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Sean P Curtis - One of the best experts on this subject based on the ideXlab platform.
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perioperative use of Etoricoxib reduces pain and opioid side effects after total abdominal hysterectomy a double blind randomized placebo controlled phase iii study
Current Medical Research and Opinion, 2012Co-Authors: Eugene R Viscusi, Tara L Frenkl, Craig T Hartrick, Narinder Rawal, Henrik Kehlet, Dimitris Papanicolaou, Arnold R Gammaitoni, L Morgan, Anish Mehta, Sean P CurtisAbstract:AbstractObjective:To evaluate the effects of two different doses of Etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively.Research design and methods:In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or Etoricoxib administered 90 min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (n = 144), Etoricoxib 90 mg/day (n = 142), or Etoricoxib 120 mg/day (n = 144). Average Pain Intensity at Rest over days 1–3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1–3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1–3.Clinical trial registration...
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baseline factors associated with congestive heart failure in patients receiving Etoricoxib or diclofenac multivariate analysis of the medal program
European Journal of Heart Failure, 2009Co-Authors: Henry Krum, Sean P Curtis, Amarjot Kaur, Loren Laine, Hongwei Wang, Steven S Smugar, Matthew R Weir, Craig D Brater, Christopher P CannonAbstract:Aims Non-steroidal anti-inflammatory drugs have been associated with increased risk of congestive heart failure (CHF). We aimed to assess the impact of treatment with Etoricoxib or diclofenac on risk of CHF relative to baseline risk factors. Methods and results We performed a multivariate analysis of 34 701 patients with arthritis receiving Etoricoxib 60 or 90 mg, or diclofenac 150 mg, daily for a mean of 18 months, to assess the incidence of confirmed, adjudicated CHF events resulting in emergency room visit or hospitalization. Analyses were performed using a Cox proportional hazard model to evaluate the hazard ratio (HR) between the levels of each risk marker for the incidence of CHF. Significant risk markers included history of CHF (HR: 6.69, 95% CI 3.59–12.47; P <0.0001), age ≥65 years (2.56, 1.65–3.98; P <0.0001), and history of hypertension (1.83, 1.16–2.89; P = 0.0094) or diabetes (1.83, 1.15–2.94; P = 0.0116). Etoricoxib vs. diclofenac was a significant risk factor only when pooling the Etoricoxib 90 mg cohorts (1.88; 1.13–3.10; P = 0.0143). Etoricoxib 60 mg did not significantly increase risk vs. diclofenac. Conclusion History of CHF was highly associated with risk for CHF hospitalization. Hypertension, diabetes, and older age also increased risk modestly. There appeared to be a dose-related increase in CHF with Etoricoxib compared with diclofenac, which reached statistical significance when the Etoricoxib 90 mg groups (osteoarthritis and rheumatoid arthritis) were pooled. (Clinicaltrials.gov: NCT00092703, NCT00092742, NCT00250445).
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cardiovascular safety and gastrointestinal tolerability of Etoricoxib vs diclofenac in a randomized controlled clinical trial the medal study
Rheumatology, 2009Co-Authors: B Combe, Sean P Curtis, Gary Swergold, James S Mclay, Timothy Mccarthy, C Zerbini, Paul Emery, Laurine Connors, Amarjot Kaur, Loren LaineAbstract:Objective. To compare cardiovascular (CV) and other safety and efficacy parameters of Etoricoxib 60 and 90 mg, and diclofenac 150 mg. Methods. This double-blind study randomized OA patients to Etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to Etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of Etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on Etoricoxib dose and disease. Results. A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR) (Etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of Etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for Etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with Etoricoxib was 3.4–3.6 mmHg (diastolic BP: 1.0–1.5 mmHg), while diclofenac produced a maximum average change of 0.9–1.9 mmHg (diastolic BP: 0.0–0.5 mmHg). Both agents resulted in similar efficacy regardless of Etoricoxib dose. Conclusion. Long-term Etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, Etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.
