute

MI (

ICD

9 di

agno

sis c

ode

410)

Retr

o ob

s co

hort

des

ign

[82]

PEM

dat

abas

e of

eve

ntsa

repo

rted

in

GP

in E

ngla

nd. P

t coh

ort f

rom

rof P

EM

stud

y [7

8] a

nd m

el P

EM st

udy

[83]

New

use

rs o

f rof

(n=1

5 26

8) v

s new

U

sers

of m

el (n

=19

087,

refe

renc

e co

hort

)P-

T fro

m d

ate

of 1

st p

res d

ispe

nsed

to

stud

y en

d (2

70d)

or e

ndpo

int.

Firs

t eve

nt in

cide

nce

rate

s; cr

ude

and

adju

sted

RR

calc

ulat

ed u

sing

PR

M. K

M ti

me

to e

vent

ana

lysi

s.

Firs

t rep

orte

d TE

ass

ocia

ted

even

ta :

CV, C

BV, p

erip

hera

l ve

nous

thro

mbo

tic

Retr

o ob

s co

hort

des

ign

[84]

PEM

dat

abas

e of

eve

ntsa

repo

rted

in

GP

in E

ngla

nd. P

t coh

ort f

rom

cel

PEM

st

udy

[79]

and

mel

PEM

stud

y [8

3]

New

use

rs o

f cel

(n=1

7 45

8) v

s new

U

sers

of m

el (n

=19

087)

, ref

eren

ce

coho

rt) P

-T a

s abo

ve [8

2]

As a

bove

[82]

As a

bove

[82]

Retr

o ob

s, m

atch

ed

case

-con

trol

st

udy

[85]

Stat

e sp

onso

red

bene

fits p

rogr

amm

e in

Pen

nsyl

vani

a an

d N

ew Je

rsey

, U

S. 5

4 47

5 pt

s, ag

ed 6

5+y,

rece

ivin

g m

edic

atio

n vi

a be

nefit

pro

gram

me,

19

99-2

000.

Case

: prim

ary

outc

ome;

eith

er c

urre

nt

stud

y N

SAID

use

r (ro

f, ce

l, no

n-se

lect

ive

NSA

IDs)

, or n

on-N

SAID

use

r (n=

10 8

95)

Cont

rol:

no h

ospi

talis

atio

n, e

xpos

ure

as

for c

ase

(n=4

3 58

0, 1

:4 c

ases

to C

ontr

ols)

CLRM

for a

djus

ted

RR fo

r all

dose

s an

d do

se sp

ecifi

c (h

igh

vs lo

w

equi

vale

nt d

oses

).

Prim

ary:

hos

pita

lisat

ion

for

acut

e M

I

a any

new

dia

gnos

is, a

ny re

ason

for r

eferr

al to

cons

ulta

nt o

r adm

issio

n to

hos

pita

l, an

y un

expe

cted

deter

iora

tion

(or i

mpr

ovem

ent)

in a

conc

urre

nt il

lnes

s, an

y su

spec

ted

drug

reac

tion,

or a

ny ot

her c

ompl

aint

whi

ch w

as co

nsid

ered

of su

fficie

nt n

otice

to en

ter in

to p

ts’ n

otes.

cel =

celec

oxib

; CH

D =

coro

nary

hea

rt di

seas

e; C

BV

= ce

rebr

ovas

cula

r; C

LRM

= co

nditi

onal

logi

stic r

egre

ssio

n m

odell

ing;

ICD

= I

nter

natio

nal C

lass

ifica

tion

of D

iseas

es; G

p= g

ener

al p

racti

ce; M

H =

Man

tel-H

aens

zel;

ibu

= ib

upro

fen; I

D

= in

ciden

ce d

ensit

y; K

M =

Kap

lan-

Meie

r; m

el =

melo

xica

m; M

I = m

yoca

rdia

l inf

arcti

on; N

HS

= N

atio

nal H

ealth

Ser

vice

; NR

= n

ot re

porte

d; N

SAID

= n

on-s

teroi

dal

anti-

infla

mm

ator

y dr

ug; O

A =

oste

oarth

ritis;

obs

= o

bser

vatio

nal;

