Nonselective Nonselective Nonsteroidal Anti-inflammatory Drugs Research Articles

Parecoxib – getting to the heart of the matter

Parecoxib – getting to the heart of the matter

Channeling and prevalence of cardiovascular contraindications in users of cyclooxygenase 2 selective nonsteroidal antiinflammatory drugs

To assess use and channeling of cyclooxygenase 2 selective inhibitors (coxibs) over time and to estimate the percentage of coxib users with cardiovascular contraindications. The study population comprised all coxib and nonselective nonsteroidal antiinflammatory drug (NSAID) users in the Integrated Primary Care Information project between January 2000 and December 2004. The prevalence of risk factors for NSAID-related upper gastrointestinal ulcer complications, cardiovascular disease, and cerebrovascular disease at the start of treatment was compared between users of coxibs and users of nonselective NSAIDs. The study population included 72,841 nonselective NSAID users and 10,739 coxib users. The prevalence of risk factors for NSAID-related gastrointestinal complications was higher in coxib users than nonselective NSAID users (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.10-1.26). Similarly, the prevalence of prior cardiovascular disease was higher in coxib users than in nonselective NSAID users (OR 1.35, 95% CI 1.28-1.43). Channeling of coxibs to patients with NSAID-related gastrointestinal risk factors declined after 2001 but increased again in 2004, whereas the channeling of coxibs to patients with cardiovascular disease remained constant. Less than 15% of all coxib users had history of ischemic coronary or cerebrovascular disease. Among coxib users with increased risk for NSAID-related gastrointestinal disorders, 27% had history of ischemic coronary or cerebrovascular disease. This study demonstrates that coxibs were preferentially prescribed to patients with risk factors for NSAID-related gastrointestinal disorders and/or cardiovascular diseases. Only one-quarter of coxib users with increased risk for NSAID-related gastrointestinal complications had cardiovascular conditions compatible with recent European safety contraindications for coxibs.

Instrumental Variable Analysis of Secondary Pharmacoepidemiologic Data

Instrumental Variable Analysis of Secondary Pharmacoepidemiologic Data

Meta-Analysis: Cardiovascular Events Associated with Nonsteroidal Anti-inflammatory Drugs

Purpose We performed a meta-analysis of randomized controlled trials to assess the effect of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) on cardiovascular events in trials of joint disease and Alzheimer’s disease. Methods We performed comprehensive searches of MEDLINE, EMBASE, CINAHL and Cochrane databases from 1966 to July 2005, and references of identified articles and reviews. We included randomized placebo-controlled trials of at least 6 weeks duration that evaluated nonselective NSAIDs in trials of joint disease or Alzheimer’s disease, and reported at least one cardiovascular event or death. The outcome measured was the composite of death, myocardial infarction or cerebrovascular accident, with the pooled results reported as odds ratios (OR). Subgroup analyses evaluated the difference between trials of joint disease and Alzheimer’s disease, and for naproxen and non-naproxen NSAIDs. Results Pooled data from 13 trials with 7718 participants showed that nonselective NSAIDs had no significant effect on cardiovascular events (OR 1.3; 95% confidence interval [CI], 0.8 to 2.1). No significant effect was seen for joint disease trials (OR 0.6; 95% CI, 0.2 to 1.7) or Alzheimer disease trials (OR 1.6; 95% CI, 0.9 to 2.7). There was no significant difference in results for naproxen and non-naproxen NSAIDs. Conclusion Nonselective NSAIDs have no significant effect on cardiovascular events or death in trials of joint disease and Alzheimer disease, but a small adverse effect could not be excluded. An indication for risk was present in trials of Alzheimer’s disease but not in joint disease trials. There was no significant adverse or cardioprotective effect of naproxen.

Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction

The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. We analyzed the risk of rehospitalization for acute myocardial infarction (MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with prior MI. All patients with first-time MI between 1995 and 2002 as well as all prescription claims for NSAIDs after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was studied with the use of multivariable proportional hazards models and case-crossover analysis. A total of 58 432 patients were discharged alive and included in the study; 9773 experienced rehospitalization for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI and should therefore be used with particular caution in these patients.

