Adjusted indirect comparison of celecoxib versus rofecoxib on cardiovascular risk

To compare the magnitude of celecoxib versus rofecoxib on the cardiovascular risk. We performed adjusted indirect comparison of celecoxib versus rofecoxib for cardiovascular events using two data on The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and Adenoma Prevention with Celecoxib (APC) trial. Baseline characteristics of the patients and placebos were comparable in both trials, in terms of age, sex, hypertension, diabetes mellitus, smoking, and hypercholesterolemia. The overall incidence of cardiovascular events was similar in both groups (rofecoxib 48/1,287 versus celecoxib 48/1,356, p = 0.79). The relative risks (RRs) of all myocardial infarction or sudden death from cardiac causes were increased in both rofecoxib and celecoxib groups [rofecoxib versus placebo; RR 1.35, 95% confidence interval (CI) 1.07–1.69, p = 0.03, celecoxib versus placebo; RR 1.35, 95% CI 1.14–1.51, p = 0.01]. The RRs for cardiovascular events derived from the adjusted indirect comparisons of the two coxibs did not significantly differ from unity (celecoxib versus rofecoxib; RR 0.95, 95% CI 0.76–1.19, p = 0.67). The adjusted indirect comparison analysis shows that celecoxib and rofecoxib may have similarly effect of cardiovascular events when used for 3 years.     

Gastro-duodenal protection in an era of cyclo-oxygenase-2-selective nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective and necessary for the relief of pain and inflammation in patients with arthritis. NSAIDs are however also associated with an increased risk for ulceration in the stomach and in the duodenum, and many NSAID users experience bothersome dyspeptic symptoms during continued NSAID therapy. PPIs like omeprazole, have been shown to heal and to prevent ulcers and dyspeptic symptoms during continued NSAID therapy, and during continued NSAID therapy the prostaglandin analogue, misoprostol, has been shown to reduce the risk for ulcer complications. The COX-2 selective NSAID, rofecoxib, is in comparison with naproxen, a non-selective NSAID, associated with fewer clinically important upper gastrointestinal events. The incidence of myocardial infarctions seems, however, to be lower with naproxen than with rofecoxib, and this is expected to lead to low-dose aspirin use in rofecoxib users at risk for cardiovascular events. Co-administration of the COX-2 selective NSAID, celecoxib, and low-dose aspirin, is associated with the same risk for upper gastrointestinal ulcer complications alone and combined with symptomatic ulcers, as the non-selective NSAIDs, ibuprofen and diclofenac. A proton pump inhibitor (PPI) should be used for healing of NSAID-associated ulcers, and a PPI or misoprostol should be considered for prevention of ulceration in non-selective NSAID users at risk for ulceration. The experience with COX-2 selective NSAIDs is still limited, and it remains to be studied whether subpopulations of COX-2 selective NSAID users will benefit from gastro-duodenal protection.     

Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.     

An economic model of long-term use of celecoxib in patients with osteoarthritis

Background  

Previous evaluations of the cost-effectiveness of the cyclooxygenase-2 selective inhibitor celecoxib (Celebrex, Pfizer Inc, USA) have produced conflicting results. The recent controversy over the cardiovascular (CV) risks of rofecoxib and other coxibs has renewed interest in the economic profile of celecoxib, the only coxib now available in the United States. The objective of our study was to evaluate the long-term cost-effectiveness of celecoxib compared with nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in a population of 60-year-old osteoarthritis (OA) patients with average risks of upper gastrointestinal (UGI) complications who require chronic daily NSAID therapy.     

Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin?

Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.     

