Are COX-2 Selective NSAIDs Associated with Less GI, Renal, and Cardiovascular Side Effects: Evidence from Animals Treated with NSAIDs

Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat both acute and chronic pain in animals, especially when the pain is resulted from inflammatory conditions. NSAIDs work by inhibition of cyclooxygenases (COX) enzymes and reduce the production of key inflammatory mediators prostaglandins and associated chemicals. Prostaglandins have important roles in pain signalling and haemostasis, including platelet aggregation and gastric mucosal protection. There are two known isoforms of cyclooxygenases enzymes, namely COX-1 and COX-2. Notable adverse effects commonly resulted from NSAIDs uses include gastrointestinal ulceration, compromised haemostasis and renal toxicity, which are due to inhibition of COX-1 isoform. Despite the development of COX-2 selective medicines and continuing effort to improve the safety of NSAIDs in routine veterinary practice, adverse effects of NSAIDs still exist and require closed monitoring. This study aims to summarise and evaluate the current literature on reported adverse effects of NSAIDs used in animals and to compare COX-2 selective versus non-selective agents. Methodology: Literature on reported adverse effects of NSAIDs used in animals over the last decade has been systematically reviewed. Some older sources from the primary literature search have also been included to determine the background information leading to current rationale behind NSAIDs’ therapeutic uses, dosage and route of administration, observed adverse effects and COX-2 selective versus non-selective agents. The primary focus of this study is NSAIDs administered to animals in prospective randomised placebo-controlled blinded trials. Results: A total of 12 studies that met the inclusion criteria were included in the review, with total 13 NSAIDs being discussed, including meloxicam, phenylbutazone, deracoxib, carprofen, aspirin, firocoxib, vedaprofen, etorolac, ketoprofen, tepoxalin, rofecoxib, licofelone and flunixin. It was found that there were variable findings in comparing the adverse effects associated with COX-2 selective NSAIDs and non-selective NSAIDs. COX-2 selective NSAIDs have been found associated with no adverse effects in some studies and minimal adverse effects in other studies. Severe adverse effects were reported for COX-2 selective NSAID administered at higher than recommended doses or for a long duration and some studies reported reduced adverse effects in COX-2 selective NSAIDs when compared to non-selective NSAIDs. Overall, gastrointestinal adverse effects were predominantly reported, followed by adverse findings relating to haemostasis and renal function. Conclusion: Collectively, the findings suggest COX-2 selective NSAIDs provide a clinically useful improvement over non-selective NSAIDs as well as reduce adverse effects when given at recommended dose.

Cost-effectiveness of Non-steroidal Anti-inflammatory Drugs Adjusting for Upper and Lower Gastrointestinal Toxicities in Rheumatoid Arthritis Patients

OBJECTIVE: This study was performed to assess the cost-effectiveness of cyclooxygenase-2 (COX2)-selective inhibitor, non-selective non-steroidal anti-inflammatory drugs (NSAIDs), and non-selective NSAID with proton pump inhibitors (PPIs) while considering upper and lower gastrointestinal (GI) safety in patients with rheumatoid arthritis (RA). METHODS: A Markov model was used to estimate the costs and effectiveness. Estimates of therapeutic efficacy and upper/lower GI safety were based on results from large randomized controlled trials. The main outcome measure was cost effectiveness, based on the quality-adjusted life years (QALYs) gained. Safety parameters included clinical upper GI symptoms, uncomplicated ulcer, upper GI bleeding, upper GI perforation, clinical lower GI symptoms, lower GI bleeding, and lower GI perforation. Cost data were obtained from patients treated in a tertiary referral center in Korea. RESULTS: The expected three year cost was 3,052,800 Korean won (KRW) for COX2-selective inhibitor, 3,170,800 KRW for nonselective NSAID, and 3,325,900 KRW for non-selective NSAID with PPI. QALYs were 2.87446, 2.85320, and 2.85815, respectively. The total cost for COX2-selective inhibitor use was lower than non-selective NSAID, but QALY was higher, indicating that the incremental cost effectiveness ratio of COX2-selective inhibitor is superior. CONCLUSION: COX2-selective inhibitor has reasonable cost-effectiveness adjusted for upper and lower GI toxicity for patients with RA in Korea.

