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James A Bolognese - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of the Comparative Efficacy and Tolerability of Rofecoxib and Naproxen in Children and Adolescents with Juvenile Rheumatoid Arthritis: A 12-Week Randomized Controlled Clinical Trial with a 52-Week Open-Label Extension
2020Co-Authors: Andreas Reiff, James A Bolognese, Daniel J Lovell, Janet Van Adelsberg, Maria H B Kiss, Steven Goodman, Manuel Ferrandiz Zavaler, Pei-yun Chen, Paul F Cavanaugh, Alise S ReicinAbstract:ABSTRACT. Objective. To compare the safety and efficacy of Rofecoxib* to naproxen for the treatment of juvenile rheumatoid arthritis (JRA). Methods. This was a 12-week, multicenter, randomized, double-blind, double-dummy, active comparator-controlled, non-inferiority study with a prespecified 52-week open-label active comparator-controlled extension. Children (ages 2-11 yrs) and adolescents (ages 12-17 yrs) received lower-dose (LD)-Rofecoxib [0.3 mg/kg/day up to 12.5 mg/day (base study only)]; or higher-dose (HD)-Rofecoxib (0.6 mg/kg/day up to 25 mg/day) or naproxen 15 mg/kg/day as oral suspensions. Adolescents received daily Rofecoxib (LD) 12.5 (base study only) or (HD) 25 mg, or naproxen 15 mg/kg/day (maximum 1000 mg/day) as tablets. The primary endpoint was the time-weighted average proportion of patients meeting the American College of Rheumatology Pediatric-30 (ACR Pedi 30) response criteria. A prespecified bound for the 95% confidence interval for the ratio of the percentage of ACR Pedi 30 responders was used to assess non-inferiority of treatment response between groups. Safety was assessed throughout the study
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peptic ulcer and bleeding events associated with Rofecoxib in a 3 year colorectal adenoma chemoprevention trial
Gastroenterology, 2007Co-Authors: Angel Lanas, Douglas J Watson, Hui Quan, James A Bolognese, John A Baron, Robert S Sandler, Kevin J Horgan, Bettina Oxenius, Tomas J Cook, Robert E SchoenAbstract:Background & Aims: Our aim was to establish the incidence of symptomatic upper gastrointestinal ulcers, ulcer perforation, ulcer obstruction, or bleeding episodes (PUBs) associated with the use of selective cyclooxygenase-2 inhibitors at standard clinical doses compared with placebo. We report here on the PUB outcomes associated with the use of Rofecoxib 25 mg in a 3-year, multicenter, double-blind, placebo-controlled trial designed to determine the effect of Rofecoxib on the risk of recurrent neoplastic polyps of the colon. Methods: A total of 2587 patients with a history of colorectal adenomas underwent randomization to 25 mg/day of Rofecoxib or to placebo. Investigator-reported PUBs were adjudicated by an external blinded committee. Kaplan–Meier and Cox proportional hazards techniques were used to estimate incidence and relative risks of PUBs in an intention-to-treat analysis. Results: Patients assigned to Rofecoxib had a higher incidence of confirmed PUBs than those randomized to placebo (.88 vs .18 events per 100 patient-years; relative risk, 4.9; 95% confidence interval, 1.98–14.54). The incidence of confirmed complicated PUBs (ulcer perforation, obstruction, or bleeds) was low, but was numerically higher in the Rofecoxib than in the placebo group (.23 vs .06 events per 100 patient-years; relative risk, 3.8; 95% confidence interval, .72–37.46; P = .14). Rofecoxib increased the incidence of confirmed PUBs vs placebo in both low-dose aspirin users and nonusers. Conclusions: Among patients with a history of colorectal adenomas, the long-term use of 25 mg/day of Rofecoxib was associated with an increased risk of clinically relevant upper gastrointestinal events when compared with placebo.
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cardiovascular events associated with Rofecoxib in a colorectal adenoma chemoprevention trial
The New England Journal of Medicine, 2005Co-Authors: Robert S Bresalier, Hui Quan, James A Bolognese, Robert S Sandler, Kevin J Horgan, Bettina Oxenius, Christopher Lines, Robert H Riddell, Dion Morton, Angel LanasAbstract:background Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor Rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with Rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. methods A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of Rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. results A total of 46 patients in the Rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the Rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the Rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. conclusions Among patients with a history of colorectal adenomas, the use of Rofecoxib was associated with an increased cardiovascular risk.
