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Celecoxib for Rheumatoid Arthritis
CLINICAL QUESTION: Does celecoxib relieve pain and inflammation in rheumatoid arthritis without the adverse gastrointestinal (GI) effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs)?
BACKGROUND: NSAIDs are widely prescribed to control the pain and inflammation of rheumatoid arthritis. Their use can be limited by the risk of GI toxicity, an adverse event that is thought to be mediated by nonspecific cyclooxygenase (COX) inhibition. Celecoxib, a COX-2-specific inhibitor, offers the possibility of relieving pain and inflammation in rheumatoid arthritis without GI injury.
POPULATION STUDIED: This study included 1149 adult patients with a mean age of 54 years, 73% of whom were women. All met the American College of Rheumatology diagnostic criteria for rheumatoid arthritis for at least 3 months and were in a functional class of I, II, or III. Stable doses of glucocorticoids or disease-modifying antirheumatic drugs were permitted. Concomitant NSAIDs, injectable corticosteroids, anticoagulants, and antiulcer drugs were prohibited.
STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled multicenter 12-week trial funded by the manufacturer of celecoxib. Before enrollment, appropriate baseline clinical and laboratory assessments (including Helicobacter pylori antibody testing and upper endoscopy) were conducted. There were 5 treatment arms: patients received placebo, celecoxib (100 mg, 200 mg, or 400 mg twice daily) or naproxen 500 mg twice daily. All patients underwent a second upper GI endoscopy at treatment termination.
OUTCOMES MEASURED: The primary outcome was improvement in signs and symptoms of rheumatoid arthritis using American College of Rheumatology criteria. The incidence of gastroduodenal ulceration (defined as mucosal breaks Ž3 mm in diameter with unequivocal depth) was a secondary outcome.
RESULTS: Forty percent of the patients withdrew from the study; the majority of withdrawals were because of treatment failure. The rate of treatment failure was similar for all 4 active treatment groups (21%-29%) and higher in the placebo group (45%). In general, all celecoxib doses provided efficacy similar to naproxen and superior to placebo. Compared with placebo recipients (29%), there were significantly more responders in the celecoxib groups (39%-44%; P <.05; number needed to treat [NNT] = 8) and the naproxen group (36%; P <.05). Maximal treatment effects with celecoxib were apparent and significant by week 2 and sustained through week 12.
The authors of this study demonstrated that for patients with rheumatoid arthritis, celecoxib offers comparable efficacy to NSAIDs, with fewer endoscopic ulcers. It is unknown if these results will translate into reduced rates of clinically significant GI complications, such as perforations, hemorrhages, and obstructions. However, in the same issue of The Journal of the American Medical Association, a pooled analysis of 8 rofecoxib (another COX-2 inhibitor) trials demonstrated reduced rates of GI complications in osteoarthritis patients.1 An economic analysis of COX-2 inhibitors (based on published costs for these agents and incidence rates for NSAID-induced ulcers) suggests that these agents are probably cost-effective in high-risk patients (those aged 75 years or older or with a history of ulcer or GI bleed).2
On the basis of these findings, we recommend using celecoxib in high-risk patients. Considering the time to maximum benefit of 2 weeks and the relatively large number of nonresponders, it seems reasonable to discontinue celecoxib in patients who have not experienced a benefit after a relatively short therapeutic trial.
CLINICAL QUESTION: Does celecoxib relieve pain and inflammation in rheumatoid arthritis without the adverse gastrointestinal (GI) effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs)?
BACKGROUND: NSAIDs are widely prescribed to control the pain and inflammation of rheumatoid arthritis. Their use can be limited by the risk of GI toxicity, an adverse event that is thought to be mediated by nonspecific cyclooxygenase (COX) inhibition. Celecoxib, a COX-2-specific inhibitor, offers the possibility of relieving pain and inflammation in rheumatoid arthritis without GI injury.
POPULATION STUDIED: This study included 1149 adult patients with a mean age of 54 years, 73% of whom were women. All met the American College of Rheumatology diagnostic criteria for rheumatoid arthritis for at least 3 months and were in a functional class of I, II, or III. Stable doses of glucocorticoids or disease-modifying antirheumatic drugs were permitted. Concomitant NSAIDs, injectable corticosteroids, anticoagulants, and antiulcer drugs were prohibited.
STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled multicenter 12-week trial funded by the manufacturer of celecoxib. Before enrollment, appropriate baseline clinical and laboratory assessments (including Helicobacter pylori antibody testing and upper endoscopy) were conducted. There were 5 treatment arms: patients received placebo, celecoxib (100 mg, 200 mg, or 400 mg twice daily) or naproxen 500 mg twice daily. All patients underwent a second upper GI endoscopy at treatment termination.
OUTCOMES MEASURED: The primary outcome was improvement in signs and symptoms of rheumatoid arthritis using American College of Rheumatology criteria. The incidence of gastroduodenal ulceration (defined as mucosal breaks Ž3 mm in diameter with unequivocal depth) was a secondary outcome.
RESULTS: Forty percent of the patients withdrew from the study; the majority of withdrawals were because of treatment failure. The rate of treatment failure was similar for all 4 active treatment groups (21%-29%) and higher in the placebo group (45%). In general, all celecoxib doses provided efficacy similar to naproxen and superior to placebo. Compared with placebo recipients (29%), there were significantly more responders in the celecoxib groups (39%-44%; P <.05; number needed to treat [NNT] = 8) and the naproxen group (36%; P <.05). Maximal treatment effects with celecoxib were apparent and significant by week 2 and sustained through week 12.
The authors of this study demonstrated that for patients with rheumatoid arthritis, celecoxib offers comparable efficacy to NSAIDs, with fewer endoscopic ulcers. It is unknown if these results will translate into reduced rates of clinically significant GI complications, such as perforations, hemorrhages, and obstructions. However, in the same issue of The Journal of the American Medical Association, a pooled analysis of 8 rofecoxib (another COX-2 inhibitor) trials demonstrated reduced rates of GI complications in osteoarthritis patients.1 An economic analysis of COX-2 inhibitors (based on published costs for these agents and incidence rates for NSAID-induced ulcers) suggests that these agents are probably cost-effective in high-risk patients (those aged 75 years or older or with a history of ulcer or GI bleed).2
On the basis of these findings, we recommend using celecoxib in high-risk patients. Considering the time to maximum benefit of 2 weeks and the relatively large number of nonresponders, it seems reasonable to discontinue celecoxib in patients who have not experienced a benefit after a relatively short therapeutic trial.
CLINICAL QUESTION: Does celecoxib relieve pain and inflammation in rheumatoid arthritis without the adverse gastrointestinal (GI) effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs)?
BACKGROUND: NSAIDs are widely prescribed to control the pain and inflammation of rheumatoid arthritis. Their use can be limited by the risk of GI toxicity, an adverse event that is thought to be mediated by nonspecific cyclooxygenase (COX) inhibition. Celecoxib, a COX-2-specific inhibitor, offers the possibility of relieving pain and inflammation in rheumatoid arthritis without GI injury.
POPULATION STUDIED: This study included 1149 adult patients with a mean age of 54 years, 73% of whom were women. All met the American College of Rheumatology diagnostic criteria for rheumatoid arthritis for at least 3 months and were in a functional class of I, II, or III. Stable doses of glucocorticoids or disease-modifying antirheumatic drugs were permitted. Concomitant NSAIDs, injectable corticosteroids, anticoagulants, and antiulcer drugs were prohibited.
STUDY DESIGN AND VALIDITY: This was a randomized double-blind placebo-controlled multicenter 12-week trial funded by the manufacturer of celecoxib. Before enrollment, appropriate baseline clinical and laboratory assessments (including Helicobacter pylori antibody testing and upper endoscopy) were conducted. There were 5 treatment arms: patients received placebo, celecoxib (100 mg, 200 mg, or 400 mg twice daily) or naproxen 500 mg twice daily. All patients underwent a second upper GI endoscopy at treatment termination.
OUTCOMES MEASURED: The primary outcome was improvement in signs and symptoms of rheumatoid arthritis using American College of Rheumatology criteria. The incidence of gastroduodenal ulceration (defined as mucosal breaks Ž3 mm in diameter with unequivocal depth) was a secondary outcome.
RESULTS: Forty percent of the patients withdrew from the study; the majority of withdrawals were because of treatment failure. The rate of treatment failure was similar for all 4 active treatment groups (21%-29%) and higher in the placebo group (45%). In general, all celecoxib doses provided efficacy similar to naproxen and superior to placebo. Compared with placebo recipients (29%), there were significantly more responders in the celecoxib groups (39%-44%; P <.05; number needed to treat [NNT] = 8) and the naproxen group (36%; P <.05). Maximal treatment effects with celecoxib were apparent and significant by week 2 and sustained through week 12.
