Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase-1 (COX-1), an enzyme critical to normal platelet function, and COX-2, which mediates inflammatory ...response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses, is expected to have minimal effects on platelet function. A double-blind, randomized, placebo-controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 a thromboxane A2 receptor agonist), bleeding time, and serum thromboxane B2 (TxB2) level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX), which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostaglandins. Gastrointestinal ...injury is a common outcome. We compared the efficacy, safety, and tolerability of long-term therapy with celecoxib, a COX-1 sparing inhibitor of COX-2, with diclofenac, a non-specific COX inhibitor.
655 patients with adult-onset rheumatoid arthritis of at least 6 months' duration were randomly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks. Anti-inflammatory and analgesic activity and tolerability were assessed at baseline, every 4 weeks, and at week 24. We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available. Analysis was by intention-to-treat.
430 patients underwent endoscopy (celecoxib n=212, diclofenac n=218). The two drugs were similar in management of rheumatoid arthritis pain and inflammation. Gastroduodenal ulcers were detected endoscopically in 33 (15%) patients treated with diclofenac and in eight (4%) in the celecoxib group (p<0.001). The rate of withdrawal for any gastrointestinal-related adverse event, most commonly abdominal pain, diarrhoea, and dyspepsia, was nearly three times higher in the diclofenac-treated group than in the celecoxib group (16 vs 6%; p<0.001).
Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac, with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events, and tolerability was better.
It has been hypothesized that cyclooxgenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and ...lack of an effect on platelet thromboxane A
2 production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (≤325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxgenase 2 specific inhibitors on the CV system.
The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 ...inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs).
A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2-24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25-400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100-400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patient's treatment assignment or the study in which the patient participated.
In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05 vs placebo) and 1.68% for NSAIDs (p = 0.002 vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%.
The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.
To compare the efficacy and safety of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with those of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), and placebo in the treatment of ...osteoarthritis of the knee.
In this multicenter, randomized, double-blind, placebo-controlled trial, 1003 patients with symptomatic osteoarthritis of the knee were randomly assigned to receive celecoxib at doses of 50, 100, or 200 mg twice a day; naproxen, 500 mg twice a day; or placebo for 12 weeks. Patients were evaluated with standard measures of efficacy 2 to 7 days after discontinuing previous NSAID or analgesic therapy and after 2, 6, and 12 weeks of treatment with the study drug.
Celecoxib treatment led to significant improvement in the signs and symptoms of osteoarthritis as determined by all efficacy measures. Significant pain relief occurred within 2 days of the initiation of treatment, and maximum anti-inflammatory and analgesic activity, evident within 2 weeks, was sustained throughout the 12-week study. All celecoxib doses were efficacious compared with placebo, although the 50-mg twice-daily dosage regimen was minimally effective. The higher doses of celecoxib (100 and 200 mg twice a day) were similarly efficacious, and the magnitude of improvement observed with these dosing regimens was comparable to that seen with naproxen at a dose of 500 mg twice a day. All doses of celecoxib and naproxen were well tolerated.
COX-2 inhibition with celecoxib is an effective approach for the treatment of osteoarthritis, as seen by clinical improvement in signs and symptoms comparable to treatment with naproxen.
CONTEXT In vitro studies have shown that celecoxib inhibits cyclooxygenase 2
(COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory
and analgesic activity without adverse upper ...gastrointestinal (GI) tract effects
that result from COX-1 inhibition. OBJECTIVE To test whether celecoxib has efficacy as an anti-inflammatory and analgesic
with reduced GI tract mucosal damage compared with conventional nonsteroidal
anti-inflammatory drugs in patients with rheumatoid arthritis. DESIGN Randomized, multicenter, placebo-controlled, double-blind trial lasting
12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh
February 1998. SETTING Seventy-nine clinical sites in the United States and Canada. PATIENTS A total of 1149 patients aged 18 years or older with symptomatic rheumatoid
arthritis who met inclusion criteria were randomized; 688 (60%) of these completed
the study. INTERVENTIONS Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400
mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice
per day (n = 225); or placebo (n = 231). MAIN OUTCOME MEASURES Improvement in signs and symptoms of rheumatoid arthritis as assessed
using standard measures of efficacy and GI tract safety as assessed by upper
GI tract endoscopy before and after treatment, compared among treatment groups. RESULTS All dosages of celecoxib and naproxen significantly improved the signs
and symptoms of arthritis compared with placebo. Maximal anti-inflammatory
and analgesic activity was evident within 2 weeks of initiating treatment
and was sustained throughout the 12 weeks. The incidence of endoscopically
determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of
99, and the incidences across all dosages of celecoxib were not significantly
different (P>.40): 9 (6%) of 148 with 100 mg twice
per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400
mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of
137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were
19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg
twice per day, respectively; and 31% for naproxen. CONCLUSION In this study, all dosages of celecoxib were efficacious in the treatment
of rheumatoid arthritis and did not affect COX-1 activity in the GI tract
mucosa as evidenced by less frequent incidence of endoscopic ulcers compared
with naproxen.
Background:
Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal anti-inflammatory drugs; however, both types of medications are associated ...with side effects that can limit their usefulness in the outpatient setting.
Objective:
Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy and tolerability of celecoxib, a specific cyclooxygenase-2 inhibitor, in the treatment of acute pain after orthopedic surgery.
