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Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events
Meta-analysis of Randomized Trials
Jingjing Zhang, MD, PhD;
Eric L. Ding, BA;
Yiqing Song, MD, ScD
JAMA. 2006;296:(doi:10.1001/jama.296.13.jrv60015).
ABSTRACT
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Context Adverse effects of selective cyclooxygenase 2 (COX-2) inhibitors on renal events and arrhythmia have been controversial, with suggestions of a class effect.
Objective To quantitatively evaluate adverse risks of renal events (renal dysfunction, hypertension, and peripheral edema) and arrhythmia events and to explore drug class effects and temporal trends of apparent effects of the COX-2 inhibitors: rofecoxib, celecoxib, valdecoxib, parecoxib, etoricoxib, and lumiracoxib.
Data Sources A systematic search of EMBASE and MEDLINE (through June 2006), bibliographies, US Food and Drug Administration reports, and pharmaceutical industry clinical trial databases.
Study Selection From relevant reports, 114 randomized double-blind clinical trials were included.
Data Extraction Information on publication year, participant characteristics, trial duration, drug, control, dose, and events were extracted using a standardized protocol.
Data Synthesis Results were pooled via random-effects models and meta-regressions. Of 116 094 participants from 114 trial reports including 127 trial populations (40 rofecoxib, 37 celecoxib, 29 valdecoxib + parecoxib, 15 etoricoxib, and 6 lumiracoxib), there were a total of 6394 composite renal events (2670 peripheral edema, 3489 hypertension, 235 renal dysfunction) and 286 arrhythmia events. Results indicated significant heterogeneity of renal effects across agents (P for interaction = .02), indicating no class effect. Compared with controls, rofecoxib was associated with increased risk of arrhythmia (relative risk [RR], 2.90; 95% confidence interval [CI], 1.07-7.88) and composite renal events (RR, 1.53; 95% CI, 1.33-1.76); adverse renal effects increased with greater dose and duration (both P .05). For all individual renal end points, rofecoxib was associated with increased risk of peripheral edema (RR, 1.43; 95% CI, 1.23-1.66), hypertension (RR, 1.55; 95% CI, 1.29-1.85), and renal dysfunction (RR, 2.31; 95% CI, 1.05-5.07). In contrast, celecoxib was associated with lower risk of both renal dysfunction (RR, 0.61; 95% CI, 0.40-0.94) and hypertension (RR, 0.83; 95% CI, 0.71-0.97) compared with controls. Other agents were not significantly associated with risk. Time-cumulative analyses indicated that for rofecoxib the adverse risks for peripheral edema and hypertension were evident by the end of year 2000 and for risk of arrhythmia by 2004.
CONCLUSIONS In this comprehensive analysis of 114 randomized trials with 116 094 participants, rofecoxib was associated with increased renal and arrhythmia risks. A COX-2 inhibitor class effect was not evident. Future safety monitoring is warranted and may benefit from an active and continuous cumulative surveillance system.
Published online: September 12, 2006 (doi:10.1001/jama.296.13.jrv60015).
INTRODUCTION
It is estimated that more than 30 million people worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs) daily for treatment of pain and inflammation.1 Conventional NSAIDs block both cyclooxygenase (COX) enzyme isoforms, COX-1, and COX-2.2-4 However, COX-1 inhibition by conventional NSAIDs is known to cause toxic gastrointestinal (GI) effects,5-6 as well as exert adverse renal effects,7 such as decreased renal perfusion, decreased glomerular filtration rate (GFR), edema, increased blood pressure, and interstitial nephritis.8-10 Overall, an estimated 2.5 million individuals in the United States annually experience adverse renal effects caused by use of NSAIDs.11
With decreased risk of adverse GI effects, a class of drugs that selectively inhibits COX-2 enzyme was introduced for analgesia and the treatment of arthritis. Rofecoxib and celecoxib were the first 2 members of selective COX-2 inhibitor class that were approved by the US Food and Drug Administration (FDA) in December 1998 and May 1999, respectively. However, rofecoxib was recently recognized to significantly increase risk of myocardial infarction.12-14 Accumulating evidence on the cardiovascular safety of many COX-2 inhibitors has been systematically studied and suggests a potential class effect of COX-2 inhibitors on cardiovascular risk.14-20
Although the nephrotoxic potential by COX inhibition via either nonselective NSAIDs or selective COX-2 inhibitors has also been recognized, the adverse renal effects of selective COX-2 inhibition are less clear.21 By October 2000, the FDA had received 233 reports of renal failure associated with the administration of rofecoxib and celecoxib.22 Some studies showed that selective COX-2 inhibitors had mild and transient effects on renal blood flow and sodium excretion in salt-depleted or elderly patients.23-25 Other trials showed COX-2 inhibitors may increase blood pressure.26-28 Due to inconsistent results from individual trials,11 the renal safety profile of selective COX-2 inhibitors has yet to be clearly documented. Additionally, the evidence for potential effects of COX-2 inhibitors on risk of arrhythmia, a possible cardiorenal-related event, also has not been clearly documented.
To comprehensively quantify adverse risks and potential class effect for renal outcomes and arrhythmia, we therefore conducted a comprehensive class-wide meta-analysis of randomized double-blinded trials of the COX-2 inhibitors: rofecoxib, celecoxib, valdecoxib, parecoxib, etoricoxib, and lumiracoxib. We also conducted time-cumulative meta-analysis to assess the temporal consistency and robustness of the evidence for the adverse effects on renal and arrhythmia events.
METHODS
Study Selection
We conducted a systematic search of EMBASE and MEDLINE (through June 2006) for double-blind randomized clinical trials of the COX-2 inhibitors: rofecoxib, celecoxib, valdecoxib, parecoxib, etoricoxib, and lumiracoxib. We expanded our search for trials in the Cochrane Controlled Trials Register, the Computer Retrieval of Information on Scientific Projects (CRISP) database of the National Institutes of Health, direct contact with relevant investigators, references of retrieved articles, relevant FDA reports, and the online clinical trial information centers, and trial result repositories (http://www.ClinicalTrialResults.org and http://www.ClinicalStudyResults.org).
