There has been considerable interest in the development of COX-2 inhibitors in the hope that they may be associated with an improved side-effect profile. This was initially with the aim of reducing the gastrointestinal side effects and to avoid the antiplatelet effect of traditional NSAIDs. Studies suggest that this is the case.23[II], 24[II], 25
Since the launch of NSAIDs in the late 1990s, it has become apparent that there is also an associated increased cardiovascular risk. This led to the withdrawal of rofe-coxib and a significant review of the literature.26,22 28 There is now reliable evidence confirming increased risk of cardiovascular complications with both selective and nonselective NSAIDs taken long term. The evidence points to a potential COX-2 inhibitor class effect on cardiovascular events.
The evidence against celecoxib comes from the National Cancer Institute's Colorectal Adenoma Prevention with Celecoxib (APC) trial which showed a two- to three-fold increase in adverse cardiovascular events, such as myocardial infarction and stroke, with celecoxib compared to placebo after a mean duration treatment of 33 months.29 These results were not replicated in two other trials that compared celecoxib 400 mg daily with placebo.30,31 Evidence against rofecoxib emerged in the Adenomatous Polyp Prevention on Vioxx (APPROVe)
trial. For serious adverse cardiovascular events, a relative risk of approximately two was seen for rofecoxib compared to placebo over a three-year period.32 This led to the withdrawal of rofecoxib in 2004 by the manufacturer. In contrast, two long-term placebo-controlled trials in patients with early Alzheimer's disease did not show a significant difference in cardiovascular events between rofecoxib 25 mg once daily and placebo.31 In April 2005, the European Medicines Agency withdrew another COX-2 inhibitor, valdecoxib, following frequent reports of skin reactions, such as toxic epidermal necrolysis, in the USA. This warning was in addition to the associated cardiovascular risks.33 There is also evidence as to the increased risk of cardiac events with nonselective NSAIDs in gen-eral.22[III] A population-based nested case-control analysis to determine the comparative risk of myocardial infarction in patients taking COX-2 and conventional NSAIDs in primary care between 2000 and 2004 in the UK suggested an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen, despite adjustment for many potential con-founders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. In a meta-analysis,34, 35 selective COX-2 inhibitors were associated with a moderate increase in the risk of vascular events, as are high-dose regimens of ibuprofen and diclofenac, but high-dose naproxen is not. In the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac, the results show that patients with arthritis treated with etoricoxib and those given diclofenac have nearly identical rates of thrombotic cardiovascular events.36 In a matched case-control study of the relationship between recent use of NSAIDs and hospitalization with congestive heart failure (CHF), NSAIDs were responsible for approximately 19 percent of hospital admissions with CHF.37 These concerns may warrant a reconsideration of the cardiovascular safety of all NSAIDs.38 Currently, there continues to be debate as to the role of the COX-2 antagonists and how they should be prescribed.26, 27,39,40[I] There is also debate as to the risk of cardiac events with NSAIDs in general.22[III] In June 2005, after reviewing evidence for all COX-2 inhibitors available in the European Union, the European Medical Agency suggested the following measures:41 (1) all COX-2 inhibitors are contraindicated in patients with established ischemic heart disease, stroke, and peripheral arterial disease; (2) physicians should exercise caution when prescribing COX-2 inhibitors to patients with cardiovascular risk factors; (3) the lowest effective dose should be used for the shortest possible duration of treatment; (4) the balance of cardiovascular and gastrointestinal risks should be carefully considered for patients who do not have heart disease but are taking low-dose aspirin (75-100 mg daily), as evidence indicates that any gastrointestinal safety advantage for COX-2 inhibitors is substantially reduced when given with aspirin; and (5) though hypersensitivity reactions are rare, serious, and sometimes fatal, skin reactions might occur with all COX-2 inhibitors. The majority of these reactions occur in the first month of use, and prescribers are warned that patients with a history of drug allergies may be at greater risk.
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