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factors associated with blood pressure changes in patients receiving diclofenac or Etoricoxib results from the medal study
Journal of Hypertension, 2009Co-Authors: Henry Krum, Sean P Curtis, Gary Swergold, Amarjot Kaur, Loren Laine, Hongwei Wang, Steven S Smugar, Matthew R Weir, Craig D Brater, Christopher P CannonAbstract:ObjectiveTo evaluate the hypertensive effects of Etoricoxib and diclofenac relative to baseline hypertension risk factors in arthritis patients.MethodsMultivariate analysis of data from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study (n = 23 504). We evaluated risk fact
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evaluation of the efficacy and safety of Etoricoxib compared with naproxen in two 138 week randomised studies of patients with osteoarthritis
Annals of the Rheumatic Diseases, 2007Co-Authors: Jeanyves Reginster, Sean P Curtis, K Malmstrom, A Mehta, G Bergman, Alise S ReicinAbstract:Objectives: To assess the efficacy and safety of Etoricoxib 60 mg once daily and naproxen 500 mg twice daily over a 138-week treatment period in patients with osteoarthritis (OA). Methods: Two 1-year randomized, double-blind, parallel-group 2-part base studies (Part I 12 weeks; Part II 40 weeks), followed by an 86-week extension, in OA (hip or knee) patients were conducted at 80 clinical centers (19 countries). The studies had identical designs. Patients taking placebo in Part I received Etoricoxib or naproxen (1:1 ratio) in Part II and the Extension; patients taking Etoricoxib or naproxen in Part I remained on the same treatment throughout the entire length of the studies. Co-primary efficacy endpoints were Patient Global Assessment of Disease Status, and WOMAC questionnaire Pain Subscale and Physical Function Subscale (100mm VAS). Efficacy over 138-weeks was assessed by graphical analysis. Safety was assessed by observation of adverse experiences and laboratory and physical evaluations. Results: There were 997 patients who entered (615 completed) the Base studies. Of these patients, 463 patients entered the Extensions. A total of 161 and 151 patients in the Etoricoxib and naproxen groups, respectively, completed 138-treatment weeks. Etoricoxib and naproxen showed similar efficacy throughout the 138 weeks of therapy. For Etoricoxib and naproxen, respectively, WOMAC Pain assessments were: 67 and 67 mm (baseline); 28 and 29 mm (1-year), and 34 and 33mm (138- weeks). Results for the other efficacy endpoints were similar to those seen with the WOMAC Pain assessments. Both Etoricoxib and naproxen were generally well tolerated. Conclusion: Both Etoricoxib and naproxen demonstrated long-term clinical efficacy for the treatment of OA. Etoricoxib and naproxen were generally well tolerated.
Alise S Reicin - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the efficacy and safety of Etoricoxib compared with naproxen in two 138 week randomised studies of patients with osteoarthritis
Annals of the Rheumatic Diseases, 2007Co-Authors: Jeanyves Reginster, Sean P Curtis, K Malmstrom, A Mehta, G Bergman, Alise S ReicinAbstract:Objectives: To assess the efficacy and safety of Etoricoxib 60 mg once daily and naproxen 500 mg twice daily over a 138-week treatment period in patients with osteoarthritis (OA). Methods: Two 1-year randomized, double-blind, parallel-group 2-part base studies (Part I 12 weeks; Part II 40 weeks), followed by an 86-week extension, in OA (hip or knee) patients were conducted at 80 clinical centers (19 countries). The studies had identical designs. Patients taking placebo in Part I received Etoricoxib or naproxen (1:1 ratio) in Part II and the Extension; patients taking Etoricoxib or naproxen in Part I remained on the same treatment throughout the entire length of the studies. Co-primary efficacy endpoints were Patient Global Assessment of Disease Status, and WOMAC questionnaire Pain Subscale and Physical Function Subscale (100mm VAS). Efficacy over 138-weeks was assessed by graphical analysis. Safety was assessed by observation of adverse experiences and laboratory and physical evaluations. Results: There were 997 patients who entered (615 completed) the Base studies. Of these patients, 463 patients entered the Extensions. A total of 161 and 151 patients in the Etoricoxib and naproxen groups, respectively, completed 138-treatment weeks. Etoricoxib and naproxen showed similar efficacy throughout the 138 weeks of therapy. For Etoricoxib and naproxen, respectively, WOMAC Pain assessments were: 67 and 67 mm (baseline); 28 and 29 mm (1-year), and 34 and 33mm (138- weeks). Results for the other efficacy endpoints were similar to those seen with the WOMAC Pain assessments. Both Etoricoxib and naproxen were generally well tolerated. Conclusion: Both Etoricoxib and naproxen demonstrated long-term clinical efficacy for the treatment of OA. Etoricoxib and naproxen were generally well tolerated.