The authors of this study demonstrated that for patients with rheumatoid arthritis, celecoxib offers comparable efficacy to NSAIDs, with fewer endoscopic ulcers. It is unknown if these results will translate into reduced rates of clinically significant GI complications, such as perforations, hemorrhages, and obstructions. However, in the same issue of The Journal of the American Medical Association, a pooled analysis of 8 rofecoxib (another COX-2 inhibitor) trials demonstrated reduced rates of GI complications in osteoarthritis patients.1 An economic analysis of COX-2 inhibitors (based on published costs for these agents and incidence rates for NSAID-induced ulcers) suggests that these agents are probably cost-effective in high-risk patients (those aged 75 years or older or with a history of ulcer or GI bleed).2
On the basis of these findings, we recommend using celecoxib in high-risk patients. Considering the time to maximum benefit of 2 weeks and the relatively large number of nonresponders, it seems reasonable to discontinue celecoxib in patients who have not experienced a benefit after a relatively short therapeutic trial.
Neuroleptics for Behavioral Symptoms of Dementia
CLINICAL QUESTION: What is the efficacy and tolerability of risperidone for treating elderly demented patients with aggression and other behavioral symptoms?
BACKGROUND: Aggression and other behavioral symptoms of dementia are significant predictors of caregiver burden and may underlie the decision to institutionalize demented patients. Conventional neuroleptics are often used to manage disruptive behaviors. Adverse drug effects, however, such as movement disorders, extrapyramidal symptoms (EPS), anticholinergic effects, and drug-drug interactions limit their usefulness. Atypical antipsychotics such as risperidone may offer added benefit in elderly patients with dementia.
POPULATION STUDIED: The study recruited 371 nursing home patients from 51 centers in 8 countries. All had been given a diagnosis of primary degenerative dementia of the Alzheimer’s type, vascular dementia, or mixed dementia. Ages ranged from 56 to 97 years; 99% were white; and 56% were women. The median duration of institutionalization was 4 months. According to standardized measures, these patients had cognitive and functional deficits severe enough to affect basic daily activities. Mean Mini-Mental State Examination (MMSE) scores were 7.9 to 8.8.
STUDY DESIGN AND VALIDITY: Following a 1-week single-blind washout phase during which all psychotropic medications were discontinued, 344 patients were randomized to double-blind treatment with risperidone, haloperidol, or placebo. The study groups were comparable at baseline. The 12-week treatment period started with 0.25 mg (1 mg/mL oral solution) per day of risperidone or haloperidol. The dose was increased by 0.25 mg every 4 days up to a maximum of 2 mg twice daily. Efficacy was judged using several established behavioral assessment tools. Assessment of tolerability included evaluation for EPS, the level of sedation, Functional Assessment Staging, MMSE score, and the incidence of adverse drug effects. Outcomes were analyzed both by intention to treat (end point data) and observed case analysis that included only the 223 patients who continued treatment for 12 weeks (week 12 data). Of note, supplemental lorazepam was allowed in the first 4 weeks of the study, but concomitant use of antipsychotics, antidepressants, lithium, carbamazepine, and valproic acid was not otherwise permitted. This study was funded in part by Janssen Pharmaceuticals, maker of Risperdal (risperidone).
OUTCOMES MEASURED: The primary outcome was clinically significant improvement of disturbing behavior defined as a 30% or greater change on the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total score. Many secondary outcomes were reported regarding the efficacy of risperidone compared with placebo and its tolerability compared with both placebo and haloperidol.
RESULTS: The percentage of patients with clinical improvement (30% improvement in BEHAVE-AD total score) in the risperidone, haloperidol, and placebo groups was 54%, 63%, and 47% respectively by intention-to-treat analysis. This difference was not statistically significant (P = .25 with 80% power to detect a difference of 20%). The high placebo response may explain the poor effect overall of active treatment.1 Non-intention-to-treat analysis and secondary measures of behavior, particularly those assessing aggression, showed a statistically significant benefit of risperidone over placebo. This study was not intended to compare the efficacy of risperidone with that of haloperidol although a post hoc analysis was reported. In terms of tolerability, the severity of EPS was significantly greater with haloperidol than risperidone. There was no significant difference in the occurrence of serious adverse events. Dropout rates for the risperidone, haloperidol, and placebo groups were high (41%, 30%, and 35%, respectively). The most common reasons cited for discontinuation were adverse events (50.4%) and lack of efficacy (43.8%). The mean dose of medication was approximately 1 mg per day in both active groups.
