Prescriptions For Celecoxib Research Articles

Does Celecoxib Prescription for Pain Management Affect Post-tonsillectomy Hemorrhage Requiring Surgery? A Retrospective Observational Cohort Study.

Adenotonsillectomy and tonsillectomy (referred to as tonsillectomy hereafter) are common pediatric surgeries. Postoperative complications include hemorrhage requiring surgery (2 to 3% of cases) and pain. Although nonsteroidal anti-inflammatory drugs are commonly administered for postsurgical pain, controversy exists regarding bleeding risk with cyclooxygenase-1 inhibition and associated platelet dysfunction. Preliminary evidence suggests selective cyclooxygenase-2 inhibitors, for example celecoxib, effectively manage pain without adverse events including bleeding. Given the paucity of data for routine celecoxib use after tonsillectomy, this study was designed to investigate the association between postoperative celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery using chart-review data from the Children's Hospital of Eastern Ontario. After ethics approval, a retrospective single-center observational cohort study was performed in children less than 18 yr of age undergoing tonsillectomy from January 2007 to December 2017. Cases of adenoidectomy alone were excluded due to low bleed rates. The primary outcome was the proportion of patients with post-tonsillectomy hemorrhage requiring surgery. The association between a celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery was estimated using inverse probability of treatment weighting based on propensity scores and using generalized estimating equations to accommodate clustering by surgeon. An initial patient cohort of 6,468 was identified, and 5,846 children with complete data were included in analyses. Median (interquartile range) age was 6.10 (4.40, 9.00) yr, and 46% were female. In the cohort, 28.1% (n = 1,644) were prescribed celecoxib. Among the 4,996 tonsillectomy patients, 1.7% (n = 86) experienced post-tonsillectomy hemorrhage requiring surgery. The proportion with post-tonsillectomy hemorrhage requiring surgery among patients who had a tonsillectomy and were or were not prescribed celecoxib was 1.94% (30 of 1,548; 95% CI, 1.36 to 2.75) and 1.62% (56 of 3,448; 95% CI, 1.25 to 2.10), respectively. Modeling did not identify an association between celecoxib prescription and increased odds of post-tonsillectomy hemorrhage requiring surgery (odds ratio = 1.4; 95% CI, 0.85 to 2.31; P = 0.20). Celecoxib does not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery, after adjusting for covariates. This large pediatric cohort study of celecoxib administered after tonsillectomy provides compelling evidence for safety but requires confirmation with a multisite randomized controlled trial.

Differentiated approach to the treatment of musculoskeletal pain: higher doses of analgesics provide a better effect. A brief narrative review

Effective pain control is one of the main goals in the treatment of patient with musculoskeletal disorders. The main suffering of patients is associated with pain: decrease in working capacity and quality of life, disability and severe psycho-emotional disturbances. The pathogenesis of musculoskeletal pain is complex and includes damage (due to an autoimmune process, mechanical or metabolic stress), inflammation, peripheral and central sensitization, degenerative processes (neoangiogenesis, heterotopic ossification, fibrosis), muscle tension, psychoemotional disorders (depression, anxiety), negative behavioral reactions. Pain treatment should be comprehensive and include pharmacotherapy as well as non-pharmacological therapy and rehabilitation methods.Nonsteroidal anti-inflammatory drugs (NSAIDs) are at the forefront of pain treatment. They are effective, convenient and affordable, but can cause a wide range of complications. A personalized approach to pain management is therefore based on the choice of the “right” NSAID. Based on the balance between efficacy and safety, celecoxib can be considered the first choice. It has an extensive evidence base confirming its therapeutic potential in acute pain, osteoarthritis, chronic back pain, systemic rheumatic diseases and other pathologies, as well as a relatively low risk of gastrointestinal and cardiovascular complications. The prescription of celecoxib should be personalized: for severe pain and systemic rheumatic diseases, treatment should be started with a dose of 400 mg/day (600 mg can be used on the first day), followed by a transition to a maintenance dose of 200 mg/day once pain control is achieved.

Efficacy of Anti-inflammatory Treatment Versus Rescue Analgesia After Arthroscopic Partial Meniscectomy in Nonarthritic Knees: A 3-Arm Controlled Study.