We focused on studies with renal end points of interest (peripheral edema, hypertension, renal dysfunction) and arrhythmia. We excluded pooling analyses of other adverse events and any trials with no control group, no relevant events in either drug or control group, not double-blinded, abnormal baseline renal function, and combined simultaneous intervention of more than 1 COX-2 inhibitor. For multiple reports of a same study, the duplicate trial report from FDA and pharmaceutical company sources was used to supplement published data when applicable, with FDA data given precedence. From the systematic search, 114 informative reports were included in this analysis. The study selection process is summarized in Figure 1.
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Figure 1. Trial Selection Process
COX indicates cyclooxygenase.
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Data Extraction
Using a standardized data extraction form, 2 independent investigators (J.J.Z. and E.L.D.) extracted and tabulated all data. Discrepancies were resolved via referencing the original report(s) and group discussions. Information extracted include first author, publication year, mean age of participants, sex proportion, comorbidity status (osteoarthritis, rheumatoid arthritis, other pain, hypertension, coronary heart disease, cancer, neurological dysfunction, healthy status), trial duration, type of COX-2 inhibitor agent, type of control(s), drug dose (weighted average of doses if multiple arms of the same COX-2 inhibitor were included in the same trial), number of participants in drug and control groups, and number of events of interest (peripheral edema, hypertension, renal dysfunction, and arrhythmia) in the drug and control groups.
The end point of hypertensive events included onset of hypertension, clinically recognized increased blood pressure event, or clinically recognized aggravated hypertension event as defined using routine clinical criteria by each trial ascertained via double-blinded manner. The renal dysfunction end point included significant changes of serum urea or creatinine levels as defined by the trial, clinically diagnosed kidney disease, or renal failure. The arrhythmia end point included atrial fibrillation, ventricular fibrillation, tachycardia, cardiac arrest, sudden cardiac death, or unspecified arrhythmia. However, bradycardia, an arrhythmia event of low clinical significance, was not included as an arrhythmia end point.
Statistical Analyses
Relative risks (risk ratios, RRs) by an intent-to-treat analytic approach were calculated as the measure of association. Natural log transformations were performed on the RR measures. Relative risks in each analysis were pooled via DerSimonian and Laird random-effects models.29 All analyses were stratified by each COX-2 inhibitor. Because oral valdecoxib and intravenous parecoxib share the identical functional compound, analyses were conducted pooling these 2 agents. Because peripheral edema, hypertension, and renal dysfunction share common pathophysiologies and are already well recognized to be adverse renal effects of conventional NSAIDs, a composite renal end point was formed. Our primary analyses examined pooled RRs of each COX-2 inhibitor vs controls with risk of composite renal events and arrhythmia events. Secondary analyses examined renal event-specific RRs of COX-2 inhibitor vs controls.
Additionally, we conducted subgroup analyses for composite renal end point using meta-regressions to assess potential effect modification by type of control (placebo, NSAID, mixed/other; other included aspirin, acetaminophen, rizatriptan, doloteffin, morphine, or salicin), drug dose (dosage dichotomy for each drug; eg, rofecoxib >25 vs 25 mg/d; celecoxib >400 vs 400 mg/d), duration ( 6 vs <6 months), mean age (65 vs <65 years), sex, and comorbidity (osteoarthritis, rheumatoid arthritis, other morbidity). A sparse number of trials precluded further informative stratification for other comorbidites and for specific arrhythmia subtypes. In addition, a time-cumulative meta-analysis was conducted for any COX-2 inhibitor found with increased risk of renal events and arrhythmia. Analyzed by calendar year of trial report, sequential series of cumulative random-effects pooling were conducted to identify the earliest calendar year, at the end of which, the increased risk of the specified end point became significantly apparent.
Conventional random-effects weighting was used in all analyses. To avoid statistical duplication of data, multiple control groups in a trial were collapsed as 1 independent control group for comparison to a COX-2 inhibitor agent. For studies reporting 0 events in a trial group, yet an informative trial as a whole, the classic half-integer correction was applied to calculate the RRs and variances. Further sensitivity analyses of arrhythmia data were conducted using Mantel-Haenszel–weighted pooling of trials and using the Fisher exact test of overall number of events and participants,30 both established methods for sparse-events data without need of continuity correction.
To assess heterogeneity, the I2 statistic31-32 was used to describe the percentage of total variation across studies that is due to heterogeneity rather than chance; a value of 0% indicates no observed heterogeneity, while larger values between 0% and 100% show increasing heterogeneity. Although we included unpublished trials in our analysis, we used both the Egger test and Begg test for assessment of potential publication bias33 and examined relative symmetry of individual study estimates around the overall estimate using Begg funnel plots in which log RRs were plotted against their corresponding standard errors, stratified by COX-2 inhibitor.
All primary analyses were conducted using STATA version 8.2 (STATACorp, College Station, Tex); Mantel-Haenszel pooled analyses were conducted using EPISHEET version 2003 (developed by Rothman34). All tests were 2-sided; P.05 was considered statistically significant.
RESULTS
The analysis included 114 informative reports, consisting of 127 trial populations (40 rofecoxib, 37 celecoxib, 29 valdecoxib/parecoxib, 15 etoricoxib, and 6 lumiracoxib trials) and included 116 094 total participants (Table 1, Table 2, Table 3, and Table 4). There were a total of 6394 composite renal events (2670 peripheral edema, 3489 hypertension, 235 renal dysfunction) and 286 arrhythmia events. Descriptive summary statistics of participants, detailed number of renal events, age, sex, duration, dose, control type, and comorbidities for each COX-2 inhibitor are summarized in Table 5. The number of arrhythmia events is shown in Table 6.
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Table 1. Included Trials of Rofecoxib*
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Table 2. Included Trials of Celecoxib*
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Table 3. Included Trials of Valdecoxib and Parecoxib*
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Table 4. Included Trials of Etoricoxib and Lumiracoxib
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Table 5. Descriptive Characteristics of Included Randomized Double-Blind Clinical Trials of Cyclooxygenase 2 Inhibitors
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Table 6. Number of Arrhythmia Events by Reported Subtypes
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Overall pooled analysis of composite renal events ignoring COX-2 inhibitor type indicated substantial heterogeneity (I2 = 57, 95% CI, 47-64; P<.001). Different COX-2 inhibitor agent was an important explanatory factor for the observed heterogeneous effects (overall P for interaction by agent = .02), indicating no class effect. Based on stratification by type of COX-2 inhibitor, there was overall decreased and nonsignificant heterogeneity of renal effect estimates within drug categories, with exception of etoricoxib. Primary results are summarized in Table 7. Forest plots for COX-2 drug categorical component renal effects and for arrhythmia events are available at http://www.Cox2DrugReview.org, or by request.
