Economic evaluation of etoricoxib versus non-selective NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis patients in the UK

INTRODUCTION: The objective of this study was to evaluate the potential economic implications of using etoricoxib versus non-selective NSAID alternatives in the treatment of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in the UK. STUDY DESIGN: Decision-analytical modelling was used to calculate the expected costs and consequences of the use of etoricoxib compared with non-selective NSAIDs alone, NSAIDs plus proton pump inhibitors (PPIs), NSAIDs plus histamine H2 receptor antagonists and NSAIDs plus misoprostol over a continuous treatment period of 1 year. METHODS: The model considered direct medical costs from the perspective of the UK National Health Service (NHS) and used data from phase IIb and III clinical trials of etoricoxib to determine probabilities of gastrointestinal (GI) events. Model outcomes were defined as resource-consuming GI-related events, including clinically evident gastroduodenal perforations, symptomatic gastroduodenal ulcers, or upper GI bleeding (collectively, PUBs ['perforation, ulcers and/or bleeding']). Resource utilisation and costs (2002 values) for the treatment of OA and RA as well as GI events were based on published literature and information available from UK-specific sources. MAIN OUTCOME MEASURES AND RESULTS: The model suggests that etoricoxib is cost saving compared with non-selective NSAIDs plus PPIs or non-selective NSAIDs plus misoprostol. The model also suggests that etoricoxib is cost effective in terms of the incremental cost per QALY gained for non-selective NSAIDs alone (pound 19,766) and for non-selective NSAIDs plus H2 antagonists (pound 9350). The incremental cost of etoricoxib per PUB avoided was pound 12,446 versus non-selective NSAIDs alone and pound 6438 versus NSAIDs co-prescribed with H2 antagonists. For patients without the presence of specific GI risk factors (history of GI event, corticosteroid use or disability), etoricoxib may be cost effective for patients over age 56 years, assuming a cost-effectiveness threshold of pound 30,000 per QALY gained. Etoricoxib may also be cost effective in patients of all ages who had at least one specific GI risk factor. CONCLUSIONS: The model suggests, with its underlying assumptions and data, that etoricoxib is a cost-effective alternative to therapeutic regimens involving non-selective NSAIDs for OA or RA, from the UK NHS perspective. Etoricoxib may be cost saving and dominant over non-selective NSAIDs used together with a PPI or misoprostol. When compared with non-selective NSAIDs alone or non-selective NSAIDs co-prescribed with H2 antagonists, the incremental cost per QALY gained with use of etoricoxib was within the generally accepted threshold for cost effectiveness (less than pound 30,000 per QALY gained).     

Temporal relationship between use of NSAIDs, including selective COX-2 inhibitors, and cardiovascular risk.

BACKGROUND AND OBJECTIVE: The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. However, following their introduction into the market, concerns have developed regarding their safety, particularly their cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included were myocardial infarction, stroke and myocardial infarction-related deaths) associated with long-term (>180 days of exposure) and short-term (or=35 years of age who received celecoxib, rofecoxib, ibuprofen, etodolac and naproxen from 1 January 1999 through 31 December 2001, were included. Multivariate Cox proportional hazard models were used to analyse the relationship between cardiovascular risk and NSAID use, including selective COX-2 inhibitor use, while adjusting for various risk factors. RESULTS: We identified 12 188 exposure periods (11 930 persons) and 146 cardiovascular events over the entire study period. Compared with long-term ibuprofen use, long-term use of celecoxib (adjusted hazard ratio [HR] 3.64; 95% CI 1.36, 9.70) and rofecoxib (adjusted HR 6.64; 95% CI 2.17, 20.28) was associated with a significant increase in cardiovascular risk. When restricted to patients >or=65 years of age, the cardiovascular risks associated with long-term celecoxib (adjusted HR 7.36; 95% CI 1.62, 33.48) and rofecoxib (adjusted HR 13.24; 95% CI 2.59, 67.68) use increased. Short-term use of celecoxib (adjusted HR 0.75; 95% CI 0.42, 1.35) and rofecoxib (adjusted HR 0.85; 95% CI 0.39, 1.86) was not associated with any significant change in cardiovascular risk when compared with short-term ibuprofen use. Neither long- nor short-term exposure to naproxen and etodolac was associated with cardionegative or cardioprotective effects when compared with ibuprofen use. CONCLUSIONS: The findings of this observational study, along with recent clinical trial results, suggest that prolonged exposure to selective COX-2 inhibitors may be associated with an increased risk of adverse cardiovascular outcomes.     

