Cardiovascular Safety of Other Cox-2 Inhibitors

CARDIOVASCULAR SAFETY OF OTHER COX-2 INHIBITORS

VALDECOXIB AND PARECOXIB

Parecoxib is the only COX-2 inhibitor available for intravenous or intramuscular administration and is indicated for post-operative pain. Parecoxib is a prodrug of valdecoxib, which is available in oral form. Cardiovascular safety profiles of the two drugs are assumed to be the same. Ott and colleagues reported general safety information from a placebo-controlled trial of parecoxib and valdecoxib in patients after coronary artery bypass graft (CABG) surgery, in which patients assigned to the active treatment group received intravenous parecoxib 40 mg every 12 hours during the first 3 days, followed by oral valde-coxib 40 mg every 12 hours for up to 11 days (Ott et al., 2003). All serious adverse events occurred more frequently among the parecoxib–valdecoxib group than among the placebo group (19 versus, 9.9%), but the difference in cardiovascular adverse events did not reach statistical significance.

White and colleagues reviewed cardiovascular safety data from 10 clinical trials of oral valde-coxib in approximately 8000 patients with osteoarthri-tis or rheumatoid arthritis and found no increased risk of thrombotic events among the valdecoxib users when compared with patients who used non-selective NSAIDs or placebo (White et al., 2004).

Nussmeier and colleagues reported a larger trial of parecoxib–valdecoxib among CABG patients than that reported by Ott and colleagues (Nussmeier et al., 2005). In the three-arm study, one group of patients was randomly assigned to receive one dose of intravenous parecoxib 40 mg followed by 20 mg every 12 hours for 3 days and oral valdecoxib 20 mg once-daily for up to 10 days; the second arm of patients received intra-venous placebo for three days followed by the same regimen of oral valdecoxib as in the first arm; the third arm received both intravenous and oral placebo. Increased frequency of thromboembolic events was found in the active drug groups (Table 47.1). Data from the two post-CABG trials clearly showed an increased cardiovascular risk for parecoxib–valdecoxib if used for post-CABG pain management, therefore this regimen is contraindicated for use in CABG patients in countries where the regimen is available.

In addition to increased cardiovascular risk, report-ing rates of Stevens–Johnson syndrome and toxic epidermal necrolysis were higher for valdecoxib than that for other COX-2 inhibitors or NSAIDs (La Grenade et al., 2005). The increased risk of cutaneous toxicity led to the market suspension of valdecoxib in the US in April 2005.

LUMIRACOXIB

A large-scale randomized trial, the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), was conducted to evaluate the efficacy and safety of lumiracoxib (Schnitzer et al., 2004 and Farkouh et al., 2004; Table 47.1). During one year of follow-up, risk of upper gastrointestinal ulcer compli-cations was substantially lower in the lumiracoxib group when compared with patients on naproxen or ibuprofen (relative risk 0.34; 95% CI, 0.22–0.52). The risk reduction was more pronounced among patients not receiving low dose aspirin (relative risk 0.21; 95% CI, 0.12–0.37), but the 95% CI of the relative risk estimate for patients who received low dose aspirin included one. Cardiovascular outcomes of interest were defined by the APTC criteria. In the primary analysis of all subjects, lumiracoxib– naproxen and lumiracoxib–ibuprofen comparisons, and subgroups stratified by low dose aspirin use, 95% CIs of the relative risk estimates for adverse cardiovascular events all included one. Scientists from the manufacturer of lumiracoxib combined data from all lumiracoxib trials of duration between one week and one year and reported the cardiovascular safety information in 2005 (Matchaba et al., 2005). For ATPC end points, relative risk was 1.08 (95% CI, 0.41–2.86) for the lumiracoxib–placebo comparison,0.83 (95% CI, 0.46–1.51) for the lumiracoxib–non-naproxen NSAIDs comparison, and 1.49 (95% CI, 0.94–2.36) for the lumiracoxib–naproxen compari-son. Twelve and six trials involving lumiracoxib were included in the meta-analysis reports by Kearney and colleagues and Zhang and colleagues, respec-tively, but the number of adverse cardiovascular events reported in the trials was not large enough to provide definitive inference (Kearney et al., 2006; Zhang, Ding and Song, 2006).

ETORICOXIB

Etoricoxib is developed by the same manufacturer of rofecoxib. At the time of market withdrawal of rofe-coxib, a large trial by the name of Etoricoxib versus Diclofenac sodium Gastrointestinal Tolerability and Effectiveness (EDGE) was ongoing to evaluate the tolerability and efficacy of etoricoxib 90 mg daily versus diclofenac sodium 50 mg three times a day in patients with osteoarthritis. Some results have been reported in professional society meetings and an FDA advisory committee meeting, but the results have not been published in peer-reviewed journals (Schiffen-bauer, 2005). Seventeen and fifteen trials involving etoricoxib were included in the meta-analysis reports by Kearney and colleagues (Kearney et al., 2006) and Zhang and colleagues (Zhang, Ding and Song, 2006), respectively. Aldington and colleagues independently reviewed cardiovascular safety information from five published etoricoxib trials (Aldington et al., 2005), but the number of adverse cardiovascular events reported in the trials in these three meta-analysis reports was not large enough to provide definitive inference.

As etoricoxib is already available in some coun-tries, it is anticipated that more safety reports based on observational studies will be available in the near future. For example, Andersohn reported that etori-coxib was associated with an increased risk of stroke when compared with no NSAID use (relative risk 2.38; 95% CI, 1.10–5.13).