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(Circulation. 2006;113:1950-1957.)
© 2006 American Heart Association, Inc.

Epidemiology

Use of First- and Second-Generation Cyclooxygenase-2–Selective Nonsteroidal Antiinflammatory Drugs and Risk of Acute Myocardial Infarction

From the Department of Clinical Pharmacology, Charité–Universitaetsmedizin Berlin, Berlin, Germany (F.A., E.G.); and McGill Pharmacoepidemiology Research Unit, Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada (S.S.).

Correspondence to Edeltraut Garbe, MD, PhD, Department of Clinical Pharmacology, Charité–Universitaetsmedizin Berlin, Schumannstrasse 20/21, 10117 Berlin, Germany. E-mail edeltraut.garbe{at}charite.de

Received November 18, 2005; revision 1 received December 19, 2005; revision 2 received February 15, 2006; accepted February 15, 2006.

	Abstract

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Background— The cardiovascular safety of cyclooxygenase (COX)-2–selective nonsteroidal antiinflammatory drugs (NSAIDs) has come under scrutiny after the withdrawal of rofecoxib and halting of the Adenoma Prevention with Celecoxib trial. Whether the newer second-generation COX-2 inhibitors (etoricoxib, valdecoxib) also increase the cardiovascular risk is unknown.

Methods and Results— We performed a nested case-control study in a cohort of 486 378 persons registered within the United Kingdom General Practice Research Database with at least 1 prescription of an NSAID between June 1, 2000, and October 31, 2004. A total of 3643 cases with acute myocardial infarction (AMI) were matched to 13 918 controls on age, sex, year of cohort entry, and general practice. Rate ratios (RRs) of AMI associated with use of COX-2–selective and –nonselective NSAIDs were calculated. Current use of etoricoxib was associated with a 2.09-fold (95% confidence interval [CI], 1.10 to 3.97) risk of AMI compared with no use of NSAIDs during the prior year. Current use of rofecoxib (RR=1.29; 95% CI, 1.02 to 1.63), celecoxib (RR=1.56; 95% CI, 1.22 to 2.00), and diclofenac (RR=1.37; 95% CI, 1.17 to 1.59) also significantly increased the AMI risk. For current use of valdecoxib, the RR was 4.60 (95% CI, 0.61 to 34.51). RRs appeared to increase with higher daily doses of COX-2 inhibitors and were also increased in patients without major cardiovascular risk factors.

Conclusions— Our study supports the hypothesis that the elevated risk of AMI is a class effect of COX-2 inhibitors. The increase in risk appears to be dose dependent, but further data are needed to verify this observation.

Key Words: drugs • epidemiology • myocardial infarction

	Introduction

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The recent withdrawal of rofecoxib from the market based on an increased risk of acute myocardial infarction (AMI) and stroke in the placebo-controlled Adenomatous Polyp Prevention on Vioxx (APPROVe) trial¹ has led to a revaluation of the cardiovascular safety of all cyclooxygenase (COX)-2–selective nonsteroidal antiinflammatory drugs (NSAIDs). Meanwhile, similar results from 1 placebo-controlled trial have been published for celecoxib,² whereas another randomized trial did not show a significant cardiovascular risk.^3,4 Some epidemiological studies have also shown an increased cardiovascular risk for either rofecoxib^5–9 or rofecoxib and celecoxib,¹⁰ whereas others have not.¹¹

Clinical Perspective p 1957

Data on the cardiovascular safety of the more COX-2–selective, so-called second-generation COX-2 inhibitors are sparse. A randomized trial that evaluated the use of intravenous parecoxib followed by oral valdecoxib for 10 days in patients after coronary artery bypass grafting showed a 3.7-fold elevation in adverse cardiovascular events versus placebo.¹² In the randomized controlled etoricoxib trials investigating its efficacy primarily in short-term studies including <1000 patients, there were either no or only few cardiovascular events, which did not permit any conclusions on the cardiovascular safety of the drug.¹³ Data from the large Etoricoxib-Diclofenac Gastrointestinal Evaluation (EDGE) trial have not yet been published. The Food and Drug Administration (FDA) has recently delayed approval of the new drug application (NDA) of etoricoxib in the United States and has requested further cardiovascular safety data because "data from the NDA suggests a cardiovascular safety signal."¹⁴ The second-generation COX-2 inhibitors have been licensed in several countries in Europe, Mexico, and South America. Etoricoxib and valdecoxib have been launched in the United Kingdom in 2002 and 2003, respectively.

