Nonselective Nonselective Nonsteroidal Anti-inflammatory Drugs Research Articles

High-dimensional Propensity Score Adjustment in Studies of Treatment Effects Using Health Care Claims Data

Adjusting for large numbers of covariates ascertained from patients' health care claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Here, we develop and test an algorithm that empirically identifies candidate covariates, prioritizes covariates, and integrates them into a propensity-score-based confounder adjustment model. We developed a multistep algorithm to implement high-dimensional proxy adjustment in claims data. Steps include (1) identifying data dimensions, eg, diagnoses, procedures, and medications; (2) empirically identifying candidate covariates; (3) assessing recurrence of codes; (4) prioritizing covariates; (5) selecting covariates for adjustment; (6) estimating the exposure propensity score; and (7) estimating an outcome model. This algorithm was tested in Medicare claims data, including a study on the effect of Cox-2 inhibitors on reduced gastric toxicity compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). In a population of 49,653 new users of Cox-2 inhibitors or nonselective NSAIDs, a crude relative risk (RR) for upper GI toxicity (RR = 1.09 [95% confidence interval = 0.91-1.30]) was initially observed. Adjusting for 15 predefined covariates resulted in a possible gastroprotective effect (0.94 [0.78-1.12]). A gastroprotective effect became stronger when adjusting for an additional 500 algorithm-derived covariates (0.88 [0.73-1.06]). Results of a study on the effect of statin on reduced mortality were similar. Using the algorithm adjustment confirmed a null finding between influenza vaccination and hip fracture (1.02 [0.85-1.21]). In typical pharmacoepidemiologic studies, the proposed high-dimensional propensity score resulted in improved effect estimates compared with adjustment limited to predefined covariates, when benchmarked against results expected from randomized trials.

The hepatic safety and tolerability of the cyclooxygenase-2 selective NSAID celecoxib: pooled analysis of 41 randomized controlled trials

ABSTRACTObjective: To assess the hepatic safety and tolerability of celecoxib versus placebo and three commonly prescribed nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).Research design and methods: This was a retrospective, pooled analysis of a 41-study dataset involving patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, and Alzheimer's disease. Criteria for selection of studies were:(1) Randomized, parallel-group design and planned treatment duration of ≥2 weeks(2) ≥1 placebo or NSAID comparator(3) ≥1 arm with celecoxib at total daily dose of ≥200 mg(4) Data available as of October 31, 2004Data were pooled by treatment and subject from the safety analysis population of included studies. Treatment-emergent hepatobiliary adverse events (AEs) were compared for celecoxib <200 mg/day (943 patients), 200 mg/day (12 008 patients), 400 mg/day (7380 patients), and 800 mg/day (4602 patients); placebo (4057 patients); diclofenac 100–150 mg/day (7639 patients); naproxen 1000 mg/day (2953 patients); and ibuprofen 2400 mg/day (2484 patients). Hepatobiliary laboratory abnormalities were also analyzed.Results: There were no cases of liver failure, treatment-related liver transplant, or treatment-related hepatobiliary death. Incidence of serious hepatic AEs was low, with 13 (0.05%) serious hepatic AEs among 24 933 celecoxib-treated patients, and 16 (0.21%) among 7639 diclofenac-treated patients. No patients receiving celecoxib or any nonselective NSAID met criteria for Hy's rule (alanine aminotransferase [ALT] ≥3 × upper limit of normal [ULN] with bilirubin ≥2 × ULN). The incidence of notable (≥5 × ULN) and severe (≥10 × ULN) ALT elevations was similar for all treatment groups except diclofenac. Significantly fewer hepatobiliary AEs were reported for celecoxib (any dose; 1.11%) than for diclofenac (vs. 4.24%, p < 0.0001); for ibuprofen (vs. 1.53%, p = 0.06) and placebo (vs. 0.89%, p = 0.21) the incidence of AEs was comparable to celecoxib.Limitations: A number of limitations should be considered when evaluating the results: findings were limited by the quality and reporting of the studies selected; difficulty in estimating the incidence of AEs due to the low frequency of events; acetaminophen not included as an active comparator.Conclusions: In this pooled analysis, the incidence of hepatic AEs in patients treated with celecoxib was similar to that for both placebo-treated patients and patients treated with ibuprofen or naproxen, but lower than for diclofenac.