Background:There is currently no consensus regarding the appropriate treatment for postoperative pain after arthroscopic partial meniscectomy (APM). Prescribing a mild non–anti-inflammatory protocol of rescue analgesia may be sufficient to avoid the side effects of opioids or anti-inflammatories.Purpose/Hypothesis:The purpose was to compare the efficacy of pain reduction after APM in nonarthritic knees using betamethasone or celecoxib as anti-inflammatory analgesics versus acetaminophen or tramadol as rescue analgesics. The hypothesis was that there is no advantage for anti-inflammatories in achieving postoperative immediate pain relief after APM in nonarthritic knees compared with a simple nonopioid treatment.Study Design:Cohort study; Level of evidence, 2.Methods:This 3-arm controlled study evaluated postoperative pain levels and analgesic consumption in patients who underwent primary APM (under general anesthesia) at a single institution from December 2018 to December 2019. Patients were prospectively divided into 3 treatment groups: (1) betamethasone injection at the end of the procedure, (2) oral celecoxib prescription, or (3) neither treatment (control). All groups were instructed to take supplementary acetaminophen as needed. Patients were also allowed to take tramadol as needed to evaluate the need for opioids. At postoperative weeks 1, 2, and 3, patients completed the Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale, and results were compared between time points and groups.Results:A total of 99 patients were included in the treatment groups: betamethasone group (32 patients), celecoxib group (30 patients), and control group (37 patients). At baseline, there were no statistically significant differences between the groups in age, sex, body mass index, level of activity, comorbidities, or surgical findings. KOOS Pain scores improved at every time point for all 3 groups (P < .001), and no differences in scores were observed among groups. The consumption of acetaminophen or tramadol as rescue analgesia throughout the follow-up period was negligible among groups.Conclusion:During the first 3 postoperative weeks after APM in nonarthritic knees, pain was efficiently controlled by betamethasone or celecoxib; however, pain was also efficiently controlled by minimal consumption of acetaminophen with negligible use of tramadol. Therefore, acetaminophen could be prescribed as an effective first-line postoperative analgesic after APM.

Cardiovascular Safety of Celecoxib after Cardiac Surgery with Cardiopulmonary Bypass: A Retrospective Cohort Study.

Cardiac surgery is a highly invasive procedure resulting in hypercoagulability due to thoracotomy and cardiopulmonary bypass (CPB). The long-term use of selective cyclooxygenase-2 inhibitors has been shown to increase the risk of adverse cardiovascular (CV) events such as myocardial infarction. This study aimed to determine whether short-term prescription of celecoxib increases CV events in patients who have undergone cardiac surgery with CPB. This retrospective observational study included 16,141 patients (≥20 years) who had undergone cardiac surgery with CPB between April 1, 2008 and March 31, 2016. Patients who underwent coronary artery bypass grafting were excluded. Patients who received celecoxib (n = 904) and acetaminophen (n = 5,002) from postoperative day 0 to 30 were extracted and matched by propensity score (PS). The primary outcomes were all-cause death and CV events, defined as coronary artery disease, ischemic stroke, pulmonary embolism, and venous thrombosis, coded using International Classification of Diseases-10 within 30 days after the first postoperative prescription of either medication. Results were assessed using Kaplan-Meier survival analysis and multivariate Cox regression analysis. PS matching created 885 pairs. Multivariate Cox regression analysis showed that prescription of celecoxib after cardiac surgery was not associated with an increase in the primary outcomes when compared with prescription of acetaminophen (hazard ratio, 0.76; 95% confidence interval, 0.35-1.65). The prescription of celecoxib in patients who had undergone cardiac surgery with cardiopulmonary bypass was not statistically different from the prescription of acetaminophen in the incidence of CV events and death.

Celecoxib for the treatment of musculoskeletal arthritis

ABSTRACTIntroduction: The cyclooxygenase (COX)-2 inhibitor celecoxib is an approved compound for rheumatoid (RA) and osteoarthritis (OA), combining both anti-inflammatory and analgesic properties with a good gastrointestinal tolerability.Areas covered: This article covers the pharmacological properties and clinical efficacy as well as the latest safety data available for celecoxib with emphasis on the treatment of RA and OA. It is based primarily on a current literature search on PubMed and Web of Science, but also on the professional rheumatological expertise of the authors.Expert opinion: Celecoxib has been shown to be superior to placebo and equivalent to traditional non-steroidal anti-inflammatory drugs (tNSAIDs). Many studies have been published making celecoxib a good and safe treatment option in particular in moderate arthritis and patients without established cardiovascular (CV) disease. Moreover, older patients might gain significant benefits compared to tNSAIDs due to reduced gastrointestinal events even when having a history of ulcer bleedings. Nonetheless, there is still much to learn, especially regarding the prescription of celecoxib in patients with cardiovascular co-morbidities. While low doses seem to be safe according to present data, the knowledge on the more effective, higher doses >400 mg/day is still limited.

