Introduction (2006)

The cyclooxygenases play an important role in the homeostasis of many organs. Indeed, several isoforms have been characterized during the last few decades, in particular cyclooxygenase-1 (COX-1), which is responsible for the production of thromboxane A2 in platelets and for the formation of prostacyclin in endothelial cells. The importance of thromboxane A2 for platelet aggregation has long been recognized as have the effects of acetylsalicylic acid, the inhibitor of this process. Aspirin, one of the most frequently used drugs in medicine, acetylates COX-1 and in turn inhibits platelet activation. However, this drug, as with many other nonsteroidal anti-inflammatory drugs (NSAIDs), also inhibits prostacyclin and prostaglandin E2 formation in vascular and gastrointestinal (GI) cells. COX-2, in contrast to the first isoform of the enzyme, is mainly an inducible form that is upregulated in inflammatory states in many organs including the cardiovascular system. Soon after its discovery it was recognized that NSAIDs not only inhibit COX-1 but also COX-2, and the latter effect has been mainly held responsible for the anti-inflammatory effects seen in patients with osteoarthritis and rheumatoid arthritis. Because NSAIDs were associated with many undesirable effects, particularly in the GI system where bleeding is a common complication of treatment with these compounds, more selective agents were developed. In the 1990s, COX-2 inhibitors were rapidly introduced as first-line products for the treatment of osteoarthritis and rheumatoid arthritis. Their advantage was seen particularly in their potent anti-inflammatory action and the potential of a lower risk of GI bleeding because these drugs leave COX-1–mediated gastroprotective prostaglandins unopposed. Randomized clinical trials confirmed their efficacy in controlling pain and inflammation and their greater GI safety. Some questions of GI safety, particularly whether the benefit is maintained in patients with background aspirin therapy, still await answers from randomized clinical trials, such as the ongoing CONDOR study. An obvious disadvantage of COX-2 inhibitors is the fact that they do not reduce thromboxane formation in platelets; therefore, particularly in patients with activated platelets such as those with cardiovascular disease, they do provide cardiovascular protection, as do drugs that also inhibit COX-1. In line with this interpretation, additional analysis of large trials such as the VIGOR (VIoxx Gastrointestinal Outcomes Research) trial found an increased incidence of myocardial infarction in patients with arthritis treated with rofecoxib as compared with traditional nonsteroid antirheumatic drugs. Similar observations were made in smaller studies that aimed to expand the indication for COX-2 inhibitors to patients with GI polyps. Basic science studies and initial clinical observations suggested that COX-2 may be involved in the growth of GI polyps and hence in the development of colon cancer. In line with this concept, the APPROVE trial comparing rofecoxib with placebo found less polyp growth, which appeared to come at the cost of more frequent cardiovascular events in patients treated with rofecoxib as compared with placebo. Hence, this study led to the withdrawal of rofecoxib from the market in October 2004 and to unprecedented controversy about the use of COX enzyme inhibitors in general in patients with rheumatoid, GI, and/or cardiovascular disorders. The COX-2 controversy is a true interdisciplinary problem that needs to be addressed from different angles. In particular, expert opinions from oncologists, rheumatologists, gastroenterologists, as well as cardiovascular scientists and clinical pharmacologists are required to understand the clinical relevance and importance. To that end, the first COX-2 summit was organized in Zürich on September 7–8, 2005, involving experts from all of the above-mentioned specialties in medicine. This supplement of the Journal of Cardiovascular Pharmacology contains the contributions of this first COX-2 summit. Thanks to the interdisciplinary nature of the symposium and the manuscripts included in this supplement, the controversy could be analyzed from several perspectives. The first contribution aims to assess and review the complexity of the prostaglandin H2-synthase system and of isozyme-selective inhibition. An important and novel aspect of this symposium was the focus on pharmacologic effects of COX-2 inhibitors beyond the COX system. Indeed, several studies strongly suggest differences between rofecoxib and celecoxib in many regards. These effects may be relevant for tissue factor expression and coagulation and nitric oxide expression and function, and in atherosclerosis. Besides its effects in the cardiovascular system, in the joints and the GI tract, COX-2 also plays an important role in the kidney and blood pressure control. The effects of COX-2 inhibitors on water and sodium handling are crucial in understanding their effects in the body and their potential for cardiovascular and renal side effects. On the basis of the current knowledge, the use of NSAIDs and selective COX-2 inhibitors still on the market in patients with osteoarthritis is a clinical challenge. Their beneficial effects on pain and inflammation have been extensively discussed in the context of possible cardiovascular and GI side effects. The possible advantages of COX-2 inhibitors compared with NSAIDs remains an important issue. Clinical medication has been extended from osteoarthritic pain to postoperative pain where these drugs are also commonly used. Finally, cancer prevention is an important piece of the COX-2 controversy, particularly because of the studies of patients with GI polyps that eventually led to the withdrawal of some of the COX-2 inhibitors. The first COX-2 summit and this supplement that reflects its content ended with a discussion on how to resolve the current clinical and intellectual controversy in this area. The problem was highlighted both from American and from European perspectives. We are proud to present a comprehensive documentation of the COX-2 controversy involving the molecular action of these drugs as well as the clinical implications of this enzyme and its pharmacologic inhibitors in various disciplines of medicine. We sincerely hope that this supplement helps in furthering understanding of this complex and fascinating area and contributes to a rational approach to a controversy that has reached far beyond medicine to the media and the public and has confused many patients with disorders of the joints, GI, and cardiovascular systems who are in need of appropriate care.