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evaluation of the efficacy and safety of Etoricoxib in the treatment of hemophilic arthropathy
Blood, 2006Co-Authors: Christos M Tsoukas, Elaine M Eyster, Sumiko Shingo, Saurabh Mukhopadhyay, Karen M Giallella, Sean P Curtis, Alise S Reicin, Agustin MelianAbstract:This 2-part, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of Etoricoxib, a COX-2 selective inhibitor, for the treatment of hemophilic arthropathy. In part 1 (6 weeks), 102 patients (≥ 12 years old) with hemophilic arthropathy were randomized to receive 90 mg Etoricoxib once daily or placebo (1:1 ratio). In part 2 (6 months), 51 patients taking placebo in part 1 were randomized to receive 90 mg Etoricoxib or 25 mg rofecoxib once daily; patients taking Etoricoxib in part 1 continued the same treatment. Efficacy end points included Patient Assessment of Arthropathy Pain, Patient Global Assessment of Arthropathy Disease Status, and Investigator Global Assessment of Arthropathy Disease Status. Safety was evaluated at each study visit. Etoricoxib provided significant improvement in all end points versus placebo (P < .001). Fewer patients taking Etoricoxib discontinued due to a lack of efficacy versus placebo (P = .048). During part 2, efficacy was maintained; Etoricoxib and rofecoxib demonstrated similar results. The most common adverse experiences were upper respiratory infection and headache. The incidence of joint bleeding during part 1 was similar between Etoricoxib (66.7%) and placebo (72.6%) and during part 2 between Etoricoxib (77.0%) and rofecoxib (78.9%). We conclude that Etoricoxib provided superior efficacy versus placebo for the treatment of hemophilic arthropathy and was generally safe and well tolerated.
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the incidence of upper gastrointestinal adverse events in clinical trials of Etoricoxib vs non selective nsaids an updated combined analysis
Current Medical Research and Opinion, 2005Co-Authors: Dena R Ramey, Sean P Curtis, James A Bolognese, Douglas J Watson, Alise S ReicinAbstract:ABSTRACTObjective: In spite of numerous studies demonstrating the serious gastrointestinal (GI) toxicity associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), many patients at high GI risk continue to receive prescriptions for these drugs, often without gastroprotective agents. Etoricoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than non-selective NSAIDs. We compared the incidence of upper GI Perforations, symptomatic gastroduodenal Ulcers, and upper GI Bleeding (PUBs) in a combined analysis of all randomized, double-blind, clinical trials of chronic treatment with Etoricoxib versus NSAIDs completed by June 2003.Research design and methods: Data for 5441 individual subjects with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis were pooled from all 10 multinational Etoricoxib trials completed by June 2003. Information on suspected PUBs was prospectively collected in all protocols, and all investigator-reported PUBs we...
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evaluation of the efficacy of Etoricoxib in ankylosing spondylitis results of a fifty two week randomized controlled study
Arthritis & Rheumatism, 2005Co-Authors: Desiree Van Der Heijde, Alise S Reicin, Herbert S B Baraf, Cesar Ramosremus, A Calin, Arthur L Weaver, Michael Schiff, Margaret James, Jan E Markind, Agustin MelianAbstract:Objective To assess the efficacy, safety, and tolerability of Etoricoxib, a cyclooxygenase 2 (COX-2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS). Methods This 2-part, multicenter, double-blind, parallel-group, 52-week study evaluated 2 doses of Etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6-week, active-comparator- and placebo-controlled period (part I) was followed by a 46-week active-comparator-controlled period (part II). The primary outcome measures (on 100-mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index. Results Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg Etoricoxib, 120 mg Etoricoxib, and naproxen demonstrated significantly (P Conclusion Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that Etoricoxib is generally safe, well-tolerated, and efficacious for the treatment of AS.
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evaluation of the comparative efficacy of Etoricoxib and ibuprofen for treatment of patients with osteoarthritis a randomized double blind placebo controlled trial
Mayo Clinic Proceedings, 2005Co-Authors: Craig W Wiesenhutter, Judith A Boice, Eric A Sheldon, Frederick T Murphy, Bret A Wittmer, Michelle L Aversano, Alise S ReicinAbstract:OBJECTIVE To directly compare the efficacy and safety of Etoricoxib, 30 mg once daily, ibuprofen, 800 mg 3 times daily, and placebo for treatment of osteoarthritis (OA) of the hip and knee. PATIENTS AND METHODS A randomized, double-blind, placebocontrolled trial of patients with OA of the knee or hip was performed between February 2003 and November 2003 in 61 medical centers in the United States. Qualified patients aged 40 to 89 years were randomized to receive placebo, Etoricoxib, 30 mg once daily, or ibuprofen, 800 mg 3 times daily, for 12 weeks. Primary efficacy end points included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales and Patient Global Assessment of Disease Status. Response to treatment was assessed by the time-weighted average change from baseline over 12 weeks. RESULTS In 528 patients, baseline values for the 3 primary end points ranged from 67.78 to 72.60 mm (0-100 mm visual analog scale). Near-maximal efficacy was achieved by week 2 with both active treatments and sustained over the course of the trial. During the 12-week period, least squares mean changes in the primary end points (Western Ontario and McMaster Universities Osteoarthritis Index and Patient Global Assessment of Disease Status subscales) ranged from −16.53 to −13.55 mm, −27.89 to −23.68 mm, and −26.53 to −22.97 mm in the placebo, Etoricoxib, and ibuprofen groups, respectively. Both Etoricoxib and ibuprofen were more effective ( P CONCLUSIONS For patients with OA, treatment with Etoricoxib, 30 mg/d, is well tolerated and provides sustained clinical effectiveness that is superior to placebo and comparable to ibuprofen, 2400 mg/d.