Update on guidelines for the treatment of chronic musculoskeletal pain

Chronic musculoskeletal pain is a major - and growing - burden on today's ageing populations. Professional organisations including the American College of Rheumatology (ACR), American Pain Society (APS) and European League Against Rheumatism (EULAR) have published treatment guidelines within the past 5 years to assist clinicians achieve effective pain management. Safety is a core concern in all these guidelines, especially for chronic conditions such as osteoarthritis that require long-term treatment. Hence, there is a consensus among recommendations that paracetamol should be the first-line analgesic agent due to its favourable side effect and safety profile, despite being somewhat less effective in pain relief than anti-inflammatory drugs. Cyclooxygenase-2 (COX-2)-selective anti-inflammatory drugs were developed with the goal of delivering effective pain relief without the serious gastrointestinal (GI) side effects linked with traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trial evidence supported these benefits, and COX-2 inhibitors were widely adopted, both in clinical practice and in official guidelines. Recently, accumulating data have linked COX-2 inhibitors with serious cardiovascular and/or cardiorenal effects and/or serious cutaneous adverse reactions (SCARs), particularly at anti-inflammatory doses or when used long term. Regulatory authorities in both Europe and the USA have responded to these data with the withdrawal of rofecoxib and valdecoxib, and the strengthening of prescribing advice on all anti-inflammatory drugs. COX-2 inhibitors and non-selective NSAIDs should now be used with increased caution in patients at increased cardiovascular and/or cardiorenal risk, e.g., patients with congestive heart failure, hypertension, etc. Regulatory advice and good clinical practice are to use anti-inflammatory drugs at the lowest effective dose and for the shortest possible time. There are as yet no updated official guidelines that incorporate these new data and regulatory advice. An international multidisciplinary panel, the Working Group on Pain Management, has generated new recommendations for the treatment of moderate-to-severe musculoskeletal pain. These guidelines, formulated in response to recent developments concerning COX-2 inhibitors and other NSAIDs, focus on paracetamol as the baseline drug for chronic pain management; when greater analgesia is desired, the addition of weak opioids is recommended based on a preferable GI and cardiovascular profile, compared with non-steroidal anti-inflammatory drugs.

Pain management today—optimising the benefit/risk ratio: defining the role of weak opioids and combination analgesics

Long-term use of both cyclooxygenase-2-specific (COX-2) inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with cardiovascular, gastrointestinal and cutaneous adverse events. In response, the European Medicines Agency (EMEA) and the United States Food and Drug Administration (FDA) reviewed the evidence and issued a series of recommendations for prescribers and consumers of these drugs. Labelling changes, including boxed warnings, were requested by FDA on all prescription NSAIDs, while the COX-2 inhibitors rofecoxib and valdecoxib were withdrawn from the market. These developments mean that anti-inflammatory drugs, the traditional first choice for pain management, should be used with caution in many patients with chronic pain requiring long-term pharmacological treatment. However, no official advice has been provided on alternative approaches to pain management in these patients. Against this background, a satellite symposium was organized at EULAR 2005 in Vienna entitled “Pain Management Today—Optimizing the Benefit/Risk Ratio: Defining the Role of Weak Opioids and Combination Analgesics” to review the evidence base for alternative, weak opioid-based analgesic regimens. This supplement to Clinical Rheumatology comprises papers developed based on the four keynote presentations at this symposium. The first article, by Professor Richard Langford, provides an overview of the issues currently facing prescribers managing patients with chronic pain. Regulatory authorities have advised caution when prescribing COX-2 inhibitors, particularly for patients at increased cardiovascular risk, and for long-term use, and have advised that nonselective NSAIDs be used at the lowest effective dose for the shortest duration. These warnings have left physicians seeking safer alternatives to anti-inflammatory drugs. In his paper, Professor Langford describes alternative analgesic strategies, focusing, in particular, on multimodal analgesia. Fixed-dose combinations outlined include paracetamol plus codeine, paracetamol plus dextropropoxyphene and paracetamol plus tramadol. He concludes that a re-evaluation of the role of weak opioids, particularly when used as part of a combination, may be the way forward in the management of chronic pain. The review by Professor Robert Raffa discusses the pharmacology that underlies these therapies, illustrating how atypical weak opioids, such as tramadol, can target pain through multiple sites of action, and that by combining two well-known analgesics, paracetamol and tramadol, synergistic analgesia can be achieved by complementary mechanisms of action. He also illuminates the pharmacological rationale behind combinational therapy that optimises onset and duration while minimising adverse events. In the third paper, Professor Stephan Schug describes clinical data on the combination of paracetamol plus tramadol. This combination has been extensively investigated in acute, subacute, and chronic pain, and as an add-on treatment to NSAIDs and COX-2 inhibitors, and has demonstrated striking efficacy and an acceptable level of side effects. The final paper reviews current guidelines on musculoskeletal pain management and presents new recommendations based on a consensus obtained at the second meeting of the Working Group on Pain Management (WGPM), an international multidisciplinary panel that was established in December 2004 to review alternatives to anti-inflammatory drugs in the management of moderate-to-severe pain. These guidelines highlight the role of paracetamol as the foundation for chronic pain management and, while acknowledging the importance of anti-inflammatory drugs in certain specific situations, strongly recommend the use of weak opioids and the combinations of paracetamol plus tramadol, in particular, in many chronic pain situations. Grunenthal is gratefully acknowledged for providing support for the symposium and the development and publication of this supplement.