Use of celecoxib correlates with increased relative risk of acute pancreatitis: a case-control study in Taiwan.

This study evaluated whether there is an association between the use of celecoxib and acute pancreatitis in Taiwan. We conducted a case-control study using the database of the Taiwan National Health Insurance Program. The participants comprised 5,095 subjects, aged 20-84 years, with a first admission episode of acute pancreatitis from 2000 to 2011 as the cases and 20,380 randomly selected sex-matched and age-matched subjects without acute pancreatitis as the controls. The absence of celecoxib prescription was defined as "never used." Current use of celecoxib was defined as subjects who had received at least one prescription for celecoxib within 3 days before diagnosis with acute pancreatitis. A multivariate unconditional logistic regression model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for acute pancreatitis associated with the use of celecoxib. Compared with subjects who never used celecoxib, the adjusted OR of acute pancreatitis was 5.62 in subjects with current use of celecoxib (95% CI=3.33-9.46). The current use of celecoxib is associated with an increased risk of acute pancreatitis.

Fluvoxamine and celecoxib may have caused adverse events in an elderly patient

FLUVOXAMINE, WHICH DOES not have anticholinergic activity, is suitable for elderly patients. Selective serotonin re-uptake inhibitors (SSRI), however, are metabolized by and inhibit isozymes of cytochrome P450 (CYP).1 Therefore, when SSRI are prescribed, drug interactions are a concern. Here we report the case of an elderly patient whose mental state had been controlled by fluvoxamine for several years, and who developed delirium following the additional prescription of celecoxib. Informed consent was obtained from her proxy. The patient was a 94-year-old woman at the time of the present episode. Six years previously she had become amnesic, and her daily life had been supported by her family. She was anxious because of the amnesia. At 4 years before the present episode she was referred to Showa University Fujigaoka Hospital. Her score on the Revised Hasegawa Dementia Scale was 25. We diagnosed her with Alzheimer's disease. Because her cognitive functions were relatively preserved, we decided to treat her anxiety first. Therefore, we prescribed fluvoxamine (25 mg) to be taken after dinner. Subsequently, her mental state was stable for 4 years. Just before the present episode she developed a swelling in her ankle due to arthritis for which celecoxib was prescribed by another physician, without knowledge of her fluvoxamine medication history. On the first night of taking both medications, she became restless and said ‘I should go to work,’ and tried to leave her home. Her family was upset and stopped both medications. However, because she became irritable and her ankle was swollen, they restarted fluvoxamine, and her physician changed her prescription from celecoxib to loxoprofen. Since then, her mental state and ankle swelling have improved. This episode was narrated to us by her proxy once she started recovering. Therefore, we cannot elucidate the true nature of the symptoms. We suggest, however, that this condition was caused by drug interaction. Because fluvoxamine is metabolized by1 and celecoxib inhibited the CYP2D6 enzyme,2 blood concentrations of fluvoxamine seem to be increased by celecoxib. The time at which maximum concentration occurs for fluvoxamine and celecoxib is approximately 5 h and 2 h after oral intake, respectively. The plasma half-life of celecoxib is 5 h. When the patient took this medication around 8 pm, the concentration of fluvoxamine may have reached a peak and the concentration of celecoxib may have reached half of its peak by midnight. Therefore, the blood concentration of fluvoxamine reached toxic levels because of inhibition of CYP2D6 by celecoxib. Moreover, loxoprofen does not inhibit the CYP2D6 enzyme and is not metabolized by the CYP1A2 enzyme. Therefore, loxoprofen and fluvoxamine do not interact. Although we have not found any reports on this issue, SSRI should be carefully prescribed when combined with other medicines, particularly in elderly patients.

Cardiovascular disease and non‐steroidal anti‐inflammatory drug prescribing in the midst of evolving guidelines

Responding to safety concerns, the American Heart Association (AHA) published guidelines for non-steroidal anti-inflammatory drug (NSAID) use in patients with pre-existing cardiovascular disease (CVD) during 2005 and revised them in 2007. In the revision, a stepped approach to pain management recommended non-selective NSAIDs over highly selective NSAIDs. This research evaluated NSAID prescribing during and after guideline dissemination. A cross-sectional sample of 8666 adult, community-based practice visits with one NSAID prescription representing approximately 305 million visits from the National Ambulatory Medical Care Survey (NAMCS) from 2005 to 2010 was studied. Multivariable logistic regression controlling for patient, provider and visit characteristics assessed the associations between diagnosis of CVD and NSAID type prescribed during each calendar year. Visits were stratified by arthritis diagnosis to model short-term/intermittent and long-term NSAID use. Approximately one-third (36.8%) of visits involving a NSAID prescription included at least one of four diagnoses for CVD (i.e. hypertension, congestive heart failure, ischaemic heart disease or cerebrovascular disease). Visits involving a CVD diagnosis had increased odds of a prescription for celecoxib, a highly selective NSAIDs, overall [adjusted odds ratio (AOR) = 1.29, 95% confidence interval (CI): 1.06-1.57] and in the subgroup of visits without an arthritis diagnosis (AOR = 1.45, 95% CI: 1.11-1.89). Results were not statistically significant for visits with an arthritis diagnosis (AOR = 1.10, 95% CI: 0.47-2.57). When analysed by year, the relationship was statistically significant in 2005 and 2006, but not statistically significant in each subsequent year. National prescribing trends suggest partial implementation of AHA guidelines for NSAID prescribing in CVD from 2005 to 2010.