Christopher P Cannon - One of the best experts on this subject based on the ideXlab platform.
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baseline factors associated with congestive heart failure in patients receiving Etoricoxib or diclofenac multivariate analysis of the medal program
European Journal of Heart Failure, 2009Co-Authors: Henry Krum, Sean P Curtis, Amarjot Kaur, Loren Laine, Hongwei Wang, Steven S Smugar, Matthew R Weir, Craig D Brater, Christopher P CannonAbstract:Aims Non-steroidal anti-inflammatory drugs have been associated with increased risk of congestive heart failure (CHF). We aimed to assess the impact of treatment with Etoricoxib or diclofenac on risk of CHF relative to baseline risk factors. Methods and results We performed a multivariate analysis of 34 701 patients with arthritis receiving Etoricoxib 60 or 90 mg, or diclofenac 150 mg, daily for a mean of 18 months, to assess the incidence of confirmed, adjudicated CHF events resulting in emergency room visit or hospitalization. Analyses were performed using a Cox proportional hazard model to evaluate the hazard ratio (HR) between the levels of each risk marker for the incidence of CHF. Significant risk markers included history of CHF (HR: 6.69, 95% CI 3.59–12.47; P <0.0001), age ≥65 years (2.56, 1.65–3.98; P <0.0001), and history of hypertension (1.83, 1.16–2.89; P = 0.0094) or diabetes (1.83, 1.15–2.94; P = 0.0116). Etoricoxib vs. diclofenac was a significant risk factor only when pooling the Etoricoxib 90 mg cohorts (1.88; 1.13–3.10; P = 0.0143). Etoricoxib 60 mg did not significantly increase risk vs. diclofenac. Conclusion History of CHF was highly associated with risk for CHF hospitalization. Hypertension, diabetes, and older age also increased risk modestly. There appeared to be a dose-related increase in CHF with Etoricoxib compared with diclofenac, which reached statistical significance when the Etoricoxib 90 mg groups (osteoarthritis and rheumatoid arthritis) were pooled. (Clinicaltrials.gov: NCT00092703, NCT00092742, NCT00250445).
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factors associated with blood pressure changes in patients receiving diclofenac or Etoricoxib results from the medal study
Journal of Hypertension, 2009Co-Authors: Henry Krum, Sean P Curtis, Gary Swergold, Amarjot Kaur, Loren Laine, Hongwei Wang, Steven S Smugar, Matthew R Weir, Craig D Brater, Christopher P CannonAbstract:ObjectiveTo evaluate the hypertensive effects of Etoricoxib and diclofenac relative to baseline hypertension risk factors in arthritis patients.MethodsMultivariate analysis of data from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study (n = 23 504). We evaluated risk fact
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assessment of upper gastrointestinal safety of Etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the multinational Etoricoxib and diclofenac arthritis long term medal programme a randomised comparison
The Lancet, 2007Co-Authors: Loren Laine, Sean P Curtis, Amarjot Kaur, Byron L Cryer, Christopher P CannonAbstract:Summary Background Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy. Methods A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of Etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with ClinicalTrials.gov, with the numbers NCT00092703, NCT00092742, and NCT00250445. Findings Overall upper gastrointestinal clinical events were significantly less common with Etoricoxib than with diclofenac (hazard ratio [HR] 0·69, 95% CI 0·57–0·83; p=0·0001). There were significantly fewer uncomplicated gastrointestinal events with Etoricoxib than there were with diclofenac (0·57, 0·45–0·74; p Interpretation There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor Etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with Etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.