Coxibs Versus Combination NSAID and PPI Therapy for Chronic Pain: An Exploration of the Risks, Benefits, and Costs

To systematically review studies qualitatively to compare the risks (gastrointestinal [GI] and cardiovascular) and benefits (pain control) of cyclooxygenase-2 inhibitors (coxibs) relative to an alternative therapy of a nonselective nonsteroidal antiinflammatory drug (NSAID) combined with a proton-pump inhibitor (PPI) and explore circumstances when coxibs may be appropriate. Relevant studies were identified through a search of MEDLINE (Ovid Technologies, 1985-November 2005; English language, clinical trial), PubMed (1985-November 2005; English language, clinical trial, humans), and the Cochrane Collaboration using the terms selective COX-2 inhibitors and coxibs, as well as the various chemical names for specific coxib agents. Studies that compared a coxib with a nonselective NSAID and provided data concerning our outcomes of interest were included and categorized by the outcome variable, as well as by the specific coxib studied. The majority of the numerous studies that evaluated pain as an endpoint showed no difference between coxib and nonselective NSAID therapy. However, while limited, preliminary safety data regarding the effects of both classes on the upper and lower GI tract suggest coxib superiority. Although coxibs are associated with an increased risk of cardiovascular adverse events (CVEs) compared with placebo, this effect has not been conclusively shown compared with nonselective NSAIDs. Currently, coxib therapy is more expensive than combination therapy using a nonselective NSAID plus a PPI. Compared with combination therapy including a nonselective NSAID and PPI, coxibs provide equivalent pain control and may have a lower GI tract complication profile, but at an unknown increased risk of CVEs and a greater financial cost. Coxib therapy may be an appropriate treatment for chronic pain in select patients with higher risks of GI complications, lower risk of CVEs, and in whom greater cost is not a restraint.

Non‐selective nonsteroidal anti‐inflammatory drugs and cardiovascular events: is aldosterone the silent partner in crime?

Non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) have long been known to cause gastrointestinal and renal toxicity. More recently, adverse cardiovascular effects have been associated with the selective COX-2 inhibitors. However, current studies that show an increased cardiovascular risk with non-selective NSAIDs raise the question of the exclusive contribution of COX-2 to this type of toxicity. Aldosterone, a key cardiovascular hormone, can induce deleterious effects, such as myocardial fibrosis and vascular stiffening. Non-selective NSAIDs inhibit the metabolism of aldosterone in vitro by human renal tissue, predicating an increased plasma aldosterone concentration in vivo. The question remains whether inhibition of aldosterone metabolism by non-selective NSAIDs is a casual or causal factor in NSAID-induced cardiovascular toxicity.

Increased risk of myocardial infarction as first manifestation of ischaemic heart disease and nonselective nonsteroidal anti‐inflammatory drugs

