Even before the first selective COX-2 inhibitor was marketed, specialists began to suspect that there might be a cardiovascular risk associated with this class of medicines. In the VIGOR study (Vioxx Gastrointestinal Outcomes Research), rofecoxib (Vioxx) was compared to naproxen. After a short time, it became evident that there was a fivefold higher risk of myocardial infarction in the rofecoxib group compared to the group that received naproxen. The authors suggested that the difference was due to the cardioprotective effects of naproxen. The APPROVe (Adenomatous Poly Prevention on Vioxx) study was a multicentre, randomized, placebo-controlled, double blind trial aimed to assess the effect of three-year treatment with rofecoxib on recurrence of neoplastic polyps in individuals with a history of colorectal adenomas. In 2000 and 2001, 2587 patients with a history of colorectal adenomas were recruited and followed. The trial was stopped early (2 months before expected completion) on recommendations of its data safety and monitoring board because of concerns about cardiovascular toxicity. When looking at the results of the study, it showed a statistically significant increase in cardiovascular risk when taking rofecoxib compared to placebo beginning after 18 months of treatment. Then on 30 September Merck gave out a news release announcing their voluntary worldwide withdrawal of Vioxx.
Some studies of other coxibs have also shown increase in the risk of cardiovascular events, while others have not. For instance, the Adenoma Prevention with Celecoxib study (APC) showed a dose-related increase in risk of cardiovascular death, myocardial infarction, stroke, or heart failure when taking celecoxib compared to placebo; and the Successive Celecoxib Efficacy and Safety Study I (SUCCESS-I) showed increased risk of myocardial infarction when taking 100 mg twice a day of celecoxib compared to diclofenac and naproxen; but taking 200 mg twice a day had lower incidence of myocardial infarction compared to diclofenac and naproxen. Nussmeier et al. (2005) showed in a study increase in incidence of cardiovascular events when taking parecoxib and valdecoxib (compared to placebo) after coronary artery bypass surgery.