If a pharmacological agent is deemed necessary in the management of behavior disturbances in patients with dementia, then risperidone offers comparable efficacy with haloperidol with less EPS. A cost-effectiveness analysis may be needed to justify the added expense of risperidone ($73.00 for 30 1-mg tablets vs $8.50 for haloperidol). Although secondary outcomes and the observed case analysis suggest a benefit compared with haloperidol and placebo, further study is needed to confirm the statistical validity and clinical significance of these results. Future trials should investigate whether the use of neuroleptics for behavior disturbances actually delays admission to extended-care facilities.
CLINICAL QUESTION: What is the efficacy and tolerability of risperidone for treating elderly demented patients with aggression and other behavioral symptoms?
BACKGROUND: Aggression and other behavioral symptoms of dementia are significant predictors of caregiver burden and may underlie the decision to institutionalize demented patients. Conventional neuroleptics are often used to manage disruptive behaviors. Adverse drug effects, however, such as movement disorders, extrapyramidal symptoms (EPS), anticholinergic effects, and drug-drug interactions limit their usefulness. Atypical antipsychotics such as risperidone may offer added benefit in elderly patients with dementia.
POPULATION STUDIED: The study recruited 371 nursing home patients from 51 centers in 8 countries. All had been given a diagnosis of primary degenerative dementia of the Alzheimer’s type, vascular dementia, or mixed dementia. Ages ranged from 56 to 97 years; 99% were white; and 56% were women. The median duration of institutionalization was 4 months. According to standardized measures, these patients had cognitive and functional deficits severe enough to affect basic daily activities. Mean Mini-Mental State Examination (MMSE) scores were 7.9 to 8.8.
STUDY DESIGN AND VALIDITY: Following a 1-week single-blind washout phase during which all psychotropic medications were discontinued, 344 patients were randomized to double-blind treatment with risperidone, haloperidol, or placebo. The study groups were comparable at baseline. The 12-week treatment period started with 0.25 mg (1 mg/mL oral solution) per day of risperidone or haloperidol. The dose was increased by 0.25 mg every 4 days up to a maximum of 2 mg twice daily. Efficacy was judged using several established behavioral assessment tools. Assessment of tolerability included evaluation for EPS, the level of sedation, Functional Assessment Staging, MMSE score, and the incidence of adverse drug effects. Outcomes were analyzed both by intention to treat (end point data) and observed case analysis that included only the 223 patients who continued treatment for 12 weeks (week 12 data). Of note, supplemental lorazepam was allowed in the first 4 weeks of the study, but concomitant use of antipsychotics, antidepressants, lithium, carbamazepine, and valproic acid was not otherwise permitted. This study was funded in part by Janssen Pharmaceuticals, maker of Risperdal (risperidone).
OUTCOMES MEASURED: The primary outcome was clinically significant improvement of disturbing behavior defined as a 30% or greater change on the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total score. Many secondary outcomes were reported regarding the efficacy of risperidone compared with placebo and its tolerability compared with both placebo and haloperidol.
RESULTS: The percentage of patients with clinical improvement (30% improvement in BEHAVE-AD total score) in the risperidone, haloperidol, and placebo groups was 54%, 63%, and 47% respectively by intention-to-treat analysis. This difference was not statistically significant (P = .25 with 80% power to detect a difference of 20%). The high placebo response may explain the poor effect overall of active treatment.1 Non-intention-to-treat analysis and secondary measures of behavior, particularly those assessing aggression, showed a statistically significant benefit of risperidone over placebo. This study was not intended to compare the efficacy of risperidone with that of haloperidol although a post hoc analysis was reported. In terms of tolerability, the severity of EPS was significantly greater with haloperidol than risperidone. There was no significant difference in the occurrence of serious adverse events. Dropout rates for the risperidone, haloperidol, and placebo groups were high (41%, 30%, and 35%, respectively). The most common reasons cited for discontinuation were adverse events (50.4%) and lack of efficacy (43.8%). The mean dose of medication was approximately 1 mg per day in both active groups.