We conducted a large nested case-control study using data from the UK General Practice Research Database (GPRD) to investigate the risk of AMI associated with first- and second-generation COX-2 inhibitors. Further objectives of our study included investigation of the influence of the daily dose, duration of use, and cardiovascular risk factors on the risk of AMI associated with these COX-2–selective and –nonselective NSAIDs.

	Methods

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Data Source
Data were abstracted from the GPRD, which was established in 1987 and is currently managed by the Medicines and Healthcare Products Regulatory Agency in the United Kingdom. Its data are licensed for use exclusively for medical and health research purposes on a nonprofit basis. The GPRD contains the computerized medical records of >8.9 million patients. Patients are being enrolled by selected general practitioners who have agreed to provide data for research purposes to the GPRD. The general practitioners initially received 12 months of instruction on the standardized recording of medical information on computer. Data validity and quality are checked on an ongoing basis by GPRD staff.¹⁵ The recorded information includes the patient’s characteristics (eg, age, sex, smoking, height, and weight), drugs prescribed, clinical diagnoses, notation of referrals to consultants and hospitals, and historical information. Validation studies have shown the high quality of recorded drug exposure and diagnoses,^16,17 including the diagnosis of AMI.¹⁸ This study was approved by the Scientific and Ethical Advisory Group of the GPRD.

Study Design and Study Population
We performed a nested case-control study in a cohort of NSAID users. The cohort consisted of all subjects with at least 1 prescription for a NSAID between June 1, 2000, and October 31, 2004, including patients with a history of AMI. Cohort entry was defined as the date of the first of these prescriptions. Patients were required to be at least 40 years of age at the time of cohort entry and to have been registered with a practice with ensured quality standards of data recording for at least 1 year. Cohort exit was defined by the first of the following dates: date of AMI, death, end of registration with the practice, or end of the study period (October 31, 2004).

We included as potential cases all patients with a diagnosis of AMI, death from AMI, and sudden or unexpected death from coronary heart disease (CHD) (n=5127). We reviewed the computerized medical records of these potential cases blinded to NSAID prescription data. Patients were excluded if there were no additional codes indicating the acuteness of the disease (eg, hospitalization, treatment with a fibrinolytic drug, chest pain, coronary intervention, testing for troponin T; n=1244) or if the duration of the hospital stay was <3 days (n=58). Patients developing an AMI after an operation were excluded (n=31) because medication information preceding the AMI would not be available from the hospital. Deaths from AMI were excluded if there was another disease (eg, sepsis) that might have caused the death (n=151). The earliest date of the recorded AMI, symptoms (such as acute chest pain), hospitalization for AMI, or death was defined as the index date. A total of 3643 patients were included as cases in our analysis.

For each case, we randomly selected up to 4 controls among the risk set of cohort members who were still followed up and had not developed an AMI. Controls were matched to cases on age (±2 years), sex, practice, and year of cohort entry. The date that resulted in the same time of follow-up as for the respective case was designated as the index date of the control.

NSAID Exposure
We identified all NSAIDs that had been prescribed in the year preceding the index date. We grouped NSAID use into the following main exposure categories: rofecoxib, celecoxib, etoricoxib, valdecoxib, diclofenac, ibuprofen, and naproxen. Use of 1 or more other NSAIDs was grouped into the category of "other NSAIDs" and used as a dichotomous variable in the regression model. We determined the duration of each prescription by dividing the quantity of prescribed tablets by the number of tablets to be taken daily. We defined "current" exposure as a prescription of an NSAID that lasted into the 14-day period before the index date. Exposure was termed "recent" if the supply ended between 15 and 183 days before the index date and "past" if it ended between 184 days and 1 year, respectively. "Nonuse" was defined as no use of any NSAID during the year before the index date. Additionally, we performed a sensitivity analysis using a 7-day time window to define current use.

We determined the daily dose of NSAIDs in current users by multiplying the tablet strength by the prescribed number of tablets per day and categorized it into low-dose and medium-high-dose use. The doses separating between these 2 categories were 25 mg for rofecoxib, 200 mg for celecoxib, 60 mg for etoricoxib, 10 mg for valdecoxib, 100 mg for diclofenac, 1200 mg for ibuprofen, and 750 mg for naproxen. In current, recent, and past users, we calculated the duration of continuous NSAID use before the index date by adding the duration of consecutive prescriptions. We categorized continuous use into <3 months, 3 to 12 months, and >12 months.

