Balancing gastroprotection and cardioprotection with selective cyclo-oxygenase-2 inhibitors: clinical implications.

NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with chronic inflammatory disorders. They are effective. However, complications arising from chronic NSAID use are common and are primarily due to gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulceration and GI bleeds. GI toxicity has been attributed to the blockade of the cyclo-oxygenase (COX)-1-mediated generation of the cytoprotective prostanoids, such as prostaglandin (PG) E2 and PGI2 (prostacyclin). More recently, selective COX-2 inhibitors ('coxibs') were designed to inhibit the production of COX-2-dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products. The coxibs, while exhibiting similar efficacy to traditional NSAIDs in controlled clinical trials of their efficacy in chronic inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, have been associated with a reduced incidence of surrogate or actual indices of GI toxicity. However, concerns regarding cardiovascular safety in high-risk patients have evolved. These concerns were driven initially by the concept that inhibition of COX-2-derived endothelial PGI2 without concomitant inhibition of platelet thromboxane A2 would result in increased cardiovascular risk. This was borne out in the Vioxx Gastrointestinal Outcomes Research study of rofecoxib, but not demonstrated in the Celecoxib Long Term Arthritis Safety Study trial. Further elucidation of the relative roles of COX-1- and COX-2-generated prostanoids has enabled a greater understanding of the biology of these pathways. However, it is still not completely clear how this understanding may be appropriately translated into clinical medicine.     

Cardiovascular and renovascular implications of COX-2 inhibition

A group of chemical mediators, the eicosanoids, is critical players in a multitude of physiological processes. Generated by the action of the cyclooxygenase (COX) enzyme on arachidonic acid they are responsible for diverse and often opposing actions such as platelet function, vasomotor tone, gastric cytoprotection and inflammation. Since their discovery several decades ago, our knowledge concerning their synthesis, function as natural ligands and methods to manipulate their activity through drug development has expanded. Traditional Non Steroidal Anti-Inflammatory Drugs (NSAIDs) are nonselective inhibitors of the COX enzyme, of which two isoforms are known to exist - COX-1 and COX-2. NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with acute and chronic inflammatory conditions that affect more than 10 million Americans. Their efficacy in this regard is not questioned. However, gastrointestinal toxicity arising from chronic NSAID ingestion is common and limits their use in clinical practice. Gastrointestinal toxicity has been attributed to the blockade of the COX-1 mediated generation of the cytoprotective prostanoids, such as PGE(2) and PGI(2). Selective COX-2 inhibitors were designed to inhibit the production of COX-2 dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products. The first of a new class of these selective COX-2 inhibitors - the coxibs- were introduced to the market in 1999. These compounds, while exhibiting similar efficacy to traditional NSAIDs, were associated with a reduced incidence of surrogate or actual indices of GI toxicity. Questions have been raised concerning the cardiovascular and renal profiles of these agents based on data from both small and large clinical studies. More recently, our increasing understanding of the relative contributions of both isoforms of the COX enzyme to individual components of vascular homeostais has allowed us to appreciate the cardiovascular and renovascular implications of selective COX-2 inhibition.     

The safety of rofecoxib

Like all COX-2 inhibitors, rofecoxib has been developed based on the hypothesis that at comparable therapeutic efficacy, it would have a better safety and tolerability profile than conventional NSAIDs. The Vioxx GI Outcomes Research trial has demonstrated that rofecoxib is indeed safer for the gastrointestinal tract than NSAIDs. However, this study has also raised questions regarding the cardiovascular safety of rofecoxib. Thereafter, several epidemiological and case-control studies have reinforced the association between rofecoxib and a higher risk of cardiovascular events. However, at this time, no prospective controlled study is available to conclude definitively on this issue. Several pathogenic mechanisms are evoked to explain why rofecoxib increases the cardiovascular risk. These include the development of a prothrombotic state, a sodium retention and an increase in systemic blood pressure. Recently, new evidence have become available indicating that rofecoxib indeed increases the number of thrombo-embolic events. These data have resulted in the complete withdrawal of rofecoxib from the market. Was it scientifically reasonable to withdraw rofecoxib rather than to adapt its label? Is the safety profile of rofecoxib really much worse than that of aspirin or other traditional NSAIDs? The main consequence of this withdrawal is a considerable threat on the entire class of selective COX-2 inhibitors without a clear evalua-tion of the balance between the risks and benefits of these com-pounds.     