Concordance with Guideline Recommendations: previous and more recent Nonsteroidal anti‐inflammatory Drug prescriptions in Quebec, Canada

Clinical practice guidelines for appropriate nonsteroidal anti-inflammatory drug (NSAID) utilisation focus on preventing NSAID-related gastrointestinal (GI), cardiovascular (CV), congestive heart failure (CHF) and renal adverse events. We compared concordance of NSAID prescriptions with clinical practice guideline recommendations in Quebec, pre and post rofecoxib withdrawal from market. Data were obtained from the Quebec Health Insurance Agency (RAMQ). All prescriptions for celecoxib and traditional NSAIDs (tNSAIDs) dispensed to patients ≥50 years of age were evaluated for concordance with clinical practice guidelines. Prescriptions were stratified by time period (pre and post rofecoxib withdrawal) and, GI, CV, CHF and renal risk factors at the dispensing date. Gastro-protective agent (GPA) co-prescriptions were also evaluated. We assessed 1,966,793 celecoxib and 1,743,481 tNSAIDs prescriptions. Of celecoxib prescriptions, 87.2% and 86.5% were appropriate in the post- and pre-periods, respectively, compared to 72.6% and 70.1% of tNSAIDs prescriptions, respectively. In logistic regression, 'appropriateness' of celecoxib prescriptions increased with age, rheumatoid arthritis and osteoarthritis (OA), and was higher in the post- versus pre-period (odds ratio 1.22, 95% confidence interval 1.18-1.26); it was lower in women and in patients with higher income. 'Appropriateness' of tNSAID prescriptions decreased in the post-period (0.92, 0.89-0.95), was lower in older persons and those with OA, and higher in women and in higher income patients. Of tNSAID prescriptions that should have received a GPA co-prescription, only 45.6% did. Concordance with guideline recommendations increased for celecoxib and decreased for tNSAIDs after rofecoxib withdrawal; GPA co-prescription with tNSAIDs remained suboptimal.

Persistence with non-selective NSAIDs and celecoxib among patients with gastroesophageal reflux disease and osteoarthritis or rheumatoid arthritis

Objective:Gastrointestinal (GI) symptoms are common in patients taking nonselective, nonsteroidal anti-inflammatory drugs (nsNSAIDs) and are often a reason for therapy discontinuation. In osteoarthritis (OA) and rheumatoid arthritis (RA) patients requiring pain control, selective COX-2 NSAID use is typically associated with less dyspepsia than is nsNSAID use. Little is known about NSAID tolerance in patients with gastroesophageal reflux disease (GERD). This study assessed nsNSAID and celecoxib prescription patterns, in particular persistence, in OA/RA patients with concomitant diagnosis of GERD.Methods:An observational study of GERD patients with a diagnosis of OA/RA using two separate databases, the IMS Lifelink Health Plan Claims Database (PharMetrics) and Market Scan Claims Database (Medstat) was conducted. In each database, parallel and separate analyses were performed in adult patients who had their first GERD diagnosis in 2006 and who were subsequently diagnosed with OA or RA in the same year. From this subset of patients, celecoxib-naïve and nsNSAID-naïve cohorts were identified and patients were selected. Patients with pre-existing GI conditions were excluded from the study. Persistence, measured as time to discontinuation, was evaluated by Kaplan–Meier survival curves and Cox proportional hazards models. Reasons for discontinuations were not available in these databases.Results:Fewer patients discontinued celecoxib as compared to nsNSAIDs during the 60 days of the first prescription and throughout the entire follow-up period. After adjusting for baseline characteristics, celecoxib patients still had significantly decreased risk of discontinuation as compared to nsNSAID patients (p < 0.0001). Replication of these observations in two separate, large patient databases increases the confidence in this study’s conclusion.Limitations:Limitations include those inherent to claims data analyses and retrospective review, e.g. these data do not provide clinical information related to reasons for medication discontinuation.Conclusion:In patients with concomitant GERD and OA or RA who require anti-inflammatory treatment, significantly more patients treated with celecoxib were persistent with their treatment than were patients treated with nsNSAIDs.