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Table 7. Overall Relative Risks of Renal and Arrhythmia Events, Cyclooxygenase 2 Inhibitors vs Controls
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Results indicated that those taking rofecoxib experienced significantly increased risks of composite renal events compared with those in the control groups (RR, 1.53; 95% CI, 1.33-1.76). For specific renal end points, rofecoxib robustly increased risk of all 3 sub–end points: peripheral edema (RR, 1.43; 95% CI, 1.23-1.66), hypertension (RR, 1.55; 95% CI, 1.29-1.85), and renal dysfunction (RR, 2.31; 95% CI, 1.05-5.07). Although there was suggestion that valdecoxib plus parecoxib was associated with composite renal events (RR, 1.24; 95% CI, 1.00-1.55; P = .054), other COX-2 inhibitors overall were not significantly associated with increased renal events. Furthermore, celecoxib appeared to be associated with lower risk of both renal dysfunction (RR, 0.61; 95% CI, 0.40-0.94) and hypertension (RR, 0.83; 95% CI, 0.71-0.97) compared with controls. The I2 statistic did not show significant heterogeneity for any individual events.
In addition, the recent Pre SAP celecoxob trial for prevention of colorectal adenova recurrence111 (which was published after our study’s protocol review period) suggested renal risks but a sensitivity analysis further incorporating the pre SAP trial results still consistently indicated a lack of COX-2 inhibitor renal class effect (P=.02) and no overall risk of composite renal events across 38 celecoxib trials (RR, 1.06; 95% CI, 0.90-1.24).
For arrhythmia events, only those taking rofecoxib were at increased risk compared with controls (RR, 2.90; 95% CI, 1.07-7.88). Despite relatively few arrhythmia events in rofecoxib trials, results were robust, for sensitivity analysis via Mantel-Haenszel pooling and Fisher exact test, methods more exact and optimal for sparse-events data, both further affirmed the increased risk of arrhythmia with rofecoxib (Mantel-Haenszel RR, 6.52; 95% CI, 1.48-28.8; Fisher exact P value = .004). Celecoxib showed no effect on arrhythmia, whereas valdecoxib plus parecoxib were related to a marginally lower arrhythmia risk. Additionally, results for etoricoxib and lumiracoxib for risk of arrhythmia were inconclusive due to limited number of available trials.
Potential sources of between-trial heterogeneity were further explored via meta-regression stratified analyses; lumiracoxib was not further stratified due to limited studies. Stratified results are summarized in Table 8. Consistently, increased risk of renal events was evident for rofecoxib regardless of comparison to either placebo (RR, 1.70; 95% CI, 1.35-2.14), nonselective NSAIDs (RR, 1.32; 95% CI, 1.08-1.61), or mixed comparison of other controls (RR, 1.68; 95% CI, 1.31-2.15); rofecoxib effects vs placebo control had a nonsignificant trend toward being stronger than NSAID controls (P = .10 ). Moreover, the stratified results suggested that both higher dose (>25 mg/d) and longer trial duration (6 months) may potentially further increase risk of renal events (P = .05 and P = .006, respectively); results also suggested that adverse effects of rofecoxib may be stronger among rheumatoid arthritis patients than other patients (P<.001). Stratified results for celecoxib, valdecoxib plus parecoxib, and etoricoxib did not reveal significant effect modifications.
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Table 8. Relative Risk of Composite Renal Events (Renal Dysfunction, Peripheral Edema, Hypertension) by COX-2 Inhibitors, Meta-Regression Stratified by Study Characteristics*
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In time-cumulative analyses by calendar year of trial report to examine earliest year of apparent adverse effects, the trial evidence showed that it was evident by the end of the year 2000 that rofecoxib was associated with overall adverse renal events (P<.001; and for all subsequent years), as well as specific events of hypertension and peripheral edema (P<.01 for both; and for all subsequent years); the evidence for adverse effects on renal dysfunction became apparent by 2005 (Figure 2). Furthermore, rofecoxib's adverse effects on arrhythmia first became significant by the end of year 2004 (P = .05), and became further apparent by the end of 2005 (P = .04; Figure 2).
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Figure 2. Time-Cumulative Analysis of Rofecoxib and Risk of Renal and Arrhythmia Events
*Sensitivity analyses of the 9 trials with 20 300 participants (10 126 drug, 10 174 control group) and 15 arrhythmia events (13 drug, 2 control group) without half-integer correction using sparse-events exact methods: Fisher exact test P =.004, and Mantel-Haenszel pooled relative risk 6.52 (95% CI, 1.48-28.8; P=.004).
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COMMENT
In this comprehensive meta-analysis of 114 randomized trials of COX-2 inhibitors comprised of 116 094 participants, rofecoxib uniquely increased risks of renal events (peripheral edema, renal dysfunction, hypertension) and arrhythmia events, with apparent adverse effects by the end of year 2000 and 2004, respectively. However, the results did not show adverse effects of other COX-2 inhibitors on renal events and arrhythmia, indicating no overall evidence for a COX-2 inhibitor class effect.