The safety of rofecoxib

Like all COX-2 inhibitors, rofecoxib has been developed based on the hypothesis that at comparable therapeutic efficacy, it would have a better safety and tolerability profile than conventional NSAIDs. The Vioxx GI Outcomes Research trial has demonstrated that rofecoxib is indeed safer for the gastrointestinal tract than NSAIDs. However, this study has also raised questions regarding the cardiovascular safety of rofecoxib. Thereafter, several epidemiological and case-control studies have reinforced the association between rofecoxib and a higher risk of cardiovascular events. However, at this time, no prospective controlled study is available to conclude definitively on this issue. Several pathogenic mechanisms are evoked to explain why rofecoxib increases the cardiovascular risk. These include the development of a prothrombotic state, a sodium retention and an increase in systemic blood pressure. Recently, new evidence have become available indicating that rofecoxib indeed increases the number of thrombo-embolic events. These data have resulted in the complete withdrawal of rofecoxib from the market. Was it scientifically reasonable to withdraw rofecoxib rather than to adapt its label? Is the safety profile of rofecoxib really much worse than that of aspirin or other traditional NSAIDs? The main consequence of this withdrawal is a considerable threat on the entire class of selective COX-2 inhibitors without a clear evaluation of the balance between the risks and benefits of these compounds.     

Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.     

Rofecoxib

Rofecoxib (Vioxx?, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.     

Rofecoxib

Rofecoxib (Vioxx, Merck & Co., Inc.) is a new orally-effective non-steroidal anti-inflammatory drug (NSAID) approved for treatment of acute pain, fever, primary dysmenorrhea and pain and inflammation in osteoarthritis (OA). It is also being evaluated for treatment of rheumatoid arthritis and adenomatous polyps of the colon. Rofecoxib is a specific inhibitor of cyclooxygenase-2 (COX-2), thereby inhibiting prostanoid synthesis in cells that express COX-2, including inflammatory cells. As cells in the gastrointestinal (GI) tract principally express COX-1, a different isoform of cyclooxygenase, it is predicted that rofecoxib will have less GI toxicity than other less selective NSAIDs. In clinical trials, rofecoxib was found to be as effective as other NSAIDs for management of pain and inflammation. In trials that compare rofecoxib with ibuprofen, diclofenac and indomethacin, less GI toxicity has been observed, as assayed by a decrease in lesions visible on endoscopy, by GI blood loss and, in a meta-analysis, by frequency of serious adverse GI events. The presence of COX-2 in cells other than inflammatory cells results in side effects common among NSAIDs, including peripheral oedema and hypertension. These side effects are dose-dependent. Rofecoxib, together with other branded NSAIDs, are relatively expensive, which has led to concern regarding costs versus benefits. There is also concern regarding potential risks associated with the use of rofecoxib by populations that would otherwise not tolerate NSAIDs.     

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs. OBJECTIVE: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs. Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17,072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5 mg, 25 mg, or 50 mg (combined, N = 10 026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046). RESULTS: The incidence of PUBs over 24.8 months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors. DISCUSSION: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8 months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib. CONCLUSIONS: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.     

Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks

Selective inhibitors of cyclooxygenase-2 (COX-2) were designed to minimize gastrointestinal complications of traditional non-steroidal anti-inflammatory drugs (NSAIDs) attributed to the suppression of COX-1-derived prostanoids. Selective COX-2 inhibitors (coxibs) are effective anti-inflammatory and analgesic drugs. However, recently it has become apparent that some coxibs increase the risk of serious cardiovascular events, including myocardial infarction and stroke. This has led to the withdrawal of rofecoxib from markets and has raised the concern about an inherent atherothrombotic risk of this class of drugs. This question should be carefully analyzed in the light of the current knowledge on COX-2 functions in the cardiovascular system. COX-2 is regarded as an inducible enzyme involved in the pathophysiology of inflammation and pain. In the cardiovascular system, COX-2 has also been associated with pro-inflammatory/pro-atherogenic stages, due to its up-regulation in monocyte-derived macrophages present in atherosclerotic lesions. However, experimental and clinical studies suggest that COX-2 is "constitutively" expressed in some tissues, among them in the vascular endothelium, where COX-2-derived prostanoids, especially prostacyclin (PGI(2)), contribute in the maintenance of vascular homeostasis and integrity. This review provides an updated overview on the functions of COX-2 in the cardiovascular system addressing key issues that could help to understand why chronic COX-2 inhibition may have undesirable effects in patients at cardiovascular risk.     

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis*

SUMMARY

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs.

Objective: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs.

Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17?072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5?mg, 25?mg, or 50?mg (combined, N = 10?026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046).

Results: The incidence of PUBs over 24.8?months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors.

Discussion: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8?months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib.

Conclusions: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.     

Are rofecoxib and celecoxib safer NSAIDS?

NSAIDs work by inhibiting the enzyme cyclo-oxygenase (COX), responsible for prostaglandin synthesis. This enzyme exists in two isoforms, COX-1 and COX-2. Inhibition of COX-1 is thought to be the main cause of the gastrointestinal unwanted effects of NSAIDs, whilst inhibition of COX-2 results in anti-inflammatory effects. [symbol: see text]Rofecoxib (Vioxx--MSD) and [symbol: see text]celecoxib (Celebrex--Searle) have been developed as selective inhibitors of COX-2. Rofecoxib is licensed for the symptomatic treatment of osteoarthritis, but not for rheumatoid arthritis. The manufacturer claims that "in clinical studies rofecoxib inhibits COX-2 but not COX-1", has "the power of high-dose NSAIDs--diclofenac and ibuprofen" and "superior GI safety profile compared to conventional NSAIDs". Celecoxib is licensed for symptom relief in osteoarthritis and rheumatoid arthritis. The manufacturer claims that celecoxib has "comparable efficacy and superior GI tolerability when compared to diclofenac or naproxen". Here, we review rofecoxib and celecoxib and consider whether they are safer than conventional NSAIDs.     

Clinical pharmacology of celecoxib, a COX-2 selective inhibitor

NSAIDs are extensively used worldwide; nonetheless, they are associated with adverse gastrointestinal (GI) effects. COX-2 inhibitors (coxibs) have been developed to reduce pain and inflammation without associated GI and bleeding risks. Celecoxib was the first COX-2 inhibitor introduced on the market, and it still remains so, whereas rofecoxib and valdecoxib were withdrawn due to excess cardiovascular (CV) risk. There is consequently a concern that CV toxicity reflects a class effect of all COX-2 inhibitors. Celecoxib possesses anti-inflammatory and analgesic properties, and the evidence for CV risk is rather small and comparable to that of other traditional NSAIDs in short-term treatments (of < 4 weeks). It could be suggested that the use of low doses of celecoxib (100 mg b.i.d.) in short-treatment, especially in patients with previous experience of GI events and the recommendation of avoiding use of celecoxib in patients with CV history or risk, contribute in the decision-making process of prescribing COX-2 or NSAIDs.     

Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity

The hypothesis that the anti-inflammatory activity of NSAIDs derives from COX inhibition is well established. It also underpins the accepted mechanism of the gastrointestinal and renal toxicity of NSAIDs. However, in terms of NSAID-induced cardiovascular toxicity, is COX inhibition then guilty by association? Multiple experimental models of COX-1/COX-2 inhibition have enabled ranking of the relative inhibitory activity of NSAIDs. Inhibition is expressed as an IC(50) value and the index of COX selectivity as the ratio of the IC(50) value for COX-2 and COX-1. These data informed the 'imbalance hypothesis' that the cardiovascular risk of NSAIDs results from an imbalance in the detrimental actions of COX-1-derived thromboxane A(2) and the beneficial actions of COX-2-derived prostacyclin (PGI(2)). Data derived from in vitro models used to generate NSAID IC(50) values are discussed in the context of the difficulties in defining COX selectivity and hence understanding the toxicity of NSAIDs in current clinical use.     

