Cardiovascular Effects

Introduction

The adverse effects of cyclooxygenase-2 (COX-2) inhibitors (coxibs) have demanded attention over the past few years, and questions have been raised about their safety. Coxibs arrived on the market in 1998 with the hope of offering a treatment with a lower risk of gastrointestinal (GI) toxicity compared with other nonsteroidal anti-inflammatory drugs (NSAIDs). Even though clinical trials show that coxibs carry a lower risk of GI adverse drug events (ADEs), none of the literature supports the superior efficacy of coxibs over NSAIDs.

In view of these findings, coxibs should be reserved for patients with the greatest risk for GI complications. Unfortunately, this recommendation has not been followed. In a 2002 review of patterns of coxib use, one third of patients taking these agents were found to be at the lowest risk of having NSAID-induced complications. Clearly, the coxib medication class has been overprescribed, possibly because of the influence of direct marketing in the U.S. With millions of patients receiving these medications, often inappropriately, the safety of these drugs is a concern. canadian discount pharmacy

Results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial suggested an increased risk of cardiovascular (CV) events in patients taking coxibs. Since then, conflicting results regarding CV risk have come to light in many studies, including randomized clinical trials, case-control and cohort studies, and pooled meta-analyses. On the basis of these findings, rofecoxib (Vioxx, Merck) and valdecoxib (Bextra, Pfizer) have been withdrawn from the market in the U.S.

Table 1 Basic Differences between COX-2 Inhibitors

Selectivity!

Drug

Normal

(COX-2/

Half-Life

Chemical

(Brand/Generic)

Dose*

COX-1)

(Hours)

Structure

Market Status

Vioxx (rofecoxib)

12.5-50 mg q.d.

272

15-18 hours

Sulfone

Withdrawn in September 2004

 

100-400 mg q.d.

30

6-12 hours

Sulfonamide

Still available in U.S.

or b.i.d.

Bextra (valdecoxib)

10-20 mg q.d.

61

6-10 hours

Sulfonamide

Withdrawn in April 2005

 (etoricoxib canadiab)

30-120 mg q.d.

344

20-26 hours

Sulfone

Approved in Europe, not available in U.S.

Prexige (lumiracoxib)

100-400 mg q.d.

700

2-6 hours

Arylacetic acid

Not available in U.S. or Europe

Even with mounting evidence in clinical trials, an explanation for the increased CV risk has remained elusive. With celecoxib (Celebrex, Pfizer) still available for sale in the U.S. and with two other coxibs—lumiracoxib (Prexige, Novartis) and etoricoxib (Arcoxia, Merck)—being considered for Food and Drug Administration (FDA) approval, the question of whether one coxib agent has a greater risk than others must be answered.

Figure 1 presents a timeline of events involving the coxibs. A complete list of coxibs and their distinct characteristics are provided in Table 1.

Figure 1 Chronology of critical cardiovascular

Figure 1 Chronology of critical cardiovascular (CV) events associated with COX-2 inhibitors.

The following review summarizes the major clinical studies that have raised concerns about coxibs and the risk of CV disease along with a discussion of the possible causes of these increased risks.