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gastrointestinal tolerability of the selective cyclooxygenase 2 cox 2 inhibitor Rofecoxib compared with nonselective cox 1 and cox 2 inhibitors in osteoarthritis
JAMA Internal Medicine, 2000Co-Authors: Douglas J Watson, Sean E Harper, Pengliang Zhao, Hui Quan, James A Bolognese, Thomas J SimonAbstract:Background Most nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective cyclooxygenase (COX-1 and COX-2) inhibitors and are associated with a variety of upper gastrointestinal (GI) tract symptoms. The roles of COX-1 and COX-2 in the pathogenesis of these symptoms are unclear. To test whether COX-2 inhibition with Rofecoxib would have greater GI tolerability than nonselective COX-1 and COX-2 inhibition, we compared the incidences of (1) treatment discontinuations for GI adverse events (AEs) and (2) prespecified dyspeptic-type GI AEs among patients with osteoarthritis treated with Rofecoxib vs NSAIDs. Methods A prespecified, combined analysis of investigator-reported GI AEs in all 8 double-blind, randomized, phase 2b/3 osteoarthritis trials of Rofecoxib was conducted. Patients included men and women with osteoarthritis (N = 5435); there was no upper age limit for entry. Treatments tested included Rofecoxib, 12.5, 25, or 50 mg (combined), vs ibuprofen, diclofenac, or nabumetone (combined). Primary outcomes were the time (by survival analysis) to (1) treatment discontinuation due to GI AEs and (2) first reported dyspeptic-type GI AE. Between-treatment comparisons were made by log-rank test. Results The number of treatment discontinuations caused by GI AEs during 12 months was significantly lower ( P = .02) with Rofecoxib vs NSAIDs (8.2 vs 12.0 per 100 patient-years; relative risk, 0.70; 95% confidence interval, 0.52-0.94). The incidence of prespecified dyspeptic-type GI AEs during the first 6 months was significantly lower ( P = .02) with Rofecoxib vs NSAIDs (69.3 vs 85.2 per 100 patient-years; relative risk, 0.85; 95% confidence interval, 0.74-0.97). However, the difference between treatments in dyspeptic-type GI AEs was attenuated after 6 months. Conclusion Rofecoxib was associated with a lower incidence of treatment discontinuations due to GI AEs over 12 months and a lower incidence of dyspeptic-type GI AEs over 6 months than treatment with nonselective COX inhibitors, or NSAIDs.
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a randomized trial of the efficacy and tolerability of the cox 2 inhibitor Rofecoxib vs ibuprofen in patients with osteoarthritis
JAMA Internal Medicine, 2000Co-Authors: Ric O Day, Briggs W Morrison, Brian Daniels, Armando Luza, Oswaldo Castaneda, Alberto Strusberg, Menachem Nahir, Knut Bjorn Helgetveit, Barbara Kress, James A BologneseAbstract:Background Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). It is not known whether a specific inhibitor of COX-2 will provide efficacy in osteoarthritis (OA) comparable with NSAIDs. Therefore, we compared the efficacy and safety of the Rofecoxib, which specifically inhibits COX-2, with those of the NSAID ibuprofen in patients with OA. Objective To compare the clinical efficacy and tolerability of Rofecoxib (12.5 and 25 mg once daily) with ibuprofen (800 mg 3 times daily). Methods A randomized, double-blind trial of 809 adults with OA was conducted. Patients with OA in whom the knee or hip was the primary source of pain were randomized to 1 of 4 treatment groups on demonstration of disease activity: placebo; Rofecoxib, 12.5 or 25 mg once daily; or ibuprofen, 800 mg 3 times daily. Clinical efficacy and safety were monitored during a 6-week treatment period. Results Both doses of Rofecoxib demonstrated efficacy clinically comparable with ibuprofen as assessed by 3 primary end points (pain walking on a flat surface [Western Ontario and McMaster Universities Osteoarthritis Index], patient global assessment of response to therapy, and investigator global assessment of disease status) according to predefined comparability criteria. Both Rofecoxib doses and the ibuprofen dose provided significantly (P .05) among the treatment groups. Conclusion Rofecoxib was well tolerated and provided clinical efficacy comparable with a high dose of the NSAID ibuprofen.