Statistical Analyses
The incidence rate ratio (RR) of AMI for exclusive use of each NSAID category was estimated from odds ratios calculated by conditional logistic regression with the use of the SAS PHREG program (SAS 9.1 Institute Inc, Cary, NC). Patients simultaneously exposed to different exposure categories were grouped into a category of multiple users that was included as an additional variable in the multivariate model (RR not shown). We constructed individual models characterizing patients according to the daily dose or continuous duration of NSAID use. We restricted 1 analysis of the AMI risk associated with each COX-2–selective NSAID to new users of these drugs, defined by no recorded use of any COX-2 inhibitor during the year preceding the start of the COX-2–selective NSAID. We restricted another analysis to validated cases of AMI and their matched controls because ascertainment of cases with sudden or unexpected death from CHD may be less accurate in the database. We conducted stratified analyses with respect to sex, age, and the coexistence of cardiovascular risk factors and tested for interaction with these variables using the likelihood ratio test. This test compares for each variable the full model including interaction terms against the model without interaction terms. For all these analyses, the reference category was the absence of exposure to any NSAID in the year before the index date. P<0.05, 2 tailed, was considered significant, and 95% confidence intervals (CIs) were calculated for all RRs.

All models controlled for NSAID use and the potential confounders CHD, hypertension, diabetes mellitus, cerebrovascular disease, hyperlipidemia (defined by a diagnosis of hyperlipidemia or use of lipid-lowering drugs), rheumatoid arthritis, body mass index (<20, 20 to 24, 25 to 29, >29, unknown), and smoking status (current, past, never, unknown).

The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

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There were 486 378 patients in the GPRD database fulfilling our cohort definition. Of those, 3643 patients had suffered an AMI (59.2% men). In total, there were 997 908 person-years of follow-up, resulting in an overall incidence of AMI of 3.7 per 1000 person-years (5.3 in men and 2.5 in women). For the COX-2–selective NSAIDs, there were 23 125, 19 524, 2457, and 210 person-years of exposure for rofecoxib, celecoxib, etoricoxib, and valdecoxib, respectively. We randomly selected 13 918 matched controls from the cohort risk set, which is an average of 3.82 controls per case. The mean follow-up time was 542 days (SD 390.2 days) for cases and controls. Table 1 shows the baseline characteristics of cases and controls. Our analysis confirmed CHD, diabetes, rheumatoid arthritis, and current smoking as major independent risk factors for AMI (data not shown).

A total of 2848 cases (78.2%) and 10 653 controls (76.5%) had been exposed to any NSAID during the year before their index date. Of those, 1315 (36.1%) of cases and 4637 (33.3%) of controls were current users of NSAIDs. Current use of rofecoxib, diclofenac, celecoxib, and etoricoxib was associated with a significantly increased risk of AMI, which ranged between 1.29 and 2.09 (Table 2). For valdecoxib, the RR was 4.60; however, the CI was wide because of the low number of valdecoxib users (Table 2). The use of a 7-day time window to define current use resulted in similar risk estimates. The risk remained significant for rofecoxib (RR, 1.42; 95% CI, 1.06 to 1.89) and celecoxib (RR, 1.82; 95% CI, 1.37 to 2.42) when we limited the analysis to new users but was no longer significant for etoricoxib (RR, 1.74; 95% CI, 0.80 to 3.81) and diclofenac (RR, 1.33; 95% CI, 0.99 to 1.77), most likely because of reduced study power. Recent or past use of the NSAIDs was not associated with an increased risk, with the exception of recent use of diclofenac (RR, 1.24; 95% CI, 1.05 to 1.47) and etoricoxib (RR, 2.43; 95% CI, 1.02 to 5.76).

The risks appeared to increase with higher daily doses of rofecoxib, etoricoxib, and celecoxib in comparison with the lower doses (Table 3). The analysis of the duration of continuous NSAID use before the index date revealed no consistent trend in current (Table 4), recent, or past users.

For the COX-2 inhibitors, RRs tended to be higher in patients aged <60 years compared with patients aged >60 years, but there was no significant interaction with age (P=0.56) (Table 5). No significant interaction between gender and NSAID use was identified (P=0.96; data not shown). We did not observe a significant modification of the risk for COX-2–selective NSAIDs by the presence or absence of CHD (P=0.12) (Table 5). Even in patients who had none of the cardiovascular risk factors CHD, hypertension, and diabetes, RRs were elevated, and there was no significant interaction apparent by these risk factors (P=0.87) (Table 5). Similar results were observed in nonselective NSAIDS (data not shown). The analysis restricted to cases of AMI and their matched controls did not change the results materially.