PEM

= P

resc

riptio

n-E

vent

Mon

itorin

g; P

HM

= P

ropo

rtion

al H

azar

d M

odell

ing;

PR

M =

poi

sson

re

gres

sion

mod

ellin

g; P

MS

= p

ostm

arke

ting

surv

eilla

nce;

pres

= p

resc

riptio

n; P

-T =

pers

on-ti

me;

Que

st =

que

stion

naire

; retr

o =

retr

ospe

ctive

; rof

= r

ofec

oxib

; RR

=

rela

tive r

isk; W

OM

AC =

Wes

tern

Ont

ario

and

McM

aster

Uni

versi

ties O

A In

dex.

Tab

le 3

. Sum

mar

y of

rofec

oxib

and

celec

oxib

pos

tmar

ketin

g obs

erva

tiona

l stu

dies

and

retro

ana

lyse

s of

postm

arke

ting d

atab

ases,

repo

rting

on ca

rdio

vasc

ular

th

rom

boem

bolic

(CV

TE

) eve

nts.

Des

ign

[Ref

eren

ce]

Sett

ing,

stud

y po

pula

tion

Dru

g ex

posu

re, f

ollo

w-u

p du

ratio

n,

stud

y si

zeSt

atis

tical

ana

lysi

sSt

udy

endp

oint

s

Post

mar

ketin

g st

udie

s.

A re

tro

PMS

stud

y [7

7]G

P in

Wes

t Ger

man

y, M

ay 2

000

-Jan

20

01. 2

-pha

se re

crui

tmen

t by

11 8

51

phys

icia

ns.

Pts r

equi

ring

1st t

reat

men

t for

OA,

or

switc

h fro

m e

xist

ing

med

icat

ion,

and

no

kno

wn

cont

rain

dica

tions

to ro

f

Dat

e of

pre

s to

(at l

east

) 2nd

follo

w-u

p m

inim

um 2

8d a

fter s

tart

of t

reat

men

t. M

ean

dura

tion

of tr

eatm

ent N

R.

n=80

371

(1st

wav

e, n

=42

140;

2nd

w

ave,

n=3

8 23

1)

Des

crip

tive

stat

s and

mea

n ch

ange

in p

ain

scor

e, st

ratifi

ed b

y re

crui

tmen

t wav

e

Prim

ary:

effi

cacy

(WO

MAC

scor

e)

; cha

nge

in q

ualit

y of

life

(3-p

oint

sc

ale)

Seco

ndar

y : a

ll re

port

ed A

E

PEM

po

pula

tion

base

d ob

s co

hort

stud

y [7

8]

GP

in E

ngla

nd, U

K Al

l NH

S pt

s pr

escr

ibed

and

dis

pens

ed ro

f bet

wee

n Ju

l-Oct

199

9

P-T

from

dat

e of

dis

pens

ing

to st

op d

ate

or e

nd o

f sur

vey

date

. Que

st se

nt to

pr

escr

ibin

g ph

ysic

ians

Feb

-Nov

2000

(n=1

5 26

8)

Des

crip

tive

stat

s; un

adju

sted

rate

s (ID

) per

100

0 pt

-mo

of tr

eatm

ent

and

ID d

iffer

ence

(mo

1 - m

o 2

to 6

); st

ratifi

catio

n of

sele

cted

GI e

vent

s ac

cord

ing

to p

oten

tial r

isk

fact

ors

usin

g M

-H m

etho

d.

Hea

lth re

late

d ev

ents

a re

port

ed

by p

rimar

y ca

re p

hysi

cian

s du

ring

the

stud

y pe

riod.