Searching for a Safe Analgesic in Patients With Cardiovascular Disease

Painful musculoskeletal conditions commonly coexist with cardiovascular disease. Older persons with elevated body mass index are at risk of degenerative arthritis, and low back pain as well as cardiovascular disease. Inflammatory arthritis, including rheumatoid arthritis, lupus, and psoriatic arthritis, are associated with an elevated risk of cardiovascular events. The overlapping epidemiology of arthritis and cardiovascular disease ensures that analgesics will always be widely prescribed to patients at risk for future cardiac events. Thus, even though the selective and some nonselective nonsteroidal antiinflammatory drugs (NSAIDs) are known to be associated with cardiac events, they are widely used even in patients with known cardiovascular disease. Article see p 155 Several randomized controlled trials comparing COX-2 selective NSAIDs (eg, celecoxib, rofecoxib, and valdeoxib) with nonselective agents or placebo found an elevated risk of cardiac events with the selective agents.1–3 The cardiac risk observed with the COX-2 selective agents appears to differ by agent and by dosage. However, a number of nonselective NSAIDs also may be associated with cardiovascular risk, such as diclofenac.4 Information about nonselective NSAID risk has primarily been derived from observational data, as few randomized controlled trials of adequate duration have examined cardiovascular risk with these agents. What can be learned from observational data regarding the cardiovascular risk of NSAIDs? Although randomized controlled trials serve as the standard for judging a drug’s efficacy, there are many reasons why trials may not be as useful for assessing toxicity. First, efficacy for arthritis is typically judged at 12 weeks of follow-up and does not require more than several hundred subjects, resulting in too little person-time to accrue adequate numbers of cardiac events. The cardiovascular risk of selective COX-2 NSAIDs was best observed in the longer-term gastrointestinal safety studies that enrolled thousands …

Pooled analysis of GI tolerability of 21 randomized controlled trials of celecoxib and nonselective NSAIDs

ABSTRACTObjective: To compare the gastrointestinal (GI) tolerability of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at approved doses in patients with common musculoskeletal conditions.Research design and methods: This was a retrospective, pooled analysis of studies selected from the Pfizer Corporate Clinical Trials Registry. Study selection criteria were: (1) Data available as of October 31, 2004; (2) Randomized, parallel-group study design and planned treatment duration of ≥ 2 weeks; (3) At least one nonselective NSAID (naproxen, ibuprofen, or diclofenac) as a comparator; (4) At least one arm with 200 mg or 400 mg celecoxib per day; (5) Patients with osteoarthritis (OA), adult rheumatoid arthritis (RA), or ankylosing spondylitis (AS).Data were pooled by treatment and by subject from the safety analysis population of each included study. Joint primary end points were the combined incidence of tolerability-related GI adverse events (AEs) (abdominal pain, dyspepsia, nausea, diarrhea, and flatulence), and time to study discontinuation due to any GI AE.Results: In all, 21 studies met the selection criteria. Across the safety analysis populations of the included studies, 7797 patients received celecoxib total daily dose 200 mg/day, 6653 received celecoxib total daily dose 400 mg/day, 2953 received naproxen, 499 received ibuprofen, and 5643 received diclofenac. Tolerability-related GI AEs were reported by significantly fewer celecoxib-treated patients (16.0%) than by those treated with naproxen (24.3%), ibuprofen (24.2%), or diclofenac (19.9%) (p < 0.0001 vs. each comparator). Time to study discontinuation due to any GI AE was significantly longer for celecoxib than for naproxen (p < 0.0001), ibuprofen (p = 0.002), or diclofenac (p = 0.048). In the RA subpopulation (n = 2857), there was no significant difference between the celecoxib and naproxen or ibuprofen groups in incidence of tolerability-related GI AEs and GI AEs.Limitations: The limitations are inherent to the retrospective analysis design.Conclusions: In this pooled analysis of celecoxib at approved doses in OA, RA, and AS, fewer celecoxib-treated patients in the overall population had tolerability-related GI AEs than patients treated with naproxen, ibuprofen, or diclofenac. In addition, celecoxib-treated patients had a significantly longer time to study discontinuation due to GI AEs.

