Dose-Related Effects

The VIGOR trial used doses of rofecoxib 50 mg daily, whereas the APPROVe trial used doses of only 25 mg daily. Among observational studies, a greater risk was observed with doses of rofecoxib above 25 mg/day than with doses of 25 mg/day or less. In a study by Graham et al., doses of 25 mg/day or less produced a 47% greater risk of MIs compared with celecoxib, whereas doses higher than 25 mg/day produced more than three times the risk.

In two trials by Solomon et al. and Levesque et al., rofecoxib doses higher than 25 mg were more likely to cause a CV event when compared with other NSAIDs.

For, the Adenoma Prevention with Celecoxib (APC) trial used two doses (200 mg twice daily and 400 mg twice daily), and an increased CV risk was evident at the higher doses. Other trials using both doses did not show an increase in CV events, but other factors such as patient population and study duration may account for this.

It is interesting that in the Prevention of Sporadic Adenoma-tous Polyps (PreSAP) trial (which was similar in design to the APC trial), a dose of 400 mg once daily did not demonstrate an increased risk. This may be a result of the more constant serum concentration of drug seen when it is given twice daily, as compared with once daily.

In the CABG trials, very high doses of valdecoxib were used. In each instance, there was a clear increase in CV events. It is difficult to draw firm conclusions, because graduated doses were not examined and all patients were at high risk for CV events when they began the study.

Lumiracoxib and have not been studied in large multiple, long-term trials evaluating different dosage strategies, thus making these coxibs difficult to assess. However, high doses of both agents were used in the TARGET and EDGE trials; neither trial showed an increased risk of CV events.

From this limited information, it appears that higher doses of either rofecoxib or celecoxib may be associated with a greater risk of CV events.

Duration of Trials

The clinical trials that showed an increased risk of CV events had a common trend in terms of their length:

  • The association of rofecoxib with CV events was seen in trials completed over nine and 33 months, with evidence of risk beginning at 18 months.
  • For celecoxib, the APC trial demonstrated a risk by 33 months.
  • The two valdecoxib CABG studies were short-term trials of 10 to 14 days, but they differed from other coxib studies because they included higher-risk patients at the baseline evaluation.
  • The two large trials with lumiracoxib (TARGET) and tablet etoricoxib (EDGE) were completed over only 12 and 9 months, respectively, with neither trial showing an increased risk of CV events.
  • The shorter trials of rofecoxib and canadian celecoxib did not show an increased risk.

In view of these findings, it appears that the long-term use of coxibs plays a role in the risk of CV events.