Rheumatoid Arthritis: Bolognese JA

Curtis SP, Ko AT, Bolognese JA, Cavanaugh PF, Reicin AS. · Merck Research Laboratories, Rahway, NJ 07065, USA. · Curr Med Res Opin. · Pubmed #17265571 No free full text.

Abstract: BACKGROUND: A pooled analysis of randomized clinical trials data was performed to compare the rate of thrombotic cardiovascular events (thrombotic events) in patients taking the COX-2 selective inhibitor (coxib) etoricoxib, a traditional NSAID, or placebo. METHODS: Data collected during all phase IIb/III etoricoxib clinical trials > or = 4 weeks in duration were evaluated. The pooled data set includes clinical information from approximately 6500 patient-years (PYs) of drug exposure in patients diagnosed with rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), or chronic low back pain (CLBP). Patients were treated with either etoricoxib (> or = 60 mg/day), the traditional NSAIDs naproxen (1000 mg/day), ibuprofen (2400 mg/day), diclofenac (150 mg/day), or placebo. The Relative risks (RRs) based on time to first occurrence of a thrombotic event in the etoricoxib group versus the comparator traditional NSAIDs or versus placebo were determined using patient-level data. RESULTS: In the pooled dataset, a total of 74 thrombotic events occurred in 69 patients. The RRs for thrombotic events were 1.11 (95%CI: 0.32, 3.81) for etoricoxib (N = 2818) versus placebo (N = 1767); 0.83 (95%CI: 0.26, 2.64) for etoricoxib (N = 1266) versus the combined non-naproxen traditional NSAID group (ibuprofen and diclofenac; N = 718); and 1.70 (95%CI: 0.91, 3.18) for etoricoxib (N = 1960) versus naproxen (N = 1497). CONCLUSIONS: There was no discernible difference in the incidence of thrombotic events in patients treated with etoricoxib versus non-naproxen traditional NSAIDs in this limited dataset. A trend toward more events with etoricoxib versus naproxen was observed. Despite the limited dataset available for this pooled analysis, these results are consistent with findings for other coxibs.

Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, van der Heijde D, Erdmann E, Laine L, Anonymous00100. · Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Lancet. · Pubmed #17113426 No free full text.

Abstract: 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.

Cannon CP, Curtis SP, Bolognese JA, Laine L, Anonymous00220. · The TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Am Heart J. · Pubmed #16875903 No free full text.

Abstract: 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 < 1.30. With the planned 635 observed events from approximately 40,000 patient-years of exposure, using an estimated annual event rate of 1.30% in the control arm, the maximum annual event rate for etoricoxib that would meet the noninferiority criteria would be approximately 1.46%, yielding a hazard ratio of 1.12. A total of 34,701 patients have been enrolled in the MEDAL program. Roughly 13,000 and 10,000 patients will, respectively, have had > or = 18 or > or = 24 months of exposure, with maximum exposure of approximately 40 months. The MEDAL program will help to better define the risk-to-benefit ratio of 2 NSAIDs, that differ in their selectivity for COX-2, notably diclofenac and etoricoxib.

Reiff A, Lovell DJ, Adelsberg JV, Kiss MH, Goodman S, Zavaler MF, Chen PY, Bolognese JA, Cavanaugh P, Reicin AS, Giannini EH. · Children's Hospital Los Angeles, Los Angeles, CA, USA. · J Rheumatol. · Pubmed #16583464 No free full text.

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 1,000 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. RESULTS: A total of 310 patients ages 2-17 years (181 (3/4) age 11) were randomized to receive LD-rofecoxib (N=109), HD-rofecoxib (N=100), or naproxen (N=101). The ACR Pedi 30 response rates following 12 weeks of treatment were 46.2%, 54.5%, and 55.1%, respectively. The relative rates of response compared to naproxen were 0.81 (95% CI 0.61, 1.07) and 0.98 (95% CI 0.76, 1.26) for LD- and HD-rofecoxib, respectively. Both rofecoxib doses were not inferior to naproxen. Patients (N=227) entering the extension received HD-rofecoxib or naproxen with efficacy maintained during the extension. All treatments were generally well tolerated throughout the study. CONCLUSION: Daily treatment of JRA patients with rofecoxib up to 12.5 or 25 mg was well tolerated, providing sustained clinical effectiveness comparable to naproxen 15 mg/kg. *On September 30, 2004, Merck & Co., Inc. announced the voluntary worldwide withdrawal of rofecoxib from the market.

Ramey DR, Watson DJ, Yu C, Bolognese JA, Curtis SP, Reicin AS. · Epidemiology, Merck Research Laboratories, West Point, PA 19486, USA. · Curr Med Res Opin. · Pubmed #15974563 No free full text.

Abstract: OBJECTIVE: 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 were judged by a blinded, external adjudication committee using pre-specified criteria. PUBs were analyzed using COX proportional hazards models using terms for treatment and known PUB risk factors. MAIN OUTCOME MEASURE: The incidence of confirmed PUBs among patients treated with etoricoxib 60 mg, 90 mg, or 120 mg (combined N=3226) was compared to that among patients treated with ibuprofen, diclofenac, or naproxen (combined N=2215). RESULTS: The incidence of PUBs over 44.3 months was significantly lower with etoricoxib vs. NSAIDs [cumulative incidence 1.24% vs. 2.48%, p < 0.001; rate/100 patient-years 1.00 vs. 2.47; relative risk 0.48, 95% Confidence Interval (CI) 0.32, 0.73]. Results of analysis of events occurring during the first year of treatment and subgroup analyses were consistent with the primary result. CONCLUSIONS: Treatment with etoricoxib was associated with a significantly lower incidence of PUBs than was treatment with non-selective NSAIDs. The difference was consistent in subgroups of patients defined by a variety of known risk factors.