COX inhibition and NSAID-induced gastric damage--roles in various pathogenic events

This article reviews our recent studies on NSAID-induced gastric damage, focusing on the relation between COX inhibition and pathogenic events. Conventional NSAIDs such as indomethacin, at a dose that inhibits PG production, enhance gastric motility, resulting in an increase in mucosal permeability and MPO activity, and eventually, gastric lesions. The development of these lesions can be prevented by administering PGE2 or antisecretory drugs, and also via an atropine-sensitive mechanism, not related to any antisecretory action. The selective COX-2 inhibitor rofecoxib has no effect on PG production and does not induce damage in the stomach. The selective COX-1 inhibitor SC-560 also does not cause damage, despite evoking a decrease in the PGE2 level. The combined administration of SC-560 and rofecoxib, however, provokes the formation of gastric lesions. SC-560, but not rofecoxib, causes gastric hypermotility and an increase in mucosal permeability, although the level of MPO activity increases only when rofecoxib is co-administered. COX-2 mRNA is expressed in the stomach after administration of SC-560 and indomethacin but not rofecoxib. The up-regulation of COX-2 expression in response to indomethacin is prevented by atropine at a dose that inhibits gastric hypermotility but not by omeprazole at an antisecretory dose. We conclude that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by the inhibition of COX-1 and require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 up-regulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition.     

Selective COX-2 inhibitors and human inflammatory bowel disease

BACKGROUND: Much recent effort has been made to produce selective inhibitors of cyclo-oxygenase-2 (COX-2) in the belief that these will lack the gastrointestinal damaging effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs). Inflammatory bowel disease is associated with increased local production of prostanoids. These prostanoids, particularly PGE2 and PGI2, may well be protective as inflammatory bowel disease is aggravated by NSAID use. AIM: To examine the effects of a traditional NSAID and a highly selective COX-2 inhibitor on the production of these prostanoids in human inflammatory bowel disease. METHODS: Colonic mucosal biopsies were obtained from patients undergoing routine colonoscopy and biopsy for diagnostic or surveillance purposes. Biopsies were incubated in culture medium containing 10% foetal calf serum and antibiotics, plus test drugs or vehicle for 24 h, after which time the medium was removed and the content of PGE2, PGI2 (measured as 6 keto-PGF1alpha) and thromboxane (Tx) A2 (measured as TxB2) determined. RESULTS: Biopsies obtained from diseased colonic mucosa produced significantly more PGE2, PGI2 and thromboxane A2 than did controls (for example, PGE2: ulcerative colitis, 4.17+/-1.06; Crohn's disease, 3.97+/-1.66; control, 0.12 +/-0.13 ng/mL, n = 8-12). These increases were inhibited to a similar extent by either a highly selective COX-2 inhibitor (L-745,337) or a traditional non-selective NSAID (indomethacin). CONCLUSIONS: Until selective COX-2 inhibitors have been assessed adequately in human inflammatory bowel disease, these compounds should not be assumed to be safe for the gastrointestinal tract in inflammatory bowel disease.     

Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.     