Selective cyclooxygenase (COX)-2 inhibitors have recently been implicated as enhancing risk of myocardial infarction (MI). Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective COX-2 inhibitors, so we investigated the hypothesis that they too increase risk of MI. We conducted a case-control study with direct structured interview of cases and controls. Cases were all subjects (N = 205) with a first nonfatal MI who had no previously recognized cardiovascular disease. Community controls (N = 258) were randomly selected from the same practice as the index case. Hospital controls (N = 205) were those admitted at the same time as index cases for nonmyocardial conditions not influenced by NSAID use. The effects of aspirin, NSAIDs and previously recognized influences on MI were investigated by unconditional logistic regression analysis. NSAID use was associated with an increase risk of MI with an odds ratio of 1.77 (1.03, 3.03) vs. community controls and 2.61 (1.38, 4.95) vs. hospital controls. These values were 5.00 (1.18, 21.28) and 7.66 (0.87, 67.48), respectively, in aspirin users. Results were similar when naproxen was grouped with aspirin. Odds ratios for smoking and for use of antidiabetic medication were 3.91 (2.52, 6.04) and 3.92 (1.25, 12,33), respectively, vs. community controls. Like selective COX-2 inhibitors, non-selective NSAIDs [corrected] are associated with an increased risk of MI. The extent to which this reflects interference with aspirin warrants further investigation.

Tolerance of diclofenac after hypersensitivity to celecoxib and to nabumetone

An 82-year-old woman suffering from chronic bilateral knee osteoarthritis had been treated for 2 years with rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, until its international withdrawal in September 2004, when nabumetone, a partial COX-2 inhibitor was introduced. Four days later, she experienced a generalized urticaria with buccal oedema. Nabumetone was stopped and the symptoms quickly resolved. Another COX-2 selective inhibitor, celecoxib, 200 mg daily, was introduced. Five days later, the patient suffered from high-grade fever (40 °C), diffuse burning rash without mucosal involvement, shortness of breath, headache and acute diarrhoea. Celecoxib was stopped and she was hospitalized with a severe generalized rash, bronchospasm, normal blood cell count, ASAT 107 U l–1 (<35 U l–1), ALAT 54 U l–1 (<45 U l–1), C reactive protein 280 mg l–1 (<10 mg l–1), and sterile blood and urine. All symptoms resolved within 1 week on treatment with antihistaminics and bronchodilators. The abrupt onset of fever, associated with cutaneous, hepatic and respiratory symptoms, was highly suggestive of celecoxib hypersensitivity. Knee arthralgia recurred and was resistant to level 2 analgesics. The patient insisted on resuming diclofenac, which she had tolerated well previously. As we found many reports of celecoxib tolerance in patients with allergy to diclofenac, we decided to resume diclofenac 50 mg twice a day under close monitoring. No adverse reaction was observed over 6 months of follow-up. Many studies have evaluated whether patients sensitive to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) tolerate COX-2 inhibitors. Cross-reactions to celecoxib have been reported in about 11% of them [1]. Conversely, we did not find any report that diclofenac can be safely reintroduced after COX-2 inhibitor intolerance. Among the six cases of celecoxib hypersensitivity transmitted to the French pharmacovigilance network, no rechallenge has been registered. The tolerance of nonselective NSAIDs should be cautiously evaluated in patients sensitive to COX-2 inhibitors, but further studies are needed before generalizing this recommendation.

Endoscopic Ulcers in Patients Taking Low-Dose Aspirin and NSAIDs

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin each increase the risk for endoscopic ulcers and complications, and this risk might be further increased by the simultaneous use of these drugs. Although ulcer risk is lower with cyclooxygenase (COX)-2 inhibitors than with nonselective NSAIDs, it too might be increased by the simultaneous use of low-dose aspirin. To determine the incidence of endoscopic ulcers in patients taking combinations …

An update on nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors

Selective inhibitors of the cyclooxygenase-2 enzyme were developed to treat pain and inflammation while reducing the risk of the serious gastrointestinal side effects seen with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). The results of several clinical trials have demonstrated an apparent increased risk of serious cardiovascular events in patients taking the COX-2-selective inhibitors. Although the risk was observed originally with trials conducted with rofecoxib, it was attributed generally to the entire class of COX-2-selective drugs based on a similar mechanism of action and a hypothesis that predicted the possibility of a prothrombotic effect of the drugs compared with nonselective NSAIDs. Subsequent studies have demonstrated that elevated cardiovascular risk is not limited to the use of COX-2-specific inhibitors. An increase in cardiovascular risk actually has been seen with anti-inflammatory drugs of the NSAID class, regardless of whether they are selective or nonselective inhibitors. The US Food and Drug Administration has recommended that all such drugs carry a black box warning for gastrointestinal and cardiovascular risks.