Cardiovascular effects of coxibs

A new class of drugs, the selective cyclooxygenase-2 (COX-2) inhibitors, or coxibs, have recently been marketed as an alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) on the basis of a lower risk of gastrointestinal side effects. The recent withdrawal of rofecoxib, along with safety concerns about other COX-2 selective inhibitors raises important questions about the cardiovascular toxicity of these drugs. Recently some concerns arose even for a possible cardiotoxicity of nonselective nonsteroidal anti-inflammatory drugs. From data available so far, it seems that coxibs still remain a rational choice for patients with low cardiovascular risk and high gastrointestinal risk. Long-term studies with a cardiovascular endpoint involving both selective and nonselective anti-inflammatory drugs are warranted.     

Effects of rofecoxib and naproxen on life expectancy among patients with rheumatoid arthritis: a decision analysis

BACKGROUND: The VIOXX Gastrointestinal Outcomes Research (VIGOR) trial showed a 53% decrease in the risk of upper gastrointestinal toxicity and a fivefold increase in the risk of myocardial infarction for rofecoxib (a selective cyclooxygenase-2 inhibitor) compared with naproxen. We examined the effects of these competing adverse events on life expectancy in patients with rheumatoid arthritis. METHODS: We used decision analysis to compare the life expectancy of a cohort of rheumatoid arthritis patients taking naproxen versus a similar cohort taking rofecoxib, using data from the VIGOR trial. We incorporated the competing risks of upper gastrointestinal toxicity and myocardial infarction, as well as their long-term health consequences, on the basis of population-based studies. RESULTS: For 58-year-old women with rheumatoid arthritis (i.e., typical of participants in the VIGOR trial), naproxen was associated with a longer life expectancy than was rofecoxib (difference = 4.4 months). This difference was larger among 58-year-old men (7.8 months). The probability that naproxen is associated with a longer life expectancy than rofecoxib among 58-year-old patients was 92% for women and 98% for men. Life expectancy became the same between the two treatments when the risk of upper gastrointestinal toxicity was 70% higher or the risk of myocardial infarction was 40% lower than that of the base case among women, and when the risk of upper gastrointestinal toxicity was 4.4-fold higher or the risk of myocardial infarction was 70% lower among men. CONCLUSION: Our analysis suggests that the competing risks of upper gastrointestinal toxicity and myocardial infarction shown in the VIGOR trial would project a longer life expectancy with naproxen than rofecoxib among patients with rheumatoid arthritis, except in those at low risk of myocardial infarction or at high risk of upper gastrointestinal toxicity.     

Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program

Cyclo-oxygenase-2 (COX-2) inhibitors appear to alter the balance of vasoactive eicosanoids (prostacyclin and thromboxane) and to suppress the inflammatory mediators implicated in the progression of atherogenesis and ischemic myocardial injury. Neutral, harmful, and beneficial cardiovascular (CV) effects have all been postulated to result from these changes. Investigations conducted with rofecoxib, a selective COX-2 inhibitor, have substantially contributed to our understanding of this scientific area. Rofecoxib had little or no effect on platelet aggregation or platelet-derived thromboxane synthesis but reduced systemic prostacyclin synthesis by 50% to 60%. These findings prompted extensive analyses of CV thrombotic events within the rofecoxib development program. Among 5435 osteoarthritis trial participants, similar rates of CV thrombotic events were reported with rofecoxib, placebo, and comparator, nonselective NSAIDs (ibuprofen, diclofenac, and nabumetone). In the VIGOR gastrointestinal outcomes trial of >8000 patients, naproxen (an NSAID with aspirin-like sustained antiplatelet effects throughout its dosing interval) was associated with a significantly lower risk of CV events than was rofecoxib. A subsequent pooled analysis from 23 studies (including VIGOR) encompassing multiple disease states and including more than 14,000 patient-years at risk also demonstrated that rofecoxib was not associated with excess CV thrombotic events compared with either placebo or nonnaproxen NSAIDs. Again, naproxen appeared to be the outlier, suggesting a cardioprotective benefit of naproxen. Finally, among the predominantly elderly, male population participating in Alzheimer trials, both rofecoxib- and placebo-treated patients had similar rates of CV thrombotic events. The totality of data is not consistent with an increased CV risk among patients taking rofecoxib.     

Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis

OBJECTIVE: To evaluate the role of common internal controls in a meta-analysis of the relative efficacy of cyclooxygenase 2-selective inhibitors (coxibs) in the treatment of osteoarthritis (OA). METHODS: A systematic search of Medline and US Food and Drug Administration electronic databases was performed to identify randomized, placebo-controlled clinical trials of coxibs (etoricoxib, celecoxib, rofecoxib, valdecoxib) in patients with hip and/or knee OA. The effect size for coxibs and common active internal controls (nonsteroidal antiinflammatory drugs [NSAIDs], naproxen) were determined by the mean changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain subscores as compared with placebo. RESULTS: The effect size for all coxib groups combined (0.44) indicated greater efficacy as compared with placebo, but significant heterogeneity (P < 0.0001) was observed. Rofecoxib at dosages of 12.5 mg/day and 25 mg/day and etoricoxib at a dosage of 60 mg/day had similar effect sizes (0.68 and 0.73, respectively), but these effect sizes were comparatively greater than those for both celecoxib at dosages of 200 mg/day and 100 mg twice daily or valdecoxib at a dosage of 10 mg/day (0.26 and 0.16, respectively). The effect sizes for NSAIDs or naproxen versus placebo, as determined using data from rofecoxib/etoricoxib trials, were consistently higher than the effect sizes derived from trials of celecoxib/valdecoxib. Significant heterogeneity was present in the overall effect size for NSAIDs (P = 0.007) and naproxen (P = 0.04) groups based on data available from all coxib trials. CONCLUSION: Coxibs and common active internal controls showed larger effect sizes versus placebo in the rofecoxib/etoricoxib trials than in the celecoxib/valdecoxib trials. These findings suggest systematic differences among published coxib trials and emphasize the need for direct-comparison trials. In the absence of such trials, common internal controls should be assessed when performing indirect meta-analytic comparisons.     

Cardiovascular risk associated with nonsteroidal anti-inflammatory drugs

Since the introduction of selective cyclooxygenase-2 inhibitors (coxibs), there has been an ongoing discussion about the cardiovascular (CV) safety of coxibs and the traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Available data about the CV safety of NSAIDs come mostly from meta-analyses and a few clinical trials. Current evidence suggests that NSAIDs may increase the risk of CV events. Naproxen might be associated with lower risk, but available data are not conclusive. Recent recommendations on the treatment of patients with NSAIDs favor the use of naproxen in patients with increased CV risk. Therefore, this review focuses on data about naproxen and examines CV risk with ibuprofen and non-naproxen NSAIDs. In addition, data about CV safety of paracetamol (acetaminophen) are presented.     

Motion--Cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs are as safe as placebo for the stomach: arguments for the motion.

Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastritis, gastric and duodenal ulcers, and gastrointestinal (GI) blood loss, as well as alterations in small bowel permeability. Patients at a high risk for these complications include those who are older than 60 years of age, those with a previous history of complicated peptic disease and bleeding, and those who take high dose or multiple NSAIDs, including low dose aspirin, corticosteroids or anticoagulants. The introduction of selective inhibitors of cyclo-oxygenase-2 (COX-2) has provided effective treatment of inflammatory arthritis and musculoskeletal pain, with dramatic reductions in the risk of GI adverse events. The two most widely prescribed coxibs are celecoxib and rofecoxib, and others are being developed. Endoscopic studies have revealed that coxibs are only half as likely to induce upper GI ulceration than are traditional NSAIDs, and are as safe as placebo. Furthermore, the newer drugs do not cause excessive blood loss from the GI tract and do not affect small bowel permeability. The Vioxx Gastrointestinal Outcomes Research Study (VIGOR) revealed that the incidence of myocardial infarction was significantly lower with naproxen than rofecoxib, although this study was not designed to look at this endpoint. Coxibs are an important addition to the pharmacotherapy of inflammatory disease.     

