Risk of Cardiovascular Events with Rofecoxib

Risk of Cardiovascular Events with Rofecoxib

Abstract

Rofecoxib causes cardiotoxicity through the suppression of prostaglandin I2 - an anti-clotting agent in blood. Rofecoxib use is associated with an increase in risk of myocardial infarction, ischemic stroke and also myocardial reinfarction. High-dose rofecoxib use further increases the risk of adverse cardiovascular events. This justifies the withdrawal of rofecoxib from the market.

Introduction

Rofecoxib is a non-steroidal anti-inflammatory drug (NSAID) which selectively inhibits the cyclooxygenase-2 (COX-2) enzyme.1 It was developed by Merck & Co. for the treatment of acute inflammation in joints, without causing the gastrointestinal side effects associated with traditional NSAIDs.1,2,3 Although evidence indicates that rofecoxib is as effective as traditional NSAIDs in relieving pain, serious concerns about its cardiovascular safety have arisen.1 In the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, patients taking rofecoxib had a much higher risk of myocardial infarction (MI) than patients taking the comparator drug naproxen (See Fig.1).3 Initial suggestions attributed this difference to a cardioprotective effect of naproxen rather than a deleterious effect of rofecoxib.3 However, this is now known not to be the case and on September 30, 2004, Merck voluntarily ordered the immediate worldwide withdrawal of rofecoxib because of its adverse cardiovascular profile.1,4

Mechanism of Cardiotoxicity

The chief mechanism proposed to explain rofecoxib's cardiotoxicity is the suppression of prostaglandin I2.4 The development of rofecoxib was based on the hypothesis that COX-2 is the source of prostaglandins E2 and I2 - which mediate inflammation, and that cyclooxygenase-1 (COX-1) is the source of the same prostaglandins in gastric epithelium - where they afford cytoprotection (See Fig. 2).4 Studies in mice and humans showed that COX-2 is the dominant source of prostaglandin I2, causing vasodilation as well as inhibiting platelet aggregation and vascular proliferation.4 The individual cardiovascular effects of prostaglandin I2 contrast with those of thromboxane A2 - the major COX-1 product of platelets which cause platelet aggregation, vasoconstriction and vascular proliferation.4 Whereas aspirin and traditional NSAIDs inhibit both thromboxane A2 and prostaglandin I2, rofecoxib does not affect the production of thromboxane A2, thus reflecting the absence of COX-2 in platelets.4 According to this mechanism, rofecoxib's suppression of the COX-2 dependent formation of prostaglandin I2 will alter the prostaglandin/thromboxane balance which is likely to elevate blood pressure and accelerate atherogenesis.5 This may predispose patients to adverse cardiovascular events such as myocardial infarction or thrombotic stroke (See Fig. 3).6

Cardiovascular Risk

Since the VIGOR study, several research papers have associated rofecoxib with cardiovascular side effects - primarily myocardial infarction.1,2,6-10 For example, a study conducted by Hippisley-Cox et al. identified that 'a significantly increased risk of myocardial infarction was associated with current use of rofecoxib' (adjusted odds ratio: 1.32).1

A study published this year by Andersohn et al. has shown that the current use of rofecoxib is also associated with an increased risk of acute ischemic stroke (odds ratio: 1.71).6 This study is of particular importance because prior to its publication, there was limited data regarding the association between rofecoxib use and the risk of ischemic stroke.6 In this nested case-control study, it is of note that all information was recorded prospectively so that recall bias can be ruled out. This further improves the validity of these findings. The results of this study are also in agreement with the results from the placebo-controlled APPROVe (Adenomatous Polyp PRevention On Vioxx) study, which showed a relative risk of 1.92 for ischemic stroke in patients taking rofecoxib versus placebo.6,9

In contrast, a study by Konstam et al. provides no evidence that rofecoxib is associated with excess cardiovascular events compared to placebo.5 This finding was based on a pooled analysis of over 14,000 patients treated with rofecoxib in 23 rofecoxib trials conducted by Merck.5 The Antiplatelet Trialists'

Collaboration (APTC) end point was used as the outcome measure in this study to help ensure consistency between trials that used adjudicated data and those that used investigator-reported data.5 This study was co-authored by one clinician and three employees of Merck, hence the lack of a conflict of interest statement on the report raises questions about its validity.

Risk of Myocardial Reinfarction

A study published this year by Brophy et al. provided evidence that the risk of myocardial infarction associated with rofecoxib is approximately doubled by the history of previous MI.7 This population-based retrospective cohort study was analysed using a time-matched, nested case-control approach.7 Two limitations of this study are of particular distinction. Firstly, only MIs admitted to hospital were considered in the analysis as cases.7 Therefore, missing events due to silent myocardial infarctions and sudden death could have resulted in incomplete case ascertainment. Secondly, information on smoking status,