The underlying mechanisms for potential nephrotoxic effects of selective COX-2 inhibitors are not fully understood, although several explanations have been proposed. In the most basic framework, conventional NSAIDs block both COX-1 and COX-2 enzyme isoforms, whereas selective COX-2 inhibitors primarily antagonize COX-2. Prostaglandins (PGs), derived from arachidonic acid by various COX enzymes, can function as important mediators of inflammation and modulate a variety of physiological processes, including maintenance of gastric mucosal integrity, renal hemodynamics, renin synthesis and release, and tubular reabsorption of sodium and water.111 Because PGs are involved in renal function, nonselective NSAIDs are already recognized to exhibit adverse renal effects, including renal failure due to hemodynamic changes, acute tubular necrosis, tubuolinterstitial nephritis, or papillary necrosis, as well as disturbances and disorders of electrolyte balance (hyponatremia, hyperkalemia) such as hypertension and edema.8-10
Although COX-2 was originally designated as an "inducible" enzyme because of its up-regulation by inflammatory and proliferating stimuli, COX-2 is constitutively expressed in adult mammalian kidney tissues, including the cortex, macula densa, thick ascending limb, interstitial cells in inner medulla, and papilla and podocyte.113-116 COX-2 expression has been found to be up-regulated in renal ischemia, salt depletion status, which suggests COX-2-derived prostanoids may play a role in maintaining renal medulla blood supply, renal salt excretion, and systemic blood pressure.113-116 Furthermore, prostacyclin synthesis and renin-release from the kidney have also been found to be COX-2 dependent.117 Some evidence indicate that specific COX-2 inhibition may induce renal ischemia, electrolyte imbalance, and abnormal blood pressure,8 ultimately leading to fluid and sodium retention as well as decreased GFR.23, 25, 118-119
However, a class effect for all COX-2 inhibitors has previously remained unclear.120 Although all study agents are considered selective COX-2 inhibitors, the various agents are known to somewhat differ in terms of potency and specificity of COX-2 inhibition as well as their respective pharmacokinetics and metabolism in the human body.121 These characteristics may contribute to observed differences of the effect across various COX-2 inhibitors. Consistent with evidence that rofecoxib has stronger COX-2 selectivity than other COX-2 inhibitors,120 our results indicate substantially different effects between rofecoxib and other agents in its class. Notably, we found a higher risk of renal dysfunction, hypertension, and peripheral edema with rofecoxib, whereas in contrast, we found lower risk of hypertension and renal dysfunction with celecoxib and no effect with other agents. Although this finding may be due to chance, our results are supported by multiple animal studies that showed rofecoxib and celecoxib to have different or opposite effects on blood pressure, glomerular injury, inflammatory reaction, and endothelial dysfunction—all of which rofecoxib was generally more adverse compared with celecoxib.122-124 Furthermore, clinical trials have also shown that rofecoxib elicits significantly greater blood pressure increases compared with celecoxib,26 and that celecoxib may protect against the adverse renal effects of aspirin.125 The degree and relative inhibition of different COX isoforms may be important, with modest differences between agents in the relative potency and selectivity of COX-2 vs COX-1 inhibition potentially mediating differential effects. Our results do not support a class effect of COX-2 inhibitors on renal events.
Our study is the first to our knowledge to highlight that rofecoxib may increase risk of arrhythmia and appears to differ in arrhythmia effects than other COX-2 inhibitors, although the exact mechanisms underlying such effects remain uncertain. Although myocardial infarction is a frequent cause of arrhythmia, the recognized cardiovascular class effect of rofecoxib, celecoxib, and valdecoxib12, 14-17,19-20 suggests that cardiac events might not be the underlying explanation for the differential arrhythmia effects of rofecoxib from other COX-2 inhibitors.
On the other hand, another recognized and established cause of arrhythmia is disturbance of electrolyte balance, especially hyperkalemia. Consistent with the divergent adverse renal effects of rofecoxib compared with other COX-2 inhibitors, these renal mechanisms may, at least in part, explain the parallel increased risk of arrhythmia uniquely associated with rofecoxib but not associated with other agents. Although there were suggestions of renal risk but lower risk of arrhythmia in valdecoxib and parecoxib trials, results were not statistically significant and these trials included mostly atrial arrhythmias, which are generally less fatal.
In contrast, the arrhythmia results for rofecoxib appear more clinically relevant and significant, as the vast majority of rofecoxib arrhythmia events were ventricular fibrillation, cardiac arrest, and sudden cardiac death (Table 6). However, due to limited number of trials and cases, insufficient power was available to further evaluate specific types of arrhythmia. Further mechanistic investigations are warranted to study the divergent effects of COX-2 inhibitors on renal events and subtypes of arrhythmia.
Our study has several limitations that merit consideration. First, although tests for publication bias did not reveal such biases for any drug, we cannot exclude the potential for bias in reporting drug-related adverse events, as recently highlighted in a controversy over reporting of rofecoxib cardiovascular events.13, 126-128 However, we believe such reporting bias is minimal because our meta-analysis had supplemented publication data with FDA reports and unpublished pharmaceutical company trial safety reports whenever available. Moreover, because renal effects of conventional NSAIDs are already well recognized, renal events are unlikely to have influenced decisions for publication.
Second, although diagnostic criteria for hypertensive events and renal dysfunction sometimes varied by trial-specific criteria or were not clearly defined because these adverse events were not commonly prespecified, it is difficult to conceive that trials did not use conventional definitions for hypertension and renal dysfunction consistent with routine clinical criteria. In addition, besides the inherent advantage of random-effects models' in conservatively incorporating any potential heterogeneity, the informative power gained from such trials substantially outweighs the alternative of wastefully excluding the majority of these highly relevant trials. Furthermore, this study's definition of hypertensive events is also consistent with composite hypertension end points frequently reported in clinical trials. Most important, because all included trials were optimally double-blinded and evaluated with intent-to-treat analysis in our study, there would not be inherent biases in the ascertainment of any end point or bias of any trial-specific RR.
Third, due to less power in stratified analyses, we were limited in our ability to fully and clearly assess heterogeneity by variety of characteristics, such as underlying comorbidity, and evaluate age and sex differences beyond crude trial means and trial proportions. Also, our time-cumulative results are conservative, as pharmaceutical companies would have had data and results of all industry-sponsored trials available much earlier, likely months and years prior to publication, submission to FDA, or uploading on an online pharmaceutical industry database. Additionally, due to the limited number of trials of the newer drugs etoricoxib and lumiracoxib, results for these agents still remain tentative and inconclusive; additional safety monitoring investigations are needed.
Nevertheless, this systematic review and meta-analysis, overall, has the advantage of having a greater sample size to detect adverse effects,129 which previous trials of COX-2 inhibitors were often underpowered to assess.130 Furthermore, this comprehensive class-wide evidence-based assessment has the unique advantage of assessing class effects, which may help guide policy decisions regarding the overall safety of the drug class and the development of future drugs in this class.
