Background: The association between rofecoxib use and ischemic stroke has not been shown in clinical trials. These trials were limited by short-term follow-up and non-placebo controls. Extended follow-up data from the APPROVe trial has shed some light on the incidence of ischemic stroke after rofecoxib use.
Materials and methods: Review of published and unpublished data from APPROVe. We searched the Food and Drug Administration and Merck websites to obtain unpublished data. Statistical analyses were performed by the APPROVe investigators and are reported as relative risks (RR) with their 95% confidence intervals (CI).
Results: APPROVe evaluated the effect of rofecoxib 25 mg/d versus matching placebo on recurrent colon polyps in 2,586 patients with a history of colorectal adenomas. Although the published data from APPROVe showed a nonsignificant relative risk of ischemic stroke (RR 1.99, 95% CI 0.74 to 5.39, p = 0.174), extended follow-up data from Merck's website recently revealed a significant three-fold increase in ischemic stroke in patients randomized to rofecoxib (RR 2.91, 95% CI 1.15 to 7.39, p = 0.024). Notably, seven out of eighteen ischemic strokes occurred after rofecoxib use had been discontinued.
Conclusions: Based on extended follow-up data, APPROVe is the first trial to report an increase in ischemic stroke risk with rofecoxib compared to placebo. The finding of ischemic strokes after rofecoxib use had been discontinued should be further studied to determine whether patients previously exposed to rofecoxib remain at an increased risk.