Time Course and Pattern of Blood Loss With Ibuprofen Treatment in Healthy Subjects

Nonselective nonsteroidal anti-inflammatory drug (NSAID) users are at increased risk of gastrointestinal bleeding. We aimed to assess the pattern and extent of fecal blood loss (FBL) with ibuprofen, which is considered to have a favorable gastrointestinal safety profile. We conducted a post hoc analysis of 2 separate randomized, parallel-group, double-blind studies, in which ibuprofen was used as a positive control. FBL was measured by radioactive analysis of chromium-51 labeled red cells in stools during baseline and then followed by 4 weeks of treatment with ibuprofen (800 mg 3 times daily) or placebo in 68 healthy volunteers. FBL was considered significant when blood loss was >2 mL daily. The baseline period was identical for all subjects, with an average FBL of 0.36 mL (standard deviation, +/-0.075) per day. During the study period, all subjects receiving ibuprofen had a daily mean FBL >2 mL, with a group daily mean loss 3.64-fold greater than in the placebo group (2.55 mL [+/-3.2] vs 0.7 mL [+/-0.37], P < .001). In the ibuprofen group (n = 31), 26 subjects had between 1 and 7 random episodes of microbleeding with FBL >3 mL. Nine had a maximum FBL >10 mL (29.35 +/- 23.32 mL), and in 2 subjects blood loss reached 73 mL and 66 mL, respectively. Treatment with a therapeutic dose of ibuprofen, a commonly used nonselective NSAID, in healthy subjects is associated with significant FBL, which occurs randomly with spikes of bleeding, sometimes exceeding 66 mL in a single day. Chronic anemia or gastrointestinal bleeding in patients taking nonselective NSAIDs should be thoroughly investigated.

Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications

PurposeSelective cyclooxygenase-2 (COX-2) inhibitors cause significantly fewer peptic ulcers than conventional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at low risk or high risk for peptic ulcers. On the other hand, proton pump inhibitor co-therapy has also been shown to be effective in preventing relapse of peptic ulcers in high-risk patients using nonselective NSAIDs. We compared the efficacy of a selective COX-2 inhibitor with that of proton pump inhibitor co-therapy in the reduction in the incidence of ulcer relapse in patients with a history of NSAID-related peptic ulcers. Materials and methodsFor this study, we recruited 224 patients who developed ulcer complications after NSAID use. We excluded patients who required concomitant aspirin treatment and who had renal impairment. After healing of ulcers and eradication of Helicobacter pylori, patients were randomly assigned to treatment with celecoxib 200 mg daily (n = 120) or naproxen 750 mg daily and lansoprazole 30 mg daily (n = 122) for 24 weeks. The primary endpoint was recurrent ulcer complications. ResultsDuring a median follow-up of 24 weeks, 4 (3.7%, 95% confidence interval [CI] 0.0%-7.3%) patients in the celecoxib group, compared with 7 patients (6.3%, 95% CI 1.6%-11.1%) in the lansoprazole group, developed recurrent ulcer complications (absolute difference −2.6%; 95% CI for the difference −9.1%-3.7%). Celecoxib was statistically non-inferior to lansoprazole co-therapy in the prevention of recurrent ulcer complications. Concomitant illness (hazard ratio 4.72, 95% CI 1.24-18.18) and age 65 years or more (hazard ratio 18.52, 95% CI 2.26-142.86) were independent risk factors for ulcer recurrences. Significantly more patients receiving celecoxib (15.0%, 95% CI 9.7-22.5) developed dyspepsia than patients receiving lansoprazole (5.7%, 95% CI 2.8-11.4. P = .02). ConclusionsCelecoxib was as effective as lansoprazole co-therapy in the prevention of recurrences of ulcer complications in subjects with a history of NSAID-related complicated peptic ulcers. However, celecoxib, similar to lansoprazole co-therapy, was still associated with a significant proportion of ulcer complication recurrences. In addition, more patients receiving celecoxib developed dyspepsia than patients receiving lansoprazole and naproxen.