Notably for policy and clinical decision making, our results also suggest that a time-cumulative meta-analytic approach for examining available trial safety data would have helped clarify apparent adverse effects several years earlier than the current report. The knowledge of all potential adverse effects is important and indeed time-sensitive, for physicians and patients both need complete information about risks and benefits to properly use COX-2 inhibitors and other clinical treatments.130 However, the current system of postmarketing surveillance has been recognized to possess a variety of shortcomings, including an overall lack of vigilance.131-132 Therefore, as alluded to by other reviews of clinical trial safety130, 132-133 and supported by other teams of systematic review experts,14, 134 future drug safety monitoring of emerging clinical treatments may benefit from continuous, cumulative meta-analytic aggregation of safety data for all drug-approval applications and experimental agents. Of further benefit, the establishment of an independent postmarketing surveillance system based on such an active and continuous data aggregation structure would have many advantages over the current passive reporting system.131, 135
CONCLUSIONS
In conclusion, our analysis of 114 randomized trials involving 116 094 participants indicates that rofecoxib increased risk of renal events and arrhythmia events. Overall, a class effect was not evident for renal events and arrhythmia events across all COX-2 inhibitors, although further safety monitoring current and emerging treatments are warranted and may benefit from a cumulative and active surveillance system.
AUTHOR INFORMATION
Corresponding Author: Eric L. Ding, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Kresge Ninth Floor, Boston, MA 02115 (eding{at}jhu.edu).
Published Online: September 12, 2006 (doi:10.1001/jama.296.13.jrv60015).
Author Contributions: Mr Ding had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and presentation.
Study concept and design: Ding, Zhang, Song.
Acquisition of data: Zhang, Ding.
Analysis and interpretation of data: Ding, Song.
Drafting of the manuscript: Ding, Zhang.
Critical revision of the manuscript for important intellectual content: Ding, Zhang, Song.
Statistical analysis: Ding, Song.
Obtained funding: Ding, Song.
Administrative, technical, or material support: Ding, Zhang, Song.
Study supervision: Ding, Song.
Mr Ding and Dr Zhang contributed equally to the study.
Financial Disclosures: None reported.
Funding/Support: Mr Ding was supported by grant R01-DK066401 from the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) and by institutional training grant T32-CA009001 from the National Cancer Institute, National Institutes of Health. Dr Song was supported by grants R01-DK062290 and R01-DK066401 from the NIDDK, National Institutes of Health.
Role of the Sponsor: The National Institutes of Health had no role in the study conduct, analysis, and interpretation of the results.
Previous Presentation: A preliminary abstract of this study was presented at the American Heart Association 46th Annual Conference on Cardiovascular Disease Epidemiology and Prevention, March 2006.
Additional Sources: Supplementary information is available from the authors or online at http://www.Cox2DrugReview.org or contact the authors.
Acknowledgment: We thank Simin Liu, MD, ScD, MPH, University of California, Los Angeles School of Public Health, and Harvard School of Public Health, for his encouragement and support.
Author Affiliations: Renal Division (Dr Zhang) and Division of Preventive Medicine (Mr Ding and Dr Song), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; Departments of Epidemiology and Nutrition (Mr Ding), Harvard School of Public Health, Boston, Mass.
REFERENCES
| |
1. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999;56:18-24.
PUBMED
2. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991;266:12866-12872.
FREE FULL TEXT
3. O'Banion MK, Winn VD, Young DA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci U S A. 1992;89:4888-4892.
FREE FULL TEXT
4. Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A. 1991;88:2692-2696.
FREE FULL TEXT
5. Kargman S, Charleson S, Cartwright M, et al. Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology. 1996;111:445-454.
PUBMED
6. Ofman JJ, MacLean CH, Straus WL, et al. A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. J Rheumatol. 2002;29:804-812.
FREE FULL TEXT
7. Stichtenoth DO, Frolich JC. COX-2 and the kidneys. Curr Pharm Des. 2000;6:1737-1753.
PUBMED
8. Harris RC, Breyer MD. Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol. 2001;281:F1-F11.
FREE FULL TEXT
9. Palmer BF. Renal complications associated with use of nonsteroidal anti-inflammatory agents. J Investig Med. 1995;43:516-533.
PUBMED
10. Schlondorff D. Renal complications of nonsteroidal anti-inflammatory drugs. Kidney Int. 1993;44:643-653.
PUBMED
11. Sandhu GK, Heyneman CA. Nephrotoxic potential of selective cyclooxygenase-2 inhibitors. Ann Pharmacother. 2004;38:700-704.
FREE FULL TEXT
12. Bombardier C, Laine L, Reicin A, et al, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520-1528, 1522 p following 1528.
FREE FULL TEXT
13. Curfman GD, Morrissey S, Drazen JM. Expression of concern: Bombardier et al., "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis," N Engl J Med 2000;343:1520-8. N Engl J Med. 2005;353:2813-2814.
FREE FULL TEXT
14. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364:2021-2029.
PUBMED
15. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092-1102.
FREE FULL TEXT
16. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071-1080.
FREE FULL TEXT
17. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005;352:1081-1091.
FREE FULL TEXT
18. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959.
FREE FULL TEXT
19. Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med. 2006;99:132-140.
FREE FULL TEXT
20. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? meta-analysis of randomised trials. BMJ. 2006;332:1302-1308.
FREE FULL TEXT
21. Cheng HF, Harris RC. Renal effects of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. Curr Pharm Des. 2005;11:1795-1804.
PUBMED
22. Ahmad SR, Kortepeter C, Brinker A, Chen M, Beitz J. Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf. 2002;25:537-544.
PUBMED
23. Rossat J, Maillard M, Nussberger J, Brunner HR, Burnier M. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther. 1999;66:76-84.
PUBMED
24. Schwartz JI, Vandormael K, Malice MP, et al. Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet. Clin Pharmacol Ther. 2002;72:50-61.
PUBMED
25. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet: a randomized, controlled trial. Ann Intern Med. 2000;133:1-9.
FREE FULL TEXT
26. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165:490-496.