PEM

po

pula

tion

base

d ob

s co

hort

stud

y [7

9]

GP

in E

ngla

nd, U

K Al

l NH

S pt

s pr

escr

ibed

and

dis

pens

ed c

el b

etw

een

May

-Dec

200

0

P-T

as a

bove

. [78

] Que

st se

nt to

pr

escr

ibin

g ph

ysic

ians

Jan-

Oct

200

1 ( n

=17

458)

As a

bove

[78]

As a

bove

[78]

Retr

o ob

s co

hort

des

ign

[80]

Tenn

esse

Med

icai

d pr

ogra

mm

e, U

S. A

ll pt

s enr

olle

d in

Med

icai

d be

twee

n 1

Jan

1999

and

30

Jun

2001

, age

d 50

-84y

, el

igib

le fo

r ben

efits

for p

ast 3

65d,

not

in

a n

ursi

ng h

ome

and

no h

isto

ry o

f no

n-CV

life

-thr

eate

ning

illn

ess

Four

exp

osur

e ca

tego

ries:N

SAID

use

r, ne

w N

SAID

use

r, fo

rmer

NSA

ID u

ser (

n=

181

441)

,Co

ntro

ls [

no N

SAID

use

] (n=

181

441)

P-T:

stud

y st

art d

ate

to e

nd o

f elig

ibili

ty,

365d

afte

r las

t NSA

ID u

se, s

tudy

end

, or

endp

oint

.

PRM

for a

djus

ted

inci

denc

e RR

for

NSA

ID e

xpos

ure

grou

ps.

Prim

ary

: Ser

ious

CH

D (d

efine

d as

hos

pita

l adm

issi

on fo

r acu

te

MI o

r dea

th fr

om C

HD

)


on other non-aspirin NSAIDs was analysed as for the other exposure categories and if

the effect of recent use within 60 days was examined. In addition, it would have been

useful to specifically examine the effect of concomitant low-dose aspirin in users of

celecoxib and rofecoxib, especially by dose to determine whether the cardioprotective

effect of aspirin persisted in rofecoxib users and/or was abolished in high-dose celecoxib

users as suggested by the experimental study of Ouellet et al. [38]

A further retrospective observational study was conducted using administrative

healthcare data from Ontario, Canada (Table 3). [81] The authors concluded that no

significant difference was observed in acute MI risk for new users of celecoxib, rofecoxib,

naproxen or non-naproxen NSAIDs (continuously for >30 days) compared with non-

users. Notably patients who were reported to have taken one of the study drugs for 30

days or less were excluded, and the effect of this on the estimate of RR of MI in the

short term (<30 days) is unclear.

In order to compare the safety profiles of these drugs as prescribed in general practice

in the UK, two retrospective analyses of selected TE events were undertaken using patient

event data collected during the large PEM studies for the individual COX-2 inhibitors:

rofecoxib, [78] celecoxib, [79] and meloxicam, [83] considered to be COX-2 selective

but less so than celecoxib and rofecoxib (Table 1). For these two comparisons, [82;84] the

TE events were categorised into three groups to mirror those endpoints as reported in

randomized controlled trials, as presented earlier. After adjustment for age and sex, these

two studies revealed a statistically significant higher rate of cerebrovascular TE events

for both rofecoxib and celecoxib compared with meloxicam, a statistically significant

lower rate of peripheral venous thrombotic events for the rofecoxib cohort compared

with meloxicam, but neither revealed a difference in the rate of the cardiovascular TE

event group.

A fifth analysis was presented recently at a scientific meeting in October 2003

(Table 3). [85] Information was available only from the abstract and has not yet been

published in a peer review journal. This matched case-control study was also conducted

using the Medicaid database in the US and directly compared the RR of acute MI

between celecoxib and rofecoxib. The authors reported that current use of rofecoxib was

associated with an increased adjusted RR of MI (of borderline significance) compared

with celecoxib or non-NSAID users. Dose-specific comparisons suggested that the risk

was highest for higher doses of rofecoxib (>25mg). Risk was also reported to be highest

in the first 90 days.