Surveillance colonoscopy or chemoprevention with COX-2 inhibitors in average-risk post-polypectomy patients: a decision analysis

OBJECTIVES: Clinical trials are currently underway evaluating the efficacy of COX-2 inhibitors in decreasing the incidence of adenomas and colorectal carcinoma in 'average' risk individuals. AIM: To use decision analysis to compare the cost-effectiveness of celecoxib to surveillance colonoscopy in 'average' risk patients who had undergone prior adenoma resection. METHODS: A model of the natural history of adenomas after endoscopic polypectomy was constructed using probabilities from the literature. Cost estimates were obtained from available Medicare reimbursement rates and supplemented by the literature. Three strategies were evaluated: (i) no surveillance; (ii) colonoscopic surveillance; and (iii) celecoxib chemoprevention. We compared total costs and performed cost-effectiveness analysis between these strategies. The outcome measures were years of life saved and 'high-grade' adenoma prevented. Sensitivity analyses were performed on selected variables. RESULTS: Our base-case analysis assumed a 50% risk reduction in the incidence of adenomas among patients using celecoxib. No surveillance was associated with a cost of $1014 per patient, and colonoscopic surveillance with a cost of $1572 per patient, whereas celecoxib use was associated with a total cost of $11,503. Ten years after the index colonoscopy, 15% of patients in the no surveillance strategy developed 'high-grade' lesions compared to 13% of patients in the colonoscopic surveillance group and 6% in the celecoxib group. There was a small gain in years of life saved (0.006) favouring celecoxib over colonoscopic surveillance. The incremental cost-effectiveness ratio of celecoxib vs. colonoscopy was $141 871 per 'high-grade' adenoma prevented and $1,715,199 per year of life saved. The most important variables in determining the cost-effectiveness of celecoxib were its cost and its efficacy. CONCLUSION: Chemoprevention with COX-2 inhibitors in 'average-risk' postpolypectomy patients is a more expensive strategy compared to colonoscopic surveillance.     

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.     

抗风湿新药的概述

综述了20世纪90年代涌现的抗风湿药。最新一类的选择性COX－2抑制剂，包括塞米昔布和罗非昔布，它们具有与现有NSAID相似的镇痛抗炎效果，但其胃肠道不反应发生率明显较低，尤其在胃肠道溃疡、出血、穿孔方面。属改变病情药的来氟米特，对RA患者具有与MTX相似的疗效。生物制剂包括TNF阻断剂及IL－1受体拮抗剂。前者有重组可溶性TNF受体融合蛋白和TNFα单克隆抗体。临床试验显示，它们对RA患者疗效较好且均无严重不良反应。     

Clinical implications of drug interactions with coxibs

Nonsteroidal antiinflammatory drugs (NSAIDs) often are prescribed to patients who are taking concomitant drugs. Cyclooxygenase (COX)-2 inhibitors (coxibs) rofecoxib and celecoxib are highly selective inhibitors of COX-2, differentiating them from nonselective NSAIDs, which substantially inhibit both COX-1 and COX-2. Like nonselective NSAIDs, coxibs are hepatically metabolized: rofecoxib primarily by reduction by cytosolic enzymes and celecoxib by the cytochrome P450 (CYP) enzyme system. Because rofecoxib is not significantly metabolized by CYP, it has fewer confirmed or potential drug interactions than celecoxib. However, potent inducers of CYP, such as rifampin, may decrease rofecoxib concentrations because of induction of general hepatic metabolic activity. Celecoxib is metabolized by CYP2C9 and may be increased or decreased by CYP2C9 modifiers. It also inhibits CYP2D6 and may affect concentrations of CYP2D6 substrates. Similar to NSAIDs, many pharmacodynamic interactions involving coxibs are related to inhibition of production of renal prostaglandins. However, coxibs have no antiplatelet activity and may be preferred to NSAIDs in patients receiving antithrombotic therapy. Nonetheless, when a potential for an interaction exists, standard monitoring is recommended when starting or discontinuing a coxib. Due to lack of data to support these interactions, which are primarily theoretical, additional studies are necessary to establish the drug interaction profiles of coxibs.     

