Rheumatology 2007;46:435438

Advance Access publication 25 January 2007

doi:10.1093/rheumatology/kel428

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

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

COX-2 inhibitors for pain relief and may be inadequate for

many patients [3032]. It is therefore important to assess the GI
and CV risks and benefits of COX-2 inhibitors vs NS-NSAIDs and vs
acetaminophen, so that the appropriate therapy choices can be made.
This study evaluated the associations between rofecoxib, celecoxib,
ibuprofen, diclofenac, naproxen and acetaminophen, and the risk
of hospitalization for AMI, hospitalization for GI bleeding and
the combined outcome AMI/GI bleeding, whichever occurred first
among elderly patients, both users and non-users of aspirin.

Introduction
The risks and benefits of COX-2 inhibitors vs non-selective
non-steroidal anti-inflammatory drugs (NS-NSAIDs) are not
clear. COX-2 inhibitors have a lower potential for causing
gastrointestinal (GI) bleeding compared with NS-NSAIDs [1, 2],
but may have a higher potential for causing acute myocardial
infarction (AMI) compared with naproxen [24]. Clinical practice
guidelines recommend the concurrent use of low-dose aspirin
with COX-2 inhibitors for patients in need of cardiovascular
(CV) protection [57]. However, aspirin use with COX-2
inhibitors may offset their GI benefit [1] and, the use of some
NS-NSAIDs with aspirin may have a deleterious effect on
aspirins anti-platelet activity [810].
The CV safety of NS-NSAIDs has not been adequately studied
[6, 11, 12]. While one clinical trial found higher rates of AMI
in patients randomized to rofecoxib as opposed to those
randomized to naproxen [2], other published clinical trials and
a meta-analysis of published and unpublished trials did not
find any difference in CV risks between rofecoxib or celecoxib and
either ibuprofen or diclofenac and found an increased risk
associated with ibuprofen and diclofenac vs placebo [24, 13
15]. Epidemiological studies assessing the CV risk of NS-NSAIDs
have had conflicting results [1627]. A recent meta-analysis of
observational studies found an increased CV risk with diclofenac
but not with any other NS-NSAID [28].
Acetaminophen use at more than 500 mg per day has been
found to increase the risk of hypertension in older women [29]
and acetaminophen alone is less effective than NS-NSAIDs and

Methods
We conducted a population-based retrospective cohort study
using health-care records of patients aged 65 years who filled
at least one prescription for rofecoxib, celecoxib, NS-NSAIDs
or acetaminophen between April 1999 and December 2002
in Quebec, Canada. Hospitalization records for AMI and for
GI bleeding between January 1997 and December 2002 were also
obtained for these patients from the hospital discharge summary
database. AMI and upper GI bleeding were identified using
the international classification of disease 9th review (ICD-9)
diagnosis codes: AMI: 410.x; GI bleeding: 531.x534.x, 578.0,
578.1 and 578.9.
Permission from the Government of Quebec ethics committee, the
Commission dacce`s a` linformation, was obtained to use the data.
The date of the first filled prescription for rofecoxib, celecoxib,
any NS-NSAIDs or acetaminophen was considered as the
patients index date. Patients with any hospitalization for AMI
or GI bleeding in the 27 months prior to the index date
were excluded. Patients who filled prescriptions for two different
study drugs (e.g. celecoxib and ibuprofen) on the index date were
also excluded.

Department of Medicine and 2Research Institute, McGill University Health Centre,

Montreal, Canada.
Submitted 16 August 2006; revised version accepted 30 November 2006.
Correspondence to: E. Rahme, Division of Clinical Epidemiology,
McGill University Health Centre, Division of Clinical Epidemiology (V), 687
Pine Avenue West, V Building Montreal, Quebec Canada, H3A 1A1.
E-mail: elham.rahme@mcgill.ca

Outcome measure
The primary outcome of interest was the first hospitalization
for AMI or GI bleeding. Only hospitalization for patients
435

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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 19992002. 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.

E. Rahme and H. Nedjar

436

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].

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
Drug exposures

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

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
(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

No. of patients
No. prescriptions
Duration (yrs)
N hospitalization
GI
AMI
Female
Age 6674 yrs
OA
RA
CHF
IHD
CVD
Hypertension
Diabetes
Vasodilators
Lipid-lowering agents
Renal failure
COPD
Anaemia
Ulcer disease
Upper GI test
GPA
GPA at index date

Aspirin

Rofecoxib

Celecoxib

NS-NSAID

Acetaminophen

Rofecoxib

Celecoxib

NS-NSAID

Acetaminophen

55 867
622 283
42 671

81 932
954 835
65 860

102 021
592 437
37 495

158 910
1467 439
75 761

14 843
225 206
14 671

20 421
347 251
22 875

22 374
159 963
9 832

54 503
710 124
38 048

167
317
63.8
62.7
16.4
1.1
4.6
9.1
2.4
35.4
8.4
6.5
20.3
0.7
6.0
4.3
1.0
6.6
20.9
5.8