Residual confounding, confounding by indication and bias are particularly

important in observational studies that report a low RR estimate. Observational studies

are vulnerable to various kinds of bias, which may have contributed to the failure to

confirm the hypothesis of a consistent difference in cardiovascular TE risk between the

COX-2 inhibitors. For example, for data retrieved from medical insurance data-bases,

the longitudinal follow-up of an individual patient is dependent on their participation

in the insurance program, thus selection bias could be introduced by exclusion of

patients with incomplete records of exposure. Another example is that inconsistent

information on baseline cardiovascular risk of patients, no direct measure of adherence

and the use of confounding variables such as use of aspirin, other concomitant drugs

and past or present medical history of CHD could bias the summary effect estimate

either towards or away from the null value. Furthermore, in observational studies,

residual confounding by unknown risk factors should always be considered. Thus, the

information from observational studies must be taken into consideration with other

large-scale pharmacoepidemiological investigations on the same topic which examine

these risk factors.

3. Spontaneous Reporting Schemes of Adverse Drug ReactionsA major source of information on suspected ADRs includes databases of

postmarketing spontaneous reports held by pharmacovigilance centres, regulatory

authorities or manufacturers. Such data give a different but complementary perspective

on adverse reactions compared with randomised controlled trials or observational

studies, since they are derived from populations of national proportions, operate for the

lifetime of the drug and include all drugs in both general practice and hospital settings.

Spontaneous reporting schemes are effective for signal generation, particularly for very

rare ADRs; however, a limitation of these databases is that the data in individual case

reports is often incomplete. Comparisons between drugs based on spontaneous reports

are inherently difficult given that reports of suspected ADRs are not homogenous with

respect to the sources of the information, or time on the market between the drugs of

interest. A variety of other factors may influence spontaneous reporting including the

number of drugs on the market, drug prescribing policies, drug safety alerts, training of

physicians and other healthcare professionals, reporting and publication bias between

new entities versus other ‘me-too’ drugs, confounding by indication and confounding by

unknown risk factors. It is also important to recognise that these are case reports based

on suspicions of a causal relationship. The likelihood that the pharmaceutical product

caused the suspected ADR requires further evaluation of the individual cases making


up the safety signals by expert clinical reviewers. These factors and other strengths

and limitations are discussed in detail elsewhere, [89] and should be considered when

assessing the evidence regarding TE risk based on voluntary reporting schemes as

presented below.

The WHO Uppsala Monitoring Centre (UMC) in Sweden maintains a database of

spontaneous reports received from the national monitoring centres worldwide. Suspected

adverse reactions are coded onto the WHO database according to the WHO Adverse

Reaction Terminology (WHO-ART) hierarchical system. Signal scores are calculated

for each drug-reaction (preferred term) combination for each pharmaceutical product

recorded within the WHO database according to the Bayesian Confidence Propagation

Neural Network (BCPNN), [90] and hypotheses created of associations between drugs

and ADRs among the case reports on the WHO UMC database. An independent

study of adverse reactions, primarily adverse renal effects, reported for rofecoxib

(n=2720) and celecoxib (n=8434) reported to the WHO UMC up until the end of the

second quarter of 2000, was conducted by Zhao et al. [91] Drug-reaction combination

information component (IC) values and 95% CIs were calculated between both drugs

and also compared with background expectation. In this study, TE events were also

examined and compared (Table 4).

Table 4. Information component (IC)a and 95% CIb values for thromboembolic-related adverse drug reactions (ADRs) with rofecoxib and celecoxib, using ADR groups based on WHO adverse reaction (WHO-ART) preferred terms. [91]