Changes in physicians' practice of prescribing cyclooxygenase-2 inhibitor after market withdrawal of rofecoxib: A retrospective study of physician-patient pairs in Taiwan

Background: Safety concerns regarding severe cardiovascular events associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors resulted in the market withdrawal of rofecoxib in September 2004. Objective: Using Taiwan's National Health Insurance 2003—;2004 claims database, this population-based retrospective cohort study assessed changes in physicians' practice of prescribing a COX-2 inhibitor after market withdrawal of rofecoxib. Methods: Patients with rheumatoid arthritis (RA) or osteoarthritis (OA) who were chronic users of COX-2 inhibitors before market withdrawal of rofecoxib were identified. Eligible chronic users of COX-2 inhibitors were patients who received ≥3 consecutive prescriptions for celecoxib or rofecoxib to treat RA or OA between April 1 and September 30, 2004. The main outcome evaluated in this study was the volume of celecoxib prescribing for each patient by his or her prescribing physician at the first postwithdrawal outpatient visit related to RA or OA. For each matched physician, we calculated the prescribing practice indexes before and after the withdrawal of rofecoxib to assess changes in prescribing practice. A higher value of the index represented less potential that patients with a history of cardiovascular events who were seen by a physician received a prescription for a COX-2 inhibitor. A 2-stage model analysis was used to assess changes, in physicians' prescribing practice after rofecoxib's withdrawal, in the volume of prescribing a COX-2 inhibitor for each matched patient by his or her prescribing physician. Results: Of the chronic users of COX-2 inhibitors identified, 13,101 were taking celecoxib and 8763 were taking rofecoxib before rofecoxib was withdrawn from the market. Concerns about safety after the mar- ket withdrawal of rofecoxib reduced physicians' volume of prescribing a COX-2 inhibitor, particularly in patients who had previously received rofecoxib. After rofecoxib's withdrawal, 72.50% of previous rofecoxib users (n = 6353) and 49.50% of previous celecoxib users (n = 6485) stopped taking COX-2 inhibitors. Only 27.50% of the rofecoxib users (n = 2410) were switched to celecoxib after rofecoxib's withdrawal. Overall, physicians' prescribing practice for celecoxib increased, from baseline to 3 months after rofecoxib's withdrawal, from 0.66 to 0.79 for academic medical center physicians, 0.71 to 0.82 for metropolitan hospital physicians, 0.77 to 0.88 for local community hospital physicians, and 0.86 to 0.92 for primary care clinic physicians. After controlling for patients' demographics, the linear regression analysis revealed that changes in physicians' prescribing practice after the withdrawal of rofecoxib affected the volume of prescribing a COX-2 inhibitor ( P < 0.001). Conclusions: The volume of celecoxib prescribing was greatly reduced after rofecoxib was withdrawn from the market. Physicians' prescribing practice for COX-2 inhibitors significantly changed after the withdrawal, and it had a significant impact on the postwithdrawal volume of celecoxib prescribing.

What happened to the prescribing of other COX‐2 inhibitors, paracetamol and non‐steroidal anti‐inflammatory drugs when rofecoxib was withdrawn in Australia?

To analyse how the prescribing of cyclooxygenase-2 (COX-2) inhibitors, non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and paracetamol (acetaminophen) changed when rofecoxib was withdrawn in 2004. COX-2 inhibitors, paracetamol and ns-NSAID's use was measured using dispensing data for concession beneficiaries subsidized by the Australian Pharmaceutical Benefit Scheme (PBS) for the period of 1997-2005. Data were downloaded from the Medicare Australia website and converted, according to the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) (2005), to DDD/1000 concession beneficiaries/day. In the period 2000-2004, the use of COX-2 inhibitors was progressively increased. Overall NSAID's use changed from approximately 80 to 105 DDD/1000 concession beneficiaries/day while a decrease of ns-NSAIDs from about 70 to 40 DDD/1000 concession beneficiaries/day was observed. Following rofecoxib withdrawal, the overall NSAIDs use declined. In 2005, celecoxib prescription declined (23%) while prescription of meloxicam increased by 62%. Use of paracetamol was steady over the period 1997-2004 (around 40 DDD/1000 concession beneficiaries/day). In April 2005, a slight increase in paracetamol use was observed. Our analysis showed that COX-2 inhibitors prescribing markedly influenced the overall NSAIDs prescribing in Australia. When COX-2 inhibitors were introduced their uptake was rapid and extensive. Following rofecoxib withdrawal, the total overall dispensing of NSAIDs returned to a similar value as before COX-2 inhibitors' introduction. The decrease was due both to rofecoxib withdrawal and to a reduction in celecoxib prescribing. However, meloxicam use increased. Paracetamol prescribing was steady, between 1997 and 2005 and was not affected when the COX-2 inhibitors were introduced on to the market and after rofecoxib withdrawal, rather than increasing as might have been anticipated after rofecoxib withdrawal.