436
139
67.2
60.6
21.9
2.0
5.6
10.2
2.5
37.9
9.2
8.1
20.0
0.8
6.4
4.4
1.2
6.9
24.4
5.8

167
280
59.9
65.5
20.1
3.4
5.3
9.3
2.0
36.8
9.7
7.6
18.5
0.9
6.2
4.2
1.0
6.0
23.1
9.3

300
735
63.2
47.2
14.1
1.7
11.7
16.2
5.0
45.8
12.9
14.1
18.3
2.4
10.1
8.3
1.8
10.9
30.2
8.5

131
185
56.1
52.7
14.0
0.8
15.2
33.2
7.2
60.3
16.8
29.3
47.1
1.7
7.2
4.4
0.9
6.1
26.2
6.3

122
275
59.3
49.9
19.2
1.6
16.8
34.1
8.0
59.7
16.9
31.5
43.1
1.5
7.5
4.6
1.0
6.4
28.7
6.6

74
121
50.7
54.2
18.6
2.3
18.2
34.1
8.6
57.4
17.5
32.8
40.8
1.8
8.1
4.8
1.0
5.9
27.9
10.6

225
583
58.5
38.0
12.8
1.1
23.5
37.0
11.8
63.7
19.8
36.9
34.7
3.7
11.0
7.4
1.4
9.3
33.2
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.

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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
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.

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

Acetaminophen
Rofecoxib
Celecoxib
Ibuprofen
Diclofenac
Naproxen
Rofecoxib and aspirin
Celecoxib and aspirin
Ibuprofen and aspirin
Diclofenac and aspirin
Naproxen and aspirin
Acetaminophen and aspirin

OA patients

AMI

GI

AMI/GI

AMI/GI

1 (reference)
1.14 (1.00, 1.31)
0.97 (0.86, 1.10)
1.04 (0.68, 1.59)
1.17 (0.96, 1.43)
1.16 (0.89, 1.51)
1.28 (1.08, 1.51)
1.17 (1.01, 1.35)
1.39 (0.80, 2.41)
1.25 (0.94, 1.67)
1.03 (0.67, 1.58)
1.18 (1.05, 1.32)

1 (reference)
1.60 (1.31, 1.95)
0.82 (0.66, 1.01)
1.11 (0.56, 2.16)
1.18 (0.86, 1.62)
2.75 (2.05, 3.69)
3.22 (2.59, 4.00)
1.85 (1.48, 2.31)
1.81 (0.75, 4.40)
3.06 (2.16, 4.35)
2.37 (1.40, 3.99)
1.56 (1.31, 1.87)

1 (reference)
1.27 (1.13, 1.42)
0.93 (0.83, 1.03)
1.05 (0.74, 1.51)
1.17 (0.99, 1.38)
1.59 (1.31, 1.93)
1.73 (1.52, 1.98)
1.34 (1.19, 1.52)
1.51 (0.95, 2.41)
1.69 (1.35, 2.10)
1.35 (0.97, 1.88)
1.29 (1.17, 1.42)

1 (reference)
1.36 (1.07, 1.72)
1.13 (0.92, 1.40)
0.61 (0.19, 1.91)
1.54 (1.12, 2.11)
1.86 (1.23, 2.80)
2.35 (1.79, 3.07)
1.70 (1.33, 2.17)
1.78 (0.57, 5.57)
1.81 (1.13, 2.89)
2.24 (1.18, 4.25)
1.58 (1.26, 1.95)

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 advantageous 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 corroborating 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

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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.

438

E. Rahme and H. Nedjar

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.

Reference
1 Silverstein FE, Faich G, Goldstein JL et al. Gastrointestinal toxicity with celecoxib vs
nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the
CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety
Study. JAMA 2000;284:124755.
2 Bombardier C, Laine L, Reicin A et al. Comparison of upper gastrointestinal toxicity of
rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.
N Engl J Med 2000;343:15208.
3 Solomon SD, McMurray JJV, Pfeffer MA et al. Cardiovascular risk associated with
celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med
2005;352:107180.
4 Bresalier RS, Sandler RS, Quan H et al. Cardiovascular events associated with
rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med
2005;352:1092102.
5 Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum
2002;46:32846.
6 American College of Rheumatology Committee on Osteoarthritis Guidelines. Arthritis
Rheum 2000;43:190515.
7 Tannenbaum H, Peloso PM, Russell AS, Marlow B. An evidence-based approach to
prescribing NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis. Can J
Clin Pharmacol 2000;7(Suppl A):416A.
8 Catella-Lawson IA, Reilly MP, Kapoor SC et al. Cyclooxygenase inhibitors and the
antiplatelet effects of aspirin. N Engl J Med 2001;345:180917.
9 Saitoh Y, Waxman I, West AB et al. Prevalence and distinctive biologic features of
flat colorectal adenomas in a North American population. Gastroenterol
2001;120:165765.
10 MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin.
Lancet 2003;361:5734.

