Rheumatology 2007;46:435–438 doi:10.

1093/rheumatology/kel428
Advance Access publication 25 January 2007

Risks and benefits of COX-2 inhibitors vs non-selective

NSAIDs: does their cardiovascular risk exceed their
gastrointestinal benefit? A retrospective cohort study
E. Rahme1,2 and H. Nedjar2

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Objectives. The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared
with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI
bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen.
Methods. We conducted a retrospective cohort study using administrative data of patients 65 years of age who filled a prescription for
NSAID or acetaminophen during 1999–2002. Outcomes were compared using Cox regression models with time-dependent exposures.
Results. Person-years of exposure among non-users of aspirin were: 75 761 to acetaminophen, 42 671 to rofecoxib 65 860 to celecoxib,
and 37 495 to NS-NSAIDs. Among users of aspirin, they were: 14 671 to rofecoxib, 22 875 to celecoxib, 9 832 to NS-NSAIDs and 38 048
to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the
acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac
1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52),
ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42).
Conclusion. Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI toxicity of celecoxib
was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both
celecoxib and naproxen seemed to be the least toxic.

KEYWORDS: Non-steroidal antiinflammatory drugs, COX-2 inhibitors, Acetaminophen, Acute myocardial infarction, Gastrointestinal bleeding, Elderly
patients, Administrative database, Retrospective cohort.

Introduction COX-2 inhibitors for pain relief and may be inadequate for
many patients [30–32]. It is therefore important to assess the GI
The risks and benefits of COX-2 inhibitors vs non-selective and CV risks and benefits of COX-2 inhibitors vs NS-NSAIDs and vs
non-steroidal anti-inflammatory drugs (NS-NSAIDs) are not acetaminophen, so that the appropriate therapy choices can be made.
clear. COX-2 inhibitors have a lower potential for causing This study evaluated the associations between rofecoxib, celecoxib,
gastrointestinal (GI) bleeding compared with NS-NSAIDs [1, 2], ibuprofen, diclofenac, naproxen and acetaminophen, and the risk
but may have a higher potential for causing acute myocardial of hospitalization for AMI, hospitalization for GI bleeding and
infarction (AMI) compared with naproxen [2–4]. Clinical practice the combined outcome AMI/GI bleeding, whichever occurred first
guidelines recommend the concurrent use of low-dose aspirin among elderly patients, both users and non-users of aspirin.
with COX-2 inhibitors for patients in need of cardiovascular
(CV) protection [5–7]. However, aspirin use with COX-2
inhibitors may offset their GI benefit [1] and, the use of some Methods
NS-NSAIDs with aspirin may have a deleterious effect on
We conducted a population-based retrospective cohort study
aspirin’s anti-platelet activity [8–10].
using health-care records of patients aged 65 years who filled
The CV safety of NS-NSAIDs has not been adequately studied
at least one prescription for rofecoxib, celecoxib, NS-NSAIDs
[6, 11, 12]. While one clinical trial found higher rates of AMI
or acetaminophen between April 1999 and December 2002
in patients randomized to rofecoxib as opposed to those
in Quebec, Canada. Hospitalization records for AMI and for
randomized to naproxen [2], other published clinical trials and
GI bleeding between January 1997 and December 2002 were also
a meta-analysis of published and unpublished trials did not
obtained for these patients from the hospital discharge summary
find any difference in CV risks between rofecoxib or celecoxib and
database. AMI and upper GI bleeding were identified using
either ibuprofen or diclofenac and found an increased risk
the international classification of disease 9th review (ICD-9)
associated with ibuprofen and diclofenac vs placebo [2–4, 13–
diagnosis codes: AMI: 410.x; GI bleeding: 531.x–534.x, 578.0,
15]. Epidemiological studies assessing the CV risk of NS-NSAIDs
578.1 and 578.9.
have had conflicting results [16–27]. A recent meta-analysis of
Permission from the Government of Quebec ethics committee, the
observational studies found an increased CV risk with diclofenac
Commission d’accès à l’information, was obtained to use the data.
but not with any other NS-NSAID [28].
The date of the first filled prescription for rofecoxib, celecoxib,
Acetaminophen use at more than 500 mg per day has been
any NS-NSAIDs or acetaminophen was considered as the
found to increase the risk of hypertension in older women [29]
patient’s index date. Patients with any hospitalization for AMI
and acetaminophen alone is less effective than NS-NSAIDs and
or GI bleeding in the 27 months prior to the index date
1
were excluded. Patients who filled prescriptions for two different
Department of Medicine and 2Research Institute, McGill University Health Centre,
study drugs (e.g. celecoxib and ibuprofen) on the index date were
Montreal, Canada.
also excluded.
Submitted 16 August 2006; revised version accepted 30 November 2006.
Correspondence to: E. Rahme, Division of Clinical Epidemiology, Outcome measure
McGill University Health Centre, Division of Clinical Epidemiology (V), 687
Pine Avenue West, V Building Montreal, Quebec Canada, H3A 1A1. The primary outcome of interest was the first hospitalization
E-mail: elham.rahme@mcgill.ca for AMI or GI bleeding. Only hospitalization for patients
435
ß The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
436 E. Rahme and H. Nedjar