Alise S Reicin - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of the Comparative Efficacy and Tolerability of Rofecoxib and Naproxen in Children and Adolescents with Juvenile Rheumatoid Arthritis: A 12-Week Randomized Controlled Clinical Trial with a 52-Week Open-Label Extension
2020Co-Authors: Andreas Reiff, James A Bolognese, Daniel J Lovell, Janet Van Adelsberg, Maria H B Kiss, Steven Goodman, Manuel Ferrandiz Zavaler, Pei-yun Chen, Paul F Cavanaugh, Alise S ReicinAbstract:ABSTRACT. Objective. To compare the safety and efficacy of Rofecoxib* to naproxen for the treatment of juvenile rheumatoid arthritis (JRA). Methods. This was a 12-week, multicenter, randomized, double-blind, double-dummy, active comparator-controlled, non-inferiority study with a prespecified 52-week open-label active comparator-controlled extension. Children (ages 2-11 yrs) and adolescents (ages 12-17 yrs) received lower-dose (LD)-Rofecoxib [0.3 mg/kg/day up to 12.5 mg/day (base study only)]; or higher-dose (HD)-Rofecoxib (0.6 mg/kg/day up to 25 mg/day) or naproxen 15 mg/kg/day as oral suspensions. Adolescents received daily Rofecoxib (LD) 12.5 (base study only) or (HD) 25 mg, or naproxen 15 mg/kg/day (maximum 1000 mg/day) as tablets. The primary endpoint was the time-weighted average proportion of patients meeting the American College of Rheumatology Pediatric-30 (ACR Pedi 30) response criteria. A prespecified bound for the 95% confidence interval for the ratio of the percentage of ACR Pedi 30 responders was used to assess non-inferiority of treatment response between groups. Safety was assessed throughout the study
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cardiovascular thrombotic events in controlled clinical trials of Rofecoxib
Circulation, 2002Co-Authors: Marvin A Konstam, Matthew R Weir, Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav Barr, Barry J GertzAbstract:Background In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor Rofecoxib, one study demonstrated a significant difference between Rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with Rofecoxib compared with those treated with placebo or nonselective NSAIDs. Methods and Results CV thrombotic events were assessed across 23 phase IIb to V Rofecoxib studies. Comparisons were made between patients taking Rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonsele...
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comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti inflammatory drugs ibuprofen diclofenac and nabumetone
American Journal of Cardiology, 2002Co-Authors: Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav Barr, Qinfen YuAbstract:Abstract Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1–mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving Rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists’ Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared Rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the Rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared Rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the Rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the Rofecoxib osteoarthritis development program, there was no difference between Rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
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comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti inflammatory drugs ibuprofen diclofenac and nabumetone
American Journal of Cardiology, 2002Co-Authors: Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav BarrAbstract:Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving Rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared Rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the Rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared Rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the Rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the Rofecoxib osteoarthritis development program, there was no difference between Rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
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comparison of upper gastrointestinal toxicity of Rofecoxib and naproxen in patients with rheumatoid arthritis
The New England Journal of Medicine, 2000Co-Authors: Claire Bombardier, C J Hawkey, Loren Laine, Alise S Reicin, Deborah R Shapiro, Ruben Burgosvargas, Barry R Davis, Marcos Bosi Ferraz, Marc C Hochberg, Tore K KvienAbstract:Background Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether Rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. Methods We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of Rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Results Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed ga...
Eliav Barr - One of the best experts on this subject based on the ideXlab platform.
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cardiovascular thrombotic events in controlled clinical trials of Rofecoxib
Circulation, 2002Co-Authors: Marvin A Konstam, Matthew R Weir, Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav Barr, Barry J GertzAbstract:Background In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor Rofecoxib, one study demonstrated a significant difference between Rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with Rofecoxib compared with those treated with placebo or nonselective NSAIDs. Methods and Results CV thrombotic events were assessed across 23 phase IIb to V Rofecoxib studies. Comparisons were made between patients taking Rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonsele...
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comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti inflammatory drugs ibuprofen diclofenac and nabumetone
American Journal of Cardiology, 2002Co-Authors: Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav Barr, Qinfen YuAbstract:Abstract Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1–mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving Rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists’ Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared Rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the Rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared Rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the Rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the Rofecoxib osteoarthritis development program, there was no difference between Rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
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comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti inflammatory drugs ibuprofen diclofenac and nabumetone
American Journal of Cardiology, 2002Co-Authors: Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav BarrAbstract:Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving Rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared Rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the Rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared Rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the Rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the Rofecoxib osteoarthritis development program, there was no difference between Rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
Peggy Wong - One of the best experts on this subject based on the ideXlab platform.
