Rofecoxib

Reines, Scott A.; Block, Gilbert A.; Morris, John C.; Liu, G.; Nessly, Michael L.; Lines, Christopher; Norman, B. A.; Baranak, Christine C.

doi:10.1212/wnl.62.1.66

Cited by 367 publications

(186 citation statements)

References 44 publications

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“…To summarize the efficacy data, the unexpected primary finding in the present study suggesting that rofecoxib might accelerate the rate of AD diagnosis in patients with MCI was not supported by data on secondary measures in the same study, nor by other data from previous studies that assessed cognitive and functional decline in AD patients (Aisen et al, 2003;Reines et al, 2004). These observations suggest that the finding may not be indicative of a true treatment effect.…”

Section: Discussioncontrasting

confidence: 79%

“…The post hoc analysis comparing test scores in overlapping subgroups of patients with MMSE scores of 24-26 in the present study (the subgroup with the worst prognosis) and a previous AD treatment study (Reines et al, 2004) included a total of 405 patients (rofecoxib N ¼ 189, placebo N ¼ 216) from the present MCI study, and 205 patients (rofecoxib N ¼ 91, placebo N ¼ 114) from the previous AD treatment study. There was no consistent evidence of a differential treatment effect of rofecoxib in the A total of 1451 patients were included in the on-drug safety analysis (723 in the rofecoxib group and 728 in the placebo group).…”

Section: Resultsmentioning

confidence: 99%

“…The present study had a broadly similar design (randomized, double-blind, placebo-controlled) and utilized some similar assessments (ADAS-Cog and CDR) to a previous 1-year AD treatment study of rofecoxib 25 mg in patients who had MMSE scores of 14-26 (Reines et al, 2004). Since there were overlapping subgroups of patients who had MMSE scores of 24-26 in both studies, indicating a similar level of cognitive impairment despite the difference in diagnosis, we also conducted a post hoc analysis to compare change from baseline scores on measures of cognition (ADAS-Cog) and global function (CDR-sum of boxes) in the overlapping subgroups in the two studies.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore conducted a post hoc analysis of test scores in subgroups of patients with MMSE scores of 24-26 in the present study (ie those patients who were most likely to receive a diagnosis of AD) and in a previous AD treatment study (Reines et al, 2004). These studies had similar designs and utilized similar assessments.…”

Section: Discussionmentioning

confidence: 99%

“…However, interpretation of the results from both studies was confounded by high dropout rates, mainly due to gastrointestinal side effects thought to be mediated via inhibition of COX-1 (nonselective NSAIDs inhibit both COX-1 and COX-2) (Warner et al, 1999). More recently, three larger randomized, controlled, 1-year clinical studies with the selective COX-2 inhibitors rofecoxib or celecoxib failed to show any effects of treatment on the progression of AD (Sainati et al, 2000;Aisen et al, 2003;Reines et al, 2004). One of these studies included the nonselective NSAID naproxen, which also failed to show any effects (Aisen et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment

Thal

Ferris

Kirby

et al. 2005

Neuropsychopharmacol

369

219

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Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients X65 years were randomized to rofecoxib 25 mg (N ¼ 725) or placebo (N ¼ 732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio ¼ 1.46 (95% CI: 1.09, 1.94), p ¼ 0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

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Section: Discussioncontrasting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment

Thal

Ferris

Kirby

et al. 2005

Neuropsychopharmacol

369

219

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Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data

Ross

Madigan²,

Hill³

et al. 2009

Arch Intern Med

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Background In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future post-market pharmaceutical safety surveillance efforts. Methods We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event. Results We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled 20,152 subjects. Trial duration ranged from 4 weeks to 4 years, enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo, and rofecoxib dosage ranged from 12.5 mg to 50 mg. As of December 2000, 21 (70%) of these trials had been completed and the risk of CVT adverse event or death was greater among subjects assigned to rofecoxib, with the difference being borderline statistically significant (Rate Ratio [RR]=2.18, 95% Confidence Interval [CI], 0.93–5.81; p=0.07). Subsequently collected data strengthened the statistical association (as of June 2001: RR=1.35, 95% CI, 1.00–1.96; p=0.05; as of April 2002: RR=1.39, 95% CI, 1.07–1.80; p=0.02). Conclusion Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a progressing trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, reaching a P value of 0.05 by June 2001, nearly 3 and a half years before the manufacturer’s voluntary market withdrawal.

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Cognitive Function Over Time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT)

Martin

Szekely

Brandt³

et al. 2008

Arch Neurol

307

135

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Rofecoxib

Abstract: The failure of selective cyclo-oxygenase-2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase-2 does not play a significant role in the pathogenesis of the disorder.

Cited by 367 publications

References 44 publications

A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment

A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment

Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data

Cognitive Function Over Time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT)

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