11 Fries JF, Murtagh KN, Bennett M, Zatarain E, Lingala B, Bruce B. The rise and
decline of nonsteroidal anti-inflammatory drug-associated gastropathy in rheumatoid
arthritis. Arthritis Rheum 2004;50:243340.
12 Silverstein FE, Graham DY, Senior JR et al. Misoprostol reduces serious
gastrointestinal complications in patients with rheumatoid arthritis receiving
nonsteroidal anti-inflammatory drugs. A randomized double-blind placebo-controlled
trial. Ann Intern Med 1995;123:2419.
13 Konstam MA, Weir MR, Reicin A et al. Cardiovascular thrombotic events in
controlled, clinical trials of rofecoxib. Circulation 2001;104:22808.
14 Weir MR, Sperling RS, Reicin A, Gertz BJ. Selective COX-2 inhibition and
cardiovascular effects: a review of the rofecoxib development program. Am Heart J
2003;146:591604.
15 White WB, Faich G, Whelton A et al. Comparison of thromboembolic events in
patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus
ibuprofen or diclofenac. Am J Cardiol 2002;89:42530.
16 Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection
against acute myocardial infarction. Arch Int Med 2002;162:11115.
17 Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use
and acute myocardial infarction. Arch Intern Med 2002;162:1099104.
18 Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic
cardiovascular events with naproxen among patients with rheumatoid arthritis.
Arch Intern Med 2002;162:110510.
19 Mamdani M, Rochon P, Juurlink DN et al. Effect of selective cyclo-oxygenase 2
inhibitors and naproxen on short-term risk of acute myocardial infarction in the
elderly. Arch Int Med 2003;163:4816.
20 Schlienger RG, Jick H, Meier CR. Use of nonsteroidal anti-inflammatory drugs
and the risk of first-time acute myocardial infarction. Br J Clin Pharmacol
2002;54:32732.
21 Graham DJ, Campen D, Hui R et al. Risk of acute myocardial infarction and sudden
cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective
non-steroidal anti-inflammatory drugs: nested case-control study. Lancet
2005;365:47581.
22 Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclooxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs:
population based nested case-control analysis. Br Med J 2005;330:13669.
23 Kurth T, Glynn RJ, Walker AM et al. Inhibition of clinical benefits of aspirin on first
myocardial infarction by nonsteroidal anti-inflammatory drugs. Circulation
2003;108:11915.
24 Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. Nonsteroidal
anti-inflammatory drugs and the risk of myocardial infarction in the general
population. Circulation 2004;109:30006.
25 Fischer LM, Schlienger RG, Matter CM, Jick H, Meier CR. Current use of
nonsteroidal anti-inflammatory drugs and the risk of acute myocardial infarction.
Pharmacotherapy 2005;25:50310.
26 Patel TN, Goldberg KC. Use of aspirin and ibuprofen compared with aspirin alone
and the risk of myocardial infarction. Arch Intern Med 2004;164:8526.
27 Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective
cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs
increase the risk of atherothrombosis? Meta-analysis of randomised trials. Br Med J
2006;332:13028.
28 McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a
systematic review of the observational studies of selective and nonselective
inhibitors of cyclooxygenase 2. JAMA 2006;296:163344.
29 Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of
incident hypertension in US women. Hypertension 2005;46:50007.
30 Schnitzer TJ, Weaver AL, Polis AB, Petruschke RA, Geba GP. Efficacy of rofecoxib,
celecoxib, and acetaminophen in patients with osteoarthritis of the knee. A combined
analysis of the VACT studies. J Rheumatol 2005;32:1093105.
31 Pincus T, Koch G, Lei H et al. Patient Preference for Placebo, Acetaminophen
(paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind,
placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis.
Ann Rheum Dis 2004;63:9319.
32 Battisti WP, Katz NP, Weaver AL et al. Pain management in osteoarthritis: a focus on
onset of efficacya comparison of rofecoxib, celecoxib, acetaminophen, and
nabumetone across four clinical trials. J Pain 2004;5:51120.
33 Austin PC, Daly PA, Tu JV. A multicenter study of the coding accuracy of hospital
discharge administrative data for patients admitted to cardiac care units in Ontario.
Am Heart J 2002;144:2906.
34 Rahme E, Bardou M, Dasgupta K, Toubouti Y, Ghosn J, Barkun AN. Hospitalization
for gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs
among elderly patients using low-dose aspirin: a retrospective cohort study.
Rheumatol 2006; 13 July, (Epub ahead of print).
35 Fleming T, Harrington D. Counting process and Survival analysis. New York: Wiley,
1991.

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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 Sante Quebec, the
government health agency, 17.0%, 2.2% and 46.3% of the elderly
who consumed NS-NSAIDs, aspirin and acetaminophen, respectively, acquired them over-the-counter (D. Sante Quebec 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.