	Discussion

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In this study, current use of etoricoxib was associated with a 2-fold elevated risk of AMI. Increased RRs were also observed for current use of the first-generation COX-2 inhibitors rofecoxib and celecoxib, which were associated with a statistically significant 1.29 and 1.56 elevated risk of myocardial infarction, respectively. The RRs for COX-2–selective NSAIDs increased with the daily dose but not with the duration of use. We observed similar RRs for rofecoxib, celecoxib, and etoricoxib in patients with and without major cardiovascular risk factors.

For rofecoxib, our study supports previous findings from randomized clinical trials,^1,19 observational studies,^5–10 and a meta-analysis²⁰ of an increased AMI risk. In contrast, the available data for celecoxib are inconsistent: the placebo-controlled Adenoma Prevention with Celecoxib (APC) trial² revealed an increased cardiovascular risk in celecoxib users, whereas the randomized Celecoxib Long-term Arthritis Safety Study (CLASS) trial³ did not show an increased risk of AMI associated with celecoxib compared with nonselective NSAIDs. Some observational studies^5,6,9,11,21 also failed to show a significantly increased risk for celecoxib users, whereas 1 study showed an increased risk in new users of celecoxib.¹⁰

The finding of an increased risk of AMI associated with current use of etoricoxib is in concordance with the recent FDA review of the cardiovascular safety of etoricoxib.¹⁴ In the same document, the FDA also released safety information from the EDGE trial including &7100 osteoarthritis patients with a follow-up of up to 16 months. In this study, daily doses of 90 mg of etoricoxib were compared with 150 mg of diclofenac. The rates of AMI were 0.65 per 100 patient-years for etoricoxib versus 0.42 per 100 patient-years for diclofenac, corresponding to a RR of 1.6. Data from an overview analysis of randomized etoricoxib trials has also been reported to show a divergence in the incidence of cardiovascular events between etoricoxib and naproxen similar to that observed in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study.²² The second-generation COX-2 inhibitor valdecoxib was only licensed in the United Kingdom in 2003 and is not as widely used as the other COX-2–selective NSAIDs. The elevated RRs for current use of valdecoxib had wide CIs, and the small number of exposed patients did not permit assessment of the risk in more detail.

The cardiovascular risk appeared to increase with higher doses of rofecoxib and celecoxib. Other epidemiological studies have shown similar results for rofecoxib.^5,7–9 For celecoxib, there are hardly any data on a possible dose-response relationship of the risk available. In the APC trial,² the risk of the composite end point of cardiovascular death, AMI, and stroke was higher for a daily dose of 800 mg than for a daily dose of 400 mg celecoxib. We did not observe a consistent trend for a higher risk associated with longer continuous duration of COX-2–selective NSAID use, which is possibly a problem of the relatively small patient numbers contained in our subgroups with long treatment duration. In the randomized APPROVe and APC trials, the increased cardiovascular risks of rofecoxib and celecoxib became apparent only after 18 months¹ and after 9 to 12 months² of treatment, respectively. In contrast, a randomized trial of 3 days of parecoxib followed by 7 days of valdecoxib showed a significantly increased cardiovascular risk versus placebo after only 10 days of use in a high-risk population,¹² and 2 epidemiological studies^10,23 found no significant impact of the duration of NSAID use on the risk of AMI. Further data are needed in this respect.

Recently, the FDA requested labeling changes from the pharmaceutical manufacturers of NSAIDs that state in a boxed warning that "patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk" of cardiovascular outcomes.²⁴ Our study shows that the use of COX-2–selective NSAIDS in patients without major cardiovascular risk factors may also cause important harmful effects. We also observed elevated AMI risks for rofecoxib, celecoxib, and etoricoxib in patients who did not have CHD, hypertension, and diabetes mellitus. Two other recent epidemiological studies have also reported increased risks associated with NSAID use in patients without CHD⁶ and in patients with a low risk for developing AMI.¹⁰ We did not observe a higher risk in patients with cardiovascular risk factors; however, our stratified analysis had limited statistical power to detect such an interaction.