discharged from acute care hospitals with AMI or GI bleeding
recorded as the most responsible diagnosis (primary discharge
diagnosis) were considered. Hospitalizations with AMI or
GI bleeding recorded as in-hospital complications were not
counted, and AMI hospitalizations where patients were
discharged alive and the total length of stay was <3 days
were also not counted [33].
Drug exposures
Exposure to a study drug was defined as the number of days
of medication supplied, as recorded in the database, in addition
to a grace period of 25% of this number [34]. A hospitalization
were not included in the model to facilitate the analysis.
Discontinuous time intervals removes the subjects from the risk
sets during the time of no-exposure [35]. HRs were adjusted for
baseline patient characteristics. All statistical analyses were
performed using SAS for Unix, version 8.2 (SAS Institute Inc.,
Cary, NC, USA).
Subgroup analyses
Two subgroup analyses were conducted. First, the main analysis
was repeated including only the subgroup of patients who did
not have any prescription for a COX-2 inhibitor, an NS-NSAID
or acetaminophen during the year preceding the index date

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for AMI or GI bleeding that occurred during an exposure period
was attributed to that period. Patients who, while exposed to a
study drug, were dispensed another study drug were considered to
have stopped the first treatment and started the second treatment
on the date for the second prescription dispensed. Exposure
episodes were classified into 14 categories: 7 categories defined
exposure among aspirin users (rofecoxib and aspirin, celecoxib
and aspirin, ibuprofen and aspirin, diclofenac and aspirin,
naproxen and aspirin, other NS-NSAIDs and aspirin and
acetaminophen and aspirin); the other 7 defined exposure
among non-users for aspirin (rofecoxib, celecoxib, naproxen,
ibuprofen, diclofenac, other NS-NSAIDs and acetaminophen). A
prescription of acetaminophen was classified as acetaminophen
and aspirin if the aspirin was filled at or before the filling date
of acetaminophen and the days supplied for aspirin overlapped
those supplied for acetaminophen. The rofecoxib and aspirin,
celecoxib and aspirin and NS-NSAIDs and aspirin categories
were defined in a similar manner. Patients in these categories
were termed ‘users of aspirin’.
Statistical analyses
The hazard ratio (HR) and 95% confidence interval (CI) of
AMI hospitalizations, GI hospitalizations and the combined
outcome AMI/GI hospitalizations were calculated for all study
drugs vs acetaminophen using multivariable Cox regression
models with time-dependent exposure. Times of non-exposure
(new users). Second, the main analysis was repeated including
only patients with a diagnosis of osteoarthritis in the prior year.
Sensitivity analyses
Four sensitivity analyses were conducted. The first sensitivity
analysis examined the effect of attributing AMI and GI
hospitalizations that occurred within the 125% of the days of
medication supplied to that medication; the 25% grace period
was removed and only AMI/GI hospitalizations that occurred
during the actual days of medication supplied were counted.
In a second sensitivity analysis, we added a grace period of 100%
to the days of medication supplied. In a third sensitivity analysis,
an AMI or GI hospitalization that occurred during overlapping
days supplied with two different study drugs were attributed
solely to the drug dispensed first; because some of the GI bleeding
could have been resolved without requiring hospitalization,
we considered all emergency room visits where an endoscopy
was performed and a diagnosis of GI bleeding was set. In a
fourth sensitivity analysis, we repeated the analyses combining
emergency room visits for GI bleeding with hospitalization
for GI bleeding.
Results
Patient characteristics, calculated at the index date, are shown
in Table 1. Of the 510 871 patients included in the study, 112 141