Assessment of the safety of selective cyclo-oxygenase-2 inhibitors: where are we in 2003?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide despite their well-documented adverse gastrointestinal (GI) effects. The risk of developing a severe GI event varies from patient to patient and NSAID to NSAID. Selective cyclo-oxygenase-2 inhibitors (coxibs) have been designed to have similar efficacy but less GI toxicity than traditional NSAIDs, and have been shown to have an improved GI tolerability and less adverse events across a range of different GI safety assessments. In clinical trials, particularly VIGOR and CLASS, rofecoxib and celecoxib, respectively, significantly reduce the risk of ulcers and ulcer complications than nonselective NSAID comparators with ulcer rates comparable to placebo. The real benefit of a coxib comes from the sparing of the thromboxane and hence preservation of normal platelet function. Thus, there is less risk of bleeding with selective inhibition of COX-2, which is the most common and serious complication of non-selective NSAIDs. Moreover, bleeding can occur anywhere in the GI tract. Although some concern has been raised about the cardiovascular safety of coxibs, when used in recommended doses, there is no convincing evidence that patients treated with a coxib have an increased risk of cardiovascular thrombotic events. Different approaches have been advocated to minimize NSAID-related GI toxicity. Choice of less harmful NSAIDs such as coxib has been one of the strategies promoted in guidelines. The introduction of coxibs with a higher benefit-risk ratio has dramatically changed the therapeutic scenario for anti-inflammatory treatment in the clinical practice.     

Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers

In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX-2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.     

Gastroduodenal safety of cyclooxygenase-2 inhibitors

Cyclooxygenase-1 (COX-1) derived eicosanoids promote gastroprotective mucosal defenses and induce platelet aggregation. By sparing COX-1, COX-2 specific inhibitors provide effective anti-inflammatory and analgesic activity while substantially reducing the risk of peptic ulcer disease and GI bleeding compared to dual COX inhibitors (traditional NSAIDs). Clinical studies of the COX-2-selective inhibitors have demonstrated efficacy equivalent to nonselective NSAIDs with significantly lower rates of GI toxicity. The incidence of endoscopic ulcers in some studies with coxibs has approximated placebo. However, as the detection of endoscopic lesions is not always correlated with symptomatic ulcers and ulcer complications, outcome studies of GI safety were performed. The results of large outcome studies have evaluated rofecoxib and celecoxib in over 39,000 patients with osteoarthritis or rheumatoid arthritis. Results of these studies showed that patients taking a supratherapeutic dose of rofecoxib or celecoxib had significantly lower rates of GI-related adverse events than those taking a nonselective NSAID. The GI safety of coxibs for patients using low dose aspirin concomitantly with a coxib appears to be reduced, particularly with regard to ulcer complications. Such data provide support for the COX-2 hypothesis and demonstrate that coxibs provide effective treatment of pain and inflammation with a reduced risk of gastropathy.     

The trade-off between cardiovascular and gastrointestinal effects of rofecoxib

BACKGROUND: The cyclooxygenase-2 (COX-2) inhibitor rofecoxib was registered in 1999. By 2000, the first reports were published indicating that the agent was possibly associated with an increased risk of myocardial infarction. Since then a surge of data supporting this association has become available. To interpret these data it is essential to ascertain the cardiovascular risk profile of users of rofecoxib relative to other non-steroidal anti-inflammatory drug (NSAID) recipients. OBJECTIVE: To assess differences in cardiovascular risk between starters of rofecoxib versus starters of any other NSAID. SETTING: Data sampled from a representative research network of Dutch general practitioners (GPs) in 2001. DESIGN: New users (starters) of rofecoxib were compared to starters of any other NSAID, unmatched and matched on age, gender, and indication nested in the cohort of the second Dutch National Survey of General Practice. RESULTS: A total of 40.4% of patients starting on rofecoxib had cardiovascular co-morbidity. Patients starting on rofecoxib were twice more likely to have a history of gastrointestinal (GI) morbidity, compared to patients starting on other NSAIDs (OR(adj) = 2.09; 95%CI = 1.65-2.66). These patients were also more likely to have cardiovascular co-morbidity (OR = 1.90; 95%CI = 1.60-2.24) compared to recipients of rofecoxib with no GI co-morbidity. Cardiovascular morbidity was present at the time of rofecoxib exposure in over 61% of carriers of a composite risk profile including age 60 years or older, GI co-morbidity and diagnosis of rheumatoid arthritis and osteoarthritis. CONCLUSIONS: In general, a typical recipient of an NSAID is aged and carrier of a serious cardiovascular risk profile. Selective prescribing of rofecoxib to provide claimed gastroprotection, indirectly and unintentionally resulted in prescribing rofecoxib in a population with high frequencies of cardiovascular morbidities.