FREE FULL TEXT
27. Whelton A. COX-2-specific inhibitors and the kidney: effect on hypertension and oedema. J Hypertens Suppl. 2002;20:S31-S35.
PUBMED
28. Whelton A, White WB, Bello AE, Puma JA, Fort JG. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol. 2002;90:959-963.
PUBMED
29. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188.
PUBMED
30. Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.31. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558.
PUBMED
32. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-560.
FREE FULL TEXT
33. Egger M, ed, Altman DG, ed, Smith GD, ed. Systematic Reviews in Health Care: Meta-analysis in Context. 2nd ed. London, England: BMJ Books; 2001.34. Rothman KJ. EPISHEET: spreadsheets for the analysis of epidemiologic data. September 17, 2003. http://members.aol.com/krothman/episheet.xls. Accessed August 16, 2006.35. Schwartz JI, Agrawal NG, Wong PH, et al. Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients. J Clin Pharmacol. 2001;41:1120-1130.
ABSTRACT
36. Bogaty P, Brophy JM, Noel M, et al. Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study. Circulation. 2004;110:934-939.
FREE FULL TEXT
37. Fenwick SW, Toogood GJ, Lodge JP, Hull MA. The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases. Gastroenterology. 2003;125:716-729.
PUBMED
38. Chrubasik S, Model A, Black A, Pollak S. A randomized double-blind pilot study comparing Doloteffin and Vioxx in the treatment of low back pain. Rheumatology. 2003;42:141-148.
FREE FULL TEXT
39. Niccoli L, Bellino S, Cantini F. Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis. Clin Exp Rheumatol. 2002;20:201-207.
PUBMED
40. Krymchantowski AV, Bigal ME. Rizatriptan versus rizatriptan plus rofecoxib versus rizatriptan plus tolfenamic acid in the acute treatment of migraine. BMC Neurol. 2004;4:10.
PUBMED
41. Lanza FL, Rack MF, Simon TJ, et al. Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen. Aliment Pharmacol Ther. 1999;13:761-767.
PUBMED
42. Chrubasik S, Kunzel O, Model A, Conradt C, Black A. Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low back pain. Rheumatology. 2001;40:1388-1393.
FREE FULL TEXT
43. Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289:2819-2826.
FREE FULL TEXT
44. Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ, Vioxx, Acetaminophen, Celecoxib Trial (VACT) Group. Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial. JAMA. 2002;287:64-71.
FREE FULL TEXT
45. Gibofsky A, Williams GW, McKenna F, Fort JG. Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial. Arthritis Rheum. 2003;48:3102-3111.
PUBMED
46. Schnitzer TJ, Kivitz AJ, Lipetz RS, Sanders N, Hee A. Comparison of the COX-inhibiting nitric oxide donator AZD3582 and rofecoxib in treating the signs and symptoms of Osteoarthritis of the knee. Arthritis Rheum. 2005;53:827-837.
PUBMED
47. Truitt KE, Sperling RS, Ettinger WH Jr, et al. A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and efficacy of rofecoxib in advanced elderly patients with osteoarthritis. Aging (Milano). 2001;13:112-121.
PUBMED
48. Acevedo E, Castaneda O, Ugaz M, et al. Tolerability profiles of rofecoxib (Vioxx) and Arthrotec: a comparison of six weeks treatment in patients with osteoarthritis. Scand J Rheumatol. 2001;30:19-24.
PUBMED
49. Schnitzer TJ, Truitt K, Fleischmann R, et al, Phase II Rofecoxib Rheumatoid Arthritis Study Group. The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Clin Ther. 1999;21:1688-1702.
PUBMED
50. Hawkey CJ, Laine L, Simon T, Quan H, Shingo S, Evans J, Rofecoxib Rheumatoid Arthritis Endoscopy Study Group. Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study. Gut. 2003;52:820-826.
FREE FULL TEXT
51. Katz N, Ju WD, Krupa DA, et al. Efficacy and safety of rofecoxib in patients with chronic low back pain: results from two 4-week, randomized, placebo-controlled, parallel-group, double-blind trials. Spine. 2003;28:851-858.
PUBMED
52. Reines SA, Block GA, Morris JC, et al. Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004;62:66-71.
FREE FULL TEXT
53. Saag K, van der Heijde D, Fisher C, et al, Osteoarthritis Studies Group. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Arch Fam Med. 2000;9:1124-1134.
FREE FULL TEXT
54. Cannon GW, Caldwell JR, Holt P, et al, Rofecoxib Phase III Protocol 035 Study Group. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum. 2000;43:978-987.
PUBMED
55. Myllykangas-Luosujarvi R, Lu HS, Chen SL, et al. Comparison of low-dose rofecoxib versus 1000 mg naproxen in patients with osteoarthritis: results of two randomized treatment trals of six weeks duration. Scand J Rheumatol. 2002;31:337-344.
PUBMED
56. Targum SL. Consultation on NDA 21-042, S-007: review of cardiovascular safety database (on Vioxx or rofecoxib). US Food and Drug Administration memorandum. February 1, 2001. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.doc. Accessed August 25, 2006.57. Geusens PP, Truitt K, Sfikakis P, et al. A placebo and active comparator-controlled trial of rofecoxib for the treatment of rheumatoid arthritis. Scand J Rheumatol. 2002;31:230-238.
PUBMED
58. Kivitz AJ, Greenwald MW, Cohen SB, et al. Efficacy and safety of rofecoxib 12.5 mg versus nabumetone 1,000 mg in patients with osteoarthritis of the knee: a randomized controlled trial. J Am Geriatr Soc. 2004;52:666-674.
PUBMED
59. Schnitzer TJ, Weaver AL, Polis AB, Petruschke RA, Geba GP, VACT-1 and VACT-2 (Protocols 106 and 150) Study Groups. Efficacy of rofecoxib, celecoxib, and acetaminophen in patients with osteoarthritis of the knee. A combined analysis of the VACT studies. J Rheumatol. 2005;32:1093-1105.
FREE FULL TEXT
60. Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology. 2004;127:395-402.
PUBMED
61. Thal LJ, Ferris SH, Kirby L, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology. 2005;30:1204-1215.
PUBMED
62. Lisse JR, Perlman M, Johansson G, et al. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med. 2003;139:539-546. ADVANTAGE Study Group.