TABLE 1. Patient characteristics at the index date (%) and exposure and outcome occurrence during follow-up

No aspirin Aspirin

Rofecoxib Celecoxib NS-NSAID Acetaminophen Rofecoxib Celecoxib NS-NSAID Acetaminophen

No. of patients 55 867 81 932 102 021 158 910 14 843 20 421 22 374 54 503
No. prescriptions 622 283 954 835 592 437 1467 439 225 206 347 251 159 963 710 124
Duration (yrs) 42 671 65 860 37 495 75 761 14 671 22 875 9 832 38 048
N hospitalization
GI 167 436 167 300 131 122 74 225
AMI 317 139 280 735 185 275 121 583
Female 63.8 67.2 59.9 63.2 56.1 59.3 50.7 58.5
Age 66–74 yrs 62.7 60.6 65.5 47.2 52.7 49.9 54.2 38.0
OA 16.4 21.9 20.1 14.1 14.0 19.2 18.6 12.8
RA 1.1 2.0 3.4 1.7 0.8 1.6 2.3 1.1
CHF 4.6 5.6 5.3 11.7 15.2 16.8 18.2 23.5
IHD 9.1 10.2 9.3 16.2 33.2 34.1 34.1 37.0
CVD 2.4 2.5 2.0 5.0 7.2 8.0 8.6 11.8
Hypertension 35.4 37.9 36.8 45.8 60.3 59.7 57.4 63.7
Diabetes 8.4 9.2 9.7 12.9 16.8 16.9 17.5 19.8
Vasodilators 6.5 8.1 7.6 14.1 29.3 31.5 32.8 36.9
Lipid-lowering agents 20.3 20.0 18.5 18.3 47.1 43.1 40.8 34.7
Renal failure 0.7 0.8 0.9 2.4 1.7 1.5 1.8 3.7
COPD 6.0 6.4 6.2 10.1 7.2 7.5 8.1 11.0
Anaemia 4.3 4.4 4.2 8.3 4.4 4.6 4.8 7.4
Ulcer disease 1.0 1.2 1.0 1.8 0.9 1.0 1.0 1.4
Upper GI test 6.6 6.9 6.0 10.9 6.1 6.4 5.9 9.3
GPA 20.9 24.4 23.1 30.2 26.2 28.7 27.9 33.2
GPA at index date 5.8 5.8 9.3 8.5 6.3 6.6 10.6 11.0

OA, osteoarthritis; RA, rheumatoid arthritis; CHF, congestive heart failure; IHD, ischaemic heart disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; GPA,
gastroprotective agents; AMI, acute myocardial infarction.
 Risks and benefits of COX-2 inhibitors vs non-selective NSAIDS 437

TABLE 2. Results of Cox regression model with time-dependent exposure to determine the association between drug exposure and AMI, GI and AMI/GI
hospitalization among all patients and among patients with osteoarthritis

HR (95% CI)
All patients OA patients

AMI GI AMI/GI AMI/GI

Acetaminophen 1 (reference) 1 (reference) 1 (reference) 1 (reference)
Rofecoxib 1.14 (1.00, 1.31) 1.60 (1.31, 1.95) 1.27 (1.13, 1.42) 1.36 (1.07, 1.72)
Celecoxib 0.97 (0.86, 1.10) 0.82 (0.66, 1.01) 0.93 (0.83, 1.03) 1.13 (0.92, 1.40)
Ibuprofen 1.04 (0.68, 1.59) 1.11 (0.56, 2.16) 1.05 (0.74, 1.51) 0.61 (0.19, 1.91)
Diclofenac 1.17 (0.96, 1.43) 1.18 (0.86, 1.62) 1.17 (0.99, 1.38) 1.54 (1.12, 2.11)
Naproxen 1.16 (0.89, 1.51) 2.75 (2.05, 3.69) 1.59 (1.31, 1.93) 1.86 (1.23, 2.80)
Rofecoxib and aspirin 1.28 (1.08, 1.51) 3.22 (2.59, 4.00) 1.73 (1.52, 1.98) 2.35 (1.79, 3.07)
Celecoxib and aspirin 1.17 (1.01, 1.35) 1.85 (1.48, 2.31) 1.34 (1.19, 1.52) 1.70 (1.33, 2.17)