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cardiovascular outcomes with Etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the multinational Etoricoxib and diclofenac arthritis long term medal programme a randomised comparison
The Lancet, 2006Co-Authors: Christopher P Cannon, Sean P Curtis, Amarjot Kaur, Henry Krum, Garret A Fitzgerald, James A Bolognese, Alise Reicin, Claire Bombardier, Michael E Weinblatt, Desiree Van Der HeijdeAbstract:Summary Background Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials, but no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor Etoricoxib versus the traditional NSAID diclofenac. Methods We designed a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to Etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). The primary hypothesis stated that Etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1·30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis. Intention-to-treat analyses were also done to assess consistency of results. These trials are registered at http://www.clinicaltrials.gov with the numbers NCT00092703, NCT00092742, and NCT00250445. Findings 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11·8). 320 patients in the Etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1·24 and 1·30 per 100 patient-years and a hazard ratio of 0·95 (95% CI 0·81–1·11) for Etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with Etoricoxib than with diclofenac (0·67 vs 0·97 per 100 patient-years; hazard ratio 0·69 [0·57–0·83]), but the rates of complicated upper gastrointestinal events were similar for Etoricoxib (0·30) and diclofenac (0·32). Interpretation Rates of thrombotic cardiovascular events in patients with arthritis on Etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.
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clinical trial design and patient demographics of the multinational Etoricoxib and diclofenac arthritis long term medal study program cardiovascular outcomes with Etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis
American Heart Journal, 2006Co-Authors: Christopher P Cannon, Sean P Curtis, James A Bolognese, Loren LaineAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently needed for the treatment of patients with arthritis. However, long-term use of such drugs that are cyclooxygenase-2 (COX-2) selective inhibitors has been reported to increase cardiovascular risk as compared with placebo, whereas long-term, randomized controlled trials assessing the risk of traditional NSAIDs versus placebo are lacking. The MEDAL program is designed to provide a precise estimate of the relative cardiovascular event rates with the COX-2 selective inhibitor Etoricoxib in comparison to the traditional NSAID diclofenac in patients with osteoarthritis and rheumatoid arthritis. The MEDAL program consists of 3 multinational, randomized, double-blind trials in patients with osteoarthritis and rheumatoid arthritis comparing Etoricoxib (60 or 90 mg daily) to diclofenac (150 mg daily). All investigator-reported thrombotic cardiovascular events will be adjudicated by an independent panel of experts blinded to treatment assignment. The primary analysis is a noninferiority comparison of Etoricoxib versus diclofenac for confirmed thrombotic cardiovascular events, defined as an upper bound of the 95% CI for a hazard ratio of
Loren Laine - One of the best experts on this subject based on the ideXlab platform.
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baseline factors associated with congestive heart failure in patients receiving Etoricoxib or diclofenac multivariate analysis of the medal program
European Journal of Heart Failure, 2009Co-Authors: Henry Krum, Sean P Curtis, Amarjot Kaur, Loren Laine, Hongwei Wang, Steven S Smugar, Matthew R Weir, Craig D Brater, Christopher P CannonAbstract:Aims Non-steroidal anti-inflammatory drugs have been associated with increased risk of congestive heart failure (CHF). We aimed to assess the impact of treatment with Etoricoxib or diclofenac on risk of CHF relative to baseline risk factors. Methods and results We performed a multivariate analysis of 34 701 patients with arthritis receiving Etoricoxib 60 or 90 mg, or diclofenac 150 mg, daily for a mean of 18 months, to assess the incidence of confirmed, adjudicated CHF events resulting in emergency room visit or hospitalization. Analyses were performed using a Cox proportional hazard model to evaluate the hazard ratio (HR) between the levels of each risk marker for the incidence of CHF. Significant risk markers included history of CHF (HR: 6.69, 95% CI 3.59–12.47; P <0.0001), age ≥65 years (2.56, 1.65–3.98; P <0.0001), and history of hypertension (1.83, 1.16–2.89; P = 0.0094) or diabetes (1.83, 1.15–2.94; P = 0.0116). Etoricoxib vs. diclofenac was a significant risk factor only when pooling the Etoricoxib 90 mg cohorts (1.88; 1.13–3.10; P = 0.0143). Etoricoxib 60 mg did not significantly increase risk vs. diclofenac. Conclusion History of CHF was highly associated with risk for CHF hospitalization. Hypertension, diabetes, and older age also increased risk modestly. There appeared to be a dose-related increase in CHF with Etoricoxib compared with diclofenac, which reached statistical significance when the Etoricoxib 90 mg groups (osteoarthritis and rheumatoid arthritis) were pooled. (Clinicaltrials.gov: NCT00092703, NCT00092742, NCT00250445).
