Cardiovascular complications of COX2 selective inhibitors cause considerable concern

On September 30, the Food and Drug Administration (FDA) acknowledged a voluntary withdrawal of the cyclooxygenase 2 (COX2) inhibitor rofecoxib (Brand name Vioxx) (1). The reason according to FDA why this drug was withdrawn from the market were concerns of “an increase in risk of serious cardiovascular events, including heart attacks and strokes, among study patients taking Vioxx compared to patients receiving placebo” (1). The most recent study showing an excess cardiovascular risk in rofecoxib treated patients was a long-term study in patients with increased risk of colon polyps. According to the Acting FDA Commissioner Dr Lester M Crawford; “Merck did the right thing by promptly reporting these findings to the FDA and voluntarily withdrawing the product from the market. Although the risk that an individual patient would have a heart attack or stroke related to Vioxx is very small, the study that was halted suggests that, overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving placebo” (1). Concerns about an increased cardiovascular risk were raised already with the VIGORstudy (2). According to the FDA News release issued on September 30, 2004 (1); “In June 2000, Merck submitted to FDA a safety study called VIGOR (Vioxx Gastrointestinal Outcomes Research) that found an increased risk of serious cardiovascular events, including heart attacks and strokes, in patients taking Vioxx compared to patients taking naproxen. After reviewing the results of the VIGOR study and other available data from controlled clinical trials, FDA consulted with its Arthritis Advisory Committee in February 2001 regarding the clinical interpretation of this new safety information. In April 2002, FDA implemented changes to reflect the findings from the VIGOR study. The labelling changes included information about the increase in risk of cardiovascular events, including heart attack and stroke. Recently other studies in patients taking Vioxx have also suggested an increased risk of cardiovascular events. FDA was in the process of carefully reviewing these results, to determine whether further labelling changes were warranted, when Merck informed the agency of the results of the new trial and its decision to withdraw Vioxx from the market” (1). COX2 selective inhibitors were first introduced in 1999 for the management of pain and inflammation primarily in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) on the premises that they would have similar efficacy but a lower risk of gastrointestinal (GI) complications, primarily perforations, ulcers and bleedings (PUBs) compared to existing non-selective COX1/COX2 inhibitors (3). The gastrointestinal adverse events, in particular serious PUBs have been a major concern for non-selective COX inhibitors over the years. Additional, but less common, adverse events of the COX inhibitors include cardiovascular and renal effects that have been linked to most non-selective COX1/COX2 inhibitors as well as COX2 selective inhibitors (4, 5). These events include hypertension, peripheral oedema and renal dysfunction as well as myocardial infarction, congestive heart failure and stroke. While there has been a reasonable incidence of such reported complications for most conventional or non-selective COX inhibitors, a number of database and cohort studies recently alerted the medical community that there seemed to be a rising incidence of serious cardiovascular disease (CVD) complications by the COX 2 selective inhibitors (6, 7). In fact, there were worries that there might even be an excess risk for cardiovascular complications with the COX2 selective agents, compared to the non-selective COX inhibitors. Since it still remains a concern that this may be not only specific to rofecoxib, but a class effect for the COX2 selective inhibitors, FDA will continue to closely monitor other drugs in this class for similar side effects, i.e. heart attacks and stroke (1). From a scientific point of view, the potential mechanisms behind the untoward effects of the COX2 selective inhibitor rofecoxib are of considerable interest. Early studies clearly demonstrated that, due to its COX2 selective profile, rofecoxib as well as the other major COX2 selective inhibitors lacked the platelet anti-aggregatory properties of non-selective COX inhibitors (8). In addition to that, there were even concerns that some of the COX2 selective inhibitors may act slightly pro-aggregatory (8). In fact, this concern may be supported by the recent events showing that patients taking rofecoxib had about twice the risk of a heart attack compared to patients taking placebo (1). Moreover, Whelton and co-workers observed in a 6-week, double blind, randomized trial in elderly hypertensive patients that rofecoxib raised the systolic blood pressure more often than celecoxib did (9). Similarly, Brinker and co-workers found more spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib than celecoxib (10). Of interest, no cases were identified for either nabumetone or oxaproziw. As yet, there are no regulatory actions