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Rheumatology Advance Access originally published online on January 25, 2007
Rheumatology 2007 46(3):435-438; doi:10.1093/rheumatology/kel428
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© 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

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

1Department of Medicine and 2Research Institute, McGill University Health Centre, Montreal, Canada.

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{at}mcgill.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Reference
 
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.

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


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 Reference
 
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 [2–4]. Clinical practice guidelines recommend the concurrent use of low-dose 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 NS-NSAIDs with aspirin may have a deleterious effect on aspirin's anti-platelet activity [8–10].

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 [2–4, 13–15]. Epidemiological studies assessing the CV risk of NS-NSAIDs have had conflicting results [16–27]. 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 COX-2 inhibitors for pain relief and may be inadequate for many patients [30–32]. 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.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 Reference
 
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.x–534.x, 578.0, 578.1 and 578.9.

Permission from the Government of Quebec ethics committee, the Commission d’accès à l’information, 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 patient's 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.

Outcome measure
The primary outcome of interest was the first hospitalization for AMI or GI bleeding. Only hospitalization for patients 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 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 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 (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
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 Reference
 
Patient characteristics, calculated at the index date, are shown in Table 1. Of the 510 871 patients included in the study, 112 141 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).


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

 
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).


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  		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

 
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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 Reference
 
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 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, respectively, 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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
Reference
 
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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Reference
 

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Submitted 16 August 2006; revised version accepted 30 November 2006.
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