Efficacy and safety of parecoxib in the treatment of acute renal colic: a randomized clinical trial

PURPOSE: Although nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) and opioids are effective treatments for acute renal colic, they are associated with adverse events (AEs). As cyclooxygenase-2 selective NSAIDs may provide a safer alternative, we compared the efficacy and safety of parecoxib versus an nsNSAID in subjects with acute renal colic. MATERIALS AND METHODS: Phase IV., multicenter, double-blind, noninferiority, active-controlled study: 338 subjects with acute renal colic were randomized to parecoxib 40 mg i.v. plus placebo (n = 174) or ketoprofen 100 mg IV plus placebo (n = 164). 338 subjects with acute renal colic were randomized to parecoxib 40 mg IV (n = 174) or ketoprofen 100 mg IV(n = 164) plus placebo. Subjects were evaluated 15, 30, 45, 60, 90 and 120 minutes after treatment start and 24 hours after discharge. Primary endpoint was the mean pain intensity difference (PID) at 30 minutes by visual analog scale (VAS) (per-protocol population). An ANCOVA model was used with treatment group, country, and baseline score as covariates. Non-inferiority of parecoxib to ketoprofen was declared if the lower bound of the 95 percent confidence interval (CI) for the difference between the two groups excluded the pre-established margin of 10 mm for the primary endpoint. RESULTS: Baseline demographics were similar. The mean (SD) mPID30 min was 33.84 (24.61) and 35.16 (26.01) for parecoxib and ketoprofen, respectively. For treatment difference (parecoxib-ketoprofen) the lower bound of the 95 percent CI was 6.53. The mean change from baseline in VAS 30 minutes after study medication was ~43 mm; AEs were comparable between treatments. CONCLUSIONS: Parecoxib is as effective as ketoprofen in the treatment of pain due to acute renal colic, is well tolerated, and has a comparable safety profile.

The Use of COX-2 Selective Nonsteroidal Anti-inflammatory Drugs for the Treatment of Osteoarthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs), are characterized by their anti-inflammatory, analgesic, and antipyretic activities; they have been widely used for the management of acute pain and chronic inflammation. The mechanism of action of NSAIDs is inhibition of prostaglandin biosynthesis. Inflammatory prostaglandins are primarily derived from COX-2, while the prostaglandins formed by COX-1 have in general a more homeostatic role. Based on their selectivity for COX-1 or COX-2, NSAIDs are classified into non-selective NSAIDs and COX-2 selective NSAIDs. Non-selective NSAIDs and COX-2 selective NSAIDs have similar effects on pain relief and inflammation. One major problem associated with the use of non-selective NSAIDs is their adverse effects on the gastrointestinal tract, caused by inhibition of COX-1. Compared with non-selective NSAIDS, the main advantage of COX-2 selective NSAIDs is reduced gastrointestinal complications. Reviews have suggested that COX-2 selective NSAIDs increase the risk of cardiovascular events; however, cardiovascular risk may vary among the selective NSAIDs. Because of their anti-inflammatory properties, the use of NSAIDs is essential for the relief of pain and the symptoms associated with inflammatory conditions such as active osteoarthritis. When NSAIDs are prescribed, age, additional medication such as aspirin, gastrointestinal and cardiovascular status, and co-morbidity must be taken into account. COX-2 selective NSAIDs have minimal effects on platelet function and thus, can also be used for pre and postoperative pain control in patients with osteoarthritis waiting for the surgery.

Cyclooxygenase-2 Inhibitors and Cardivascular Risk / 한양의대학술지

Serious concerns about the cardiovascular safety of rofecoxib had been present since the VIOXX(R) Gastrointestinal Outcomes Research (VIGOR) study first suggested that the drug may increase the risk of myocardial infarction. Subsequent data from major observational studies further implicated the association of rofecoxib with arterial thromboembolic disease. In September 2004, rofecoxib was withdrawn from the worldwide market based on the safety findings of the Adenomatous Polyp Prevention on VIOXX (APPROVe) study, which indicated an increase risk of myocardial infarction and stroke among subjects randomized to rofecoxib. In December 2004, the results of the Adenoma Prevention with Celecoxib (APC) study demonstrated a dose-related increase in the risk of cardiovascular events among patients randomized to celecoxib when compared with placebo. Two other large prospective prevention studies of celecoxib, the Prevention of Spontaneous Adenomatous Polyps (Pre SAP) trial and the Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT) did not show any sign of increased cardiovascular risk. None of the reported randomized trials studying any COX-2 selective imhibitor, thus far, has been specifically designed to examine cardiovascular outcomes. Hence, no cardiovascular hypotheses have yet been formally tested. Long-term and adequately powered prospective randomized clinical trials in relevant patient populations with clinically appropriate pre-specified cardiovascular end-points, ideally comparing COX-2 selective inhibitors with traditional NSAIDs, are required. Until these trials are completed, careful risk:benefit analysis of any putative increase in cardiovascular risk versus known gastrointestinal benefit for individual agents needs to be undertaken.