ADR groupRofecoxib Celecoxib

Celecoxib vs rofecoxib p-valueIC value 95% CI IC value 95% CI

Myocardial infarction 1.44 0.92,1.96 0.37 -0.07,0.81 <0.05

Cerebrovascular eventsc 1.48 1.09,1.87 0.03 -0.35,0.41 <0.001

Thrombotic eventsd 0.46 -0.13,1.05 -2.0 -0.64,0.24 >0.05

aA positive IC value indicates that a drug-reaction combination has been reported more frequently than expected compared with the background of all reactions reported to the WHO database; bIf the lower level of the 95% CI is greater than zero, the IC value is significantly higher than background expectation; c Category including cerebral infarction, cerebral ischaemia, cerebrovascular disorder, intracraniel haemorrhage, transient ischaemic attack, cerebral haemorrahge and heamorrhagic stroke; dCategory including thromboembolism, deep thrombophlebitis, thrombophlebitis, thromboisi, pulmonary embolism, embolism-blood clot, arterial embolism, arterial thrombosis and arm or leg arterial thrombosis.

The IC values for MI and cerebrovascular events was significantly higher for

rofecoxib compared with background expectations but not significantly different for

celecoxib. IC values calculated for thrombotic reactions were not significantly different

compared with the background expectation. The authors concluded that COX-2

specific inhibitors were not associated with thrombotic reactions. Given that the primary

outcome of the study revealed a difference in renal adverse reactions between the two

drugs, the investigators suggested that the higher risk of cardiovascular events observed

in patients treated with rofecoxib was likely to be associated with the higher risk of

renal adverse reactions, particularly hypertension, rather than secondary to thrombotic

episodes. However, it is important to recognise that such conclusions were based on

analytical comparisons of IC values, and that the individual case reports were not

clinically reviewed.

In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA,

formerly Medicines Control Agency, MCA) receives spontaneous reports submitted to

the Committee on Safety of Medicines (CSM) via the Yellow Card Scheme and provides

one of the major sources of data for pharmacovigilance. Statistical methods used in the

quantitative analysis of anecdotal spontaneous ADRs at the MHRA include the use

of Proportional Reporting Ratios (PRRs). [92] This technique tests the null hypothesis

that the proportion of individual ADR reported for a drug of interest does not differ

from the rest of the database. Signal generation using PRR within the MHRA Adverse

Drug Reaction Online Information Tracking (ADROIT) database is automated and

performed routinely on a weekly basis for monitoring purposes. Possible safety signals

which fall above pre-specified statistical criterion (PRR >2, χ2 >4) are then highlighted

for further examination by clinicians.

As discussed previously, one cannot make direct comparisons of reporting rates between

drugs based on spontaneous reports and it is important to acknowledge that rofecoxib was

the first of these two drugs to be marketed in the UK and thus the number of spontaneous

reports will reflect this. Figure 3 and Figure 4 represent graphically PRRs by systems order

class (SOC) for rofecoxib and celecoxib. Clearly the ADR reports received for both drugs is

dominated by the total number of reactions reported for the GI SOC, which is significantly

different from the overall reporting profile for the database. The number of reports within

the cardiovascular SOC is small (567 and 157, respectively) and the proportions of reports

for each drug do not differ significantly from background expectation. However, one cannot

draw any firm conclusions about differences between these drugs regarding cardiovascular

risk, since ADR reporting rates are influenced by many factors, as highlighted earlier.


Figure 3. The proportion of adverse drug reaction reports (percentages) for rofecoxib (total 6144 reports for rofecoxib on 3523 yellow cards) compared with the overall reporting profile for the Adverse Drug Reaction Online Information Tracking (ADROIT) database, by system order class up to 30 July 2003 (reproduced with permission from the UK Medicines and Healthcare products Regulatory Agency).

Figure 4. The proportion of adverse drug reaction reports (percentages) for celecoxib (total 2943 reports for celecoxib on 1724 yellow cards) compared with the overall reporting profile for the Adverse Drug Reaction Online Information (ADROIT) database, by system order class up to 30 July 2003 (reproduced with permission from the UK Medicines and Healthcare products Regulatory Agency).