Watson DJ, Bolognese JA, Yu C, Krupa D, Curtis S. · Merck Research Laboratories, West Point, PA 19486, USA. · Curr Med Res Opin. · Pubmed #15701208 No free full text.

Abstract: BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are non-selective cyclooxygenase-1 (COX-1) and COX-2 inhibitors and are associated with upper gastrointestinal (GI) dyspeptic symptoms often resulting in GI co-medication usage or treatment discontinuation. OBJECTIVE: To compare the rates of new use of gastroprotective agents and discontinuations due to dyspepsia with the COX-2 selective inhibitor etoricoxib compared with non-selective NSAIDs. RESEARCH DESIGN AND METHODS: This pre-specified combined analysis used data from nine randomized, double-blind, controlled, clinical trials with etoricoxib in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis. The cumulative incidences of (1) new use (new prescription or increased dose) of gastroprotective agents (GPA) and (2) discontinuation due to dyspeptic symptoms were compared among patients treated with etoricoxib (60 mg, 90 mg, or 120 mg daily) vs. non-selective NSAIDs (diclofenac 50 mg. t.i.d. or naproxen 500 mg. b.i.d.). RESULTS: The overall rates/100 patient-years for new use of GPAs were 9.1 and 13.0 for etoricoxib and NSAIDs, respectively (RR = 0.75; 95% confidence interval [CI] 0.64, 0.89; p < 0.001). A benefit with etoricoxib was seen in the first 6 months when most new GPA usage occurred; after 6 months new use of GPAs was similar between etoricoxib and NSAIDs. The rates/100 patient-years of treatment discontinuation due to dyspeptic symptoms with etoricoxib and NSAIDs were 1.5 and 2.7, respectively (RR = 0.60; 95% CI 0.41, 0.87; p = 0.007). Analyses of placebo-controlled treatment periods showed significantly more new GPA use and more discontinuations due to dyspeptic symptoms with NSAIDs vs. placebo, but not with etoricoxib vs. placebo. CONCLUSION: In this combined analysis of clinical trials of patients with OA, RA, chronic low back pain, or AS, new use of gastroprotective agents was significantly lower with etoricoxib than with the comparator non-selective NSAIDs during the initial 6 months of treatment and similar thereafter. There were significantly fewer discontinuations for dyspeptic symptoms with etoricoxib than with NSAIDs over the entire follow-up period.

Watson DJ, Yu Q, Bolognese JA, Reicin AS, Simon TJ. · Merck Research Laboratories, West Point, PA, USA. · Curr Med Res Opin. · Pubmed #15462687 No free full text.

Abstract: BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs. OBJECTIVE: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs. Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17,072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5 mg, 25 mg, or 50 mg (combined, N = 10 026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046). RESULTS: The incidence of PUBs over 24.8 months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors. DISCUSSION: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8 months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib. CONCLUSIONS: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.

Anderson JJ, Bolognese JA, Felson DT. · Boston University, Boston, Massachusetts 02118, USA. · Arthritis Rheum. · Pubmed #14613263 links to  free full text

Abstract: OBJECTIVE: Isolated studies have suggested that continuous measures of response may be better than predefined, dichotomous definitions (e.g., the American College of Rheumatology 20% improvement criteria [ACR20]) for discriminating between rheumatoid arthritis (RA) treatments. Our goal was to determine the statistical power of predefined dichotomous outcome measures (termed "a priori"), compared with that of continuous measures derived from trial data in which there was no predefined response threshold (termed "data driven"), and to evaluate the sensitivity to change of these measures in the context of different treatments and early versus later-stage disease. In order to generalize beyond results from a single trial, we performed simulation studies. METHODS: We obtained summary data from trials comparing disease-modifying antirheumatic drugs (DMARDs) and from comparative coxib-placebo trials to test the power of 2 a priori outcomes, the ACR20 and improvement of the Disease Activity Score (DDAS), as well as 2 data-driven outcomes. We studied patients with early RA and those with later-stage RA (duration of <4 years and 4-9 years, respectively). We performed simulation studies, using the interrelationship of ACR core set measures in the trials to generate multiple trial data sets consistent with the original data. RESULTS: The data-driven outcomes had greater power than did the a priori measures. The DMARD comparison was more powerful in early disease than in later-stage disease (the sample sizes needed to achieve 80% power for the most powerful test were 64 for early disease versus 100 for later disease), but the coxib-versus-placebo comparison was less powerful in early disease than in later disease (the sample sizes needed to achieve 80% power were 200 and 100, respectively). When the effects of treatment on core set items were small and/or inconsistent, power was reduced, particularly for a less broadly based outcome (e.g., DDAS) compared with the ACR20. CONCLUSION: The simulation studies demonstrate that data-driven outcome definitions can provide better sensitivity to change than does the ACR20 or DDAS. Using such methods would improve power, but at the expense of trial standardization. The studies also show how patient population and treatment characteristics affect the power of specific outcome measures in RA clinical trials, and provide quantification of those effects.