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Ibuprofen and aspirin 1.39 (0.80, 2.41) 1.81 (0.75, 4.40) 1.51 (0.95, 2.41) 1.78 (0.57, 5.57)
Diclofenac and aspirin 1.25 (0.94, 1.67) 3.06 (2.16, 4.35) 1.69 (1.35, 2.10) 1.81 (1.13, 2.89)
Naproxen and aspirin 1.03 (0.67, 1.58) 2.37 (1.40, 3.99) 1.35 (0.97, 1.88) 2.24 (1.18, 4.25)
Acetaminophen and aspirin 1.18 (1.05, 1.32) 1.56 (1.31, 1.87) 1.29 (1.17, 1.42) 1.58 (1.26, 1.95)

Adjusted for age; sex; diagnosis in the prior year of ischaemic heart disease, heart failure, renal failure, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis,
anaemia or blood disease, alcohol or drug abuse, gastric ulcers; prescriptions in the prior year for antihypertensive agents, lipid-lowering agents, antidiabetic agents, vasodilators,
gastroprotective agents; prescriptions in the prior 90 days for anticoagulants or corticosteroids; prescriptions for gastroprotective agents at the index date; chest pain in the prior 30
days.

were receiving aspirin at the index date. Among the 3 98 730
who were not receiving aspirin at the index date, 55 867 received
rofecoxib, 81 932 celecoxib, 102 021 NS-NSAIDs and 158 910
acetaminophen. Among the 112 141 patients who were receiving
aspirin at the index date, 14 843 received rofecoxib and aspirin,
20 421 celecoxib and aspirin, 22 374 NS-NSAIDs and aspirin
and 54 503 acetaminophen and aspirin. Patients receiving
acetaminophen on the index date, whether users or non-users
of aspirin, were older, more likely to be women, more likely
to have a risk factor for AMI and more likely to have a risk
factor for GI bleeding compared with patients receiving either
a COX-2 inhibitor or an NS-NSAID (Table 1).
The results of the time-dependent Cox regression models
are shown in Table 2. Compared with acetaminophen use
(with no aspirin), the adjusted HR (95% CI) for AMI
hospitalization among non-users of aspirin were as follows:
rofecoxib 1.14 (1.00, 1.31), celecoxib 0.97 (0.86, 1.10), ibuprofen
1.04 (0.68, 1.59), diclofenac 1.17 (0.96, 1.43) and naproxen
1.16 (0.89, 1.51); and among users of aspirin, they were: rofecoxib
1.28 (1.08, 1.51), celecoxib 1.17 (1.01, 1.35), ibuprofen 1.39 (0.80,
2.41), diclofenac 1.25 (0.94, 1.67), naproxen 1.03 (0.67, 1.58), and
acetaminophen 1.18 (1.05, 1.32); while the adjusted HR (95% CI)
of hospitalization for GI bleeding among non-users of
aspirin were: rofecoxib 1.60 (1.31, 1.95), celecoxib 0.82 (0.66,
1.01), ibuprofen 1.11 (0.56, 2.16), diclofenac 1.18 (0.86, 1.62),
naproxen 2.75 (2.05, 3.69); and among users of aspirin they were:
rofecoxib 3.22 (2.59, 4.00), celecoxib 1.85 (1.48, 2.31), ibuprofen
1.81 (0.75, 4.40), diclofenac 3.06 (2.16, 4.35), naproxen 2.37
(1.40, 3.99), and acetaminophen 1.56 (1.31, 1.87).
Among non-users of aspirin, naproxen seemed the least
advantageous, increasing the risk of AMI/GI hospitalization
by 59% compared with acetaminophen, while celecoxib was the
most advantageous carrying a similar AMI/GI risk compared
with acetaminophen. Among users of aspirin, the overall AMI/GI
risk of naproxen was not statistically different from that
of acetaminophen. Both naproxen and celecoxib were the least
toxic in this patient group.
Subgroup analyses
Lower HR of hospitalization for AMI or GI bleeding were
observed in general among all NS-NSAIDs or COX-2 inhibitors
vs acetaminophen groups when we considered new users, with
the exception of the naproxen group who exhibited a higher HR.
In the comparison of HR between exposure categories, similar
trends to those observed in the main analysis were found (data not
shown). Compared with patients included in the main analysis,
patients with osteoarthritis exhibited higher HR of AMI/GI
hospitalization in all exposure categories vs acetaminophen.
While celecoxib remained the least toxic NSAID among both
aspirin and non-aspirin users, rofecoxib also seemed advanta-
geous among non-users of aspirin and naproxen lost its advantage
among aspirin users (Table 2).
Sensitivity analyses