Anti-inflammatory drugs suppress proliferation and induce apoptosis through altering expressions of cell cycle regulators and pro-apoptotic factors in cultured human osteoblasts

It has been reported that anti-inflammatory drugs (AIDs) inhibited bone repair in animal studies, and suppressed proliferation and induced cell death in rat osteoblast cultures. In this study, we further investigated the molecular mechanisms of AID effects on proliferation and cell death in human osteoblasts (hOBs). We examined the effects of dexamethasone (10 −7 and 10 −6 M), non-selective non-steroidal anti-inflammatory drugs (NSAIDs): indomethacin, ketorolac, piroxicam and diclofenac (10 −5 and 10 −4 M), and COX-2 inhibitor: celecoxib (10 −6 and 10 −5 M) on proliferation, cytotoxicity, cell death, and mRNA and protein levels of cell cycle and apoptosis-related regulators in hOBs. All the tested AIDs significantly inhibited proliferation and arrested cell cycle at G0/G1 phase in hOBs. Celecoxib and dexamethasone, but not non-selective NSAIDs, were found to have cytotoxic effects on hOB, and further demonstrated to induce apoptosis and necrosis (at higher concentration) in hOBs. We further found that indomethacin, celecoxib and dexamethasone increased the mRNA and protein expressions of p27 kip1 and decreased those of cyclin D2 and p-cdk2 in hOBs. Bak expression was increased by celecoxib and dexamethasone, while Bcl-XL level was declined only by dexamethasone. Furthermore, the replenishment of PGE1, PGE2 or PGF2α did not reverse the effects of AIDs on proliferation and expressions of p27 kip1 and cyclin D2 in hOBs. We conclude that the changes in expressions of regulators of cell cycle (p27 kip1 and cyclin D2) and/or apoptosis (Bak and Bcl-XL) by AIDs may contribute to AIDs caused proliferation suppression and apoptosis in hOBs. This effect might not relate to the blockage of prostaglandin synthesis by AIDs.

Cost-utility of celecoxib use in different treatment strategies for osteoarthritis and rheumatoid arthritis from the Quebec healthcare system perspective

Objective: To assess the cost-utility of celecoxib in three treatment strategies for arthritis in Quebec, considering both upper gastrointestinal (GI) and cardiovascular (CV) events.Methods: A Markov analytic framework was used to model patients with osteoarthritis and rheumatoid arthritis at low/average and high risk of GI and CV toxicity over 5 years with monthly cycles. Treatment strategies were modelled in line with Canadian clinical practice. In first-line treatment, patients started on celecoxib; second-line, patients started on a non-selective non-steroidal anti-inflammatory drug (NSAID) and switched to celecoxib after a first GI event; third-line, patients started on a non-selective NSAID, added a proton pump inhibitor (PPI) after a first GI event, and switched to celecoxib after a second GI event (while maintaining the PPI). Model inputs were determined through comprehensive literature searches (MEDLINE and EMBASE) from 1995 to 2006. Included studies evaluated GI (dyspepsia, uncomplicated and complicated ulcers, death) and CV (myocardial infarction, stroke, death) events. Drug and procedure costs were derived from Canadian published sources (Can$2005).Results: Total costs per patient for celecoxib first-, second-, and third-line treatment were Can$4,790, $3,390, and $3,466, and total quality-adjusted life-years (QALY) were 3.251, 3.231, and 3.230, respectively. In all risk categories, celecoxib second-line was less costly and as effective as celecoxib third-line, producing savings to the healthcare system. Although celecoxib first-line generated incremental expenditures versus celecoxib second-line, it was also more effective. The resulting cost-utility ratio for the high-risk population was Can$54,696/QALY. Based on this analytical approach, a treatment strategy where celecoxib is used before the combination of a non-selective NSAID plus a PPI possesses cost advantages for the Quebec provincial drug programme. One-way sensitivity analysis (varying GI and CV event rates, utilities, and cost) generally showed second-line treatment with celecoxib as the dominant strategy compared with third-line treatment with celecoxib.Conclusion: Although effectiveness of second- and third-line celecoxib use is similar, total cost is lower for second-line. These results suggest that the use of celecoxib before the combination of a non-selective NSAID plus a PPI is relatively cost-effective in the treatment of arthritis pain and support the full benefit listing of celecoxib in Quebec's drug programme.