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Rofecoxib a cox 2 inhibitor does not inhibit human gastric mucosal prostaglandin production
Gastroenterology, 2001Co-Authors: Nicholas J Wight, Peggy Wong, Barry J Gertz, Keith Gottesdiener, Nigel M Garlick, Clare T Atherton, S U E Novak, Nicole Calder, Josee Cote, Aimee DallobAbstract:Abstract Background & Aims: Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof. Methods: Twenty-four healthy, nonsmoking Helicobacter pylori –negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received Rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E 2 (PGE 2 ) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB) 2 - and COX-2 activity as lipopolysaccharide (LPS)-induced PGE 2 . Results: Naproxen decreased gastric mucosal PGE 2 synthesis by 65% (90% confidence interval [CI], 53%–74%; P = 0.001 vs. placebo) in contrast to an 18% increase after Rofecoxib (90% CI, −11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB 2 by 94% and LPS-induced PGE 2 production by 77% (both P ≤ 0.002 vs. placebo), but Rofecoxib only inhibited COX-2–dependent LPS-induced PGE 2 (by 79%; P Conclusions: Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins. GASTROENTEROLOGY 2001;120:867-873
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comparative inhibitory activity of Rofecoxib meloxicam diclofenac ibuprofen and naproxen on cox 2 versus cox 1 in healthy volunteers
The Journal of Clinical Pharmacology, 2000Co-Authors: Anne Van Hecken, Aimee Dallob, Jules I Schwartz, Marleen Depre, Inge De Lepeleire, Wesley Tanaka, Kathleen Wynants, Agnes Buntinx, Jef Arnout, Peggy WongAbstract:Steady-state inhibitory activity of Rofecoxib (Vioxx™) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, Rofecoxib 12.5 mg qd, Rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was −2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, Rofecoxib 12.5 mg, Rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were −5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX- 1-derived product. These data support the contention that Rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.
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comparative inhibitory activity of Rofecoxib meloxicam diclofenac ibuprofen and naproxen on cox 2 versus cox 1 in healthy volunteers
The Journal of Clinical Pharmacology, 2000Co-Authors: Anne Van Hecken, Aimee Dallob, Jules I Schwartz, Marleen Depre, Inge De Lepeleire, Wesley Tanaka, Kathleen Wynants, Agnes Buntinx, Jef Arnout, Peggy WongAbstract:Steady-state inhibitory activity of Rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, Rofecoxib 12.5 mg qd, Rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, Rofecoxib 12.5 mg, Rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that Rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.
Deborah R Shapiro - One of the best experts on this subject based on the ideXlab platform.
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cardiovascular thrombotic events in controlled clinical trials of Rofecoxib
Circulation, 2002Co-Authors: Marvin A Konstam, Matthew R Weir, Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav Barr, Barry J GertzAbstract:Background In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor Rofecoxib, one study demonstrated a significant difference between Rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with Rofecoxib compared with those treated with placebo or nonselective NSAIDs. Methods and Results CV thrombotic events were assessed across 23 phase IIb to V Rofecoxib studies. Comparisons were made between patients taking Rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonsele...
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comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti inflammatory drugs ibuprofen diclofenac and nabumetone
American Journal of Cardiology, 2002Co-Authors: Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav Barr, Qinfen YuAbstract:Abstract Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1–mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving Rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists’ Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared Rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the Rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared Rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the Rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the Rofecoxib osteoarthritis development program, there was no difference between Rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
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comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with Rofecoxib versus nonselective nonsteroidal anti inflammatory drugs ibuprofen diclofenac and nabumetone
American Journal of Cardiology, 2002Co-Authors: Alise S Reicin, Deborah R Shapiro, Rhoda S Sperling, Eliav BarrAbstract:Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving Rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared Rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the Rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared Rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the Rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with Rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the Rofecoxib osteoarthritis development program, there was no difference between Rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
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comparison of upper gastrointestinal toxicity of Rofecoxib and naproxen in patients with rheumatoid arthritis
The New England Journal of Medicine, 2000Co-Authors: Claire Bombardier, C J Hawkey, Loren Laine, Alise S Reicin, Deborah R Shapiro, Ruben Burgosvargas, Barry R Davis, Marcos Bosi Ferraz, Marc C Hochberg, Tore K KvienAbstract:Background Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether Rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. Methods We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of Rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Results Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed ga...