If a pharmacological agent is deemed necessary in the management of behavior disturbances in patients with dementia, then risperidone offers comparable efficacy with haloperidol with less EPS. A cost-effectiveness analysis may be needed to justify the added expense of risperidone ($73.00 for 30 1-mg tablets vs $8.50 for haloperidol). Although secondary outcomes and the observed case analysis suggest a benefit compared with haloperidol and placebo, further study is needed to confirm the statistical validity and clinical significance of these results. Future trials should investigate whether the use of neuroleptics for behavior disturbances actually delays admission to extended-care facilities.
CLINICAL QUESTION: What is the efficacy and tolerability of risperidone for treating elderly demented patients with aggression and other behavioral symptoms?
BACKGROUND: Aggression and other behavioral symptoms of dementia are significant predictors of caregiver burden and may underlie the decision to institutionalize demented patients. Conventional neuroleptics are often used to manage disruptive behaviors. Adverse drug effects, however, such as movement disorders, extrapyramidal symptoms (EPS), anticholinergic effects, and drug-drug interactions limit their usefulness. Atypical antipsychotics such as risperidone may offer added benefit in elderly patients with dementia.
POPULATION STUDIED: The study recruited 371 nursing home patients from 51 centers in 8 countries. All had been given a diagnosis of primary degenerative dementia of the Alzheimer’s type, vascular dementia, or mixed dementia. Ages ranged from 56 to 97 years; 99% were white; and 56% were women. The median duration of institutionalization was 4 months. According to standardized measures, these patients had cognitive and functional deficits severe enough to affect basic daily activities. Mean Mini-Mental State Examination (MMSE) scores were 7.9 to 8.8.
STUDY DESIGN AND VALIDITY: Following a 1-week single-blind washout phase during which all psychotropic medications were discontinued, 344 patients were randomized to double-blind treatment with risperidone, haloperidol, or placebo. The study groups were comparable at baseline. The 12-week treatment period started with 0.25 mg (1 mg/mL oral solution) per day of risperidone or haloperidol. The dose was increased by 0.25 mg every 4 days up to a maximum of 2 mg twice daily. Efficacy was judged using several established behavioral assessment tools. Assessment of tolerability included evaluation for EPS, the level of sedation, Functional Assessment Staging, MMSE score, and the incidence of adverse drug effects. Outcomes were analyzed both by intention to treat (end point data) and observed case analysis that included only the 223 patients who continued treatment for 12 weeks (week 12 data). Of note, supplemental lorazepam was allowed in the first 4 weeks of the study, but concomitant use of antipsychotics, antidepressants, lithium, carbamazepine, and valproic acid was not otherwise permitted. This study was funded in part by Janssen Pharmaceuticals, maker of Risperdal (risperidone).
OUTCOMES MEASURED: The primary outcome was clinically significant improvement of disturbing behavior defined as a 30% or greater change on the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total score. Many secondary outcomes were reported regarding the efficacy of risperidone compared with placebo and its tolerability compared with both placebo and haloperidol.
RESULTS: The percentage of patients with clinical improvement (30% improvement in BEHAVE-AD total score) in the risperidone, haloperidol, and placebo groups was 54%, 63%, and 47% respectively by intention-to-treat analysis. This difference was not statistically significant (P = .25 with 80% power to detect a difference of 20%). The high placebo response may explain the poor effect overall of active treatment.1 Non-intention-to-treat analysis and secondary measures of behavior, particularly those assessing aggression, showed a statistically significant benefit of risperidone over placebo. This study was not intended to compare the efficacy of risperidone with that of haloperidol although a post hoc analysis was reported. In terms of tolerability, the severity of EPS was significantly greater with haloperidol than risperidone. There was no significant difference in the occurrence of serious adverse events. Dropout rates for the risperidone, haloperidol, and placebo groups were high (41%, 30%, and 35%, respectively). The most common reasons cited for discontinuation were adverse events (50.4%) and lack of efficacy (43.8%). The mean dose of medication was approximately 1 mg per day in both active groups.
If a pharmacological agent is deemed necessary in the management of behavior disturbances in patients with dementia, then risperidone offers comparable efficacy with haloperidol with less EPS. A cost-effectiveness analysis may be needed to justify the added expense of risperidone ($73.00 for 30 1-mg tablets vs $8.50 for haloperidol). Although secondary outcomes and the observed case analysis suggest a benefit compared with haloperidol and placebo, further study is needed to confirm the statistical validity and clinical significance of these results. Future trials should investigate whether the use of neuroleptics for behavior disturbances actually delays admission to extended-care facilities.