Hospitalization for peptic ulcer and bleeding in users of selective COX‐2 inhibitors and nonselective NSAIDs with special reference to celecoxib

To assess the relative incidence of peptic ulcer bleeding and perforation (PUBP) in users of selective cyclooxygenase-2 (COX-2) inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This was a retrospective case-control study based on insurance claims, with chart review to confirm cases. The base population consisted of 2.2 million adult users of celecoxib, diclofenac, ibuprofen, naproxen, rofecoxib, or valdecoxib who were covered by commercial health insurance in the United States from 1999-2003. For 790 persons hospitalized for PUBP and 7887 controls, most recent NSAID/COX-2 use and a variety of medical and pharmacy risk factors were ascertained from the insurance files and analyzed by conditional logistic regression. The main outcome measure was the odds ratio (OR) associated with use of each drug by comparison to naproxen, and in successive intervals after last dispensing. Hospitalization for PUBP was highest from the date of NSAID/COX-2 dispensing through the end of an exposure period that corresponded to the days supply; the rate dropped steadily thereafter. The covariate-adjusted ORs by comparison to naproxen were: ibuprofen 0.86 (95% confidence interval (CI) 0.68, 1.09), rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66 (0.47, 0.94), valdecoxib 0.50 (0.26, 0.97), and celecoxib 0.45 (0.35, 0.58). The nonselective NSAIDs had an OR for PUBP of 1.51 (1.26, 1.98) compared to the selective COX-2 inhibitors. Nonselective NSAIDs convey half again as much risk of hospitalization for PUBP as do COX-2 inhibitors. Celecoxib users had about half the hospitalization rate of users of naproxen.

Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups

To explore the extent to which clinical characteristics influence the association between cyclooxygenase 2 inhibitors (coxibs) and/or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and increased cardiovascular disease (CVD) risk in specific patient subgroups. There is substantial concern regarding the potential cardiovascular adverse effects of selective coxibs and nonselective NSAIDs, but many patients with arthritis experience important clinical benefits from these agents. The study population consisted of Medicare beneficiaries also eligible for a drug benefits program for older adults during the years 1999-2004. We calculated the relative risk (RR) for CVD events (myocardial infarction [MI], stroke, congestive heart failure, and cardiovascular death) among users of coxibs or nonselective NSAIDs in the prior 6 months compared with nonusers. We assessed biologic interaction between these medication exposures and important patient characteristics. In the primary cohort, we identified 76,082 new users of coxibs, 53,014 new users of nonselective NSAIDs, and 46,558 nonusers. Compared with nonusers, the adjusted RR of CVD events for new users of each agent increased for rofecoxib (RR 1.22, 95% confidence interval [95% CI] 1.14, 1.30) and decreased for naproxen (RR 0.79, 95% CI 0.67, 0.93). Several patient characteristics were found to increase the risk of CVD events among users of some agents in both the primary and secondary cohorts, including age >/=80 years, hypertension, prior MI, prior CVD, rheumatoid arthritis, chronic renal disease, and chronic obstructive pulmonary disease. Rofecoxib and ibuprofen appeared to confer an increased risk in multiple patient subgroups. Many nonselective NSAIDs and coxibs are not associated with an increased risk of CVD events. However, several patient characteristics identify important subgroups that may be at an increased risk when using specific agents.