The Tell-Tale Heart: Population-Based Surveillance Reveals an Association of Rofecoxib and Celecoxib with Myocardial Infarction

BackgroundCOX-2 selective inhibitors are associated with myocardial infarction (MI). We sought to determine whether population health monitoring would have revealed the effect of COX-2 inhibitors on population-level patterns of MI.Methodology/Principal FindingsWe conducted a retrospective study of inpatients at two Boston hospitals, from January 1997 to March 2006. There was a population-level rise in the rate of MI that reached 52.0 MI-related hospitalizations per 100,000 (a two standard deviation exceedence) in January of 2000, eight months after the introduction of rofecoxib and one year after celecoxib. The exceedence vanished within one month of the withdrawal of rofecoxib. Trends in inpatient stay due to MI were tightly coupled to the rise and fall of prescriptions of COX-2 inhibitors, with an 18.5% increase in inpatient stays for MI when both rofecoxib and celecoxib were on the market (P<0.001). For every million prescriptions of rofecoxib and celecoxib, there was a 0.5% increase in MI (95%CI 0.1 to 0.9) explaining 50.3% of the deviance in yearly variation of MI-related hospitalizations. There was a negative association between mean age at MI and volume of prescriptions for celecoxib and rofecoxib (Spearman correlation, −0.67, P<0.05).Conclusions/SignificanceThe strong relationship between prescribing and outcome time series supports a population-level impact of COX-2 inhibitors on MI incidence. Further, mean age at MI appears to have been lowered by use of these medications. Use of a population monitoring approach as an adjunct to pharmacovigilence methods might have helped confirm the suspected association, providing earlier support for the market withdrawal of rofecoxib.

New Diagnosis of Hypertension among Celecoxib and Nonselective NSAID Users: A Population-Based Cohort Study

The use of nonsteroidal antiinflammatory drugs (NSAIDs) has been associated with increased blood pressure and hypertension. However, less is known about how the risk of hypertension is associated with cyclooxygenase 2 selective inhibitors (coxibs), especially celecoxib, the only coxib remaining on the market. To compare the risk of incident hypertension associated with the use of celecoxib and nonselective (NS) NSAIDs. A cohort study was conducted using secondary data from the GE Centricity Electronic Medical Record database, which contains millions of patient records seen by thousands of physicians across the US. The index date was defined as the date of the first NSNSAID or celecoxib prescription between January 1, 1999, and June 30, 2004. Patients were included if they were aged 18 years or older and were enrolled for at least 365 days prior to the index date. Excluded were patients who had any prior diagnosis of hypertension or pregnancy-related hypertension during the pre- or postindex date period. Also excluded were patients who had any prior prescription for antihypertensive drugs, coxibs, or NSNSAIDs. After applying inclusion/exclusion criteria, each celecoxib user was matched to 2 NSNSAID users by sex, age (+/-5 y), propensity score (within 0.2 SD), and number of unique drugs (+/-20%). Descriptive and survival analyses were conducted. The final sample consisted of 51,444 patients, of whom 17,148 were on celecoxib and 34,296 were on NSNSAIDs. Relative to NSNSAID users, patients on celecoxib had a similar rate of postexposure hypertension incidence (HR 1.013; 95% CI 0.862 to 1.190). Results from a population-based cohort analysis of electronic medical records did not show any difference in the hazard rates of incident hypertension between celecoxib and NSNSAID users.

Do proton‐pump inhibitors confer additional gastrointestinal protection in patients given celecoxib?