In Canada, spontaneous reports are submitted to the regulatory authority,

Health Canada through the Canadian Adverse Drug reaction Monitoring Program

(CADRMP). By 12 October 2001, Health Canada had received 70 reports of suspected

cardiovascular/ cerebrovascular reactions for celecoxib (out of 528 in total) and 68

similar reports for rofecoxib (out of 348) since the date of marketing in Canada (April

and November 1999, respectively). [93] The authors of the Canadian report commented

that when interpreting whether the above cardiovascular effects are related to COX-2

inhibitor use, several factors must be considered such as pre-existing medical conditions,

the prevalence of cardiovascular disease in the population for whom the drugs are

indicated and concomitant use of drugs that can cause cardiovascular reactions or drug

interactions. Of the seven fatal cases reported in patients prescribed celecoxib, two were

cases of cerebral haemorrhage in patients prescribed warfarin concomitantly.

In New Zealand, the New Zealand Pharmacovigilance Centre (NZ PhvC)

receives spontaneous adverse reaction reports through the Centre for Adverse reactions

Monitoring (CARM) which, through the Intensive Medicines Monitoring Programme

(IMMP) [94] also undertakes PEM supplemented by spontaneous event reports. The

IMMP prepares adverse event profiles for the monitored medicines, measures the

incidence and is able to identify high-risk groups amongst the patients being treated.

The total IMMP cohorts for celecoxib and rofecoxib are 32 630 and 52 874 patients,

respectively. These cohorts are presently being followed up and analysed. At a recent

scientific meeting October 2003, [95] an interim analysis reported that 1825 events for

971 patients had been processed for celecoxib with corresponding figures for rofecoxib

reported as 1094 and 631, respectively. Of these, 17% (n=315) of events for celecoxib

and 20% (n=214) of those for rofecoxib were cardiovascular related. Of 179 deaths

reported for celecoxib, 68 were cardiovascular in origin of which 23 (12.9%) were

causally related to treatment. The corresponding figures for rofecoxib were 293, 116

and 34 (11.6%). Concern was expressed at the high rate of cardiovascular reactions and

the relatively high death rates. The authors also commented that there was substantial

prescribing to patients at high risk such as the very elderly (80+ years), and those with a

history of cardiovascular disease. Further information from the IMMP will be published

in articles presently in preparation.

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4 . 0 C o n c l u s i o n

The pharmacological evidence suggests that highly selective COX-2 inhibitors

such as rofecoxib, which have little or no affinity for COX-1, do not inhibit the synthesis

of prothombotic prostanoids. Potent and highly selective COX-2 inhibitors thus appear

to be more likely to contribute both to unwanted cardiovascular effects precipitating

thrombotic events, such as MI and angina, than are the less selective COX-2 inhibitors.

This is consistent with findings from some clinical observations. However, where aspirin is

used concomitantly to protect against thrombotic events, less selective COX-2 inhibitors

(celecoxib), but not highly selective COX-2 inhibitors (rofecoxib) may, at least partially,

antagonise the protective effect of aspirin. Further studies are needed to evaluate the

clinical use of COX-2 inhibitors in patients on low-dose aspirin.

In randomised controlled trials, the VIGOR study suggests that an excess risk of

cardiovascular events may be associated with use of rofecoxib compared with naproxen.

The reasons for this observation remain unclear, especially given the conflicting evidence

in the literature regarding the cardioprotective effect of naproxen or the weak evidence

to support a dose-response relationship of rofecoxib. To date, the data from other

randomised controlled trials, retrospective observational studies and voluntary reporting

schemes provide a conflicting body of evidence such that the hypothesis that proposes

that use of COX-2 inhibitors as a class, or individually, may be associated with an excess

thromboembolic risk can neither be supported or refuted.

