Elsevier

The Lancet

Volume 359, Issue 9301, 12 January 2002, Pages 118-123
The Lancet

Articles
Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study

https://doi.org/10.1016/S0140-6736(02)07370-1Get rights and content

Summary

Background

Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs) have complex effects that could either prevent or promote coronary heart disease. Comparison of the NANSAID rofexocib with naproxen showed a substantial difference in acute myocardial infarction risk, which has been interpreted as a protective effect of naproxen. We did an observational study to measure the effects of NANSAIDs, including naproxen, on risk of serious coronary heart disease.

Methods

We used data from the Tennessee Medicaid programme obtained between Jan 1, 1987, and Dec 31, 1998, to identify a cohort of new NANSAID users (n=181 441) and an equal number of non-users, matched for age, sex, and date NANSAID use began. Both groups were 50–84 years of age, were not resident in a nursing home, and did not have life-threatening illness. The study endpoint was hospital admission for acute myocardial infarction or death from coronary heart disease.

Findings

During 532634 person-years of follow-up, 6362 cases of serious coronary heart disease occurred, or 11·9 per 1000 person-years. Multivariate-adjusted rate ratios for current and former use of NANSAIDs were 1·05 (95% CI 0·97–1·14) and 1·02 (0·97–1·08), respectively. Rate ratios for naproxen, ibuprofen, and other NANSAIDs were 0·95 (0·82–1·09), 1·15 (1·02–1·28), and 1·03 (0·92–1·16), respectively. There was no protection among long-term NANSAID users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1·05 (0·91–1·21). When naproxen was directly compared with ibuprofen, the current-use rate ratio was 0·83 (0·69–0·98).

Interpretation

Absence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection.

Introduction

Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs)1, 2 could affect risk of acute myocardial infarction and other serious coronary heart disease. Findings of ex-vivo studies suggest that prediction of whether these effects are beneficial or harmful might be difficult because NANSAIDs have complex properties that could either prevent or promote coronary artery disease. Many NANSAIDs inhibit production of thromboxane and thus also inhibit platelet aggregation. Prevention of nonfatal myocardial infarctions by low-dose aspirin suggests that NANSAIDs could prevent coronary artery disease, an effect thought to be attributable to irreversible and almost complete inhibition of thromboxane produced by platelets.3 Inflammation seems to have an important role in pathogenesis of atherosclerosis,4, 5 which suggests that NSAIDs in anti-inflammatory doses could reduce clinical manifestations of coronary artery disease.6 Conversely, high doses of NSAIDs inhibit synthesis of prostacyclin, a potent endogenous platelet inhibitor,7 which could raise risk of coronary heart disease, as could other dose-related effects of NSAIDs, such as hypertension.8 However, up to now there have been few population-based studies of whether or not NANSAIDs affect risk of clinically important coronary heart disease in human beings.9

Results from a large trial of the new cyclooxygenase-2 (COX-2)-selective drug, rofecoxib,10 have stimulated increased interest in this topic. That trial, which was designed to assess gastrointestinal safety of rofecoxib, compared patients randomly assigned to daily doses of either 50 mg rofecoxib or 1 g naproxen. The rofexocib and naproxen patients differed by occurrence of myocardial infarctions, 0·4% and 0·1%, respectively. Because there was no untreated group, we do not know whether this finding suggests a protective effect of naproxen or a harmful effect of rofexocib. Some data suggest that naproxen suppresses production of thromboxane and inhibits platelet aggregation by 88% for up to 8 h.11 By contrast, because rofecoxib and other COX-2-selective drugs do not inhibit thromboxane synthesis,10, 11 they should not affect platelet aggregation by this mechanism. However, these drugs could increase risk of coronary heart disease because they inhibit prostacyclin formation.7 In view of the widespread use of naproxen and other non-selective NANSAIDs, and the likelihood that such use will probably decline as that of COX-2-selective drugs rises, a differential effect of these two types of NANSAIDs on the risk of coronary heart disease has important public health ramifications.

We sought to quantify risk of myocardial infarction and fatal coronary heart disease among new users of generally prescribed NANSAIDs. We did the study before marketing of new COX-2-selective agents (celecoxib and rofecoxib) and thus did not include these drugs.

Section snippets

Study data

We obtained study data from Medicaid in Tennessee.12 Medicaid computerised files allowed cohort identification, classification of cardiovascular risk factor status, and endpoint ascertainment. The files included: a central registry of all individuals enrolled, linked with death certificates; records of prescriptions filled at the pharmacy; records of hospital admissions for people enrolled in Medicaid; records of visits to the emergency room, hospital outpatient department, outpatient surgical

Results

Table 1 shows characteristics of NANSAID and control cohorts. 70% of the cohort were women, and 67% were white. Duration of follow-up and demographic factors did not differ by much between NANSAID users and controls.

Both NANSAID users and controls had high baseline risk for cardiovascular disease (table 1). A fifth of the cohort had serious cardiovascular disease in the year before cohort entry, usually obstructive coronary artery disease or heart failure. Two-thirds had previously used one or

Discussion

Although effects of aspirin on coronary artery disease have been studied extensively,3 there has been little investigation of widely used NANSAIDs. Our data suggest that, in a high-risk population of people 50 years of age or older, non-selective NANSAIDs neither increase nor decrease risk of serious coronary heart disease. Our rate ratio estimate for serious coronary heart disease is consistent with data from a case-control study of myocardial infarctions nested in a cohort of 164769 women,9

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