Cyclooxygenase 2-Selective and Nonselective Nonsteroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Up-Regulating Vascular NADPH Oxidases

Cyclooxygenase 2-selective inhibitors (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increase in cardiovascular events. The current study was designed to test the effect of coxibs and nonselective NSAIDs on vascular superoxide and nitric oxide (NO) production. mRNA expression of endothelial NO synthase (eNOS) and of the vascular NADPH oxidases was studied in spontaneously hypertensive rats (SHR) and in human endothelial cells. The expression of Nox1, Nox2, Nox4, and p22phox was increased markedly by the nonselective NSAIDs diclofenac or naproxen and moderately by rofecoxib or celecoxib in the aorta and heart of SHR. The up-regulation of NADPH oxidases by NSAIDs was associated with increased superoxide content in aorta and heart, which could be prevented by the NADPH oxidase inhibitor apocynin. NSAIDs reduced plasma nitrite and diminished the phosphorylation of vasodilator-stimulated phosphoprotein. This demonstrates a reduction in vascular NO production. Aortas from diclofenac-treated SHR showed an enhanced protein nitrotyrosine accumulation, indicative of vascular peroxynitrite formation. Peroxynitrite can uncouple oxygen reduction from NO synthesis in eNOS. Accordingly, the eNOS inhibitor N(G)-nitro-L-arginine methyl ester reduced superoxide content in aortas of NSAID-treated animals, demonstrating eNOS uncoupling under those conditions. Also in human endothelial cells, NSAIDs increased Nox2 expression and diminished production of bioactive NO. In healthy volunteers, NSAID treatment reduced nitroglycerin-induced, NO-mediated vasodilatation of the brachial artery. These results indicate that NSAIDs may increase cardiovascular risk by inducing oxidative stress in the vasculature, with nonselective NSAIDs being even more critical than coxibs in this respect.

Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs in High Doses Increases Mortality and Risk of Reinfarction in Patients With Prior 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. In the present study, we analyzed the risk of rehospitalization for acute myocardial infarction (re-MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with a prior myocardial infarction (MI). We included 58,432 patients discharged alive after a first MI, and subsequent use of all NSAIDs was identified from a nationwide register of drug dispensing from pharmacies. We found a dose-dependent increase in risk of death for both the selective COX-2 inhibitors and the nonselective NSAIDs (all of the drugs tested). There were trends for increased risk of re-MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs (high dosages). Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages should be used with particular caution in patients with a prior MI.

Role of nitric oxide in the gastrointestinal tract

Worldwide osteoarthritis (OA) affects more than 9.6% of men and 18% of women older that 60 years. Treatment for OA often requires chronic use of selective or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which have been associated with gastrointestinal and cardiovascular complications. An increased risk for upper gastrointestinal bleeding with NSAIDs alone and when combined with low-dose aspirin has been described in numerous studies. Although cyclo-oxygenase-2 inhibitors have been shown to carry a lower risk for gastrointestinal injury than nonselective NSAIDs, research continues to identify new treatments that not only are effective but also provide an improved benefit/risk profile, including better gastrointestinal tolerability. Nitric oxide (NO) is known to have a protective effect on the gastrointestinal tract. In preclinical studies NO was shown to help maintain gastric mucosal integrity, to inhibit leukocyte adherence to the endothelium, and to repair NSAID-induced damage. In addition, epidemiologic studies have shown that the use of NO-donating agents with NSAIDs or aspirin resulted in reduced risk for gastrointestinal bleeding. Recent studies have shown that cyclo-oxygenase inhibiting NO-donating drugs (CINODs), in which a NO molecule is chemically linked to an NSAID, are effective anti-inflammatory agents and may result in less gastrointestinal damage than is associated with NSAID use. Therefore, these agents provide a potential therapeutic option for patients with arthritis who require long-term NSAID therapy.