Explanatory or pragmatic randomised controlled trials aim to measure the effect

of a particular intervention using the principle of randomisation to minimise bias and

the study sample size is chosen with the aim of testing a specific hypothesis. However,

randomised controlled trials suffer from selection bias in that the study participants may

not be representative of the intended target treatment groups. Although considered as the

gold standard for efficacy, the randomised controlled trials discussed in this paper provide

insufficient evidence to support the conclusion that COX-2 inhibitors are associated

with an increased risk of thromboembolic events; the majority of randomised controlled

trials were not designed to assess thromboembolic events and were statistically under-

powered and of insufficient duration to detect differences in the occurrence of relatively

rare and serious events such as MI, cerebrovascular accident or other thromboembolic

events. Furthermore, the baseline cardiovascular risk profiles of the study populations

involved in the CLASS and VIGOR study were clearly different, and given that RA

may be an independent risk factor for such cardiovascular events, one cannot draw any

conclusions regarding differences in risk between these two drugs from these trials.

The observational studies conducted with COX-2 inhibitors were retrospective

analyses of systematically collected data on the health-related experiences of patients

for whom the baseline cardiovascular risk factors were often unknown or inconsistently

recorded and were not prospective studies specifically designed to investigate the

cardiovascular risk of COX-2 inhibitors in patients with similar pre-existing cardiovascular

risk factors. Spontaneous reports together with case reports and case series currently

appear to be the cornerstone of postmarketing surveillance and regulatory decision

making. [96] While these systems are effective in generating signals of rare events, they

are not designed to compare adverse event frequency between drugs.

It is clear that all the information provided from the pharmacoepidemiological

studies must be taken into consideration before attempting to quantify the risk. Small

scale in vitro and in vivo studies must also be used to understand the pharmacological

mechanisms of such hazards. We have described how the association between the use

of COX-2 inhibitors and cardiovascular TE events may be related to pharmacological

characteristics of these products such as the selectivity of COX inhibition, which vary

between different products and is influenced by doses received. Furthermore, the

concomitant use of aspirin with COX-2 inhibitors may influence the likelihood of the

development of cardiovascular TE events. There is a need to control for differences

in baseline cardiovascular risk between study populations, not only the prevalence of

cardiovascular disease but also other risk factors associated with cardiovascular disease.

Complications may also arise from the apparent preferential prescribing of COX-2

inhibitors to patients at higher risk of GI and cardiovascular events than nonspecific

NSAIDs. [97] Therefore such factors should be taken into account through adequate

control of confounding when assessing the safety and risk/benefit of these drugs

With the available data, the concerns that COX-2 inhibitors may be associated

with prothrombotic effects remain and these need to be addressed in large-scale

randomised controlled trials and pharmacoepidemiological studies designed specifically

to investigate the possibility of an excess of adverse cardiovascular outcomes in users of

some or all selective COX-2 inhibitors, both with and without concomitant low-dose

aspirin. Consideration must also be given to other pathophysiological mechanisms for

potential cardiovascular risk linked to inhibition of COX-2, including imbalance of

PG I2 and TX A2 and concomitant disease states. Altered renal perfusion leading to

hypervolaemia and sodium retention both contribute to hypertension [98] and therefore

modify cardiovascular risk. Given the association between COX-2 expression and states


of intravascular inflammation arising from for example, atherosclerosis or intravascular

laminar shear forces, the clinical importance of COX-2 expression in the vascular

endothelium needs further investigation.

Although some of the evidence from large-scale clinical trials and

pharmacoepidemiological studies is contradictory, the pharmacological evidence

together with concerns arising from some clinical studies suggests that an increased

cardiovascular risk associated with COX-2 inhibitor use remains a possibility. Selective

COX-2 inhibitors should be prescribed with caution and with careful monitoring of

outcomes and adverse events. This is particularly important in the elderly, in patients

with cardiovascular/renal disease and in patients with other risk factors that might

predispose them to adverse events.

A c k n o w l e d g m e n t s

The authors would like to thank Dr David Coulter (Intensive Medicines Monitoring

Programme), Dr Rafe Suvarna (Pharmacovigilance Risk Assessment Unit, Medicines &

Healthcare Products Regulatory Agency, London, United Kingdom), and Ms Monica

Petterson (The Uppsala Monitoring Centre, Uppsala, Sweden) for their support of and

contributions to this review.

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