Sensitivity analyses results were similar to those of the
main analysis when the grace period was reduced from 25% of
the days of medication supplied to 0% or increased to 100%.
Results were also similar to those of the main analysis when
outcomes that occurred when two different study drugs had
been supplied during overlapping days were attributed to the
medication dispensed first. The HR for the combined outcome
of GI bleeding (hospitalization and emergency room), or for
AMI/GI, were not different from those of the main analysis (data
not shown).
Discussion
Our results show that in general, celecoxib was the least AMI/GI
toxic among both users and non-users of aspirin. In contrast to
the Adenoma Prevention with Celecoxib (APC) study, the risk of
AMI with celecoxib was similar to that of acetaminophen in
general but seemed higher among patients with osteoarthritis [3].
The increase in AMI hospitalizations observed with rofecoxib vs
acetaminophen was similar to that observed with ibuprofen and
diclofenac but higher than that observed with naproxen corrobor-
ating the results of the rofecoxib clinical trials [13, 14].
Surprisingly, the rates of GI bleeding observed in those
receiving diclofenac and ibuprofen were lower than expected
and were not consistent with the results of the rofecoxib and
celecoxib trials [1, 2]. It was difficult to determine from the data if
these differences in results were due to chance, given the multiple
modelling conducted in this study, or to differences in patient
characteristics that were not fully adjusted for in the models.
These analyses were conducted using a large, population-based,
well-validated medical database.
Nevertheless, this study has limitations. First, differences may
exist between patients prescribed acetaminophen and those
prescribed COX-2 inhibitors or NS-NSAIDs in variables that
were not available in the database such as smoking, obesity and
alcohol consumption. As with the measured concomitant diseases,
the prevalence of these conditions is expected to be higher in the
acetaminophen group and in COX-2 inhibitors groups relative to
438 E. Rahme and H. Nedjar
the NS-NSAID group. Therefore, the overall risk of AMI/GI with
NS-NSAIDs may have been underestimated. A second limitation
is that the information on compliance with the prescription
regimen is not available from the database and could not be
accounted for in the analyses. A third limitation is that the data on
over-the-counter medication purchases are not available from the
database, so non-prescription use of ibuprofen, acetaminophen or
aspirin could not be assessed. However, patients had strong
financial incentives to obtain these drugs via prescription rather
than by over-the-counter purchases, which are not reimbursed by
the provincial drug plan. In 1998, according to Santé Québec, the
government health agency, 17.0%, 2.2% and 46.3% of the elderly
who consumed NS-NSAIDs, aspirin and acetaminophen, respec-
tively, acquired them over-the-counter (D. Santé Québec 2000).
In summary, our results suggest that for those patients not
using aspirin and requiring anti-inflammatory therapy, celecoxib
may be a better choice over NS-NSAIDs. While, for those using
aspirin, naproxen seems to have the lowest AMI risk but the
highest GI risk resulting in a similar AMI/GI risk as that of
celecoxib. Further investigation is needed to assess whether
naproxen in combination with a Photon Pump Inhibitor would
be a better choice compared with celecoxib for these patients.
Acknowledgements
E.R. had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis. This study was supported in part by the Canadian
Institutes of Health Research.
E.R. is a research scholar funded by The Arthritis Society. She has
received grants and consultant fees from Merck & Co., Inc., the
previous manufacturer of rofecoxib, from Pfizer, Inc., the
manufacturer of celecoxib and from Boehringer Ingelheim, the
manufacturer of meloxicam.
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