We observed a significantly increased risk for current use of diclofenac but not for current use of naproxen and ibuprofen. Data from epidemiological studies have revealed conflicting results. Whereas some studies reported an increase in the risk associated with nonselective NSAIDs,^5,6,10,23 others showed no increased or even a decreased risk.^25–29 The FDA has recently released a memorandum stating that both selective and nonselective NSAIDs may increase the risk of cardiovascular events and requested all manufacturers of nonselective NSAIDs to include a boxed warning about the potential cardiovascular risk in their labeling.³⁰ There may be differences in the risk for nonselective NSAIDs because of their different COX-1/COX-2 selectivity. Diclofenac is known to be more COX-2 selective than ibuprofen,³¹ and its selectivity for COX-2 in fact approximates that of celecoxib.²² Interestingly, a post hoc analysis of nonusers of aspirin in the CLASS study showed a higher risk of serious thromboembolic adverse events for diclofenac and celecoxib in comparison with ibuprofen.²² These and our data suggest that the cardiovascular risk for nonselective NSAIDs may not be alike, and further data should be gathered in this respect.

One strength of our study is that all information was recorded prospectively so that recall bias can be ruled out. Selection bias in the choice of controls is unlikely because the study was designed as a nested case-control study in a defined population of NSAID users providing both cases and controls. We assessed all electronic patient records following a defined algorithm and blinded to exposure to validate the diagnosis of AMI. Validation studies have shown that >90% of computerized diagnoses of AMI were confirmed after hospital discharge letters of &400 patients were reviewed.^32,33 Some limitations also need to be considered. We included in our outcome definition sudden or unexpected death from CHD because AMI may manifest as sudden death outside the hospital in a substantial number of patients.³⁴ Because this diagnosis may be less accurate than the diagnosis of AMI, we conducted an analysis restricted to patients with validated AMI and their matched controls. This analysis did not change the results materially. One problem of all prescription-based database studies is the incomplete information on over-the-counter (OTC) drugs and certain confounders. In the United Kingdom, ibuprofen is the only nonaspirin NSAID available OTC. Patients exposed to ibuprofen from nonprescription sources may have been included in our reference group of nonusers. Because ibuprofen was not associated with an increased or decreased risk of AMI in our study, we would not expect that including these patients in our reference group will change the results materially. Our study included 29.5% of cases and 21.1% of controls with low-dose aspirin use before the index date. Because of this small number of patients and incomplete information on patients buying aspirin OTC, we could not investigate whether aspirin use would modify the risk of COX-2–selective or other NSAID use. In some patients, we also lacked information on smoking and body mass index. We therefore conducted a subgroup analysis in patients with complete information on smoking and body mass index (78.7% of study patients) that showed results similar to those of our main analysis. We included only NSAID users in our cohort to indirectly control for confounding associated with the indication for NSAID use. This may not completely rule out confounding bias if patients with a higher preexisting risk of AMI were more likely to be prescribed COX-2–selective drugs than nonselective NSAIDs, as has been shown in some studies.³⁵ To minimize this potential bias, we included multiple cardiovascular risk factors in the multivariate model; however, we did not have information on lifestyle factors such as physical activity, which may also influence the risk. With the exception of hyperlipidemia, we defined these cardiovascular risk factors by their respective diagnoses and not additionally by drug use because this is usually not specific enough (eg, ACE inhibitors or ß-blockers are used not only for arterial hypertension but also for congestive heart failure).

In summary, our study adds further support to the hypothesis that the elevated risk of AMI is a class effect of COX-2–selective NSAIDs. Selective COX-2 inhibitors suppress vascular production of prostacyclin (prostaglandin I₂) without affecting thromboxane A₂ synthesis.³⁶ Prostaglandin I₂ in endothelium inhibits platelet aggregation, causes vasodilation, and prevents the proliferation of vascular smooth muscle cells in vitro. Depression of prostaglandin I₂ formation by COX-2 inhibitors could thus elevate blood pressure, accelerate atherogenesis, and lead to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque.³⁷ The increase in risk of both first- and second-generation COX-2–selective NSAIDs appears to be dose dependent, but further data are needed to verify this observation.

	Acknowledgments

 
Database acquisition was funded by a grant from the Canadian Foundation for Innovation, the Canadian Institutes of Health Research, and an unrestricted grant from Schering AG. Dr Suissa is the recipient of a distinguished scientist award from the Canadian Institute of Health Research. The funding sources were not involved in design, realization, analysis, or publication of the study. We thank the participating general practitioners for their cooperation.

Disclosures

Dr Suissa was an external consultant for Merck in preparation of the FDA COX-2 Advisory Committee Meeting. The other authors report no conflicts of interest.

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