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cardiovascular safety and gastrointestinal tolerability of Etoricoxib vs diclofenac in a randomized controlled clinical trial the medal study
Rheumatology, 2009Co-Authors: B Combe, Sean P Curtis, Gary Swergold, James S Mclay, Timothy Mccarthy, C Zerbini, Paul Emery, Laurine Connors, Amarjot Kaur, Loren LaineAbstract:Objective. To compare cardiovascular (CV) and other safety and efficacy parameters of Etoricoxib 60 and 90 mg, and diclofenac 150 mg. Methods. This double-blind study randomized OA patients to Etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to Etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of Etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on Etoricoxib dose and disease. Results. A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR) (Etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of Etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for Etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with Etoricoxib was 3.4–3.6 mmHg (diastolic BP: 1.0–1.5 mmHg), while diclofenac produced a maximum average change of 0.9–1.9 mmHg (diastolic BP: 0.0–0.5 mmHg). Both agents resulted in similar efficacy regardless of Etoricoxib dose. Conclusion. Long-term Etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, Etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.
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factors associated with blood pressure changes in patients receiving diclofenac or Etoricoxib results from the medal study
Journal of Hypertension, 2009Co-Authors: Henry Krum, Sean P Curtis, Gary Swergold, Amarjot Kaur, Loren Laine, Hongwei Wang, Steven S Smugar, Matthew R Weir, Craig D Brater, Christopher P CannonAbstract:ObjectiveTo evaluate the hypertensive effects of Etoricoxib and diclofenac relative to baseline hypertension risk factors in arthritis patients.MethodsMultivariate analysis of data from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study (n = 23 504). We evaluated risk fact
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assessment of upper gastrointestinal safety of Etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the multinational Etoricoxib and diclofenac arthritis long term medal programme a randomised comparison
The Lancet, 2007Co-Authors: Loren Laine, Sean P Curtis, Amarjot Kaur, Byron L Cryer, Christopher P CannonAbstract:Summary Background Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy. Methods A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of Etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with ClinicalTrials.gov, with the numbers NCT00092703, NCT00092742, and NCT00250445. Findings Overall upper gastrointestinal clinical events were significantly less common with Etoricoxib than with diclofenac (hazard ratio [HR] 0·69, 95% CI 0·57–0·83; p=0·0001). There were significantly fewer uncomplicated gastrointestinal events with Etoricoxib than there were with diclofenac (0·57, 0·45–0·74; p Interpretation There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor Etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with Etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.
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clinical trial design and patient demographics of the multinational Etoricoxib and diclofenac arthritis long term medal study program cardiovascular outcomes with Etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis
American Heart Journal, 2006Co-Authors: Christopher P Cannon, Sean P Curtis, James A Bolognese, Loren LaineAbstract:Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently needed for the treatment of patients with arthritis. However, long-term use of such drugs that are cyclooxygenase-2 (COX-2) selective inhibitors has been reported to increase cardiovascular risk as compared with placebo, whereas long-term, randomized controlled trials assessing the risk of traditional NSAIDs versus placebo are lacking. The MEDAL program is designed to provide a precise estimate of the relative cardiovascular event rates with the COX-2 selective inhibitor Etoricoxib in comparison to the traditional NSAID diclofenac in patients with osteoarthritis and rheumatoid arthritis. The MEDAL program consists of 3 multinational, randomized, double-blind trials in patients with osteoarthritis and rheumatoid arthritis comparing Etoricoxib (60 or 90 mg daily) to diclofenac (150 mg daily). All investigator-reported thrombotic cardiovascular events will be adjudicated by an independent panel of experts blinded to treatment assignment. The primary analysis is a noninferiority comparison of Etoricoxib versus diclofenac for confirmed thrombotic cardiovascular events, defined as an upper bound of the 95% CI for a hazard ratio of
Nancy G B Agrawal - One of the best experts on this subject based on the ideXlab platform.