FREE FULL TEXT
63. Reid MS, Angrist B, Baker S, et al. A placebo-controlled screening trial of celecoxib for the treatment of cocaine dependence. Addiction. 2005;100(suppl 1):32-42.
PUBMED
64. Ta LE, Dionne RA. Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen. Pain. 2004;111:13-21.
PUBMED
65. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol. 2006;24:2723-2728.
FREE FULL TEXT
66. White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension. 2002;39:929-934.
FREE FULL TEXT
67. Jajic Z, Malaise M, Nekam K, et al. Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2005;23:809-818.
PUBMED
68. Dougados M, Behier JM, Jolchine I, et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum. 2001;44:180-185.
PUBMED
69. Chan FK, Hung LC, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002;347:2104-2110.
FREE FULL TEXT
70. Palmer R, Weiss R, Zusman RM, Haig A, Flavin S, MacDonald B. Effects of nabumetone, celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors. Am J Hypertens. 2003;16:135-139.
PUBMED
71. Kivitz AJ, Nayiager S, Schimansky T, Gimona A, Thurston HJ, Hawkey C. Reduced incidence of gastroduodenal ulcers associated with lumiracoxib compared with ibuprofen in patients with rheumatoid arthritis. Aliment Pharmacol Ther. 2004;19:1189-1198.
PUBMED
72. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol. 2001;30:11-18.
PUBMED
73. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet. 1999;354:2106-2111.
PUBMED
74. Fleischmann R, Sheldon E, Maldonado-Cocco J, Dutta D, Yu S, Sloan VS. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib. Clin Rheumatol. 2006;25:42-53.
PUBMED
75. Tannenbaum H, Berenbaum F, Reginster JY, et al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Ann Rheum Dis. 2004;63:1419-1426.
FREE FULL TEXT
76. Lisse J, Espinoza L, Zhao SZ, Dedhiya SD, Osterhaus JT. Functional status and health-related quality of life of elderly osteoarthritic patients treated with celecoxib. J Gerontol A Biol Sci Med Sci. 2001;56:M167-M175.
FREE FULL TEXT
77. Lehmann R, Brzosko M, Kopsa P, et al. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib. Curr Med Res Opin. 2005;21:517-526.
PUBMED
78. Zhao SZ, McMillen JI, Markenson JA, et al. Evaluation of the functional status aspects of health-related quality of life of patients with osteoarthritis treated with celecoxib. Pharmacotherapy. 1999;19:1269-1278.
PUBMED
79. Kivitz AJ, Moskowitz RW, Woods E, et al. Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip. J Int Med Res. 2001;29:467-479.
PUBMED
80. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999;282:1921-1928.
FREE FULL TEXT
81. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:1247-1255.
FREE FULL TEXT
82. White WB, Faich G, Whelton A, et al. Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol. 2002;89:425-430.
PUBMED
83. Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med. 2006;119:255-266.
PUBMED
84. Camu F, Beecher T, Recker DP, Verburg KM. Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty. Am J Ther. 2002;9:43-51.
PUBMED
85. Reynolds LW, Hoo RK, Brill RJ, North J, Recker DP, Verburg KM. The COX-2 specific inhibitor, valdecoxib, is an effective, opioid-sparing analgesic in patients undergoing total knee arthroplasty. J Pain Symptom Manage. 2003;25:133-141.
PUBMED
86. Coats TL, Borenstein DG, Nangia NK, Brown MT. Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial. Clin Ther. 2004;26:1249-1260.
PUBMED
87. Sikes DH, Agrawal NM, Zhao WW, Kent JD, Recker DP, Verburg KM. Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur J Gastroenterol Hepatol. 2002;14:1101-1111.
PUBMED
88. Bensen W, Weaver A, Espinoza L, et al. Efficacy and safety of valdecoxib in treating the signs and symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen. Rheumatology (Oxford). 2002;41:1008-1016.
FREE FULL TEXT
89. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125:1481-1492.
FREE FULL TEXT
90. Desjardins PJ, Traylor L, Hubbard RC. Analgesic efficacy of preoperative parecoxib sodium in an orthopedic pain model. J Am Podiatr Med Assoc. 2004;94:305-314.
FREE FULL TEXT
91. Stoltz RR, Harris SI, Kuss ME, et al. Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. Am J Gastroenterol. 2002;97:65-71.
PUBMED
92. Hubbard RC, Naumann TM, Traylor L, Dhadda S. Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia. Br J Anaesth. 2003;90:166-172.
FREE FULL TEXT
93. Rasmussen GL, Steckner K, Hogue C, Torri S, Hubbard RC. Intravenous parecoxib sodium foracute pain after orthopedic knee surgery. Am J Orthop. 2002;31:336-343.
PUBMED
94. Tsoukas C, Eyster ME, Shingo S, et al. Evaluation of the efficacy and safety of etoricoxib in the treatment of hemophilic arthropathy. Blood. 2006;107:1785-1790.
FREE FULL TEXT
95. Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum. 2004;50:598-606.
PUBMED
96. Rasmussen GL, Malmstrom K, Bourne MH, et al. Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery: a randomized, double-blind, placebo-controlled study. Anesth Analg. 2005;101:1104-1111.
FREE FULL TEXT
97. van der Heijde D, Baraf HS, Ramos-Remus C, et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study. Arthritis Rheum. 2005;52:1205-1215.
PUBMED
98. Pallay RM, Seger W, Adler JL, et al. Etoricoxib reduced pain and disability and improved quality of life in patients with chronic low back pain: a 3 month, randomized, controlled trial. Scand J Rheumatol. 2004;33:257-266.
PUBMED
99. Zerbini C, Ozturk ZE, Grifka J, et al. Efficacy of etoricoxib 60 mg/day and diclofenac 150 mg/day in reduction of pain and disability in patients with chronic low back pain: results of a 4-week, multinational, randomized, double-blind study. Curr Med Res Opin. 2005;21:2037-2049.
PUBMED
100. Leung AT, Malmstrom K, Gallacher AE, et al. Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: a randomized, double-blind, placebo and active-comparator controlled 12-week efficacy trial. Curr Med Res Opin. 2002;18:49-58.