Management Options for Patients with Aspirin and Nonsteroidal Antiinflammatory Drug Sensitivity

To evaluate and provide management strategies for patients with aspirin or nonselective nonsteroidal antiinflammatory drug (NSAID) sensitivity. Literature retrieval was accessed through MEDLINE (1966-March 2007) using the terms acetaminophen, aspirin, antiinflammatory agents nonsteroidal, urticaria, angioedema, asthma, leukotriene antagonists, desensitization, and tacrolimus. Article references retrieved were hand-searched for other relevant articles. All studies published in English were evaluated. Studies, review articles, and commentaries on aspirin-induced asthma and aspirin- or NSAID-induced urticaria/angioedema were included in the review. Aspirin sensitivity is most often manifested as respiratory reactions (eg, bronchospasm, profuse rhinorrhea, conjunctival injection) or urticaria/angioedema. The primary mechanism is believed to be inhibition of the cyclooxygenase 1 (COX-1) enzyme; as such, patients with aspirin sensitivity often display cross-reactions to nonselective NSAIDs that inhibit the COX-1 enzyme. Management strategies include avoidance of aspirin and cross-reacting nonselective NSAIDs. However, desensitization to aspirin is a viable option for patients with aspirin-induced respiratory reactions, especially for those who require aspirin for thromboembolic prophylaxis. Aspirin desensitization is maintained indefinitely with a daily aspirin dose. There is limited evidence of the use of leukotriene modifiers in preventing aspirin-induced asthma. COX-2 selective NSAIDs, especially in patients with aspirin-induced asthma, have not been found to cross-react. However, approximately 4% of patients with a history of aspirin-induced skin reactions may experience a cutaneous reaction following a challenge to a COX-2 selective NSAID. Since acetaminophen is a weak inhibitor of the COX-1 enzyme, patients with aspirin-induced asthma should not take more than 1000 mg of acetaminophen in a single dose. Management of patients with aspirin/NSAID sensitivity includes avoidance of aspirin/nonselective NSAIDs, use of COX-2 selective NSAIDs, acetaminophen in doses less than 1000 mg, and desensitization. The role of leukotriene modifiers requires further study before they can be recommended for patients.

Nonselective Nonsteroidal Antiinflammatory Drugs and Cardiovascular Risk: Are They Safe?

To assess possible cardiovascular risks associated with use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs). MEDLINE and EMBASE were searched from January 1985 through April 2007 and relevant studies were retrieved. Peer-reviewed, prospective, double-blind, case-control, and cohort-design studies published in the English language literature were considered eligible for review. Previous meta-analyses and systematic reviews were also analyzed. In total, 17 case-control studies; 9 cohort studies; 1 prospective, double-blind study; 3 meta-analyses; and 1 systematic review of observational studies were identified. Three studies were prospective and the remainder consisted of observational, retrospective studies, with most reporting acute fatal or nonfatal myocardial infarction as the cardiovascular endpoint. Among the nonselective NSAIDs, diclofenac appears to pose the highest risk for cardiovascular toxicity; other agents trend toward a neutral effect with respect to cardiovascular risk. Although the data are suggestive, it remains unclear whether naproxen provides protective cardiovascular effects among patients on chronic therapy. Currently available data are insufficient for defining evidence-based clinical guidelines for the use of NSAIDs, and the need for additional research, specifically randomized controlled trials, is evident. Diclofenac demonstrates a significant risk while naproxen appears to pose the lowest, albeit nonsignificant, risk for cardiovascular morbidity. Although the current clinical evidence may not warrant recommending naproxen as the preferred NSAID treatment, it may be prudent to avoid diclofenac for patients with cardiovascular risk factors requiring NSAID treatment.

Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization

ABSTRACTObjective: Cyclo-oxygenase-2 (COX-2) inhibitors rofecoxib and valdecoxib were withdrawn from the market because of their association with cardiovascular problems. There is a lack of information on the impact of the COX-2 inhibitors withdrawal on the prescribing and utilization of related drugs. The main objective of this study was to evaluate to what extent prescriptions of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and gastroprotective drugs changed after the removal of the two COX-2 inhibitors.Research design and methods: A segmented regression of interrupted time series approach was used to analyze prescription data from July 1, 2003 through December 31,2005 from a pharmacy claims database maintained by a large pharmacy benefit manager (PBM). Patients continuously eligible for the pharmacy benefit but not enrolled in COX-2 or proton pump inhibitor (PPI) Step Care programs during the study period were included. The number of prescriptions per thousand patients per month for targeted drugs were analyzed and compared.Results: A total of 175 193 patients were included in the analysis. After the withdrawal of the COX-2 inhibitor, the average monthly non-selective NSAID and PPI prescriptions per thousand patients increased from 13.96 to 19.63 (a change of 40.62%, p < 0.0001) and from 38.67 to 43.33 (a change of 12.05%, p < 0.0001) respectively, whereas COX-2 prescriptions decreased by 54.51% (from 23.61 to 10.74, p < 0.0001). Among non-selective NSAIDs, the five drugs with highest percentage increase were meloxicam (167.12%, from 1.46 to 3.90, p < 0.0001), etodolac (72.06%, from 0.68 to 1.17, p < 0.0001), piroxicam (58.33%, from 0.36 to 0.57, p < 0.0001), nabumetone (52.38%, from 1.26 to 1.92, p < 0.0001), and diclofenac (37.89%, from 1.61 to 2.22, p < 0.0001).Limitations: This study was restricted to patients with employer-sponsored drug coverage which might not be representative of the national population. Since over-the-counter (OTC) PPI, non-selective NSAID and H2RA were not captured in our claims data, we were unable to examine whether and to what extent the utilization of these drugs has changed. Additionally, the direct impact of these changes on population based outcomes is unknown.Conclusions: After the withdrawal of COX-2 inhibitors rofecoxib and valdecoxib, there were significant increases in non-selective NSAID and PPI prescriptions but not H2RA and misoprostol. Given the safety concerns with the NSAIDs, further studies are warranted regarding the clinical outcomes associated with the increased use of non-selective NSAIDs with or without gastroprotective agents.

Gastrointestinal Safety of Cyclooxygenase-2 Inhibitors: A Cochrane Collaboration Systematic Review

Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors (COX-2s) are used to treat a variety of arthritic and inflammatory conditions. The aim of this study was to assess the upper gastrointestinal (GI) harms of the long-term use of COX-2s, compared with nonselective NSAIDs and placebo, in arthritis sufferers. A systematic review of randomized controlled trials (RCTs) was conducted. Searches were conducted in (1) Cochrane Central Register of Controlled Trials (CENTRAL), (2) the Cochrane Collaboration Library (2005), (3) MEDLINE (to December 2006), and (4) Excerpta Medica Database (EMBASE) (to June 2005). Reference lists from trials and abstracts of conference proceedings were searched by hand, and experts were contacted to identify further relevant trials. RCTs of celecoxib, rofecoxib, etoricoxib, valdecoxib, and lumiracoxib were included if they reported on endoscopic ulcers, clinically important ulcer complications, or adverse gastrointestinal (GI) symptoms with the use of these COX-2s, compared with placebo or with nonselective NSAIDs. Study selection and data extraction were performed in duplicate by independent reviewers. Data were analyzed by using Review Manager 4.2 in accordance with accepted meta-analysis techniques. Compared with nonselective NSAIDs, COX-2s produced significantly fewer gastroduodenal ulcers (relative risk, 0.26; 95% confidence interval, 0.23-0.30) and clinically important ulcer complications (relative risk, 0.39; 95% confidence interval, 0.31-0.50), as well as fewer treatment withdrawals caused by GI symptoms. The co-administration of acetylsalicylic acid appears to reduce the GI safety of COX-2s in subgroup analyses. COX-2s appear to offer greater upper GI safety and are better tolerated than nonselective NSAIDs. The co-administration of acetylsalicylic acid might reduce the safety advantage of COX-2s over that of nonselective NSAIDs.

Upper GI Complications with Coxibs or Nonselective NSAIDs

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with three- to fivefold increased risk for upper gastrointestinal (UGI)

Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors

AbstractThe cardiovascular safety of COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has recently been called into question. The factors that predispose to adverse events by NSAIDs are unknown. Because patients with arthritis have decreased nitric oxide (NO) bioavailability, the in vivo effects of NSAIDs on murine vascular tone and platelet activity in the presence or absence of NO were examined. Here, we show that acute hypertensive and prothrombotic activities of the COX-2–selective inhibitor celecoxib are revealed only after in vivo inhibition of NO generation. The nonselective NSAID indomethacin was hypertensive but antithrombotic when NO was absent. In vitro myography of aortic rings confirmed that vasoconstriction required inhibition of both NOS and COX-2 and was abolished by supplementation with exogenous NO. These data indicate that NO suppresses vascular side effects of NSAIDs, suggesting that risk will be greatest in patients with impaired vascular function associated with decreased NO bioavailability.