Factors that Influence Prescribers in their Selection and use of COX-2 Selective Inhibitors as Opposed to Non-selective NSAIDs*

To identify factors that influence prescribers in their selection and use of cyclo-oxygenase-2 (COX-2) selective inhibitors as opposed to non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and report the tendency to co-prescribe gastro-protection with these agents. All 579 general practitioners (GPs) in one geographical area, Lothian, Scotland, UK. Postal questionnaires; simple and factorial designed case series questionnaire. Categorisation of responses to clinical and non-clinical factors into highly, partially or not influential. The quantitative influence of the most prominent clinical factors on prescribing choice and the tendency of co-prescription of gastro-protection with these agents. Responses from 229 (40%) GPs suggested the following as most influential: Drug Evaluation Panel recommendations, Lothian Joint Formulary, local practice formulary, history of peptic ulcer disease (PUD), history of gastro-intestinal (GI) adverse effects with NSAIDs and advanced age. Advice from other physicians, patient demand, history of alcohol gastritis, history of gastro-oesophageal reflux disease, history of functional dyspepsia, concomitant use of low dose aspirin and concomitant use of gastro-protective agents were regarded to have moderate influence. Information directly from pharmaceutical industry and regular smoking were regarded as having weak influence. An 18% response to the factorial designed questionnaire using the most prominent clinical factors suggested that history of either GI adverse effects associated with non-selective NSAIDs or PUD resulted in more pronounced increase in the frequency (15%) of decision to prescribe COX-2 selective inhibitors than advanced age (10%). Concomitant use of low dose aspirin had little effect on GPs' decisions. The mean percentage of GPs choosing to co-prescribe gastro-protection was higher with non-selective NSAIDs (64%) than with COX-2 selective inhibitors (22%). Local authoritative guidance and history of GI complications highly influenced the GPs in their use and choice of either COX-2 selective inhibitors or non-selective NSAIDs. As expected the use of gastro-protection was more frequently chosen with non-selective NSAIDs than COX-2 selective inhibitors.

Meta-analysis of Cyclooxygenase-2 Inhibitors and Their Effects on Blood Pressure

Background: Nonselective nonsteroidal antiinflammatorydrugs(NSAIDs)arewidelyprescribedand are associated with blood pressure (BP) elevation. The development of selective cyclooxygenase-2 inhibitors (coxibs) raises the issue of the magnitude of BP response compared with nonselective NSAIDs. We therefore performed a meta-analysis comparing the effects of coxibswithplacebo,nonselectiveNSAIDs,andeachother on BP elevation and hypertension. Methods: Nineteen randomized controlled trials involving coxibs were published before May 2004, with a total of 45451 participants in which BP data were available.TheCohenmethodstatisticallycombinedweighted mean difference (WMD). The Der Simonian and Laird method pooled results concerning the relative risk (RR) of developing hypertension and the RR of clinically important BP elevations. Results:Amongthetrialsanalyzed,coxibscausedaWMD point estimate increase in systolic and diastolic BP compared with placebo (3.85/1.06 mm Hg) and nonselective NSAIDs (2.83/1.34 mm Hg). Cyclooxygenase-2 inhibitors were associated with a nonsignificantly higher RRof causing hypertension compared withplacebo (RR, 1.61;95%confidenceinterval[CI],0.91-2.84;P=.10)and nonselective NSAIDs (RR, 1.25; 95% CI, 0.87-1.78; P=.23). Rofecoxib induced a WMD point estimate increase in systolic BP (2.83 mm Hg) and a nonsignificantly higher risk of developing clinically important systolic BP elevation (RR, 1.50; 95% CI, 1.00-2.26; P=.05) compared with celecoxib. Conclusions: Cyclooxygenase-2 inhibitors were associated with a point-estimate BP elevation compared with placebo and nonselective NSAIDs. There was a nonsignificantly higher incidence of developing hypertension comparedwithnonselectiveNSAIDs,aswasobservedwith rofecoxib compared with celecoxib. These BP elevations may be clinically significant in relation to increased cardiovascular risk. Arch Intern Med. 2005;165:490-496

COX-2 Selective Inhibitors in the Treatment of Arthritis: A Rheumatologist Perspective