NSAIDs, coxibs, CINOD and H2S-releasing NSAIDs: What lies beyond the horizon

Nonsteroidal anti-inflammatory drugs are widely prescribed for treatment of pain and inflammation, despite their association with gastrointestinal complications, including bleeding and perforation. Inhibition of cyclo-oxygenases, is the main mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs. Non-selective nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. Inhibition of cyclo-oxygenase-1 derived prostanoids in the stomach represent the underlying mechanism involved in development of gastric and duodenal ulcers in patients taking nonsteroidal anti-inflammatory drugs. Selective cyclo-oxygenases-2 inhibitor (coxibs) spare cyclo-oxygenase-1 show enhanced safety profile in the gastrointestinal tract, but increase the risk of heart attack and stroke. Spurred by these findings, two coxibs, rofecoxib and valdecoxib, were withdrawn from the market. In addition to prostanoids, two gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H₂S) exert protective effects in gastric mucosa. The inhibitory effects of NO on nonsteroidal anti-inflammatory drugs-induced leukocyte adherence have been exploited in the development of NO-releasing nonsteroidal anti-inflammatory drugs, also indicated as cyclo-oxygenase-inhibiting NO-donating drugs. Despite its non-selective profile versus cyclo-oxygenase isoenzymes, naprocyclo-oxygenase-inhibiting NO-donating drugs, the prototype of this class of anti-inflammatory agents, reduces systemic blood pressure and might have enhanced cardiovascular safety than coxibs, while causing less gastrointestinal damage than its parent drug, the naproxen. H₂S-releasing nonsteroidal anti-inflammatory drugs derivatives have been recently developed, based on the observed ability of this gaseous mediator to cause vasodilation and to prevent leukocyte adherence. In pre-clinical settings, H₂S-releasing nonsteroidal anti-inflammatory drugs produce less gastric damage as compared to the parent drugs. Cyclo-oxygenases-inhibiting NO-donating drugs and H₂S-releasing nonsteroidal anti-inflammatory drugs represent examples of new anti-inflammatory drugs created through the exploitation of the beneficial effects of endogenous gaseous mediators in the gastrointestinal and cardiovascular systems.     

Appropriate use of NSAIDs: considering cardiovascular risk in the elderly

In the first of this two-part article, we reviewed essential gastrointestinal (GI) data necessary for choosing selective COX-2 inhibitors (coxibs) versus nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other NSAID-related GI issues. Although GI considerations are critical to appropriate NSAID selection, the worldwide withdrawal of rofecoxib because of adverse cardiovascular (CV) events has changed the focus of appropriate NSAID selection. In part 2, we discuss relevant CV adverse effects related to NSAID use. Based upon data reviewed, we believe there are differences between coxibs and that all NSAIDs, including nonselective agents, have some degree of CV risk. Their use should be based upon patient's risks and benefits. Our clinical use pathway or algorithm will continue to frame the ongoing discussion and guide clinicians along what has become a difficult decision in daily practice.     

The Risk of Major NSAID Toxicity with Celecoxib,Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION Trial

Background

The relative safety of long-term use of nonsteroidal anti-inflammatory drugs is unclear. Patients and providers are interested in an integrated view of risk . We examined the risk of major nonsteroidal anti-inflammatory drug toxicity in the PRECISION trial.

Valdecoxib

Valdecoxib is a selective COX-2 inhibitor that is similar in anti-inflammatory activity to the other selective COX-2 inhibitors (e.g., celecoxib and rofecoxib). Valdecoxib is at least equally as effective as ibuprofen, naproxen, and diclofenac in the treatment of osteoarthritis and rheumatoid arthritis, but is safer in terms of gastrointestinal toxicity. Valdecoxib is also indicated for treatment of dysmenorrhea and useful in other pain conditions. There have been no head-to-head comparisons of valdecoxib and celecoxib or rofecoxib in the treatment of osteoarthritis, rheumatoid arthritis, or various pain conditions.