Elsevier

The Lancet

Volume 365, Issue 9458, 5–11 February 2005, Pages 475-481
The Lancet

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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

https://doi.org/10.1016/S0140-6736(05)17864-7Get rights and content

Summary

Background

Controversy has surrounded the question about whether high-dose rofecoxib increases or naproxen decreases the risk of serious coronary heart disease. We sought to establish if risk was enhanced with rofecoxib at either high or standard doses compared with remote non-steroidal anti-inflammatory drug (NSAID) use or celecoxib use, because celecoxib was the most common alternative to rofecoxib.

Methods

We used data from Kaiser Permanente in California to assemble a cohort of all patients age 18–84 years treated with a NSAID between Jan 1, 1999, and Dec 31, 2001, within which we did a nested case-control study. Cases of serious coronary heart disease (acute myocardial infarction and sudden cardiac death) were risk-set matched with four controls for age, sex, and health plan region. Current exposure to cyclo-oxygenase 2 selective and non-selective NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib.

Findings

During 2 302 029 person-years of follow-up, 8143 cases of serious coronary heart disease occurred, of which 2210 (27·1%) were fatal. Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses), 1·59 (95% CI 1·10–2·32, p=0·015); for rofecoxib 25 mg/day or less, 1·47 (0·99–2·17, p=0·054); and for rofecoxib greater than 25 mg/day, 3·58 (1·27–10·11, p=0·016). For naproxen versus remote NSAID use the adjusted odds ratio was 1·14 (1·00–1·30, p=0·05).

Interpretation

Rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious coronary heart disease.

Introduction

Cyclo-oxygenase 2 (COX2) selective non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for the treatment of arthritis and other musculoskeletal complaints because of the reduced occurrence of gastrointestinal toxic effects compared with non-selective NSAIDs.1, 2 Questions about cardiovascular risk with these COX2-selective drugs were raised by the finding of a five-fold difference in incidence of acute myocardial infarction between patients treated with rofecoxib 50 mg/day and naproxen 1000 mg/day in a large randomised clinical trial (Vioxx Gastrointestinal Outcomes Research; VIGOR),2 and by a meta-analysis of clinical trials of celecoxib and rofecoxib.3 Because the VIGOR trial did not have a placebo group, its findings could have suggested either an adverse effect of rofecoxib, an adverse effect of coxibs in general, or a hitherto unrecognised protective effect of naproxen.4, 5 In view of the high use of COX2 drugs in the USA, even a small increase in adverse cardiovascular events would have substantial public-health effects.

Several observational studies have sought to clarify the findings of the VIGOR trial. High-dose rofecoxib (>25 mg/day) has been reported to enhance the risk of adverse cardiovascular events relative to non-users of any NSAID6 or users of celexoxib.7 In one study, no increased risk was noted with rofecoxib compared with other NSAIDs, but high-dose rofecoxib was not assessed separately.8 Studies investigating the effect of naproxen on cardiovascular risk have yielded conflicting results. In three cohort studies, no reduction in risk was reported with naproxen use,6, 7, 9 whereas a cardioprotective effect was noted in three other studies.10, 11, 12 We sought to address these important questions about the cardiovascular effects of NSAIDs.

Section snippets

Methods

Kaiser Permanente is a national integrated managed care organisation providing comprehensive health care to more than 6 million residents in the state of California.13 The enrolled population varies with respect to age, educational attainment, family income, and ethnic origin. The organisation maintains computer files of eligibility for care, outpatient visits, admissions, medical procedures, emergency room visits, laboratory testing, and outpatient drug prescriptions for all its members.

Results

A total of 1 394 764 people contributed 2 302 029 person-years of observation time to the study cohort of NSAID users. Patients received various NSAIDs, including celecoxib (n=40 405), ibuprofen (991 261), naproxen (435 492), and rofecoxib (26 748). From this cohort, we identified 8199 cases of serious coronary heart disease and 32 796 matched controls. Of these, we excluded 56 cases and 1300 controls who did not meet the enrolment criteria, resulting in 8143 cases and 31 496 controls.

Of the

Discussion

The data from the present study provide further evidence that rofecoxib increases the risk of serious coronary heart disease.

Our study has several limitations. NSAID exposure was established from records of filled prescriptions and thus would not include data for drugs obtained over the counter. A telephone survey of a random sample of controls established that use of over-the-counter NSAIDs did not differ by prescription NSAID use status. Therefore, any misclassification of exposure should be

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