PUBMED
101. Zacher J, Feldman D, Gerli R, et al. A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis. Curr Med Res Opin. 2003;19:725-736.
PUBMED
102. Wiesenhutter CW, Boice JA, Ko A, et al. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2005;80:470-479.
FREE FULL TEXT
103. Curtis SP, Bockow B, Fisher C, et al. Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double-blind, active-comparator controlled trial [NCT00242489]. BMC Musculoskelet Disord. 2005;6:58.
PUBMED
104. Gottesdiener K, Schnitzer T, Fisher C, et al. Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis. Rheumatology (Oxford). 2002;41:1052-1061.
FREE FULL TEXT
105. Hunt RH, Harper S, Callegari P, et al. Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib. Aliment Pharmacol Ther. 2003;17:201-210.
PUBMED
106. Matsumoto AK, Melian A, Mandel DR, et al. A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol. 2002;29:1581-1582.
FREE FULL TEXT
107. Collantes E, Curtis SP, Lee KW, et al. A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273]. BMC Fam Pract. 2002;3:10.
PUBMED
108. Arthritis & Drug Safety and Risk Management Advisory Committee Briefing Package. NDA 21-389 Etoricoxib. February 16-18, 2005. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090b1-01.htm. Accessed August 25, 2006.109. Schnitzer TJ, Beier J, Geusens P, et al. Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;51:549-557.
PUBMED
110. Geusens P, Alten R, Rovensky J, et al. Efficacy, safety and tolerability of lumiracoxib in patients with rheumatoid arthritis. Int J Clin Pract. 2004;58:1033-1041.
PUBMED
111. Arber N, Eagle CJ, Spicak J, et al, PreSAP Trial Investigators. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885-895.
FREE FULL TEXT
112. Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB. Arachidonic acid metabolism. Annu Rev Biochem. 1986;55:69-102.
PUBMED
113. Guan Y, Chang M, Cho W, et al. Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol. 1997;273:F18-F26.
PUBMED
114. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994;94:2504-2510.
PUBMED
115. Komhoff M, Grone HJ, Klein T, Seyberth HW, Nusing RM. Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function. Am J Physiol. 1997;272:F460-F468.
PUBMED
116. Nantel F, Meadows E, Denis D, Connolly B, Metters KM, Giaid A. Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly. FEBS Lett. 1999;457:475-477.
PUBMED
117. Stichtenoth DO, Marhauer V, Tsikas D, Gutzki FM, Frolich JC. Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers. Kidney Int. 2005;68:2197-2207.
PUBMED
118. Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med. 2000;160:1465-1470.
FREE FULL TEXT
119. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther. 1999;289:735-741.
FREE FULL TEXT
120. Chang IJ, Harris RC. Are all COX-2 inhibitors created equal? Hypertension. 2005;45:178-180.
FREE FULL TEXT
121. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96:7563-7568.
FREE FULL TEXT
122. Hermann M, Shaw S, Kiss E, et al. Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension. Hypertension. 2005;45:193-197.
FREE FULL TEXT
123. Hocherl K, Endemann D, Kammerl MC, Grobecker HF, Kurtz A. Cyclo-oxygenase-2 inhibition increases blood pressure in rats. Br J Pharmacol. 2002;136:1117-1126.
PUBMED
124. Richter CM, Godes M, Wagner C, et al. Chronic cyclooxygenase-2 inhibition does not alter blood pressure and kidney function in renovascular hypertensive rats. J Hypertens. 2004;22:191-198.
PUBMED
125. Pamuk ON, Cakir N. The renal effects of the addition of low-dose aspirin to COX-2 selective and nonselective antiinflammatory drugs. Clin Rheumatol. 2006;25:123-125.
PUBMED
126. Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. N Engl J Med. 2006;354:1193.
FREE FULL TEXT
127. Bombardier C, Laine L, Burgos-Vargas R, et al. Response to expression of concern regarding VIGOR study. N Engl J Med. 2006;354:1196-1199.
FREE FULL TEXT
128. Reicin A, Shapiro D. Response to expression of concern regarding VIGOR study. N Engl J Med. 2006;354:1196-1199.
FREE FULL TEXT
129. Egger M, Smith GD. Meta-analysis: potentials and promise. BMJ. 1997;315:1371-1374.
FREE FULL TEXT
130. Psaty BM, Furberg CD. COX-2 inhibitors–lessons in drug safety. N Engl J Med. 2005;352:1133-1135.
FREE FULL TEXT
131. Fontanarosa PB, Rennie D, DeAngelis CD. Postmarketing surveillance—lack of vigilance, lack of trust. JAMA. 2004;292:2647-2650.
FREE FULL TEXT
132. Ray WA, Stein CM. Reform of drug regulation—beyond an independent drug-safety board. N Engl J Med. 2006;354:194-201.
FREE FULL TEXT
133. Dieppe PA, Ebrahim S, Martin RM, Juni P. Lessons from the withdrawal of rofecoxib. BMJ. 2004;329:867-868.
FREE FULL TEXT
134. Berlin JA, Colditz GA. The role of meta-analysis in the regulatory process for foods, drugs, and devices. JAMA. 1999;281:830-834.
FREE FULL TEXT
135. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs. JAMA. 1999;281:824-829.
FREE FULL TEXT
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Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction
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Cyclooxygenase-2 Inhibitors and Most Traditional Nonsteroidal Anti-inflammatory Drugs Cause Similar Moderately Increased Risks of Cardiovascular Disease
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J CARDIOVASC PHARMACOL THER 2008;13:41-50.
ABSTRACT
Perioperative Versus Postoperative Celecoxib on Patient Outcomes After Major Plastic Surgery Procedures
Sun et al.
Anesth. Analg. 2008;106:950-958.
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Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?
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Ther Adv Cardiovasc Dis 2008;2:53-66.
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The patient, the drug and the kidney
DTB 2006;44:89-95.
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JDR 2006;85:1061-1073.
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COX-2 Inhibitors and NSAIDs: More Data on CV Risk
Journal Watch Cardiology 2006;2006:2-2.
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COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk: The Seduction of Common Sense
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