Do selective COX-2 inhibitors increase the risk of cerebrovascular events? A meta-analysis of randomized controlled trials

To evaluate the risk of cerebrovascular events (CVEs) associated with selective cyclooxygenase-2 inhibitors (coxibs). Systematic review and meta-analysis of randomized controlled trials (RCTs). A fixed-effect model was used to estimate the odds ratios (ORs) for risk of CVE associated with coxibs compared against placebo, non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and other coxibs. Forty trials (88 116 patients) were included in the meta-analysis. The overall pooled OR for CVE for any coxib against placebo was 1.03 (95% CI: 0.71, 1.50). Comparing individual coxibs against placebo, we found that celecoxib, rofecoxib, etoricoxib and lumiracoxib were associated with higher CVE risks and valdecoxib was associated with a lower CVE risk, although there were no significant differences detected. There was also no significant difference in risk of CVE when comparing coxibs against any non-selective NSAIDs; the corresponding pooled OR was 0.86 (95% CI: 0.64, 1.16). On the basis of a detailed analysis of available RCTs, there does not appear to be any significant difference in risk of CVEs associated with coxibs when compared against placebo or non-selective NSAIDs. It is likely that the increased risk of thrombotic vascular events associated with coxibs is largely attributable to an increased risk of myocardial infarction, rather than CVEs.

Simultaneous assessment of short‐term gastrointestinal benefits and cardiovascular risks of selective cyclooxygenase 2 inhibitors and nonselective nonsteroidal antiinflammatory drugs: An instrumental variable analysis

To simultaneously assess the short-term reduction in risk of gastrointestinal (GI) complications and increase in risk of acute myocardial infarction (MI) by celecoxib compared with rofecoxib and several nonselective nonsteroidal antiinflammatory drugs (NSAIDs) using instrumental variable analysis. A population of 49,711 Medicare beneficiaries ages 65 years and older who initiated nonselective NSAID or selective cyclooxygenase 2 inhibitor therapy between January 1, 1999, and December 31, 2002, was identified. The increase in risk of GI complications and MI within 180 days after initiation of NSAID (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) therapy was assessed using instrumental variable analysis. Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] -0.20, 3.01) and diclofenac (RD 6.07, 95% CI -0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD -0.30, 95% CI -2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs. In this instrumental variable analysis, diclofenac and rofecoxib had the least favorable benefit-risk balance among NSAIDs in older adults.

Les AINS sont-ils susceptibles de compromettre l’efficacité cardiopréventive de l’aspirine?

Some studies have recently suggested a potential pharmacodynamic interaction between aspirin and some non-selective non-steroidal anti-inflammatory drugs (NSAIDs). We have evaluated the reality of this pharmacodynamic interaction and analyse its clinical pertinence.Literature review (Medline search - December 2005).Several ex vivo studies show that some non-selective NSAIDs can block the active site of Cox1 thus preventing aspirin from exerting its platelet anti-aggregating cardio-preventive action. Cox2 selective molecules do not act at this site. The few studies, mainly case reports, have analysed the potential loss of the cardiovascular preventive benefit of aspirin in patients receiving concomitantly non-selective anti-inflammatory drugs with controversial results.It seems necessary to know the existence of this pharmacodynamic interaction between aspirin at a low dose and some non-selective anti-inflammatory drugs notably ibuprofen and naproxen. In the absence of a clear clinical demonstration, it is advisable to avoid the non-selective NSAIDs in patients treated with a low dose of aspirin. It might be advisable to switch to an anti-aggregating treatment other than aspirin (clopidrogel, etc.) in these cases. At the present time, however, there are no data on which to base such a recommendation.