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Etoricoxib in acute pain associated with dental surgery a randomized double blind placebo and active comparator controlled dose ranging study
Clinical Therapeutics, 2004Co-Authors: Kerstin Malmstrom, Aditi Sapre, Heather Couglin, Nancy G B Agrawal, Ralph S Mazenko, James R. FrickeAbstract:Abstract Background: Patients experiencing acute pain after surgery, including dental surgery, often require analgesia. Ideally, the chosen analgesic should have a rapid onset and sustained effect. Etoricoxib is a new cyclooxygenase-2-selective inhibitor that has demonstrated analgesic efficacy in the treatment of acute pain with a rapid onset and long-lasting pain relief. Objective: The goal of this study was to determine the analgesic effect of single oral doses of Etoricoxib 60, 120, 180, and 240 mg compared with placebo in the treatment of pain after dental surgery. Ibuprofen was used as an active control. Methods: This was a randomized, double-blind, parallel-group, single-dose, placebo- and active comparator-controlled study performed at a single center. It consisted of 3 visits (prestudy, treatment, and poststudy). Eligible patients were aged ≥16 years with moderate or severe pain after surgical extraction of ≥2 third molars, of which ≥1 was an impacted mandibular molar. Patients were assessed over 24 hours and reported pain intensity and pain relied at 14 predefined time points. Plasma samples for a pharmacokinetic/pharmacodynamic analysis were collected from a subset of patients at baseline and the 14 predefined time points. The end points included total pain relief over 8 hours (TOPAR8, the primary end point), sum of pain intensity difference over 8 hours, patient's global evaluation of treatment, median time to onset of pain relief (2-stopwatch method), peak pain relief, and duration of analgesic effect (median time to use of rescue medication). Adverse events were collected up to 14 days postdose. Results: Three hundred ninety-eight (63.1% women, 36.9% men; mean age, 21.1 years; 72.1% white, 27.9% other; mean number of third molars removed, 3.5; 65.2% experiencing moderate pain) were randomly allocated to receive Etoricoxib 60 mg (n = 75), Etoricoxib 120 mg (n = 76), Etoricoxib 180 mg (n = 74), Etoricoxib 240 mg (n = 76), ibuprofen 400 mg (n = 48), and placebo (n = 49). All active treatments had significantly greater overall analgesic effect (TOPAR8) compared with placebo ( P ≤ 0.001). Patients who received Etoricoxib 120 and 180 mg had significantly higher TOPAR8 scores than those who received Etoricoxib 60 mg ( P ≤ 0.001) and ibuprofen ( P P ≤ 0.001 Etoricoxib 180 mg). Least-squares mean TOPAR8 scores for Etoricoxib 60, 120, 180, and 240 mg, ibuprofen, and placebo were 16.0, 22.0, 23.5, 20.7, 18.6, and 5.2, respectively. The median time to onset of analgesia was 24 minutes for Etoricoxib 120, 180, and 240 mg, and 30 minutes for Etoricoxib 60 mg and ibuprofen. There were no significant differences in the onset of analgesia between Etoricoxib 120, 180, and 240 mg and ibuprofen. The duration of analgesic effect was >24 hours for Etoricoxib 120, 180, and 240 mg, and 12.1 hours for Etoricoxib 60 mg. The duration of effect was significantly longer with all 4 Etoricoxib doses compared with ibuprofen (10.1 hours; P P ≤ 0.001 Etoricoxib 120, 180, and 240 mg) and compared with placebo (2.1 hours; P ≤ 0.001). In the pharmacokinetic/pharmacodynamic analysis (n ≈ 120), there was a linear relationship between plasma Etoricoxib concentrations and pain relief scores up to the maximum observed concentration, followed by a decline in plasma concentrations with persistent analgesia. The most common adverse events were postextraction alveolitis and nausea. Conclusions: In this dose-ranging study, Etoricoxib 120 mg was determined to be the minimum dose that had maximal efficacy in patients with moderate to severe acute pain associated with dental surgery. Both Etoricoxib and ibuprofen were generally well tolerated.
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characterization of Etoricoxib a novel selective cox 2 inhibitor
The Journal of Clinical Pharmacology, 2003Co-Authors: Aimee Dallob, C J Hawkey, Howard E Greenberg, Nicholas J Wight, Paul J De Schepper, Scott A Waldman, Peggy Wong, Lisa Detora, Barry J Gertz, Nancy G B AgrawalAbstract:Etoricoxib is a potent selective COX-2 inhibitor in man. Ex vivo whole-blood assays assessed COX-2 inhibition after oral administration of Etoricoxib in single (5-500 mg) and multiple (25-150 mg) once-daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE2 synthesis after Etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect of Etoricoxib 120 mg qd on the COX-1-mediated antiplatelet effects of low-dose aspirin (ASA) was also assessed. The mean (time)-weighted average inhibition (WAI) of lipopolysaccharide (LPS)-stimulated PGE2 (COX-2 assay) vcrsus placebo was dose related after single (range: 3.1%-99.1%) and multiple doses (range: 52.5%-96.7%). PGE2 remained significantly inhibited 24 hours postdose at steady state. Inhibition of LPS-stimulated PGE2 showed a strong relationship with Etoricoxib plasma concentrations; ex vivo, IC50 was almost identical to in vitro. Multiple dosing of Etoricoxib (up to 150 mg qd) showed no important effects on serum TXB2, bleeding time, or platelet aggregation (COX-1-mediated effects). The nonselective nonsteroidal anti-inflammatory (NSAID) naproxen significantly inhibited (approximately 78%) ex vivo prostaglandin synthesis in gastric mucosa; Etoricoxib had no effect. Etoricoxib did not interfere with the antiplatelet effects of low-dose ASA, as assessed by serum TXB2 and platelet aggregation. Etoricoxib was generally well tolerated, even at doses above the clinical dose range. Based on these results, Etoricoxib is a potent selective inhibitor of COX-2 after single and multiple dosing regimens and does not inhibit prostaglandin synthesis in the gastric mucosa, even at doses above the clinical dose range of 60 to 120 mg.