Celecoxib has a superior upper-gastrointestinal (GI) safety profile compared with nonselective nonsteroidal antiinflammatory drugs (NS-NSAIDs). It is unclear whether the utilization of a proton-pump inhibitor (PPI) with celecoxib confers additional protection in elderly patients. We assessed the association between GI hospitalizations and use of celecoxib with a PPI versus celecoxib alone, and NS-NSAIDs with a PPI or NS-NSAIDs alone in elderly patients. We conducted a population-based retrospective cohort study using the government of Quebec health services administrative databases. Elderly patients were included at their first dispensing date for celecoxib or an NS-NSAID between April 1999 and December 2002. Prescriptions were separated into 4 groups: celecoxib, celecoxib plus PPI, NS-NSAIDs, and NS-NSAIDs plus PPI. Cox regression models with time-dependent exposure were used to compare the hazard rates of GI hospitalization between the 4 groups adjusting for patient characteristics at baseline. There were 1,161,508 prescriptions for celecoxib, 360,799 for celecoxib plus PPI, 715,176 for NS-NSAIDs, and 148,470 for NS-NSAIDs plus PPI. The adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) were 0.69 (0.52-0.93) for celecoxib plus PPI versus celecoxib, 0.98 (0.67-1.45) for NS-NSAIDs plus PPI versus celecoxib, and 2.18 (1.82-2.61) for NS-NSAIDs versus celecoxib. Subgroup analyses showed that use of a PPI with celecoxib may be beneficial in patients ages >/=75 years but was not better than celecoxib alone among those ages 66-74 years (HR 0.98, 95% CI 0.63-1.52). Addition of a PPI to celecoxib conferred extra protection for patients ages >/=75 years. PPI did not seem necessary with celecoxib for patients ages 66-74 years.

The cyclooxygenase 2 genetic variant −765G&gt;C does not modulate the effects of celecoxib on prostaglandin E2 production

Our objective was to assess the role of the reportedly functional PTGS2 (prostaglandin-endoperoxide synthase 2/cyclooxygenase [COX] 2) promoter mutation -765G>C for the COX-2-inhibiting effects of celecoxib. Twenty healthy carriers of the -765GG genotype and -765CC genotype (n = 10 each) received 200 mg of celecoxib orally. Blood samples were drawn at baseline and at 1, 3, 6, 9, and 24 hours after administration. Plasma concentrations of celecoxib and concentrations of prostaglandin E(2) (PGE(2)) produced by peripheral blood monocytes stimulated ex vivo with bacterial lipopolysaccharide (LPS) were analyzed by liquid chromatography-tandem mass spectrometry. Expression of COX-2 messenger ribonucleic acid and protein expression with and without LPS stimulation were analyzed by real-time polymerase chain reaction and Western blotting, respectively. LPS induced PGE(2) production (P < .001), and celecoxib reduced PGE(2) production from 19.3 +/- 7.2 ng/mL at baseline to 7.4 +/- 4.8 ng/mL at 1 hour (P < .001). The effect of celecoxib lasted for 9 hours (repeated-measures ANOVA, P <or= .001). Celecoxib inhibited PGE(2) production at a potency (ie, 50% effective concentration [EC(50)]) of 155.1 ng/mL (95% confidence interval, 101.6-208.5 ng/mL) in the homozygous carriers of the PTGS2 wild-type -765G allele and at a potency (EC(50)) of 186.6 ng/mL (95% confidence interval, 142.6-230.5 ng/mL) in the homozygous carriers of the PTGS2 variant -765C allele, which was not statistically significantly different (P = .36). Baseline PGE(2) concentrations, minimum baseline PGE(2) concentrations, and areas under the PGE(2) concentration versus time curve also did not differ between PTGS2 genotypes (P > .28). LPS up-regulated COX-2 messenger ribonucleic acid expression (P = .016) but was independent of genotype (P = .36). COX-2 protein expression was similar for both -765G>C genotypes (P = .63). The PTGS2 -765G>C single-nucleotide polymorphism does not modulate COX-2 inhibitory effects of celecoxib as assessed by an ex vivo whole blood assay. Thus the results indicate the need for further investigation toward PTGS2 pharmacogenetics-based prescription of celecoxib.

Hospitalization for gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs among elderly patients using low-dose aspirin: a retrospective cohort study