Comparison of reporting of Stevens-Johnson syndrome and toxic epidermal necrolysis in association with selective COX-2 inhibitors.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides. OBJECTIVE: The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate. METHODS: We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature. RESULTS: Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8-9 times that of celecoxib and approximately 25 times that of the background rate. CONCLUSION: There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.     

Cyclooxygenase-2 inhibitors and coronary occlusion--exploring dose-response relationships

AIMS: To investigate the relationship between acute coronary syndrome (ACS) and ingested doses of selective cyclooxygenase-2 (COX-2) inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Case-control study, commenced August 2003. Cases were patients admitted to hospital with ACS (myocardial infarction/unstable angina). Controls were hospital patients admitted for reasons other than acute vascular ischaemia or conditions that are believed to be complications of treatment with COX-2 inhibitors or NSAIDs. Structured interviews were undertaken within 7 days of admission, collecting information on cardiovascular events and risk factors and all ingested drugs, including the doses of COX-2 inhibitors and NSAID consumed in the previous week and month. RESULTS: An interim analysis of the data was conducted in late 2004 to inform a review of the COX-2 inhibitors by the Australian drug regulatory agency. Between August 2003 and October 2004, we recruited 328 ACS cases and 478 controls. With non-use of COX-2 inhibitors or NSAIDs as the reference the adjusted odds ratios (OR) for ACS were: celecoxib 1.11 (95% confidence interval 0.59, 2.11), rofecoxib 0.63 (0.31, 1.28) and other NSAIDs 0.67 (0.41, 1.09). Among control subjects, median daily ingested doses of celecoxib and rofecoxib were 200 mg and 13.4 mg, respectively. Using these to stratify risk, adjusted ORs for ACS were: 'low' dose (< median) 0.44 (0.19, 1.03); 'high' dose (>/= median) 1.22 (0.67, 2.21). A test for interaction across doses was statistically significant, OR 2.8 (1.0, 7.7), suggesting that at low doses, COX-2 inhibitors may be protective, becoming risk-inducing only at higher doses. CONCLUSION: The possibility that the gradient of cardiovascular risk with COX-2 inhibitors runs from protective to risk-inducing has biological plausibility and merits further investigation.     

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.     

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.     

Impact of COX-2 inhibitors in common clinical practice a gastroenterologist's perspective

Non-selective NSAIDs enhance the risk of serious ulcer complications (bleeding, perforation, obstruction), hospitalization and death about 3-10-fold. The gastrointestinal side effects of NSAIDs have a considerable economical burden, since they are responsible for 5-10 billion dollars in hospitalization charges and lost work time. NSAIDs cause gastrointestinal damage by both topical and systemic effects. COX-1-mediated inhibition of prostaglandin synthesis is probably the most relevant mechanism, but NSAIDs can cause gastrointestinal injury also by COX-independent pathways. COX-2-selective inhibitors (Coxibs) such as celecoxib, rofecoxib or valdecoxib have been developed to achieve an equal relief of pain and inflammation as classical NSAIDs but without their risk of gastrointestinal side effects. Within the first three months, celecoxib became the fastest selling drug in history. The gastrointestinal safety of classical NSAIDs and Coxibs has been compared in a variety of endoscopic investigations, meta-analyses and outcome studies. In conclusion, these studies have clearly shown, that Coxibs are associated with significantly less dyspeptic symptoms, erosions, ulcers and ulcer complications. In contrast, Coxibs seem to delay gastric ulcer healing to the same extent as traditional NSAIDs. Besides their effects on the upper gastrointestinal tract, NSAIDs can cause small intestinal inflammation, ulcers of the small and large intestine, ileal dysfunction, intestinal strictures, colitis and NSAID enteropathy. In addition, NSAIDs increase the risk of lower gastrointestinal complications including bleeding, perforation and obstruction. Current data suggest, that Coxibs are associated with a significantly lower risk of serious lower GI events than traditional NSAIDs. It is now under debate, who should receive COX-2-selective inhibitors instead of classical NSAIDs, since Coxibs are much more expensive. Data from cost-effectiveness studies suggest, that Coxibs should currently be used only in patients with high risks of GI complications.     

Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis

Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment.     

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.     

NSAID use in individuals at risk of renal adverse events: an observational study to investigate trends in Australian veterans

BACKGROUND: Cyclo-oxygenase (COX)-2 inhibitors were introduced to world markets with claims of improved gastrointestinal safety compared with traditional NSAIDs. Randomized clinical trials had demonstrated fewer adverse gastrointestinal events with COX-2 inhibitors, but no difference with other adverse events, including adverse renal events. There was a rapid uptake of these medicines. OBJECTIVE: To compare uptake rates of NSAIDs, including COX-2 inhibitors, in a reference population with those in two high-risk populations: a population taking medicines affecting the renin-angiotensin system and loop diuretics, and a population taking medicines for diabetes mellitus. METHOD: An observational study was undertaken in which the Department of Veterans' Affairs claims dataset was used to identify: veterans dispensed ACE inhibitors (ACEIs) or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) and furosemide (ACEI-ARB/furosemide cohort); veterans dispensed medicines for diabetes (diabetes cohort); and all other veterans (reference cohort) from July 1999 to July 2007. Concurrent dispensing of NSAIDs was assessed. RESULTS: Prior to celecoxib becoming subsidized in Australia, the baseline level of NSAID use was 19.5% in the reference cohort, 15.3% in the diabetes cohort and 15.6% in the ACEI-ARB/furosemide cohort. After the listing of celecoxib, utilization of NSAIDs increased by 42.2% in the reference cohort, with similar increases in the diabetes cohort (40.8%; p = 0.88 compared with the reference cohort) and the ACEI-ARB/furosemide cohort (49.6%; p = 0.09 compared with the reference cohort). With the withdrawal of rofecoxib, utilization of NSAIDs in the reference cohort fell by 25.3%, with similar falls in the diabetes cohort (24%; p = 0.28 compared with the reference cohort) and the ACEI-ARB/furosemide cohort (26.1%; p = 0.43 compared with the reference cohort). CONCLUSIONS: Despite the increased vulnerability of veterans receiving ACEI-ARB/furosemide or diabetes medicines to adverse events of NSAIDs, uptake rates of COX inhibitors were equivalent to the rest of the veteran population. This suggests the gastrointestinal safety messages were interpreted broadly by prescribers and the adverse renal effects were not considered.     

COX-2 inhibitors and arterial hypertension: an analysis of spontaneous case reports in the Pharmacovigilance database

Objective To evaluate the main characteristics of case reports of arterial hypertension (AH) related to COX-2 inhibitor (coxib) use in real-life practice.Methods This study was based on spontaneous reports of adverse drug reactions (ADRs) submitted to the French Pharmacovigilance system. Associations between AH and the different groups of those using non-steroidal anti-inflammatory drugs (NSAIDs: rofecoxib, celecoxib and non-selective NSAIDs) were compared using calculation of the odds ratio (OR) with 95% confidence intervals (CIs).Results In France, between 1 April 2000 and 30 November 2003, 34 AH cases related to coxibs were reported. Case reports include predominantly patients older than 65 years, with a previous story of essential AH. Most AH (60%) occurred during the first 15 days of treatment. The AH was reported significantly more frequently for rofecoxib than celecoxib. The OR for development of AH with rofecoxib versus celecoxib was 3.3 (1.6–6.9). The AH was also reported more frequently with coxib (2.8%) than with non-selective NSAID (0.5%) use, OR = 5.9 (3.8–9.0).Conclusion This study shows that coxibs are associated with a risk of AH in real-life practice. More spontaneous reports of AH to the French Pharmacovigilance system concern rofecoxib than celecoxib (and coxibs than non-selective NSAIDs). This ADR is of special epidemiological importance due to both the risks of AH and the large use of coxibs.