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single and multiple dose pharmacokinetics of Etoricoxib a selective inhibitor of cyclooxygenase 2 in man
The Journal of Clinical Pharmacology, 2003Co-Authors: Nancy G B Agrawal, Arturo G Porras, Catherine Z Matthews, Eric Woolf, Mark J Rose, Bret J Musser, Andrea L Dynder, Katherine E Mazina, Kenneth C Lasseter, Thomas L HuntAbstract:The single- and multiple-dose pharmacokinetics of Etoricoxib, a selective inhibitor of cyclooxygenase-2, were examined in two clinical studies. Single-dose pharmacokinetics-including dose proportionality, absolute bioavailability of the highest dose-strength (120-mg) tablet, and the effect of a high-fat meal on the bioavailability of that tablet-were investigated in a two-part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady-state pharmacokinetics were investigated in an open-label study in which 24 healthy subjects were administered 120-mg single and multiple (once daily for 10 days) oral doses of Etoricoxib tablets. The pharmacokinetics of Etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high-fat meal decreased the rate of absorption without affecting the extent of absorption of Etoricoxib; therefore, Etoricoxib can be dosed irrespective of food. Steady-state pharmacokinetics of Etoricoxib, achieved following 7 days of once-daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t 1/2 averaged 22 hours, supporting once-daily dosing. Etoricoxib was generally well tolerated.
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absorption metabolism and excretion of Etoricoxib a potent and selective cyclooxygenase 2 inhibitor in healthy male volunteers
Drug Metabolism and Disposition, 2003Co-Authors: David A Rodrigues, Catherine Z Matthews, Eric Woolf, Keith Gottesdiener, Kenneth C Lasseter, Leslie A Geer, Rita A Halpin, Donghui Cui, Patrick J Larson, Nancy G B AgrawalAbstract:[14C]Etoricoxib (100 μCi/dose) was administered to six healthy male subjects (i.v., 25 mg; p.o., 100 mg). Following the i.v. dose, the plasma clearance was 57 ml/min, and the harmonic mean half-life was 24.8 h. Etoricoxib accounted for the majority of the radioactivity (∼75%) present in plasma following both i.v. and p.o. doses. The oral dose, administered as a solution in polyethylene glycol-400, was well absorbed (absolute bioavailability of ∼83%). Total recovery of radioactivity in the excreta was 90% (i.v.) and 80% (p.o.), with 70% (i.v.) and 60% (p.o.) excreted in urine and 20% in feces after either route of administration. Radiochromatographic analysis of the excreta revealed that Etoricoxib was metabolized extensively, and only a minor fraction of the dose ( 1′-N-oxidation), and the metabolites are excreted largely in the urine.
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dose proportionality of oral Etoricoxib a highly selective cyclooxygenase 2 inhibitor in healthy volunteers
The Journal of Clinical Pharmacology, 2001Co-Authors: Nancy G B Agrawal, Saurabh Mukhopadhyay, Arturo G Porras, Catherine Z Matthews, Eric Woolf, Jutta Miller, Donald C Neu, Keith GottesdienerAbstract:To assess dose proportionality of Etoricoxib across the anticipated clinical dose range, a single panel of 12 healthy subjects was administered single oral doses of Etoricoxib of 5, 10, 20, 40, and 120 mg in an open, two-part, five-period crossover study. Plasma samples were collected aftereach dose and analyzed for Etoricoxib concentrations. The pharmacokinetics of Etoricoxib appear to be linear over the entire dose range examined, from 5 to 120 mg. Etoricoxib was found to be well tolerated across the 5 to 120 mg dose range.