Many elderly patients are prescribed both low-dose aspirin (ASA), for cardiovascular protection and non-steroidal anti-inflammatory drugs (NSAIDs) for pain control. Compared with non-selective NSAIDs (NS-NSAIDs), celecoxib has a superior gastrointestinal (GI) safety profile in general. It is unclear, however, whether this fact holds good among patients taking ASA. We compared GI hospitalization rates among elderly patients taking celecoxib, NS-NSAIDs, celecoxib and ASA or NS-NSAIDs and ASA. This was a retrospective cohort study using Quebec government databases. All patients 65 yrs of age or older who filled a prescription for celecoxib or an NS-NSAID between April 1999 and December 2002 were included. Cox regression models were used to compare the GI hospitalization rates between the four exposure categories adjusting for potential confounders. A total of 332 491 patients were included. Among 1 522 307 celecoxib prescriptions, 430 214 were filled by patients concurrently receiving ASA (celecoxib and ASA); 195 369 of 863 646 NS-NSAID prescriptions were filled by patients receiving ASA (NS-NSAID and ASA). Celecoxib without ASA was less likely than NS-NSAID without ASA to be associated with GI hospitalization [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.33-0.50]; celecoxib and ASA was also less likely to be associated with GI hospitalization than NS-NSAID and ASA (HR 0.62, 95% CI 0.48-0.80); GI hospitalization rates were similar for celecoxib and ASA and NS-NSAID without ASA (HR 1.01, 95% CI 0.81-1.25). Among elderly patients receiving cardiovascular protection with ASA and pain control with anti-inflammatory drugs, celecoxib may be safer with regards to GI toxicity than NS-NSAIDs.

Accounting for the increase in NSAID expenditure: substitution or leakage?

BackgroundNational Institute of Health and Clinical Excellence (NICE) guidance stated that a new form of non-steroidal anti-inflammatory drug (NSAID) (selective COX-2 inhibitors) should only be an option for arthritis patients at high risk of a gastro-intestinal (GI) event. Total expenditure on NSAIDs has risen by 57% over five years, to £247 million in 2004. We assess whether this expenditure increase can be accounted for by substitution – an increased prescribing of two (more expensive) selective COX-2 inhibitors (celecoxib and rofecoxib) and a simultaneous equivalent reduction in the prescribing volume of three (cheaper) older NSAIDs (diclofenac, ibuprofen and naproxen).MethodsQuarterly prescription data was collated from January 1999 to September 2004. Over this period, the level of correlation between the total prescribing volumes for i) celecoxib and rofecoxib, and ii) diclofenac, ibuprofen, and naproxen were compared, the change in total expenditure on the five NSAIDs was also estimated. The latter was apportioned into that which was estimated to have arisen due to i) substitution, and ii) increased NSAID prescription volume.ResultsTotal prescription volumes for the two NSAID groups were negatively correlated (r = -0.97, p < 0.001). In the last quarter there were 1.23 million prescriptions for celecoxib and rofecoxib, and 0.46 million fewer prescriptions for naproxen, diclofenac, and ibuprofen (than in the first quarter, when celecoxib and rofecoxib were not prescribed). Total expenditure for the five NSAIDs was £32.7 million higher in the last quarter, than the first, £12.2 million of which was estimated to be due to substitution, and £20.4 million due to increased volume.ConclusionThe introduction of celecoxib and rofecoxib was associated with a reduction in the prescription volume for naproxen, diclofenac, and ibuprofen. However, overall quarterly prescription volume for these five NSAIDs increased by 0.76 million, and we estimate that quarterly expenditure increased by £20.4 million more than would have been expected if overall NSAID volume had remained constant. This suggests that the prescription of both celecoxib and rofecoxib may have 'leaked' to population groups who would not previously have received an older NSAID.

The effect of the withdrawal of rofecoxib on prescribing patterns of COX‐2 inhibitors in Scotland

Concerns have been raised regarding the cardiovascular safety of the COX-2 inhibitors. In September 2004, rofecoxib was withdrawn from the market as a result of concerns regarding its cardiovascular safety. We set out to examine the effect of the withdrawal of rofecoxib on the prescription of other COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) in Scotland, using a national prescription database. The withdrawal of rofecoxib led to an initial increase in the prescription of celecoxib as prescribers presumably switched to this alternative agent. However, this rise was short-lived, presumably as a result of concerns that the safety concerning rofecoxib may be a class effect. A parallel increase in the prescription of diclofenac and ibuprofen was also noted, suggesting that prescribers were prescribing these medications as alternatives to COX-2 inhibitors. While prescribers and their patients may have initially interpreted safety concerns regarding rofecoxib to be drug specific, prescribers appear to have interpreted this effect to be class specific.

COX-2 inhibitors: a story of greed, deception and death

In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over 100 million prescriptions for celecoxib (Celebrex) and rofecoxib (Vioxx). Celebrex is the sixth best-selling drug, with sales of more than US$ 4 billion since its debut in 1999. Vioxx had sales of US$ 2.6 billion in 2001. However, the coxibs increase the risk of heart attacks and strokes, and their price, in the USA, is obscene. The manufacturers faced a possibly complicit, toothless and bloodless FDA, and used every maneuvering to fleece the patients. We must now reflect on attitudes that we thought only belong to the tobacco industry. Fortunately, safe and active alternatives exist.