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The Lancet

Volume 364, Issue 9450, 4–10 December 2004, Pages 2021-2029
The Lancet

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Risk of cardiovascular events and rofecoxib: cumulative meta-analysis

https://doi.org/10.1016/S0140-6736(04)17514-4Get rights and content

Summary

Background

The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004.

Methods

We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint.

Findings

We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2·30 (95% CI 1·22–4·33, p=0·010), and 1 year later (64 events, 21432 patients) it was 2·24 (1·24–4·02, p=0·007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0·41) or trial duration (p=0·82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0·86 [95% CI 0·75–0·99]) and could not have explained the findings of the VIGOR trial.

Interpretation

Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.

Introduction

On Sept 30, 2004, a press release from Merck announced the withdrawal of rofecoxib (Vioxx) because of an increased cardiovascular risk in patients taking the drug for more than 18 months.1 The decision was based on the 3-year results of the unpublished Adenomatous Polyp Prevention on Vioxx (APPROVe) study, a placebo-controlled trial of rofecoxib for the prevention of recurrence of colorectal polyps in patients with a history of colorectal adenomas. By the time it was withdrawn, rofecoxib had been taken by an estimated 80 million people and sales had reached US$2·5 billion in 2003.2

Rofecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclo-oxygenase 2 (COX2). The COX enzyme is crucial to the formation of prostaglandins and exists in two isoforms, a constitutive isoform (COX1) and an inducible isoform that is expressed at sites of inflammation (COX2). The idea that anti-inflammatory effects are mediated through inhibition of COX2, whereas adverse gastrointestinal effects are attributable to inhibition of COX1, whose prostaglandins protect the gastric mucosa, led to the development of selective COX2 inhibitors.3 Approved by the US Food and Drug Administration (FDA) in 1999, COX2 inhibitors soon dominated the prescription-drug market for NSAIDs.

The safety profile of rofecoxib has been questioned since the Vioxx Gastrointestinal Outcomes Research trial (VIGOR),4 which noted a five-fold higher incidence of myocardial infarction in the rofecoxib group compared with the naproxen group.5, 6 Naproxen inhibits the production of thromboxane and platelet aggregation, and the difference in cardiovascular risk was attributed to a cardioprotective effect of naproxen, rather than a cardiotoxic effect of rofecoxib.4 This interpretation was reiterated in a 2001 meta-analysis of randomised trials of rofecoxib7 and three case-control studies of naproxen and myocardial infarction published in 2002.8, 9, 10

We report the results of a cumulative meta-analysis to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004.

Section snippets

Methods

Literature search and inclusion criteria

We aimed to identify all randomised clinical trials that compared rofecoxib with another NSAID or placebo. We searched the Cochrane Controlled Trials Register (issue 3, 2004), and MEDLINE, EMBASE, and CINAHL (from inception to September, 2004). We combined a search for articles relating to rofecoxib with the Cochrane search strategy for randomised trials. We examined citations of key papers in the Science Citation Index, searched conference proceedings,

Results

Figure 1 summarises the process of identifying eligible clinical trials. 18 randomised controlled trials met inclusion criteria.4, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 We also identified 126 reports of observational studies on naproxen and cardiovascular risk. We excluded 62 articles on the basis of their abstracts and obtained the full-text articles for the remaining 64 reports. 11 observational studies met inclusion criteria.8, 9, 10, 29, 30, 31, 32, 33, 34, 35, 36

Discussion

The voluntary withdrawal of rofecoxib by its manufacturer, Merck, on the basis of a fairly small trial that was designed for a different purpose raises several questions.37 In particular, we must establish whether the drug should have been withdrawn earlier. Our cumulative meta-analysis of randomised controlled trials indicates that an increased risk of myocardial infarction was evident from 2000 onwards. At the end of 2000, the effect was both substantial and unlikely to be a chance finding.

We

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