COX-2 selective inhibitors were developed in order to provide similar efficacy to traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) but with improved upper gastrointestinal safety. This paper presents an overview of randomized clinical trials demonstrating the efficacy of COX-2 selective inhibitors for the treatment of patients with arthritis, particularly osteoarthritis and rheumatoid arthritis. In osteoarthritis and rheumatoid arthritis, COX-2 selective inhibitors have been shown to be more effective than placebo and similarly effective as standard doses of nonselective NSAIDs. There are currently few randomized clinical trials comparing the efficacy of the 2 first-generation COX-2 selective inhibitors, celecoxib and rofecoxib, in osteoarthritis. Of 4 head-to-head studies comparing the 2 agents, 3 indicated similar efficacy, while the other demonstrated superiority of rofecoxib at a dose of 25 mg qd compared with celecoxib at a dose of 200 mg qd. There are no clinical trials comparing the efficacy of different agents for treatment of patients with rheumatoid arthritis. Some studies have also demonstrated efficacy for COX-2 selective inhibitors in patients with ankylosing spondylitis and gout. In aggregate, these data show that COX-2 selective inhibitors provide effective relief of pain in patients with osteoarthritis and rheumatoid arthritis, with efficacy that is similar to traditional NSAIDs. Cost-effectiveness and cost-utility studies suggest, however, that their use should be limited to patients at high risk of serious upper gastrointestinal side effects, including complicated ulcers.

The Effects of Non-Steroidal Anti-Inflammatory Drugs (Selective and Non-Selective) on the Treatment of Periodontal Diseases

The objective was to review the literature on the effects of selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) on the treatment of periodontal diseases. A search of MEDLINE was conducted and articles published in English until December 2003 were included. The results from in vitro and animal experiments as well as from human clinical trials are presented. Non-selective cyclooxygenase-1 (COX-1) inhibitors used in periodontal research include compounds such as aspirin, flurbiprofen, ibuprofen, naproxen and piroxicam. Selective cyclooxygenase-2 (COX-2) inhibitors represent a new group of pharmaceutical products termed "coxibs" that include meloxicam, nimesulide, etodolac and celecoxib. Evidence from animal experiments and clinical trials documents that selective and non-selective NSAIDs are mainly responsible for the stabilization of periodontal conditions by reducing the rate of alveolar bone resorption. This is achieved through local inhibition of both enzymes (e.g. COX-1 and COX-2) responsible for the synthesis of arachidonic acid metabolites. Evidence shows that the effects of NSAIDs drop off rapidly after drug withdrawal. One of the major advantages of selective COX-2 inhibition is the reduction of adverse systemic effects. Although some studies present promising results, no data from long-term, multicenter prospective clinical trials are yet available for determining whether these therapeutic effects can be retained on a long-term basis. Many of these compounds, such as flurbiprofen, are readily absorbed through the gingival tissues. Therefore, the development of topical NSAIDs formulations (e.g. gels, toothpastes, rinses) with a daily application seems to be of particular interest. This may help to further reduce adverse systemic effects of non-selective NSAIDs in the long-term host modulation of periodontitis-susceptible patients.

The incidence of upper gastrointestinal adverse events in clinical trials of etoricoxib vs. non-selective NSAIDs: an updated combined analysis

ABSTRACTObjective: In spite of numerous studies demonstrating the serious gastrointestinal (GI) toxicity associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), many patients at high GI risk continue to receive prescriptions for these drugs, often without gastroprotective agents. Etoricoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than non-selective NSAIDs. We compared the incidence of upper GI Perforations, symptomatic gastroduodenal Ulcers, and upper GI Bleeding (PUBs) in a combined analysis of all randomized, double-blind, clinical trials of chronic treatment with etoricoxib versus NSAIDs completed by June 2003.Research design and methods: Data for 5441 individual subjects with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis were pooled from all 10 multinational etoricoxib trials completed by June 2003. Information on suspected PUBs was prospectively collected in all protocols, and all investigator-reported PUBs were judged by a blinded, external adjudication committee using pre-specified criteria. PUBs were analyzed using Cox proportional hazards models using terms for treatment and known PUB risk factors.Main outcome measure: The incidence of confirmed PUBs among patients treated with etoricoxib 60 mg, 90 mg, or 120 mg (combined N = 3226) was compared to that among patients treated with ibuprofen, diclofenac, or naproxen (combined N = 2215).Results: The incidence of PUBs over 44.3 months was significantly lower with etoricoxib vs. NSAIDs [cumulative incidence 1.24% vs. 2.48%, p < 0.001; rate/100 patient-years 1.00 vs. 2.47; relative risk 0.48, 95% Confidence Interval (CI) 0.32, 0.73]. Results of analysis of events occurring during the first year of treatment and subgroup analyses were consistent with the primary result.Conclusions: Treatment with etoricoxib was associated with a significantly lower incidence of PUBs than was treatment with non-selective NSAIDs. The difference was consistent in subgroups of patients defined by a variety of known risk factors.