Methods:
These were multicenter, randomized, placebo- and active-controlled, double-blind, parallel-group trials conducted between January and June 1998. Both consisted of a single-dose assessment period (SDAP) and a multiple-dose assessment period (MDAP). In the SDAP, patients who had undergone orthopedic surgery received a single oral dose of celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo within 24 hours after the end of anesthesia, with pain assessments conducted over the following 8-hour period. In the MDAP, extending from 8 hours after the first dose of study medication up to 5 days, patients who had received ≤1 dose of rescue medication during the SDAP continued on study medication (placebo recipients were rerandomized to active treatment), which could be taken up to 3 times a day as needed.
Results:
A total of 418 patients were enrolled in the 2 trials. During the SDAP, 141 patients received celecoxib, 136 received hydrocodone/acetaminophen, and 141 received placebo. During the MDAP, 185 patients received celecoxib and 181 received hydrocodone/acetaminophen. When the combined data were analyzed, mean pain intensity difference (PID) scores generally favored the active treatments over placebo from 1 to 6 hours (with the exception of 1.5 hours) after dosing (
P ≤ 0.016) and favored celecoxib over the other treatments at 7 and 8 hours after dosing (
P < 0.001). The active treatments demonstrated superior summed PID scores through 8 hours (
P < 0.001), significantly shorter median times to onset of analgesia (
P < 0.05), and significantly longer median times to first use of rescue medication (
P < 0.05). During the MDAP, more hydrocodone/acetaminophen-treated patients (20%) than celecoxib-treated patients (12%) required rescue medication (
P < 0.05), and the celecoxib group had significantly lower maximum pain intensity scores (
P < 0.001, days 2–5), required fewer doses of study medication (
P ≤ 0.01, days 3–5), and had superior scores on a modified American Pain Society Patient Outcome Questionnaire (
P ≤ 0.013). In addition, a significantly lower proportion of celecoxib-treated patients experienced adverse events (43%) compared with hydrocodone/acetaminophen-treated patients (89%;
P < 0.001).
Conclusions:
Over 8 hours, patients with moderate to severe pain after orthopedic surgery experienced comparable analgesia with single doses of celecoxib and hydrocodone/acetaminophen. Over a 5-day period, oral doses of celecoxib 200 mg taken 3 times a day demonstrated superior analgesia and tolerability compared with hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day. Most patients required no more than 2 daily doses of celecoxib 200 mg for the control of their postorthopedic surgical pain.
CONTEXT Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated
with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because
of inhibition of cyclooxygenase ...(COX)-1. Whether COX-2–specific inhibitors
are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE To determine whether celecoxib, a COX-2–specific inhibitor, is
associated with a lower incidence of significant upper GI toxic effects and
other adverse effects compared with conventional NSAIDs. DESIGN The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind,
randomized controlled trial conducted from September 1998 to March 2000. SETTING Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS A total of 8059 patients (≥18 years old) with osteoarthritis (OA)
or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received
at least 1 dose of study drug. A total of 4573 patients (57%) received treatment
for 6 months. INTERVENTIONS Patients were randomly assigned to receive celecoxib, 400 mg twice per
day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987);
ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per
day (n = 1996). Aspirin use for cardiovascular prophylaxis (≤325 mg/d)
was permitted. MAIN OUTCOME MEASURES Incidence of prospectively defined symptomatic upper GI ulcers and ulcer
complications (bleeding, perforation, and obstruction) and other adverse effects
during the 6-month treatment period. RESULTS For all patients, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76%
vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized
incidence rates of upper GI ulcer complications alone and combined with symptomatic
ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P
= .04) and 1.40% vs 2.91% (P = .02). For patients
taking aspirin, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01%
vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients
experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal
toxicity. No difference was noted in the incidence of cardiovascular events
between celecoxib and NSAIDs, irrespective of aspirin use. CONCLUSIONS In this study, celecoxib, at dosages greater than those indicated clinically,
was associated with a lower incidence of symptomatic ulcers and ulcer complications
combined, as well as other clinically important toxic effects, compared with
NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest
among patients not taking aspirin concomitantly.
To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, ...in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs).
6-month randomized, double-blind, placebo-controlled trial.
664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada.
8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993.
Patients were randomly assigned to receive 200 micrograms of misoprostol or placebo four times a day.
Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy).
Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 95% CI, 0.364 to 0.982; P = 0.049) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P < 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months.
In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo.
Objective:
The purpose of this study was to compare the efficacy and tolerability of a celecoxib 200 mg QD regimen with a 100 mg BID regimen in patients with osteoarthritis (OA) of the knee.
Methods:
...Patients enrolled in this prospective, double-blind, placebo-controlled, parallel-group, multicenter study were randomly assigned to receive celecoxib 100 mg BID, celecoxib 200 mg QD, or placebo for 6 weeks. Assessments of OA severity (Patient's and Physician's Global Assessments of Arthritis, Patient's Assessment of Arthritis Pain—Visual Analog Scale, Lequesne Osteoarthritis Severity Index, and the Western Ontario and McMaster Universities Osteoarthritis Index) were performed at baseline and at week 2 and/or 6. Patients who discontinued treatment underwent assessments at the time of withdrawal from the study.
Results:
Of the 718 patients enrolled, 243 received celecoxib 100 mg BID, 231 received celecoxib 200 mg QD, and 244 received placebo. For all measures of efficacy, at all assessments, improvements from baseline in both celecoxib groups were superior to that seen in the placebo group (
P < 0.05). No significant differences in efficacy between the celecoxib groups were observed. The overall incidence of adverse events was similar in the 2 celecoxib treatment groups.
Conclusions:
Dosing regimens of celecoxib 200 mg QD and 100 mg BID are equally effective and well tolerated in patients with OA of the knee. The availability of 2 effective regimens provides patients and physicians with increased flexibility in the selection of an appropriate dosing regimen for celecoxib therapy.
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